Cleveland Clinic Journal of Medicine

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.

Cardiac implantable electronic devices (CIEDs) have become common tools to improve the quality of life and longevity of patients with cardiac disease over the last few decades.^1–4 CIEDs include implantable cardioverter defibrillators (ICDs), permanent pacemakers, biventricular pacemakers providing cardiac resynchronization therapy with or without a defibrillator, subcutaneous ICDs, and implantable loop recorders. With increasing approved indications, the number of CIEDs implanted each year continues to grow. This, paired with the aging population of patients receiving devices and their medical complexity, has led to a corresponding increase in device-related complications.^2,3 One of the most serious complications is CIED infection, which leads to significant morbidity and death. These infections also represent a significant cost burden to the healthcare system, with treatment costs for a CIED infection estimated at over $146,000 in 2008.⁵

SCOPE OF THE PROBLEM

More than half a million permanent pacemakers and ICDs are implanted each year in the United States, with more than 4 million implanted between 1993 and 2008.⁵ The risk of infection is 0.5% to 1%, for a first-time implantation and 1% to 5% for a device replacement or upgrade.^1,2,5–9 These infections can involve the generator pocket, bloodstream, or cardiac structures, leading to infective endocarditis.¹⁰ The timing of CIED infection appears to be bimodal in distribution: early infections usually occur as a result of the implantation procedure itself, whereas late infections occur in patients who are generally unwell or because of an insidious process that eventually crosses a threshold of clinical significance.^3,11,12

Incidence and risk factors

Klug et al¹³ investigated the incidence rate and risk factors of CIED infection prospectively in a large cohort of patients from 44 centers who underwent CIED implantation. Of 6,319 procedures, 4,465 were first implants and the other 1,854 were a replacement or revision; 42 patients (0.68%) developed CIED infection by 12 months after the procedure, and the incidence of infection in replacement or revision cases was nearly twice the rate found in first implants.¹³ Risk factors for CIED infection included renal failure, heart failure, diabetes, and fever within last 24 hours before CIED implantation.¹⁴ The Implantable Cardiac Pulse Generator Replacement (REPLACE) registry found the 6-month incidence rate of CIED infection to be 1.4% after CIED replacement.⁶

Recently, there has been concern that the rate of newly infected CIEDs has outpaced the rate of newly implanted ones.^5,15 Voigt et al¹⁵ reported a 12% increase in the rate of CIED implantation from 2004 to 2006 and an out-of-proportion 57% increase in the rate of CIED infection. A review from 2011 confirmed these findings, showing the annual CIED implantation incidence increased an average of 4.7% per year between 1993 and 2008.⁵ This was probably driven by clinical trials that broadened the indications for ICD implantation for primary prevention.^16–19 Between 1993 and 2008, the rate of newly implanted devices increased by 96%, while the rate for newly infected CIEDs increased by 210%; the majority of this increase occurred after 2004.⁵ The study showed that comorbidities in patients receiving CIEDs increased sharply starting in 2004—alluding to the contribution of comorbid medical conditions such as renal failure, respiratory failure, heart failure, and diabetes to infection risk.⁵

However, a major obstacle to defining the true incidence rate of CIED infection is the lack of a clear denominator. CIED infection is not limited to the first few months after implantation. In fact, over half of these patients present more than 1 year after the last CIED intervention.¹² Therefore, the number of patients at risk continues to grow each year and includes patients who underwent implantation that year or before, making it very difficult to compare infection rates. Additionally, the lack of a clear definition of CIED infection and the variations in duration of follow-up in different studies make it difficult to accurately assess the incidence of CIED infection.

PATHOGENESIS

Prompt and accurate diagnosis of CIED infection is critical as it allows for early management with antibiotic therapy and device removal. As the number of CIED implantations increases, providers on the front lines—emergency, family practice, and internal medicine physicians—will play an increasing role in recognizing and diagnosing CIED infection. Patients with CIED infection present with a range of signs and symptoms including fever, chills, erythema, swelling, drainage, tenderness, malaise, erosion, and warmth of the skin overlying the generator pocket.² In 55% of cases, patients present with localized pocket infection, while the remaining patients have signs of an endovascular infection without obvious pocket involvement.¹² Localized pocket infection is more common during the first year after device implantation. CIED-associated endovascular infections occur more commonly in patients with multiple comorbidities including diabetes, renal failure, prior heart valve operation, rheumatic heart disease, and prior bloodstream infection.² Despite the theoretical divide in CIED infections (endovascular vs pocket), overlap is common: many patients with pocket infection show evidence of bacteremia and vegetations on the leads.

Diagnosing pocket infection from the physical examination can be difficult due to the often subtle manifestations of the underlying pathophysiology and because visible changes to the pocket can occur over weeks and months. Furthermore, differentiating superficial infection, hematoma, seroma, and allergic reactions from deep pocket infection can be challenging. In cases when the diagnosis is not clear and there are no systemic findings of infection, conservative management with close follow-up is reasonable. Similarly, the diagnosis of endovascular infection is sometimes delayed because the symptoms are not very specific or because of a lack of awareness of the presence of a CIED and its role in endovascular infection.

MANAGEMENT

A multidisciplinary approach involving cardiology, infectious disease, electrophysiology, and cardiothoracic surgery teams is required to optimize outcomes in patients with CIED infection. CIED infection is particularly difficult to treat with antibiotic therapy alone because it involves infection of an implanted device and an associated biofilm that is resistant to the effects of antibiotics. Once infection is confirmed, antibiotic therapy serves as an adjunct to the complete removal of the hardware. Most patients receive 2 weeks of intravenous antibiotics after removal of an infected CIED, with longer courses for patients with Staphylococcus aureus infection or documented endocarditis.²¹

Infectious disease consultation is paramount in order to choose the appropriate type and duration of antibiotic therapy. Conservative approaches that involve using antibiotics alone or incomplete system removal have high failure rates with high rates of morbidity and mortality.^13,21–28 However, chronic antibiotic suppressive therapy may be considered as a palliative measure for patients who are not candidates for lead extraction.

DEVICE REMOVAL

Confirmation of CIED infection is a class I indication for device removal and the patient should be referred to an electrophysiologist. Transvenous lead extraction (TLE) is a percutaneous procedure performed by the electrophysiologist in the electrophysiology laboratory or hybrid operating room with cardiothoracic surgery support, and it is generally performed under general anesthesia with invasive hemodynamic monitoring. After opening and debriding the infected pocket, the generator is disconnected from the leads. After the lead tips are unscrewed from the myocardium, gentle traction is applied to determine if the leads can easily be removed. If traction is unsuccessful, additional tools (both powered or mechanical sheaths) are used to complete the lead extraction²⁹; the goal is to lyse and free the fibrotic attachments between parallel leads and between the leads and vessel wall or the myocardium. Once the lead is freed from the adhesions it can be removed safely.

The need for reimplantation after removal of an infected CIED should be thought about before the extraction. In general, extracting an infected CIED should be viewed as an opportunity to reassess the need for the device. Almost one-third of patients who undergo extraction of infected CIED do not require immediate reimplantation.² This could be due to reversal of the initial indication, emergence of new clinical conditions, patient preference, or the lack of an absolute indication. If reimplantation is necessary, the new device is typically placed on the opposite side of the chest from the previously infected pocket site after blood cultures are negative for at least 72 hours.²¹

CIED INFECTION MORTALITY

Despite proper management with CIED removal supported by antibiotic therapy, CIED infection carries a high risk of death. The 30-day mortality is estimated to be between 5% and 6%.³³ In a large case series of 412 CIED extractions, there were 19 in-hospital deaths. Of these 19 deaths, 2 were related to the extraction itself with the other 17 related to sepsis, multiorgan failure, stroke, renal failure, or heart failure.² The 1-year mortality rate is also increased for this population; recent data show 1-year mortality rates of 8% to 17% despite device removal and antibiotic therapy.^2,34,35 This increased mortality rate was also demonstrated in a large cohort of Medicare patients undergoing CIED procedures.³⁶ Medicare patients with CIED infection had double the risk of death at 1 year compared with patients without infection.³⁶

Risk factors for death at 1 year include worse baseline functional status, renal failure, and type of infection; eg, endovascular infection carries a risk of death 2 times higher than pocket infection.³⁷

PREVENTION

Because CIED infection carries significant short-term and long-term mortality rates despite optimal management, the best strategy is prevention. Preventing CIED infection begins with the decision to implant a device with careful assessment of the indication, the timing of the procedure, and the patient’s clinical status. CIED procedures are performed under strict sterile surgical techniques with great attention to the incision and proper closure. Surgical data favor the use of chlorhexidine-alcohol solutions for skin preparation compared with povidone-iodine solutions to prevent both superficial and deep surgical wound infections.³⁸ However, recent studies showed no significant difference between the 2 preparation methods in reducing rates of CIED infection.^39,40 In individuals colonized with S aureus, the risk of CIED infection can be reduced using a body wash containing chlorhexidine and a nasal spray containing mupirocin.^41,42

Preoperative antibiotics

The use of preoperative antibiotics has been shown to reduce the risk of infection.⁴³ In a large prospective cohort of patients undergoing a de novo or secondary CIED procedure, the use of perioperative antibiotics was negatively associated with the risk of CIED infection.¹³ This was later confirmed by a double-blind randomized trial of 1,000 patients undergoing permanent pacemaker or ICD initial implantation or generator replacement. This study was stopped prematurely as the use of antibiotics was clearly associated with a lower risk of CIED infection.⁴⁴ Therefore, prophylaxis with an antibiotic active against staphylococci before the incision is made is a class I indication to prevent infection.¹

Currently, no data support giving prophylactic antibiotics after the procedure; however, the Prevention of Arrhythmia Device Infection Trial (PADIT) is currently comparing the risk of infection with conventional preoperative antibiotics vs a regimen of pre- and post-procedure antibiotics (clinicaltrial.gov: NCT01628666).

Hemostasis

Adequate hemostasis is critical, since the risk of CIED infection is 7 times greater with formation of a hematoma.⁴⁵ Heparin products, especially low-molecular-weight heparin, should be avoided at the time of CIED implantation. In patients at high risk for thromboembolism who are on warfarin therapy, the continuation of warfarin is associated with a lower incidence of hematoma compared with bridging with heparin in patients undergoing CIED procedures.⁴⁶ Therefore, if anticoagulation can be withheld, it is better to stop the anticoagulant before the procedure. When this is not possible or when it carries significant risk (eg, a patient with a mechanical mitral valve who needs a CIED implantation), it is better to maintain the patient on warfarin therapy with a therapeutic international normalized ratio rather than bridging with heparin products.

Antibacterial envelop and new devices

CIED infection is a major complication that carries significant risk of morbidity and death. Early diagnosis and referral to a multidisciplinary treatment team is crucial to increasing the possibility of a cure. While device extraction has risks, it is nevertheless typically required for complete resolution of the infection. Large clinical trials are under way to address current knowledge gaps about CIED infection, including our understanding of the true incidence rate, risk factors, and efficacy of various implantation techniques. Future trends to minimize the risk of CIED infection include better screening, better diagnostic tools, new devices with fewer or no leads, longer battery life to minimize the need for additional procedures, and the use of supportive tools and products to minimize the risk of infection.

