The evolution of coronary artery bypass grafting (CABG) has been a key component in significantly reducing the morbidity and mortality associated with occlusive coronary artery disease (CAD). Cleveland Clinic surgeons, through their technical interventions and innovations, have led the evolution in coronary revascularization starting in the 1960s and continuing today. This article provides a brief overview of the evolution and describes the issues associated with current CABG approaches.

EARLY WORK IN RECONSTRUCTIVE CORONARY ARTERY SURGERY

Results from the first large series of venous grafting for CAD were reported in 1970 by Favaloro and colleagues at Cleveland Clinic.¹ They showed the efficacy of grafting in treating CAD, with low associated morbidity and mortality, thus establishing this surgery as the treatment modality for CAD.

The technique of surgical myocardial revascularization was a culmination of developments that began years earlier with the Vineberg procedure, involving suturing of the mammary artery to the muscle rather than a vessel-to-vessel anastomosis. From this followed the coronary patch, end-to-end bypass, and then end-to-side bypass.

In the 1970s, the refinement of suturing the left internal mammary artery (LIMA) directly to the left anterior descending (LAD) artery using magnifying loops was pioneered and popularized at Cleveland Clinic. This later became the cornerstone of future coronary revascularizations.

As a direct result of the successful technical advances and excellent clinical outcomes, the volume of CABG procedures in the United States rose steadily during the 1980s and reached its peak in 1995. It then began a slow decline that continued until 2013, when the trend began to reverse. It was still rising through 2015.

WHY THE RENEWED INTEREST IN CABG?

A key component to continued use of CABG is that it appears to have a clinical edge over other treatments. This has been shown in several high-profile studies: SYNTAX,^2,3 FREEDOM,^4,5 BEST,⁶ and NOBLE.⁷ For example, in the SYNTAX trial, which compared CABG vs percutaneous coronary intervention (PCI), the conclusion from both the 1-year² and the 5-year³ results was that CABG should remain the standard of care for patients with complex lesions—those with an intermediate or high burden of CAD.

The 5-year outcomes showed that the rate of major adverse cardiac and cerebrovascular events favored CABG over PCI (26.9% vs 37.3%, respectively; P < .0001).³ All-cause mortality, although not statistically significant, also was better for CABG (11.4% vs 13.9%). This indicates that as the complexity and burden of disease increase, the benefit of CABG over PCI becomes more prominent. In short, the worse the disease, the better the results with CABG.

Why is CABG better?

One rationale is that CABG not only bypasses the culprit-lesion vessel, it also protects against future lesions. An elegant study published in 2010 showed that in most cases of acute myocardial infarction (MI), the culprit coronary lesion is in the first 7 cm of the LAD.⁸ With CABG, most distal anastomoses are beyond 7 cm and, thus, are beyond the location of the vast majority of potential future culprit lesions.

An important factor is the modern-day safety record of CABG. According to the Society of Thoracic
Surgeons Adult Cardiac Surgery Database,⁹ in 2016 the expected operative mortality for CABG was just over 2%. At the Cleveland Clinic, CABG mortality has consistently been below 1% despite the complexity of the cases and the higher percentage of reoperations performed at the Clinic. In addition, the low incidence of major complications after CABG has contributed to its endurance as an important therapeutic option for CAD over the decades.

IMPROVING LONG-TERM CABG OUTCOMES

Improving vein graft patency

The Achilles heel of CABG is the decline of patency of saphenous vein grafts. The occlusion rate of these veins is 6% to 8% at hospital discharge and approximately 10% at 1 year after CABG. By 10 years, half of the vein grafts are diseased or occluded, with progression of atherosclerotic disease over time.

There has been controversy about whether open harvesting of the saphenous vein is better than endoscopic vein harvesting for patency-related outcomes. This arose after the publication of an ad hoc analysis that gave poor marks to endoscopic vein-graft harvesting.¹⁰ Its major finding was that endoscopic vein harvesting had higher rates of vein-graft failure at 12 to 18 months than open vein harvesting (46.7% vs 38.0%, respectively; P < .001). At 3 years, endoscopic harvesting was associated with higher rates of death, MI, or repeat revascularization (20.2% vs 17.4%, P = .04).

A US Food and Drug Administration-sanctioned Society of Thoracic Surgeons observational study, however, reviewed outcomes from 235,394 patients who underwent CABG from 2003 through 2008 and found no significant increase in 5-year mortality rates with use of endoscopic vein-graft harvesting vs open harvesting.¹¹ This study showed that the less invasive endoscopic approach is still an option.

In 2015, Taggart and colleagues¹² reported on a pioneering procedure that wraps the saphenous vein graft with a stent. Initial results showed external stenting had the potential to improve vein-graft lumen and reduce intimal hyperplasia at 1 year postoperatively. Surgeons can expect more data on this technology in the future.

Arterial vs venous grafts

The 1986 report by Loop and colleagues from Cleveland Clinic showed that the patency of the mammary artery graft was superior to that of the saphenous vein and that patients receiving a mammary bypass had significantly better 10-year survival (82.6% vs 71.0%, respectively; P < .0001).¹³ The findings of this landmark study established the LIMA-to-LAD bypass as the technical standard for surgical coronary revascularization.

Single vs bilateral mammary artery grafts

In December 2016, results of the Arterial Revascularization Trial (ART) were published comparing single vs double mammary artery grafts.¹⁴ In this prospective randomized trial, the 5-year results showed no significant difference between these mammary grafts in terms of all-cause mortality, MI, or stroke. Bilateral mammary artery grafts, however, were associated with a higher risk of sternal wound complications (3.5% vs 1.9%, respectively; P = .005) and sternal reconstruction (1.9% vs 0.6%; P = .002).

Radial artery vs saphenous vein grafts

In the largest randomized study comparing these two graft options,¹⁶ the 1-year results showed no difference in graft patency; a follow-up analysis is in progress. In contrast, randomized studies from Canada¹⁷ and the United Kingdom¹⁸ suggest that there are potential benefits associated with use of radial artery grafts in terms of patency and clinical outcomes. In addition, observational data from centers experienced in radial artery grafting have demonstrated favorable outcomes. Radial arteries perform best when bypassing totally occluded or severely stenotic vessels in which there is no or little risk of competitive flow from the native circulation.

Right internal mammary vs radial artery grafts

A propensity-matched comparison study looking at multiple studies (N = 15,374 patients) concluded that use of the right internal mammary artery provides better outcomes.¹⁹ It was associated with a 25% risk reduction for late death and a 63% risk reduction for repeat vascularization, both statistically significant vs the radial artery rates. But there is a randomized study showing that the radial artery is as good as or better than the right internal mammary artery. At this point, it is not clear which artery is better as an adjunct for the LIMA-to-LAD bypass.

GUIDELINES FOR GRAFT SELECTION

In 2016, the Society of Thoracic Surgeons published guidelines that encouraged the use of arterial grafts, giving it a class IIa designation, meaning that the evidence indicates it is reasonable to consider.²⁰

The guidelines note the following:

• The internal mammary artery should be used to bypass the LAD when bypass of the LAD is indicated.
• As an adjunct to the left internal mammary artery, a second arterial graft (the right internal mammary artery or radial artery) should be considered in appropriate patients.
• Use of bilateral internal mammary arteries should be considered in patients who are not at high risk for sternal complications.

COMPARING SURGICAL APPROACHES

Traditional CABG performed via median sternotomy and with the use of cardiopulmonary bypass remains the technical standard in surgical coronary revascularization. However, technologies have allowed surgeons to use different and sometimes less invasive approaches that may have good outcomes in select patients with suitable risk profiles and favorable coronary anatomies.

On-pump vs off-pump CABG

The popularity of CABG without cardiopulmonary bypass (“off-pump”) peaked in 2002, when it constituted approximately 23% of CABG procedures and then declined to 17% by 2012.²¹ The ROOBY (Veterans Affairs Randomized On/Off Bypass) trial of 2,203 VA patients showed that at 1 year, those in the off-pump group had worse composite outcomes, poorer graft patency, and greater incidence of incomplete revascularization than the on-pump group.²² However, the use of off-pump CABG was vindicated in two other trials—CORONARY and GOPCABE—in which experienced surgeons in high-volume centers with high-risk patients had no difference in outcomes at 1 and 5 years.^23–25 The recommendation is to tailor the procedure to the patient rather than the patient to the procedure. The best option is always to do what is right for the patient. For example, patients with diseased ascending aortas or liver disease may benefit from an off-pump approach.

Robotic CABG

This procedure has advantages and disadvantages. The advantages are primarily related to the minimally invasive approach:

• There is no surgeon hand tremor
• It is less invasive
• It provides better cosmetic results
• It is expected to result in less pain, fewer transfusions, fewer complications, and shorter length of hospital stay, although those have not been proven.

Disadvantages include the following:

• Compromised completeness of revascularization—with some “difficult” vessels left unbypassed
• Longer operative times
• Higher cost
• Concern about graft patency with inexperienced surgeons
• Higher-than-expected mortality in some reports.

In 2013, a study of 500 patients treated with robotic totally endoscopic CABG showed that this procedure could be safe and effective, although the best outcomes were achieved in patients with less severe disease requiring fewer bypasses.²⁶ In other words, it is more appropriate for LIMA-to-LAD suturing and less complex anatomy, and it is best performed with cardiopulmonary bypass with the heart arrested.

Hybrid revascularization

This procedure is a combination of minimally invasive CABG (MIDCAB or robotic CABG) to revascularize the LAD and PCI to treat the remaining vessels in multivessel CAD. The CABG and PCI can be concurrent or staged. The hybrid approach has the attraction of being less invasive and uses the technical standard LIMA-to-LAD approach, but it has the obvious limitation of not incorporating additional arterial grafting and the possibility of a compromised technical outcome in less experienced hands.

A collaborative task force from several cardiovascular medical societies developed evidence-based guidelines to address the hybrid coronary revascularization approach. They give it a class IIa recommendation, indicating that it is a reasonable approach to treating patients in whom there are limitations and challenges to traditional CABG. For other patients, they gave it a class IIb recommendation, indicating that it may be reasonable to use as an alternative to multivessel PCI or CABG.²⁷

THE EVOLUTION CONTINUES: CABG VS PCI

As CABG and PCI continue to evolve, surgical approaches to CAD are becoming more sophisticated with the use of more arterial conduits, less invasive surgical approaches, and development of new types of stents for PCI; however, expect the debate to continue regarding which approach to CAD is best. This is not a battle between surgical and nonsurgical specialties. Rather, the goal should be an amicable, collaborative heart-care team. After all, the most important question is, as always, which therapy is best for the individual patient.

The evolution of coronary artery bypass grafting (CABG) has been a key component in significantly reducing the morbidity and mortality associated with occlusive coronary artery disease (CAD). Cleveland Clinic surgeons, through their technical interventions and innovations, have led the evolution in coronary revascularization starting in the 1960s and continuing today. This article provides a brief overview of the evolution and describes the issues associated with current CABG approaches.

EARLY WORK IN RECONSTRUCTIVE CORONARY ARTERY SURGERY

Results from the first large series of venous grafting for CAD were reported in 1970 by Favaloro and colleagues at Cleveland Clinic.¹ They showed the efficacy of grafting in treating CAD, with low associated morbidity and mortality, thus establishing this surgery as the treatment modality for CAD.

The technique of surgical myocardial revascularization was a culmination of developments that began years earlier with the Vineberg procedure, involving suturing of the mammary artery to the muscle rather than a vessel-to-vessel anastomosis. From this followed the coronary patch, end-to-end bypass, and then end-to-side bypass.

In the 1970s, the refinement of suturing the left internal mammary artery (LIMA) directly to the left anterior descending (LAD) artery using magnifying loops was pioneered and popularized at Cleveland Clinic. This later became the cornerstone of future coronary revascularizations.

As a direct result of the successful technical advances and excellent clinical outcomes, the volume of CABG procedures in the United States rose steadily during the 1980s and reached its peak in 1995. It then began a slow decline that continued until 2013, when the trend began to reverse. It was still rising through 2015.

WHY THE RENEWED INTEREST IN CABG?

A key component to continued use of CABG is that it appears to have a clinical edge over other treatments. This has been shown in several high-profile studies: SYNTAX,^2,3 FREEDOM,^4,5 BEST,⁶ and NOBLE.⁷ For example, in the SYNTAX trial, which compared CABG vs percutaneous coronary intervention (PCI), the conclusion from both the 1-year² and the 5-year³ results was that CABG should remain the standard of care for patients with complex lesions—those with an intermediate or high burden of CAD.

The 5-year outcomes showed that the rate of major adverse cardiac and cerebrovascular events favored CABG over PCI (26.9% vs 37.3%, respectively; P < .0001).³ All-cause mortality, although not statistically significant, also was better for CABG (11.4% vs 13.9%). This indicates that as the complexity and burden of disease increase, the benefit of CABG over PCI becomes more prominent. In short, the worse the disease, the better the results with CABG.

Why is CABG better?

One rationale is that CABG not only bypasses the culprit-lesion vessel, it also protects against future lesions. An elegant study published in 2010 showed that in most cases of acute myocardial infarction (MI), the culprit coronary lesion is in the first 7 cm of the LAD.⁸ With CABG, most distal anastomoses are beyond 7 cm and, thus, are beyond the location of the vast majority of potential future culprit lesions.

An important factor is the modern-day safety record of CABG. According to the Society of Thoracic
Surgeons Adult Cardiac Surgery Database,⁹ in 2016 the expected operative mortality for CABG was just over 2%. At the Cleveland Clinic, CABG mortality has consistently been below 1% despite the complexity of the cases and the higher percentage of reoperations performed at the Clinic. In addition, the low incidence of major complications after CABG has contributed to its endurance as an important therapeutic option for CAD over the decades.

IMPROVING LONG-TERM CABG OUTCOMES

Improving vein graft patency

The Achilles heel of CABG is the decline of patency of saphenous vein grafts. The occlusion rate of these veins is 6% to 8% at hospital discharge and approximately 10% at 1 year after CABG. By 10 years, half of the vein grafts are diseased or occluded, with progression of atherosclerotic disease over time.

There has been controversy about whether open harvesting of the saphenous vein is better than endoscopic vein harvesting for patency-related outcomes. This arose after the publication of an ad hoc analysis that gave poor marks to endoscopic vein-graft harvesting.¹⁰ Its major finding was that endoscopic vein harvesting had higher rates of vein-graft failure at 12 to 18 months than open vein harvesting (46.7% vs 38.0%, respectively; P < .001). At 3 years, endoscopic harvesting was associated with higher rates of death, MI, or repeat revascularization (20.2% vs 17.4%, P = .04).

A US Food and Drug Administration-sanctioned Society of Thoracic Surgeons observational study, however, reviewed outcomes from 235,394 patients who underwent CABG from 2003 through 2008 and found no significant increase in 5-year mortality rates with use of endoscopic vein-graft harvesting vs open harvesting.¹¹ This study showed that the less invasive endoscopic approach is still an option.

In 2015, Taggart and colleagues¹² reported on a pioneering procedure that wraps the saphenous vein graft with a stent. Initial results showed external stenting had the potential to improve vein-graft lumen and reduce intimal hyperplasia at 1 year postoperatively. Surgeons can expect more data on this technology in the future.

Arterial vs venous grafts

The 1986 report by Loop and colleagues from Cleveland Clinic showed that the patency of the mammary artery graft was superior to that of the saphenous vein and that patients receiving a mammary bypass had significantly better 10-year survival (82.6% vs 71.0%, respectively; P < .0001).¹³ The findings of this landmark study established the LIMA-to-LAD bypass as the technical standard for surgical coronary revascularization.

Single vs bilateral mammary artery grafts

In December 2016, results of the Arterial Revascularization Trial (ART) were published comparing single vs double mammary artery grafts.¹⁴ In this prospective randomized trial, the 5-year results showed no significant difference between these mammary grafts in terms of all-cause mortality, MI, or stroke. Bilateral mammary artery grafts, however, were associated with a higher risk of sternal wound complications (3.5% vs 1.9%, respectively; P = .005) and sternal reconstruction (1.9% vs 0.6%; P = .002).

Radial artery vs saphenous vein grafts

In the largest randomized study comparing these two graft options,¹⁶ the 1-year results showed no difference in graft patency; a follow-up analysis is in progress. In contrast, randomized studies from Canada¹⁷ and the United Kingdom¹⁸ suggest that there are potential benefits associated with use of radial artery grafts in terms of patency and clinical outcomes. In addition, observational data from centers experienced in radial artery grafting have demonstrated favorable outcomes. Radial arteries perform best when bypassing totally occluded or severely stenotic vessels in which there is no or little risk of competitive flow from the native circulation.

Right internal mammary vs radial artery grafts

A propensity-matched comparison study looking at multiple studies (N = 15,374 patients) concluded that use of the right internal mammary artery provides better outcomes.¹⁹ It was associated with a 25% risk reduction for late death and a 63% risk reduction for repeat vascularization, both statistically significant vs the radial artery rates. But there is a randomized study showing that the radial artery is as good as or better than the right internal mammary artery. At this point, it is not clear which artery is better as an adjunct for the LIMA-to-LAD bypass.

GUIDELINES FOR GRAFT SELECTION

In 2016, the Society of Thoracic Surgeons published guidelines that encouraged the use of arterial grafts, giving it a class IIa designation, meaning that the evidence indicates it is reasonable to consider.²⁰

The guidelines note the following:

• The internal mammary artery should be used to bypass the LAD when bypass of the LAD is indicated.
• As an adjunct to the left internal mammary artery, a second arterial graft (the right internal mammary artery or radial artery) should be considered in appropriate patients.
• Use of bilateral internal mammary arteries should be considered in patients who are not at high risk for sternal complications.

COMPARING SURGICAL APPROACHES

Traditional CABG performed via median sternotomy and with the use of cardiopulmonary bypass remains the technical standard in surgical coronary revascularization. However, technologies have allowed surgeons to use different and sometimes less invasive approaches that may have good outcomes in select patients with suitable risk profiles and favorable coronary anatomies.

On-pump vs off-pump CABG

The popularity of CABG without cardiopulmonary bypass (“off-pump”) peaked in 2002, when it constituted approximately 23% of CABG procedures and then declined to 17% by 2012.²¹ The ROOBY (Veterans Affairs Randomized On/Off Bypass) trial of 2,203 VA patients showed that at 1 year, those in the off-pump group had worse composite outcomes, poorer graft patency, and greater incidence of incomplete revascularization than the on-pump group.²² However, the use of off-pump CABG was vindicated in two other trials—CORONARY and GOPCABE—in which experienced surgeons in high-volume centers with high-risk patients had no difference in outcomes at 1 and 5 years.^23–25 The recommendation is to tailor the procedure to the patient rather than the patient to the procedure. The best option is always to do what is right for the patient. For example, patients with diseased ascending aortas or liver disease may benefit from an off-pump approach.

Robotic CABG

This procedure has advantages and disadvantages. The advantages are primarily related to the minimally invasive approach:

• There is no surgeon hand tremor
• It is less invasive
• It provides better cosmetic results
• It is expected to result in less pain, fewer transfusions, fewer complications, and shorter length of hospital stay, although those have not been proven.

Disadvantages include the following:

• Compromised completeness of revascularization—with some “difficult” vessels left unbypassed
• Longer operative times
• Higher cost
• Concern about graft patency with inexperienced surgeons
• Higher-than-expected mortality in some reports.

In 2013, a study of 500 patients treated with robotic totally endoscopic CABG showed that this procedure could be safe and effective, although the best outcomes were achieved in patients with less severe disease requiring fewer bypasses.²⁶ In other words, it is more appropriate for LIMA-to-LAD suturing and less complex anatomy, and it is best performed with cardiopulmonary bypass with the heart arrested.

Hybrid revascularization

This procedure is a combination of minimally invasive CABG (MIDCAB or robotic CABG) to revascularize the LAD and PCI to treat the remaining vessels in multivessel CAD. The CABG and PCI can be concurrent or staged. The hybrid approach has the attraction of being less invasive and uses the technical standard LIMA-to-LAD approach, but it has the obvious limitation of not incorporating additional arterial grafting and the possibility of a compromised technical outcome in less experienced hands.

A collaborative task force from several cardiovascular medical societies developed evidence-based guidelines to address the hybrid coronary revascularization approach. They give it a class IIa recommendation, indicating that it is a reasonable approach to treating patients in whom there are limitations and challenges to traditional CABG. For other patients, they gave it a class IIb recommendation, indicating that it may be reasonable to use as an alternative to multivessel PCI or CABG.²⁷

THE EVOLUTION CONTINUES: CABG VS PCI

As CABG and PCI continue to evolve, surgical approaches to CAD are becoming more sophisticated with the use of more arterial conduits, less invasive surgical approaches, and development of new types of stents for PCI; however, expect the debate to continue regarding which approach to CAD is best. This is not a battle between surgical and nonsurgical specialties. Rather, the goal should be an amicable, collaborative heart-care team. After all, the most important question is, as always, which therapy is best for the individual patient.

The evolution of coronary artery bypass grafting (CABG) has been a key component in significantly reducing the morbidity and mortality associated with occlusive coronary artery disease (CAD). Cleveland Clinic surgeons, through their technical interventions and innovations, have led the evolution in coronary revascularization starting in the 1960s and continuing today. This article provides a brief overview of the evolution and describes the issues associated with current CABG approaches.

EARLY WORK IN RECONSTRUCTIVE CORONARY ARTERY SURGERY

Results from the first large series of venous grafting for CAD were reported in 1970 by Favaloro and colleagues at Cleveland Clinic.¹ They showed the efficacy of grafting in treating CAD, with low associated morbidity and mortality, thus establishing this surgery as the treatment modality for CAD.

The technique of surgical myocardial revascularization was a culmination of developments that began years earlier with the Vineberg procedure, involving suturing of the mammary artery to the muscle rather than a vessel-to-vessel anastomosis. From this followed the coronary patch, end-to-end bypass, and then end-to-side bypass.

In the 1970s, the refinement of suturing the left internal mammary artery (LIMA) directly to the left anterior descending (LAD) artery using magnifying loops was pioneered and popularized at Cleveland Clinic. This later became the cornerstone of future coronary revascularizations.

As a direct result of the successful technical advances and excellent clinical outcomes, the volume of CABG procedures in the United States rose steadily during the 1980s and reached its peak in 1995. It then began a slow decline that continued until 2013, when the trend began to reverse. It was still rising through 2015.

WHY THE RENEWED INTEREST IN CABG?

A key component to continued use of CABG is that it appears to have a clinical edge over other treatments. This has been shown in several high-profile studies: SYNTAX,^2,3 FREEDOM,^4,5 BEST,⁶ and NOBLE.⁷ For example, in the SYNTAX trial, which compared CABG vs percutaneous coronary intervention (PCI), the conclusion from both the 1-year² and the 5-year³ results was that CABG should remain the standard of care for patients with complex lesions—those with an intermediate or high burden of CAD.

The 5-year outcomes showed that the rate of major adverse cardiac and cerebrovascular events favored CABG over PCI (26.9% vs 37.3%, respectively; P < .0001).³ All-cause mortality, although not statistically significant, also was better for CABG (11.4% vs 13.9%). This indicates that as the complexity and burden of disease increase, the benefit of CABG over PCI becomes more prominent. In short, the worse the disease, the better the results with CABG.

Why is CABG better?

One rationale is that CABG not only bypasses the culprit-lesion vessel, it also protects against future lesions. An elegant study published in 2010 showed that in most cases of acute myocardial infarction (MI), the culprit coronary lesion is in the first 7 cm of the LAD.⁸ With CABG, most distal anastomoses are beyond 7 cm and, thus, are beyond the location of the vast majority of potential future culprit lesions.

An important factor is the modern-day safety record of CABG. According to the Society of Thoracic
Surgeons Adult Cardiac Surgery Database,⁹ in 2016 the expected operative mortality for CABG was just over 2%. At the Cleveland Clinic, CABG mortality has consistently been below 1% despite the complexity of the cases and the higher percentage of reoperations performed at the Clinic. In addition, the low incidence of major complications after CABG has contributed to its endurance as an important therapeutic option for CAD over the decades.

IMPROVING LONG-TERM CABG OUTCOMES

Improving vein graft patency

The Achilles heel of CABG is the decline of patency of saphenous vein grafts. The occlusion rate of these veins is 6% to 8% at hospital discharge and approximately 10% at 1 year after CABG. By 10 years, half of the vein grafts are diseased or occluded, with progression of atherosclerotic disease over time.

There has been controversy about whether open harvesting of the saphenous vein is better than endoscopic vein harvesting for patency-related outcomes. This arose after the publication of an ad hoc analysis that gave poor marks to endoscopic vein-graft harvesting.¹⁰ Its major finding was that endoscopic vein harvesting had higher rates of vein-graft failure at 12 to 18 months than open vein harvesting (46.7% vs 38.0%, respectively; P < .001). At 3 years, endoscopic harvesting was associated with higher rates of death, MI, or repeat revascularization (20.2% vs 17.4%, P = .04).

A US Food and Drug Administration-sanctioned Society of Thoracic Surgeons observational study, however, reviewed outcomes from 235,394 patients who underwent CABG from 2003 through 2008 and found no significant increase in 5-year mortality rates with use of endoscopic vein-graft harvesting vs open harvesting.¹¹ This study showed that the less invasive endoscopic approach is still an option.

In 2015, Taggart and colleagues¹² reported on a pioneering procedure that wraps the saphenous vein graft with a stent. Initial results showed external stenting had the potential to improve vein-graft lumen and reduce intimal hyperplasia at 1 year postoperatively. Surgeons can expect more data on this technology in the future.

Arterial vs venous grafts

The 1986 report by Loop and colleagues from Cleveland Clinic showed that the patency of the mammary artery graft was superior to that of the saphenous vein and that patients receiving a mammary bypass had significantly better 10-year survival (82.6% vs 71.0%, respectively; P < .0001).¹³ The findings of this landmark study established the LIMA-to-LAD bypass as the technical standard for surgical coronary revascularization.

Single vs bilateral mammary artery grafts

In December 2016, results of the Arterial Revascularization Trial (ART) were published comparing single vs double mammary artery grafts.¹⁴ In this prospective randomized trial, the 5-year results showed no significant difference between these mammary grafts in terms of all-cause mortality, MI, or stroke. Bilateral mammary artery grafts, however, were associated with a higher risk of sternal wound complications (3.5% vs 1.9%, respectively; P = .005) and sternal reconstruction (1.9% vs 0.6%; P = .002).

Radial artery vs saphenous vein grafts

In the largest randomized study comparing these two graft options,¹⁶ the 1-year results showed no difference in graft patency; a follow-up analysis is in progress. In contrast, randomized studies from Canada¹⁷ and the United Kingdom¹⁸ suggest that there are potential benefits associated with use of radial artery grafts in terms of patency and clinical outcomes. In addition, observational data from centers experienced in radial artery grafting have demonstrated favorable outcomes. Radial arteries perform best when bypassing totally occluded or severely stenotic vessels in which there is no or little risk of competitive flow from the native circulation.

Right internal mammary vs radial artery grafts

A propensity-matched comparison study looking at multiple studies (N = 15,374 patients) concluded that use of the right internal mammary artery provides better outcomes.¹⁹ It was associated with a 25% risk reduction for late death and a 63% risk reduction for repeat vascularization, both statistically significant vs the radial artery rates. But there is a randomized study showing that the radial artery is as good as or better than the right internal mammary artery. At this point, it is not clear which artery is better as an adjunct for the LIMA-to-LAD bypass.

GUIDELINES FOR GRAFT SELECTION

In 2016, the Society of Thoracic Surgeons published guidelines that encouraged the use of arterial grafts, giving it a class IIa designation, meaning that the evidence indicates it is reasonable to consider.²⁰

The guidelines note the following:

• The internal mammary artery should be used to bypass the LAD when bypass of the LAD is indicated.
• As an adjunct to the left internal mammary artery, a second arterial graft (the right internal mammary artery or radial artery) should be considered in appropriate patients.
• Use of bilateral internal mammary arteries should be considered in patients who are not at high risk for sternal complications.

COMPARING SURGICAL APPROACHES

Traditional CABG performed via median sternotomy and with the use of cardiopulmonary bypass remains the technical standard in surgical coronary revascularization. However, technologies have allowed surgeons to use different and sometimes less invasive approaches that may have good outcomes in select patients with suitable risk profiles and favorable coronary anatomies.

On-pump vs off-pump CABG

The popularity of CABG without cardiopulmonary bypass (“off-pump”) peaked in 2002, when it constituted approximately 23% of CABG procedures and then declined to 17% by 2012.²¹ The ROOBY (Veterans Affairs Randomized On/Off Bypass) trial of 2,203 VA patients showed that at 1 year, those in the off-pump group had worse composite outcomes, poorer graft patency, and greater incidence of incomplete revascularization than the on-pump group.²² However, the use of off-pump CABG was vindicated in two other trials—CORONARY and GOPCABE—in which experienced surgeons in high-volume centers with high-risk patients had no difference in outcomes at 1 and 5 years.^23–25 The recommendation is to tailor the procedure to the patient rather than the patient to the procedure. The best option is always to do what is right for the patient. For example, patients with diseased ascending aortas or liver disease may benefit from an off-pump approach.

Robotic CABG

This procedure has advantages and disadvantages. The advantages are primarily related to the minimally invasive approach:

• There is no surgeon hand tremor
• It is less invasive
• It provides better cosmetic results
• It is expected to result in less pain, fewer transfusions, fewer complications, and shorter length of hospital stay, although those have not been proven.

Disadvantages include the following:

• Compromised completeness of revascularization—with some “difficult” vessels left unbypassed
• Longer operative times
• Higher cost
• Concern about graft patency with inexperienced surgeons
• Higher-than-expected mortality in some reports.

In 2013, a study of 500 patients treated with robotic totally endoscopic CABG showed that this procedure could be safe and effective, although the best outcomes were achieved in patients with less severe disease requiring fewer bypasses.²⁶ In other words, it is more appropriate for LIMA-to-LAD suturing and less complex anatomy, and it is best performed with cardiopulmonary bypass with the heart arrested.

Hybrid revascularization

This procedure is a combination of minimally invasive CABG (MIDCAB or robotic CABG) to revascularize the LAD and PCI to treat the remaining vessels in multivessel CAD. The CABG and PCI can be concurrent or staged. The hybrid approach has the attraction of being less invasive and uses the technical standard LIMA-to-LAD approach, but it has the obvious limitation of not incorporating additional arterial grafting and the possibility of a compromised technical outcome in less experienced hands.

A collaborative task force from several cardiovascular medical societies developed evidence-based guidelines to address the hybrid coronary revascularization approach. They give it a class IIa recommendation, indicating that it is a reasonable approach to treating patients in whom there are limitations and challenges to traditional CABG. For other patients, they gave it a class IIb recommendation, indicating that it may be reasonable to use as an alternative to multivessel PCI or CABG.²⁷

THE EVOLUTION CONTINUES: CABG VS PCI

As CABG and PCI continue to evolve, surgical approaches to CAD are becoming more sophisticated with the use of more arterial conduits, less invasive surgical approaches, and development of new types of stents for PCI; however, expect the debate to continue regarding which approach to CAD is best. This is not a battle between surgical and nonsurgical specialties. Rather, the goal should be an amicable, collaborative heart-care team. After all, the most important question is, as always, which therapy is best for the individual patient.

The development of a new generation of drug-eluting stents (DES) has had a dramatic impact on the number of stents used for percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease (CAD). But even second- and third-generation DES fall short when compared with coronary artery bypass grafting (CABG) with regards to the need for repeat reavascularization. CABG is advantageous because it bypasses the entire disease segment of the vessel. Thus for multivessel complex CAD, it is still considered the best choice. Nevertheless, most patients prefer the less-invasive option of stents, so practitioners need to provide the best stent available.

There are 3 primary criteria for DES selection:

• Efficacy for a broad range of patients and lesion complexities that primarily provides consistency in improving measures of angiographic and clinical efficacy
• Safety as determined by the following:
  • Enable healing and promote endothelialization
  • Permit functional endothelium
  • Obtaining complete apposition
  • Reduction or elimination of late and very late stent thrombosis
  • Minimizing the need for long-term dual antiplatelet therapy

• Performance provided by reliable delivery capabilities to the lesion site.

GREAT EXPECTATIONS

New DES must be shown to be superior to previous generation stents. Although preclinical endothelialization and other mechanistic surrogates are good enough to claim an improvement, the traditional method is to compare clinical outcomes with the new stent versus the existing stent in a randomized clinical trial.

PROBLEMS WITH DURABLE POLYMER STENTS

Complications with durable polymer DES have included increased local inflammation and neoatherosclerosis. There are reports of subacute stent thrombosis due to lack of adequate expansion and stent apposition. Also reported was late thrombosis, resulting in increased rates of myocardial infarction and death.

These issues motivated engineers to improve and iterate the DES technology. One important technological change is the decrease in strut thickness from 140 µm to as low as 60 µm. The thickness of the polymer coating also has been reduced. The polymer became thinner, more biocompatible, and in some stents, only abluminal. Further developments were to substitute the durable polymer with a biodegradable polymer and perhaps even design a polymer-free stent.

BIORESORBABLE POLYMERS EMERGE

The time course for resorption of bioresorbable polymers ranges from 2 to 15 months, but they all degrade, which should improve long-term outcomes. A meta-analysis of data from the LEADERS trial and ISAR-TEST 3 and 4 found that the bioresorbable polymer stents were associated with significantly lower rates of target-lesion revascularization (P = .029) and stent thrombosis (P = .015) than durable polymer DES at 4 years after implantation.¹ Those results led to the notion that stents with a biodegradable polymer would result in lower rates of stent thrombosis than durable polymer stents; however, that was not the case when stents with biodegradable polymers were compared with second-generation DES.

In the COMPARE II trial,² the rates of stent thrombosis and target-lesion revascularization were not statistically different for the thick-strut biodegradable polymer biolimus-eluting stent (Nobori) compared with the second-generation thin-strut permanent-polymer stents (Xience). In the CENTURY II trial,³ a third-generation biodegradable sirolimus-eluting stent (Ultimaster) had stent thrombosis rates similar to those of a durable polymer everolimus-eluting stent (Xience) 300 days after insertion (4.36% vs 5.27%, respectively). Target-lesion revascularization rates were also about the same for the stents. In the EVOLVE II trial comparing the thin-strut biodegradable everolimus-eluting stent (Synergy) vs the thin-strut permanent-polymer everolimus-eluting stent (Promus), the 12-month target lesion failure rates for the stents were essentially the same.⁴

Another approach was to use biodegradable scaffolds that will be eliminating from the vessel wall once it “completes the job.” The main bioresorbable materials used were polylactic acid or biodegradable metal-like magnesium. These materials pose a technological challenge. While the biodegradable scaffolds are completely eliminated overtime, they still need to equate the performance of best-in-class drug-eluting stent with respect to efficacy and safety. After the Absorb everolimus-eluting BVS system (Absorb BVS) was launched in Europe, initial studies showed scaffold-related thrombosis rates as high as 3.4%.^5–7 That compares with 0.4% for second-generation DES—a troubling result for a new technology.

Rates of restenosis and stent thrombosis are similar for bioresorbable stents and standard durable polymer stents. But what are the potential added benefits of bioresorbable stents? And will they improve patient outcomes?

Bioresorbable stents certainly appeal to patients who do not want a permanent, rigid, metallic implant. Also appealing are the proposed benefits of restoration of vasomotion, late luminal enlargement, preservation of CABG targets, and relief of angina. Whether bioresorbable stents improve these outcomes has not been established. Currently, there is no long-term evidence of reduced rates of adverse events, although in 1 study, optical coherence tomography images recorded 10 years after implantation of the first bioresorbable stents showed a pristine vessel with no signs of the struts.⁸

Several facts are known about the Absorb BVS:

• Preclinical evidence shows complete resorption and return of vascular function, but this takes 3 to 4 years.
• Imaging data at 5 years from the Absorb cohort B trial show complete resorption of struts, lumen preservation, return of function, and plaque regression.⁹
• In ABSORB III, the pivotal US trial, the stent was within the primary end point showing noninferiority in safety and effectiveness compared with Xience in the first year.¹⁰
• Absorb clinical trials in Japan and China confirmed ABSORB III results.
• Meta-analysis (> 3,300 patients) confirmed safety and effectiveness of Absorb.¹¹
• Real-world Absorb clinical evidence continues to show improving outcomes with optimized implant techniques.
• Absorb stent was approved by the US Food and Drug Administration (FDA) in July 2016; more than 150,000 have been implanted worldwide.

The increased rates of target-lesion revascularization and stent thrombosis were likely attributable to inserting the stents into small-diameter vessels that are probably too small for the Absorb BVS. When small vessels (< 2.25 mm) are eliminated from the analysis, the rates were as follows.

Results for vessels > 2.25 mm:

• Target-lesion revascularization: 6.7 % vs 5.5%
• Stent thrombosis: 0.9% vs 0.6%.
• Results for small vessels (< 2.25 mm):
• Target-lesion revascularization: 12.9% vs 8.3%
• Stent thrombosis: 4.6% vs 1.5%.

The lesson is that the Absorb BVS should not be placed in arteries smaller than 2.25 mm in diameter.

Another concern was uncovered in July 2016 when results were published from the ABSORB II trial on vasomotor reactivity at 3 years.¹³ This clinical trial randomized 501 patients in a 2:1 ratio to the Absorb BVS or the Xience DES at 46 sites outside the United States. Assessment for changes in mean lumen diameter between pre- and post-nitrate administration showed no differences between the groups; thus, the Absorb BVS did not achieve a level of superior vasomotor reactivity. There was vasomotor reactivity probably because the surrogate marker was angiographic follow-up and not intravascular ultrasound or tomography.

Further, the coprimary end point of angiographic late luminal loss at 3 years did not meet its noninferiority standard. The Absorb BVS was expected to have lower rates of late lumen loss because the struts are gone and there is less new intimal formation; however, at 3 years, that was not the case.

The rate of acute stent thrombosis also was alarming: 8 cases for Absorb BVS versus none for Xience. This caused alarm, raising the question of why it was happening in these patients 2 to 3 years after implantation.

Animal studies investigating the association of thicker struts and increased thrombogenicity have reported that the 157-µm BVS had much more platelet buildup and thrombogenicity than a 120-µm biomatrix stent. The 74-µm Synergy stent had even lower rates of thrombosis. The reason for increased thrombogenicity with thicker struts requires further study.

Also, an analysis of the secondary cardiac end points at 3 years in ABSORB II found no clinical patient-oriented differences between the Absorb BVS and the Xience stent (20.8% vs 24.0%, respectively; P = .44). However, rates of device-oriented clinical end points were significantly higher for Absorb BVS (10.4% vs 4.9%; P = .043).¹³

Clearly, the results for Absorb BVS in this study were not positive. One explanation is suboptimal implantation techniques that did not appose the polymer to the wall. A few years ago, focus shifted to an optimal technique for scaffold deployment, which included predilation, appropriate sizing of the scaffold to the size of the vessel, and postdilation with the intention of embedding the polymer in the vessel wall. Multiple studies have reported fewer incidents of stent thrombosis with the implementation of this protocol.¹⁴

Further studies have continued to report increased rates of late scaffold thrombosis in follow-ups of 30 days to 3 years. This resulted in an advisory letter from the FDA focused on appropriate clinical use of the device and withdrawal of ABSORB from commercial use in Europe and Australia.

BIORESORBABLE SCAFFOLDS PIPELINE

This is questionable because one has to believe in the vulnerable plaque theory, which assumes potential eruption of plaques. The Absorb can actually seal a thin cap atheroma and necrotic core over time. It seems that this technology can cause some late lumen enlargement and seal an existing plaque, which may have implications for the future.

SUMMARY

This is the current state of the Absorb BVS:

• More than 150,000 implanted globally
• Received FDA approval in July 2016
• Should not be used in small vessels (ie, lumen diameter < 2.25 mm)
• Thrombosis rates 2 to 3 years after implantation are of concern
• Focusing on appropriate surgical implantation technique can improve outcomes.

Overall, use of bioresorbable stent technology is intriguing. While there is ongoing patient preference for bioresorbable technology, clinical trial results raise the question of whether bioresorbable scaffolds are inferior to best-in-class DES. Improving the scaffold technology and the implantation techniques may equate the short-term outcome of the bioresorbable scaffolds with metallic stents with the hope that over time (when the scaffold is gone), the advantage will be with the bioresorbable scaffolds. Meanwhile, the technology is still seeking its best clinical utility, and a matching performance to the best-in-class DES.

Time will tell whether 5 to 10 years after implantation, BRS technology will outperform durable metallic stents.

The development of a new generation of drug-eluting stents (DES) has had a dramatic impact on the number of stents used for percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease (CAD). But even second- and third-generation DES fall short when compared with coronary artery bypass grafting (CABG) with regards to the need for repeat reavascularization. CABG is advantageous because it bypasses the entire disease segment of the vessel. Thus for multivessel complex CAD, it is still considered the best choice. Nevertheless, most patients prefer the less-invasive option of stents, so practitioners need to provide the best stent available.

There are 3 primary criteria for DES selection:

• Efficacy for a broad range of patients and lesion complexities that primarily provides consistency in improving measures of angiographic and clinical efficacy
• Safety as determined by the following:
  • Enable healing and promote endothelialization
  • Permit functional endothelium
  • Obtaining complete apposition
  • Reduction or elimination of late and very late stent thrombosis
  • Minimizing the need for long-term dual antiplatelet therapy

• Performance provided by reliable delivery capabilities to the lesion site.

GREAT EXPECTATIONS

New DES must be shown to be superior to previous generation stents. Although preclinical endothelialization and other mechanistic surrogates are good enough to claim an improvement, the traditional method is to compare clinical outcomes with the new stent versus the existing stent in a randomized clinical trial.