Cardiac implantable electronic devices (CIEDs) have become common tools to improve the quality of life and longevity of patients with cardiac disease over the last few decades.^1–4 CIEDs include implantable cardioverter defibrillators (ICDs), permanent pacemakers, biventricular pacemakers providing cardiac resynchronization therapy with or without a defibrillator, subcutaneous ICDs, and implantable loop recorders. With increasing approved indications, the number of CIEDs implanted each year continues to grow. This, paired with the aging population of patients receiving devices and their medical complexity, has led to a corresponding increase in device-related complications.^2,3 One of the most serious complications is CIED infection, which leads to significant morbidity and death. These infections also represent a significant cost burden to the healthcare system, with treatment costs for a CIED infection estimated at over $146,000 in 2008.⁵

SCOPE OF THE PROBLEM

More than half a million permanent pacemakers and ICDs are implanted each year in the United States, with more than 4 million implanted between 1993 and 2008.⁵ The risk of infection is 0.5% to 1%, for a first-time implantation and 1% to 5% for a device replacement or upgrade.^1,2,5–9 These infections can involve the generator pocket, bloodstream, or cardiac structures, leading to infective endocarditis.¹⁰ The timing of CIED infection appears to be bimodal in distribution: early infections usually occur as a result of the implantation procedure itself, whereas late infections occur in patients who are generally unwell or because of an insidious process that eventually crosses a threshold of clinical significance.^3,11,12

Incidence and risk factors

Klug et al¹³ investigated the incidence rate and risk factors of CIED infection prospectively in a large cohort of patients from 44 centers who underwent CIED implantation. Of 6,319 procedures, 4,465 were first implants and the other 1,854 were a replacement or revision; 42 patients (0.68%) developed CIED infection by 12 months after the procedure, and the incidence of infection in replacement or revision cases was nearly twice the rate found in first implants.¹³ Risk factors for CIED infection included renal failure, heart failure, diabetes, and fever within last 24 hours before CIED implantation.¹⁴ The Implantable Cardiac Pulse Generator Replacement (REPLACE) registry found the 6-month incidence rate of CIED infection to be 1.4% after CIED replacement.⁶

Recently, there has been concern that the rate of newly infected CIEDs has outpaced the rate of newly implanted ones.^5,15 Voigt et al¹⁵ reported a 12% increase in the rate of CIED implantation from 2004 to 2006 and an out-of-proportion 57% increase in the rate of CIED infection. A review from 2011 confirmed these findings, showing the annual CIED implantation incidence increased an average of 4.7% per year between 1993 and 2008.⁵ This was probably driven by clinical trials that broadened the indications for ICD implantation for primary prevention.^16–19 Between 1993 and 2008, the rate of newly implanted devices increased by 96%, while the rate for newly infected CIEDs increased by 210%; the majority of this increase occurred after 2004.⁵ The study showed that comorbidities in patients receiving CIEDs increased sharply starting in 2004—alluding to the contribution of comorbid medical conditions such as renal failure, respiratory failure, heart failure, and diabetes to infection risk.⁵

However, a major obstacle to defining the true incidence rate of CIED infection is the lack of a clear denominator. CIED infection is not limited to the first few months after implantation. In fact, over half of these patients present more than 1 year after the last CIED intervention.¹² Therefore, the number of patients at risk continues to grow each year and includes patients who underwent implantation that year or before, making it very difficult to compare infection rates. Additionally, the lack of a clear definition of CIED infection and the variations in duration of follow-up in different studies make it difficult to accurately assess the incidence of CIED infection.

PATHOGENESIS

Prompt and accurate diagnosis of CIED infection is critical as it allows for early management with antibiotic therapy and device removal. As the number of CIED implantations increases, providers on the front lines—emergency, family practice, and internal medicine physicians—will play an increasing role in recognizing and diagnosing CIED infection. Patients with CIED infection present with a range of signs and symptoms including fever, chills, erythema, swelling, drainage, tenderness, malaise, erosion, and warmth of the skin overlying the generator pocket.² In 55% of cases, patients present with localized pocket infection, while the remaining patients have signs of an endovascular infection without obvious pocket involvement.¹² Localized pocket infection is more common during the first year after device implantation. CIED-associated endovascular infections occur more commonly in patients with multiple comorbidities including diabetes, renal failure, prior heart valve operation, rheumatic heart disease, and prior bloodstream infection.² Despite the theoretical divide in CIED infections (endovascular vs pocket), overlap is common: many patients with pocket infection show evidence of bacteremia and vegetations on the leads.

Diagnosing pocket infection from the physical examination can be difficult due to the often subtle manifestations of the underlying pathophysiology and because visible changes to the pocket can occur over weeks and months. Furthermore, differentiating superficial infection, hematoma, seroma, and allergic reactions from deep pocket infection can be challenging. In cases when the diagnosis is not clear and there are no systemic findings of infection, conservative management with close follow-up is reasonable. Similarly, the diagnosis of endovascular infection is sometimes delayed because the symptoms are not very specific or because of a lack of awareness of the presence of a CIED and its role in endovascular infection.

MANAGEMENT

A multidisciplinary approach involving cardiology, infectious disease, electrophysiology, and cardiothoracic surgery teams is required to optimize outcomes in patients with CIED infection. CIED infection is particularly difficult to treat with antibiotic therapy alone because it involves infection of an implanted device and an associated biofilm that is resistant to the effects of antibiotics. Once infection is confirmed, antibiotic therapy serves as an adjunct to the complete removal of the hardware. Most patients receive 2 weeks of intravenous antibiotics after removal of an infected CIED, with longer courses for patients with Staphylococcus aureus infection or documented endocarditis.²¹

Infectious disease consultation is paramount in order to choose the appropriate type and duration of antibiotic therapy. Conservative approaches that involve using antibiotics alone or incomplete system removal have high failure rates with high rates of morbidity and mortality.^13,21–28 However, chronic antibiotic suppressive therapy may be considered as a palliative measure for patients who are not candidates for lead extraction.

DEVICE REMOVAL

Confirmation of CIED infection is a class I indication for device removal and the patient should be referred to an electrophysiologist. Transvenous lead extraction (TLE) is a percutaneous procedure performed by the electrophysiologist in the electrophysiology laboratory or hybrid operating room with cardiothoracic surgery support, and it is generally performed under general anesthesia with invasive hemodynamic monitoring. After opening and debriding the infected pocket, the generator is disconnected from the leads. After the lead tips are unscrewed from the myocardium, gentle traction is applied to determine if the leads can easily be removed. If traction is unsuccessful, additional tools (both powered or mechanical sheaths) are used to complete the lead extraction²⁹; the goal is to lyse and free the fibrotic attachments between parallel leads and between the leads and vessel wall or the myocardium. Once the lead is freed from the adhesions it can be removed safely.

The need for reimplantation after removal of an infected CIED should be thought about before the extraction. In general, extracting an infected CIED should be viewed as an opportunity to reassess the need for the device. Almost one-third of patients who undergo extraction of infected CIED do not require immediate reimplantation.² This could be due to reversal of the initial indication, emergence of new clinical conditions, patient preference, or the lack of an absolute indication. If reimplantation is necessary, the new device is typically placed on the opposite side of the chest from the previously infected pocket site after blood cultures are negative for at least 72 hours.²¹

CIED INFECTION MORTALITY

Despite proper management with CIED removal supported by antibiotic therapy, CIED infection carries a high risk of death. The 30-day mortality is estimated to be between 5% and 6%.³³ In a large case series of 412 CIED extractions, there were 19 in-hospital deaths. Of these 19 deaths, 2 were related to the extraction itself with the other 17 related to sepsis, multiorgan failure, stroke, renal failure, or heart failure.² The 1-year mortality rate is also increased for this population; recent data show 1-year mortality rates of 8% to 17% despite device removal and antibiotic therapy.^2,34,35 This increased mortality rate was also demonstrated in a large cohort of Medicare patients undergoing CIED procedures.³⁶ Medicare patients with CIED infection had double the risk of death at 1 year compared with patients without infection.³⁶

Risk factors for death at 1 year include worse baseline functional status, renal failure, and type of infection; eg, endovascular infection carries a risk of death 2 times higher than pocket infection.³⁷

PREVENTION

Because CIED infection carries significant short-term and long-term mortality rates despite optimal management, the best strategy is prevention. Preventing CIED infection begins with the decision to implant a device with careful assessment of the indication, the timing of the procedure, and the patient’s clinical status. CIED procedures are performed under strict sterile surgical techniques with great attention to the incision and proper closure. Surgical data favor the use of chlorhexidine-alcohol solutions for skin preparation compared with povidone-iodine solutions to prevent both superficial and deep surgical wound infections.³⁸ However, recent studies showed no significant difference between the 2 preparation methods in reducing rates of CIED infection.^39,40 In individuals colonized with S aureus, the risk of CIED infection can be reduced using a body wash containing chlorhexidine and a nasal spray containing mupirocin.^41,42

Preoperative antibiotics

The use of preoperative antibiotics has been shown to reduce the risk of infection.⁴³ In a large prospective cohort of patients undergoing a de novo or secondary CIED procedure, the use of perioperative antibiotics was negatively associated with the risk of CIED infection.¹³ This was later confirmed by a double-blind randomized trial of 1,000 patients undergoing permanent pacemaker or ICD initial implantation or generator replacement. This study was stopped prematurely as the use of antibiotics was clearly associated with a lower risk of CIED infection.⁴⁴ Therefore, prophylaxis with an antibiotic active against staphylococci before the incision is made is a class I indication to prevent infection.¹

Currently, no data support giving prophylactic antibiotics after the procedure; however, the Prevention of Arrhythmia Device Infection Trial (PADIT) is currently comparing the risk of infection with conventional preoperative antibiotics vs a regimen of pre- and post-procedure antibiotics (clinicaltrial.gov: NCT01628666).

Hemostasis

Adequate hemostasis is critical, since the risk of CIED infection is 7 times greater with formation of a hematoma.⁴⁵ Heparin products, especially low-molecular-weight heparin, should be avoided at the time of CIED implantation. In patients at high risk for thromboembolism who are on warfarin therapy, the continuation of warfarin is associated with a lower incidence of hematoma compared with bridging with heparin in patients undergoing CIED procedures.⁴⁶ Therefore, if anticoagulation can be withheld, it is better to stop the anticoagulant before the procedure. When this is not possible or when it carries significant risk (eg, a patient with a mechanical mitral valve who needs a CIED implantation), it is better to maintain the patient on warfarin therapy with a therapeutic international normalized ratio rather than bridging with heparin products.

Antibacterial envelop and new devices

CIED infection is a major complication that carries significant risk of morbidity and death. Early diagnosis and referral to a multidisciplinary treatment team is crucial to increasing the possibility of a cure. While device extraction has risks, it is nevertheless typically required for complete resolution of the infection. Large clinical trials are under way to address current knowledge gaps about CIED infection, including our understanding of the true incidence rate, risk factors, and efficacy of various implantation techniques. Future trends to minimize the risk of CIED infection include better screening, better diagnostic tools, new devices with fewer or no leads, longer battery life to minimize the need for additional procedures, and the use of supportive tools and products to minimize the risk of infection.

Cardiac implantable electronic devices (CIEDs) have become common tools to improve the quality of life and longevity of patients with cardiac disease over the last few decades.^1–4 CIEDs include implantable cardioverter defibrillators (ICDs), permanent pacemakers, biventricular pacemakers providing cardiac resynchronization therapy with or without a defibrillator, subcutaneous ICDs, and implantable loop recorders. With increasing approved indications, the number of CIEDs implanted each year continues to grow. This, paired with the aging population of patients receiving devices and their medical complexity, has led to a corresponding increase in device-related complications.^2,3 One of the most serious complications is CIED infection, which leads to significant morbidity and death. These infections also represent a significant cost burden to the healthcare system, with treatment costs for a CIED infection estimated at over $146,000 in 2008.⁵

SCOPE OF THE PROBLEM

More than half a million permanent pacemakers and ICDs are implanted each year in the United States, with more than 4 million implanted between 1993 and 2008.⁵ The risk of infection is 0.5% to 1%, for a first-time implantation and 1% to 5% for a device replacement or upgrade.^1,2,5–9 These infections can involve the generator pocket, bloodstream, or cardiac structures, leading to infective endocarditis.¹⁰ The timing of CIED infection appears to be bimodal in distribution: early infections usually occur as a result of the implantation procedure itself, whereas late infections occur in patients who are generally unwell or because of an insidious process that eventually crosses a threshold of clinical significance.^3,11,12

Incidence and risk factors

Klug et al¹³ investigated the incidence rate and risk factors of CIED infection prospectively in a large cohort of patients from 44 centers who underwent CIED implantation. Of 6,319 procedures, 4,465 were first implants and the other 1,854 were a replacement or revision; 42 patients (0.68%) developed CIED infection by 12 months after the procedure, and the incidence of infection in replacement or revision cases was nearly twice the rate found in first implants.¹³ Risk factors for CIED infection included renal failure, heart failure, diabetes, and fever within last 24 hours before CIED implantation.¹⁴ The Implantable Cardiac Pulse Generator Replacement (REPLACE) registry found the 6-month incidence rate of CIED infection to be 1.4% after CIED replacement.⁶

Recently, there has been concern that the rate of newly infected CIEDs has outpaced the rate of newly implanted ones.^5,15 Voigt et al¹⁵ reported a 12% increase in the rate of CIED implantation from 2004 to 2006 and an out-of-proportion 57% increase in the rate of CIED infection. A review from 2011 confirmed these findings, showing the annual CIED implantation incidence increased an average of 4.7% per year between 1993 and 2008.⁵ This was probably driven by clinical trials that broadened the indications for ICD implantation for primary prevention.^16–19 Between 1993 and 2008, the rate of newly implanted devices increased by 96%, while the rate for newly infected CIEDs increased by 210%; the majority of this increase occurred after 2004.⁵ The study showed that comorbidities in patients receiving CIEDs increased sharply starting in 2004—alluding to the contribution of comorbid medical conditions such as renal failure, respiratory failure, heart failure, and diabetes to infection risk.⁵

However, a major obstacle to defining the true incidence rate of CIED infection is the lack of a clear denominator. CIED infection is not limited to the first few months after implantation. In fact, over half of these patients present more than 1 year after the last CIED intervention.¹² Therefore, the number of patients at risk continues to grow each year and includes patients who underwent implantation that year or before, making it very difficult to compare infection rates. Additionally, the lack of a clear definition of CIED infection and the variations in duration of follow-up in different studies make it difficult to accurately assess the incidence of CIED infection.

PATHOGENESIS

Prompt and accurate diagnosis of CIED infection is critical as it allows for early management with antibiotic therapy and device removal. As the number of CIED implantations increases, providers on the front lines—emergency, family practice, and internal medicine physicians—will play an increasing role in recognizing and diagnosing CIED infection. Patients with CIED infection present with a range of signs and symptoms including fever, chills, erythema, swelling, drainage, tenderness, malaise, erosion, and warmth of the skin overlying the generator pocket.² In 55% of cases, patients present with localized pocket infection, while the remaining patients have signs of an endovascular infection without obvious pocket involvement.¹² Localized pocket infection is more common during the first year after device implantation. CIED-associated endovascular infections occur more commonly in patients with multiple comorbidities including diabetes, renal failure, prior heart valve operation, rheumatic heart disease, and prior bloodstream infection.² Despite the theoretical divide in CIED infections (endovascular vs pocket), overlap is common: many patients with pocket infection show evidence of bacteremia and vegetations on the leads.

Diagnosing pocket infection from the physical examination can be difficult due to the often subtle manifestations of the underlying pathophysiology and because visible changes to the pocket can occur over weeks and months. Furthermore, differentiating superficial infection, hematoma, seroma, and allergic reactions from deep pocket infection can be challenging. In cases when the diagnosis is not clear and there are no systemic findings of infection, conservative management with close follow-up is reasonable. Similarly, the diagnosis of endovascular infection is sometimes delayed because the symptoms are not very specific or because of a lack of awareness of the presence of a CIED and its role in endovascular infection.

MANAGEMENT

A multidisciplinary approach involving cardiology, infectious disease, electrophysiology, and cardiothoracic surgery teams is required to optimize outcomes in patients with CIED infection. CIED infection is particularly difficult to treat with antibiotic therapy alone because it involves infection of an implanted device and an associated biofilm that is resistant to the effects of antibiotics. Once infection is confirmed, antibiotic therapy serves as an adjunct to the complete removal of the hardware. Most patients receive 2 weeks of intravenous antibiotics after removal of an infected CIED, with longer courses for patients with Staphylococcus aureus infection or documented endocarditis.²¹

Infectious disease consultation is paramount in order to choose the appropriate type and duration of antibiotic therapy. Conservative approaches that involve using antibiotics alone or incomplete system removal have high failure rates with high rates of morbidity and mortality.^13,21–28 However, chronic antibiotic suppressive therapy may be considered as a palliative measure for patients who are not candidates for lead extraction.

DEVICE REMOVAL

Confirmation of CIED infection is a class I indication for device removal and the patient should be referred to an electrophysiologist. Transvenous lead extraction (TLE) is a percutaneous procedure performed by the electrophysiologist in the electrophysiology laboratory or hybrid operating room with cardiothoracic surgery support, and it is generally performed under general anesthesia with invasive hemodynamic monitoring. After opening and debriding the infected pocket, the generator is disconnected from the leads. After the lead tips are unscrewed from the myocardium, gentle traction is applied to determine if the leads can easily be removed. If traction is unsuccessful, additional tools (both powered or mechanical sheaths) are used to complete the lead extraction²⁹; the goal is to lyse and free the fibrotic attachments between parallel leads and between the leads and vessel wall or the myocardium. Once the lead is freed from the adhesions it can be removed safely.

The need for reimplantation after removal of an infected CIED should be thought about before the extraction. In general, extracting an infected CIED should be viewed as an opportunity to reassess the need for the device. Almost one-third of patients who undergo extraction of infected CIED do not require immediate reimplantation.² This could be due to reversal of the initial indication, emergence of new clinical conditions, patient preference, or the lack of an absolute indication. If reimplantation is necessary, the new device is typically placed on the opposite side of the chest from the previously infected pocket site after blood cultures are negative for at least 72 hours.²¹

CIED INFECTION MORTALITY

Despite proper management with CIED removal supported by antibiotic therapy, CIED infection carries a high risk of death. The 30-day mortality is estimated to be between 5% and 6%.³³ In a large case series of 412 CIED extractions, there were 19 in-hospital deaths. Of these 19 deaths, 2 were related to the extraction itself with the other 17 related to sepsis, multiorgan failure, stroke, renal failure, or heart failure.² The 1-year mortality rate is also increased for this population; recent data show 1-year mortality rates of 8% to 17% despite device removal and antibiotic therapy.^2,34,35 This increased mortality rate was also demonstrated in a large cohort of Medicare patients undergoing CIED procedures.³⁶ Medicare patients with CIED infection had double the risk of death at 1 year compared with patients without infection.³⁶

Risk factors for death at 1 year include worse baseline functional status, renal failure, and type of infection; eg, endovascular infection carries a risk of death 2 times higher than pocket infection.³⁷

PREVENTION

Because CIED infection carries significant short-term and long-term mortality rates despite optimal management, the best strategy is prevention. Preventing CIED infection begins with the decision to implant a device with careful assessment of the indication, the timing of the procedure, and the patient’s clinical status. CIED procedures are performed under strict sterile surgical techniques with great attention to the incision and proper closure. Surgical data favor the use of chlorhexidine-alcohol solutions for skin preparation compared with povidone-iodine solutions to prevent both superficial and deep surgical wound infections.³⁸ However, recent studies showed no significant difference between the 2 preparation methods in reducing rates of CIED infection.^39,40 In individuals colonized with S aureus, the risk of CIED infection can be reduced using a body wash containing chlorhexidine and a nasal spray containing mupirocin.^41,42

Preoperative antibiotics

The use of preoperative antibiotics has been shown to reduce the risk of infection.⁴³ In a large prospective cohort of patients undergoing a de novo or secondary CIED procedure, the use of perioperative antibiotics was negatively associated with the risk of CIED infection.¹³ This was later confirmed by a double-blind randomized trial of 1,000 patients undergoing permanent pacemaker or ICD initial implantation or generator replacement. This study was stopped prematurely as the use of antibiotics was clearly associated with a lower risk of CIED infection.⁴⁴ Therefore, prophylaxis with an antibiotic active against staphylococci before the incision is made is a class I indication to prevent infection.¹

Currently, no data support giving prophylactic antibiotics after the procedure; however, the Prevention of Arrhythmia Device Infection Trial (PADIT) is currently comparing the risk of infection with conventional preoperative antibiotics vs a regimen of pre- and post-procedure antibiotics (clinicaltrial.gov: NCT01628666).

Hemostasis

Adequate hemostasis is critical, since the risk of CIED infection is 7 times greater with formation of a hematoma.⁴⁵ Heparin products, especially low-molecular-weight heparin, should be avoided at the time of CIED implantation. In patients at high risk for thromboembolism who are on warfarin therapy, the continuation of warfarin is associated with a lower incidence of hematoma compared with bridging with heparin in patients undergoing CIED procedures.⁴⁶ Therefore, if anticoagulation can be withheld, it is better to stop the anticoagulant before the procedure. When this is not possible or when it carries significant risk (eg, a patient with a mechanical mitral valve who needs a CIED implantation), it is better to maintain the patient on warfarin therapy with a therapeutic international normalized ratio rather than bridging with heparin products.

Antibacterial envelop and new devices

CIED infection is a major complication that carries significant risk of morbidity and death. Early diagnosis and referral to a multidisciplinary treatment team is crucial to increasing the possibility of a cure. While device extraction has risks, it is nevertheless typically required for complete resolution of the infection. Large clinical trials are under way to address current knowledge gaps about CIED infection, including our understanding of the true incidence rate, risk factors, and efficacy of various implantation techniques. Future trends to minimize the risk of CIED infection include better screening, better diagnostic tools, new devices with fewer or no leads, longer battery life to minimize the need for additional procedures, and the use of supportive tools and products to minimize the risk of infection.

Lung transplant is the therapy of choice for a growing number of patients with end-stage lung diseases. Patients receiving a lung transplant are faced with many challenges including drug toxicities, infections, and the risk of rejection.¹ Despite these challenges, lung transplant may significantly prolong survival and improve quality of life for many patients.