PROBLEMS WITH DURABLE POLYMER STENTS

Complications with durable polymer DES have included increased local inflammation and neoatherosclerosis. There are reports of subacute stent thrombosis due to lack of adequate expansion and stent apposition. Also reported was late thrombosis, resulting in increased rates of myocardial infarction and death.

These issues motivated engineers to improve and iterate the DES technology. One important technological change is the decrease in strut thickness from 140 µm to as low as 60 µm. The thickness of the polymer coating also has been reduced. The polymer became thinner, more biocompatible, and in some stents, only abluminal. Further developments were to substitute the durable polymer with a biodegradable polymer and perhaps even design a polymer-free stent.

BIORESORBABLE POLYMERS EMERGE

The time course for resorption of bioresorbable polymers ranges from 2 to 15 months, but they all degrade, which should improve long-term outcomes. A meta-analysis of data from the LEADERS trial and ISAR-TEST 3 and 4 found that the bioresorbable polymer stents were associated with significantly lower rates of target-lesion revascularization (P = .029) and stent thrombosis (P = .015) than durable polymer DES at 4 years after implantation.¹ Those results led to the notion that stents with a biodegradable polymer would result in lower rates of stent thrombosis than durable polymer stents; however, that was not the case when stents with biodegradable polymers were compared with second-generation DES.

In the COMPARE II trial,² the rates of stent thrombosis and target-lesion revascularization were not statistically different for the thick-strut biodegradable polymer biolimus-eluting stent (Nobori) compared with the second-generation thin-strut permanent-polymer stents (Xience). In the CENTURY II trial,³ a third-generation biodegradable sirolimus-eluting stent (Ultimaster) had stent thrombosis rates similar to those of a durable polymer everolimus-eluting stent (Xience) 300 days after insertion (4.36% vs 5.27%, respectively). Target-lesion revascularization rates were also about the same for the stents. In the EVOLVE II trial comparing the thin-strut biodegradable everolimus-eluting stent (Synergy) vs the thin-strut permanent-polymer everolimus-eluting stent (Promus), the 12-month target lesion failure rates for the stents were essentially the same.⁴

Another approach was to use biodegradable scaffolds that will be eliminating from the vessel wall once it “completes the job.” The main bioresorbable materials used were polylactic acid or biodegradable metal-like magnesium. These materials pose a technological challenge. While the biodegradable scaffolds are completely eliminated overtime, they still need to equate the performance of best-in-class drug-eluting stent with respect to efficacy and safety. After the Absorb everolimus-eluting BVS system (Absorb BVS) was launched in Europe, initial studies showed scaffold-related thrombosis rates as high as 3.4%.^5–7 That compares with 0.4% for second-generation DES—a troubling result for a new technology.

Rates of restenosis and stent thrombosis are similar for bioresorbable stents and standard durable polymer stents. But what are the potential added benefits of bioresorbable stents? And will they improve patient outcomes?

Bioresorbable stents certainly appeal to patients who do not want a permanent, rigid, metallic implant. Also appealing are the proposed benefits of restoration of vasomotion, late luminal enlargement, preservation of CABG targets, and relief of angina. Whether bioresorbable stents improve these outcomes has not been established. Currently, there is no long-term evidence of reduced rates of adverse events, although in 1 study, optical coherence tomography images recorded 10 years after implantation of the first bioresorbable stents showed a pristine vessel with no signs of the struts.⁸

Several facts are known about the Absorb BVS:

• Preclinical evidence shows complete resorption and return of vascular function, but this takes 3 to 4 years.
• Imaging data at 5 years from the Absorb cohort B trial show complete resorption of struts, lumen preservation, return of function, and plaque regression.⁹
• In ABSORB III, the pivotal US trial, the stent was within the primary end point showing noninferiority in safety and effectiveness compared with Xience in the first year.¹⁰
• Absorb clinical trials in Japan and China confirmed ABSORB III results.
• Meta-analysis (> 3,300 patients) confirmed safety and effectiveness of Absorb.¹¹
• Real-world Absorb clinical evidence continues to show improving outcomes with optimized implant techniques.
• Absorb stent was approved by the US Food and Drug Administration (FDA) in July 2016; more than 150,000 have been implanted worldwide.

The increased rates of target-lesion revascularization and stent thrombosis were likely attributable to inserting the stents into small-diameter vessels that are probably too small for the Absorb BVS. When small vessels (< 2.25 mm) are eliminated from the analysis, the rates were as follows.

Results for vessels > 2.25 mm:

• Target-lesion revascularization: 6.7 % vs 5.5%
• Stent thrombosis: 0.9% vs 0.6%.
• Results for small vessels (< 2.25 mm):
• Target-lesion revascularization: 12.9% vs 8.3%
• Stent thrombosis: 4.6% vs 1.5%.

The lesson is that the Absorb BVS should not be placed in arteries smaller than 2.25 mm in diameter.

Another concern was uncovered in July 2016 when results were published from the ABSORB II trial on vasomotor reactivity at 3 years.¹³ This clinical trial randomized 501 patients in a 2:1 ratio to the Absorb BVS or the Xience DES at 46 sites outside the United States. Assessment for changes in mean lumen diameter between pre- and post-nitrate administration showed no differences between the groups; thus, the Absorb BVS did not achieve a level of superior vasomotor reactivity. There was vasomotor reactivity probably because the surrogate marker was angiographic follow-up and not intravascular ultrasound or tomography.

Further, the coprimary end point of angiographic late luminal loss at 3 years did not meet its noninferiority standard. The Absorb BVS was expected to have lower rates of late lumen loss because the struts are gone and there is less new intimal formation; however, at 3 years, that was not the case.

The rate of acute stent thrombosis also was alarming: 8 cases for Absorb BVS versus none for Xience. This caused alarm, raising the question of why it was happening in these patients 2 to 3 years after implantation.

Animal studies investigating the association of thicker struts and increased thrombogenicity have reported that the 157-µm BVS had much more platelet buildup and thrombogenicity than a 120-µm biomatrix stent. The 74-µm Synergy stent had even lower rates of thrombosis. The reason for increased thrombogenicity with thicker struts requires further study.

Also, an analysis of the secondary cardiac end points at 3 years in ABSORB II found no clinical patient-oriented differences between the Absorb BVS and the Xience stent (20.8% vs 24.0%, respectively; P = .44). However, rates of device-oriented clinical end points were significantly higher for Absorb BVS (10.4% vs 4.9%; P = .043).¹³

Clearly, the results for Absorb BVS in this study were not positive. One explanation is suboptimal implantation techniques that did not appose the polymer to the wall. A few years ago, focus shifted to an optimal technique for scaffold deployment, which included predilation, appropriate sizing of the scaffold to the size of the vessel, and postdilation with the intention of embedding the polymer in the vessel wall. Multiple studies have reported fewer incidents of stent thrombosis with the implementation of this protocol.¹⁴

Further studies have continued to report increased rates of late scaffold thrombosis in follow-ups of 30 days to 3 years. This resulted in an advisory letter from the FDA focused on appropriate clinical use of the device and withdrawal of ABSORB from commercial use in Europe and Australia.

BIORESORBABLE SCAFFOLDS PIPELINE

This is questionable because one has to believe in the vulnerable plaque theory, which assumes potential eruption of plaques. The Absorb can actually seal a thin cap atheroma and necrotic core over time. It seems that this technology can cause some late lumen enlargement and seal an existing plaque, which may have implications for the future.

SUMMARY

This is the current state of the Absorb BVS:

• More than 150,000 implanted globally
• Received FDA approval in July 2016
• Should not be used in small vessels (ie, lumen diameter < 2.25 mm)
• Thrombosis rates 2 to 3 years after implantation are of concern
• Focusing on appropriate surgical implantation technique can improve outcomes.

Overall, use of bioresorbable stent technology is intriguing. While there is ongoing patient preference for bioresorbable technology, clinical trial results raise the question of whether bioresorbable scaffolds are inferior to best-in-class DES. Improving the scaffold technology and the implantation techniques may equate the short-term outcome of the bioresorbable scaffolds with metallic stents with the hope that over time (when the scaffold is gone), the advantage will be with the bioresorbable scaffolds. Meanwhile, the technology is still seeking its best clinical utility, and a matching performance to the best-in-class DES.

Time will tell whether 5 to 10 years after implantation, BRS technology will outperform durable metallic stents.

The development of a new generation of drug-eluting stents (DES) has had a dramatic impact on the number of stents used for percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease (CAD). But even second- and third-generation DES fall short when compared with coronary artery bypass grafting (CABG) with regards to the need for repeat reavascularization. CABG is advantageous because it bypasses the entire disease segment of the vessel. Thus for multivessel complex CAD, it is still considered the best choice. Nevertheless, most patients prefer the less-invasive option of stents, so practitioners need to provide the best stent available.

There are 3 primary criteria for DES selection:

• Efficacy for a broad range of patients and lesion complexities that primarily provides consistency in improving measures of angiographic and clinical efficacy
• Safety as determined by the following:
  • Enable healing and promote endothelialization
  • Permit functional endothelium
  • Obtaining complete apposition
  • Reduction or elimination of late and very late stent thrombosis
  • Minimizing the need for long-term dual antiplatelet therapy

• Performance provided by reliable delivery capabilities to the lesion site.

GREAT EXPECTATIONS

New DES must be shown to be superior to previous generation stents. Although preclinical endothelialization and other mechanistic surrogates are good enough to claim an improvement, the traditional method is to compare clinical outcomes with the new stent versus the existing stent in a randomized clinical trial.

PROBLEMS WITH DURABLE POLYMER STENTS

Complications with durable polymer DES have included increased local inflammation and neoatherosclerosis. There are reports of subacute stent thrombosis due to lack of adequate expansion and stent apposition. Also reported was late thrombosis, resulting in increased rates of myocardial infarction and death.

These issues motivated engineers to improve and iterate the DES technology. One important technological change is the decrease in strut thickness from 140 µm to as low as 60 µm. The thickness of the polymer coating also has been reduced. The polymer became thinner, more biocompatible, and in some stents, only abluminal. Further developments were to substitute the durable polymer with a biodegradable polymer and perhaps even design a polymer-free stent.

BIORESORBABLE POLYMERS EMERGE

The time course for resorption of bioresorbable polymers ranges from 2 to 15 months, but they all degrade, which should improve long-term outcomes. A meta-analysis of data from the LEADERS trial and ISAR-TEST 3 and 4 found that the bioresorbable polymer stents were associated with significantly lower rates of target-lesion revascularization (P = .029) and stent thrombosis (P = .015) than durable polymer DES at 4 years after implantation.¹ Those results led to the notion that stents with a biodegradable polymer would result in lower rates of stent thrombosis than durable polymer stents; however, that was not the case when stents with biodegradable polymers were compared with second-generation DES.

In the COMPARE II trial,² the rates of stent thrombosis and target-lesion revascularization were not statistically different for the thick-strut biodegradable polymer biolimus-eluting stent (Nobori) compared with the second-generation thin-strut permanent-polymer stents (Xience). In the CENTURY II trial,³ a third-generation biodegradable sirolimus-eluting stent (Ultimaster) had stent thrombosis rates similar to those of a durable polymer everolimus-eluting stent (Xience) 300 days after insertion (4.36% vs 5.27%, respectively). Target-lesion revascularization rates were also about the same for the stents. In the EVOLVE II trial comparing the thin-strut biodegradable everolimus-eluting stent (Synergy) vs the thin-strut permanent-polymer everolimus-eluting stent (Promus), the 12-month target lesion failure rates for the stents were essentially the same.⁴

Another approach was to use biodegradable scaffolds that will be eliminating from the vessel wall once it “completes the job.” The main bioresorbable materials used were polylactic acid or biodegradable metal-like magnesium. These materials pose a technological challenge. While the biodegradable scaffolds are completely eliminated overtime, they still need to equate the performance of best-in-class drug-eluting stent with respect to efficacy and safety. After the Absorb everolimus-eluting BVS system (Absorb BVS) was launched in Europe, initial studies showed scaffold-related thrombosis rates as high as 3.4%.^5–7 That compares with 0.4% for second-generation DES—a troubling result for a new technology.

Rates of restenosis and stent thrombosis are similar for bioresorbable stents and standard durable polymer stents. But what are the potential added benefits of bioresorbable stents? And will they improve patient outcomes?

Bioresorbable stents certainly appeal to patients who do not want a permanent, rigid, metallic implant. Also appealing are the proposed benefits of restoration of vasomotion, late luminal enlargement, preservation of CABG targets, and relief of angina. Whether bioresorbable stents improve these outcomes has not been established. Currently, there is no long-term evidence of reduced rates of adverse events, although in 1 study, optical coherence tomography images recorded 10 years after implantation of the first bioresorbable stents showed a pristine vessel with no signs of the struts.⁸

Several facts are known about the Absorb BVS:

• Preclinical evidence shows complete resorption and return of vascular function, but this takes 3 to 4 years.
• Imaging data at 5 years from the Absorb cohort B trial show complete resorption of struts, lumen preservation, return of function, and plaque regression.⁹
• In ABSORB III, the pivotal US trial, the stent was within the primary end point showing noninferiority in safety and effectiveness compared with Xience in the first year.¹⁰
• Absorb clinical trials in Japan and China confirmed ABSORB III results.
• Meta-analysis (> 3,300 patients) confirmed safety and effectiveness of Absorb.¹¹
• Real-world Absorb clinical evidence continues to show improving outcomes with optimized implant techniques.
• Absorb stent was approved by the US Food and Drug Administration (FDA) in July 2016; more than 150,000 have been implanted worldwide.

The increased rates of target-lesion revascularization and stent thrombosis were likely attributable to inserting the stents into small-diameter vessels that are probably too small for the Absorb BVS. When small vessels (< 2.25 mm) are eliminated from the analysis, the rates were as follows.

Results for vessels > 2.25 mm:

• Target-lesion revascularization: 6.7 % vs 5.5%
• Stent thrombosis: 0.9% vs 0.6%.
• Results for small vessels (< 2.25 mm):
• Target-lesion revascularization: 12.9% vs 8.3%
• Stent thrombosis: 4.6% vs 1.5%.

The lesson is that the Absorb BVS should not be placed in arteries smaller than 2.25 mm in diameter.

Another concern was uncovered in July 2016 when results were published from the ABSORB II trial on vasomotor reactivity at 3 years.¹³ This clinical trial randomized 501 patients in a 2:1 ratio to the Absorb BVS or the Xience DES at 46 sites outside the United States. Assessment for changes in mean lumen diameter between pre- and post-nitrate administration showed no differences between the groups; thus, the Absorb BVS did not achieve a level of superior vasomotor reactivity. There was vasomotor reactivity probably because the surrogate marker was angiographic follow-up and not intravascular ultrasound or tomography.

Further, the coprimary end point of angiographic late luminal loss at 3 years did not meet its noninferiority standard. The Absorb BVS was expected to have lower rates of late lumen loss because the struts are gone and there is less new intimal formation; however, at 3 years, that was not the case.

The rate of acute stent thrombosis also was alarming: 8 cases for Absorb BVS versus none for Xience. This caused alarm, raising the question of why it was happening in these patients 2 to 3 years after implantation.

Animal studies investigating the association of thicker struts and increased thrombogenicity have reported that the 157-µm BVS had much more platelet buildup and thrombogenicity than a 120-µm biomatrix stent. The 74-µm Synergy stent had even lower rates of thrombosis. The reason for increased thrombogenicity with thicker struts requires further study.

Also, an analysis of the secondary cardiac end points at 3 years in ABSORB II found no clinical patient-oriented differences between the Absorb BVS and the Xience stent (20.8% vs 24.0%, respectively; P = .44). However, rates of device-oriented clinical end points were significantly higher for Absorb BVS (10.4% vs 4.9%; P = .043).¹³

Clearly, the results for Absorb BVS in this study were not positive. One explanation is suboptimal implantation techniques that did not appose the polymer to the wall. A few years ago, focus shifted to an optimal technique for scaffold deployment, which included predilation, appropriate sizing of the scaffold to the size of the vessel, and postdilation with the intention of embedding the polymer in the vessel wall. Multiple studies have reported fewer incidents of stent thrombosis with the implementation of this protocol.¹⁴

Further studies have continued to report increased rates of late scaffold thrombosis in follow-ups of 30 days to 3 years. This resulted in an advisory letter from the FDA focused on appropriate clinical use of the device and withdrawal of ABSORB from commercial use in Europe and Australia.

BIORESORBABLE SCAFFOLDS PIPELINE

This is questionable because one has to believe in the vulnerable plaque theory, which assumes potential eruption of plaques. The Absorb can actually seal a thin cap atheroma and necrotic core over time. It seems that this technology can cause some late lumen enlargement and seal an existing plaque, which may have implications for the future.

SUMMARY

This is the current state of the Absorb BVS:

• More than 150,000 implanted globally
• Received FDA approval in July 2016
• Should not be used in small vessels (ie, lumen diameter < 2.25 mm)
• Thrombosis rates 2 to 3 years after implantation are of concern
• Focusing on appropriate surgical implantation technique can improve outcomes.

Overall, use of bioresorbable stent technology is intriguing. While there is ongoing patient preference for bioresorbable technology, clinical trial results raise the question of whether bioresorbable scaffolds are inferior to best-in-class DES. Improving the scaffold technology and the implantation techniques may equate the short-term outcome of the bioresorbable scaffolds with metallic stents with the hope that over time (when the scaffold is gone), the advantage will be with the bioresorbable scaffolds. Meanwhile, the technology is still seeking its best clinical utility, and a matching performance to the best-in-class DES.

Time will tell whether 5 to 10 years after implantation, BRS technology will outperform durable metallic stents.

In the years since the introduction of robotically assisted mitral valve surgery, surgeons have looked for ways to improve techniques and procedures. A study from Cleveland Clinic presented at the American Association for Thoracic Surgery in 2016 assessed efficacy and safety outcomes associated with 1,000 consecutive robotically assisted mitral valve surgeries at Cleveland Clinic.1 The purpose of the study was to assess the clinical outcomes from these cases and analyze whether the outcomes changed over time as surgeons became more competent with robotic techniques. This analysis was also designed to identify procedural processes that improved outcomes during the trial.

STUDY METHODS

Nearly all cases (96%) were classified as degenerative mitral valve disease (N = 960). Of those, most had posterior leaflet prolapse (68%), about one-third (29%) had bileaflet prolapse, and only 3% had anterior leaflet involvement.

All surgeries were performed through right port incisions and used femoral cannulation for peripheral bypass. The aorta was occluded with either a Chitwood transthoracic clamp or a balloon.

STUDY RESULTS

It is important to remember that with femoral artery perfusion, the blood flow is opposite to the normal direction; thus, it goes up the aorta into the head vessels, which presents its own risks and challenges. Also, during retrograde perfusion, there is a risk of dislodging atherosclerotic plaque leading to brain embolus and stroke.

In these 1,000 cases, 997 were planned mitral valve repairs, 2 were mitral valve replacements, and 1 was resection of a mitral valve fibroelastoma. Results for the mitral valve repairs were excellent, with postoperative mitral regurgitation occurring in less than 1% of patients.

A primary point of interest was to identify procedural improvements that occurred during the course of the study. The areas evaluated in robotically assisted mitral valve surgery were the efficacy of the procedure in time, transfusion rates, stroke risk, how many mitral valve replacements occurred, and how many required conversion to sternotomy. These were assessed to determine whether surgical experience resulted in improvement.

Results showed that those efficiencies improved during the study. Cardiopulmonary bypass time decreased from about 140 minutes to 130 minutes. Cross-clamp time improved more dramatically from about 110 minutes to 90 minutes. And the percentage of cases requiring postoperative or intraoperative blood transfusion improved from about 24% to 10%.

PATIENT SELECTION CRITERIA: ALGORITHM

ALGORITHM IMPACT

What was the effect of this algorithm? In the 500 cases after its implementation, the stroke rate decreased by more than half—from 10 incidents before to 4 incidents after—and mitral replacements dropped from 4 to 0. The rate of conversion from robotic repair to conventional sternotomy in this patient series also improved, although this likely reflects surgical experience more than the algorithm. The conversion rate initially increased as surgeons gained experience with the robotic techniques. It rose to 4% during the first 300 to 400 cases, then dropped to 2% at the 500-case mark. It leveled off for the next 300 cases before dropping to 0 toward the end of the series.

Other metrics improved as well, which were attributed to a combination of surgical experience with robotic assistance and use of the patient-selection algorithm. The stroke risk declined to 0.8%, ischemic and cardiopulmonary bypass times declined, and the transfusion rate declined. No mitral replacements were done in the last 500 cases, and the conversion to conventional sternotomy rate declined to 1%.

In conclusion, this Cleveland Clinic study showed that a combination of a focused preoperative assessment using the patient-selection algorithm and increased surgical experience with robotic techniques enhanced clinical outcomes and improved procedural efficiency associated with robotically assisted mitral valve surgery.

In the years since the introduction of robotically assisted mitral valve surgery, surgeons have looked for ways to improve techniques and procedures. A study from Cleveland Clinic presented at the American Association for Thoracic Surgery in 2016 assessed efficacy and safety outcomes associated with 1,000 consecutive robotically assisted mitral valve surgeries at Cleveland Clinic.1 The purpose of the study was to assess the clinical outcomes from these cases and analyze whether the outcomes changed over time as surgeons became more competent with robotic techniques. This analysis was also designed to identify procedural processes that improved outcomes during the trial.

STUDY METHODS

Nearly all cases (96%) were classified as degenerative mitral valve disease (N = 960). Of those, most had posterior leaflet prolapse (68%), about one-third (29%) had bileaflet prolapse, and only 3% had anterior leaflet involvement.

All surgeries were performed through right port incisions and used femoral cannulation for peripheral bypass. The aorta was occluded with either a Chitwood transthoracic clamp or a balloon.

STUDY RESULTS

It is important to remember that with femoral artery perfusion, the blood flow is opposite to the normal direction; thus, it goes up the aorta into the head vessels, which presents its own risks and challenges. Also, during retrograde perfusion, there is a risk of dislodging atherosclerotic plaque leading to brain embolus and stroke.

In these 1,000 cases, 997 were planned mitral valve repairs, 2 were mitral valve replacements, and 1 was resection of a mitral valve fibroelastoma. Results for the mitral valve repairs were excellent, with postoperative mitral regurgitation occurring in less than 1% of patients.

A primary point of interest was to identify procedural improvements that occurred during the course of the study. The areas evaluated in robotically assisted mitral valve surgery were the efficacy of the procedure in time, transfusion rates, stroke risk, how many mitral valve replacements occurred, and how many required conversion to sternotomy. These were assessed to determine whether surgical experience resulted in improvement.

Results showed that those efficiencies improved during the study. Cardiopulmonary bypass time decreased from about 140 minutes to 130 minutes. Cross-clamp time improved more dramatically from about 110 minutes to 90 minutes. And the percentage of cases requiring postoperative or intraoperative blood transfusion improved from about 24% to 10%.

PATIENT SELECTION CRITERIA: ALGORITHM

ALGORITHM IMPACT

What was the effect of this algorithm? In the 500 cases after its implementation, the stroke rate decreased by more than half—from 10 incidents before to 4 incidents after—and mitral replacements dropped from 4 to 0. The rate of conversion from robotic repair to conventional sternotomy in this patient series also improved, although this likely reflects surgical experience more than the algorithm. The conversion rate initially increased as surgeons gained experience with the robotic techniques. It rose to 4% during the first 300 to 400 cases, then dropped to 2% at the 500-case mark. It leveled off for the next 300 cases before dropping to 0 toward the end of the series.

Other metrics improved as well, which were attributed to a combination of surgical experience with robotic assistance and use of the patient-selection algorithm. The stroke risk declined to 0.8%, ischemic and cardiopulmonary bypass times declined, and the transfusion rate declined. No mitral replacements were done in the last 500 cases, and the conversion to conventional sternotomy rate declined to 1%.

In conclusion, this Cleveland Clinic study showed that a combination of a focused preoperative assessment using the patient-selection algorithm and increased surgical experience with robotic techniques enhanced clinical outcomes and improved procedural efficiency associated with robotically assisted mitral valve surgery.

In the years since the introduction of robotically assisted mitral valve surgery, surgeons have looked for ways to improve techniques and procedures. A study from Cleveland Clinic presented at the American Association for Thoracic Surgery in 2016 assessed efficacy and safety outcomes associated with 1,000 consecutive robotically assisted mitral valve surgeries at Cleveland Clinic.1 The purpose of the study was to assess the clinical outcomes from these cases and analyze whether the outcomes changed over time as surgeons became more competent with robotic techniques. This analysis was also designed to identify procedural processes that improved outcomes during the trial.

STUDY METHODS

Nearly all cases (96%) were classified as degenerative mitral valve disease (N = 960). Of those, most had posterior leaflet prolapse (68%), about one-third (29%) had bileaflet prolapse, and only 3% had anterior leaflet involvement.

All surgeries were performed through right port incisions and used femoral cannulation for peripheral bypass. The aorta was occluded with either a Chitwood transthoracic clamp or a balloon.

STUDY RESULTS

It is important to remember that with femoral artery perfusion, the blood flow is opposite to the normal direction; thus, it goes up the aorta into the head vessels, which presents its own risks and challenges. Also, during retrograde perfusion, there is a risk of dislodging atherosclerotic plaque leading to brain embolus and stroke.

In these 1,000 cases, 997 were planned mitral valve repairs, 2 were mitral valve replacements, and 1 was resection of a mitral valve fibroelastoma. Results for the mitral valve repairs were excellent, with postoperative mitral regurgitation occurring in less than 1% of patients.

A primary point of interest was to identify procedural improvements that occurred during the course of the study. The areas evaluated in robotically assisted mitral valve surgery were the efficacy of the procedure in time, transfusion rates, stroke risk, how many mitral valve replacements occurred, and how many required conversion to sternotomy. These were assessed to determine whether surgical experience resulted in improvement.

Results showed that those efficiencies improved during the study. Cardiopulmonary bypass time decreased from about 140 minutes to 130 minutes. Cross-clamp time improved more dramatically from about 110 minutes to 90 minutes. And the percentage of cases requiring postoperative or intraoperative blood transfusion improved from about 24% to 10%.

PATIENT SELECTION CRITERIA: ALGORITHM

ALGORITHM IMPACT

What was the effect of this algorithm? In the 500 cases after its implementation, the stroke rate decreased by more than half—from 10 incidents before to 4 incidents after—and mitral replacements dropped from 4 to 0. The rate of conversion from robotic repair to conventional sternotomy in this patient series also improved, although this likely reflects surgical experience more than the algorithm. The conversion rate initially increased as surgeons gained experience with the robotic techniques. It rose to 4% during the first 300 to 400 cases, then dropped to 2% at the 500-case mark. It leveled off for the next 300 cases before dropping to 0 toward the end of the series.

Other metrics improved as well, which were attributed to a combination of surgical experience with robotic assistance and use of the patient-selection algorithm. The stroke risk declined to 0.8%, ischemic and cardiopulmonary bypass times declined, and the transfusion rate declined. No mitral replacements were done in the last 500 cases, and the conversion to conventional sternotomy rate declined to 1%.

In conclusion, this Cleveland Clinic study showed that a combination of a focused preoperative assessment using the patient-selection algorithm and increased surgical experience with robotic techniques enhanced clinical outcomes and improved procedural efficiency associated with robotically assisted mitral valve surgery.

In 2015, Cleveland Clinic cardiac and vascular surgeons performed more than 1,000 open or endovascular operations involving the thoracic aorta, the most of any US medical center. Cardioaortic operations account for a large volume of the procedures performed annually in the Department of Thoracic and Cardiovascular Surgery at Cleveland Clinic. Of the approximately 4,000 cardiac procedures performed per year at Cleveland Clinic, nearly 1 in 5 includes thoracic aorta replacement.

Providing optimal care to patients with thoracic aortic disease requires a multidisciplinary approach beginning in the preoperative phase and extending through the life of patients and their families. In the Aortic Center at Cleveland Clinic Heart & Vascular Institute, cardiovascular medicine and imaging specialists, geneticists, and cardioaortic and vascular surgeons work in unison to provide the highest quality care. This involves active analysis of outcomes to continuously improve the quality of care provided.

This paper examines trends in the treatment of thoracic aortic disease, describes the different types of therapeutic procedures, and explores details about their safety and efficacy by summarizing the key research findings on cardioaortic procedures published from our Center during the last 2 years.

SEGMENTAL PERSPECTIVE

1. Modified Bentall procedure with a mechanical composite valve graft (CVG)

2. Modified Bentall procedure with a biologic CVG

3. Homograft, or allograft, root replacement with a human cadaveric aorta

4. Valve-preserving aortic root replacement with a prosthetic graft but which leaves the patient’s native aortic valve intact with or without accompanying repair of that valve.

A Cleveland Clinic study published in 2016 analyzed 957 elective aortic root replacement procedures performed from 1995 through 2014.¹ The number of procedures in this study were evenly distributed across these 4 aortic root replacement strategies.

The perioperative mortality rate was 0.73% and the stroke rate was 1.4%. For 3 of the 4 procedure types, 15-year survival rates were excellent: above 80% for mechanical CVG, allografts, and valve-preservation surgery. The survival rate for biologic CVG was lower (57%), reflecting the difference in population, as these were typically older patients.

This study also demonstrated the durability of these operations, with a reoperation rate of approximately 15% at 15 years. Reoperation rates for patients having undergone these operations should be considered in the light of competing risk of death from other causes. As such, the risk of reoperation after mechanical CVG, biologic CVG, and valve-preserving procedures were similar, ranging from 5% to 15%. Allografts had the highest reoperation rates (approximately 30% at 15 years) because they used to be the biologic root replacement of choice for younger patients but have since been found to wear out at a similar rate as other bioprostheses.2 As a result, they are now used less frequently for elective indications.

Cleveland Clinic practitioners now perform more than 80 valve-preserving root replacement operations per year, approximately 700 overall.

Clinical implications

For patients presenting with aortic root aneurysm, consider the following:

• Valve-preserving aortic root replacement is preferred for patients with root aneurysm and a tricuspid aortic valve without valve stenosis.
• Valve-preserving aortic root replacement with either remodeling or reimplantation is also preferred for patients with a bicuspid aortic valve with a dilated annulus or root aneurysm, but without aortic-associated aortic valve stenosis
• Mechanical CVG is preferred for younger patients with root aneurysm and aortic valve stenosis (usually a bicuspid or unicuspid aortic valve); biomechanical CVG is preferred for older patients with root aneurysm and associated aortic valve stenosis.
• Allografts are now reserved primarily for patients with endocarditis and for older patients with a small aortic root.

The condition of the patient at presentation has become the strongest predictor of surgical risk. An improved understanding of these associations can improve our prediction of risks and the decision about when to operate. Patients needing aortic replacement can present with a broad spectrum of pathologies. For example, a patient who presents with acute type A dissection is quite different from a patient with an enlarging ascending aneurysm who had a previous aortic valve replacement for bicuspid aortic valve stenosis as a young adult. Further, both are different from the elderly patient with the complex constellation of coronary disease, multivalve disease, atrial fibrillation, and an ascending aneurysm—an increasingly common presentation.

Guidelines supporting the decision to replace the aorta in patients with chronic asymptomatic aortic disease are limited by a lack of data on surgical risk and long-term effectiveness.

A study from the Society of Thoracic Surgeons database assessed outcomes in patients who had surgical replacement of the ascending aorta, with or without root repair.³ The operative mortality (either in-hospital or within 30 days of surgery) was 8.3% and ranged from 3.5% for elective surgery to 9.1% for urgent surgery, and 21.5% for emergencies. End-stage kidney disease and reoperation were also shown to be independent predictors of risk in that study.

Outcomes at Cleveland Clinic for elective ascending aortic procedures are much better than these national averages. Outcomes data are important to patients when making a decision about prophylactic surgery. In a study analyzing 1,889 patients undergoing elective ascending replacement at Cleveland Clinic between 2006 and 2010, the operative mortality was only 0.5% for those undergoing isolated ascending replacement and 2% for those requiring a multicomponent operation. In the multicomponent group, 87% included aortic valve replacement, 29% coronary bypass, and 25% underwent more than 2 different combined procedures.⁴

Patient risk factors

A comparison of patient risk factors for the 2 groups showed that the isolated replacement group had larger aortic diameters, more extensive disease with dilated descending aortas, and were more frequently undergoing a reoperation than the multicomponent group.

To further define the risks, we conducted a propensity-matching study of 197 pairs of these patients, comparing 62 variables including aortic morphology data gathered from 3-dimensional analysis of computed tomography scans. Results showed no differences in survival rates between the groups during 4 years of follow-up.⁴ A comparison of the risk of other perioperative complications—death, stroke, need for dialysis, respiratory failure, and bleeding—also showed no differences between the groups.

Does adding ascending aortic replacement to other cardiac procedures increase the surgical risk?

To answer this question, we collected data on Cleveland Clinic patients between 2006 and 2011 who had aortic surgery in combination with cardiac surgery (N = 1,677) and compared them against a similar cohort who only had cardiac surgery (N = 12,617).⁵ The objectives were to determine the risk of adding aortic surgery to an elective cardiac operation. A second objective was to determine the impact of circulatory arrest on outcomes.

Comparison 1. We identified 1,284 matched pairs from the 2 groups. Data showed a slightly higher risk of stroke in patients who had cardioaortic surgery (2.4%) compared with those who had cardiac surgery alone (1.7%); however, the mortality rate was not significantly different between the groups.

Does circulatory arrest affect the stroke rate?

From the matched pairs of patients who underwent cardioaortic surgery, we identified a subset of patients who had circulatory arrest and compared them with those who did not have circulatory arrest. The circulatory arrest group had worse outcomes. Mortality rates were 4.1% vs 1.0%, respectively, and stroke rates were 3.9% vs 0.9%. 

This raised the question of whether circulatory arrest was the cause of the worse outcomes or a marker of patients with more advanced disease.

The decision to use circulatory arrest is primarily based on 2 factors:

• Patient-specific factors, such as those with advanced aortic disease in whom circulatory arrest is unavoidable.
• Surgeon preference/technical decision. For example, in a patient with a bicuspid valve, the surgeon may choose to use a brief period of circulatory arrest instead of clamping the proximal arch.

Comparison 2. To further define the impact of circulatory arrest, we grouped the patients who underwent cardioaortic surgery (N = 1,677) into those who had circulatory arrest (n = 728) or no arrest (n = 949). From those groups, we identified 324 matched pairs of patients and compared the outcomes.

Our results showed no differences associated with the use of circulatory arrest in rates of mortality (1.2% with and 0.6% without) or stroke (1.5% for both groups) when comparing patients with similar disease characteristics. These results suggest that the need for circulatory arrest was probably not the culprit but more likely a marker of patients with more complex disease. It is their more advanced disease that puts them at higher risk.

Comparison 3. To determine whether circulatory arrest has an overall impact on cardiac surgery, we took the population of matched cardioaortic patients from comparison 2 regardless of whether they had circulatory arrest and compared them to the larger group of 12,617 cardiac surgery-alone patients. Again, results indicated that the addition of aortic surgery had no real impact on outcomes. Both groups had similarly low risks for both mortality (0.9% with aortic replacement vs 0.5% without) and stroke (1.4% with aortic replacement vs 1.1% without).

Clinical implications

This multistepped comparison study found that adding ascending aortic replacement to cardiac surgery had essentially no impact on mortality or stroke. These data provide evidence indicating that cardiac surgeons should be more proactive in deciding whether to add ascending aorta replacement to cardiac surgery when treating a patient with a dilated ascending aorta. It must be noted, however, that patients with more advanced aortic disease are a higher risk population. All of these findings highlight the importance of managing thoracic aortic disease within an experienced multidisciplinary center.

These findings provided important evidence supporting the need to be more proactive in the decision to perform aortic replacement. Furthermore, the data prompted the American Heart Association and the American College of Cardiology to publish a clarification statement providing more detail to its thoracic aorta and aortic valve guidelines. This update indicates that in patients with a bicuspid aortic valve, it is reasonable to recommend surgery when the aorta is 5 cm instead of waiting until 5.5 cm in high-volume centers that have demonstrated excellent surgical outcomes. This clarification statement was based on Cleveland Clinic outcomes showing a mortality rate of 0.25% and a stroke rate of 0.75% in a population that included patients undergoing emergency aortic dissection surgery.⁶

This study also analyzed data on patients treated with expectant care with optimal medical management and imaging surveillance (ie, to monitor the dilated aorta). Results from this subset showed that the probability of needing an aortic intervention is about 60% during the next 10 years once the aorta is within the 4.5 cm to 5 cm range.

Another study addressing the correlation between risk and aortic size examined 771 patients with a dilated ascending aorta (≥ 4 cm) and a tricuspid aortic valve.⁷ This study confirmed the use of patient height as an important factor for indexing maximum aortic size to patient body size for predicting risk of late complications. Specifically, this study suggested that the risk of complications from aortic aneurysm rises when the maximum aortic area-to-height ratio exceeds 10. This serves as a follow-up to previously published data demonstrating the value of aortic cross-sectional area-to-height ratio as a predictor of risk in patients with bicuspid valves.⁸ In general, the results of all 3 studies suggest that we should be more proactive in operating on patients with a dilated ascending aorta to prevent later risk of rupture or dissection when the surgical risk is low.

When making decisions about patients who need aortic replacement, it is important to assess many patient details: their aortic disease, their other nonaortic comorbidities, and the institution’s outcomes. This decision is best made by a dedicated cardioaortic specialist at a dedicated center of excellence.

WHAT IS COMING?

Minimally invasive and endovascular surgery

More ascending aortic surgeries are being done using minimally invasive approaches. At Cleveland Clinic, about 40% of isolated ascending aortic operations are performed through a mini-sternotomy J incision approach. A Cleveland Clinic study published in 2017 evaluated outcomes from this less-invasive technique for proximal aortic surgery compared with full median sternotomy.⁹ Results showed it was an effective approach with fewer complications, shorter hospital stays, and lower costs.

Stent grafts

The role for stent-graft devices has continued to expand.¹⁰ At Cleveland Clinic, we have performed more than 40 ascending aortic stent-graft procedures, one of the largest numbers in the world. Having this stent-graft option has enabled us to provide treatment for the patients at exceedingly high risk who previously had few or no options. Industry partners are working to develop dedicated devices for these indications, and we are working with them to bring new device trials to this underserved population of patients. 

In 2015, Cleveland Clinic cardiac and vascular surgeons performed more than 1,000 open or endovascular operations involving the thoracic aorta, the most of any US medical center. Cardioaortic operations account for a large volume of the procedures performed annually in the Department of Thoracic and Cardiovascular Surgery at Cleveland Clinic. Of the approximately 4,000 cardiac procedures performed per year at Cleveland Clinic, nearly 1 in 5 includes thoracic aorta replacement.

Providing optimal care to patients with thoracic aortic disease requires a multidisciplinary approach beginning in the preoperative phase and extending through the life of patients and their families. In the Aortic Center at Cleveland Clinic Heart & Vascular Institute, cardiovascular medicine and imaging specialists, geneticists, and cardioaortic and vascular surgeons work in unison to provide the highest quality care. This involves active analysis of outcomes to continuously improve the quality of care provided.

This paper examines trends in the treatment of thoracic aortic disease, describes the different types of therapeutic procedures, and explores details about their safety and efficacy by summarizing the key research findings on cardioaortic procedures published from our Center during the last 2 years.

SEGMENTAL PERSPECTIVE

1. Modified Bentall procedure with a mechanical composite valve graft (CVG)

2. Modified Bentall procedure with a biologic CVG

3. Homograft, or allograft, root replacement with a human cadaveric aorta

4. Valve-preserving aortic root replacement with a prosthetic graft but which leaves the patient’s native aortic valve intact with or without accompanying repair of that valve.

A Cleveland Clinic study published in 2016 analyzed 957 elective aortic root replacement procedures performed from 1995 through 2014.¹ The number of procedures in this study were evenly distributed across these 4 aortic root replacement strategies.

The perioperative mortality rate was 0.73% and the stroke rate was 1.4%. For 3 of the 4 procedure types, 15-year survival rates were excellent: above 80% for mechanical CVG, allografts, and valve-preservation surgery. The survival rate for biologic CVG was lower (57%), reflecting the difference in population, as these were typically older patients.

This study also demonstrated the durability of these operations, with a reoperation rate of approximately 15% at 15 years. Reoperation rates for patients having undergone these operations should be considered in the light of competing risk of death from other causes. As such, the risk of reoperation after mechanical CVG, biologic CVG, and valve-preserving procedures were similar, ranging from 5% to 15%. Allografts had the highest reoperation rates (approximately 30% at 15 years) because they used to be the biologic root replacement of choice for younger patients but have since been found to wear out at a similar rate as other bioprostheses.2 As a result, they are now used less frequently for elective indications.

Cleveland Clinic practitioners now perform more than 80 valve-preserving root replacement operations per year, approximately 700 overall.

Clinical implications

For patients presenting with aortic root aneurysm, consider the following:

• Valve-preserving aortic root replacement is preferred for patients with root aneurysm and a tricuspid aortic valve without valve stenosis.
• Valve-preserving aortic root replacement with either remodeling or reimplantation is also preferred for patients with a bicuspid aortic valve with a dilated annulus or root aneurysm, but without aortic-associated aortic valve stenosis
• Mechanical CVG is preferred for younger patients with root aneurysm and aortic valve stenosis (usually a bicuspid or unicuspid aortic valve); biomechanical CVG is preferred for older patients with root aneurysm and associated aortic valve stenosis.
• Allografts are now reserved primarily for patients with endocarditis and for older patients with a small aortic root.

The condition of the patient at presentation has become the strongest predictor of surgical risk. An improved understanding of these associations can improve our prediction of risks and the decision about when to operate. Patients needing aortic replacement can present with a broad spectrum of pathologies. For example, a patient who presents with acute type A dissection is quite different from a patient with an enlarging ascending aneurysm who had a previous aortic valve replacement for bicuspid aortic valve stenosis as a young adult. Further, both are different from the elderly patient with the complex constellation of coronary disease, multivalve disease, atrial fibrillation, and an ascending aneurysm—an increasingly common presentation.

Guidelines supporting the decision to replace the aorta in patients with chronic asymptomatic aortic disease are limited by a lack of data on surgical risk and long-term effectiveness.

A study from the Society of Thoracic Surgeons database assessed outcomes in patients who had surgical replacement of the ascending aorta, with or without root repair.³ The operative mortality (either in-hospital or within 30 days of surgery) was 8.3% and ranged from 3.5% for elective surgery to 9.1% for urgent surgery, and 21.5% for emergencies. End-stage kidney disease and reoperation were also shown to be independent predictors of risk in that study.

Outcomes at Cleveland Clinic for elective ascending aortic procedures are much better than these national averages. Outcomes data are important to patients when making a decision about prophylactic surgery. In a study analyzing 1,889 patients undergoing elective ascending replacement at Cleveland Clinic between 2006 and 2010, the operative mortality was only 0.5% for those undergoing isolated ascending replacement and 2% for those requiring a multicomponent operation. In the multicomponent group, 87% included aortic valve replacement, 29% coronary bypass, and 25% underwent more than 2 different combined procedures.⁴

Patient risk factors

A comparison of patient risk factors for the 2 groups showed that the isolated replacement group had larger aortic diameters, more extensive disease with dilated descending aortas, and were more frequently undergoing a reoperation than the multicomponent group.

To further define the risks, we conducted a propensity-matching study of 197 pairs of these patients, comparing 62 variables including aortic morphology data gathered from 3-dimensional analysis of computed tomography scans. Results showed no differences in survival rates between the groups during 4 years of follow-up.⁴ A comparison of the risk of other perioperative complications—death, stroke, need for dialysis, respiratory failure, and bleeding—also showed no differences between the groups.

Does adding ascending aortic replacement to other cardiac procedures increase the surgical risk?

To answer this question, we collected data on Cleveland Clinic patients between 2006 and 2011 who had aortic surgery in combination with cardiac surgery (N = 1,677) and compared them against a similar cohort who only had cardiac surgery (N = 12,617).⁵ The objectives were to determine the risk of adding aortic surgery to an elective cardiac operation. A second objective was to determine the impact of circulatory arrest on outcomes.

Comparison 1. We identified 1,284 matched pairs from the 2 groups. Data showed a slightly higher risk of stroke in patients who had cardioaortic surgery (2.4%) compared with those who had cardiac surgery alone (1.7%); however, the mortality rate was not significantly different between the groups.

Does circulatory arrest affect the stroke rate?

From the matched pairs of patients who underwent cardioaortic surgery, we identified a subset of patients who had circulatory arrest and compared them with those who did not have circulatory arrest. The circulatory arrest group had worse outcomes. Mortality rates were 4.1% vs 1.0%, respectively, and stroke rates were 3.9% vs 0.9%. 

This raised the question of whether circulatory arrest was the cause of the worse outcomes or a marker of patients with more advanced disease.

The decision to use circulatory arrest is primarily based on 2 factors:

• Patient-specific factors, such as those with advanced aortic disease in whom circulatory arrest is unavoidable.
• Surgeon preference/technical decision. For example, in a patient with a bicuspid valve, the surgeon may choose to use a brief period of circulatory arrest instead of clamping the proximal arch.

Comparison 2. To further define the impact of circulatory arrest, we grouped the patients who underwent cardioaortic surgery (N = 1,677) into those who had circulatory arrest (n = 728) or no arrest (n = 949). From those groups, we identified 324 matched pairs of patients and compared the outcomes.

Our results showed no differences associated with the use of circulatory arrest in rates of mortality (1.2% with and 0.6% without) or stroke (1.5% for both groups) when comparing patients with similar disease characteristics. These results suggest that the need for circulatory arrest was probably not the culprit but more likely a marker of patients with more complex disease. It is their more advanced disease that puts them at higher risk.

Comparison 3. To determine whether circulatory arrest has an overall impact on cardiac surgery, we took the population of matched cardioaortic patients from comparison 2 regardless of whether they had circulatory arrest and compared them to the larger group of 12,617 cardiac surgery-alone patients. Again, results indicated that the addition of aortic surgery had no real impact on outcomes. Both groups had similarly low risks for both mortality (0.9% with aortic replacement vs 0.5% without) and stroke (1.4% with aortic replacement vs 1.1% without).

Clinical implications

This multistepped comparison study found that adding ascending aortic replacement to cardiac surgery had essentially no impact on mortality or stroke. These data provide evidence indicating that cardiac surgeons should be more proactive in deciding whether to add ascending aorta replacement to cardiac surgery when treating a patient with a dilated ascending aorta. It must be noted, however, that patients with more advanced aortic disease are a higher risk population. All of these findings highlight the importance of managing thoracic aortic disease within an experienced multidisciplinary center.

These findings provided important evidence supporting the need to be more proactive in the decision to perform aortic replacement. Furthermore, the data prompted the American Heart Association and the American College of Cardiology to publish a clarification statement providing more detail to its thoracic aorta and aortic valve guidelines. This update indicates that in patients with a bicuspid aortic valve, it is reasonable to recommend surgery when the aorta is 5 cm instead of waiting until 5.5 cm in high-volume centers that have demonstrated excellent surgical outcomes. This clarification statement was based on Cleveland Clinic outcomes showing a mortality rate of 0.25% and a stroke rate of 0.75% in a population that included patients undergoing emergency aortic dissection surgery.⁶

This study also analyzed data on patients treated with expectant care with optimal medical management and imaging surveillance (ie, to monitor the dilated aorta). Results from this subset showed that the probability of needing an aortic intervention is about 60% during the next 10 years once the aorta is within the 4.5 cm to 5 cm range.

Another study addressing the correlation between risk and aortic size examined 771 patients with a dilated ascending aorta (≥ 4 cm) and a tricuspid aortic valve.⁷ This study confirmed the use of patient height as an important factor for indexing maximum aortic size to patient body size for predicting risk of late complications. Specifically, this study suggested that the risk of complications from aortic aneurysm rises when the maximum aortic area-to-height ratio exceeds 10. This serves as a follow-up to previously published data demonstrating the value of aortic cross-sectional area-to-height ratio as a predictor of risk in patients with bicuspid valves.⁸ In general, the results of all 3 studies suggest that we should be more proactive in operating on patients with a dilated ascending aorta to prevent later risk of rupture or dissection when the surgical risk is low.

When making decisions about patients who need aortic replacement, it is important to assess many patient details: their aortic disease, their other nonaortic comorbidities, and the institution’s outcomes. This decision is best made by a dedicated cardioaortic specialist at a dedicated center of excellence.

WHAT IS COMING?

Minimally invasive and endovascular surgery

More ascending aortic surgeries are being done using minimally invasive approaches. At Cleveland Clinic, about 40% of isolated ascending aortic operations are performed through a mini-sternotomy J incision approach. A Cleveland Clinic study published in 2017 evaluated outcomes from this less-invasive technique for proximal aortic surgery compared with full median sternotomy.⁹ Results showed it was an effective approach with fewer complications, shorter hospital stays, and lower costs.

Stent grafts

The role for stent-graft devices has continued to expand.¹⁰ At Cleveland Clinic, we have performed more than 40 ascending aortic stent-graft procedures, one of the largest numbers in the world. Having this stent-graft option has enabled us to provide treatment for the patients at exceedingly high risk who previously had few or no options. Industry partners are working to develop dedicated devices for these indications, and we are working with them to bring new device trials to this underserved population of patients. 

In 2015, Cleveland Clinic cardiac and vascular surgeons performed more than 1,000 open or endovascular operations involving the thoracic aorta, the most of any US medical center. Cardioaortic operations account for a large volume of the procedures performed annually in the Department of Thoracic and Cardiovascular Surgery at Cleveland Clinic. Of the approximately 4,000 cardiac procedures performed per year at Cleveland Clinic, nearly 1 in 5 includes thoracic aorta replacement.

Providing optimal care to patients with thoracic aortic disease requires a multidisciplinary approach beginning in the preoperative phase and extending through the life of patients and their families. In the Aortic Center at Cleveland Clinic Heart & Vascular Institute, cardiovascular medicine and imaging specialists, geneticists, and cardioaortic and vascular surgeons work in unison to provide the highest quality care. This involves active analysis of outcomes to continuously improve the quality of care provided.

This paper examines trends in the treatment of thoracic aortic disease, describes the different types of therapeutic procedures, and explores details about their safety and efficacy by summarizing the key research findings on cardioaortic procedures published from our Center during the last 2 years.

SEGMENTAL PERSPECTIVE

1. Modified Bentall procedure with a mechanical composite valve graft (CVG)

2. Modified Bentall procedure with a biologic CVG

3. Homograft, or allograft, root replacement with a human cadaveric aorta

4. Valve-preserving aortic root replacement with a prosthetic graft but which leaves the patient’s native aortic valve intact with or without accompanying repair of that valve.

A Cleveland Clinic study published in 2016 analyzed 957 elective aortic root replacement procedures performed from 1995 through 2014.¹ The number of procedures in this study were evenly distributed across these 4 aortic root replacement strategies.

The perioperative mortality rate was 0.73% and the stroke rate was 1.4%. For 3 of the 4 procedure types, 15-year survival rates were excellent: above 80% for mechanical CVG, allografts, and valve-preservation surgery. The survival rate for biologic CVG was lower (57%), reflecting the difference in population, as these were typically older patients.

This study also demonstrated the durability of these operations, with a reoperation rate of approximately 15% at 15 years. Reoperation rates for patients having undergone these operations should be considered in the light of competing risk of death from other causes. As such, the risk of reoperation after mechanical CVG, biologic CVG, and valve-preserving procedures were similar, ranging from 5% to 15%. Allografts had the highest reoperation rates (approximately 30% at 15 years) because they used to be the biologic root replacement of choice for younger patients but have since been found to wear out at a similar rate as other bioprostheses.2 As a result, they are now used less frequently for elective indications.

Cleveland Clinic practitioners now perform more than 80 valve-preserving root replacement operations per year, approximately 700 overall.

Clinical implications

For patients presenting with aortic root aneurysm, consider the following:

• Valve-preserving aortic root replacement is preferred for patients with root aneurysm and a tricuspid aortic valve without valve stenosis.
• Valve-preserving aortic root replacement with either remodeling or reimplantation is also preferred for patients with a bicuspid aortic valve with a dilated annulus or root aneurysm, but without aortic-associated aortic valve stenosis
• Mechanical CVG is preferred for younger patients with root aneurysm and aortic valve stenosis (usually a bicuspid or unicuspid aortic valve); biomechanical CVG is preferred for older patients with root aneurysm and associated aortic valve stenosis.
• Allografts are now reserved primarily for patients with endocarditis and for older patients with a small aortic root.

The condition of the patient at presentation has become the strongest predictor of surgical risk. An improved understanding of these associations can improve our prediction of risks and the decision about when to operate. Patients needing aortic replacement can present with a broad spectrum of pathologies. For example, a patient who presents with acute type A dissection is quite different from a patient with an enlarging ascending aneurysm who had a previous aortic valve replacement for bicuspid aortic valve stenosis as a young adult. Further, both are different from the elderly patient with the complex constellation of coronary disease, multivalve disease, atrial fibrillation, and an ascending aneurysm—an increasingly common presentation.

Guidelines supporting the decision to replace the aorta in patients with chronic asymptomatic aortic disease are limited by a lack of data on surgical risk and long-term effectiveness.

A study from the Society of Thoracic Surgeons database assessed outcomes in patients who had surgical replacement of the ascending aorta, with or without root repair.³ The operative mortality (either in-hospital or within 30 days of surgery) was 8.3% and ranged from 3.5% for elective surgery to 9.1% for urgent surgery, and 21.5% for emergencies. End-stage kidney disease and reoperation were also shown to be independent predictors of risk in that study.

Outcomes at Cleveland Clinic for elective ascending aortic procedures are much better than these national averages. Outcomes data are important to patients when making a decision about prophylactic surgery. In a study analyzing 1,889 patients undergoing elective ascending replacement at Cleveland Clinic between 2006 and 2010, the operative mortality was only 0.5% for those undergoing isolated ascending replacement and 2% for those requiring a multicomponent operation. In the multicomponent group, 87% included aortic valve replacement, 29% coronary bypass, and 25% underwent more than 2 different combined procedures.⁴

Patient risk factors

A comparison of patient risk factors for the 2 groups showed that the isolated replacement group had larger aortic diameters, more extensive disease with dilated descending aortas, and were more frequently undergoing a reoperation than the multicomponent group.

To further define the risks, we conducted a propensity-matching study of 197 pairs of these patients, comparing 62 variables including aortic morphology data gathered from 3-dimensional analysis of computed tomography scans. Results showed no differences in survival rates between the groups during 4 years of follow-up.⁴ A comparison of the risk of other perioperative complications—death, stroke, need for dialysis, respiratory failure, and bleeding—also showed no differences between the groups.

Does adding ascending aortic replacement to other cardiac procedures increase the surgical risk?

To answer this question, we collected data on Cleveland Clinic patients between 2006 and 2011 who had aortic surgery in combination with cardiac surgery (N = 1,677) and compared them against a similar cohort who only had cardiac surgery (N = 12,617).⁵ The objectives were to determine the risk of adding aortic surgery to an elective cardiac operation. A second objective was to determine the impact of circulatory arrest on outcomes.

Comparison 1. We identified 1,284 matched pairs from the 2 groups. Data showed a slightly higher risk of stroke in patients who had cardioaortic surgery (2.4%) compared with those who had cardiac surgery alone (1.7%); however, the mortality rate was not significantly different between the groups.

Does circulatory arrest affect the stroke rate?

From the matched pairs of patients who underwent cardioaortic surgery, we identified a subset of patients who had circulatory arrest and compared them with those who did not have circulatory arrest. The circulatory arrest group had worse outcomes. Mortality rates were 4.1% vs 1.0%, respectively, and stroke rates were 3.9% vs 0.9%. 

This raised the question of whether circulatory arrest was the cause of the worse outcomes or a marker of patients with more advanced disease.

The decision to use circulatory arrest is primarily based on 2 factors:

• Patient-specific factors, such as those with advanced aortic disease in whom circulatory arrest is unavoidable.
• Surgeon preference/technical decision. For example, in a patient with a bicuspid valve, the surgeon may choose to use a brief period of circulatory arrest instead of clamping the proximal arch.

Comparison 2. To further define the impact of circulatory arrest, we grouped the patients who underwent cardioaortic surgery (N = 1,677) into those who had circulatory arrest (n = 728) or no arrest (n = 949). From those groups, we identified 324 matched pairs of patients and compared the outcomes.

Our results showed no differences associated with the use of circulatory arrest in rates of mortality (1.2% with and 0.6% without) or stroke (1.5% for both groups) when comparing patients with similar disease characteristics. These results suggest that the need for circulatory arrest was probably not the culprit but more likely a marker of patients with more complex disease. It is their more advanced disease that puts them at higher risk.

Comparison 3. To determine whether circulatory arrest has an overall impact on cardiac surgery, we took the population of matched cardioaortic patients from comparison 2 regardless of whether they had circulatory arrest and compared them to the larger group of 12,617 cardiac surgery-alone patients. Again, results indicated that the addition of aortic surgery had no real impact on outcomes. Both groups had similarly low risks for both mortality (0.9% with aortic replacement vs 0.5% without) and stroke (1.4% with aortic replacement vs 1.1% without).

Clinical implications

This multistepped comparison study found that adding ascending aortic replacement to cardiac surgery had essentially no impact on mortality or stroke. These data provide evidence indicating that cardiac surgeons should be more proactive in deciding whether to add ascending aorta replacement to cardiac surgery when treating a patient with a dilated ascending aorta. It must be noted, however, that patients with more advanced aortic disease are a higher risk population. All of these findings highlight the importance of managing thoracic aortic disease within an experienced multidisciplinary center.

These findings provided important evidence supporting the need to be more proactive in the decision to perform aortic replacement. Furthermore, the data prompted the American Heart Association and the American College of Cardiology to publish a clarification statement providing more detail to its thoracic aorta and aortic valve guidelines. This update indicates that in patients with a bicuspid aortic valve, it is reasonable to recommend surgery when the aorta is 5 cm instead of waiting until 5.5 cm in high-volume centers that have demonstrated excellent surgical outcomes. This clarification statement was based on Cleveland Clinic outcomes showing a mortality rate of 0.25% and a stroke rate of 0.75% in a population that included patients undergoing emergency aortic dissection surgery.⁶

This study also analyzed data on patients treated with expectant care with optimal medical management and imaging surveillance (ie, to monitor the dilated aorta). Results from this subset showed that the probability of needing an aortic intervention is about 60% during the next 10 years once the aorta is within the 4.5 cm to 5 cm range.

Another study addressing the correlation between risk and aortic size examined 771 patients with a dilated ascending aorta (≥ 4 cm) and a tricuspid aortic valve.⁷ This study confirmed the use of patient height as an important factor for indexing maximum aortic size to patient body size for predicting risk of late complications. Specifically, this study suggested that the risk of complications from aortic aneurysm rises when the maximum aortic area-to-height ratio exceeds 10. This serves as a follow-up to previously published data demonstrating the value of aortic cross-sectional area-to-height ratio as a predictor of risk in patients with bicuspid valves.⁸ In general, the results of all 3 studies suggest that we should be more proactive in operating on patients with a dilated ascending aorta to prevent later risk of rupture or dissection when the surgical risk is low.

When making decisions about patients who need aortic replacement, it is important to assess many patient details: their aortic disease, their other nonaortic comorbidities, and the institution’s outcomes. This decision is best made by a dedicated cardioaortic specialist at a dedicated center of excellence.

WHAT IS COMING?

Minimally invasive and endovascular surgery

More ascending aortic surgeries are being done using minimally invasive approaches. At Cleveland Clinic, about 40% of isolated ascending aortic operations are performed through a mini-sternotomy J incision approach. A Cleveland Clinic study published in 2017 evaluated outcomes from this less-invasive technique for proximal aortic surgery compared with full median sternotomy.⁹ Results showed it was an effective approach with fewer complications, shorter hospital stays, and lower costs.

Stent grafts

The role for stent-graft devices has continued to expand.¹⁰ At Cleveland Clinic, we have performed more than 40 ascending aortic stent-graft procedures, one of the largest numbers in the world. Having this stent-graft option has enabled us to provide treatment for the patients at exceedingly high risk who previously had few or no options. Industry partners are working to develop dedicated devices for these indications, and we are working with them to bring new device trials to this underserved population of patients. 

Adverse events (AEs) from systemic treatment of cancer have a negative impact on patient quality of life (QoL). The extent of this impact is difficult to ascertain, particularly in patients undergoing palliative treatment because of variations in QoL resulting from antitumor effect.¹ Patient-reported outcomes (PROs) are the best tool for elicitation of patient preferences, therefore helping cancer patients, oncologists, and health care managers to make better choices. Indeed, analysis of self-reported QoL during cancer chemotherapy provides new insights that are missed by other efficacy outcomes,² although patient-reported AEs correlate well with AEs reported by clinicians.³ Self-reported symptoms provide better control during cancer treatment.⁴ However, there are other instruments to measure the impact of treatments on QoL that are based on preferences of members of the general public. Use of that strategy has been strongly debated. The most obvious problem is the difficulty that persons from the general public may have in putting themselves in the patient position.⁵ In addition, there is evidence that compared with the general public, patients adapt to their illness^5,6 and then tend to downplay severity when rating values of health states.⁷ Therefore, a systematic discrepancy is observed between actual patients and the general public. It is not clear if it reflects the inability of members of the general public to fully grasp the relative severity of health problems or to the adaptation process of patients. This fact may obscure a negative impact on QoL which, in turn, could be detected using the general public as a surrogate. A combination of both approaches has been recommended for rating QoL when the ultimate purpose is making decisions on resource allocation.⁵ This debate is prolonging in time and it is far from over.^8,9

Based on this background, this study investigates the impact of AEs on QoL of cancer patients from the perspective of cancer patients who had experienced the AEs of interest (ex post population) and the perspective of members of the general public. The second group comprised participants imagining themselves as hypothetical cancer patients experiencing the AEs (ex ante population). Previous studies with this dual approach allowing for comparisons between these two populations are small or centered on a few AEs.¹⁰ Therefore, a large and comprehensive study on the impact of AEs on QoL is lacking. Supported by previous literature, the investigational hypothesis was that ex post impact would be significantly lower than that imagined in an ex ante setting. The secondary objective is to study the potential use of the EuroQol (EQ-5D) instrument for health-related QoL in the measurement of the impact of AEs in cancer patients. This generic instrument is based on interviews with members of the general public. We tried to investigate to what extent those values relate to the cancer patients’ evaluation of their own health during treatment. The ultimate goal of the study is to assist in increasing the utility that patients derive from the benefits associated with cancer treatment.
 

Methods

Selection of AEs

Five AEs related to systemic treatment of cancer – alopecia, acneiform rash, oxaliplatin-associated peripheral neuropathy, diarrhea, and vomiting – were selected for the study. Investigators set up different relevant cut-off points for severity, resulting in 10 toxic events that were ad hoc defined as the variables for the study (Table 1). We used the Common Terminology Criteria for Adverse Events (CTCAE, version 4) to classify alopecia, acneiform rash, diarrhea, and vomiting. For oxaliplatin-associated peripheral neuropathy, we adapted Misset’s oxaliplatin-specific scale¹¹ (range, grade 1-4; Table 1) in which grade 1 (neurotoxicity [NTX] 1) = paresthesias only with cold lasting a few days; grade 2 [NTX2] = paresthesias with and without cold that may last months; and grade 4 [NTX3] = paresthesias with functional consequence).

Participants

Two populations were included in the study: cancer patients who had experienced a particular AE and received treatment at the medical oncology departments of Hospital Santa Tecla and Hospital del Vendrell in Tarragona, Spain; and participants from the general public who received care at the Primary Health Care Center-Llevant in the same city.



Cancer patients. These participants had to be 18 years or older and had to have experienced 1 of the 10 toxic events in the 5 years before inclusion in the study; the treatment setting could be either curative attempt (adjuvant, neoadjuvant) or palliative, and patients with ongoing treatment should have received almost 3 months of treatment. Patients were excluded if they had an ECOG PS grade of 3 or more (Eastern Cooperative Oncology Group Performance Status; range, 0-5, where 0 = fully active, 3 = capable of limited self-care; confined to bed or chair more than 50% of waking hours, and 5 = dead). A particular patient with cancer could be included because of more than 1 study toxic event (eg, alopecia and severe vomiting or NTX1 and NTX2) but had to complete separate questionnaires for the different toxic events.

General public group. Participants in this group were selected from the records of general practitioner consultations at the aforementioned primary health care center. They had to be 18 years or older and could not have a history of cancer or symptomatic/severe chronic diseases (eg, they could have hypertension or diabetes without chronic target organ involvement, or they could be patients with either acute nonserious illness or nonserious injuries).
 

Survey procedures

Cancer patients. Participants in this group filled in 2 questionnaires provided by a medical oncologist in a face-to-face interview: the 5-dimension, 5-level EuroQol (EQ-5D-5L) questionnaire in reference to the days when patients were suffering the toxic event; and a visual analog scale (VAS) answering the question: How do you feel that this AE has impacted on your QoL the days you have experienced it?

VAS scores ranged from 0 (the poorest QoL, the highest impact) to 100 (the better QoL, the lower impact). The EQ-5D-5L has 5 dimensions (Mobility, Self-care, Daily life activities/social performance, Discomfort/pain, and Anxiety/depression) with 5 level response options each (No problem at all, Light problem, Moderate problem, Severe problem, Extreme problem/unable).¹² The combination of 5 answers is converted to a single score, which is different for different countries; in the validated version for Spanish population, the score ranges from -0.654 (the worst health state) to 1.000 (the best health state). Patients were asked to make an effort to separate and encapsulate the impact of every adverse event and separate it from others they may have experienced during the same period. Table 2 summarizes survey procedures.

General public group. Two internal medicine residents who administered the questionnaire to the participants of the public group were well trained to carefully explain what each of the 10 the toxic events meant. Some details on these explanations are shown in Table 1, and the full set of explanations is shown in Appendix 1 (online only). Participants in the general public group were asked in a face-to-face interview to imagine they were cancer patients and envision how these toxic events would impact on their QoL if they were undergoing systemic treatment of cancer. They were asked to rate the imagined impact with the VAS (1 VAS/every toxic event = 10 VAS/participant). Then, they were presented with 10 cards, each with the name of 1 of the 10 toxic events (Appendix 2 [online only]), to show them the order of the impact on QoL based on their scores (respecting ties). The participants were asked if they agreed with the order, and if they did not, they were invited to change the scores. Therefore, results in the general public group also show the rank-order of the study toxic events.
 

Statistical analysis

We calculated the sample size as follows:

Primary outcomes were VAS score in cancer patients and VAS score in the general public. Primary analyses were comparison between VAS in both populations. Secondary outcomes were EQ-5D-5L score in cancer patients, and intra-participant rank-order in the general public group. Secondary analyses were correlation between VAS score and EQ-5D-5L in cancer patients and descriptive analysis of rank-ordered data in the general public group.

It was planned to compare means of quantitative variables with the Mann-Whitney U test and to assess correlation between quantitative variables with the Spearman rho test. All tests for contrast were nonparametric because a normal distribution was not expected from quoted scores with some ceiling or floor effect. A hierarchical generalized cluster analysis was planned to study clusters of variables grouped by VAS score in the public group.
 

Ethics

The study was conducted in accordance with the Declaration of Helsinki version Fortaleza 2013 and was approved by the institutional review board of the participant institutions. All of the patients provided written informed consent before study entry. Data of the participants of the general public were anonymous, so those participants were asked to provide only oral assent, with the permission of the review board.
 

Results

Between December 1, 2013 and January 31, 2015, a total of 250 participants of the general public and 139 cancer patients were included in the study. Four participants of the general public had incompletely filled the questionnaire and were excluded from the study, resulting in 246 participants with complete data available. There were no losses in the patient group, of whom 79 (57%) were currently on treatment and 118 (85%) had received the treatment in the previous 2 years. The total number of study toxic events in the 139 cancer patients was 200 (20 by each of the 10 study toxicity variables). Of those, 42 patients (30%) experienced (and were included in the study for) more than 1 toxic event.

Of the 139 patients, 91 (65%) received the treatment with curative intent. The most frequent diagnosis was colorectal cancer in 77 patients (55%), followed by breast cancer (13 patients, 9.4%), and lung cancer (11 patients, 7.9%). Systemic treatment of cancer was one of these options: chemotherapy alone, anti-EGFR [epidermal growth factor receptor] alone, chemotherapy plus anti-EGFR, or chemotherapy plus other biologics. The chemotherapy regimen most frequently administered was mFOLFOX6 [modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin] which, alone or in combination, was administered to 51 patients (37%). An anti-EGFR agent was administered to 22 patients (16%): cetuximab (15 patients), panitumumab (4 patients), erlotinib (2 patients) and afatinib (1 patient). The baseline characteristics of the patients and participants in the study are shown in Table 3.

Discussion

The findings in this study show that impact on QoL imagined by members of the general public is higher than that declared by cancer patients who have experienced the AEs. It is worth noting that that result was observed for all 10 toxic events, thus confirming the investigational hypothesis of the study. However, the graph shows a strong parallel between the 2 groups, which means that both populations similarly perceive upward and downward variations in the impact resulting from the different toxic events (Figure).

Three previous studies have addressed the comparison of the impact of different AEs in these 2 populations and findings from all 3 showed the same systematic difference between patients and the general public participants. The first, Calhoun and colleagues used time to trade-off (TTO, a measure of the QoL a person or groups is experiencing) to compare therapies for ovarian cancer in patients and the general population (n = 39 for each group). The results showed that cancer patients valued more the health status associated with toxicity than did the general public participants.¹³ The design of the second study, by Havrilesky and colleagues, was similar to that of the present study, and they compared toxic events one by one, using VAS and TTO in 13 ovarian cancer patients and 37 women of the general public.¹⁴ The investigators found the same results as we did on the parallel of the 2 groups and also a very similar order of the toxic events. Indeed, alopecia was the less bothersome, whereas both motor neuropathy and severe vomiting were among the worst toxic events. Therefore, our results correlate perfectly with theirs. Best and colleagues found that health states values associated with oxaliplatin-related peripheral neuropathy were lower in the general public population compared with those of cancer patients.¹⁵ Besides adaptive behavior of the patients, all these results may be explained by an established awareness cancer patients have of the dual outcome of cancer treatments (AEs and benefits from the treatment).⁹ This awareness is absent in the general public participants, who can only envision the negative outcomes and who do not realize the importance of the benefits.⁹ Findings from previous studies conducted in several tumor types such as breast cancer^16-18 non–small-cell lung cancer,¹⁹ thyroid cancer,²⁰ and renal cancer²¹ have shown that patients are willing to trade-off AEs for treatment benefits.

Alopecia has been considered as one of the most distressing and troublesome AEs of cancer therapy.²² However, in the present study, alopecia was rated inside the range of mild toxic events as it is in the study by Havrilesky and colleagues.¹⁴ Our results show that alopecia was placed as the first less damaging toxic event when assessed with the EQ-5D-5L, the second less damaging when assessed with a rank-order system, and the third less damaging when assessed the VAS. This could be related to current fashion trends that promote shaving one’s hair, which minimizes the social stigma of alopecia and its association with cancer treatment.

The other esthetic event we analyzed was acneiform rash associated with anti-EGFR agents. Our results show that severe rash was rated as clearly worse than alopecia by the 2 populations, irrespective of the measuring instrument (VAS, EQ-5D-5L, or ordinal assessment). To our knowledge, the present study is the first to demonstrate the relative impact of total alopecia and severe rash on patient QoL. This result is even more significant considering that we included grade 2 acneiform rash inside the Severe Rash toxic event. Our results show that the worst AEs for both populations were severe vomiting and neurotoxicity with functional impairment. The high impact of severe vomiting, the quintessentially chemotherapy-induced AE, was to be expected because it is strongly supported by a number of previous reports,^14,23 as is also true for peripheral motor neuropathy.^14,15,24

EQ-5D is a powerful instrument for measuring health status²⁵ and is widely used to describe and evaluate patient health.²⁶ Our results from the 5 dimensions represented by a single score were well correlated with the results of the VAS. However, whereas median VAS scores were evenly distributed in the 0-100 range of the VAS, median EQ-5D-5L scores were distributed mainly in the 0.5-1.0 range (full range, -0.654-1.000, for Spanish population).

The final single score of the original EQ-5D is based on responses from the general public, and we have shown that its use is a valid option when the objective is the evaluation of AEs in patients with cancer. Management of AEs is of the utmost importance in this era of personalized cancer medicine. Basch and colleagues recently reported that an intensive web-based follow-up of AEs during chemotherapy improved overall survival compared with standard follow-up.²⁷ The results of our study show that patients have strongly defined preferences regarding AEs. Therefore, therapeutic strategies with a personalized approach in managing AEs would be associated with increased effectiveness.

There are some limitations in the present study. First, we modified slightly the EQ-5D-5L questionnaire by asking patients to recall and rate the days they experienced the adverse event instead of asking for “today’s feelings.” It is not known how this modification affects internal validity of this study. Second, we asked patients to isolate the toxic event to rate it independently from the other toxic events. We believe that this request may have been difficult for some patients to do because they might have experienced more than 1 toxic event concurrently. Third, using VAS to assess health status may be a weakness because it has been considered to be too straightforward an instrument. Likewise, there are some strengths of the study: it was performed in a face-to-face manner; it displayed cardinal and ordinal results for participants in the public group; and the results are the same as those in a previous study.¹⁴

In conclusion, patients with cancer who have experienced AEs perceive a lower impact on their QoL compared with that envisioned by participants from the general public. The EQ-5D-5L is a useful tool for evaluating cancer-therapy–related AEs. The impact of alopecia on QoL was notably low and even lower than that of severe rash. Further investigation on this issue should focus on patients’ and oncologists’ shared choices, which increasingly will be driven by patient preferences.
 

The Oncologic Association Dr Amadeu Pelegrí (AODAP), a charitable organization led by cancer patients and based in Salou, Spain, provided the financial support needed to conduct this study (www.aodapelegri.com).

Adverse events (AEs) from systemic treatment of cancer have a negative impact on patient quality of life (QoL). The extent of this impact is difficult to ascertain, particularly in patients undergoing palliative treatment because of variations in QoL resulting from antitumor effect.¹ Patient-reported outcomes (PROs) are the best tool for elicitation of patient preferences, therefore helping cancer patients, oncologists, and health care managers to make better choices. Indeed, analysis of self-reported QoL during cancer chemotherapy provides new insights that are missed by other efficacy outcomes,² although patient-reported AEs correlate well with AEs reported by clinicians.³ Self-reported symptoms provide better control during cancer treatment.⁴ However, there are other instruments to measure the impact of treatments on QoL that are based on preferences of members of the general public. Use of that strategy has been strongly debated. The most obvious problem is the difficulty that persons from the general public may have in putting themselves in the patient position.⁵ In addition, there is evidence that compared with the general public, patients adapt to their illness^5,6 and then tend to downplay severity when rating values of health states.⁷ Therefore, a systematic discrepancy is observed between actual patients and the general public. It is not clear if it reflects the inability of members of the general public to fully grasp the relative severity of health problems or to the adaptation process of patients. This fact may obscure a negative impact on QoL which, in turn, could be detected using the general public as a surrogate. A combination of both approaches has been recommended for rating QoL when the ultimate purpose is making decisions on resource allocation.⁵ This debate is prolonging in time and it is far from over.^8,9

Based on this background, this study investigates the impact of AEs on QoL of cancer patients from the perspective of cancer patients who had experienced the AEs of interest (ex post population) and the perspective of members of the general public. The second group comprised participants imagining themselves as hypothetical cancer patients experiencing the AEs (ex ante population). Previous studies with this dual approach allowing for comparisons between these two populations are small or centered on a few AEs.¹⁰ Therefore, a large and comprehensive study on the impact of AEs on QoL is lacking. Supported by previous literature, the investigational hypothesis was that ex post impact would be significantly lower than that imagined in an ex ante setting. The secondary objective is to study the potential use of the EuroQol (EQ-5D) instrument for health-related QoL in the measurement of the impact of AEs in cancer patients. This generic instrument is based on interviews with members of the general public. We tried to investigate to what extent those values relate to the cancer patients’ evaluation of their own health during treatment. The ultimate goal of the study is to assist in increasing the utility that patients derive from the benefits associated with cancer treatment.
 

Methods

Selection of AEs

Five AEs related to systemic treatment of cancer – alopecia, acneiform rash, oxaliplatin-associated peripheral neuropathy, diarrhea, and vomiting – were selected for the study. Investigators set up different relevant cut-off points for severity, resulting in 10 toxic events that were ad hoc defined as the variables for the study (Table 1). We used the Common Terminology Criteria for Adverse Events (CTCAE, version 4) to classify alopecia, acneiform rash, diarrhea, and vomiting. For oxaliplatin-associated peripheral neuropathy, we adapted Misset’s oxaliplatin-specific scale¹¹ (range, grade 1-4; Table 1) in which grade 1 (neurotoxicity [NTX] 1) = paresthesias only with cold lasting a few days; grade 2 [NTX2] = paresthesias with and without cold that may last months; and grade 4 [NTX3] = paresthesias with functional consequence).

Participants

Two populations were included in the study: cancer patients who had experienced a particular AE and received treatment at the medical oncology departments of Hospital Santa Tecla and Hospital del Vendrell in Tarragona, Spain; and participants from the general public who received care at the Primary Health Care Center-Llevant in the same city.



Cancer patients. These participants had to be 18 years or older and had to have experienced 1 of the 10 toxic events in the 5 years before inclusion in the study; the treatment setting could be either curative attempt (adjuvant, neoadjuvant) or palliative, and patients with ongoing treatment should have received almost 3 months of treatment. Patients were excluded if they had an ECOG PS grade of 3 or more (Eastern Cooperative Oncology Group Performance Status; range, 0-5, where 0 = fully active, 3 = capable of limited self-care; confined to bed or chair more than 50% of waking hours, and 5 = dead). A particular patient with cancer could be included because of more than 1 study toxic event (eg, alopecia and severe vomiting or NTX1 and NTX2) but had to complete separate questionnaires for the different toxic events.

General public group. Participants in this group were selected from the records of general practitioner consultations at the aforementioned primary health care center. They had to be 18 years or older and could not have a history of cancer or symptomatic/severe chronic diseases (eg, they could have hypertension or diabetes without chronic target organ involvement, or they could be patients with either acute nonserious illness or nonserious injuries).
 

Survey procedures

Cancer patients. Participants in this group filled in 2 questionnaires provided by a medical oncologist in a face-to-face interview: the 5-dimension, 5-level EuroQol (EQ-5D-5L) questionnaire in reference to the days when patients were suffering the toxic event; and a visual analog scale (VAS) answering the question: How do you feel that this AE has impacted on your QoL the days you have experienced it?

VAS scores ranged from 0 (the poorest QoL, the highest impact) to 100 (the better QoL, the lower impact). The EQ-5D-5L has 5 dimensions (Mobility, Self-care, Daily life activities/social performance, Discomfort/pain, and Anxiety/depression) with 5 level response options each (No problem at all, Light problem, Moderate problem, Severe problem, Extreme problem/unable).¹² The combination of 5 answers is converted to a single score, which is different for different countries; in the validated version for Spanish population, the score ranges from -0.654 (the worst health state) to 1.000 (the best health state). Patients were asked to make an effort to separate and encapsulate the impact of every adverse event and separate it from others they may have experienced during the same period. Table 2 summarizes survey procedures.

General public group. Two internal medicine residents who administered the questionnaire to the participants of the public group were well trained to carefully explain what each of the 10 the toxic events meant. Some details on these explanations are shown in Table 1, and the full set of explanations is shown in Appendix 1 (online only). Participants in the general public group were asked in a face-to-face interview to imagine they were cancer patients and envision how these toxic events would impact on their QoL if they were undergoing systemic treatment of cancer. They were asked to rate the imagined impact with the VAS (1 VAS/every toxic event = 10 VAS/participant). Then, they were presented with 10 cards, each with the name of 1 of the 10 toxic events (Appendix 2 [online only]), to show them the order of the impact on QoL based on their scores (respecting ties). The participants were asked if they agreed with the order, and if they did not, they were invited to change the scores. Therefore, results in the general public group also show the rank-order of the study toxic events.
 

Statistical analysis

We calculated the sample size as follows:

Primary outcomes were VAS score in cancer patients and VAS score in the general public. Primary analyses were comparison between VAS in both populations. Secondary outcomes were EQ-5D-5L score in cancer patients, and intra-participant rank-order in the general public group. Secondary analyses were correlation between VAS score and EQ-5D-5L in cancer patients and descriptive analysis of rank-ordered data in the general public group.

It was planned to compare means of quantitative variables with the Mann-Whitney U test and to assess correlation between quantitative variables with the Spearman rho test. All tests for contrast were nonparametric because a normal distribution was not expected from quoted scores with some ceiling or floor effect. A hierarchical generalized cluster analysis was planned to study clusters of variables grouped by VAS score in the public group.
 

Ethics

The study was conducted in accordance with the Declaration of Helsinki version Fortaleza 2013 and was approved by the institutional review board of the participant institutions. All of the patients provided written informed consent before study entry. Data of the participants of the general public were anonymous, so those participants were asked to provide only oral assent, with the permission of the review board.
 

Results

Between December 1, 2013 and January 31, 2015, a total of 250 participants of the general public and 139 cancer patients were included in the study. Four participants of the general public had incompletely filled the questionnaire and were excluded from the study, resulting in 246 participants with complete data available. There were no losses in the patient group, of whom 79 (57%) were currently on treatment and 118 (85%) had received the treatment in the previous 2 years. The total number of study toxic events in the 139 cancer patients was 200 (20 by each of the 10 study toxicity variables). Of those, 42 patients (30%) experienced (and were included in the study for) more than 1 toxic event.

Of the 139 patients, 91 (65%) received the treatment with curative intent. The most frequent diagnosis was colorectal cancer in 77 patients (55%), followed by breast cancer (13 patients, 9.4%), and lung cancer (11 patients, 7.9%). Systemic treatment of cancer was one of these options: chemotherapy alone, anti-EGFR [epidermal growth factor receptor] alone, chemotherapy plus anti-EGFR, or chemotherapy plus other biologics. The chemotherapy regimen most frequently administered was mFOLFOX6 [modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin] which, alone or in combination, was administered to 51 patients (37%). An anti-EGFR agent was administered to 22 patients (16%): cetuximab (15 patients), panitumumab (4 patients), erlotinib (2 patients) and afatinib (1 patient). The baseline characteristics of the patients and participants in the study are shown in Table 3.

Discussion

The findings in this study show that impact on QoL imagined by members of the general public is higher than that declared by cancer patients who have experienced the AEs. It is worth noting that that result was observed for all 10 toxic events, thus confirming the investigational hypothesis of the study. However, the graph shows a strong parallel between the 2 groups, which means that both populations similarly perceive upward and downward variations in the impact resulting from the different toxic events (Figure).