CANDIDATES FOR LUNG TRANSPLANT

Identifying patients who are appropriate candidates for lung transplant is important to achieving favorable transplant outcomes and to maximizing life expectancy for each patient. The most recent edition of International Society for Heart and Lung Transplant (ISHLT) Guidelines for the Selection of Lung Transplant Candidates is an excellent guide to help physicians identify when to refer potential patients and to how to identify patients who are the most likely to benefit from lung transplant.²

Adults with end-stage lung disease are generally candidates for lung transplant if they meet the following criteria:

• A greater than 50% risk of death from lung disease within 2 years if a lung transplant is not performed
• A greater than 80% likelihood of surviving at least 90 days after the lung transplant procedure
• A greater than 80% likelihood of a 5-year survival posttransplant if graft function is preserved.²

These can only be estimated by transplant programs and not by the referring team in most cases.

Once a patient is identified as a candidate for lung transplant, early referral of patients to a lung transplant program has several advantages and is essential for positive outcomes. Early patient referral allows for timely completion of the formal evaluation of candidacy, patient and family education, as well as the opportunity for the patient and family to raise funds or use other resources to overcome financial hurdles. Listing a patient on the transplant waitlist implies that the patient has a limited life expectancy without a lung transplant and that the risk-benefit ratio favors lung transplant since all other medical options have been exhausted.¹

Adapted from reference 4.

NONCANDIDATES FOR LUNG TRANSPLANT

There are very few absolute contraindications to lung transplant. Generally, most transplant centers in the United States agree that contraindications to lung transplant include conditions associated with increased risk of mortality, including:

• A recent history of a major malignancy. Patients with a 2-year, disease-free interval combined with a low predicted risk of recurrence may be considered in certain cases of localized, non-melanoma skin cancer. A 5-year, disease-free survival is strongly suggested in patients with a history of breast, bladder, or kidney cancer as well as in cases of sarcoma, melanoma, lymphoma and certain hematologic disorders.
• The presence of significant dysfunction of another major organ systems including the heart, liver, kidney, or brain unless a combined organ transplant can be considered and performed.
• Significant coronary heart disease not amenable to revascularization or intervention prior to or at the time of lung transplant.
• The presence of an acute medical condition including but not limited to sepsis and acute liver failure.
• Active Mycobacterium tuberculosis and other highly virulent or highly resistant microbes that are poorly controlled pretransplant.
• Severe obesity with a body mass index greater than 35.
• A history of nonadherence to medical therapy, psychiatric or psychological conditions that might lead to nonadherence, poor or limited social support system, and limited functional status not amenable to rehabilitation.
• Current substance abuse or dependence, including illicit substances, alcohol, and tobacco (nicotine-containing substances). Most centers require at least 6 months’ abstinence from illicit substances prior to being added to the lung transplant waitlist.²

CANDIDATE COMORBIDITIES

Age

Many transplant centers in the US define the age cutoff for lung transplant at 65; however, some centers may consider candidates older than 65. Advanced age by itself should not be considered a contraindication to lung transplant. However, increased age is usually associated with other comorbid conditions that may increase perioperative and long-term morbidity and mortality. As mentioned previously, the number of older candidates for lung transplant has increased. In the US, 29% of the patients on the national waiting list in 2015 were over age 65.⁴

Past chest surgery

It is not uncommon for lung transplant candidates to have a history of chest surgery such as lung resection, pleurodesis, or coronary artery bypass grafting. The limited literature regarding the outcomes for these patients suggests they may experience higher rates of bleeding, re-exploration, and renal dysfunction.² However, these patients should not be excluded from lung transplant and successful transplant outcomes have been achieved in this population by experienced centers.⁵ In candidates with a history of chronic obstructive pulmonary disease (COPD) and lung-volume reduction surgery (LVRS), early case series indicate that these patients did well after lung transplant.⁶ However, more recent data demonstrate that patients with prior LVRS who undergo lung transplant experience higher rates of bleeding, worse early graft dysfunction, and worse outcomes overall.⁷ As with lung transplant candidates with previous chest surgery, lung transplant candidates with previous LVRS are best served by experienced transplant centers.

Hepatitis and HIV

Patients with a history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) are candidates for lung transplant at centers experienced with lung transplant in patients with these infections. Most centers advocate that patients with a history of hepatitis B or C have viral infection levels that are controlled or reduced as low as possible and that there is no evidence of portal hypertension or severe cirrhosis.^8,9 In the case of HIV, patients should have controlled disease with a negative or undetectable viral load and have no current acquired immunodeficiency defining illness.¹⁰ Patients colonized with particular species of Burkholderia cepacia or Mycobacterium abscessus subspecies can be considered for lung transplant only at centers with established preoperative and postoperative protocols for these infections due to the increased risk of perioperative mortality associated with these organisms.^11,12

Chronic obstructive pulmonary disease

COPD (both non- and alpha-1 antitrypsin deficiency) is the most common indication for lung transplant and accounts for almost 32% of lung transplants worldwide.¹³ Patients should be referred for lung transplant when medical therapies, surgical interventions (ie, LVRS) and pulmonary rehabilitation have been maximized. In COPD, the loss of lung function occurs over a long period of time but patients are often more limited by diminished quality of life as lung function slowly declines.

Patients with COPD should be referred for lung transplant if the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index is 5 to 6.² The original BODE index developed by Celli et al,¹⁴ is a scoring system from 0 to 10 with a higher score indicating more severe disease and worse survival. A score of 5 to 6 indicates an estimated mortality of 60% at 4 yrs.^2,14,15 Other considerations for referral for lung transplant include the presence of hypercapnia with partial pressure of carbon dioxide greater than 50 mm Hg or higher or hypoxemia with partial pressure of oxygen less than 60 mm Hg or a forced expiratory volume at 1 sec (FEV₁) less than 25% predicted.

Patients with COPD should considered for listing for lung transplant if any one of the following criteria is met: BODE index of 7 or greater; FEV₁ less than 15% to 20%; 3 of more severe exacerbations during the preceding year; 1 severe exacerbation with acute hypercapnic respiratory failure; or presence of moderate to severe pulmonary hypertension.^2,16

Cystic fibrosis

In patients with cystic fibrosis, lung transplant should be considered in patients with an estimated 2-year survival of less than 50% and with a New York Heart Association (NYHA) Functional Classification III or IV. Referral for lung transplant is recommended for patients with a rapid decrease in FEV₁ despite optimal therapy, female patients with declining weight and lung function, colonization or infection with nontuberculous mycobacterial disease, or cystic fibrosis-related diabetes. The development of pulmonary hypertension, reduction in walk distance, increasing antibiotic resistance, acute respiratory failure requiring noninvasive ventilation, worsening nutritional status, pneumothorax, and life-threatening hemoptysis despite embolization are all indications for referral for lung transplant.

Patients with cystic fibrosis with hypoxia or hypercapnia with declining lung function, needing long-term noninvasive ventilation, having more frequent exacerbations or exhibiting a decline in functional status should be listed for lung transplant.^2,17–19

Restrictive lung disease

Patients with restrictive lung diseases, including interstitial pulmonary fibrosis (usual interstitial pneumonitis, nonspecific interstitial pneumonia), or interstitial lung disease, and hypersensitivity pneumonitis, should be referred for transplant evaluation at the time of diagnosis irrespective of lung function due to the unpredictable nature of these diseases.²⁰ Some clinicians may advocate for a trial of medical therapy with antifibrotics, but this should be done in conjunction with transplant referral.

Patients should be listed for transplant if a 10% or greater decrease in FEV₁ occurred in the past 6 months (of note, even a 5% decrease in FEV₁ is associated with an overall poorer prognosis and warrants consideration of listing for transplant), if the diffusing capacity of the lung for carbon monoxide decreases 15% or greater during the 6-month follow-up, or if a decline of more than 50 meters is noted on the 6-minute walking test. A documented desaturation of less than 88% or a distance of less than 250 meters on the 6-minute walking test is another indication for listing. Any evidence of secondary pulmonary hypertension on right heart catheterization or on echocardiography or hospitalization for respiratory decline are also indications for listing.²¹ In cases of scleroderma-associated interstitial lung disease or mixed connective tissue interstitial lung disease, similar guidelines for referral and listing should be followed.²

Pulmonary arterial hypertension

Patients with pulmonary arterial hypertension should be referred for lung transplant if any 1 of the following conditions is present: rapidly progressive disease; NYHA Functional Classification III or IV symptoms during escalating therapy; use of parenteral pulmonary arterial hypertension therapy; or known or suspected pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis.^2,22

Patients with pulmonary arterial hypertension should be listed for lung transplant if any of the following are present: NYHA Functional Classification III or IV symptoms despite combination therapy; right heart catheterization demonstrating a cardiac index less than 2 L/min/m²; mean right atrial pressure greater than 15 mm Hg; 6-minute walking test less than 350 meters; or development of pericardial effusion, hemoptysis, or signs of worsening right heart failure, including renal insufficiency, rising bilirubin or evidence of ascites.^2,22

BRIDGE TO TRANSPLANT

Acute respiratory decompensation may occur in some candidates for lung transplant prior to listing for transplant or while on the transplant waitlist. In patients with failure of a single lung, a bridge to transplant may be necessary until a suitable organ is available. Mechanical ventilation and extracorporeal life support (ECLS) are 2 bridge strategies for lung transplant candidates. Mechanical ventilation is the most common lung transplant bridge strategy but it is less than ideal because it can lead to deconditioning and ventilator-associated infections that can negatively impact a patient’s suitability for transplant.

ECLS techniques that allow spontaneous breathing and potentially ambulation, known as awake or ambulatory ECLS, is a popular bridge therapy. Ambulatory ECLS is used as an alternative to mechanical ventilation to avoid the complications of mechanical ventilation and allow patients to avoid sedation and participate in rehabilitation.²³ Irrespective of the therapy used as a bridge to transplant, patients considered for a bridge are optimally evaluated from a medical and psychosocial perspective prior to bridge therapy.

Both bridge therapies increase the risk of infection, bleeding, and neurologic events; thus, patients need to be assessed repeatedly for these risks to determine ongoing suitability for lung transplant. It is important to note that delayed referral of patients with advanced disease or patients in an acute exacerbation negatively impacts the evaluation for lung transplant, placement on the lung transplant waitlist, outcomes, and suitability for bridge transplant strategies.

CONCLUSION

To ensure good patient outcomes, the evaluation and selection of candidates for lung transplant requires communication between referring physicians and lung transplant centers. Physicians need basic knowledge of patient conditions appropriate for lung transplant and direct communication with lung transplant centers. The workup, required testing, and timing of listing for lung transplant varies among transplant centers across the country, making communication between the referring providers and transplant centers crucial to good patient care. An open, 2-way dialogue between referring providers and transplant centers facilitates listing patients for transplant in a timely manner, reduces delays, and improves outcomes.

Lung transplant is the therapy of choice for a growing number of patients with end-stage lung diseases. Patients receiving a lung transplant are faced with many challenges including drug toxicities, infections, and the risk of rejection.¹ Despite these challenges, lung transplant may significantly prolong survival and improve quality of life for many patients.