Three previous studies have addressed the comparison of the impact of different AEs in these 2 populations and findings from all 3 showed the same systematic difference between patients and the general public participants. The first, Calhoun and colleagues used time to trade-off (TTO, a measure of the QoL a person or groups is experiencing) to compare therapies for ovarian cancer in patients and the general population (n = 39 for each group). The results showed that cancer patients valued more the health status associated with toxicity than did the general public participants.¹³ The design of the second study, by Havrilesky and colleagues, was similar to that of the present study, and they compared toxic events one by one, using VAS and TTO in 13 ovarian cancer patients and 37 women of the general public.¹⁴ The investigators found the same results as we did on the parallel of the 2 groups and also a very similar order of the toxic events. Indeed, alopecia was the less bothersome, whereas both motor neuropathy and severe vomiting were among the worst toxic events. Therefore, our results correlate perfectly with theirs. Best and colleagues found that health states values associated with oxaliplatin-related peripheral neuropathy were lower in the general public population compared with those of cancer patients.¹⁵ Besides adaptive behavior of the patients, all these results may be explained by an established awareness cancer patients have of the dual outcome of cancer treatments (AEs and benefits from the treatment).⁹ This awareness is absent in the general public participants, who can only envision the negative outcomes and who do not realize the importance of the benefits.⁹ Findings from previous studies conducted in several tumor types such as breast cancer^16-18 non–small-cell lung cancer,¹⁹ thyroid cancer,²⁰ and renal cancer²¹ have shown that patients are willing to trade-off AEs for treatment benefits.

Alopecia has been considered as one of the most distressing and troublesome AEs of cancer therapy.²² However, in the present study, alopecia was rated inside the range of mild toxic events as it is in the study by Havrilesky and colleagues.¹⁴ Our results show that alopecia was placed as the first less damaging toxic event when assessed with the EQ-5D-5L, the second less damaging when assessed with a rank-order system, and the third less damaging when assessed the VAS. This could be related to current fashion trends that promote shaving one’s hair, which minimizes the social stigma of alopecia and its association with cancer treatment.

The other esthetic event we analyzed was acneiform rash associated with anti-EGFR agents. Our results show that severe rash was rated as clearly worse than alopecia by the 2 populations, irrespective of the measuring instrument (VAS, EQ-5D-5L, or ordinal assessment). To our knowledge, the present study is the first to demonstrate the relative impact of total alopecia and severe rash on patient QoL. This result is even more significant considering that we included grade 2 acneiform rash inside the Severe Rash toxic event. Our results show that the worst AEs for both populations were severe vomiting and neurotoxicity with functional impairment. The high impact of severe vomiting, the quintessentially chemotherapy-induced AE, was to be expected because it is strongly supported by a number of previous reports,^14,23 as is also true for peripheral motor neuropathy.^14,15,24

EQ-5D is a powerful instrument for measuring health status²⁵ and is widely used to describe and evaluate patient health.²⁶ Our results from the 5 dimensions represented by a single score were well correlated with the results of the VAS. However, whereas median VAS scores were evenly distributed in the 0-100 range of the VAS, median EQ-5D-5L scores were distributed mainly in the 0.5-1.0 range (full range, -0.654-1.000, for Spanish population).

The final single score of the original EQ-5D is based on responses from the general public, and we have shown that its use is a valid option when the objective is the evaluation of AEs in patients with cancer. Management of AEs is of the utmost importance in this era of personalized cancer medicine. Basch and colleagues recently reported that an intensive web-based follow-up of AEs during chemotherapy improved overall survival compared with standard follow-up.²⁷ The results of our study show that patients have strongly defined preferences regarding AEs. Therefore, therapeutic strategies with a personalized approach in managing AEs would be associated with increased effectiveness.

There are some limitations in the present study. First, we modified slightly the EQ-5D-5L questionnaire by asking patients to recall and rate the days they experienced the adverse event instead of asking for “today’s feelings.” It is not known how this modification affects internal validity of this study. Second, we asked patients to isolate the toxic event to rate it independently from the other toxic events. We believe that this request may have been difficult for some patients to do because they might have experienced more than 1 toxic event concurrently. Third, using VAS to assess health status may be a weakness because it has been considered to be too straightforward an instrument. Likewise, there are some strengths of the study: it was performed in a face-to-face manner; it displayed cardinal and ordinal results for participants in the public group; and the results are the same as those in a previous study.¹⁴

In conclusion, patients with cancer who have experienced AEs perceive a lower impact on their QoL compared with that envisioned by participants from the general public. The EQ-5D-5L is a useful tool for evaluating cancer-therapy–related AEs. The impact of alopecia on QoL was notably low and even lower than that of severe rash. Further investigation on this issue should focus on patients’ and oncologists’ shared choices, which increasingly will be driven by patient preferences.
 

The Oncologic Association Dr Amadeu Pelegrí (AODAP), a charitable organization led by cancer patients and based in Salou, Spain, provided the financial support needed to conduct this study (www.aodapelegri.com).

Adverse events (AEs) from systemic treatment of cancer have a negative impact on patient quality of life (QoL). The extent of this impact is difficult to ascertain, particularly in patients undergoing palliative treatment because of variations in QoL resulting from antitumor effect.¹ Patient-reported outcomes (PROs) are the best tool for elicitation of patient preferences, therefore helping cancer patients, oncologists, and health care managers to make better choices. Indeed, analysis of self-reported QoL during cancer chemotherapy provides new insights that are missed by other efficacy outcomes,² although patient-reported AEs correlate well with AEs reported by clinicians.³ Self-reported symptoms provide better control during cancer treatment.⁴ However, there are other instruments to measure the impact of treatments on QoL that are based on preferences of members of the general public. Use of that strategy has been strongly debated. The most obvious problem is the difficulty that persons from the general public may have in putting themselves in the patient position.⁵ In addition, there is evidence that compared with the general public, patients adapt to their illness^5,6 and then tend to downplay severity when rating values of health states.⁷ Therefore, a systematic discrepancy is observed between actual patients and the general public. It is not clear if it reflects the inability of members of the general public to fully grasp the relative severity of health problems or to the adaptation process of patients. This fact may obscure a negative impact on QoL which, in turn, could be detected using the general public as a surrogate. A combination of both approaches has been recommended for rating QoL when the ultimate purpose is making decisions on resource allocation.⁵ This debate is prolonging in time and it is far from over.^8,9

Based on this background, this study investigates the impact of AEs on QoL of cancer patients from the perspective of cancer patients who had experienced the AEs of interest (ex post population) and the perspective of members of the general public. The second group comprised participants imagining themselves as hypothetical cancer patients experiencing the AEs (ex ante population). Previous studies with this dual approach allowing for comparisons between these two populations are small or centered on a few AEs.¹⁰ Therefore, a large and comprehensive study on the impact of AEs on QoL is lacking. Supported by previous literature, the investigational hypothesis was that ex post impact would be significantly lower than that imagined in an ex ante setting. The secondary objective is to study the potential use of the EuroQol (EQ-5D) instrument for health-related QoL in the measurement of the impact of AEs in cancer patients. This generic instrument is based on interviews with members of the general public. We tried to investigate to what extent those values relate to the cancer patients’ evaluation of their own health during treatment. The ultimate goal of the study is to assist in increasing the utility that patients derive from the benefits associated with cancer treatment.
 

Methods

Selection of AEs

Five AEs related to systemic treatment of cancer – alopecia, acneiform rash, oxaliplatin-associated peripheral neuropathy, diarrhea, and vomiting – were selected for the study. Investigators set up different relevant cut-off points for severity, resulting in 10 toxic events that were ad hoc defined as the variables for the study (Table 1). We used the Common Terminology Criteria for Adverse Events (CTCAE, version 4) to classify alopecia, acneiform rash, diarrhea, and vomiting. For oxaliplatin-associated peripheral neuropathy, we adapted Misset’s oxaliplatin-specific scale¹¹ (range, grade 1-4; Table 1) in which grade 1 (neurotoxicity [NTX] 1) = paresthesias only with cold lasting a few days; grade 2 [NTX2] = paresthesias with and without cold that may last months; and grade 4 [NTX3] = paresthesias with functional consequence).

Participants

Two populations were included in the study: cancer patients who had experienced a particular AE and received treatment at the medical oncology departments of Hospital Santa Tecla and Hospital del Vendrell in Tarragona, Spain; and participants from the general public who received care at the Primary Health Care Center-Llevant in the same city.



Cancer patients. These participants had to be 18 years or older and had to have experienced 1 of the 10 toxic events in the 5 years before inclusion in the study; the treatment setting could be either curative attempt (adjuvant, neoadjuvant) or palliative, and patients with ongoing treatment should have received almost 3 months of treatment. Patients were excluded if they had an ECOG PS grade of 3 or more (Eastern Cooperative Oncology Group Performance Status; range, 0-5, where 0 = fully active, 3 = capable of limited self-care; confined to bed or chair more than 50% of waking hours, and 5 = dead). A particular patient with cancer could be included because of more than 1 study toxic event (eg, alopecia and severe vomiting or NTX1 and NTX2) but had to complete separate questionnaires for the different toxic events.

General public group. Participants in this group were selected from the records of general practitioner consultations at the aforementioned primary health care center. They had to be 18 years or older and could not have a history of cancer or symptomatic/severe chronic diseases (eg, they could have hypertension or diabetes without chronic target organ involvement, or they could be patients with either acute nonserious illness or nonserious injuries).
 

Survey procedures

Cancer patients. Participants in this group filled in 2 questionnaires provided by a medical oncologist in a face-to-face interview: the 5-dimension, 5-level EuroQol (EQ-5D-5L) questionnaire in reference to the days when patients were suffering the toxic event; and a visual analog scale (VAS) answering the question: How do you feel that this AE has impacted on your QoL the days you have experienced it?

VAS scores ranged from 0 (the poorest QoL, the highest impact) to 100 (the better QoL, the lower impact). The EQ-5D-5L has 5 dimensions (Mobility, Self-care, Daily life activities/social performance, Discomfort/pain, and Anxiety/depression) with 5 level response options each (No problem at all, Light problem, Moderate problem, Severe problem, Extreme problem/unable).¹² The combination of 5 answers is converted to a single score, which is different for different countries; in the validated version for Spanish population, the score ranges from -0.654 (the worst health state) to 1.000 (the best health state). Patients were asked to make an effort to separate and encapsulate the impact of every adverse event and separate it from others they may have experienced during the same period. Table 2 summarizes survey procedures.

General public group. Two internal medicine residents who administered the questionnaire to the participants of the public group were well trained to carefully explain what each of the 10 the toxic events meant. Some details on these explanations are shown in Table 1, and the full set of explanations is shown in Appendix 1 (online only). Participants in the general public group were asked in a face-to-face interview to imagine they were cancer patients and envision how these toxic events would impact on their QoL if they were undergoing systemic treatment of cancer. They were asked to rate the imagined impact with the VAS (1 VAS/every toxic event = 10 VAS/participant). Then, they were presented with 10 cards, each with the name of 1 of the 10 toxic events (Appendix 2 [online only]), to show them the order of the impact on QoL based on their scores (respecting ties). The participants were asked if they agreed with the order, and if they did not, they were invited to change the scores. Therefore, results in the general public group also show the rank-order of the study toxic events.
 

Statistical analysis

We calculated the sample size as follows:

Primary outcomes were VAS score in cancer patients and VAS score in the general public. Primary analyses were comparison between VAS in both populations. Secondary outcomes were EQ-5D-5L score in cancer patients, and intra-participant rank-order in the general public group. Secondary analyses were correlation between VAS score and EQ-5D-5L in cancer patients and descriptive analysis of rank-ordered data in the general public group.

It was planned to compare means of quantitative variables with the Mann-Whitney U test and to assess correlation between quantitative variables with the Spearman rho test. All tests for contrast were nonparametric because a normal distribution was not expected from quoted scores with some ceiling or floor effect. A hierarchical generalized cluster analysis was planned to study clusters of variables grouped by VAS score in the public group.
 

Ethics

The study was conducted in accordance with the Declaration of Helsinki version Fortaleza 2013 and was approved by the institutional review board of the participant institutions. All of the patients provided written informed consent before study entry. Data of the participants of the general public were anonymous, so those participants were asked to provide only oral assent, with the permission of the review board.
 

Results

Between December 1, 2013 and January 31, 2015, a total of 250 participants of the general public and 139 cancer patients were included in the study. Four participants of the general public had incompletely filled the questionnaire and were excluded from the study, resulting in 246 participants with complete data available. There were no losses in the patient group, of whom 79 (57%) were currently on treatment and 118 (85%) had received the treatment in the previous 2 years. The total number of study toxic events in the 139 cancer patients was 200 (20 by each of the 10 study toxicity variables). Of those, 42 patients (30%) experienced (and were included in the study for) more than 1 toxic event.

Of the 139 patients, 91 (65%) received the treatment with curative intent. The most frequent diagnosis was colorectal cancer in 77 patients (55%), followed by breast cancer (13 patients, 9.4%), and lung cancer (11 patients, 7.9%). Systemic treatment of cancer was one of these options: chemotherapy alone, anti-EGFR [epidermal growth factor receptor] alone, chemotherapy plus anti-EGFR, or chemotherapy plus other biologics. The chemotherapy regimen most frequently administered was mFOLFOX6 [modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin] which, alone or in combination, was administered to 51 patients (37%). An anti-EGFR agent was administered to 22 patients (16%): cetuximab (15 patients), panitumumab (4 patients), erlotinib (2 patients) and afatinib (1 patient). The baseline characteristics of the patients and participants in the study are shown in Table 3.

Discussion

The findings in this study show that impact on QoL imagined by members of the general public is higher than that declared by cancer patients who have experienced the AEs. It is worth noting that that result was observed for all 10 toxic events, thus confirming the investigational hypothesis of the study. However, the graph shows a strong parallel between the 2 groups, which means that both populations similarly perceive upward and downward variations in the impact resulting from the different toxic events (Figure).

Three previous studies have addressed the comparison of the impact of different AEs in these 2 populations and findings from all 3 showed the same systematic difference between patients and the general public participants. The first, Calhoun and colleagues used time to trade-off (TTO, a measure of the QoL a person or groups is experiencing) to compare therapies for ovarian cancer in patients and the general population (n = 39 for each group). The results showed that cancer patients valued more the health status associated with toxicity than did the general public participants.¹³ The design of the second study, by Havrilesky and colleagues, was similar to that of the present study, and they compared toxic events one by one, using VAS and TTO in 13 ovarian cancer patients and 37 women of the general public.¹⁴ The investigators found the same results as we did on the parallel of the 2 groups and also a very similar order of the toxic events. Indeed, alopecia was the less bothersome, whereas both motor neuropathy and severe vomiting were among the worst toxic events. Therefore, our results correlate perfectly with theirs. Best and colleagues found that health states values associated with oxaliplatin-related peripheral neuropathy were lower in the general public population compared with those of cancer patients.¹⁵ Besides adaptive behavior of the patients, all these results may be explained by an established awareness cancer patients have of the dual outcome of cancer treatments (AEs and benefits from the treatment).⁹ This awareness is absent in the general public participants, who can only envision the negative outcomes and who do not realize the importance of the benefits.⁹ Findings from previous studies conducted in several tumor types such as breast cancer^16-18 non–small-cell lung cancer,¹⁹ thyroid cancer,²⁰ and renal cancer²¹ have shown that patients are willing to trade-off AEs for treatment benefits.

Alopecia has been considered as one of the most distressing and troublesome AEs of cancer therapy.²² However, in the present study, alopecia was rated inside the range of mild toxic events as it is in the study by Havrilesky and colleagues.¹⁴ Our results show that alopecia was placed as the first less damaging toxic event when assessed with the EQ-5D-5L, the second less damaging when assessed with a rank-order system, and the third less damaging when assessed the VAS. This could be related to current fashion trends that promote shaving one’s hair, which minimizes the social stigma of alopecia and its association with cancer treatment.

The other esthetic event we analyzed was acneiform rash associated with anti-EGFR agents. Our results show that severe rash was rated as clearly worse than alopecia by the 2 populations, irrespective of the measuring instrument (VAS, EQ-5D-5L, or ordinal assessment). To our knowledge, the present study is the first to demonstrate the relative impact of total alopecia and severe rash on patient QoL. This result is even more significant considering that we included grade 2 acneiform rash inside the Severe Rash toxic event. Our results show that the worst AEs for both populations were severe vomiting and neurotoxicity with functional impairment. The high impact of severe vomiting, the quintessentially chemotherapy-induced AE, was to be expected because it is strongly supported by a number of previous reports,^14,23 as is also true for peripheral motor neuropathy.^14,15,24

EQ-5D is a powerful instrument for measuring health status²⁵ and is widely used to describe and evaluate patient health.²⁶ Our results from the 5 dimensions represented by a single score were well correlated with the results of the VAS. However, whereas median VAS scores were evenly distributed in the 0-100 range of the VAS, median EQ-5D-5L scores were distributed mainly in the 0.5-1.0 range (full range, -0.654-1.000, for Spanish population).

The final single score of the original EQ-5D is based on responses from the general public, and we have shown that its use is a valid option when the objective is the evaluation of AEs in patients with cancer. Management of AEs is of the utmost importance in this era of personalized cancer medicine. Basch and colleagues recently reported that an intensive web-based follow-up of AEs during chemotherapy improved overall survival compared with standard follow-up.²⁷ The results of our study show that patients have strongly defined preferences regarding AEs. Therefore, therapeutic strategies with a personalized approach in managing AEs would be associated with increased effectiveness.

There are some limitations in the present study. First, we modified slightly the EQ-5D-5L questionnaire by asking patients to recall and rate the days they experienced the adverse event instead of asking for “today’s feelings.” It is not known how this modification affects internal validity of this study. Second, we asked patients to isolate the toxic event to rate it independently from the other toxic events. We believe that this request may have been difficult for some patients to do because they might have experienced more than 1 toxic event concurrently. Third, using VAS to assess health status may be a weakness because it has been considered to be too straightforward an instrument. Likewise, there are some strengths of the study: it was performed in a face-to-face manner; it displayed cardinal and ordinal results for participants in the public group; and the results are the same as those in a previous study.¹⁴

In conclusion, patients with cancer who have experienced AEs perceive a lower impact on their QoL compared with that envisioned by participants from the general public. The EQ-5D-5L is a useful tool for evaluating cancer-therapy–related AEs. The impact of alopecia on QoL was notably low and even lower than that of severe rash. Further investigation on this issue should focus on patients’ and oncologists’ shared choices, which increasingly will be driven by patient preferences.
 

The Oncologic Association Dr Amadeu Pelegrí (AODAP), a charitable organization led by cancer patients and based in Salou, Spain, provided the financial support needed to conduct this study (www.aodapelegri.com).

Supplement Editor:
Maan A. Fares, MD

Contents

Introduction: Challenges and advances in cardiovascular disease
Maan A. Fares

Cardiac amyloidosis: An update on diagnosis and treatment
Joseph P. Donnelly and Mazen Hanna

Management of coronary chronic total occlusion
Jaikirshan Khatri, Mouin Abdallah, and Stephen Ellis

Update on the management of venous thromboembolism
John R. Bartholomew

Cardiac implantable electronic device infection
Cameron T. Lambert and Khaldoun G. Tarakji

Lung transplant: Candidates for referral and the waiting list
Kenneth R. McCurry and Marie M. Budev

Supplement Editor:
Maan A. Fares, MD

Contents

Introduction: Challenges and advances in cardiovascular disease
Maan A. Fares

Cardiac amyloidosis: An update on diagnosis and treatment
Joseph P. Donnelly and Mazen Hanna

Management of coronary chronic total occlusion
Jaikirshan Khatri, Mouin Abdallah, and Stephen Ellis

Update on the management of venous thromboembolism
John R. Bartholomew

Cardiac implantable electronic device infection
Cameron T. Lambert and Khaldoun G. Tarakji

Lung transplant: Candidates for referral and the waiting list
Kenneth R. McCurry and Marie M. Budev

Supplement Editor:
Maan A. Fares, MD

Contents

Introduction: Challenges and advances in cardiovascular disease
Maan A. Fares

Cardiac amyloidosis: An update on diagnosis and treatment
Joseph P. Donnelly and Mazen Hanna

Management of coronary chronic total occlusion
Jaikirshan Khatri, Mouin Abdallah, and Stephen Ellis

Update on the management of venous thromboembolism
John R. Bartholomew

Cardiac implantable electronic device infection
Cameron T. Lambert and Khaldoun G. Tarakji

Lung transplant: Candidates for referral and the waiting list
Kenneth R. McCurry and Marie M. Budev

In cardiovascular medicine, advances in our understanding of disease processes, medical management, and interventional and surgical techniques have gone a long way toward improving the health of patients. But we face challenges and opportunities in how best to apply these discoveries to improve the quality of care we provide and do so without driving up costs or wasting resources.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease aims to illuminate some of the challenges and advances in the management of cardiac amyloidosis, coronary artery chronic total occlusion, venous thromboembolism, implantable device infection, and lung transplant. In so doing, my colleagues present insights into which advances will benefit which patients to improve quality and contain cost.

Cardiac amyloidosis, sometimes called stiff heart syndrome, is the most common restrictive cardiomyopathy. Amyloid deposits in the heart muscle can affect conduction of electrical signals leading to arrhythmias and heart block. Joseph P. Donnelly, MD, and Mazen Hanna, MD, present a comprehensive review of cardiac amyloidosis and share exciting advances in the detection and treatment of this condition and clues to identify patients who may be affected by this often overlooked condition.

Also in this supplement, Jaikirshan Khatri, MD, and colleagues review the use of percutaneous coronary intervention (PCI) for patients with coronary artery chronic total occlusion (CTO). Though CTO is often considered benign, the affected myocardium is ischemic and patients with significant ischemic burden may benefit clinically from CTO PCI. A technically demanding procedure, CTO PCI success rates are highly operator-dependent.

John R. Bartholomew, MD, presents information about the management of venous thromboembolism (VTE) including recent changes to treatment guidelines. Patients with VTE require immediate treatment with anticoagulation therapy. Recent changes to treatment guidelines now recommend direct oral anticoagulants for patients with VTE and no cancer. Direct oral anticoagulants are an important new option for patients and further study would be beneficial to strengthen the level of evidence regarding which anticoagulation therapy is best for which patients.

Cardiac implantable electronic devices (CIEDs) improve quality of life and longevity for increasing numbers of patients with cardiac disease. Cameron T. Lambert, MD, and Khaldoun G. Tarakji, MD, MPH, discuss the types of CIED infections that occur in about 1% of patients receiving a first CIED. Prompt diagnosis improves the success of antibiotic therapy, device removal, and resolution of the infection.

Finally, Kenneth R. McCurry, MD, and Marie M. Budev, DO, MPH, discuss lung transplant for patients with end-stage lung disease. Lung transplant may be an option to extend survival and improve the quality of life for some patients. In this article, the authors review the selection criteria for lung transplant candidates, including when physicians should refer patients to lung transplant centers for evaluation and placement on the lung transplant waiting list.

We hope this supplement is a useful review of some of the challenges and advances in cardiovascular medicine and is beneficial to you and your clinical practice.

In cardiovascular medicine, advances in our understanding of disease processes, medical management, and interventional and surgical techniques have gone a long way toward improving the health of patients. But we face challenges and opportunities in how best to apply these discoveries to improve the quality of care we provide and do so without driving up costs or wasting resources.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease aims to illuminate some of the challenges and advances in the management of cardiac amyloidosis, coronary artery chronic total occlusion, venous thromboembolism, implantable device infection, and lung transplant. In so doing, my colleagues present insights into which advances will benefit which patients to improve quality and contain cost.

Cardiac amyloidosis, sometimes called stiff heart syndrome, is the most common restrictive cardiomyopathy. Amyloid deposits in the heart muscle can affect conduction of electrical signals leading to arrhythmias and heart block. Joseph P. Donnelly, MD, and Mazen Hanna, MD, present a comprehensive review of cardiac amyloidosis and share exciting advances in the detection and treatment of this condition and clues to identify patients who may be affected by this often overlooked condition.

Also in this supplement, Jaikirshan Khatri, MD, and colleagues review the use of percutaneous coronary intervention (PCI) for patients with coronary artery chronic total occlusion (CTO). Though CTO is often considered benign, the affected myocardium is ischemic and patients with significant ischemic burden may benefit clinically from CTO PCI. A technically demanding procedure, CTO PCI success rates are highly operator-dependent.

John R. Bartholomew, MD, presents information about the management of venous thromboembolism (VTE) including recent changes to treatment guidelines. Patients with VTE require immediate treatment with anticoagulation therapy. Recent changes to treatment guidelines now recommend direct oral anticoagulants for patients with VTE and no cancer. Direct oral anticoagulants are an important new option for patients and further study would be beneficial to strengthen the level of evidence regarding which anticoagulation therapy is best for which patients.

Cardiac implantable electronic devices (CIEDs) improve quality of life and longevity for increasing numbers of patients with cardiac disease. Cameron T. Lambert, MD, and Khaldoun G. Tarakji, MD, MPH, discuss the types of CIED infections that occur in about 1% of patients receiving a first CIED. Prompt diagnosis improves the success of antibiotic therapy, device removal, and resolution of the infection.

Finally, Kenneth R. McCurry, MD, and Marie M. Budev, DO, MPH, discuss lung transplant for patients with end-stage lung disease. Lung transplant may be an option to extend survival and improve the quality of life for some patients. In this article, the authors review the selection criteria for lung transplant candidates, including when physicians should refer patients to lung transplant centers for evaluation and placement on the lung transplant waiting list.

We hope this supplement is a useful review of some of the challenges and advances in cardiovascular medicine and is beneficial to you and your clinical practice.

In cardiovascular medicine, advances in our understanding of disease processes, medical management, and interventional and surgical techniques have gone a long way toward improving the health of patients. But we face challenges and opportunities in how best to apply these discoveries to improve the quality of care we provide and do so without driving up costs or wasting resources.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease aims to illuminate some of the challenges and advances in the management of cardiac amyloidosis, coronary artery chronic total occlusion, venous thromboembolism, implantable device infection, and lung transplant. In so doing, my colleagues present insights into which advances will benefit which patients to improve quality and contain cost.

Cardiac amyloidosis, sometimes called stiff heart syndrome, is the most common restrictive cardiomyopathy. Amyloid deposits in the heart muscle can affect conduction of electrical signals leading to arrhythmias and heart block. Joseph P. Donnelly, MD, and Mazen Hanna, MD, present a comprehensive review of cardiac amyloidosis and share exciting advances in the detection and treatment of this condition and clues to identify patients who may be affected by this often overlooked condition.

Also in this supplement, Jaikirshan Khatri, MD, and colleagues review the use of percutaneous coronary intervention (PCI) for patients with coronary artery chronic total occlusion (CTO). Though CTO is often considered benign, the affected myocardium is ischemic and patients with significant ischemic burden may benefit clinically from CTO PCI. A technically demanding procedure, CTO PCI success rates are highly operator-dependent.

John R. Bartholomew, MD, presents information about the management of venous thromboembolism (VTE) including recent changes to treatment guidelines. Patients with VTE require immediate treatment with anticoagulation therapy. Recent changes to treatment guidelines now recommend direct oral anticoagulants for patients with VTE and no cancer. Direct oral anticoagulants are an important new option for patients and further study would be beneficial to strengthen the level of evidence regarding which anticoagulation therapy is best for which patients.

Cardiac implantable electronic devices (CIEDs) improve quality of life and longevity for increasing numbers of patients with cardiac disease. Cameron T. Lambert, MD, and Khaldoun G. Tarakji, MD, MPH, discuss the types of CIED infections that occur in about 1% of patients receiving a first CIED. Prompt diagnosis improves the success of antibiotic therapy, device removal, and resolution of the infection.

Finally, Kenneth R. McCurry, MD, and Marie M. Budev, DO, MPH, discuss lung transplant for patients with end-stage lung disease. Lung transplant may be an option to extend survival and improve the quality of life for some patients. In this article, the authors review the selection criteria for lung transplant candidates, including when physicians should refer patients to lung transplant centers for evaluation and placement on the lung transplant waiting list.

We hope this supplement is a useful review of some of the challenges and advances in cardiovascular medicine and is beneficial to you and your clinical practice.

WHAT IS AMYLOIDOSIS?

Amyloidosis is a protein deposition disease in which a specific precursor protein pathologically misfolds from its physiologic tertiary structure into a more linear shape dominated by beta-pleated sheets. The misfolded protein aggregates into oligomers, eventually forming insoluble amyloid fibrils that deposit extracellularly in tissues. Both the circulating oligomers, which are cytotoxic, and the fibrils, which cause distortion of the tissue architecture, lead to organ dysfunction. Amyloid fibrils are rigid, nonbranching structures, 7 to 10 nanometers in diameter, with a characteristic appearance on electron microscopy. Affinity for Congo red staining, which binds to the beta-pleated sheets, produces the pathognomonic “apple-green” birefringence when visualized under polarized light microscopy. Universal to all amyloid fibrils are chaperone proteins such as serum amyloid P (SAP) and glycosaminoglycans, as well as calcium. There are more than 30 different precursor proteins implicated in various amyloid diseases, arising as hereditary or nonhereditary, localized or systemic, with different organ involvement and prognosis.^1–3

TWO MAIN TYPES OF CARDIAC AMYLOIDOSIS

Light chain amyloidosis (AL)

AL, formerly called primary amyloidosis, is a clonal plasma cell disorder due to the overproduction and misfolding of antibody light chain fragments. It is a rare disease with about 3,000 new cases per year in the United States.⁵ The median age at diagnosis is 63, although it can present in patients in their 30s and 40s.^5,6 It is a systemic disease that often affects the heart, but it can affect several other organs, most commonly the kidneys, gastrointestinal (GI) tract, and nervous system.⁷

AL is a more aggressive disease than ATTR, with a median untreated survival of less than 6 months in patients who present with heart failure.⁸ Early diagnosis is crucial as mortality is high without prompt treatment.

Transthyretin amyloidosis (ATTR)

ATTR is due to misfolding of the liver-derived precursor protein transthyretin (TTR) (previously called prealbumin), either as an acquired wild-type variant (ATTRwt) or as a hereditary mutant variant (ATTRm). ATTRwt, known previously as senile CA, typically affects older males and presents as a late onset hypertrophic restrictive cardiomyopathy, often preceded by carpal tunnel syndrome or spinal stenosis or both. The ATTRm variant, caused by one of many different point mutations in the TTR gene, can manifest as a polyneuropathy, cardiomyopathy, or a mixed phenotype that varies according to the specific mutation.

While ATTR portends a better prognosis than AL, it is still a progressive disorder with significantly reduced survival and quality of life. The median survival of patients with the ATTRwt variant is about 4 years and for patients with the ATTRm variant, survival depends on the mutation.⁹ TTR is a protein tetramer composed of 4 identical 127-amino acid monomers noncovalently bound at a dimer-dimer interface (Figure 1). It is a transport protein for thyroxine and retinol binding protein. The dissociation of the tetramer is the rate-limiting step for amyloid fibrillogenesis. Differentiating the ATTRwt variant and the ATTRm variant is done by testing the TTR gene for a mutation.^1,3

How common is the ATTRwt variant? The ATTRwt variant is often an unrecognized cause of diastolic heart failure in the elderly, with up to 25% of patients 85 and older showing ATTRwt amyloid deposits on autopsy studies.¹⁰ A recent study showed that 13% of patients 60 and older hospitalized with heart failure with preserved ejection fraction had grade 2 to 3 uptake on ^99mtechnetium-pyrophosphate (^99mTcPYP) scintigraphy, which is consistent with ATTR-CA.¹¹ In 43 consecutive patients undergoing transcatheter aortic valve replacement, 11.6% were found to have significant uptake on ^99mTcPYP scan.¹² It is clear given the aging population that the ATTRwt variant will become the most common form of amyloidosis. It is much more common in white males, with a median age at diagnosis of 75.¹³ Carpal tunnel syndrome (almost always bilateral) and spinal stenosis are present in about 50% of patients diagnosed with ATTRwt-CA and often precede clinical presentation of heart failure by 5 to 15 years.^14–17

How common is the ATTRm variant? There are more than 100 point mutations in the TTR gene that lead to various familial TTR-related amyloid syndromes, either neuropathic (familial amyloid polyneuropathy [FAP]) or cardiomyopathic (familial amyloid cardiomyopathy).¹⁸ The most common mutation in the United States is V122I in which there is an isoleucine substitution for valine at the 122nd amino acid position. This mutation is seen in African Americans, 3% to 4% of whom are heterozygote carriers.¹⁹ Although the true penetrance is unknown, this mutation can lead to a late-onset restrictive cardiomyopathy with minimal neuropathy and is frequently misdiagnosed as hypertensive heart disease or diastolic heart failure. The median survival for V122I ATTRm-CA is about 2 years but likely depends on the stage at the time of diagnosis.²⁰ The second most common mutation in the United States, T60A, is seen in patients of Irish descent and causes a mixed neuropathy and cardiomyopathy.¹⁷

PATHOLOGY AND PATHOPHYSIOLOGY OF CA

The atria are universally involved with interatrial septal thickening, which can lead to poor atrial function and increased rates of atrial fibrillation (ATTR more so than AL).^21,29 The conduction system can be affected causing varying degrees of heart block, as well as bundle branch block (ATTR more so than AL).³⁰ The valves are usually thickened, often associated with mild to moderate regurgitation. Pericardial involvement can lead to small pericardial effusions (large effusions are rare), and coronary involvement (classically, small intramural vessels) can lead to ischemia and angina with normal epicardial coronaries (AL more so than ATTR).^31–33

Thickened left and right ventricular walls result in a nondilated ventricle that is stiff and poorly compliant, resulting in progressive diastolic filling abnormalities. Systolic dysfunction can be seen in severe and advanced disease. Importantly, ejection fraction measured by echocardiography is misleading in CA, as reduced end-diastolic volume produces a low stroke volume. For example, an ejection fraction of 50%, when starting at a significantly reduced end-diastolic volume (for example, 70 mL), leads to a significantly reduced stroke volume (35 mL) and, thus, cardiac output. This explains why patients with CA cannot usually tolerate reduced heart rates, as their cardiac output is dependent on heart rate.^34–36

Patients with CA typically exhibit heart failure with preserved ejection fraction (otherwise known as diastolic heart failure). Dyspnea on exertion is common; however, some patients can present with more right-sided heart failure symptoms such as lower-extremity edema and ascites. Fatigue and weakness are related to low cardiac output and often attributed to nonspecific symptoms of aging. Because of the thickened ventricles, patients can often be misdiagnosed as having HCM with or without obstruction.^7,34 The first manifestation of CA may be atrial fibrillation, most commonly in ATTRwt-CA, or cardioembolic stroke. Atrial fibrillation can be present for years before CA is considered. Bundle branch block and complete heart block (more common in ATTR-CA than AL-CA) may lead to pacemaker implantation.³⁰ Angina with normal coronaries can occur, and a rare presentation may be cardiogenic shock due to diffuse ischemia.^31–33 Elderly patients with CA can present with low-flow, low-gradient aortic stenosis.³⁷

DIAGNOSIS

ECG

As opposed to that seen in true left ventricular hypertrophy (LVH), which leads to increased voltage on ECG, amyloid infiltration of the myocardium leads to lower voltage. Thus, what is indicative of LVH on echocardiogram combined with low voltage on the ECG is a classic finding for CA. However, only about 50% of patients with AL-CA and about 30% of patients with ATTR-CA meet true low-voltage criteria (QRS amplitude less than 5 mm in limb leads or less than 10 mm in precordial leads).^30,38 Hence, the absence of low-voltage criteria does not exclude the diagnosis of CA. Approximately 10% of patients with CA confirmed by biopsy met ECG criteria for LVH.³⁸ The key point is to consider the overall degree of voltage on the ECG relative to the degree of LV thickening on the echocardiogram, recognizing that lower voltage than what would be expected may indicate possible infiltrative disease such as CA. The other main finding on the ECG in patients with CA is a pseudoinfarct pattern with Q waves in the early precordial leads mimicking a prior anteroseptal myocardial infarction.^38,39 This finding is seen in about 50% of patients (Figure 3).³⁹ Wide QRS complexes are more frequent in ATTR-CA and lower limb voltages are more frequent in AL-CA.³⁰

Echocardiogram

The echocardiographic finding of LVH in patients with CA is misleading in that the LV thickening is due to infiltrating amyloid fibrils and not to myocyte hypertrophy. That said, the terms LVH and LV thickening are used interchangeably when describing the echocardiographic phenotype. LV wall thickness greater than 12 mm (6 mm to 10 mm is normal) in the absence of hypertension should prompt suspicion for CA.³⁴ LV thickening most often appears symmetric; however, occasionally it may exhibit asymmetric septal hypertrophy, particularly in ATTRwt-CA. In some cases, there may be a smaller subset that can actually have dynamic LV outflow obstruction similar to that seen in hypertrophic obstructive cardiomyopathy.^22–24 An important echocardiographic clue that can differentiate CA from other diseases is thickening of both the LV and right ventricle (Figure 3). Septal wall thickness and LV mass index are greater in ATTR-CA compared with AL-CA.³⁰ On average, the LV septum is around 15 mm in AL-CA and around 18 mm in ATTRwt-CA.⁴⁰ Historically, the characteristic myocardial “granular sparking” or “speckling” pattern has low sensitivity and specificity.¹⁶ The left ventricle is not dilated; rather, the ventricular dimensions are usually smaller than normal. Although ejection fraction is usually preserved, cardiac output is low due to decreased ventricular volume.³⁷ Systolic dysfunction occurs late in the disease.¹⁶ Diastolic dysfunction is universal, with a mitral inflow pattern that can range from stage I (abnormal relaxation) in early disease to stage III (restrictive filling pattern) in more advanced disease. Septal and lateral tissue Doppler velocities are very low in amyloid heart disease.⁴¹ Another echocardiographic clue to diagnosis is thickening of the heart valves, which is not seen in hypertensive heart disease or hypertrophic cardiomyopathy. Biatrial dilation is common, and there can be thickening of the interatrial septum.

Laboratory testing

N-terminal pro-b-type natriuretic peptide (NT-proBNP) is universally elevated in CA and is typically higher in AL-CA than in ATTR-CA. Troponin T or troponin I or both may be chronically elevated in CA and likely signify small-vessel ischemia. In the appropriate clinical context of a thickened ventricle and heart failure, an elevated troponin value (outside of an acute coronary syndrome) should trigger suspicion for CA. Workup for a monoclonal protein process should always be done when considering CA to rule out AL. Serum and urine protein electrophoresis are insensitive tests to detect AL and should not be relied upon as a screening test. The serum free light chain (sFLC) assay, which measures free kappa and lambda light chain levels and reports the ratio, is a sensitive test that should be measured routinely along with immunofixation of the serum and urine. In AL, sFLC will reveal an abnormal kappa-lambda ratio. An abnormally low ratio (less than 0.26) suggests a monoclonal lambda light chain process, while an abnormally high ratio (greater than 1.65) suggests a monoclonal kappa light chain process. Immunofixation will reveal an M-protein. Because light chains are excreted by the kidney, the serum levels of both kappa and lambda will be elevated in renal dysfunction, but the ratio should remain normal.^{16,31,34,40,42–47}

Over the past decade, the ability to diagnose CA noninvasively has dramatically improved with strain imaging using 2D speckle tracking echocardiography, cardiac magnetic resonance imaging (MRI), and nuclear bone scintigraphy. These diagnostic tools have given clinicians options to pursue the diagnosis of CA without directly proceeding to endomyocardial biopsy.

Cardiac MRI. Cardiac MRI is useful for the diagnosis of CA (Figure 4B, 4C). Imaging after administration of gadolinium contrast shows a characteristic late gadolinium enhancement (LGE) pattern that is diffuse and subendocardial, and does not follow any particular coronary distribution.⁴⁹ LGE can also be seen in the right ventricle and the atrial walls, and can be transmural and patchy in ATTRwt-CA. This pattern is highly sensitive (93%) and specific (70%) for CA with an overall negative predictive accuracy of 84%.⁵⁰

One of the main limitations of cardiac MRI for the diagnosis of CA is the inability to give contrast in patients with reduced glomerular filtration rate. However, native T1-myocardial mapping techniques that do not require contrast show significantly increased native T1 times in CA and offer a promising alternative. Cardiac MRI parameters such as LGE, the difference in inversion time between the LV cavity and myocardium, native T1 mapping, and extracellular volume offer prognostic information. A greater than fivefold mortality increase is seen in CA patients with transmural LGE compared with those without LGE.^49,50

^99mTcPYP scintigraphy. ^99mTcPYP, a radiotracer used in bone scans, was initially used in cardiology to quantify myocardial infarction due to its ability to localize calcium.⁵¹ Its potential utility in CA came in 1982 when diffuse myocardial ^99mTcPYP uptake on cardiac radionucleotide imaging was noted in 10 patients with tissue-proven amyloidosis.⁵² Several subsequent studies reproduced and expanded upon this observation and revealed its diagnostic value, specifically showing that there is significant uptake in ATTR-CA and no to mild uptake in AL-CA. This offers a significant advantage over other noninvasive modalities in that it not only confirms the diagnosis of CA but differentiates ATTR-CA.¹⁶

^99mTcPYP myocardial radiotracer uptake is graded by the semiquantitative visual score of cardiac retention, where grade 0 = no cardiac uptake, grade 1 = mild uptake less than bone, grade 2 = moderate uptake equal to bone, and grade 3 = high uptake greater than bone (Figure 4D).⁴² Additionally, quantitative analysis of heart retention can be calculated drawing circular regions of interest over the heart and mirrored on the contralateral chest wall. A heart-to-contralateral ratio greater than 1.5 is consistent with the diagnosis of ATTR-CA.^53,54 In 2016, a multicenter study showed that grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy in the absence of evidence of a monoclonal gammopathy was diagnostic for ATTR-CA, providing a cost-effective and non-invasive technique with a specificity and positive predictive value of 100% (confidence interval, 99.0–100%).⁴²

Endomyocardial biopsy, right heart catheterization, and fat biopsy

Endomyocardial biopsy is essentially 100% sensitive for the diagnosis of CA.²⁵ The main risk of pursuing endomyocardial biopsy is about a 1% risk of right ventricular perforation leading to cardiac tamponade.⁵⁵ The other limitation to this approach is that not all centers are equipped to perform this procedure. Birefringence under polarized light microscopy is histopathologically diagnostic of CA; however, further subtyping by the pathologist to determine if it is AL or ATTR is absolutely crucial. Subtyping can be performed by immunohistochemistry with caution taken for misinterpretation. If there is any question of accuracy, the specimen should be sent for laser microdissection and mass spectroscopy for accurate identification of the precursor protein type (some centers routinely perform mass spectroscopy on all myocardial specimens).^16,31

Right heart catheterization is nonspecific and shows restrictive hemodynamics. The right atrial waveform shows rapid x and y descents and the right ventriclular tracing may show a dip-and-plateau pattern typical of restrictive cardiomyopathy. Cardiac output can be preserved but more commonly is low.^16,31

Fat pad biopsy is 60% to 80% sensitive in AL, 65% to 85% sensitive in ATTRm, and only 14% sensitive in ATTRwt, with the accuracy dependent on the operator, pathologist, and how much tissue is removed (fat pad aspirate vs biopsy specimen).^56–58 Fat pad biopsy has diagnostic limitations, and a negative fat pad biopsy does not rule out amyloidosis.

DIAGNOSTIC ALGORITHM FOR CARDIAC AMYLOIDOSIS

In conjunction with laboratory tests, ^99mTcPYP scan of the heart can be ordered to investigate the possibility of ATTR-CA. Grade 2 to 3 myocardial uptake in the absence of a monoclonal plasma cell process is consistent with the diagnosis of ATTR-CA. Grade 0 or 1 myocardial uptake on ^99mTcPYP scan with an abnormal sFLC ratio or positive M protein on immunofixation suggests AL-CA and a bone marrow biopsy should be performed. If the patient has an abnormal sFLC ratio and grade 2 to 3 uptake on ^99mTcPYP scan, the diagnosis of ATTR-CA with unrelated monoclonal gammopathy of undetermined significance should be considered. However, this would need to be reconciled by pursuing endomyocardial biopsy and accurate tissue typing. If the ^99mTcPYP scan is negative, and the sFLC ratio is normal, and immunofixation is negative, a diagnosis of CA is very unlikely.^{16,31,40,42–47}

If the diagnosis of ATTR-CA is made, genetic testing can determine the presence or absence of a mutation to differentiate ATTRm or ATTRwt, respectively. If the diagnosis of AL-CA is suggested, a bone marrow biopsy is necessary to identify and quantify the plasma cell clone.^{16,31,40,42–47}

TREATMENT

Management of heart failure in cardiac amyloidosis

The main treatment of heart failure revolves around sodium restriction and diuretics to relieve congestion. This can prove challenging in many patients due to the narrow window between too high or too low filling pressures. A combination of loop diuretics and an aldosterone antagonist is most effective.^31,34,44,45 Torsemide is preferred over furosemide due to its superior bioavailability and longer duration of action, particularly since these patients have issues with gut edema and GI absorption. Due to dependence of the cardiac output on heart rate and the tendency for orthostatic hypotension, traditional neurohormonal antagonists including beta blockers and angiotensin-converting enzyme inhibitors are neither effective nor well tolerated.⁶⁰ However, in patients with atrial fibrillation, beta blockers may need to be used for rate control. Nondihydropyridine calcium channel blockers bind avidly to amyloid fibrils and are contraindicated due to risk of profound hypotension and syncope.^{30,31,34,44,45} Digoxin is usually avoided in CA due to concerns of increased risk of toxicity; however, it may be used with caution for rate control in atrial fibrillation given its lack of negative inotropy.⁶¹ Maintenance of normal sinus rhythm is preferable due to the importance of atrial contribution to cardiac output.

Anticoagulation in patients with atrial fibrillation and even in patients with normal sinus rhythm and poor atrial function is important due to the high risk of thromboembolic complications.⁶² Pacemakers are indicated for heart block or symptomatic bradycardia.⁶³ The role of intracardiac defibrillators is controversial, but may be warranted in selected patients with AL-CA.^64,65

Risk stratification and prognostication for AL. The most important determinant of clinical outcome in AL is the extent of cardiac involvement, as congestive heart failure and sudden cardiac death are the most common causes of death. The level of NT-proBNP and the level of either troponin T or troponin I have strong prognostic value and form the basis for the staging system in AL. Various iterations have evolved over the years, but the most widely adopted is the 4-stage system developed and validated by Mayo Clinic. This system uses a cutoff value at diagnosis for NT-proBNP greater than 1,800 ng/mL, troponin T greater than 0.025 μg/L, and the difference between kappa and lambda free light chain levels greater than 180 mg/L. Stage level increases by the number of cutoff values exceeded, with stage IV carrying a median survival of 6 months.⁴⁷ Additionally, the troponin T level can help risk-stratify patients being considered for autologous stem cell transplant. In a retrospective study, troponin T greater than 0.06 μg/L was associated with increased mortality following stem cell transplant.⁶⁶ Ultimately, prognosis in AL-CA is related to the hematologic response to chemotherapy.

Current treatment strategies for AL. The survival of patients with AL has improved over the years with the advent of more effective chemotherapeutic regimens that kill the underlying plasma cell clone producing the unstable light chains. The goal of treatment is to achieve a complete hematologic response with normalization of the affected light chain and sFLC ratio as well as elimination of the M protein on immunofixation.

The development of the proteasome inhibitor bortezomib has improved efficacy and survival in AL causing a faster and more complete hematologic response than prior regimens.^43,67,68

The most commonly used first-line treatment consists of a 3-drug combination with the alkylating agent cyclophosphamide, the proteasome inhibitor bortezomib, and the steroid dexamethasone, which is given weekly.⁴³ A retrospective study by Sperry et al⁸ showed that patients receiving an alkylating agent, bortezomib, and a steroid had the best outcomes compared with other regimens.

For patients with refractory or relapsed disease, the CD38 monoclonal antibody daratumumab can be used if patients meet myeloma criteria and has been found to be effective thus far.^68,69 Newer proteasome inhibitors such as ixazomib, which is taken orally, are being studied in alternative combination regimens.⁷⁰ High-dose chemotherapy with autologous stem cell transplant can be considered in patients with an acceptable cardiac risk profile and may offer more complete and durable remission than chemotherapy, although this is controversial.^43,71

The cardiologist’s role in AL-CA. The hematologist directs the chemotherapy for AL but works closely with the cardiologist when there is cardiac involvement. The main role of the cardiologist is to manage volume status with diuretics, monitor for arrhythmia, and evaluate the cardiac response to treatment.^43,71 Cardiac response was traditionally measured by echocardiographic changes of wall thickness, diastolic function, and ejection fraction, as well as changes in New York Heart Association (NYHA) functional class.⁶⁷ However, it is uncommon to see reduction in LV wall thickness or significant improvement in ejection fraction and if it does occur, it is a slow process that usually takes more than 1 year. With the advent of longitudinal myocardial strain imaging, improvements in strain can be seen despite the lack of structural changes on echocardiogram.⁷² In 2012, consensus criteria defined a cardiac response as a greater than 30% reduction in NT-proBNP.⁷³ Misfolded light chains are toxic to cardiomyocytes by causing increased oxidative stress and impairing contractility. Thus, reduction in light chain levels can lead to clinical improvement and significant reductions in NT-proBNP without changing amyloid fibril burden in the heart.

Heart transplant for patients with AL-CA. For patients who have a good hematologic response to initial chemotherapy but have limited predicted survival due to severe heart failure, heart transplant followed by autologous stem cell transplant, is a treatment strategy that can be considered. The patient must have clinically isolated severe cardiac disease, minimal amyloid burden in other organs, and a plasma cell clone that is responsive to therapy. Initial reports of heart transplant showed poor survival rates due to recurrent amyloid in the transplanted heart and progressive amyloid deposition in other organs. However, due to improved anti-plasma-cell-directed therapy and refinement in patient selection, outcomes have improved. Contemporary series of patients undergoing heart transplant followed by stem cell transplant showed that outcomes are almost comparable to heart transplant for other indications, with a 5-year survival rate of approximately 65%.⁷⁴

Future therapies for AL. There is an AL amyloid-directed monoclonal antibody designed to remove amyloid fibrils from affected organs and is currently undergoing clinical trials. NEOD001, a humanized murine monoclonal antibody that targets an epitope exposed during light chain misfolding, binds to the light chain amyloid fibril and signals an immune response to clear the deposits. This agent has completed phase 1 and 2 clinical trials of 27 patients previously treated with at least 1 plasma cell-directed therapy. It showed good tolerability and achieved both renal and cardiac responses in most patients.⁷⁵

A phase 2b clinical trial (NCT02632786) of patients with AL with a previous hematologic response to treatment and persistent heart dysfunction is underway and expected to be completed in January 2018. A phase 3 clinical trial (NCT02312206) of NEOD001 as an adjunct to chemotherapy is also ongoing and results are expected in February 2019.

Liver transplant for ATTRm amyloidosis for the V30M mutation that causes FAP was first described in 1990, but it has not been well validated in other mutations and is not a solution for ATTRwt.⁷⁶ Significant progress has been made over the past 2 decades in the understanding of the pathophysiologyy of ATTR, paving the way for promising advancements in pharmacotherapy. Presently, there are 3 classes of pharmacologic agents, grouped by the point of disease process each strategy targets:

• Block TTR synthesis at the translational level in hepatocytes
• Stabilize the TTR tetramer to inhibit the rate-determining step of amyloidogenesis
• Disrupt and clear the ATTR amyloid fibril.⁷⁷

Block TTR synthesis. TTR messenger RNA (mRNA) can be targeted by “silencers” preventing translation, thereby reducing the production TTR protein by hepatocytes. The resultant sustained reduction of plasma TTR should decrease or halt amyloid deposition by making less TTR available to dissociate and deposit in the heart and nerves. There are 2 approaches to silencing TTR mRNA translation: small interfering RNA (siRNA) and antisense oligonucleotide (ASO).⁷⁷

An siRNA, packaged in a lipid nanoparticle to ensure delivery to the liver, has been designed to bind to a conserved region of TTR mRNA, degrading the mRNA and reducing TTR protein expression. One siRNA, patisiran, completed the phase 3 APOLLO clinical trial (NCT01960348) in August 2017. It is an intravenous medication that requires premedication. The APOLLO trial studied patients with neuropathic variants of ATTRm, with a primary end point of neuropathy progression over 18 months. Patisrian met the primary end point and will likely be approved by the US Food and Drug Administration (FDA) by the third quarter of 2018. Given its target of a conserved 3’ untranslated region of TTR mRNA, patisiran should theoretically yield benefits not just in FAP but to both ATTRm-CA and ATTRwt-CA.^68,77

ASOs are single-stranded oligonucleotides, typically 20 nucleotides in length, that bind to mRNA and elicit enzymatic mRNA degradation and reduced protein expression. Inotersen (IONIS-TTR_Rx) is an ASO drug that targets a conserved region of TTR mRNA. Inotersen is administered by weekly subcutaneous injection. A phase 2/3 clinical trial (NCT01737398) completed in October 2017 studied the drug's efficacy in treating FAP, with a primary end point of neuropathy progression over 65 weeks. It met the primary end point and a subset of patients actually improved. Like patisiran, inotersen is likely to be approved by the FDA for a neuropathy indication by the third quarter of 2018 and may benefit patients with ATTRm-CA and ATTRwt-CA. More studies are needed in the ATTR cardiac population.^68,77

Stabilize the TTR tetramer. The TTR tetramer has 2 thyroxine binding pockets that stabilize the structure when bound preventing dissociation. Dissociation of the tetramer, the rate limiting step for ATTR fibrillogenesis, can be reduced using pharmacologic agents that bind to the thyroxine binding pockets. Both new and repurposed agents have been found to stabilize the TTR tetramer, including diflunisal, tafamidis, tolcapone, and AG10.^68,77

Diflunisal (Dolobid) is a nonacetylated salicylate nonsteroidal anti-inflammatory drug used for over 3 decades to treat arthritis and musculoskeletal pain. Unrelated to its anti-inflammatory properties, it interacts with TTR’s thyroxine binding pocket to increase the stability of the tetramer. A 2013 randomized, placebo-controlled, international multicenter trial of 130 patients with FAP demonstrated a statistically significant slowing of polyneuropathy progression; however, 67 patients (diflunisal n = 27, placebo n = 40) did not complete the study.⁷⁸ A small study revealed diflunisal to be reasonably well-tolerated in ATTR-CA, and to date it is the only readily available pharmacotherapy for ATTR supported by a randomized, placebo-controlled trial.^79,80 Diflunisal may be considered for off-label use in patients with ATTR-CA with relatively preserved kidney function and no increased bleeding risk, taken under the supervision of a cardiologist who will monitor for fluid retention and changes in renal function.⁷⁷

Tafamidis (Vyndaqel), like diflunisal, interacts with TTR’s thyroxine binding pocket and increases tetrameric stability. A phase 2 open-label clinical trial studied the efficacy and tolerance of tafamidis in 31 patients with ATTRwt and NYHA functional class 1 and 2 followed for 1 year. Twenty-eight patients completed the study and 2 patients died. TTR stabilization at 6 weeks was achieved in 30 of 31 patients (96.8%), and success at 1 year in 25 of 28 patients (89.3%). No clinical progression occurred in 16 of 31 patients (51.5%), and tafamidis was generally well-tolerated, with diarrhea the most common side effect in 7 of 31 patients (22.6% ).^81,82

A phase 3 clinical trial (NCT01994889) is studying tafamidis vs placebo in patients with ATTRm-CA or ATTRwt-CA (excluding NYHA functional class 4) with the primary outcome measure of all-cause mortality and heart failure-related hospitalizations over 30 months. This is a large trial that enrolled 446 patients and data collection is expected to be completed in February 2018.

Tolcapone, approved by the FDA for Parkinson disease, has been found to be a potent TTR stabilizer by binding both thyroxine binding pockets of the TTR tetramer simultaneously. However, tolcapone has an FDA “black box” warning due to the risk of potentially fatal acute fulminant liver failure and is not currently used in ATTR therapy.⁶⁸ Nonetheless, it will likely undergo further study for ATTR.

Recruiting is underway for a phase 1 clinical trial of AG10, a potent selective TTR stabilizer (NCT03294707).⁶⁸

Disruption and clearance of the ATTR amyloid fibril. Even though treatment directed at blocking TTR synthesis or stabilizing the tetramer may be effective at preventing further deposition, the residual amyloid deposits persist and continue to affect organ function. With that need in mind, several agents that disrupt the amyloid formation process further downstream have been evaluated at a basic science level and in a few small nonrandomized open-label studies.⁷⁷

Doxycycline is a tetracycline antibiotic with demonstrated effectiveness in disrupting mature amyloid fibrils in mouse models.⁸³ Tauroursodeoxycholic acid  is a bile acid with the ability to disrupt prefibrillar amyloid components. This combination has been studied in patients with ATTR-CA in 2 small open-label trials, with only 1 having results published. There was no progression in NT-proBNP or wall thickness in a cohort of 7 patients who completed 12 months of treatment.⁸⁴ These data are nonrandomized and hypothesis-generating, as adequate studies would need to be performed to evaluate this hypothesis further. Because there are currently no FDA-approved therapies for ATTR, patients may be offered this combination fully informed that the data are limited. (Note: ursodiol is substituted for tauroursodeoxycholic acid, which is not available in the United States.)⁶⁸

Green tea extract contains the polyphenol epigallocatechin-3-gallate, which has shown the ability for fibril disruption as well as TTR stabilization, importantly using a binding site separate from the thyroxine binding pocket (utilized in diflunisal and tafamidis). A small open-label study of 19 patients with ATTR-CA of whom 14 took green tea extract for 1 year reported a reduction in intraventricular septal wall  thickness at 1 year, and in 9 patients a reduction of 12.5% in LV mass measured by cardiac MRI.⁸⁵

Curcumin, the active ingredient in the household spice turmeric, has displayed in vitro promise as a TTR stabilizer by binding to the thyroxine binding pocket, and as an amyloid fibril disruptor by increasing macrophage degradation activity. Although there have only been preliminary animal studies, this supplement may be promising for further study in humans with ATTR-CA.⁶⁸

PRX004 is a synthetic antibody designed to bind to non-native misfolded forms of TTR with the goal of potentially preventing deposition and promoting clearance of TTR aggregates.⁸⁶ A phase 1 open-label escalation trial (NCT03336580) in 36 patients with ATTRm is planned and, hopefully, will pave the way for further study.

Heart transplant for patients with ATTR-CA. Patients with ATTRwt-CA who are young enough to undergo heart transplant have displayed favorable outcomes given that it causes clinically isolated heart disease and is an indolent process that should not affect the transplanted heart over the average life span of the allograft. Patients with the ATTRm mutation V122I have been treated with heart transplant alone, with the thought process that again, due to the indolent nature of amyloid deposition, concomitant liver transplant may not be needed.⁷⁴ Thus far, 6 patients with this mutation have undergone successful transplant at our institution with heart alone, 1 of whom is 9 years posttransplant without any recurrent amyloid in the allograft. Patients with the T60A mutation that causes both polyneuropathy and cardiomyopathy require combined heart and liver transplant.⁷⁴

Are there other therapies being studied to clear amyloid deposits and reverse organ dysfunction?

Extracellular deposits of amyloid fibrils, regardless of precursor protein, contain common elements such as calcium, glycosaminoglycans, and an SAP component. SAP stabilizes amyloid fibrils and makes them resistant to degradation. A monoclonal immunoglobulin G1 anti-SAP antibody has been designed to target the ubiquitous SAP component, signaling an immune response that leads to macrophage mediated clearance of amyloid fibrils, regardless of the type. Treatment with this approach was studied in a pilot trial of 16 patients mostly with AL, and within a 6-week period some of the patients had dramatic reversal of liver amyloid deposition.² This has paved the way for a phase 2 open-label trial to be performed in patients with AL-CA and ATTR-CA (NCT03044353) and plans for a randomized phase 3 trial in CA are in discussion. There is optimism that this therapy may achieve the holy grail of removing amyloid rather than just preventing further deposition.

The diagnosis of CA requires a high index of suspicion. The diagnostic tools have improved due to the availability of modern imaging techniques, and the advent of measuring the sFLC assay along with immunofixation of the serum and urine. The prognosis for patients with AL-CA used to be dismal, with very poor survival rates. The current treatment strategies that include proteasome inhibitors have significantly improved survival, emphasizing the importance of early diagnosis and prompt initiation of therapy. Monoclonal antibodies against plasma cells (daratumumab) and light chain amyloid deposits (NEOD001) have the potential to further improve outcomes. The diagnosis of ATTR-CA used to be a futile academic pursuit given the lack of available therapies. However, there are several new FDA-approved agents on the horizon, including TTR gene silencers and stabilizers. CA is no longer considered to be rare and hopeless. Rather, it is more common than previously recognized and even more treatable.

WHAT IS AMYLOIDOSIS?

Amyloidosis is a protein deposition disease in which a specific precursor protein pathologically misfolds from its physiologic tertiary structure into a more linear shape dominated by beta-pleated sheets. The misfolded protein aggregates into oligomers, eventually forming insoluble amyloid fibrils that deposit extracellularly in tissues. Both the circulating oligomers, which are cytotoxic, and the fibrils, which cause distortion of the tissue architecture, lead to organ dysfunction. Amyloid fibrils are rigid, nonbranching structures, 7 to 10 nanometers in diameter, with a characteristic appearance on electron microscopy. Affinity for Congo red staining, which binds to the beta-pleated sheets, produces the pathognomonic “apple-green” birefringence when visualized under polarized light microscopy. Universal to all amyloid fibrils are chaperone proteins such as serum amyloid P (SAP) and glycosaminoglycans, as well as calcium. There are more than 30 different precursor proteins implicated in various amyloid diseases, arising as hereditary or nonhereditary, localized or systemic, with different organ involvement and prognosis.^1–3

TWO MAIN TYPES OF CARDIAC AMYLOIDOSIS

Light chain amyloidosis (AL)

AL, formerly called primary amyloidosis, is a clonal plasma cell disorder due to the overproduction and misfolding of antibody light chain fragments. It is a rare disease with about 3,000 new cases per year in the United States.⁵ The median age at diagnosis is 63, although it can present in patients in their 30s and 40s.^5,6 It is a systemic disease that often affects the heart, but it can affect several other organs, most commonly the kidneys, gastrointestinal (GI) tract, and nervous system.⁷

AL is a more aggressive disease than ATTR, with a median untreated survival of less than 6 months in patients who present with heart failure.⁸ Early diagnosis is crucial as mortality is high without prompt treatment.

Transthyretin amyloidosis (ATTR)

ATTR is due to misfolding of the liver-derived precursor protein transthyretin (TTR) (previously called prealbumin), either as an acquired wild-type variant (ATTRwt) or as a hereditary mutant variant (ATTRm). ATTRwt, known previously as senile CA, typically affects older males and presents as a late onset hypertrophic restrictive cardiomyopathy, often preceded by carpal tunnel syndrome or spinal stenosis or both. The ATTRm variant, caused by one of many different point mutations in the TTR gene, can manifest as a polyneuropathy, cardiomyopathy, or a mixed phenotype that varies according to the specific mutation.

While ATTR portends a better prognosis than AL, it is still a progressive disorder with significantly reduced survival and quality of life. The median survival of patients with the ATTRwt variant is about 4 years and for patients with the ATTRm variant, survival depends on the mutation.⁹ TTR is a protein tetramer composed of 4 identical 127-amino acid monomers noncovalently bound at a dimer-dimer interface (Figure 1). It is a transport protein for thyroxine and retinol binding protein. The dissociation of the tetramer is the rate-limiting step for amyloid fibrillogenesis. Differentiating the ATTRwt variant and the ATTRm variant is done by testing the TTR gene for a mutation.^1,3

How common is the ATTRwt variant? The ATTRwt variant is often an unrecognized cause of diastolic heart failure in the elderly, with up to 25% of patients 85 and older showing ATTRwt amyloid deposits on autopsy studies.¹⁰ A recent study showed that 13% of patients 60 and older hospitalized with heart failure with preserved ejection fraction had grade 2 to 3 uptake on ^99mtechnetium-pyrophosphate (^99mTcPYP) scintigraphy, which is consistent with ATTR-CA.¹¹ In 43 consecutive patients undergoing transcatheter aortic valve replacement, 11.6% were found to have significant uptake on ^99mTcPYP scan.¹² It is clear given the aging population that the ATTRwt variant will become the most common form of amyloidosis. It is much more common in white males, with a median age at diagnosis of 75.¹³ Carpal tunnel syndrome (almost always bilateral) and spinal stenosis are present in about 50% of patients diagnosed with ATTRwt-CA and often precede clinical presentation of heart failure by 5 to 15 years.^14–17

How common is the ATTRm variant? There are more than 100 point mutations in the TTR gene that lead to various familial TTR-related amyloid syndromes, either neuropathic (familial amyloid polyneuropathy [FAP]) or cardiomyopathic (familial amyloid cardiomyopathy).¹⁸ The most common mutation in the United States is V122I in which there is an isoleucine substitution for valine at the 122nd amino acid position. This mutation is seen in African Americans, 3% to 4% of whom are heterozygote carriers.¹⁹ Although the true penetrance is unknown, this mutation can lead to a late-onset restrictive cardiomyopathy with minimal neuropathy and is frequently misdiagnosed as hypertensive heart disease or diastolic heart failure. The median survival for V122I ATTRm-CA is about 2 years but likely depends on the stage at the time of diagnosis.²⁰ The second most common mutation in the United States, T60A, is seen in patients of Irish descent and causes a mixed neuropathy and cardiomyopathy.¹⁷

PATHOLOGY AND PATHOPHYSIOLOGY OF CA

The atria are universally involved with interatrial septal thickening, which can lead to poor atrial function and increased rates of atrial fibrillation (ATTR more so than AL).^21,29 The conduction system can be affected causing varying degrees of heart block, as well as bundle branch block (ATTR more so than AL).³⁰ The valves are usually thickened, often associated with mild to moderate regurgitation. Pericardial involvement can lead to small pericardial effusions (large effusions are rare), and coronary involvement (classically, small intramural vessels) can lead to ischemia and angina with normal epicardial coronaries (AL more so than ATTR).^31–33

Thickened left and right ventricular walls result in a nondilated ventricle that is stiff and poorly compliant, resulting in progressive diastolic filling abnormalities. Systolic dysfunction can be seen in severe and advanced disease. Importantly, ejection fraction measured by echocardiography is misleading in CA, as reduced end-diastolic volume produces a low stroke volume. For example, an ejection fraction of 50%, when starting at a significantly reduced end-diastolic volume (for example, 70 mL), leads to a significantly reduced stroke volume (35 mL) and, thus, cardiac output. This explains why patients with CA cannot usually tolerate reduced heart rates, as their cardiac output is dependent on heart rate.^34–36

Patients with CA typically exhibit heart failure with preserved ejection fraction (otherwise known as diastolic heart failure). Dyspnea on exertion is common; however, some patients can present with more right-sided heart failure symptoms such as lower-extremity edema and ascites. Fatigue and weakness are related to low cardiac output and often attributed to nonspecific symptoms of aging. Because of the thickened ventricles, patients can often be misdiagnosed as having HCM with or without obstruction.^7,34 The first manifestation of CA may be atrial fibrillation, most commonly in ATTRwt-CA, or cardioembolic stroke. Atrial fibrillation can be present for years before CA is considered. Bundle branch block and complete heart block (more common in ATTR-CA than AL-CA) may lead to pacemaker implantation.³⁰ Angina with normal coronaries can occur, and a rare presentation may be cardiogenic shock due to diffuse ischemia.^31–33 Elderly patients with CA can present with low-flow, low-gradient aortic stenosis.³⁷

DIAGNOSIS

ECG

As opposed to that seen in true left ventricular hypertrophy (LVH), which leads to increased voltage on ECG, amyloid infiltration of the myocardium leads to lower voltage. Thus, what is indicative of LVH on echocardiogram combined with low voltage on the ECG is a classic finding for CA. However, only about 50% of patients with AL-CA and about 30% of patients with ATTR-CA meet true low-voltage criteria (QRS amplitude less than 5 mm in limb leads or less than 10 mm in precordial leads).^30,38 Hence, the absence of low-voltage criteria does not exclude the diagnosis of CA. Approximately 10% of patients with CA confirmed by biopsy met ECG criteria for LVH.³⁸ The key point is to consider the overall degree of voltage on the ECG relative to the degree of LV thickening on the echocardiogram, recognizing that lower voltage than what would be expected may indicate possible infiltrative disease such as CA. The other main finding on the ECG in patients with CA is a pseudoinfarct pattern with Q waves in the early precordial leads mimicking a prior anteroseptal myocardial infarction.^38,39 This finding is seen in about 50% of patients (Figure 3).³⁹ Wide QRS complexes are more frequent in ATTR-CA and lower limb voltages are more frequent in AL-CA.³⁰

Echocardiogram

The echocardiographic finding of LVH in patients with CA is misleading in that the LV thickening is due to infiltrating amyloid fibrils and not to myocyte hypertrophy. That said, the terms LVH and LV thickening are used interchangeably when describing the echocardiographic phenotype. LV wall thickness greater than 12 mm (6 mm to 10 mm is normal) in the absence of hypertension should prompt suspicion for CA.³⁴ LV thickening most often appears symmetric; however, occasionally it may exhibit asymmetric septal hypertrophy, particularly in ATTRwt-CA. In some cases, there may be a smaller subset that can actually have dynamic LV outflow obstruction similar to that seen in hypertrophic obstructive cardiomyopathy.^22–24 An important echocardiographic clue that can differentiate CA from other diseases is thickening of both the LV and right ventricle (Figure 3). Septal wall thickness and LV mass index are greater in ATTR-CA compared with AL-CA.³⁰ On average, the LV septum is around 15 mm in AL-CA and around 18 mm in ATTRwt-CA.⁴⁰ Historically, the characteristic myocardial “granular sparking” or “speckling” pattern has low sensitivity and specificity.¹⁶ The left ventricle is not dilated; rather, the ventricular dimensions are usually smaller than normal. Although ejection fraction is usually preserved, cardiac output is low due to decreased ventricular volume.³⁷ Systolic dysfunction occurs late in the disease.¹⁶ Diastolic dysfunction is universal, with a mitral inflow pattern that can range from stage I (abnormal relaxation) in early disease to stage III (restrictive filling pattern) in more advanced disease. Septal and lateral tissue Doppler velocities are very low in amyloid heart disease.⁴¹ Another echocardiographic clue to diagnosis is thickening of the heart valves, which is not seen in hypertensive heart disease or hypertrophic cardiomyopathy. Biatrial dilation is common, and there can be thickening of the interatrial septum.

Laboratory testing

N-terminal pro-b-type natriuretic peptide (NT-proBNP) is universally elevated in CA and is typically higher in AL-CA than in ATTR-CA. Troponin T or troponin I or both may be chronically elevated in CA and likely signify small-vessel ischemia. In the appropriate clinical context of a thickened ventricle and heart failure, an elevated troponin value (outside of an acute coronary syndrome) should trigger suspicion for CA. Workup for a monoclonal protein process should always be done when considering CA to rule out AL. Serum and urine protein electrophoresis are insensitive tests to detect AL and should not be relied upon as a screening test. The serum free light chain (sFLC) assay, which measures free kappa and lambda light chain levels and reports the ratio, is a sensitive test that should be measured routinely along with immunofixation of the serum and urine. In AL, sFLC will reveal an abnormal kappa-lambda ratio. An abnormally low ratio (less than 0.26) suggests a monoclonal lambda light chain process, while an abnormally high ratio (greater than 1.65) suggests a monoclonal kappa light chain process. Immunofixation will reveal an M-protein. Because light chains are excreted by the kidney, the serum levels of both kappa and lambda will be elevated in renal dysfunction, but the ratio should remain normal.^{16,31,34,40,42–47}

Over the past decade, the ability to diagnose CA noninvasively has dramatically improved with strain imaging using 2D speckle tracking echocardiography, cardiac magnetic resonance imaging (MRI), and nuclear bone scintigraphy. These diagnostic tools have given clinicians options to pursue the diagnosis of CA without directly proceeding to endomyocardial biopsy.

Cardiac MRI. Cardiac MRI is useful for the diagnosis of CA (Figure 4B, 4C). Imaging after administration of gadolinium contrast shows a characteristic late gadolinium enhancement (LGE) pattern that is diffuse and subendocardial, and does not follow any particular coronary distribution.⁴⁹ LGE can also be seen in the right ventricle and the atrial walls, and can be transmural and patchy in ATTRwt-CA. This pattern is highly sensitive (93%) and specific (70%) for CA with an overall negative predictive accuracy of 84%.⁵⁰

One of the main limitations of cardiac MRI for the diagnosis of CA is the inability to give contrast in patients with reduced glomerular filtration rate. However, native T1-myocardial mapping techniques that do not require contrast show significantly increased native T1 times in CA and offer a promising alternative. Cardiac MRI parameters such as LGE, the difference in inversion time between the LV cavity and myocardium, native T1 mapping, and extracellular volume offer prognostic information. A greater than fivefold mortality increase is seen in CA patients with transmural LGE compared with those without LGE.^49,50

^99mTcPYP scintigraphy. ^99mTcPYP, a radiotracer used in bone scans, was initially used in cardiology to quantify myocardial infarction due to its ability to localize calcium.⁵¹ Its potential utility in CA came in 1982 when diffuse myocardial ^99mTcPYP uptake on cardiac radionucleotide imaging was noted in 10 patients with tissue-proven amyloidosis.⁵² Several subsequent studies reproduced and expanded upon this observation and revealed its diagnostic value, specifically showing that there is significant uptake in ATTR-CA and no to mild uptake in AL-CA. This offers a significant advantage over other noninvasive modalities in that it not only confirms the diagnosis of CA but differentiates ATTR-CA.¹⁶

^99mTcPYP myocardial radiotracer uptake is graded by the semiquantitative visual score of cardiac retention, where grade 0 = no cardiac uptake, grade 1 = mild uptake less than bone, grade 2 = moderate uptake equal to bone, and grade 3 = high uptake greater than bone (Figure 4D).⁴² Additionally, quantitative analysis of heart retention can be calculated drawing circular regions of interest over the heart and mirrored on the contralateral chest wall. A heart-to-contralateral ratio greater than 1.5 is consistent with the diagnosis of ATTR-CA.^53,54 In 2016, a multicenter study showed that grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy in the absence of evidence of a monoclonal gammopathy was diagnostic for ATTR-CA, providing a cost-effective and non-invasive technique with a specificity and positive predictive value of 100% (confidence interval, 99.0–100%).⁴²

Endomyocardial biopsy, right heart catheterization, and fat biopsy

Endomyocardial biopsy is essentially 100% sensitive for the diagnosis of CA.²⁵ The main risk of pursuing endomyocardial biopsy is about a 1% risk of right ventricular perforation leading to cardiac tamponade.⁵⁵ The other limitation to this approach is that not all centers are equipped to perform this procedure. Birefringence under polarized light microscopy is histopathologically diagnostic of CA; however, further subtyping by the pathologist to determine if it is AL or ATTR is absolutely crucial. Subtyping can be performed by immunohistochemistry with caution taken for misinterpretation. If there is any question of accuracy, the specimen should be sent for laser microdissection and mass spectroscopy for accurate identification of the precursor protein type (some centers routinely perform mass spectroscopy on all myocardial specimens).^16,31

Right heart catheterization is nonspecific and shows restrictive hemodynamics. The right atrial waveform shows rapid x and y descents and the right ventriclular tracing may show a dip-and-plateau pattern typical of restrictive cardiomyopathy. Cardiac output can be preserved but more commonly is low.^16,31

Fat pad biopsy is 60% to 80% sensitive in AL, 65% to 85% sensitive in ATTRm, and only 14% sensitive in ATTRwt, with the accuracy dependent on the operator, pathologist, and how much tissue is removed (fat pad aspirate vs biopsy specimen).^56–58 Fat pad biopsy has diagnostic limitations, and a negative fat pad biopsy does not rule out amyloidosis.

DIAGNOSTIC ALGORITHM FOR CARDIAC AMYLOIDOSIS

In conjunction with laboratory tests, ^99mTcPYP scan of the heart can be ordered to investigate the possibility of ATTR-CA. Grade 2 to 3 myocardial uptake in the absence of a monoclonal plasma cell process is consistent with the diagnosis of ATTR-CA. Grade 0 or 1 myocardial uptake on ^99mTcPYP scan with an abnormal sFLC ratio or positive M protein on immunofixation suggests AL-CA and a bone marrow biopsy should be performed. If the patient has an abnormal sFLC ratio and grade 2 to 3 uptake on ^99mTcPYP scan, the diagnosis of ATTR-CA with unrelated monoclonal gammopathy of undetermined significance should be considered. However, this would need to be reconciled by pursuing endomyocardial biopsy and accurate tissue typing. If the ^99mTcPYP scan is negative, and the sFLC ratio is normal, and immunofixation is negative, a diagnosis of CA is very unlikely.^{16,31,40,42–47}

If the diagnosis of ATTR-CA is made, genetic testing can determine the presence or absence of a mutation to differentiate ATTRm or ATTRwt, respectively. If the diagnosis of AL-CA is suggested, a bone marrow biopsy is necessary to identify and quantify the plasma cell clone.^{16,31,40,42–47}

TREATMENT

Management of heart failure in cardiac amyloidosis

The main treatment of heart failure revolves around sodium restriction and diuretics to relieve congestion. This can prove challenging in many patients due to the narrow window between too high or too low filling pressures. A combination of loop diuretics and an aldosterone antagonist is most effective.^31,34,44,45 Torsemide is preferred over furosemide due to its superior bioavailability and longer duration of action, particularly since these patients have issues with gut edema and GI absorption. Due to dependence of the cardiac output on heart rate and the tendency for orthostatic hypotension, traditional neurohormonal antagonists including beta blockers and angiotensin-converting enzyme inhibitors are neither effective nor well tolerated.⁶⁰ However, in patients with atrial fibrillation, beta blockers may need to be used for rate control. Nondihydropyridine calcium channel blockers bind avidly to amyloid fibrils and are contraindicated due to risk of profound hypotension and syncope.^{30,31,34,44,45} Digoxin is usually avoided in CA due to concerns of increased risk of toxicity; however, it may be used with caution for rate control in atrial fibrillation given its lack of negative inotropy.⁶¹ Maintenance of normal sinus rhythm is preferable due to the importance of atrial contribution to cardiac output.

Anticoagulation in patients with atrial fibrillation and even in patients with normal sinus rhythm and poor atrial function is important due to the high risk of thromboembolic complications.⁶² Pacemakers are indicated for heart block or symptomatic bradycardia.⁶³ The role of intracardiac defibrillators is controversial, but may be warranted in selected patients with AL-CA.^64,65

Risk stratification and prognostication for AL. The most important determinant of clinical outcome in AL is the extent of cardiac involvement, as congestive heart failure and sudden cardiac death are the most common causes of death. The level of NT-proBNP and the level of either troponin T or troponin I have strong prognostic value and form the basis for the staging system in AL. Various iterations have evolved over the years, but the most widely adopted is the 4-stage system developed and validated by Mayo Clinic. This system uses a cutoff value at diagnosis for NT-proBNP greater than 1,800 ng/mL, troponin T greater than 0.025 μg/L, and the difference between kappa and lambda free light chain levels greater than 180 mg/L. Stage level increases by the number of cutoff values exceeded, with stage IV carrying a median survival of 6 months.⁴⁷ Additionally, the troponin T level can help risk-stratify patients being considered for autologous stem cell transplant. In a retrospective study, troponin T greater than 0.06 μg/L was associated with increased mortality following stem cell transplant.⁶⁶ Ultimately, prognosis in AL-CA is related to the hematologic response to chemotherapy.

Current treatment strategies for AL. The survival of patients with AL has improved over the years with the advent of more effective chemotherapeutic regimens that kill the underlying plasma cell clone producing the unstable light chains. The goal of treatment is to achieve a complete hematologic response with normalization of the affected light chain and sFLC ratio as well as elimination of the M protein on immunofixation.

The development of the proteasome inhibitor bortezomib has improved efficacy and survival in AL causing a faster and more complete hematologic response than prior regimens.^43,67,68

The most commonly used first-line treatment consists of a 3-drug combination with the alkylating agent cyclophosphamide, the proteasome inhibitor bortezomib, and the steroid dexamethasone, which is given weekly.⁴³ A retrospective study by Sperry et al⁸ showed that patients receiving an alkylating agent, bortezomib, and a steroid had the best outcomes compared with other regimens.

For patients with refractory or relapsed disease, the CD38 monoclonal antibody daratumumab can be used if patients meet myeloma criteria and has been found to be effective thus far.^68,69 Newer proteasome inhibitors such as ixazomib, which is taken orally, are being studied in alternative combination regimens.⁷⁰ High-dose chemotherapy with autologous stem cell transplant can be considered in patients with an acceptable cardiac risk profile and may offer more complete and durable remission than chemotherapy, although this is controversial.^43,71

The cardiologist’s role in AL-CA. The hematologist directs the chemotherapy for AL but works closely with the cardiologist when there is cardiac involvement. The main role of the cardiologist is to manage volume status with diuretics, monitor for arrhythmia, and evaluate the cardiac response to treatment.^43,71 Cardiac response was traditionally measured by echocardiographic changes of wall thickness, diastolic function, and ejection fraction, as well as changes in New York Heart Association (NYHA) functional class.⁶⁷ However, it is uncommon to see reduction in LV wall thickness or significant improvement in ejection fraction and if it does occur, it is a slow process that usually takes more than 1 year. With the advent of longitudinal myocardial strain imaging, improvements in strain can be seen despite the lack of structural changes on echocardiogram.⁷² In 2012, consensus criteria defined a cardiac response as a greater than 30% reduction in NT-proBNP.⁷³ Misfolded light chains are toxic to cardiomyocytes by causing increased oxidative stress and impairing contractility. Thus, reduction in light chain levels can lead to clinical improvement and significant reductions in NT-proBNP without changing amyloid fibril burden in the heart.

Heart transplant for patients with AL-CA. For patients who have a good hematologic response to initial chemotherapy but have limited predicted survival due to severe heart failure, heart transplant followed by autologous stem cell transplant, is a treatment strategy that can be considered. The patient must have clinically isolated severe cardiac disease, minimal amyloid burden in other organs, and a plasma cell clone that is responsive to therapy. Initial reports of heart transplant showed poor survival rates due to recurrent amyloid in the transplanted heart and progressive amyloid deposition in other organs. However, due to improved anti-plasma-cell-directed therapy and refinement in patient selection, outcomes have improved. Contemporary series of patients undergoing heart transplant followed by stem cell transplant showed that outcomes are almost comparable to heart transplant for other indications, with a 5-year survival rate of approximately 65%.⁷⁴

Future therapies for AL. There is an AL amyloid-directed monoclonal antibody designed to remove amyloid fibrils from affected organs and is currently undergoing clinical trials. NEOD001, a humanized murine monoclonal antibody that targets an epitope exposed during light chain misfolding, binds to the light chain amyloid fibril and signals an immune response to clear the deposits. This agent has completed phase 1 and 2 clinical trials of 27 patients previously treated with at least 1 plasma cell-directed therapy. It showed good tolerability and achieved both renal and cardiac responses in most patients.⁷⁵

A phase 2b clinical trial (NCT02632786) of patients with AL with a previous hematologic response to treatment and persistent heart dysfunction is underway and expected to be completed in January 2018. A phase 3 clinical trial (NCT02312206) of NEOD001 as an adjunct to chemotherapy is also ongoing and results are expected in February 2019.