CANDIDATES FOR LUNG TRANSPLANT

Identifying patients who are appropriate candidates for lung transplant is important to achieving favorable transplant outcomes and to maximizing life expectancy for each patient. The most recent edition of International Society for Heart and Lung Transplant (ISHLT) Guidelines for the Selection of Lung Transplant Candidates is an excellent guide to help physicians identify when to refer potential patients and to how to identify patients who are the most likely to benefit from lung transplant.²

Adults with end-stage lung disease are generally candidates for lung transplant if they meet the following criteria:

• A greater than 50% risk of death from lung disease within 2 years if a lung transplant is not performed
• A greater than 80% likelihood of surviving at least 90 days after the lung transplant procedure
• A greater than 80% likelihood of a 5-year survival posttransplant if graft function is preserved.²

These can only be estimated by transplant programs and not by the referring team in most cases.

Once a patient is identified as a candidate for lung transplant, early referral of patients to a lung transplant program has several advantages and is essential for positive outcomes. Early patient referral allows for timely completion of the formal evaluation of candidacy, patient and family education, as well as the opportunity for the patient and family to raise funds or use other resources to overcome financial hurdles. Listing a patient on the transplant waitlist implies that the patient has a limited life expectancy without a lung transplant and that the risk-benefit ratio favors lung transplant since all other medical options have been exhausted.¹

Adapted from reference 4.

NONCANDIDATES FOR LUNG TRANSPLANT

There are very few absolute contraindications to lung transplant. Generally, most transplant centers in the United States agree that contraindications to lung transplant include conditions associated with increased risk of mortality, including:

• A recent history of a major malignancy. Patients with a 2-year, disease-free interval combined with a low predicted risk of recurrence may be considered in certain cases of localized, non-melanoma skin cancer. A 5-year, disease-free survival is strongly suggested in patients with a history of breast, bladder, or kidney cancer as well as in cases of sarcoma, melanoma, lymphoma and certain hematologic disorders.
• The presence of significant dysfunction of another major organ systems including the heart, liver, kidney, or brain unless a combined organ transplant can be considered and performed.
• Significant coronary heart disease not amenable to revascularization or intervention prior to or at the time of lung transplant.
• The presence of an acute medical condition including but not limited to sepsis and acute liver failure.
• Active Mycobacterium tuberculosis and other highly virulent or highly resistant microbes that are poorly controlled pretransplant.
• Severe obesity with a body mass index greater than 35.
• A history of nonadherence to medical therapy, psychiatric or psychological conditions that might lead to nonadherence, poor or limited social support system, and limited functional status not amenable to rehabilitation.
• Current substance abuse or dependence, including illicit substances, alcohol, and tobacco (nicotine-containing substances). Most centers require at least 6 months’ abstinence from illicit substances prior to being added to the lung transplant waitlist.²

CANDIDATE COMORBIDITIES

Age

Many transplant centers in the US define the age cutoff for lung transplant at 65; however, some centers may consider candidates older than 65. Advanced age by itself should not be considered a contraindication to lung transplant. However, increased age is usually associated with other comorbid conditions that may increase perioperative and long-term morbidity and mortality. As mentioned previously, the number of older candidates for lung transplant has increased. In the US, 29% of the patients on the national waiting list in 2015 were over age 65.⁴

Past chest surgery

It is not uncommon for lung transplant candidates to have a history of chest surgery such as lung resection, pleurodesis, or coronary artery bypass grafting. The limited literature regarding the outcomes for these patients suggests they may experience higher rates of bleeding, re-exploration, and renal dysfunction.² However, these patients should not be excluded from lung transplant and successful transplant outcomes have been achieved in this population by experienced centers.⁵ In candidates with a history of chronic obstructive pulmonary disease (COPD) and lung-volume reduction surgery (LVRS), early case series indicate that these patients did well after lung transplant.⁶ However, more recent data demonstrate that patients with prior LVRS who undergo lung transplant experience higher rates of bleeding, worse early graft dysfunction, and worse outcomes overall.⁷ As with lung transplant candidates with previous chest surgery, lung transplant candidates with previous LVRS are best served by experienced transplant centers.

Hepatitis and HIV

Patients with a history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) are candidates for lung transplant at centers experienced with lung transplant in patients with these infections. Most centers advocate that patients with a history of hepatitis B or C have viral infection levels that are controlled or reduced as low as possible and that there is no evidence of portal hypertension or severe cirrhosis.^8,9 In the case of HIV, patients should have controlled disease with a negative or undetectable viral load and have no current acquired immunodeficiency defining illness.¹⁰ Patients colonized with particular species of Burkholderia cepacia or Mycobacterium abscessus subspecies can be considered for lung transplant only at centers with established preoperative and postoperative protocols for these infections due to the increased risk of perioperative mortality associated with these organisms.^11,12

Chronic obstructive pulmonary disease

COPD (both non- and alpha-1 antitrypsin deficiency) is the most common indication for lung transplant and accounts for almost 32% of lung transplants worldwide.¹³ Patients should be referred for lung transplant when medical therapies, surgical interventions (ie, LVRS) and pulmonary rehabilitation have been maximized. In COPD, the loss of lung function occurs over a long period of time but patients are often more limited by diminished quality of life as lung function slowly declines.

Patients with COPD should be referred for lung transplant if the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index is 5 to 6.² The original BODE index developed by Celli et al,¹⁴ is a scoring system from 0 to 10 with a higher score indicating more severe disease and worse survival. A score of 5 to 6 indicates an estimated mortality of 60% at 4 yrs.^2,14,15 Other considerations for referral for lung transplant include the presence of hypercapnia with partial pressure of carbon dioxide greater than 50 mm Hg or higher or hypoxemia with partial pressure of oxygen less than 60 mm Hg or a forced expiratory volume at 1 sec (FEV₁) less than 25% predicted.

Patients with COPD should considered for listing for lung transplant if any one of the following criteria is met: BODE index of 7 or greater; FEV₁ less than 15% to 20%; 3 of more severe exacerbations during the preceding year; 1 severe exacerbation with acute hypercapnic respiratory failure; or presence of moderate to severe pulmonary hypertension.^2,16

Cystic fibrosis

In patients with cystic fibrosis, lung transplant should be considered in patients with an estimated 2-year survival of less than 50% and with a New York Heart Association (NYHA) Functional Classification III or IV. Referral for lung transplant is recommended for patients with a rapid decrease in FEV₁ despite optimal therapy, female patients with declining weight and lung function, colonization or infection with nontuberculous mycobacterial disease, or cystic fibrosis-related diabetes. The development of pulmonary hypertension, reduction in walk distance, increasing antibiotic resistance, acute respiratory failure requiring noninvasive ventilation, worsening nutritional status, pneumothorax, and life-threatening hemoptysis despite embolization are all indications for referral for lung transplant.

Patients with cystic fibrosis with hypoxia or hypercapnia with declining lung function, needing long-term noninvasive ventilation, having more frequent exacerbations or exhibiting a decline in functional status should be listed for lung transplant.^2,17–19

Restrictive lung disease

Patients with restrictive lung diseases, including interstitial pulmonary fibrosis (usual interstitial pneumonitis, nonspecific interstitial pneumonia), or interstitial lung disease, and hypersensitivity pneumonitis, should be referred for transplant evaluation at the time of diagnosis irrespective of lung function due to the unpredictable nature of these diseases.²⁰ Some clinicians may advocate for a trial of medical therapy with antifibrotics, but this should be done in conjunction with transplant referral.

Patients should be listed for transplant if a 10% or greater decrease in FEV₁ occurred in the past 6 months (of note, even a 5% decrease in FEV₁ is associated with an overall poorer prognosis and warrants consideration of listing for transplant), if the diffusing capacity of the lung for carbon monoxide decreases 15% or greater during the 6-month follow-up, or if a decline of more than 50 meters is noted on the 6-minute walking test. A documented desaturation of less than 88% or a distance of less than 250 meters on the 6-minute walking test is another indication for listing. Any evidence of secondary pulmonary hypertension on right heart catheterization or on echocardiography or hospitalization for respiratory decline are also indications for listing.²¹ In cases of scleroderma-associated interstitial lung disease or mixed connective tissue interstitial lung disease, similar guidelines for referral and listing should be followed.²

Pulmonary arterial hypertension

Patients with pulmonary arterial hypertension should be referred for lung transplant if any 1 of the following conditions is present: rapidly progressive disease; NYHA Functional Classification III or IV symptoms during escalating therapy; use of parenteral pulmonary arterial hypertension therapy; or known or suspected pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis.^2,22

Patients with pulmonary arterial hypertension should be listed for lung transplant if any of the following are present: NYHA Functional Classification III or IV symptoms despite combination therapy; right heart catheterization demonstrating a cardiac index less than 2 L/min/m²; mean right atrial pressure greater than 15 mm Hg; 6-minute walking test less than 350 meters; or development of pericardial effusion, hemoptysis, or signs of worsening right heart failure, including renal insufficiency, rising bilirubin or evidence of ascites.^2,22

BRIDGE TO TRANSPLANT

Acute respiratory decompensation may occur in some candidates for lung transplant prior to listing for transplant or while on the transplant waitlist. In patients with failure of a single lung, a bridge to transplant may be necessary until a suitable organ is available. Mechanical ventilation and extracorporeal life support (ECLS) are 2 bridge strategies for lung transplant candidates. Mechanical ventilation is the most common lung transplant bridge strategy but it is less than ideal because it can lead to deconditioning and ventilator-associated infections that can negatively impact a patient’s suitability for transplant.

ECLS techniques that allow spontaneous breathing and potentially ambulation, known as awake or ambulatory ECLS, is a popular bridge therapy. Ambulatory ECLS is used as an alternative to mechanical ventilation to avoid the complications of mechanical ventilation and allow patients to avoid sedation and participate in rehabilitation.²³ Irrespective of the therapy used as a bridge to transplant, patients considered for a bridge are optimally evaluated from a medical and psychosocial perspective prior to bridge therapy.

Both bridge therapies increase the risk of infection, bleeding, and neurologic events; thus, patients need to be assessed repeatedly for these risks to determine ongoing suitability for lung transplant. It is important to note that delayed referral of patients with advanced disease or patients in an acute exacerbation negatively impacts the evaluation for lung transplant, placement on the lung transplant waitlist, outcomes, and suitability for bridge transplant strategies.

CONCLUSION

To ensure good patient outcomes, the evaluation and selection of candidates for lung transplant requires communication between referring physicians and lung transplant centers. Physicians need basic knowledge of patient conditions appropriate for lung transplant and direct communication with lung transplant centers. The workup, required testing, and timing of listing for lung transplant varies among transplant centers across the country, making communication between the referring providers and transplant centers crucial to good patient care. An open, 2-way dialogue between referring providers and transplant centers facilitates listing patients for transplant in a timely manner, reduces delays, and improves outcomes.

Lung transplant is the therapy of choice for a growing number of patients with end-stage lung diseases. Patients receiving a lung transplant are faced with many challenges including drug toxicities, infections, and the risk of rejection.¹ Despite these challenges, lung transplant may significantly prolong survival and improve quality of life for many patients.

CANDIDATES FOR LUNG TRANSPLANT

Identifying patients who are appropriate candidates for lung transplant is important to achieving favorable transplant outcomes and to maximizing life expectancy for each patient. The most recent edition of International Society for Heart and Lung Transplant (ISHLT) Guidelines for the Selection of Lung Transplant Candidates is an excellent guide to help physicians identify when to refer potential patients and to how to identify patients who are the most likely to benefit from lung transplant.²

Adults with end-stage lung disease are generally candidates for lung transplant if they meet the following criteria:

• A greater than 50% risk of death from lung disease within 2 years if a lung transplant is not performed
• A greater than 80% likelihood of surviving at least 90 days after the lung transplant procedure
• A greater than 80% likelihood of a 5-year survival posttransplant if graft function is preserved.²

These can only be estimated by transplant programs and not by the referring team in most cases.