Liver transplant for ATTRm amyloidosis for the V30M mutation that causes FAP was first described in 1990, but it has not been well validated in other mutations and is not a solution for ATTRwt.⁷⁶ Significant progress has been made over the past 2 decades in the understanding of the pathophysiologyy of ATTR, paving the way for promising advancements in pharmacotherapy. Presently, there are 3 classes of pharmacologic agents, grouped by the point of disease process each strategy targets:

• Block TTR synthesis at the translational level in hepatocytes
• Stabilize the TTR tetramer to inhibit the rate-determining step of amyloidogenesis
• Disrupt and clear the ATTR amyloid fibril.⁷⁷

Block TTR synthesis. TTR messenger RNA (mRNA) can be targeted by “silencers” preventing translation, thereby reducing the production TTR protein by hepatocytes. The resultant sustained reduction of plasma TTR should decrease or halt amyloid deposition by making less TTR available to dissociate and deposit in the heart and nerves. There are 2 approaches to silencing TTR mRNA translation: small interfering RNA (siRNA) and antisense oligonucleotide (ASO).⁷⁷

An siRNA, packaged in a lipid nanoparticle to ensure delivery to the liver, has been designed to bind to a conserved region of TTR mRNA, degrading the mRNA and reducing TTR protein expression. One siRNA, patisiran, completed the phase 3 APOLLO clinical trial (NCT01960348) in August 2017. It is an intravenous medication that requires premedication. The APOLLO trial studied patients with neuropathic variants of ATTRm, with a primary end point of neuropathy progression over 18 months. Patisrian met the primary end point and will likely be approved by the US Food and Drug Administration (FDA) by the third quarter of 2018. Given its target of a conserved 3’ untranslated region of TTR mRNA, patisiran should theoretically yield benefits not just in FAP but to both ATTRm-CA and ATTRwt-CA.^68,77

ASOs are single-stranded oligonucleotides, typically 20 nucleotides in length, that bind to mRNA and elicit enzymatic mRNA degradation and reduced protein expression. Inotersen (IONIS-TTR_Rx) is an ASO drug that targets a conserved region of TTR mRNA. Inotersen is administered by weekly subcutaneous injection. A phase 2/3 clinical trial (NCT01737398) completed in October 2017 studied the drug's efficacy in treating FAP, with a primary end point of neuropathy progression over 65 weeks. It met the primary end point and a subset of patients actually improved. Like patisiran, inotersen is likely to be approved by the FDA for a neuropathy indication by the third quarter of 2018 and may benefit patients with ATTRm-CA and ATTRwt-CA. More studies are needed in the ATTR cardiac population.^68,77

Stabilize the TTR tetramer. The TTR tetramer has 2 thyroxine binding pockets that stabilize the structure when bound preventing dissociation. Dissociation of the tetramer, the rate limiting step for ATTR fibrillogenesis, can be reduced using pharmacologic agents that bind to the thyroxine binding pockets. Both new and repurposed agents have been found to stabilize the TTR tetramer, including diflunisal, tafamidis, tolcapone, and AG10.^68,77

Diflunisal (Dolobid) is a nonacetylated salicylate nonsteroidal anti-inflammatory drug used for over 3 decades to treat arthritis and musculoskeletal pain. Unrelated to its anti-inflammatory properties, it interacts with TTR’s thyroxine binding pocket to increase the stability of the tetramer. A 2013 randomized, placebo-controlled, international multicenter trial of 130 patients with FAP demonstrated a statistically significant slowing of polyneuropathy progression; however, 67 patients (diflunisal n = 27, placebo n = 40) did not complete the study.⁷⁸ A small study revealed diflunisal to be reasonably well-tolerated in ATTR-CA, and to date it is the only readily available pharmacotherapy for ATTR supported by a randomized, placebo-controlled trial.^79,80 Diflunisal may be considered for off-label use in patients with ATTR-CA with relatively preserved kidney function and no increased bleeding risk, taken under the supervision of a cardiologist who will monitor for fluid retention and changes in renal function.⁷⁷

Tafamidis (Vyndaqel), like diflunisal, interacts with TTR’s thyroxine binding pocket and increases tetrameric stability. A phase 2 open-label clinical trial studied the efficacy and tolerance of tafamidis in 31 patients with ATTRwt and NYHA functional class 1 and 2 followed for 1 year. Twenty-eight patients completed the study and 2 patients died. TTR stabilization at 6 weeks was achieved in 30 of 31 patients (96.8%), and success at 1 year in 25 of 28 patients (89.3%). No clinical progression occurred in 16 of 31 patients (51.5%), and tafamidis was generally well-tolerated, with diarrhea the most common side effect in 7 of 31 patients (22.6% ).^81,82

A phase 3 clinical trial (NCT01994889) is studying tafamidis vs placebo in patients with ATTRm-CA or ATTRwt-CA (excluding NYHA functional class 4) with the primary outcome measure of all-cause mortality and heart failure-related hospitalizations over 30 months. This is a large trial that enrolled 446 patients and data collection is expected to be completed in February 2018.

Tolcapone, approved by the FDA for Parkinson disease, has been found to be a potent TTR stabilizer by binding both thyroxine binding pockets of the TTR tetramer simultaneously. However, tolcapone has an FDA “black box” warning due to the risk of potentially fatal acute fulminant liver failure and is not currently used in ATTR therapy.⁶⁸ Nonetheless, it will likely undergo further study for ATTR.

Recruiting is underway for a phase 1 clinical trial of AG10, a potent selective TTR stabilizer (NCT03294707).⁶⁸

Disruption and clearance of the ATTR amyloid fibril. Even though treatment directed at blocking TTR synthesis or stabilizing the tetramer may be effective at preventing further deposition, the residual amyloid deposits persist and continue to affect organ function. With that need in mind, several agents that disrupt the amyloid formation process further downstream have been evaluated at a basic science level and in a few small nonrandomized open-label studies.⁷⁷

Doxycycline is a tetracycline antibiotic with demonstrated effectiveness in disrupting mature amyloid fibrils in mouse models.⁸³ Tauroursodeoxycholic acid  is a bile acid with the ability to disrupt prefibrillar amyloid components. This combination has been studied in patients with ATTR-CA in 2 small open-label trials, with only 1 having results published. There was no progression in NT-proBNP or wall thickness in a cohort of 7 patients who completed 12 months of treatment.⁸⁴ These data are nonrandomized and hypothesis-generating, as adequate studies would need to be performed to evaluate this hypothesis further. Because there are currently no FDA-approved therapies for ATTR, patients may be offered this combination fully informed that the data are limited. (Note: ursodiol is substituted for tauroursodeoxycholic acid, which is not available in the United States.)⁶⁸

Green tea extract contains the polyphenol epigallocatechin-3-gallate, which has shown the ability for fibril disruption as well as TTR stabilization, importantly using a binding site separate from the thyroxine binding pocket (utilized in diflunisal and tafamidis). A small open-label study of 19 patients with ATTR-CA of whom 14 took green tea extract for 1 year reported a reduction in intraventricular septal wall  thickness at 1 year, and in 9 patients a reduction of 12.5% in LV mass measured by cardiac MRI.⁸⁵

Curcumin, the active ingredient in the household spice turmeric, has displayed in vitro promise as a TTR stabilizer by binding to the thyroxine binding pocket, and as an amyloid fibril disruptor by increasing macrophage degradation activity. Although there have only been preliminary animal studies, this supplement may be promising for further study in humans with ATTR-CA.⁶⁸

PRX004 is a synthetic antibody designed to bind to non-native misfolded forms of TTR with the goal of potentially preventing deposition and promoting clearance of TTR aggregates.⁸⁶ A phase 1 open-label escalation trial (NCT03336580) in 36 patients with ATTRm is planned and, hopefully, will pave the way for further study.

Heart transplant for patients with ATTR-CA. Patients with ATTRwt-CA who are young enough to undergo heart transplant have displayed favorable outcomes given that it causes clinically isolated heart disease and is an indolent process that should not affect the transplanted heart over the average life span of the allograft. Patients with the ATTRm mutation V122I have been treated with heart transplant alone, with the thought process that again, due to the indolent nature of amyloid deposition, concomitant liver transplant may not be needed.⁷⁴ Thus far, 6 patients with this mutation have undergone successful transplant at our institution with heart alone, 1 of whom is 9 years posttransplant without any recurrent amyloid in the allograft. Patients with the T60A mutation that causes both polyneuropathy and cardiomyopathy require combined heart and liver transplant.⁷⁴

Are there other therapies being studied to clear amyloid deposits and reverse organ dysfunction?

Extracellular deposits of amyloid fibrils, regardless of precursor protein, contain common elements such as calcium, glycosaminoglycans, and an SAP component. SAP stabilizes amyloid fibrils and makes them resistant to degradation. A monoclonal immunoglobulin G1 anti-SAP antibody has been designed to target the ubiquitous SAP component, signaling an immune response that leads to macrophage mediated clearance of amyloid fibrils, regardless of the type. Treatment with this approach was studied in a pilot trial of 16 patients mostly with AL, and within a 6-week period some of the patients had dramatic reversal of liver amyloid deposition.² This has paved the way for a phase 2 open-label trial to be performed in patients with AL-CA and ATTR-CA (NCT03044353) and plans for a randomized phase 3 trial in CA are in discussion. There is optimism that this therapy may achieve the holy grail of removing amyloid rather than just preventing further deposition.

The diagnosis of CA requires a high index of suspicion. The diagnostic tools have improved due to the availability of modern imaging techniques, and the advent of measuring the sFLC assay along with immunofixation of the serum and urine. The prognosis for patients with AL-CA used to be dismal, with very poor survival rates. The current treatment strategies that include proteasome inhibitors have significantly improved survival, emphasizing the importance of early diagnosis and prompt initiation of therapy. Monoclonal antibodies against plasma cells (daratumumab) and light chain amyloid deposits (NEOD001) have the potential to further improve outcomes. The diagnosis of ATTR-CA used to be a futile academic pursuit given the lack of available therapies. However, there are several new FDA-approved agents on the horizon, including TTR gene silencers and stabilizers. CA is no longer considered to be rare and hopeless. Rather, it is more common than previously recognized and even more treatable.

WHAT IS AMYLOIDOSIS?

Amyloidosis is a protein deposition disease in which a specific precursor protein pathologically misfolds from its physiologic tertiary structure into a more linear shape dominated by beta-pleated sheets. The misfolded protein aggregates into oligomers, eventually forming insoluble amyloid fibrils that deposit extracellularly in tissues. Both the circulating oligomers, which are cytotoxic, and the fibrils, which cause distortion of the tissue architecture, lead to organ dysfunction. Amyloid fibrils are rigid, nonbranching structures, 7 to 10 nanometers in diameter, with a characteristic appearance on electron microscopy. Affinity for Congo red staining, which binds to the beta-pleated sheets, produces the pathognomonic “apple-green” birefringence when visualized under polarized light microscopy. Universal to all amyloid fibrils are chaperone proteins such as serum amyloid P (SAP) and glycosaminoglycans, as well as calcium. There are more than 30 different precursor proteins implicated in various amyloid diseases, arising as hereditary or nonhereditary, localized or systemic, with different organ involvement and prognosis.^1–3

TWO MAIN TYPES OF CARDIAC AMYLOIDOSIS

Light chain amyloidosis (AL)

AL, formerly called primary amyloidosis, is a clonal plasma cell disorder due to the overproduction and misfolding of antibody light chain fragments. It is a rare disease with about 3,000 new cases per year in the United States.⁵ The median age at diagnosis is 63, although it can present in patients in their 30s and 40s.^5,6 It is a systemic disease that often affects the heart, but it can affect several other organs, most commonly the kidneys, gastrointestinal (GI) tract, and nervous system.⁷

AL is a more aggressive disease than ATTR, with a median untreated survival of less than 6 months in patients who present with heart failure.⁸ Early diagnosis is crucial as mortality is high without prompt treatment.

Transthyretin amyloidosis (ATTR)

ATTR is due to misfolding of the liver-derived precursor protein transthyretin (TTR) (previously called prealbumin), either as an acquired wild-type variant (ATTRwt) or as a hereditary mutant variant (ATTRm). ATTRwt, known previously as senile CA, typically affects older males and presents as a late onset hypertrophic restrictive cardiomyopathy, often preceded by carpal tunnel syndrome or spinal stenosis or both. The ATTRm variant, caused by one of many different point mutations in the TTR gene, can manifest as a polyneuropathy, cardiomyopathy, or a mixed phenotype that varies according to the specific mutation.

While ATTR portends a better prognosis than AL, it is still a progressive disorder with significantly reduced survival and quality of life. The median survival of patients with the ATTRwt variant is about 4 years and for patients with the ATTRm variant, survival depends on the mutation.⁹ TTR is a protein tetramer composed of 4 identical 127-amino acid monomers noncovalently bound at a dimer-dimer interface (Figure 1). It is a transport protein for thyroxine and retinol binding protein. The dissociation of the tetramer is the rate-limiting step for amyloid fibrillogenesis. Differentiating the ATTRwt variant and the ATTRm variant is done by testing the TTR gene for a mutation.^1,3

How common is the ATTRwt variant? The ATTRwt variant is often an unrecognized cause of diastolic heart failure in the elderly, with up to 25% of patients 85 and older showing ATTRwt amyloid deposits on autopsy studies.¹⁰ A recent study showed that 13% of patients 60 and older hospitalized with heart failure with preserved ejection fraction had grade 2 to 3 uptake on ^99mtechnetium-pyrophosphate (^99mTcPYP) scintigraphy, which is consistent with ATTR-CA.¹¹ In 43 consecutive patients undergoing transcatheter aortic valve replacement, 11.6% were found to have significant uptake on ^99mTcPYP scan.¹² It is clear given the aging population that the ATTRwt variant will become the most common form of amyloidosis. It is much more common in white males, with a median age at diagnosis of 75.¹³ Carpal tunnel syndrome (almost always bilateral) and spinal stenosis are present in about 50% of patients diagnosed with ATTRwt-CA and often precede clinical presentation of heart failure by 5 to 15 years.^14–17

How common is the ATTRm variant? There are more than 100 point mutations in the TTR gene that lead to various familial TTR-related amyloid syndromes, either neuropathic (familial amyloid polyneuropathy [FAP]) or cardiomyopathic (familial amyloid cardiomyopathy).¹⁸ The most common mutation in the United States is V122I in which there is an isoleucine substitution for valine at the 122nd amino acid position. This mutation is seen in African Americans, 3% to 4% of whom are heterozygote carriers.¹⁹ Although the true penetrance is unknown, this mutation can lead to a late-onset restrictive cardiomyopathy with minimal neuropathy and is frequently misdiagnosed as hypertensive heart disease or diastolic heart failure. The median survival for V122I ATTRm-CA is about 2 years but likely depends on the stage at the time of diagnosis.²⁰ The second most common mutation in the United States, T60A, is seen in patients of Irish descent and causes a mixed neuropathy and cardiomyopathy.¹⁷

PATHOLOGY AND PATHOPHYSIOLOGY OF CA

The atria are universally involved with interatrial septal thickening, which can lead to poor atrial function and increased rates of atrial fibrillation (ATTR more so than AL).^21,29 The conduction system can be affected causing varying degrees of heart block, as well as bundle branch block (ATTR more so than AL).³⁰ The valves are usually thickened, often associated with mild to moderate regurgitation. Pericardial involvement can lead to small pericardial effusions (large effusions are rare), and coronary involvement (classically, small intramural vessels) can lead to ischemia and angina with normal epicardial coronaries (AL more so than ATTR).^31–33

Thickened left and right ventricular walls result in a nondilated ventricle that is stiff and poorly compliant, resulting in progressive diastolic filling abnormalities. Systolic dysfunction can be seen in severe and advanced disease. Importantly, ejection fraction measured by echocardiography is misleading in CA, as reduced end-diastolic volume produces a low stroke volume. For example, an ejection fraction of 50%, when starting at a significantly reduced end-diastolic volume (for example, 70 mL), leads to a significantly reduced stroke volume (35 mL) and, thus, cardiac output. This explains why patients with CA cannot usually tolerate reduced heart rates, as their cardiac output is dependent on heart rate.^34–36

Patients with CA typically exhibit heart failure with preserved ejection fraction (otherwise known as diastolic heart failure). Dyspnea on exertion is common; however, some patients can present with more right-sided heart failure symptoms such as lower-extremity edema and ascites. Fatigue and weakness are related to low cardiac output and often attributed to nonspecific symptoms of aging. Because of the thickened ventricles, patients can often be misdiagnosed as having HCM with or without obstruction.^7,34 The first manifestation of CA may be atrial fibrillation, most commonly in ATTRwt-CA, or cardioembolic stroke. Atrial fibrillation can be present for years before CA is considered. Bundle branch block and complete heart block (more common in ATTR-CA than AL-CA) may lead to pacemaker implantation.³⁰ Angina with normal coronaries can occur, and a rare presentation may be cardiogenic shock due to diffuse ischemia.^31–33 Elderly patients with CA can present with low-flow, low-gradient aortic stenosis.³⁷

DIAGNOSIS

ECG

As opposed to that seen in true left ventricular hypertrophy (LVH), which leads to increased voltage on ECG, amyloid infiltration of the myocardium leads to lower voltage. Thus, what is indicative of LVH on echocardiogram combined with low voltage on the ECG is a classic finding for CA. However, only about 50% of patients with AL-CA and about 30% of patients with ATTR-CA meet true low-voltage criteria (QRS amplitude less than 5 mm in limb leads or less than 10 mm in precordial leads).^30,38 Hence, the absence of low-voltage criteria does not exclude the diagnosis of CA. Approximately 10% of patients with CA confirmed by biopsy met ECG criteria for LVH.³⁸ The key point is to consider the overall degree of voltage on the ECG relative to the degree of LV thickening on the echocardiogram, recognizing that lower voltage than what would be expected may indicate possible infiltrative disease such as CA. The other main finding on the ECG in patients with CA is a pseudoinfarct pattern with Q waves in the early precordial leads mimicking a prior anteroseptal myocardial infarction.^38,39 This finding is seen in about 50% of patients (Figure 3).³⁹ Wide QRS complexes are more frequent in ATTR-CA and lower limb voltages are more frequent in AL-CA.³⁰

Echocardiogram

The echocardiographic finding of LVH in patients with CA is misleading in that the LV thickening is due to infiltrating amyloid fibrils and not to myocyte hypertrophy. That said, the terms LVH and LV thickening are used interchangeably when describing the echocardiographic phenotype. LV wall thickness greater than 12 mm (6 mm to 10 mm is normal) in the absence of hypertension should prompt suspicion for CA.³⁴ LV thickening most often appears symmetric; however, occasionally it may exhibit asymmetric septal hypertrophy, particularly in ATTRwt-CA. In some cases, there may be a smaller subset that can actually have dynamic LV outflow obstruction similar to that seen in hypertrophic obstructive cardiomyopathy.^22–24 An important echocardiographic clue that can differentiate CA from other diseases is thickening of both the LV and right ventricle (Figure 3). Septal wall thickness and LV mass index are greater in ATTR-CA compared with AL-CA.³⁰ On average, the LV septum is around 15 mm in AL-CA and around 18 mm in ATTRwt-CA.⁴⁰ Historically, the characteristic myocardial “granular sparking” or “speckling” pattern has low sensitivity and specificity.¹⁶ The left ventricle is not dilated; rather, the ventricular dimensions are usually smaller than normal. Although ejection fraction is usually preserved, cardiac output is low due to decreased ventricular volume.³⁷ Systolic dysfunction occurs late in the disease.¹⁶ Diastolic dysfunction is universal, with a mitral inflow pattern that can range from stage I (abnormal relaxation) in early disease to stage III (restrictive filling pattern) in more advanced disease. Septal and lateral tissue Doppler velocities are very low in amyloid heart disease.⁴¹ Another echocardiographic clue to diagnosis is thickening of the heart valves, which is not seen in hypertensive heart disease or hypertrophic cardiomyopathy. Biatrial dilation is common, and there can be thickening of the interatrial septum.

Laboratory testing

N-terminal pro-b-type natriuretic peptide (NT-proBNP) is universally elevated in CA and is typically higher in AL-CA than in ATTR-CA. Troponin T or troponin I or both may be chronically elevated in CA and likely signify small-vessel ischemia. In the appropriate clinical context of a thickened ventricle and heart failure, an elevated troponin value (outside of an acute coronary syndrome) should trigger suspicion for CA. Workup for a monoclonal protein process should always be done when considering CA to rule out AL. Serum and urine protein electrophoresis are insensitive tests to detect AL and should not be relied upon as a screening test. The serum free light chain (sFLC) assay, which measures free kappa and lambda light chain levels and reports the ratio, is a sensitive test that should be measured routinely along with immunofixation of the serum and urine. In AL, sFLC will reveal an abnormal kappa-lambda ratio. An abnormally low ratio (less than 0.26) suggests a monoclonal lambda light chain process, while an abnormally high ratio (greater than 1.65) suggests a monoclonal kappa light chain process. Immunofixation will reveal an M-protein. Because light chains are excreted by the kidney, the serum levels of both kappa and lambda will be elevated in renal dysfunction, but the ratio should remain normal.^{16,31,34,40,42–47}

Over the past decade, the ability to diagnose CA noninvasively has dramatically improved with strain imaging using 2D speckle tracking echocardiography, cardiac magnetic resonance imaging (MRI), and nuclear bone scintigraphy. These diagnostic tools have given clinicians options to pursue the diagnosis of CA without directly proceeding to endomyocardial biopsy.

Cardiac MRI. Cardiac MRI is useful for the diagnosis of CA (Figure 4B, 4C). Imaging after administration of gadolinium contrast shows a characteristic late gadolinium enhancement (LGE) pattern that is diffuse and subendocardial, and does not follow any particular coronary distribution.⁴⁹ LGE can also be seen in the right ventricle and the atrial walls, and can be transmural and patchy in ATTRwt-CA. This pattern is highly sensitive (93%) and specific (70%) for CA with an overall negative predictive accuracy of 84%.⁵⁰

One of the main limitations of cardiac MRI for the diagnosis of CA is the inability to give contrast in patients with reduced glomerular filtration rate. However, native T1-myocardial mapping techniques that do not require contrast show significantly increased native T1 times in CA and offer a promising alternative. Cardiac MRI parameters such as LGE, the difference in inversion time between the LV cavity and myocardium, native T1 mapping, and extracellular volume offer prognostic information. A greater than fivefold mortality increase is seen in CA patients with transmural LGE compared with those without LGE.^49,50

^99mTcPYP scintigraphy. ^99mTcPYP, a radiotracer used in bone scans, was initially used in cardiology to quantify myocardial infarction due to its ability to localize calcium.⁵¹ Its potential utility in CA came in 1982 when diffuse myocardial ^99mTcPYP uptake on cardiac radionucleotide imaging was noted in 10 patients with tissue-proven amyloidosis.⁵² Several subsequent studies reproduced and expanded upon this observation and revealed its diagnostic value, specifically showing that there is significant uptake in ATTR-CA and no to mild uptake in AL-CA. This offers a significant advantage over other noninvasive modalities in that it not only confirms the diagnosis of CA but differentiates ATTR-CA.¹⁶

^99mTcPYP myocardial radiotracer uptake is graded by the semiquantitative visual score of cardiac retention, where grade 0 = no cardiac uptake, grade 1 = mild uptake less than bone, grade 2 = moderate uptake equal to bone, and grade 3 = high uptake greater than bone (Figure 4D).⁴² Additionally, quantitative analysis of heart retention can be calculated drawing circular regions of interest over the heart and mirrored on the contralateral chest wall. A heart-to-contralateral ratio greater than 1.5 is consistent with the diagnosis of ATTR-CA.^53,54 In 2016, a multicenter study showed that grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy in the absence of evidence of a monoclonal gammopathy was diagnostic for ATTR-CA, providing a cost-effective and non-invasive technique with a specificity and positive predictive value of 100% (confidence interval, 99.0–100%).⁴²

Endomyocardial biopsy, right heart catheterization, and fat biopsy

Endomyocardial biopsy is essentially 100% sensitive for the diagnosis of CA.²⁵ The main risk of pursuing endomyocardial biopsy is about a 1% risk of right ventricular perforation leading to cardiac tamponade.⁵⁵ The other limitation to this approach is that not all centers are equipped to perform this procedure. Birefringence under polarized light microscopy is histopathologically diagnostic of CA; however, further subtyping by the pathologist to determine if it is AL or ATTR is absolutely crucial. Subtyping can be performed by immunohistochemistry with caution taken for misinterpretation. If there is any question of accuracy, the specimen should be sent for laser microdissection and mass spectroscopy for accurate identification of the precursor protein type (some centers routinely perform mass spectroscopy on all myocardial specimens).^16,31

Right heart catheterization is nonspecific and shows restrictive hemodynamics. The right atrial waveform shows rapid x and y descents and the right ventriclular tracing may show a dip-and-plateau pattern typical of restrictive cardiomyopathy. Cardiac output can be preserved but more commonly is low.^16,31

Fat pad biopsy is 60% to 80% sensitive in AL, 65% to 85% sensitive in ATTRm, and only 14% sensitive in ATTRwt, with the accuracy dependent on the operator, pathologist, and how much tissue is removed (fat pad aspirate vs biopsy specimen).^56–58 Fat pad biopsy has diagnostic limitations, and a negative fat pad biopsy does not rule out amyloidosis.

DIAGNOSTIC ALGORITHM FOR CARDIAC AMYLOIDOSIS

In conjunction with laboratory tests, ^99mTcPYP scan of the heart can be ordered to investigate the possibility of ATTR-CA. Grade 2 to 3 myocardial uptake in the absence of a monoclonal plasma cell process is consistent with the diagnosis of ATTR-CA. Grade 0 or 1 myocardial uptake on ^99mTcPYP scan with an abnormal sFLC ratio or positive M protein on immunofixation suggests AL-CA and a bone marrow biopsy should be performed. If the patient has an abnormal sFLC ratio and grade 2 to 3 uptake on ^99mTcPYP scan, the diagnosis of ATTR-CA with unrelated monoclonal gammopathy of undetermined significance should be considered. However, this would need to be reconciled by pursuing endomyocardial biopsy and accurate tissue typing. If the ^99mTcPYP scan is negative, and the sFLC ratio is normal, and immunofixation is negative, a diagnosis of CA is very unlikely.^{16,31,40,42–47}

If the diagnosis of ATTR-CA is made, genetic testing can determine the presence or absence of a mutation to differentiate ATTRm or ATTRwt, respectively. If the diagnosis of AL-CA is suggested, a bone marrow biopsy is necessary to identify and quantify the plasma cell clone.^{16,31,40,42–47}

TREATMENT

Management of heart failure in cardiac amyloidosis

The main treatment of heart failure revolves around sodium restriction and diuretics to relieve congestion. This can prove challenging in many patients due to the narrow window between too high or too low filling pressures. A combination of loop diuretics and an aldosterone antagonist is most effective.^31,34,44,45 Torsemide is preferred over furosemide due to its superior bioavailability and longer duration of action, particularly since these patients have issues with gut edema and GI absorption. Due to dependence of the cardiac output on heart rate and the tendency for orthostatic hypotension, traditional neurohormonal antagonists including beta blockers and angiotensin-converting enzyme inhibitors are neither effective nor well tolerated.⁶⁰ However, in patients with atrial fibrillation, beta blockers may need to be used for rate control. Nondihydropyridine calcium channel blockers bind avidly to amyloid fibrils and are contraindicated due to risk of profound hypotension and syncope.^{30,31,34,44,45} Digoxin is usually avoided in CA due to concerns of increased risk of toxicity; however, it may be used with caution for rate control in atrial fibrillation given its lack of negative inotropy.⁶¹ Maintenance of normal sinus rhythm is preferable due to the importance of atrial contribution to cardiac output.

Anticoagulation in patients with atrial fibrillation and even in patients with normal sinus rhythm and poor atrial function is important due to the high risk of thromboembolic complications.⁶² Pacemakers are indicated for heart block or symptomatic bradycardia.⁶³ The role of intracardiac defibrillators is controversial, but may be warranted in selected patients with AL-CA.^64,65

Risk stratification and prognostication for AL. The most important determinant of clinical outcome in AL is the extent of cardiac involvement, as congestive heart failure and sudden cardiac death are the most common causes of death. The level of NT-proBNP and the level of either troponin T or troponin I have strong prognostic value and form the basis for the staging system in AL. Various iterations have evolved over the years, but the most widely adopted is the 4-stage system developed and validated by Mayo Clinic. This system uses a cutoff value at diagnosis for NT-proBNP greater than 1,800 ng/mL, troponin T greater than 0.025 μg/L, and the difference between kappa and lambda free light chain levels greater than 180 mg/L. Stage level increases by the number of cutoff values exceeded, with stage IV carrying a median survival of 6 months.⁴⁷ Additionally, the troponin T level can help risk-stratify patients being considered for autologous stem cell transplant. In a retrospective study, troponin T greater than 0.06 μg/L was associated with increased mortality following stem cell transplant.⁶⁶ Ultimately, prognosis in AL-CA is related to the hematologic response to chemotherapy.

Current treatment strategies for AL. The survival of patients with AL has improved over the years with the advent of more effective chemotherapeutic regimens that kill the underlying plasma cell clone producing the unstable light chains. The goal of treatment is to achieve a complete hematologic response with normalization of the affected light chain and sFLC ratio as well as elimination of the M protein on immunofixation.

The development of the proteasome inhibitor bortezomib has improved efficacy and survival in AL causing a faster and more complete hematologic response than prior regimens.^43,67,68

The most commonly used first-line treatment consists of a 3-drug combination with the alkylating agent cyclophosphamide, the proteasome inhibitor bortezomib, and the steroid dexamethasone, which is given weekly.⁴³ A retrospective study by Sperry et al⁸ showed that patients receiving an alkylating agent, bortezomib, and a steroid had the best outcomes compared with other regimens.

For patients with refractory or relapsed disease, the CD38 monoclonal antibody daratumumab can be used if patients meet myeloma criteria and has been found to be effective thus far.^68,69 Newer proteasome inhibitors such as ixazomib, which is taken orally, are being studied in alternative combination regimens.⁷⁰ High-dose chemotherapy with autologous stem cell transplant can be considered in patients with an acceptable cardiac risk profile and may offer more complete and durable remission than chemotherapy, although this is controversial.^43,71

The cardiologist’s role in AL-CA. The hematologist directs the chemotherapy for AL but works closely with the cardiologist when there is cardiac involvement. The main role of the cardiologist is to manage volume status with diuretics, monitor for arrhythmia, and evaluate the cardiac response to treatment.^43,71 Cardiac response was traditionally measured by echocardiographic changes of wall thickness, diastolic function, and ejection fraction, as well as changes in New York Heart Association (NYHA) functional class.⁶⁷ However, it is uncommon to see reduction in LV wall thickness or significant improvement in ejection fraction and if it does occur, it is a slow process that usually takes more than 1 year. With the advent of longitudinal myocardial strain imaging, improvements in strain can be seen despite the lack of structural changes on echocardiogram.⁷² In 2012, consensus criteria defined a cardiac response as a greater than 30% reduction in NT-proBNP.⁷³ Misfolded light chains are toxic to cardiomyocytes by causing increased oxidative stress and impairing contractility. Thus, reduction in light chain levels can lead to clinical improvement and significant reductions in NT-proBNP without changing amyloid fibril burden in the heart.

Heart transplant for patients with AL-CA. For patients who have a good hematologic response to initial chemotherapy but have limited predicted survival due to severe heart failure, heart transplant followed by autologous stem cell transplant, is a treatment strategy that can be considered. The patient must have clinically isolated severe cardiac disease, minimal amyloid burden in other organs, and a plasma cell clone that is responsive to therapy. Initial reports of heart transplant showed poor survival rates due to recurrent amyloid in the transplanted heart and progressive amyloid deposition in other organs. However, due to improved anti-plasma-cell-directed therapy and refinement in patient selection, outcomes have improved. Contemporary series of patients undergoing heart transplant followed by stem cell transplant showed that outcomes are almost comparable to heart transplant for other indications, with a 5-year survival rate of approximately 65%.⁷⁴

Future therapies for AL. There is an AL amyloid-directed monoclonal antibody designed to remove amyloid fibrils from affected organs and is currently undergoing clinical trials. NEOD001, a humanized murine monoclonal antibody that targets an epitope exposed during light chain misfolding, binds to the light chain amyloid fibril and signals an immune response to clear the deposits. This agent has completed phase 1 and 2 clinical trials of 27 patients previously treated with at least 1 plasma cell-directed therapy. It showed good tolerability and achieved both renal and cardiac responses in most patients.⁷⁵

A phase 2b clinical trial (NCT02632786) of patients with AL with a previous hematologic response to treatment and persistent heart dysfunction is underway and expected to be completed in January 2018. A phase 3 clinical trial (NCT02312206) of NEOD001 as an adjunct to chemotherapy is also ongoing and results are expected in February 2019.

Liver transplant for ATTRm amyloidosis for the V30M mutation that causes FAP was first described in 1990, but it has not been well validated in other mutations and is not a solution for ATTRwt.⁷⁶ Significant progress has been made over the past 2 decades in the understanding of the pathophysiologyy of ATTR, paving the way for promising advancements in pharmacotherapy. Presently, there are 3 classes of pharmacologic agents, grouped by the point of disease process each strategy targets:

• Block TTR synthesis at the translational level in hepatocytes
• Stabilize the TTR tetramer to inhibit the rate-determining step of amyloidogenesis
• Disrupt and clear the ATTR amyloid fibril.⁷⁷

Block TTR synthesis. TTR messenger RNA (mRNA) can be targeted by “silencers” preventing translation, thereby reducing the production TTR protein by hepatocytes. The resultant sustained reduction of plasma TTR should decrease or halt amyloid deposition by making less TTR available to dissociate and deposit in the heart and nerves. There are 2 approaches to silencing TTR mRNA translation: small interfering RNA (siRNA) and antisense oligonucleotide (ASO).⁷⁷

An siRNA, packaged in a lipid nanoparticle to ensure delivery to the liver, has been designed to bind to a conserved region of TTR mRNA, degrading the mRNA and reducing TTR protein expression. One siRNA, patisiran, completed the phase 3 APOLLO clinical trial (NCT01960348) in August 2017. It is an intravenous medication that requires premedication. The APOLLO trial studied patients with neuropathic variants of ATTRm, with a primary end point of neuropathy progression over 18 months. Patisrian met the primary end point and will likely be approved by the US Food and Drug Administration (FDA) by the third quarter of 2018. Given its target of a conserved 3’ untranslated region of TTR mRNA, patisiran should theoretically yield benefits not just in FAP but to both ATTRm-CA and ATTRwt-CA.^68,77

ASOs are single-stranded oligonucleotides, typically 20 nucleotides in length, that bind to mRNA and elicit enzymatic mRNA degradation and reduced protein expression. Inotersen (IONIS-TTR_Rx) is an ASO drug that targets a conserved region of TTR mRNA. Inotersen is administered by weekly subcutaneous injection. A phase 2/3 clinical trial (NCT01737398) completed in October 2017 studied the drug's efficacy in treating FAP, with a primary end point of neuropathy progression over 65 weeks. It met the primary end point and a subset of patients actually improved. Like patisiran, inotersen is likely to be approved by the FDA for a neuropathy indication by the third quarter of 2018 and may benefit patients with ATTRm-CA and ATTRwt-CA. More studies are needed in the ATTR cardiac population.^68,77

Stabilize the TTR tetramer. The TTR tetramer has 2 thyroxine binding pockets that stabilize the structure when bound preventing dissociation. Dissociation of the tetramer, the rate limiting step for ATTR fibrillogenesis, can be reduced using pharmacologic agents that bind to the thyroxine binding pockets. Both new and repurposed agents have been found to stabilize the TTR tetramer, including diflunisal, tafamidis, tolcapone, and AG10.^68,77

Diflunisal (Dolobid) is a nonacetylated salicylate nonsteroidal anti-inflammatory drug used for over 3 decades to treat arthritis and musculoskeletal pain. Unrelated to its anti-inflammatory properties, it interacts with TTR’s thyroxine binding pocket to increase the stability of the tetramer. A 2013 randomized, placebo-controlled, international multicenter trial of 130 patients with FAP demonstrated a statistically significant slowing of polyneuropathy progression; however, 67 patients (diflunisal n = 27, placebo n = 40) did not complete the study.⁷⁸ A small study revealed diflunisal to be reasonably well-tolerated in ATTR-CA, and to date it is the only readily available pharmacotherapy for ATTR supported by a randomized, placebo-controlled trial.^79,80 Diflunisal may be considered for off-label use in patients with ATTR-CA with relatively preserved kidney function and no increased bleeding risk, taken under the supervision of a cardiologist who will monitor for fluid retention and changes in renal function.⁷⁷

Tafamidis (Vyndaqel), like diflunisal, interacts with TTR’s thyroxine binding pocket and increases tetrameric stability. A phase 2 open-label clinical trial studied the efficacy and tolerance of tafamidis in 31 patients with ATTRwt and NYHA functional class 1 and 2 followed for 1 year. Twenty-eight patients completed the study and 2 patients died. TTR stabilization at 6 weeks was achieved in 30 of 31 patients (96.8%), and success at 1 year in 25 of 28 patients (89.3%). No clinical progression occurred in 16 of 31 patients (51.5%), and tafamidis was generally well-tolerated, with diarrhea the most common side effect in 7 of 31 patients (22.6% ).^81,82

A phase 3 clinical trial (NCT01994889) is studying tafamidis vs placebo in patients with ATTRm-CA or ATTRwt-CA (excluding NYHA functional class 4) with the primary outcome measure of all-cause mortality and heart failure-related hospitalizations over 30 months. This is a large trial that enrolled 446 patients and data collection is expected to be completed in February 2018.

Tolcapone, approved by the FDA for Parkinson disease, has been found to be a potent TTR stabilizer by binding both thyroxine binding pockets of the TTR tetramer simultaneously. However, tolcapone has an FDA “black box” warning due to the risk of potentially fatal acute fulminant liver failure and is not currently used in ATTR therapy.⁶⁸ Nonetheless, it will likely undergo further study for ATTR.

Recruiting is underway for a phase 1 clinical trial of AG10, a potent selective TTR stabilizer (NCT03294707).⁶⁸

Disruption and clearance of the ATTR amyloid fibril. Even though treatment directed at blocking TTR synthesis or stabilizing the tetramer may be effective at preventing further deposition, the residual amyloid deposits persist and continue to affect organ function. With that need in mind, several agents that disrupt the amyloid formation process further downstream have been evaluated at a basic science level and in a few small nonrandomized open-label studies.⁷⁷

Doxycycline is a tetracycline antibiotic with demonstrated effectiveness in disrupting mature amyloid fibrils in mouse models.⁸³ Tauroursodeoxycholic acid  is a bile acid with the ability to disrupt prefibrillar amyloid components. This combination has been studied in patients with ATTR-CA in 2 small open-label trials, with only 1 having results published. There was no progression in NT-proBNP or wall thickness in a cohort of 7 patients who completed 12 months of treatment.⁸⁴ These data are nonrandomized and hypothesis-generating, as adequate studies would need to be performed to evaluate this hypothesis further. Because there are currently no FDA-approved therapies for ATTR, patients may be offered this combination fully informed that the data are limited. (Note: ursodiol is substituted for tauroursodeoxycholic acid, which is not available in the United States.)⁶⁸

Green tea extract contains the polyphenol epigallocatechin-3-gallate, which has shown the ability for fibril disruption as well as TTR stabilization, importantly using a binding site separate from the thyroxine binding pocket (utilized in diflunisal and tafamidis). A small open-label study of 19 patients with ATTR-CA of whom 14 took green tea extract for 1 year reported a reduction in intraventricular septal wall  thickness at 1 year, and in 9 patients a reduction of 12.5% in LV mass measured by cardiac MRI.⁸⁵

Curcumin, the active ingredient in the household spice turmeric, has displayed in vitro promise as a TTR stabilizer by binding to the thyroxine binding pocket, and as an amyloid fibril disruptor by increasing macrophage degradation activity. Although there have only been preliminary animal studies, this supplement may be promising for further study in humans with ATTR-CA.⁶⁸

PRX004 is a synthetic antibody designed to bind to non-native misfolded forms of TTR with the goal of potentially preventing deposition and promoting clearance of TTR aggregates.⁸⁶ A phase 1 open-label escalation trial (NCT03336580) in 36 patients with ATTRm is planned and, hopefully, will pave the way for further study.

Heart transplant for patients with ATTR-CA. Patients with ATTRwt-CA who are young enough to undergo heart transplant have displayed favorable outcomes given that it causes clinically isolated heart disease and is an indolent process that should not affect the transplanted heart over the average life span of the allograft. Patients with the ATTRm mutation V122I have been treated with heart transplant alone, with the thought process that again, due to the indolent nature of amyloid deposition, concomitant liver transplant may not be needed.⁷⁴ Thus far, 6 patients with this mutation have undergone successful transplant at our institution with heart alone, 1 of whom is 9 years posttransplant without any recurrent amyloid in the allograft. Patients with the T60A mutation that causes both polyneuropathy and cardiomyopathy require combined heart and liver transplant.⁷⁴

Are there other therapies being studied to clear amyloid deposits and reverse organ dysfunction?

Extracellular deposits of amyloid fibrils, regardless of precursor protein, contain common elements such as calcium, glycosaminoglycans, and an SAP component. SAP stabilizes amyloid fibrils and makes them resistant to degradation. A monoclonal immunoglobulin G1 anti-SAP antibody has been designed to target the ubiquitous SAP component, signaling an immune response that leads to macrophage mediated clearance of amyloid fibrils, regardless of the type. Treatment with this approach was studied in a pilot trial of 16 patients mostly with AL, and within a 6-week period some of the patients had dramatic reversal of liver amyloid deposition.² This has paved the way for a phase 2 open-label trial to be performed in patients with AL-CA and ATTR-CA (NCT03044353) and plans for a randomized phase 3 trial in CA are in discussion. There is optimism that this therapy may achieve the holy grail of removing amyloid rather than just preventing further deposition.