Once a patient is identified as a candidate for lung transplant, early referral of patients to a lung transplant program has several advantages and is essential for positive outcomes. Early patient referral allows for timely completion of the formal evaluation of candidacy, patient and family education, as well as the opportunity for the patient and family to raise funds or use other resources to overcome financial hurdles. Listing a patient on the transplant waitlist implies that the patient has a limited life expectancy without a lung transplant and that the risk-benefit ratio favors lung transplant since all other medical options have been exhausted.¹

Adapted from reference 4.

NONCANDIDATES FOR LUNG TRANSPLANT

There are very few absolute contraindications to lung transplant. Generally, most transplant centers in the United States agree that contraindications to lung transplant include conditions associated with increased risk of mortality, including:

• A recent history of a major malignancy. Patients with a 2-year, disease-free interval combined with a low predicted risk of recurrence may be considered in certain cases of localized, non-melanoma skin cancer. A 5-year, disease-free survival is strongly suggested in patients with a history of breast, bladder, or kidney cancer as well as in cases of sarcoma, melanoma, lymphoma and certain hematologic disorders.
• The presence of significant dysfunction of another major organ systems including the heart, liver, kidney, or brain unless a combined organ transplant can be considered and performed.
• Significant coronary heart disease not amenable to revascularization or intervention prior to or at the time of lung transplant.
• The presence of an acute medical condition including but not limited to sepsis and acute liver failure.
• Active Mycobacterium tuberculosis and other highly virulent or highly resistant microbes that are poorly controlled pretransplant.
• Severe obesity with a body mass index greater than 35.
• A history of nonadherence to medical therapy, psychiatric or psychological conditions that might lead to nonadherence, poor or limited social support system, and limited functional status not amenable to rehabilitation.
• Current substance abuse or dependence, including illicit substances, alcohol, and tobacco (nicotine-containing substances). Most centers require at least 6 months’ abstinence from illicit substances prior to being added to the lung transplant waitlist.²

CANDIDATE COMORBIDITIES

Age

Many transplant centers in the US define the age cutoff for lung transplant at 65; however, some centers may consider candidates older than 65. Advanced age by itself should not be considered a contraindication to lung transplant. However, increased age is usually associated with other comorbid conditions that may increase perioperative and long-term morbidity and mortality. As mentioned previously, the number of older candidates for lung transplant has increased. In the US, 29% of the patients on the national waiting list in 2015 were over age 65.⁴

Past chest surgery

It is not uncommon for lung transplant candidates to have a history of chest surgery such as lung resection, pleurodesis, or coronary artery bypass grafting. The limited literature regarding the outcomes for these patients suggests they may experience higher rates of bleeding, re-exploration, and renal dysfunction.² However, these patients should not be excluded from lung transplant and successful transplant outcomes have been achieved in this population by experienced centers.⁵ In candidates with a history of chronic obstructive pulmonary disease (COPD) and lung-volume reduction surgery (LVRS), early case series indicate that these patients did well after lung transplant.⁶ However, more recent data demonstrate that patients with prior LVRS who undergo lung transplant experience higher rates of bleeding, worse early graft dysfunction, and worse outcomes overall.⁷ As with lung transplant candidates with previous chest surgery, lung transplant candidates with previous LVRS are best served by experienced transplant centers.

Hepatitis and HIV

Patients with a history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) are candidates for lung transplant at centers experienced with lung transplant in patients with these infections. Most centers advocate that patients with a history of hepatitis B or C have viral infection levels that are controlled or reduced as low as possible and that there is no evidence of portal hypertension or severe cirrhosis.^8,9 In the case of HIV, patients should have controlled disease with a negative or undetectable viral load and have no current acquired immunodeficiency defining illness.¹⁰ Patients colonized with particular species of Burkholderia cepacia or Mycobacterium abscessus subspecies can be considered for lung transplant only at centers with established preoperative and postoperative protocols for these infections due to the increased risk of perioperative mortality associated with these organisms.^11,12

Chronic obstructive pulmonary disease

COPD (both non- and alpha-1 antitrypsin deficiency) is the most common indication for lung transplant and accounts for almost 32% of lung transplants worldwide.¹³ Patients should be referred for lung transplant when medical therapies, surgical interventions (ie, LVRS) and pulmonary rehabilitation have been maximized. In COPD, the loss of lung function occurs over a long period of time but patients are often more limited by diminished quality of life as lung function slowly declines.

Patients with COPD should be referred for lung transplant if the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index is 5 to 6.² The original BODE index developed by Celli et al,¹⁴ is a scoring system from 0 to 10 with a higher score indicating more severe disease and worse survival. A score of 5 to 6 indicates an estimated mortality of 60% at 4 yrs.^2,14,15 Other considerations for referral for lung transplant include the presence of hypercapnia with partial pressure of carbon dioxide greater than 50 mm Hg or higher or hypoxemia with partial pressure of oxygen less than 60 mm Hg or a forced expiratory volume at 1 sec (FEV₁) less than 25% predicted.

Patients with COPD should considered for listing for lung transplant if any one of the following criteria is met: BODE index of 7 or greater; FEV₁ less than 15% to 20%; 3 of more severe exacerbations during the preceding year; 1 severe exacerbation with acute hypercapnic respiratory failure; or presence of moderate to severe pulmonary hypertension.^2,16

Cystic fibrosis

In patients with cystic fibrosis, lung transplant should be considered in patients with an estimated 2-year survival of less than 50% and with a New York Heart Association (NYHA) Functional Classification III or IV. Referral for lung transplant is recommended for patients with a rapid decrease in FEV₁ despite optimal therapy, female patients with declining weight and lung function, colonization or infection with nontuberculous mycobacterial disease, or cystic fibrosis-related diabetes. The development of pulmonary hypertension, reduction in walk distance, increasing antibiotic resistance, acute respiratory failure requiring noninvasive ventilation, worsening nutritional status, pneumothorax, and life-threatening hemoptysis despite embolization are all indications for referral for lung transplant.

Patients with cystic fibrosis with hypoxia or hypercapnia with declining lung function, needing long-term noninvasive ventilation, having more frequent exacerbations or exhibiting a decline in functional status should be listed for lung transplant.^2,17–19

Restrictive lung disease

Patients with restrictive lung diseases, including interstitial pulmonary fibrosis (usual interstitial pneumonitis, nonspecific interstitial pneumonia), or interstitial lung disease, and hypersensitivity pneumonitis, should be referred for transplant evaluation at the time of diagnosis irrespective of lung function due to the unpredictable nature of these diseases.²⁰ Some clinicians may advocate for a trial of medical therapy with antifibrotics, but this should be done in conjunction with transplant referral.

Patients should be listed for transplant if a 10% or greater decrease in FEV₁ occurred in the past 6 months (of note, even a 5% decrease in FEV₁ is associated with an overall poorer prognosis and warrants consideration of listing for transplant), if the diffusing capacity of the lung for carbon monoxide decreases 15% or greater during the 6-month follow-up, or if a decline of more than 50 meters is noted on the 6-minute walking test. A documented desaturation of less than 88% or a distance of less than 250 meters on the 6-minute walking test is another indication for listing. Any evidence of secondary pulmonary hypertension on right heart catheterization or on echocardiography or hospitalization for respiratory decline are also indications for listing.²¹ In cases of scleroderma-associated interstitial lung disease or mixed connective tissue interstitial lung disease, similar guidelines for referral and listing should be followed.²

Pulmonary arterial hypertension

Patients with pulmonary arterial hypertension should be referred for lung transplant if any 1 of the following conditions is present: rapidly progressive disease; NYHA Functional Classification III or IV symptoms during escalating therapy; use of parenteral pulmonary arterial hypertension therapy; or known or suspected pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis.^2,22

Patients with pulmonary arterial hypertension should be listed for lung transplant if any of the following are present: NYHA Functional Classification III or IV symptoms despite combination therapy; right heart catheterization demonstrating a cardiac index less than 2 L/min/m²; mean right atrial pressure greater than 15 mm Hg; 6-minute walking test less than 350 meters; or development of pericardial effusion, hemoptysis, or signs of worsening right heart failure, including renal insufficiency, rising bilirubin or evidence of ascites.^2,22

BRIDGE TO TRANSPLANT

Acute respiratory decompensation may occur in some candidates for lung transplant prior to listing for transplant or while on the transplant waitlist. In patients with failure of a single lung, a bridge to transplant may be necessary until a suitable organ is available. Mechanical ventilation and extracorporeal life support (ECLS) are 2 bridge strategies for lung transplant candidates. Mechanical ventilation is the most common lung transplant bridge strategy but it is less than ideal because it can lead to deconditioning and ventilator-associated infections that can negatively impact a patient’s suitability for transplant.

ECLS techniques that allow spontaneous breathing and potentially ambulation, known as awake or ambulatory ECLS, is a popular bridge therapy. Ambulatory ECLS is used as an alternative to mechanical ventilation to avoid the complications of mechanical ventilation and allow patients to avoid sedation and participate in rehabilitation.²³ Irrespective of the therapy used as a bridge to transplant, patients considered for a bridge are optimally evaluated from a medical and psychosocial perspective prior to bridge therapy.

Both bridge therapies increase the risk of infection, bleeding, and neurologic events; thus, patients need to be assessed repeatedly for these risks to determine ongoing suitability for lung transplant. It is important to note that delayed referral of patients with advanced disease or patients in an acute exacerbation negatively impacts the evaluation for lung transplant, placement on the lung transplant waitlist, outcomes, and suitability for bridge transplant strategies.

CONCLUSION

To ensure good patient outcomes, the evaluation and selection of candidates for lung transplant requires communication between referring physicians and lung transplant centers. Physicians need basic knowledge of patient conditions appropriate for lung transplant and direct communication with lung transplant centers. The workup, required testing, and timing of listing for lung transplant varies among transplant centers across the country, making communication between the referring providers and transplant centers crucial to good patient care. An open, 2-way dialogue between referring providers and transplant centers facilitates listing patients for transplant in a timely manner, reduces delays, and improves outcomes.

Perioperative care is increasingly complex, and the rapid evolution of literature in this field makes it a challenge for clinicians to stay up-to-date. To help meet this challenge, we used a systematic approach to identify appropriate articles in the medical literature and then, by consensus, to develop a list of 6 clinical questions based on their novelty and potential to change perioperative medical practice:

• How should we screen for cardiac risk in patients undergoing noncardiac surgery?
• What is the appropriate timing for surgery after coronary intervention?
• Can we use statin therapy to reduce perioperative cardiac risk?
• How should we manage sleep apnea risk perioperatively?
• Which patients with atrial fibrillation should receive perioperative bridging anticoagulation?
• Is frailty screening beneficial for elderly patients before noncardiac surgery?

The summaries in this article are a composite of perioperative medicine updates presented at the Perioperative Medicine Summit and the annual meetings of the Society for General Internal Medicine and the Society of Hospital Medicine. “Perioperative care is complex and changing”^1–10 (page 864) offers a brief overview.

HOW TO SCREEN FOR CARDIAC RISK BEFORE NONCARDIAC SURGERY

Perioperative cardiac risk can be estimated by clinical risk indexes (based on history, physical examination, common blood tests, and electrocardiography), cardiac biomarkers (natriuretic peptide or troponin levels), and noninvasive cardiac tests.

American and European guidelines

In 2014, the American College of Cardiology/American Heart Association² and the European Society of Cardiology¹¹ published guidelines on perioperative cardiovascular evaluation and management. They recommended several tools to calculate the risk of postoperative cardiac complications but did not specify a preference. These tools include:

• The Revised Cardiac Risk Index (RCRI)¹² (www.mdcalc.com/revised-cardiac-risk-index-pre-operative-risk), which has been externally validated in multiple studies and is the most widely used
• The American College of Surgeons surgical risk calculator¹³ (www.riskcalculator.facs.org), derived from the National Surgery Quality Improvement Program (NSQIP) database
• The myocardial infarction or cardiac arrest (MICA) calculator¹⁴ (www.surgicalriskcalculator.com/miorcardiacarrest), also derived from the NSQIP database.

2017 Canadian guidelines differ

In 2017, the Canadian Cardiovascular Society published its own guidelines on perioperative risk assessment and management.¹ These differ from the American and European guidelines on several points.

RCRI recommended. The Canadian guidelines suggested using the RCRI over the other risk predictors, which despite superior discrimination lacked external validation (conditional recommendation; low-quality evidence). Additionally, the Canadians believed that the NSQIP risk indexes underestimated cardiac risk because patients did not undergo routine biomarker screening.

Biomarker measurement. The Canadian  guidelines went a step further in their algorithm (Figure 1) and recommended measuring N-terminal-pro B-type natriuretic peptide (NT-proBNP) or BNP preoperatively to improve risk prediction in 3 groups (strong recommendation; moderate-quality evidence):

• Patients ages 65 and older
• Patients ages 45 to 64 with significant cardiovascular disease
• Patients with an RCRI score of 1 or more.

This differs from the American guidelines, which did not recommend measuring preoperative biomarkers but did acknowledge that they may provide incremental value. The American College of Cardiology/American Heart Association authors felt that there were no data to suggest that targeting these biomarkers for treatment and intervention would reduce postoperative risk. The European guidelines did not recommend routinely using biomarkers, but stated that they may be considered in high-risk patients (who have a functional capacity ≤ 4 metabolic equivalents or an RCRI score > 1 undergoing vascular surgery, or > 2 undergoing nonvascular surgery).

Stress testing deemphasized. The Canadian guidelines recommended biomarker testing rather than noninvasive tests to enhance risk assessment based on cost, potential delays in surgery, and absence of evidence of an overall absolute net improvement in risk reclassification. This contrasts with the American and European guidelines and algorithms, which recommended pharmacologic stress testing in patients at elevated risk with poor functional capacity undergoing intermediate- to high-risk surgery if the results would change how they are managed.

Postoperative monitoring. The Canadian guidelines recommended that if patients have an NT-proBNP level higher than 300 mg/L or a BNP level higher than 92 mg/L, they should receive  postoperative monitoring with electrocardiography in the postanesthesia care unit and daily troponin measurements for 48 to 72 hours. The American guidelines recommended postoperative electrocardiography and troponin measurement only for patients suspected of having myocardial ischemia, and the European guidelines said postoperative biomarkers may be considered in patients at high risk.

Physician judgment needed

While guidelines and risk calculators are potentially helpful in risk assessment, the lack of consensus and the conflicting recommendations force the physician to weigh the evidence and make individual decisions based on his or her interpretation of the data.

Until there are studies directly comparing the various risk calculators, physicians will most likely use the RCRI, which is simple and has been externally validated, in conjunction with the American guidelines.

At this time, it is unclear how biomarkers should be used—preoperatively, postoperatively, or both—because there are no studies demonstrating that management strategies based on the results lead to better outcomes. We do not believe that biomarker testing will be accepted in lieu of stress testing by our surgery, anesthesiology, or cardiology colleagues, but going forward, it will probably be used more frequently postoperatively, particularly in patients at moderate to high risk.

WHAT IS THE APPROPRIATE TIMING FOR SURGERY AFTER PCI?

A 2014 American College of Cardiology/American Heart Association guideline recommended delaying noncardiac surgery for 1 month after percutaneous coronary intervention (PCI) with bare-metal stents and 1 year after PCI with drug-eluting stents.¹⁵ The guideline suggested that surgery may be performed 6 months after drug-eluting stent placement if the risks of delaying surgery outweigh the risk of thrombosis.¹⁵

The primary rationale behind these timeframes was to provide dual antiplatelet therapy for a minimally acceptable duration before temporary interruption for a procedure. These recommendations were influenced largely by observational studies of first-generation devices, which are no longer used. Studies of newer-generation stents have suggested that the risk of stent thrombosis reaches a plateau considerably earlier than 6 to 12 months after PCI.

2016 Revised guideline on dual antiplatelet therapy

Although not separately delineated in the recommendations, risk factors for stent thrombosis that should influence the decision include smoking, multivessel coronary artery disease, and suboptimally controlled diabetes mellitus or hyperlipidemia.¹⁷ The presence of such stent thrombosis risk factors should be factored into the decision about proceeding with surgery within 3 to 6 months after drug-eluting stent placement.

Holcomb et al: Higher postoperative risk after PCI for myocardial infarction

Another important consideration is the indication for which PCI was performed. In a recent study, Holcomb et al¹⁶ found an association between postoperative major adverse cardiac events and PCI for myocardial infarction (MI) that was independent of stent type.

Compared with patients who underwent PCI not associated with acute coronary syndrome, the odds ratios and 95% confidence intervals (CIs) for major adverse cardiac events in those who underwent PCI for MI were:

• 5.25 (4.08–6.75) in the first 3 months
• 2.45 (1.80–3.35) in months 3 to 6
• 2.50 (1.90–3.28) in months 6 to 12.

In absolute terms, patients with stenting performed for an MI had an incidence of major adverse cardiac events of:

• 22.2% in the first 3 months
• 9.4% in months 3 to 6
• 5.8% in months 6 to 12
• 4.4% in months 12 to 24.

The perioperative risks were reduced after 12 months but still remained greater in patients whose PCI was performed for MI rather than another indication.¹⁶

The authors of this study suggested delaying noncardiac surgery for up to 6 months after PCI for MI, regardless of stent type.¹⁶

A careful, individualized approach

Optimal timing of noncardiac surgery PCI requires a careful, individualized approach and should always be coordinated with the patient’s cardiologist, surgeon, and anesthesiologist.^3,15 For most patients, surgery should be delayed for 30 days after bare-metal stent placement and 6 months after drug-eluting stent placement.³ However, for those with greater surgical need and less thrombotic risk, noncardiac surgery can be considered 3 to 6 months after drug-eluting stent placement.³

Additional discussion of the prolonged increased risk of postoperative major adverse cardiac events is warranted in patients whose PCI was performed for MI, in whom delaying noncardiac surgery for up to 6 months (irrespective of stent type) should be considered.¹⁶

CAN WE USE STATINS TO REDUCE PERIOPERATIVE RISK?

Current recommendations from the American College of Cardiology/American Heart Association support continuing statins in the perioperative period, but the evidence supporting starting statins in this period has yet to be fully determined. In 2013, a Cochrane review¹⁸ found insufficient evidence to conclude that statins reduced perioperative adverse cardiac events, though several large studies were excluded due to controversial methods and data.

In contrast, the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁴ a multicenter, prospective, cohort-matched study of approximately 7,200 patients, found a lower risk of a composite primary outcome of all-cause mortality, myocardial injury after noncardiac surgery, or stroke at 30 days for patients exposed to statin therapy (relative risk [RR] 0.83, 95% CI 0.73–0.95, P = .007).⁴

London et al retrospective study: 30-day mortality rate is lower with statins

In 2017, London et al⁵ published the results of a very large retrospective, observational cohort study of approximately 96,000 elective or emergency surgery patients in Department of Veterans Affairs hospitals. The patients were propensity-matched and evaluated for exposure to statins on the day of or the day after surgery, for a total of approximately 48,000 pairs.

The primary outcome was death at 30 days, and statin exposure was associated with a significant reduction (RR 0.82; 95% CI 0.75–0.89; P < .001). Significant risk reductions were demonstrated in nearly all secondary end points as well, except for stroke or coma and thrombosis (pulmonary embolism, deep vein thrombosis, or graft failure). Overall, the number needed to treat to prevent any complication was 67. Statin therapy did not show significant harm, though on subgroup analysis, those who received high-intensity statin therapy had a slightly higher risk of renal injury (odds ratio 1.18, 95% CI 1.02–1.37, P = .03). Also on subgroup analysis, after propensity matching, patients on long-term moderate- or high-intensity statin therapy for 6 to 12 months before surgery had a small risk reduction for many of the outcomes, including death.

The authors also noted that only 62% of the patients who were prescribed statins as outpatients received them in the hospital, which suggests that improvement is necessary in educating perioperative physicians about the benefits and widespread support for continuing statins perioperatively.⁵

Both London et al⁵ and the VISION investigators⁴ called for a large randomized controlled trial of perioperative statin initiation. The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) trial attempted to answer this call.⁶

This trial randomized 648 statin-naïve Brazilian patients at high risk of perioperative cardiac events to receive either atorvastatin or placebo before surgery and then continuously for another 7 days. The primary outcomes were the rates of death, nonfatal myocardial injury after noncardiac surgery, and cerebrovascular accident at 30 days.⁶

The investigators found no significant difference in outcomes between the two groups and estimated that the sample size would need to be approximately 7,000 patients to demonstrate a significant benefit. Nonetheless, this trial established that a prospective perioperative statin trial is feasible.

When to continue or start statins

Although we cannot recommend starting statins for all perioperative patients, perioperative statins clearly can carry significant benefit and should be continued in all patients who have been taking them. It is also likely beneficial to initiate statins in those patients who would otherwise warrant therapy based on the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk calculator.¹⁹

HOW SHOULD WE MANAGE SLEEP APNEA RISK PERIOPERATIVELY?

From 20% to 30% of US men and 10% to 15% of US women have obstructive sleep apnea, and many are undiagnosed. Obstructive sleep apnea increases the risk of perioperative respiratory failure, unplanned reintubation, unplanned transfer to the intensive care unit, and death.²⁰ Sentinel events (unexpected respiratory arrest after surgery on general surgical wards) have prompted the development of guidelines that aim to identify patients with previously undiagnosed obstructive sleep apnea before surgery and to develop approaches to reduce perioperative morbidity and mortality.

Kaw et al: Beware obesity hypoventilation syndrome

A 2016 study suggested that patients with obstructive sleep apnea and obesity hypoventilation syndrome may be at particularly high risk of perioperative complications.²¹

Kaw et al²¹ queried a database of patients with obstructive sleep apnea undergoing elective noncardiac surgery at Cleveland Clinic. All patients (N = 519) had obstructive sleep apnea confirmed by polysomnography, and a body mass index greater than 30 kg/m². The authors considered a patient to have obesity hypoventilation syndrome (n = 194) if he or she also had hypercapnia (Paco₂ ≥ 45 mm Hg) on at least 2 occasions before or after surgery.