The diagnosis of CA requires a high index of suspicion. The diagnostic tools have improved due to the availability of modern imaging techniques, and the advent of measuring the sFLC assay along with immunofixation of the serum and urine. The prognosis for patients with AL-CA used to be dismal, with very poor survival rates. The current treatment strategies that include proteasome inhibitors have significantly improved survival, emphasizing the importance of early diagnosis and prompt initiation of therapy. Monoclonal antibodies against plasma cells (daratumumab) and light chain amyloid deposits (NEOD001) have the potential to further improve outcomes. The diagnosis of ATTR-CA used to be a futile academic pursuit given the lack of available therapies. However, there are several new FDA-approved agents on the horizon, including TTR gene silencers and stabilizers. CA is no longer considered to be rare and hopeless. Rather, it is more common than previously recognized and even more treatable.

In patients with stable coronary artery disease (CAD), the cornerstone of treatment is medical management to control symptoms such as angina and dyspnea on exertion. But in a select group of patients, percutaneous coronary intervention (PCI) is indicated in addition to medical management. Invasive and noninvasive hemodynamic assessments of coronary artery stenosis in conjunction with anatomic considerations play a role in decision-making and in advising patients on revascularization vs medical management. However, in the case of coronary artery chronic total occlusion (CTO), the decision-making process remains challenging due to limited evidence supporting clinical efficacy of CTO PCI, as well as practical considerations including lower success rates and higher complication rates in comparison with patent-vessel PCI.

CLINICAL VIGNETTE

A 42-year-old man, an avid runner with hyperlipidemia and a strong family history of premature CAD, presents with several months of declining exercise tolerance. His physical examination and electrocardiogram are unremarkable. Myocardial perfusion imaging shows stress-induced ischemia affecting about 20% of the inferolateral myocardium. He is then referred for coronary angiography.

• Panel A: Discrete, high-grade stenosis of the mid-right coronary artery
• Panel B: Diffuse, multivessel disease involving the distal right coronary artery (B1) and the proximal left circumflex coronary artery (B2)
• Panel C: Total occlusion of the proximal right coronary artery with extensive left-to-right collaterals.

Treatment based on angiographic findings

In panel A, there is little to debate. The patient is likely to benefit from percutaneous revascularization of the right coronary artery to treat symptoms.

In panels B1 and B2, there is abundant evidence that the hemodynamic assessment of stenosis is superior to a visual estimate in directing PCI.^1,2 Hemodynamic assessments including fractional flow reserve (FFR) inform the risk-benefit analysis of percutaneous vs medical treatment of coronary stenosis. In the case of FFR, 0.8 represents an inflection point. The lower FFR values are below 0.8, the greater the benefit of PCI as opposed to medical therapy. Conversely, the greater FFR values are above 0.8, the greater the benefit of medical therapy as opposed to PCI.

However, in panel C, there is significant variability in the data supporting the best treatment strategy for symptomatic patients with CTO.

CORONARY CTO

Coronary CTO is defined as TIMI 0 flow for more than 3 months in an epicardial coronary artery. CTO is not uncommon, seen on 30% of routine coronary angiograms. In the United States, attempt rates of PCI for CTO remain low and have been static at around 12.4%, representing less than 5% of total PCI volume.³ In addition, success rates of CTO PCI are disappointingly low at 59% compared with success rates of patent-vessel PCI at 96%.³ The most frequently cited barriers to CTO PCI are incomplete evidence for efficacy and concerns about safety. Because of the ongoing controversy about the risks and benefits of CTO PCI, it remains a class IIa indication in current American and European practice guidelines.^4,5 In addition, these procedures remain technically challenging, and thus variability in local expertise can influence the decision to manage patients medically or refer for CTO PCI.

Patients are often advised that CTO is benign. However, the myocardium affected by a CTO is ischemic. Collateral vessels do not provide adequate flow reserve. FFR data collected from CTOs that were successfully crossed and subsequently interrogated with a pressure wire prior to stenting show that the myocardium supplied by the reconstituted distal bed remains ischemic. This ischemic burden appears to be independent of the size and quality of collaterals.^6,7 In addition, a moderate stenosis in a donor coronary artery supplying collateral vessels to a CTO may result in an ischemic FFR as a consequence of coronary “steal” from the donor artery to the collateral vessels. The ischemic FFR in the donor artery can be corrected by treating the recipient CTO vessel.⁸

Similar to FFR, noninvasive assessment using myocardial perfusion imaging can define ischemic burden and a threshold for benefit of percutaneous vs medical management of CAD. Ischemia greater than 10% on myocardial perfusion imaging is associated with a high risk of major adverse cardiac events (MACE).⁹  Similar findings were noted in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy, which showed superior reduction in angina and MACE in patients with greater than 10% ischemia on myocardial perfusion imaging treated with PCI vs medical therapy.¹⁰ In the case of coronary CTO, ischemia greater than 12.5% is predictive of significant improvement in symptoms after intervention.¹¹

PROGNOSIS AND DISEASE BURDEN

CTO is associated with adverse prognosis, implying the importance of incomplete revascularization. The Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial used a scoring system to direct surgical vs percutaneous revascularization strategies in patients with complex or multivessel CAD. A post hoc analysis of the SYNTAX trial showed that incomplete revascularization was associated with significantly higher rates of 4-year mortality and MACE.¹² This was likely from the ischemic burden remaining from incomplete revascularization. The presence of CTO was the strongest independent predictor of incomplete revascularization in the SYNTAX PCI arm. Similarly, the negative prognostic impact of having a CTO has been observed in a large population of patients followed prospectively after undergoing coronary angiography.¹³ Furthermore, the presence of CTO in a non-infarct-related artery at the time of ST-elevation myocardial infarction appears to be an independent predictor of death at 30 days, with a persistent negative prognostic impact lasting for up to 36 months of follow-up.¹⁴

In patients with significant ischemic burden, CTO PCI has multiple clinical benefits. Symptomatic relief based on the Seattle Angina Questionnaire appears to be similar to that obtained with coronary artery bypass grafting (CABG) at 1-month follow up.¹⁵ Successful CTO PCI can have a positive impact on the risk of mortality in prospective¹³ and retrospective observational studies.¹⁶

CTO intervention may also have beneficial effects on left ventricular systolic function in patients with viable myocardium in the corresponding coronary territory.¹⁷ This improvement in systolic function appears to be sustained at 3 years of follow-up.¹⁸ Meta-analysis of observational data in symptomatic and ischemic patients who underwent successful CTO PCI shows reduced rates of all-cause mortality and MACE and a reduced need for subsequent CABG.¹⁹ This is in contrast to the frequently cited Occluded Artery Trial (OAT) trial, which showed no clinical benefit of PCI for a subacutely occluded infarct-related artery.²⁰

EVIDENCE-BASED BENEFITS

Evidence of the merits of CTO PCI from randomized clinical trials is mixed. The only published study to date, the Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Segment Elevation (EXPLORE) trial, showed no difference in left ventricular systolic function 4 months after ST-elevation myocardial infarction in patients undergoing staged CTO PCI of a non-infarct-related artery vs optimal medical therapy.²¹ Two larger trials presented at scientific meetings in 2017 remain unpublished. One trial showed noninferiority of optimal medical therapy vs successful CTO PCI in reducing the composite end point of all-cause mortality, myocardial infarction, stroke, and repeat revascularization; the other trial showed significant improvement in quality of life measures using the Seattle Angina Questionnaire score and Canadian Cardiovascular Society angina classification in patients who underwent successful CTO PCI compared with medical management.

High-volume CTO PCI centers now report procedural success rates as high as 92.9%²² and a correlation between the CTO PCI volume and CTO PCI success rates.³ The dramatic improvement in success rates achieved by high-volume operators globally can be attributed to a combination of operator experience, improved technology, and widespread adoption of the hybrid algorithm, which has helped to improve efficiency and standardize treatment in CTO PCI based on angiographic criteria.²³ CTO PCI remains a highly specialized procedure, unique from patent-vessel PCI and with little correlation between total PCI volume and CTO PCI success rate. Despite recent advances, CTO PCI success remains heavily dependent on operator expertises, with a steep and long learning curve. In addition, the unique technical aspects of CTO PCI such as a retrograde and subintimal guidewire tracking that have accelerated procedural success are associated with higher rates of MACE compared with traditional antegrade and intraluminal guidewire tracking.^24,25 Therefore, CTO PCI requires unique considerations beyond standard PCI in terms of potential complications. Uncommon but potentially life-threatening complications such as donor artery thrombosis, collateral vessel trauma, gear entrapment, and radiation skin injury demand a specialized informed consent process for the patient.²⁶

In light of incomplete evidence based on extensive observational data and limited randomized clinical trials, the decision to refer patients for CTO PCI requires a comprehensive clinical evaluation. We know from data derived from patients with patent but stenotic coronary arteries that physiologically rather than angiographically driven decisions to revascularize can produce superior clinical results. There is an ischemic burden threshold beyond which revascularization is superior to optimal medical therapy. In this context, we know that CTO is not benign and is associated with ischemic burden. Consequently, patients with symptoms related to CTO represent a subset of patients with incomplete revascularization.

CONCLUSION

Despite recent advances, CTO PCI procedures remain technically demanding, and success with a low complication rate is heavily dependent on operator expertise. Therefore, CTO PCI should be used judiciously in patients with angina refractory to optimal medical therapy. It is an important tool to be used in conjunction with non-CTO PCI, CABG, and optimal medical therapy to produce favorable outcomes in patients with CAD.

In patients with stable coronary artery disease (CAD), the cornerstone of treatment is medical management to control symptoms such as angina and dyspnea on exertion. But in a select group of patients, percutaneous coronary intervention (PCI) is indicated in addition to medical management. Invasive and noninvasive hemodynamic assessments of coronary artery stenosis in conjunction with anatomic considerations play a role in decision-making and in advising patients on revascularization vs medical management. However, in the case of coronary artery chronic total occlusion (CTO), the decision-making process remains challenging due to limited evidence supporting clinical efficacy of CTO PCI, as well as practical considerations including lower success rates and higher complication rates in comparison with patent-vessel PCI.

CLINICAL VIGNETTE

A 42-year-old man, an avid runner with hyperlipidemia and a strong family history of premature CAD, presents with several months of declining exercise tolerance. His physical examination and electrocardiogram are unremarkable. Myocardial perfusion imaging shows stress-induced ischemia affecting about 20% of the inferolateral myocardium. He is then referred for coronary angiography.

• Panel A: Discrete, high-grade stenosis of the mid-right coronary artery
• Panel B: Diffuse, multivessel disease involving the distal right coronary artery (B1) and the proximal left circumflex coronary artery (B2)
• Panel C: Total occlusion of the proximal right coronary artery with extensive left-to-right collaterals.

Treatment based on angiographic findings

In panel A, there is little to debate. The patient is likely to benefit from percutaneous revascularization of the right coronary artery to treat symptoms.

In panels B1 and B2, there is abundant evidence that the hemodynamic assessment of stenosis is superior to a visual estimate in directing PCI.^1,2 Hemodynamic assessments including fractional flow reserve (FFR) inform the risk-benefit analysis of percutaneous vs medical treatment of coronary stenosis. In the case of FFR, 0.8 represents an inflection point. The lower FFR values are below 0.8, the greater the benefit of PCI as opposed to medical therapy. Conversely, the greater FFR values are above 0.8, the greater the benefit of medical therapy as opposed to PCI.

However, in panel C, there is significant variability in the data supporting the best treatment strategy for symptomatic patients with CTO.

CORONARY CTO

Coronary CTO is defined as TIMI 0 flow for more than 3 months in an epicardial coronary artery. CTO is not uncommon, seen on 30% of routine coronary angiograms. In the United States, attempt rates of PCI for CTO remain low and have been static at around 12.4%, representing less than 5% of total PCI volume.³ In addition, success rates of CTO PCI are disappointingly low at 59% compared with success rates of patent-vessel PCI at 96%.³ The most frequently cited barriers to CTO PCI are incomplete evidence for efficacy and concerns about safety. Because of the ongoing controversy about the risks and benefits of CTO PCI, it remains a class IIa indication in current American and European practice guidelines.^4,5 In addition, these procedures remain technically challenging, and thus variability in local expertise can influence the decision to manage patients medically or refer for CTO PCI.

Patients are often advised that CTO is benign. However, the myocardium affected by a CTO is ischemic. Collateral vessels do not provide adequate flow reserve. FFR data collected from CTOs that were successfully crossed and subsequently interrogated with a pressure wire prior to stenting show that the myocardium supplied by the reconstituted distal bed remains ischemic. This ischemic burden appears to be independent of the size and quality of collaterals.^6,7 In addition, a moderate stenosis in a donor coronary artery supplying collateral vessels to a CTO may result in an ischemic FFR as a consequence of coronary “steal” from the donor artery to the collateral vessels. The ischemic FFR in the donor artery can be corrected by treating the recipient CTO vessel.⁸

Similar to FFR, noninvasive assessment using myocardial perfusion imaging can define ischemic burden and a threshold for benefit of percutaneous vs medical management of CAD. Ischemia greater than 10% on myocardial perfusion imaging is associated with a high risk of major adverse cardiac events (MACE).⁹  Similar findings were noted in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy, which showed superior reduction in angina and MACE in patients with greater than 10% ischemia on myocardial perfusion imaging treated with PCI vs medical therapy.¹⁰ In the case of coronary CTO, ischemia greater than 12.5% is predictive of significant improvement in symptoms after intervention.¹¹

PROGNOSIS AND DISEASE BURDEN

CTO is associated with adverse prognosis, implying the importance of incomplete revascularization. The Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial used a scoring system to direct surgical vs percutaneous revascularization strategies in patients with complex or multivessel CAD. A post hoc analysis of the SYNTAX trial showed that incomplete revascularization was associated with significantly higher rates of 4-year mortality and MACE.¹² This was likely from the ischemic burden remaining from incomplete revascularization. The presence of CTO was the strongest independent predictor of incomplete revascularization in the SYNTAX PCI arm. Similarly, the negative prognostic impact of having a CTO has been observed in a large population of patients followed prospectively after undergoing coronary angiography.¹³ Furthermore, the presence of CTO in a non-infarct-related artery at the time of ST-elevation myocardial infarction appears to be an independent predictor of death at 30 days, with a persistent negative prognostic impact lasting for up to 36 months of follow-up.¹⁴

In patients with significant ischemic burden, CTO PCI has multiple clinical benefits. Symptomatic relief based on the Seattle Angina Questionnaire appears to be similar to that obtained with coronary artery bypass grafting (CABG) at 1-month follow up.¹⁵ Successful CTO PCI can have a positive impact on the risk of mortality in prospective¹³ and retrospective observational studies.¹⁶

CTO intervention may also have beneficial effects on left ventricular systolic function in patients with viable myocardium in the corresponding coronary territory.¹⁷ This improvement in systolic function appears to be sustained at 3 years of follow-up.¹⁸ Meta-analysis of observational data in symptomatic and ischemic patients who underwent successful CTO PCI shows reduced rates of all-cause mortality and MACE and a reduced need for subsequent CABG.¹⁹ This is in contrast to the frequently cited Occluded Artery Trial (OAT) trial, which showed no clinical benefit of PCI for a subacutely occluded infarct-related artery.²⁰

EVIDENCE-BASED BENEFITS

Evidence of the merits of CTO PCI from randomized clinical trials is mixed. The only published study to date, the Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Segment Elevation (EXPLORE) trial, showed no difference in left ventricular systolic function 4 months after ST-elevation myocardial infarction in patients undergoing staged CTO PCI of a non-infarct-related artery vs optimal medical therapy.²¹ Two larger trials presented at scientific meetings in 2017 remain unpublished. One trial showed noninferiority of optimal medical therapy vs successful CTO PCI in reducing the composite end point of all-cause mortality, myocardial infarction, stroke, and repeat revascularization; the other trial showed significant improvement in quality of life measures using the Seattle Angina Questionnaire score and Canadian Cardiovascular Society angina classification in patients who underwent successful CTO PCI compared with medical management.

High-volume CTO PCI centers now report procedural success rates as high as 92.9%²² and a correlation between the CTO PCI volume and CTO PCI success rates.³ The dramatic improvement in success rates achieved by high-volume operators globally can be attributed to a combination of operator experience, improved technology, and widespread adoption of the hybrid algorithm, which has helped to improve efficiency and standardize treatment in CTO PCI based on angiographic criteria.²³ CTO PCI remains a highly specialized procedure, unique from patent-vessel PCI and with little correlation between total PCI volume and CTO PCI success rate. Despite recent advances, CTO PCI success remains heavily dependent on operator expertises, with a steep and long learning curve. In addition, the unique technical aspects of CTO PCI such as a retrograde and subintimal guidewire tracking that have accelerated procedural success are associated with higher rates of MACE compared with traditional antegrade and intraluminal guidewire tracking.^24,25 Therefore, CTO PCI requires unique considerations beyond standard PCI in terms of potential complications. Uncommon but potentially life-threatening complications such as donor artery thrombosis, collateral vessel trauma, gear entrapment, and radiation skin injury demand a specialized informed consent process for the patient.²⁶

In light of incomplete evidence based on extensive observational data and limited randomized clinical trials, the decision to refer patients for CTO PCI requires a comprehensive clinical evaluation. We know from data derived from patients with patent but stenotic coronary arteries that physiologically rather than angiographically driven decisions to revascularize can produce superior clinical results. There is an ischemic burden threshold beyond which revascularization is superior to optimal medical therapy. In this context, we know that CTO is not benign and is associated with ischemic burden. Consequently, patients with symptoms related to CTO represent a subset of patients with incomplete revascularization.

CONCLUSION

Despite recent advances, CTO PCI procedures remain technically demanding, and success with a low complication rate is heavily dependent on operator expertise. Therefore, CTO PCI should be used judiciously in patients with angina refractory to optimal medical therapy. It is an important tool to be used in conjunction with non-CTO PCI, CABG, and optimal medical therapy to produce favorable outcomes in patients with CAD.

In patients with stable coronary artery disease (CAD), the cornerstone of treatment is medical management to control symptoms such as angina and dyspnea on exertion. But in a select group of patients, percutaneous coronary intervention (PCI) is indicated in addition to medical management. Invasive and noninvasive hemodynamic assessments of coronary artery stenosis in conjunction with anatomic considerations play a role in decision-making and in advising patients on revascularization vs medical management. However, in the case of coronary artery chronic total occlusion (CTO), the decision-making process remains challenging due to limited evidence supporting clinical efficacy of CTO PCI, as well as practical considerations including lower success rates and higher complication rates in comparison with patent-vessel PCI.

CLINICAL VIGNETTE

A 42-year-old man, an avid runner with hyperlipidemia and a strong family history of premature CAD, presents with several months of declining exercise tolerance. His physical examination and electrocardiogram are unremarkable. Myocardial perfusion imaging shows stress-induced ischemia affecting about 20% of the inferolateral myocardium. He is then referred for coronary angiography.

• Panel A: Discrete, high-grade stenosis of the mid-right coronary artery
• Panel B: Diffuse, multivessel disease involving the distal right coronary artery (B1) and the proximal left circumflex coronary artery (B2)
• Panel C: Total occlusion of the proximal right coronary artery with extensive left-to-right collaterals.

Treatment based on angiographic findings

In panel A, there is little to debate. The patient is likely to benefit from percutaneous revascularization of the right coronary artery to treat symptoms.

In panels B1 and B2, there is abundant evidence that the hemodynamic assessment of stenosis is superior to a visual estimate in directing PCI.^1,2 Hemodynamic assessments including fractional flow reserve (FFR) inform the risk-benefit analysis of percutaneous vs medical treatment of coronary stenosis. In the case of FFR, 0.8 represents an inflection point. The lower FFR values are below 0.8, the greater the benefit of PCI as opposed to medical therapy. Conversely, the greater FFR values are above 0.8, the greater the benefit of medical therapy as opposed to PCI.

However, in panel C, there is significant variability in the data supporting the best treatment strategy for symptomatic patients with CTO.

CORONARY CTO

Coronary CTO is defined as TIMI 0 flow for more than 3 months in an epicardial coronary artery. CTO is not uncommon, seen on 30% of routine coronary angiograms. In the United States, attempt rates of PCI for CTO remain low and have been static at around 12.4%, representing less than 5% of total PCI volume.³ In addition, success rates of CTO PCI are disappointingly low at 59% compared with success rates of patent-vessel PCI at 96%.³ The most frequently cited barriers to CTO PCI are incomplete evidence for efficacy and concerns about safety. Because of the ongoing controversy about the risks and benefits of CTO PCI, it remains a class IIa indication in current American and European practice guidelines.^4,5 In addition, these procedures remain technically challenging, and thus variability in local expertise can influence the decision to manage patients medically or refer for CTO PCI.

Patients are often advised that CTO is benign. However, the myocardium affected by a CTO is ischemic. Collateral vessels do not provide adequate flow reserve. FFR data collected from CTOs that were successfully crossed and subsequently interrogated with a pressure wire prior to stenting show that the myocardium supplied by the reconstituted distal bed remains ischemic. This ischemic burden appears to be independent of the size and quality of collaterals.^6,7 In addition, a moderate stenosis in a donor coronary artery supplying collateral vessels to a CTO may result in an ischemic FFR as a consequence of coronary “steal” from the donor artery to the collateral vessels. The ischemic FFR in the donor artery can be corrected by treating the recipient CTO vessel.⁸

Similar to FFR, noninvasive assessment using myocardial perfusion imaging can define ischemic burden and a threshold for benefit of percutaneous vs medical management of CAD. Ischemia greater than 10% on myocardial perfusion imaging is associated with a high risk of major adverse cardiac events (MACE).⁹  Similar findings were noted in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy, which showed superior reduction in angina and MACE in patients with greater than 10% ischemia on myocardial perfusion imaging treated with PCI vs medical therapy.¹⁰ In the case of coronary CTO, ischemia greater than 12.5% is predictive of significant improvement in symptoms after intervention.¹¹

PROGNOSIS AND DISEASE BURDEN

CTO is associated with adverse prognosis, implying the importance of incomplete revascularization. The Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial used a scoring system to direct surgical vs percutaneous revascularization strategies in patients with complex or multivessel CAD. A post hoc analysis of the SYNTAX trial showed that incomplete revascularization was associated with significantly higher rates of 4-year mortality and MACE.¹² This was likely from the ischemic burden remaining from incomplete revascularization. The presence of CTO was the strongest independent predictor of incomplete revascularization in the SYNTAX PCI arm. Similarly, the negative prognostic impact of having a CTO has been observed in a large population of patients followed prospectively after undergoing coronary angiography.¹³ Furthermore, the presence of CTO in a non-infarct-related artery at the time of ST-elevation myocardial infarction appears to be an independent predictor of death at 30 days, with a persistent negative prognostic impact lasting for up to 36 months of follow-up.¹⁴

In patients with significant ischemic burden, CTO PCI has multiple clinical benefits. Symptomatic relief based on the Seattle Angina Questionnaire appears to be similar to that obtained with coronary artery bypass grafting (CABG) at 1-month follow up.¹⁵ Successful CTO PCI can have a positive impact on the risk of mortality in prospective¹³ and retrospective observational studies.¹⁶

CTO intervention may also have beneficial effects on left ventricular systolic function in patients with viable myocardium in the corresponding coronary territory.¹⁷ This improvement in systolic function appears to be sustained at 3 years of follow-up.¹⁸ Meta-analysis of observational data in symptomatic and ischemic patients who underwent successful CTO PCI shows reduced rates of all-cause mortality and MACE and a reduced need for subsequent CABG.¹⁹ This is in contrast to the frequently cited Occluded Artery Trial (OAT) trial, which showed no clinical benefit of PCI for a subacutely occluded infarct-related artery.²⁰

EVIDENCE-BASED BENEFITS

Evidence of the merits of CTO PCI from randomized clinical trials is mixed. The only published study to date, the Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Segment Elevation (EXPLORE) trial, showed no difference in left ventricular systolic function 4 months after ST-elevation myocardial infarction in patients undergoing staged CTO PCI of a non-infarct-related artery vs optimal medical therapy.²¹ Two larger trials presented at scientific meetings in 2017 remain unpublished. One trial showed noninferiority of optimal medical therapy vs successful CTO PCI in reducing the composite end point of all-cause mortality, myocardial infarction, stroke, and repeat revascularization; the other trial showed significant improvement in quality of life measures using the Seattle Angina Questionnaire score and Canadian Cardiovascular Society angina classification in patients who underwent successful CTO PCI compared with medical management.

High-volume CTO PCI centers now report procedural success rates as high as 92.9%²² and a correlation between the CTO PCI volume and CTO PCI success rates.³ The dramatic improvement in success rates achieved by high-volume operators globally can be attributed to a combination of operator experience, improved technology, and widespread adoption of the hybrid algorithm, which has helped to improve efficiency and standardize treatment in CTO PCI based on angiographic criteria.²³ CTO PCI remains a highly specialized procedure, unique from patent-vessel PCI and with little correlation between total PCI volume and CTO PCI success rate. Despite recent advances, CTO PCI success remains heavily dependent on operator expertises, with a steep and long learning curve. In addition, the unique technical aspects of CTO PCI such as a retrograde and subintimal guidewire tracking that have accelerated procedural success are associated with higher rates of MACE compared with traditional antegrade and intraluminal guidewire tracking.^24,25 Therefore, CTO PCI requires unique considerations beyond standard PCI in terms of potential complications. Uncommon but potentially life-threatening complications such as donor artery thrombosis, collateral vessel trauma, gear entrapment, and radiation skin injury demand a specialized informed consent process for the patient.²⁶

In light of incomplete evidence based on extensive observational data and limited randomized clinical trials, the decision to refer patients for CTO PCI requires a comprehensive clinical evaluation. We know from data derived from patients with patent but stenotic coronary arteries that physiologically rather than angiographically driven decisions to revascularize can produce superior clinical results. There is an ischemic burden threshold beyond which revascularization is superior to optimal medical therapy. In this context, we know that CTO is not benign and is associated with ischemic burden. Consequently, patients with symptoms related to CTO represent a subset of patients with incomplete revascularization.

CONCLUSION

Despite recent advances, CTO PCI procedures remain technically demanding, and success with a low complication rate is heavily dependent on operator expertise. Therefore, CTO PCI should be used judiciously in patients with angina refractory to optimal medical therapy. It is an important tool to be used in conjunction with non-CTO PCI, CABG, and optimal medical therapy to produce favorable outcomes in patients with CAD.

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the exact incidence of VTE is unknown, an estimated 1 million people in the United States are affected each year, with about a third experiencing a recurrence within 10 years.¹ VTE affects hospitalized and nonhospitalized patients, is often overlooked, and results in long-term complications including postthrombotic syndrome (PTS) for DVT, postpulmonary embolism syndrome and chronic thromboembolic pulmonary hypertension for PE, and death.²

TREATMENT

Treatment for VTE should be initiated in the following cases:

• Proximal DVT of the lower extremity
• Symptomatic distal (calf vein) DVT
• Symptomatic upper extremity DVT (axillary-subclavian veins)
• PE
• Subsegmental PE in a patient at risk for recurrence
• Surveillance for subsegmental PE in a patient with no proximal DVT and a low risk of recurrence.

In addition to anticoagulants, other more aggressive therapies for VTE may be appropriate, such as systemic thrombolysis in the case of PE or catheter-directed thrombolytic or pharmacomechnical therapies for DVT or PE, surgical intervention (acute pulmonary embolectomy), or placement of an inferior vena cava (IVC) filter.

This article reviews the management of VTE, highlighting the recent changes in treatment and prevention guidelines from the American College of Chest Physicians (ACCP).³

Risk of bleeding

In assessing a patient’s risk of bleeding for anticoagulation therapy (Table 1), the absence of risk factors is considered low risk for bleeding, the presence of 1 risk factor is considered intermediate risk, and 2 or more risk factors is considered high risk. Compared with low-risk patients, moderate-risk patients have a twofold increased risk of major bleeding and high-risk patients have an eightfold increased risk of major bleeding. This equates to an annualized risk of major bleeding of 0.8% for low-risk patients, 1.6% for moderate-risk patients, and greater than 6.5% for high-risk patients.³

Anticoagulants

Deciding on which anticoagulant to use depends on the indication, the patient’s underlying condition, the patient’s preference, and the patient’s risk of bleeding. Heparin, the LMWHs, fondaparinux and the DOACs (rivaroxaban and apixaban) are the only agents approved by the US Food and Drug Administration (FDA) recommended for the acute treatment phase, while the DOACs and warfarin are anticoagulation options for the long-term and extended treatment phases. The LMWHs should be used for the patient with cancer and during pregnancy.

Unfractionated heparin. UFH is administered parenterally and can be used for the prevention and treatment of VTE. Heparin remains an option for initial treatment of patients with acute VTE and is generally preferred over LMWH for patients who may require advanced therapies, such as for hemodynamically unstable PE or iliofemoral DVT. It is also recommended for patients with renal failure.³ Weight-based dosing (80 U/kg bolus followed by 18 U/kg/hour intravenous infusion) is recommended, targeting an antifactor activated clotting factor (anti-Xa) assay level of 0.3 IU/mL to 0.7 IU/mL. Heparin may also be given subcutaneously in an outpatient setting using an initial bolus of 333 U/kg followed by a subcutaneous dose of 17,500 U twice daily.⁵

Low-molecular-weight heparin. LMWHs are administered as weight-based subcutaneous injections and have indications for patients with acute VTE and for VTE prophylaxis. LMWHs are used for transitioning to warfarin, dabigatran, or edoxaban for long-term anticoagulation and are recommended over warfarin and DOACs for treatment of VTE in patients with cancer and in pregnant women.³

Enoxaparin (Lovenox), the most commonly used agent in the United States, is given either as a once-daily injection (1.5 mg/kg/day) or a twice-daily injection (1 mg/kg every 12 hours). It is also approved for VTE prophylaxis in patients undergoing hip or knee replacement surgery or abdominal surgery, or in patients with severely restricted mobility during acute illness. LMWH can also be given in patients with renal insufficiency (creatinine clearance [CrCL] < 30 mL/minute) after dose adjustment. No monitoring is required, although it is advised in pediatric patients, pregnant women, obese patients, and patients with renal insufficiency. If monitoring is required, an anti-Xa assay using LMWH as a reference standard should be done 4 hours after subcutaneous injection. The therapeutic range for enoxaparin is 0.5 IU/mL to 1.0 IU/mL for the 12-hour regimen and greater than 1.0 IU/mL for the once-daily dose. Other LMWHs available in the United States include dalteparin (Fragmin) and tinzaparin (Innohep). Each has its own specific indications.

Fondaparinux. Fondaparinux is an indirect factor Xa inhibitor, chemically related to LMWH. It is approved for treatment of patients with acute VTE when used in combination with a VKA (warfarin) or dabigatran or edoxaban. It also has approval for VTE prophylaxis in patients undergoing hip fracture, hip or knee replacement, and abdominal surgery. Fondaparinux is administered as a once-daily subcutaneous injection of 2.5 mg for DVT prophylaxis and a body weight-based dose for the treatment of VTE (5 mg < 50 kg; 7.5 mg 50 to 100 kg; 10 mg > 100 kg).⁶ Fondaparinux is contraindicated in patients with severe renal impairment (CrCL les 30 mL/min) and bacterial endocarditis.⁶

Warfarin. Warfarin, a VKA, was the mainstay of therapy for long-term and extended treatment of VTE until the advent of the DOACs. Warfarin must be coadministered with heparin, LMWH, or fondaparinux initially and continued as overlap therapy for a minimum of 5 days until the international normalized ratio [INR] is at least 2.0 for 24 hours.⁴ Early initiation of a VKA on the first day of parenteral therapy is advised.

Warfarin remains the best option for patients on long-term or extended anticoagulation with liver dysfunction (elevated serum transaminases exceeding twice the upper limits of normal or active liver disease) or renal disease (CrCL < 30 mL/min), as well as patients unable to afford DOACs. Additionally, select patient populations may still be best served by warfarin as these groups were underrepresented or not included in DOAC trials, including pediatric patients, individuals with body weight less than 50 kg or greater than 150 kg, and patients with select types of thrombophilia (eg, antiphospholipid syndrome). Warfarin is also advised for patients with poor compliance, as international normalized ratio of prothrombin time (PT/INR) monitoring is required using a point-of-care testing device or during a visit to an anticoagulation clinic. DOACs do not require monitoring, and noncompliance will not be readily apparent.

Direct oral anticoagulants. The DOACs, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) and the direct thrombin inhibitor dabigatran (Pradaxa), been studied extensively and shown to be noninferior to VKAs for treatment of VTE.⁷ DOACs are currently recommended by the ACCP for long-term treatment of VTE, and several have extended treatment recommendations for VTE over the VKAs.³

The advantages of DOACs include no need for PT/INR monitoring, a fixed dosage, shorter half-life, rapid onset of action (for monotherapy), and in most cases, no need for bridging for interventional or surgical procedures. Additional advantages may include a decreased burden of care for the physician and improved quality of life for the patient. DOACs are also the agents of choice for patients who prefer oral therapy (avoiding parenteral therapy), have limited access to an anticoagulation clinic (home bound or geographic inaccessibility for PT/INR monitoring), or have food or drug-drug interactions. Patients at risk of gastrointestinal bleeding or dyspepsia should avoid dabigatran, while apixaban may be preferred if there is a history of gastrointestinal bleeding.⁸

Rivaroxaban or apixaban can be used as monotherapy for the initial treatment of VTE, while a 5-day course of heparin, LMWH, or fondaparinux is necessary with dabigatran or edoxaban. Rivaroxaban has been approved by the FDA for use in the prevention and treatment of VTE.^9,10 For VTE prophylaxis, rivaroxaban is given orally at 10 mg once daily for 35 days for patients undergoing total hip replacement surgery and for 12 days for patients undergoing knee replacement surgery. For the treatment of VTE, rivaroxaban is given orally at 15 mg twice a day for the initial 21 days of treatment, followed by once daily at 20 mg per day for long-term treatment. It is also approved for extended-duration therapy in both 10-mg and 20-mg doses. In a recently published randomized double-blind trial of rivaroxaban compared with aspirin, the risk of a recurrent event was lower with either dose of rivaroxaban compared with aspirin without an increase in bleeding.¹¹ Rivaroxaban is contraindicated in patients with renal insufficiency (CrCL < 30 mL/min). Both the 15-mg and 20-mg tablets must be taken with food.

Apixaban is also approved for monotherapy of VTE and was found to be noninferior to standard therapy of LMWH and warfarin with less bleeding.¹² Apixaban is used for VTE prophylaxis in patients undergoing hip or knee replacement surgery, given at 2.5 mg twice daily beginning 12 to 24 hours postoperatively for 35 days (hip) or 12 days (knee). The acute-phase dosage is 10 mg twice daily for 7 days followed by 5 mg twice daily for long-term treatment of VTE. The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater. Apixaban is also approved for extended treatment of VTE. In a randomized, double-blind study of 2 doses (2.5 mg and 5 mg, twice daily) of apixaban compared with placebo, apixaban reduced the risk of recurrent VTE without increasing the risk of bleeding.¹³

Both dabigatran and edoxaban require an initial 5-day overlap with a parenteral anticoagulant.^14,15  Dabigatran is given at 150 mg orally twice daily if the CrCL is greater than 30 mL/min for the long-term treatment of VTE. Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors. Dabigatran has been evaluated in 2 double-blind, randomized controlled trials comparing the extended use of dabigatran with warfarin or placebo in patients with VTE.¹⁶ Dabigatran carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. Dabigatran was noninferior to warfarin but significantly reduced the rate of recurrence in the placebo group.¹⁶

The major side effect observed with all DOACs is bleeding, but they have been proven safer particularly in the terms of major bleeding compared with the standard heparin-LMWH-VKA regimen for treatment of VTE.^17–19 The risk of major bleeding, and in particular intracranial bleeding, has been shown to be less with DOACs compared with VKAs in 2 meta-analysis trials.^17,18 Of the 4 new DOACs, only dabigatran currently has an anticoagulant-reversing agent (idarucizumab), although an antidote for the other 3 agents is awaiting FDA approval.²⁰

Subsegmental pulmonary embolism

There is debate as to the need for treatment of patients with subsegmental PE. The most recent guidelines advise clinical surveillance over anticoagulation for patients with a low risk for recurrent VTE and no evidence for a proximal DVT.³ However, individuals who are hospitalized, have reduced mobility, have active cancer or are being treated with chemotherapy, or have a low cardiopulmonary reserve should be considered for anticoagulation unless they have a high bleeding risk.

Thrombolytic therapy

Thrombolytic therapy may be beneficial in select patients with VTE and can be delivered systemically or locally per catheter-directed therapy (CDT). Both routes carry an increased risk of hemorrhage compared with standard anticoagulation. The Catheter-Directed-Venous Thrombolysis (CaVenT) trial and Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial compared CDT with standard therapy.^21,22 In CaVEnT, CDT resulted in increased clinical benefit during the 5-year follow-up but did not result in improved quality of life.²¹ In the TORPEDO trial, patients with proximal DVT receiving percutaneous endovenous intervention and anticoagulation compared with anticoagulation alone demonstrated superiority in the reduction of PTS at greater than 2 years.²² Early results of the Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial show that most patients with DVT did not have a long-term benefit from CDT, buy they did have reduced leg pain and swelling and some had reduced risk of moderate-to-severe PTS.²³

The 2012 and 2016 ACCP guidelines advise anticoagulant therapy over CDT for patients with acute DVT of the leg but suggest patients who may benefit are those with iliofemoral DVT with symptoms for less than 14 days, good functional status, a life expectancy greater than 1 year, and a low risk of bleeding.^3,4 This is in contrast to the 2008 CHEST guidelines that recommended patients who have extensive proximal DVT, who have a high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status be given CDT if the expertise and resources are available.²⁴ It has been suggested that CDT promotes early recanalization and minimizes the incidence of PTS.

Thrombolytic therapy for acute PE remains controversial because there is no clearly established short-term mortality benefit. In the Pulmonary Embolism Thrombolysis (PEITHO) trial, thrombolysis prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.²⁵ A lower dose (50 mg) of thrombolytic therapy was studied in the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET) trial and was found to be safe and effective in the treatment of moderate PE.²⁶

CDT has also been shown to be effective in the treatment of PE. The Ultrasound Acceleration Thrombolysis of Pulmonary Embolism (ULTIMA) trial demonstrated that catheter-directed thrombolysis with ultrasonographic guidance in patients with acute intermediate-risk PE was superior in reversing right ventricular dilatation without an increase in bleeding complications compared with UFH.²⁷ The Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) study found that this approach decreased right ventricular dilation, decreased pulmonary hypertension, decreased anatomic burden, and minimized the risk of intracranial hemorrhage in patients with massive and submassive PE.²⁸

Alteplase (Activase) is a recombinant tissue-type plasminogen activator approved by the FDA for treatment of acute PE. Alteplase is administered as a 100-mg infusion over 2 hours. Because of favorable outcomes with prompt recognition and anticoagulation for PE, the ACCP guidelines recommend systemic thrombolysis for hemodynamically unstable patients (systolic blood pressure < 90 mm Hg) with acute PE and a low risk of bleeding using a peripheral vein.³ These guidelines also recommend thrombolysis for the patient whose condition deteriorates after starting anticoagulant therapy but who have yet to develop hypotension.

If the appropriate expertise is available, CDT is suggested for patients with acute PE if they have hypotension and a high bleeding risk, have failed systemic thrombolysis, or are in shock that is likely to cause death before systemic thrombolysis can take effect.³ An area of ongoing debate is whether there is a benefit for thrombolytic therapy in patients with submassive PE who are hemodynamically stable but have evidence of right ventricular dysfunction on echocardiography or computed tomographic angiography. Bleeding remains the most serious complication of thrombolytic therapy.⁴

Pulmonary embolectomy. According to ACCP guidelines, surgical pulmonary embolectomy for the initial treatment of PE is reserved for patients with massive PE (documented angiographically, if possible), shock despite heparin and resuscitation efforts, and failure of thrombolytic therapy or a contraindication to its use.⁴ To date, there have been no randomized trials evaluating this procedure. Pooled data published by Stein et al²⁹ reported a 20% operative mortality rate in patients undergoing pulmonary embolectomy between 1985 and 2005 compared with 32% in patients undergoing the procedure before 1985. A more recent retrospective review of 214 patients undergoing surgical embolectomy for massive and submassive PE reported an in-hospital mortality rate of 11.7%, with the highest death rate (32.1%) in patients who had a preoperative cardiac arrest.³⁰ The use of surgical embolectomy has also been reported in patients with intermediate-risk to high-risk conditions (defined as elevated biomarkers and evidence of right heart strain on computed tomographic angiography or echocardiography).¹⁹

IVC filters. Current guidelines recommend against  routine use of IVC filters for patients with DVT or PE who are able to be treated with anticoagulants.³ Absolute indications for the placement of IVC filters include a contraindication to anticoagulation, complications of anticoagulation, and recurrent thromboembolism despite adequate anticoagulant therapy.⁴ Relative indications for IVC filters are massive PE, iliocaval DVT, free-floating proximal DVT, cardiac or pulmonary insufficiency, high risk of complications from anticoagulation (frequent falls, ataxia), and poor compliance.

Retrievable filters may be considered for situations in which anticoagulation is temporarily contraindicated or there is a short duration of PE risk.³¹ The current consensus guidelines advise that indications for placing a retrievable IVC filter are the same as for placing a permanent device.³¹ An IVC filter alone is not effective therapy for VTE, and resumption of anticoagulation is recommended as soon as possible after placement.

DURATION OF TREATMENT

Current guidelines recommend 3 months of anticoagulation (long-term) for patients with an episode of acute proximal or isolated distal DVT of the leg or PE resulting from surgery or a nonsurgical transient cause.³ Patients who have the antiphospholipid syndrome, who are homozygous for factor V Leiden, or who are doubly heterozygous for factor V Leiden and prothrombin gene mutation should be considered for longer (extended) anticoagulation. Extended anticoagulation is also recommended in patients with active cancer and in patients who have unexplained recurrent VTE (Table 2).³

The duration of treatment for unprovoked VTE remains controversial. In the most recent ACCP guidelines, indefinite or extended anticoagulation is indicated for patients with a low or moderate risk of bleeding for a first (and second) unprovoked VTE.⁴ Patients with a high risk of bleeding with a first (or second) unprovoked VTE that is a proximal DVT of the leg or PE be treated for 3 months.^3,4 Three DOACs (rivaroxaban, apixaban, and dabigatran) have extended-duration indications. The 2016 ACCP guidelines suggest aspirin over no treatment for the patient who has decided to stop anticoagulation therapy, although the guidelines do not consider aspirin a reasonable alternative to anticoagulation.^34,35 Use of markers such as residual venous obstruction and D-dimer level in conjunction with the DASH score have been studied in an effort to predict the risk of recurrence and thus the duration of anticoagulation.^36,37 Residual venous obstruction appears to be less useful than the D-dimer level as an indicator for recurrence. The D-dimer used in conjunction with the DASH prediction score may help to calculate recurrence risk based on the following predictors: abnormal D-dimer 3 weeks after stopping anticoagulation, age under 50, male sex, and hormone use at the time of the VTE.³⁸ DASH score assessment may help physicians decide whether to continue anticoagulation therapy but it has not been shown to be helpful in men.⁴ A more recent study confirmed the validity of the DASH score with better prediction in patients under age 65. The recurrence rate was higher in the older population, suggesting that this population should be considered for prolonged treatment if the bleeding risk is acceptable.³⁹ Other prediction tools include the Vienna prediction model and the clinical decision rule “Men continue and HER DOO2”—ie, HER = hyperpigmentation, edema, redness; DOO = D-dimer ≥ 250 μg/L, obesity body mass index ≥ 30 kg/m², old age (≥ 65); 2 = high risk if more than 2 of these factors.^40,41

SCREENING AND PREVENTION

Nearly 60% of all VTE events occur in hospitals and nursing homes.⁴² Yet anticoagulant prophylaxis is used in only 16% to 33% of at-risk hospitalized medical patients compared with 90% of at-risk hospitalized surgical patients.⁴³ Adequate prophylaxis can reduce the incidence of VTE as demonstrated in a meta-analysis involving 19,958 patients, which revealed a 64% reduction in relative risk (RR) of a fatal PE, 58% reduction in RR of a symptomic PE,  and a 53% reduction in RR of a symptomatic DVT.⁴³

The consequences of VTE include symptomatic DVT and PE, fatal PE, the cost of investigating symptomatic patients, the risk and cost of treatment (bleeding), PTS, and chronic thromboembolic pulmonary hypertension. Heparin, enoxaparin, and fondaparinux are approved agents for prophylactic but each agent has specific indications. Factor Xa inhibitors, rivaroxaban, and apixaban are approved for use in patients undergoing total knee or hip replacement. More recently, the factor Xa inhibitor, betrixaban, has been approved for VTE prophylaxis for up to 42 days in adult patients hospitalized for acute medical illness.⁴⁴ For patients with increased bleeding risk who are unable to receive pharmacologic prophylaxis, intermittent pneumatic compression devices or graduated compression stockings should be used.

Compression stockings

Current ACCP guidelines advise against routine use of compression stockings to prevent PTS in patients who have had a DVT.³ While current evidence suggests compression stockings do not prevent PTS, they reduce symptoms of acute or chronic DVT for some patients.

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the exact incidence of VTE is unknown, an estimated 1 million people in the United States are affected each year, with about a third experiencing a recurrence within 10 years.¹ VTE affects hospitalized and nonhospitalized patients, is often overlooked, and results in long-term complications including postthrombotic syndrome (PTS) for DVT, postpulmonary embolism syndrome and chronic thromboembolic pulmonary hypertension for PE, and death.²

TREATMENT

Treatment for VTE should be initiated in the following cases:

• Proximal DVT of the lower extremity
• Symptomatic distal (calf vein) DVT
• Symptomatic upper extremity DVT (axillary-subclavian veins)
• PE
• Subsegmental PE in a patient at risk for recurrence
• Surveillance for subsegmental PE in a patient with no proximal DVT and a low risk of recurrence.

In addition to anticoagulants, other more aggressive therapies for VTE may be appropriate, such as systemic thrombolysis in the case of PE or catheter-directed thrombolytic or pharmacomechnical therapies for DVT or PE, surgical intervention (acute pulmonary embolectomy), or placement of an inferior vena cava (IVC) filter.

This article reviews the management of VTE, highlighting the recent changes in treatment and prevention guidelines from the American College of Chest Physicians (ACCP).³

Risk of bleeding

In assessing a patient’s risk of bleeding for anticoagulation therapy (Table 1), the absence of risk factors is considered low risk for bleeding, the presence of 1 risk factor is considered intermediate risk, and 2 or more risk factors is considered high risk. Compared with low-risk patients, moderate-risk patients have a twofold increased risk of major bleeding and high-risk patients have an eightfold increased risk of major bleeding. This equates to an annualized risk of major bleeding of 0.8% for low-risk patients, 1.6% for moderate-risk patients, and greater than 6.5% for high-risk patients.³

Anticoagulants

Deciding on which anticoagulant to use depends on the indication, the patient’s underlying condition, the patient’s preference, and the patient’s risk of bleeding. Heparin, the LMWHs, fondaparinux and the DOACs (rivaroxaban and apixaban) are the only agents approved by the US Food and Drug Administration (FDA) recommended for the acute treatment phase, while the DOACs and warfarin are anticoagulation options for the long-term and extended treatment phases. The LMWHs should be used for the patient with cancer and during pregnancy.

Unfractionated heparin. UFH is administered parenterally and can be used for the prevention and treatment of VTE. Heparin remains an option for initial treatment of patients with acute VTE and is generally preferred over LMWH for patients who may require advanced therapies, such as for hemodynamically unstable PE or iliofemoral DVT. It is also recommended for patients with renal failure.³ Weight-based dosing (80 U/kg bolus followed by 18 U/kg/hour intravenous infusion) is recommended, targeting an antifactor activated clotting factor (anti-Xa) assay level of 0.3 IU/mL to 0.7 IU/mL. Heparin may also be given subcutaneously in an outpatient setting using an initial bolus of 333 U/kg followed by a subcutaneous dose of 17,500 U twice daily.⁵

Low-molecular-weight heparin. LMWHs are administered as weight-based subcutaneous injections and have indications for patients with acute VTE and for VTE prophylaxis. LMWHs are used for transitioning to warfarin, dabigatran, or edoxaban for long-term anticoagulation and are recommended over warfarin and DOACs for treatment of VTE in patients with cancer and in pregnant women.³

Enoxaparin (Lovenox), the most commonly used agent in the United States, is given either as a once-daily injection (1.5 mg/kg/day) or a twice-daily injection (1 mg/kg every 12 hours). It is also approved for VTE prophylaxis in patients undergoing hip or knee replacement surgery or abdominal surgery, or in patients with severely restricted mobility during acute illness. LMWH can also be given in patients with renal insufficiency (creatinine clearance [CrCL] < 30 mL/minute) after dose adjustment. No monitoring is required, although it is advised in pediatric patients, pregnant women, obese patients, and patients with renal insufficiency. If monitoring is required, an anti-Xa assay using LMWH as a reference standard should be done 4 hours after subcutaneous injection. The therapeutic range for enoxaparin is 0.5 IU/mL to 1.0 IU/mL for the 12-hour regimen and greater than 1.0 IU/mL for the once-daily dose. Other LMWHs available in the United States include dalteparin (Fragmin) and tinzaparin (Innohep). Each has its own specific indications.

Fondaparinux. Fondaparinux is an indirect factor Xa inhibitor, chemically related to LMWH. It is approved for treatment of patients with acute VTE when used in combination with a VKA (warfarin) or dabigatran or edoxaban. It also has approval for VTE prophylaxis in patients undergoing hip fracture, hip or knee replacement, and abdominal surgery. Fondaparinux is administered as a once-daily subcutaneous injection of 2.5 mg for DVT prophylaxis and a body weight-based dose for the treatment of VTE (5 mg < 50 kg; 7.5 mg 50 to 100 kg; 10 mg > 100 kg).⁶ Fondaparinux is contraindicated in patients with severe renal impairment (CrCL les 30 mL/min) and bacterial endocarditis.⁶

Warfarin. Warfarin, a VKA, was the mainstay of therapy for long-term and extended treatment of VTE until the advent of the DOACs. Warfarin must be coadministered with heparin, LMWH, or fondaparinux initially and continued as overlap therapy for a minimum of 5 days until the international normalized ratio [INR] is at least 2.0 for 24 hours.⁴ Early initiation of a VKA on the first day of parenteral therapy is advised.

Warfarin remains the best option for patients on long-term or extended anticoagulation with liver dysfunction (elevated serum transaminases exceeding twice the upper limits of normal or active liver disease) or renal disease (CrCL < 30 mL/min), as well as patients unable to afford DOACs. Additionally, select patient populations may still be best served by warfarin as these groups were underrepresented or not included in DOAC trials, including pediatric patients, individuals with body weight less than 50 kg or greater than 150 kg, and patients with select types of thrombophilia (eg, antiphospholipid syndrome). Warfarin is also advised for patients with poor compliance, as international normalized ratio of prothrombin time (PT/INR) monitoring is required using a point-of-care testing device or during a visit to an anticoagulation clinic. DOACs do not require monitoring, and noncompliance will not be readily apparent.

Direct oral anticoagulants. The DOACs, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) and the direct thrombin inhibitor dabigatran (Pradaxa), been studied extensively and shown to be noninferior to VKAs for treatment of VTE.⁷ DOACs are currently recommended by the ACCP for long-term treatment of VTE, and several have extended treatment recommendations for VTE over the VKAs.³

The advantages of DOACs include no need for PT/INR monitoring, a fixed dosage, shorter half-life, rapid onset of action (for monotherapy), and in most cases, no need for bridging for interventional or surgical procedures. Additional advantages may include a decreased burden of care for the physician and improved quality of life for the patient. DOACs are also the agents of choice for patients who prefer oral therapy (avoiding parenteral therapy), have limited access to an anticoagulation clinic (home bound or geographic inaccessibility for PT/INR monitoring), or have food or drug-drug interactions. Patients at risk of gastrointestinal bleeding or dyspepsia should avoid dabigatran, while apixaban may be preferred if there is a history of gastrointestinal bleeding.⁸

Rivaroxaban or apixaban can be used as monotherapy for the initial treatment of VTE, while a 5-day course of heparin, LMWH, or fondaparinux is necessary with dabigatran or edoxaban. Rivaroxaban has been approved by the FDA for use in the prevention and treatment of VTE.^9,10 For VTE prophylaxis, rivaroxaban is given orally at 10 mg once daily for 35 days for patients undergoing total hip replacement surgery and for 12 days for patients undergoing knee replacement surgery. For the treatment of VTE, rivaroxaban is given orally at 15 mg twice a day for the initial 21 days of treatment, followed by once daily at 20 mg per day for long-term treatment. It is also approved for extended-duration therapy in both 10-mg and 20-mg doses. In a recently published randomized double-blind trial of rivaroxaban compared with aspirin, the risk of a recurrent event was lower with either dose of rivaroxaban compared with aspirin without an increase in bleeding.¹¹ Rivaroxaban is contraindicated in patients with renal insufficiency (CrCL < 30 mL/min). Both the 15-mg and 20-mg tablets must be taken with food.

Apixaban is also approved for monotherapy of VTE and was found to be noninferior to standard therapy of LMWH and warfarin with less bleeding.¹² Apixaban is used for VTE prophylaxis in patients undergoing hip or knee replacement surgery, given at 2.5 mg twice daily beginning 12 to 24 hours postoperatively for 35 days (hip) or 12 days (knee). The acute-phase dosage is 10 mg twice daily for 7 days followed by 5 mg twice daily for long-term treatment of VTE. The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater. Apixaban is also approved for extended treatment of VTE. In a randomized, double-blind study of 2 doses (2.5 mg and 5 mg, twice daily) of apixaban compared with placebo, apixaban reduced the risk of recurrent VTE without increasing the risk of bleeding.¹³

Both dabigatran and edoxaban require an initial 5-day overlap with a parenteral anticoagulant.^14,15  Dabigatran is given at 150 mg orally twice daily if the CrCL is greater than 30 mL/min for the long-term treatment of VTE. Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors. Dabigatran has been evaluated in 2 double-blind, randomized controlled trials comparing the extended use of dabigatran with warfarin or placebo in patients with VTE.¹⁶ Dabigatran carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. Dabigatran was noninferior to warfarin but significantly reduced the rate of recurrence in the placebo group.¹⁶

The major side effect observed with all DOACs is bleeding, but they have been proven safer particularly in the terms of major bleeding compared with the standard heparin-LMWH-VKA regimen for treatment of VTE.^17–19 The risk of major bleeding, and in particular intracranial bleeding, has been shown to be less with DOACs compared with VKAs in 2 meta-analysis trials.^17,18 Of the 4 new DOACs, only dabigatran currently has an anticoagulant-reversing agent (idarucizumab), although an antidote for the other 3 agents is awaiting FDA approval.²⁰

Subsegmental pulmonary embolism

There is debate as to the need for treatment of patients with subsegmental PE. The most recent guidelines advise clinical surveillance over anticoagulation for patients with a low risk for recurrent VTE and no evidence for a proximal DVT.³ However, individuals who are hospitalized, have reduced mobility, have active cancer or are being treated with chemotherapy, or have a low cardiopulmonary reserve should be considered for anticoagulation unless they have a high bleeding risk.

Thrombolytic therapy

Thrombolytic therapy may be beneficial in select patients with VTE and can be delivered systemically or locally per catheter-directed therapy (CDT). Both routes carry an increased risk of hemorrhage compared with standard anticoagulation. The Catheter-Directed-Venous Thrombolysis (CaVenT) trial and Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial compared CDT with standard therapy.^21,22 In CaVEnT, CDT resulted in increased clinical benefit during the 5-year follow-up but did not result in improved quality of life.²¹ In the TORPEDO trial, patients with proximal DVT receiving percutaneous endovenous intervention and anticoagulation compared with anticoagulation alone demonstrated superiority in the reduction of PTS at greater than 2 years.²² Early results of the Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial show that most patients with DVT did not have a long-term benefit from CDT, buy they did have reduced leg pain and swelling and some had reduced risk of moderate-to-severe PTS.²³

The 2012 and 2016 ACCP guidelines advise anticoagulant therapy over CDT for patients with acute DVT of the leg but suggest patients who may benefit are those with iliofemoral DVT with symptoms for less than 14 days, good functional status, a life expectancy greater than 1 year, and a low risk of bleeding.^3,4 This is in contrast to the 2008 CHEST guidelines that recommended patients who have extensive proximal DVT, who have a high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status be given CDT if the expertise and resources are available.²⁴ It has been suggested that CDT promotes early recanalization and minimizes the incidence of PTS.

Thrombolytic therapy for acute PE remains controversial because there is no clearly established short-term mortality benefit. In the Pulmonary Embolism Thrombolysis (PEITHO) trial, thrombolysis prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.²⁵ A lower dose (50 mg) of thrombolytic therapy was studied in the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET) trial and was found to be safe and effective in the treatment of moderate PE.²⁶

CDT has also been shown to be effective in the treatment of PE. The Ultrasound Acceleration Thrombolysis of Pulmonary Embolism (ULTIMA) trial demonstrated that catheter-directed thrombolysis with ultrasonographic guidance in patients with acute intermediate-risk PE was superior in reversing right ventricular dilatation without an increase in bleeding complications compared with UFH.²⁷ The Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) study found that this approach decreased right ventricular dilation, decreased pulmonary hypertension, decreased anatomic burden, and minimized the risk of intracranial hemorrhage in patients with massive and submassive PE.²⁸

Alteplase (Activase) is a recombinant tissue-type plasminogen activator approved by the FDA for treatment of acute PE. Alteplase is administered as a 100-mg infusion over 2 hours. Because of favorable outcomes with prompt recognition and anticoagulation for PE, the ACCP guidelines recommend systemic thrombolysis for hemodynamically unstable patients (systolic blood pressure < 90 mm Hg) with acute PE and a low risk of bleeding using a peripheral vein.³ These guidelines also recommend thrombolysis for the patient whose condition deteriorates after starting anticoagulant therapy but who have yet to develop hypotension.

If the appropriate expertise is available, CDT is suggested for patients with acute PE if they have hypotension and a high bleeding risk, have failed systemic thrombolysis, or are in shock that is likely to cause death before systemic thrombolysis can take effect.³ An area of ongoing debate is whether there is a benefit for thrombolytic therapy in patients with submassive PE who are hemodynamically stable but have evidence of right ventricular dysfunction on echocardiography or computed tomographic angiography. Bleeding remains the most serious complication of thrombolytic therapy.⁴

Pulmonary embolectomy. According to ACCP guidelines, surgical pulmonary embolectomy for the initial treatment of PE is reserved for patients with massive PE (documented angiographically, if possible), shock despite heparin and resuscitation efforts, and failure of thrombolytic therapy or a contraindication to its use.⁴ To date, there have been no randomized trials evaluating this procedure. Pooled data published by Stein et al²⁹ reported a 20% operative mortality rate in patients undergoing pulmonary embolectomy between 1985 and 2005 compared with 32% in patients undergoing the procedure before 1985. A more recent retrospective review of 214 patients undergoing surgical embolectomy for massive and submassive PE reported an in-hospital mortality rate of 11.7%, with the highest death rate (32.1%) in patients who had a preoperative cardiac arrest.³⁰ The use of surgical embolectomy has also been reported in patients with intermediate-risk to high-risk conditions (defined as elevated biomarkers and evidence of right heart strain on computed tomographic angiography or echocardiography).¹⁹

IVC filters. Current guidelines recommend against  routine use of IVC filters for patients with DVT or PE who are able to be treated with anticoagulants.³ Absolute indications for the placement of IVC filters include a contraindication to anticoagulation, complications of anticoagulation, and recurrent thromboembolism despite adequate anticoagulant therapy.⁴ Relative indications for IVC filters are massive PE, iliocaval DVT, free-floating proximal DVT, cardiac or pulmonary insufficiency, high risk of complications from anticoagulation (frequent falls, ataxia), and poor compliance.

Retrievable filters may be considered for situations in which anticoagulation is temporarily contraindicated or there is a short duration of PE risk.³¹ The current consensus guidelines advise that indications for placing a retrievable IVC filter are the same as for placing a permanent device.³¹ An IVC filter alone is not effective therapy for VTE, and resumption of anticoagulation is recommended as soon as possible after placement.

DURATION OF TREATMENT

Current guidelines recommend 3 months of anticoagulation (long-term) for patients with an episode of acute proximal or isolated distal DVT of the leg or PE resulting from surgery or a nonsurgical transient cause.³ Patients who have the antiphospholipid syndrome, who are homozygous for factor V Leiden, or who are doubly heterozygous for factor V Leiden and prothrombin gene mutation should be considered for longer (extended) anticoagulation. Extended anticoagulation is also recommended in patients with active cancer and in patients who have unexplained recurrent VTE (Table 2).³

The duration of treatment for unprovoked VTE remains controversial. In the most recent ACCP guidelines, indefinite or extended anticoagulation is indicated for patients with a low or moderate risk of bleeding for a first (and second) unprovoked VTE.⁴ Patients with a high risk of bleeding with a first (or second) unprovoked VTE that is a proximal DVT of the leg or PE be treated for 3 months.^3,4 Three DOACs (rivaroxaban, apixaban, and dabigatran) have extended-duration indications. The 2016 ACCP guidelines suggest aspirin over no treatment for the patient who has decided to stop anticoagulation therapy, although the guidelines do not consider aspirin a reasonable alternative to anticoagulation.^34,35 Use of markers such as residual venous obstruction and D-dimer level in conjunction with the DASH score have been studied in an effort to predict the risk of recurrence and thus the duration of anticoagulation.^36,37 Residual venous obstruction appears to be less useful than the D-dimer level as an indicator for recurrence. The D-dimer used in conjunction with the DASH prediction score may help to calculate recurrence risk based on the following predictors: abnormal D-dimer 3 weeks after stopping anticoagulation, age under 50, male sex, and hormone use at the time of the VTE.³⁸ DASH score assessment may help physicians decide whether to continue anticoagulation therapy but it has not been shown to be helpful in men.⁴ A more recent study confirmed the validity of the DASH score with better prediction in patients under age 65. The recurrence rate was higher in the older population, suggesting that this population should be considered for prolonged treatment if the bleeding risk is acceptable.³⁹ Other prediction tools include the Vienna prediction model and the clinical decision rule “Men continue and HER DOO2”—ie, HER = hyperpigmentation, edema, redness; DOO = D-dimer ≥ 250 μg/L, obesity body mass index ≥ 30 kg/m², old age (≥ 65); 2 = high risk if more than 2 of these factors.^40,41

SCREENING AND PREVENTION

Nearly 60% of all VTE events occur in hospitals and nursing homes.⁴² Yet anticoagulant prophylaxis is used in only 16% to 33% of at-risk hospitalized medical patients compared with 90% of at-risk hospitalized surgical patients.⁴³ Adequate prophylaxis can reduce the incidence of VTE as demonstrated in a meta-analysis involving 19,958 patients, which revealed a 64% reduction in relative risk (RR) of a fatal PE, 58% reduction in RR of a symptomic PE,  and a 53% reduction in RR of a symptomatic DVT.⁴³

The consequences of VTE include symptomatic DVT and PE, fatal PE, the cost of investigating symptomatic patients, the risk and cost of treatment (bleeding), PTS, and chronic thromboembolic pulmonary hypertension. Heparin, enoxaparin, and fondaparinux are approved agents for prophylactic but each agent has specific indications. Factor Xa inhibitors, rivaroxaban, and apixaban are approved for use in patients undergoing total knee or hip replacement. More recently, the factor Xa inhibitor, betrixaban, has been approved for VTE prophylaxis for up to 42 days in adult patients hospitalized for acute medical illness.⁴⁴ For patients with increased bleeding risk who are unable to receive pharmacologic prophylaxis, intermittent pneumatic compression devices or graduated compression stockings should be used.

Compression stockings

Current ACCP guidelines advise against routine use of compression stockings to prevent PTS in patients who have had a DVT.³ While current evidence suggests compression stockings do not prevent PTS, they reduce symptoms of acute or chronic DVT for some patients.

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the exact incidence of VTE is unknown, an estimated 1 million people in the United States are affected each year, with about a third experiencing a recurrence within 10 years.¹ VTE affects hospitalized and nonhospitalized patients, is often overlooked, and results in long-term complications including postthrombotic syndrome (PTS) for DVT, postpulmonary embolism syndrome and chronic thromboembolic pulmonary hypertension for PE, and death.²

TREATMENT

Treatment for VTE should be initiated in the following cases:

• Proximal DVT of the lower extremity
• Symptomatic distal (calf vein) DVT
• Symptomatic upper extremity DVT (axillary-subclavian veins)
• PE
• Subsegmental PE in a patient at risk for recurrence
• Surveillance for subsegmental PE in a patient with no proximal DVT and a low risk of recurrence.

In addition to anticoagulants, other more aggressive therapies for VTE may be appropriate, such as systemic thrombolysis in the case of PE or catheter-directed thrombolytic or pharmacomechnical therapies for DVT or PE, surgical intervention (acute pulmonary embolectomy), or placement of an inferior vena cava (IVC) filter.

This article reviews the management of VTE, highlighting the recent changes in treatment and prevention guidelines from the American College of Chest Physicians (ACCP).³

Risk of bleeding

In assessing a patient’s risk of bleeding for anticoagulation therapy (Table 1), the absence of risk factors is considered low risk for bleeding, the presence of 1 risk factor is considered intermediate risk, and 2 or more risk factors is considered high risk. Compared with low-risk patients, moderate-risk patients have a twofold increased risk of major bleeding and high-risk patients have an eightfold increased risk of major bleeding. This equates to an annualized risk of major bleeding of 0.8% for low-risk patients, 1.6% for moderate-risk patients, and greater than 6.5% for high-risk patients.³

Anticoagulants

Deciding on which anticoagulant to use depends on the indication, the patient’s underlying condition, the patient’s preference, and the patient’s risk of bleeding. Heparin, the LMWHs, fondaparinux and the DOACs (rivaroxaban and apixaban) are the only agents approved by the US Food and Drug Administration (FDA) recommended for the acute treatment phase, while the DOACs and warfarin are anticoagulation options for the long-term and extended treatment phases. The LMWHs should be used for the patient with cancer and during pregnancy.

Unfractionated heparin. UFH is administered parenterally and can be used for the prevention and treatment of VTE. Heparin remains an option for initial treatment of patients with acute VTE and is generally preferred over LMWH for patients who may require advanced therapies, such as for hemodynamically unstable PE or iliofemoral DVT. It is also recommended for patients with renal failure.³ Weight-based dosing (80 U/kg bolus followed by 18 U/kg/hour intravenous infusion) is recommended, targeting an antifactor activated clotting factor (anti-Xa) assay level of 0.3 IU/mL to 0.7 IU/mL. Heparin may also be given subcutaneously in an outpatient setting using an initial bolus of 333 U/kg followed by a subcutaneous dose of 17,500 U twice daily.⁵

Low-molecular-weight heparin. LMWHs are administered as weight-based subcutaneous injections and have indications for patients with acute VTE and for VTE prophylaxis. LMWHs are used for transitioning to warfarin, dabigatran, or edoxaban for long-term anticoagulation and are recommended over warfarin and DOACs for treatment of VTE in patients with cancer and in pregnant women.³

Enoxaparin (Lovenox), the most commonly used agent in the United States, is given either as a once-daily injection (1.5 mg/kg/day) or a twice-daily injection (1 mg/kg every 12 hours). It is also approved for VTE prophylaxis in patients undergoing hip or knee replacement surgery or abdominal surgery, or in patients with severely restricted mobility during acute illness. LMWH can also be given in patients with renal insufficiency (creatinine clearance [CrCL] < 30 mL/minute) after dose adjustment. No monitoring is required, although it is advised in pediatric patients, pregnant women, obese patients, and patients with renal insufficiency. If monitoring is required, an anti-Xa assay using LMWH as a reference standard should be done 4 hours after subcutaneous injection. The therapeutic range for enoxaparin is 0.5 IU/mL to 1.0 IU/mL for the 12-hour regimen and greater than 1.0 IU/mL for the once-daily dose. Other LMWHs available in the United States include dalteparin (Fragmin) and tinzaparin (Innohep). Each has its own specific indications.

Fondaparinux. Fondaparinux is an indirect factor Xa inhibitor, chemically related to LMWH. It is approved for treatment of patients with acute VTE when used in combination with a VKA (warfarin) or dabigatran or edoxaban. It also has approval for VTE prophylaxis in patients undergoing hip fracture, hip or knee replacement, and abdominal surgery. Fondaparinux is administered as a once-daily subcutaneous injection of 2.5 mg for DVT prophylaxis and a body weight-based dose for the treatment of VTE (5 mg < 50 kg; 7.5 mg 50 to 100 kg; 10 mg > 100 kg).⁶ Fondaparinux is contraindicated in patients with severe renal impairment (CrCL les 30 mL/min) and bacterial endocarditis.⁶

Warfarin. Warfarin, a VKA, was the mainstay of therapy for long-term and extended treatment of VTE until the advent of the DOACs. Warfarin must be coadministered with heparin, LMWH, or fondaparinux initially and continued as overlap therapy for a minimum of 5 days until the international normalized ratio [INR] is at least 2.0 for 24 hours.⁴ Early initiation of a VKA on the first day of parenteral therapy is advised.

Warfarin remains the best option for patients on long-term or extended anticoagulation with liver dysfunction (elevated serum transaminases exceeding twice the upper limits of normal or active liver disease) or renal disease (CrCL < 30 mL/min), as well as patients unable to afford DOACs. Additionally, select patient populations may still be best served by warfarin as these groups were underrepresented or not included in DOAC trials, including pediatric patients, individuals with body weight less than 50 kg or greater than 150 kg, and patients with select types of thrombophilia (eg, antiphospholipid syndrome). Warfarin is also advised for patients with poor compliance, as international normalized ratio of prothrombin time (PT/INR) monitoring is required using a point-of-care testing device or during a visit to an anticoagulation clinic. DOACs do not require monitoring, and noncompliance will not be readily apparent.

Direct oral anticoagulants. The DOACs, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) and the direct thrombin inhibitor dabigatran (Pradaxa), been studied extensively and shown to be noninferior to VKAs for treatment of VTE.⁷ DOACs are currently recommended by the ACCP for long-term treatment of VTE, and several have extended treatment recommendations for VTE over the VKAs.³

The advantages of DOACs include no need for PT/INR monitoring, a fixed dosage, shorter half-life, rapid onset of action (for monotherapy), and in most cases, no need for bridging for interventional or surgical procedures. Additional advantages may include a decreased burden of care for the physician and improved quality of life for the patient. DOACs are also the agents of choice for patients who prefer oral therapy (avoiding parenteral therapy), have limited access to an anticoagulation clinic (home bound or geographic inaccessibility for PT/INR monitoring), or have food or drug-drug interactions. Patients at risk of gastrointestinal bleeding or dyspepsia should avoid dabigatran, while apixaban may be preferred if there is a history of gastrointestinal bleeding.⁸

Rivaroxaban or apixaban can be used as monotherapy for the initial treatment of VTE, while a 5-day course of heparin, LMWH, or fondaparinux is necessary with dabigatran or edoxaban. Rivaroxaban has been approved by the FDA for use in the prevention and treatment of VTE.^9,10 For VTE prophylaxis, rivaroxaban is given orally at 10 mg once daily for 35 days for patients undergoing total hip replacement surgery and for 12 days for patients undergoing knee replacement surgery. For the treatment of VTE, rivaroxaban is given orally at 15 mg twice a day for the initial 21 days of treatment, followed by once daily at 20 mg per day for long-term treatment. It is also approved for extended-duration therapy in both 10-mg and 20-mg doses. In a recently published randomized double-blind trial of rivaroxaban compared with aspirin, the risk of a recurrent event was lower with either dose of rivaroxaban compared with aspirin without an increase in bleeding.¹¹ Rivaroxaban is contraindicated in patients with renal insufficiency (CrCL < 30 mL/min). Both the 15-mg and 20-mg tablets must be taken with food.

Apixaban is also approved for monotherapy of VTE and was found to be noninferior to standard therapy of LMWH and warfarin with less bleeding.¹² Apixaban is used for VTE prophylaxis in patients undergoing hip or knee replacement surgery, given at 2.5 mg twice daily beginning 12 to 24 hours postoperatively for 35 days (hip) or 12 days (knee). The acute-phase dosage is 10 mg twice daily for 7 days followed by 5 mg twice daily for long-term treatment of VTE. The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater. Apixaban is also approved for extended treatment of VTE. In a randomized, double-blind study of 2 doses (2.5 mg and 5 mg, twice daily) of apixaban compared with placebo, apixaban reduced the risk of recurrent VTE without increasing the risk of bleeding.¹³

Both dabigatran and edoxaban require an initial 5-day overlap with a parenteral anticoagulant.^14,15  Dabigatran is given at 150 mg orally twice daily if the CrCL is greater than 30 mL/min for the long-term treatment of VTE. Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors. Dabigatran has been evaluated in 2 double-blind, randomized controlled trials comparing the extended use of dabigatran with warfarin or placebo in patients with VTE.¹⁶ Dabigatran carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. Dabigatran was noninferior to warfarin but significantly reduced the rate of recurrence in the placebo group.¹⁶

The major side effect observed with all DOACs is bleeding, but they have been proven safer particularly in the terms of major bleeding compared with the standard heparin-LMWH-VKA regimen for treatment of VTE.^17–19 The risk of major bleeding, and in particular intracranial bleeding, has been shown to be less with DOACs compared with VKAs in 2 meta-analysis trials.^17,18 Of the 4 new DOACs, only dabigatran currently has an anticoagulant-reversing agent (idarucizumab), although an antidote for the other 3 agents is awaiting FDA approval.²⁰

Subsegmental pulmonary embolism

There is debate as to the need for treatment of patients with subsegmental PE. The most recent guidelines advise clinical surveillance over anticoagulation for patients with a low risk for recurrent VTE and no evidence for a proximal DVT.³ However, individuals who are hospitalized, have reduced mobility, have active cancer or are being treated with chemotherapy, or have a low cardiopulmonary reserve should be considered for anticoagulation unless they have a high bleeding risk.

Thrombolytic therapy

Thrombolytic therapy may be beneficial in select patients with VTE and can be delivered systemically or locally per catheter-directed therapy (CDT). Both routes carry an increased risk of hemorrhage compared with standard anticoagulation. The Catheter-Directed-Venous Thrombolysis (CaVenT) trial and Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial compared CDT with standard therapy.^21,22 In CaVEnT, CDT resulted in increased clinical benefit during the 5-year follow-up but did not result in improved quality of life.²¹ In the TORPEDO trial, patients with proximal DVT receiving percutaneous endovenous intervention and anticoagulation compared with anticoagulation alone demonstrated superiority in the reduction of PTS at greater than 2 years.²² Early results of the Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial show that most patients with DVT did not have a long-term benefit from CDT, buy they did have reduced leg pain and swelling and some had reduced risk of moderate-to-severe PTS.²³

The 2012 and 2016 ACCP guidelines advise anticoagulant therapy over CDT for patients with acute DVT of the leg but suggest patients who may benefit are those with iliofemoral DVT with symptoms for less than 14 days, good functional status, a life expectancy greater than 1 year, and a low risk of bleeding.^3,4 This is in contrast to the 2008 CHEST guidelines that recommended patients who have extensive proximal DVT, who have a high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status be given CDT if the expertise and resources are available.²⁴ It has been suggested that CDT promotes early recanalization and minimizes the incidence of PTS.

Thrombolytic therapy for acute PE remains controversial because there is no clearly established short-term mortality benefit. In the Pulmonary Embolism Thrombolysis (PEITHO) trial, thrombolysis prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.²⁵ A lower dose (50 mg) of thrombolytic therapy was studied in the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET) trial and was found to be safe and effective in the treatment of moderate PE.²⁶

CDT has also been shown to be effective in the treatment of PE. The Ultrasound Acceleration Thrombolysis of Pulmonary Embolism (ULTIMA) trial demonstrated that catheter-directed thrombolysis with ultrasonographic guidance in patients with acute intermediate-risk PE was superior in reversing right ventricular dilatation without an increase in bleeding complications compared with UFH.²⁷ The Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) study found that this approach decreased right ventricular dilation, decreased pulmonary hypertension, decreased anatomic burden, and minimized the risk of intracranial hemorrhage in patients with massive and submassive PE.²⁸

Alteplase (Activase) is a recombinant tissue-type plasminogen activator approved by the FDA for treatment of acute PE. Alteplase is administered as a 100-mg infusion over 2 hours. Because of favorable outcomes with prompt recognition and anticoagulation for PE, the ACCP guidelines recommend systemic thrombolysis for hemodynamically unstable patients (systolic blood pressure < 90 mm Hg) with acute PE and a low risk of bleeding using a peripheral vein.³ These guidelines also recommend thrombolysis for the patient whose condition deteriorates after starting anticoagulant therapy but who have yet to develop hypotension.

If the appropriate expertise is available, CDT is suggested for patients with acute PE if they have hypotension and a high bleeding risk, have failed systemic thrombolysis, or are in shock that is likely to cause death before systemic thrombolysis can take effect.³ An area of ongoing debate is whether there is a benefit for thrombolytic therapy in patients with submassive PE who are hemodynamically stable but have evidence of right ventricular dysfunction on echocardiography or computed tomographic angiography. Bleeding remains the most serious complication of thrombolytic therapy.⁴

Pulmonary embolectomy. According to ACCP guidelines, surgical pulmonary embolectomy for the initial treatment of PE is reserved for patients with massive PE (documented angiographically, if possible), shock despite heparin and resuscitation efforts, and failure of thrombolytic therapy or a contraindication to its use.⁴ To date, there have been no randomized trials evaluating this procedure. Pooled data published by Stein et al²⁹ reported a 20% operative mortality rate in patients undergoing pulmonary embolectomy between 1985 and 2005 compared with 32% in patients undergoing the procedure before 1985. A more recent retrospective review of 214 patients undergoing surgical embolectomy for massive and submassive PE reported an in-hospital mortality rate of 11.7%, with the highest death rate (32.1%) in patients who had a preoperative cardiac arrest.³⁰ The use of surgical embolectomy has also been reported in patients with intermediate-risk to high-risk conditions (defined as elevated biomarkers and evidence of right heart strain on computed tomographic angiography or echocardiography).¹⁹

IVC filters. Current guidelines recommend against  routine use of IVC filters for patients with DVT or PE who are able to be treated with anticoagulants.³ Absolute indications for the placement of IVC filters include a contraindication to anticoagulation, complications of anticoagulation, and recurrent thromboembolism despite adequate anticoagulant therapy.⁴ Relative indications for IVC filters are massive PE, iliocaval DVT, free-floating proximal DVT, cardiac or pulmonary insufficiency, high risk of complications from anticoagulation (frequent falls, ataxia), and poor compliance.

Retrievable filters may be considered for situations in which anticoagulation is temporarily contraindicated or there is a short duration of PE risk.³¹ The current consensus guidelines advise that indications for placing a retrievable IVC filter are the same as for placing a permanent device.³¹ An IVC filter alone is not effective therapy for VTE, and resumption of anticoagulation is recommended as soon as possible after placement.

DURATION OF TREATMENT

Current guidelines recommend 3 months of anticoagulation (long-term) for patients with an episode of acute proximal or isolated distal DVT of the leg or PE resulting from surgery or a nonsurgical transient cause.³ Patients who have the antiphospholipid syndrome, who are homozygous for factor V Leiden, or who are doubly heterozygous for factor V Leiden and prothrombin gene mutation should be considered for longer (extended) anticoagulation. Extended anticoagulation is also recommended in patients with active cancer and in patients who have unexplained recurrent VTE (Table 2).³

The duration of treatment for unprovoked VTE remains controversial. In the most recent ACCP guidelines, indefinite or extended anticoagulation is indicated for patients with a low or moderate risk of bleeding for a first (and second) unprovoked VTE.⁴ Patients with a high risk of bleeding with a first (or second) unprovoked VTE that is a proximal DVT of the leg or PE be treated for 3 months.^3,4 Three DOACs (rivaroxaban, apixaban, and dabigatran) have extended-duration indications. The 2016 ACCP guidelines suggest aspirin over no treatment for the patient who has decided to stop anticoagulation therapy, although the guidelines do not consider aspirin a reasonable alternative to anticoagulation.^34,35 Use of markers such as residual venous obstruction and D-dimer level in conjunction with the DASH score have been studied in an effort to predict the risk of recurrence and thus the duration of anticoagulation.^36,37 Residual venous obstruction appears to be less useful than the D-dimer level as an indicator for recurrence. The D-dimer used in conjunction with the DASH prediction score may help to calculate recurrence risk based on the following predictors: abnormal D-dimer 3 weeks after stopping anticoagulation, age under 50, male sex, and hormone use at the time of the VTE.³⁸ DASH score assessment may help physicians decide whether to continue anticoagulation therapy but it has not been shown to be helpful in men.⁴ A more recent study confirmed the validity of the DASH score with better prediction in patients under age 65. The recurrence rate was higher in the older population, suggesting that this population should be considered for prolonged treatment if the bleeding risk is acceptable.³⁹ Other prediction tools include the Vienna prediction model and the clinical decision rule “Men continue and HER DOO2”—ie, HER = hyperpigmentation, edema, redness; DOO = D-dimer ≥ 250 μg/L, obesity body mass index ≥ 30 kg/m², old age (≥ 65); 2 = high risk if more than 2 of these factors.^40,41

SCREENING AND PREVENTION

Nearly 60% of all VTE events occur in hospitals and nursing homes.⁴² Yet anticoagulant prophylaxis is used in only 16% to 33% of at-risk hospitalized medical patients compared with 90% of at-risk hospitalized surgical patients.⁴³ Adequate prophylaxis can reduce the incidence of VTE as demonstrated in a meta-analysis involving 19,958 patients, which revealed a 64% reduction in relative risk (RR) of a fatal PE, 58% reduction in RR of a symptomic PE,  and a 53% reduction in RR of a symptomatic DVT.⁴³

The consequences of VTE include symptomatic DVT and PE, fatal PE, the cost of investigating symptomatic patients, the risk and cost of treatment (bleeding), PTS, and chronic thromboembolic pulmonary hypertension. Heparin, enoxaparin, and fondaparinux are approved agents for prophylactic but each agent has specific indications. Factor Xa inhibitors, rivaroxaban, and apixaban are approved for use in patients undergoing total knee or hip replacement. More recently, the factor Xa inhibitor, betrixaban, has been approved for VTE prophylaxis for up to 42 days in adult patients hospitalized for acute medical illness.⁴⁴ For patients with increased bleeding risk who are unable to receive pharmacologic prophylaxis, intermittent pneumatic compression devices or graduated compression stockings should be used.

Compression stockings

Current ACCP guidelines advise against routine use of compression stockings to prevent PTS in patients who have had a DVT.³ While current evidence suggests compression stockings do not prevent PTS, they reduce symptoms of acute or chronic DVT for some patients.