In an adjusted analysis, the odds ratios and 95% CIs for adverse outcomes in patients with obesity hypoventilation syndrome were:

• 10.9 (3.7–32.3) for respiratory failure
• 5.4 (1.9–15.7) for heart failure
• 10.9 (3.7–32.3) for intensive care unit transfer.

The absolute increases in risk in the presence of obesity hypoventilation syndrome were:

• 19% (21% vs 2%) for respiratory failure
• 8% (8% vs 0) for heart failure
• 15% (21% vs 6%) for intensive care unit transfer.

There was no difference in rates of perioperative mortality.²¹

The authors proposed an algorithm to identify patients with possible obesity hypoventilation syndrome before surgery that included prior sleep study results, STOP-BANG score (Table 2),²² and serum bicarbonate level.

Important limitations of the study were that most patients with obesity hypoventilation syndrome were undiagnosed at the time of surgery. Still, the study does offer a tool to potentially identify patients at high risk for perioperative morbidity due to obesity hypoventilation syndrome. Clinicians could then choose to cancel nonessential surgery, propose a lower-risk alternative procedure, or maximize the use of strategies known to reduce perioperative risk for patients with obstructive sleep apnea in general.

Two guidelines on obstructive sleep apnea

Two professional societies have issued guidelines aiming to improve detection of previously undiagnosed obstructive sleep apnea and perioperative outcomes in patients known to have it or suspected of having it:

• The American Society of Anesthesiologists in 2014²³ 
• The Society of Anesthesia and Sleep Medicine in 2016.⁷

Both guidelines recommend that each institution develop a local protocol to screen patients for possible obstructive sleep apnea before elective surgery. The American Society of Anesthesiologists does not recommend any particular tool, but does recommend taking a history and performing a focused examination that includes evaluation of the airway, nasopharyngeal characteristics, neck circumference, and tonsil and tongue size. The Society of Anesthesia and Sleep Medicine recommends using a validated tool such as the STOP-BANG score to estimate the risk of obstructive sleep apnea.

If this screening suggests that a patient has obstructive sleep apnea, should surgery be delayed until a formal sleep study can be done? Or should the patient be treated empirically as if he or she has obstructive sleep apnea?  Both professional societies recommend shared decision-making with the patient in this situation, with the Society of Anesthesia and Sleep Medicine recommending additional cardiopulmonary evaluation for patients with hypoventilation, severe pulmonary hypertension, or resting hypoxemia.

Both recommend using continuous positive airway pressure (CPAP) after surgery in patients with known obstructive sleep apnea, although there is not enough evidence to determine if empiric CPAP for screening-positive patients (without polysomnography-diagnosed obstructive sleep apnea) is beneficial. The Society of Anesthesia and Sleep Medicine advises that it is safe to proceed to surgery if obstructive sleep apnea is suspected as long as monitoring and risk-reduction strategies are implemented after surgery to reduce complication rates.

During surgery, the American Society of Anesthesiologists advises peripheral nerve blocks when appropriate, general anesthesia with a secure airway rather than deep sedation, capnography when using moderate sedation, awake extubation, and full reversal of neuromuscular blockade before extubation. After surgery, they recommend reducing opioid use, minimizing postoperative sedatives, supplemental oxygen, and continuous pulse oximetry. The Society of Anesthesia and Sleep Medicine guideline addresses preoperative assessment and therefore makes no recommendations regarding postoperative care.

In conclusion, use of pertinent findings from the history and physical examination and a validated obstructive sleep apnea screening tool such as STOP-BANG before surgery are recommended, with joint decision-making as to proceeding with surgery with empiric CPAP vs a formal sleep study for patients who screen as high risk. The Society of Anesthesia and Sleep Medicine recommends further cardiopulmonary evaluation if there is evidence of hypoventilation, hypoxemia, or pulmonary hypertension in addition to likely obstructive sleep apnea.

When patients receiving anticoagulation need surgery, we need to carefully assess the risks of thromboembolism without anticoagulation vs bleeding with anticoagulation.

Historically, we tended to worry more about thromboembolism²⁴; however, recent studies have revealed a significant risk of bleeding when long-term anticoagulant therapy is bridged (ie, interrupted and replaced with a shorter-acting agent in the perioperative period), with minimal to no decrease in thromboembolic events.^25–27

American College of Cardiology guideline

In 2017, the American College of Cardiology⁸  published a guideline on periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. The guideline includes a series of decision algorithms on whether and when to interrupt anticoagulation, whether and how to provide bridging anticoagulation, and how to restart postprocedural anticoagulation.

When deciding whether to interrupt anticoagulation, we need to consider the risk of bleeding posed both by patient-specific factors and by the type of surgery. Bridging anticoagulation is not indicated when direct oral anticoagulants (eg, dabigatran, apixaban, edoxaban,  rivaroxaban) are interrupted for procedures.

Unlike an earlier guideline statement by the American College of Chest Physicians,²⁴ this consensus statement emphasizes using the CHA₂DS₂-VASc score as a predictor of thromboembolic events rather than the CHADS₂ core.

Table 3 summarizes the key points in the guidance statement about which patients should receive periprocedural bridging anticoagulation.

As evidence continues to evolve in this complicated area of perioperative medicine, it will remain important to continue to create patient management plans that take individual patient and procedural risks into account.

IS FRAILTY SCREENING BENEFICIAL BEFORE NONCARDIAC SURGERY?

Frailty, defined as a composite score of a patient’s age and comorbidities, has great potential to become an obligatory factor in perioperative risk assessment. However, it remains difficult to incorporate frailty scoring into clinical practice due to variations among scoring systems,²⁸ uncertain outcome data, and the imprecise role of socioeconomic factors. In particular, the effect of frailty on perioperative mortality over longer periods of time is uncertain.

McIsaac et al: Higher risk in frail patients

McIsaac and colleagues at the University of Ottawa used a frailty scoring system developed at Johns Hopkins University to evaluate the effect of frailty on all-cause postoperative mortality in approximately 202,000 patients over a 10-year period.⁹ Although this scoring system is proprietary, it is based on factors such as malnutrition, dementia, impaired vision, decubitus ulcers, urinary incontinence, weight loss, poverty, barriers to access of care, difficulty in walking, and falls.

After adjusting for the procedure risk, patient age, sex, and neighborhood income quintile, the 1-year mortality risk was significantly higher in the frail group (absolute risk 13.6% vs 4.8%; adjusted hazard ratio 2.23; 95% CI 2.08–2.40). The risk of death in the first 3 days was much higher in frail than in nonfrail patients (hazard ratio 35.58; 95% CI 29.78–40.1), but the hazard ratio decreased to approximately 2.4 by day 90.

The authors emphasize that the elevated risk for frail patients warrants particular perioperative planning, though it is not yet clear what frailty-specific interventions should be performed. Further study is needed into the benefit of “prehabilitation” (ie, exercise training to “build up” a patient before surgery) for perioperative risk reduction.

Hall et al: Better care for frail patients

Hall et al¹⁰ instituted a quality improvement initiative for perioperative care of patients at the Omaha Veterans Affairs Hospital. Frail patients were identified using the Risk Analysis Index, a 14-question screening tool previously developed and validated over several years using Veterans Administration databases.²⁹ Questions in the Risk Analysis Index cover living situation, any diagnosis of cancer, ability to perform activities of daily living, and others.

To maximize compliance, a Risk Analysis Index score was required to schedule a surgery. Patients with high scores underwent further review by a designated team of physicians who initiated informal and formal consultations with anesthesiologists, critical care physicians, surgeons, and palliative care providers, with the goals of minimizing risk, clarifying patient goals or resuscitation wishes, and developing comprehensive perioperative planning.¹⁰

Approximately 9,100 patients were included in the cohort. The authors demonstrated a significant improvement in mortality for frail patients at 30, 180, and 365 days, but noted an improvement in postoperative mortality for the nonfrail patients as well, perhaps due to increased focus on geriatric patient care. In particular, the mortality rate at 365 days dropped from 34.5% to 11.7% for frail patients who underwent this intervention.

While this quality improvement initiative was unable to examine how surgical rates changed in frail patients, it is highly likely that very high-risk patients opted out of surgery or had their surgical plan change, though the authors point out that the overall surgical volume at the institution did not change significantly. As well, it remains unclear which particular interventions may have had the most effect in improving survival, as the perioperative plans were individualized and continually adjusted throughout the study period.

Nonetheless, this article highlights how higher vigilance, individualized planning and appreciation of the high risks of frail patients is associated with improved patient survival postoperatively. Although frailty screening is still in its early stages and further work is needed, it is likely that performing frailty screening in elderly patients and utilizing interdisciplinary collaboration for comprehensive management of frail patients can improve their postoperative course.

Perioperative care is increasingly complex, and the rapid evolution of literature in this field makes it a challenge for clinicians to stay up-to-date. To help meet this challenge, we used a systematic approach to identify appropriate articles in the medical literature and then, by consensus, to develop a list of 6 clinical questions based on their novelty and potential to change perioperative medical practice:

• How should we screen for cardiac risk in patients undergoing noncardiac surgery?
• What is the appropriate timing for surgery after coronary intervention?
• Can we use statin therapy to reduce perioperative cardiac risk?
• How should we manage sleep apnea risk perioperatively?
• Which patients with atrial fibrillation should receive perioperative bridging anticoagulation?
• Is frailty screening beneficial for elderly patients before noncardiac surgery?

The summaries in this article are a composite of perioperative medicine updates presented at the Perioperative Medicine Summit and the annual meetings of the Society for General Internal Medicine and the Society of Hospital Medicine. “Perioperative care is complex and changing”^1–10 (page 864) offers a brief overview.

HOW TO SCREEN FOR CARDIAC RISK BEFORE NONCARDIAC SURGERY

Perioperative cardiac risk can be estimated by clinical risk indexes (based on history, physical examination, common blood tests, and electrocardiography), cardiac biomarkers (natriuretic peptide or troponin levels), and noninvasive cardiac tests.

American and European guidelines

In 2014, the American College of Cardiology/American Heart Association² and the European Society of Cardiology¹¹ published guidelines on perioperative cardiovascular evaluation and management. They recommended several tools to calculate the risk of postoperative cardiac complications but did not specify a preference. These tools include:

• The Revised Cardiac Risk Index (RCRI)¹² (www.mdcalc.com/revised-cardiac-risk-index-pre-operative-risk), which has been externally validated in multiple studies and is the most widely used
• The American College of Surgeons surgical risk calculator¹³ (www.riskcalculator.facs.org), derived from the National Surgery Quality Improvement Program (NSQIP) database
• The myocardial infarction or cardiac arrest (MICA) calculator¹⁴ (www.surgicalriskcalculator.com/miorcardiacarrest), also derived from the NSQIP database.

2017 Canadian guidelines differ

In 2017, the Canadian Cardiovascular Society published its own guidelines on perioperative risk assessment and management.¹ These differ from the American and European guidelines on several points.

RCRI recommended. The Canadian guidelines suggested using the RCRI over the other risk predictors, which despite superior discrimination lacked external validation (conditional recommendation; low-quality evidence). Additionally, the Canadians believed that the NSQIP risk indexes underestimated cardiac risk because patients did not undergo routine biomarker screening.

Biomarker measurement. The Canadian  guidelines went a step further in their algorithm (Figure 1) and recommended measuring N-terminal-pro B-type natriuretic peptide (NT-proBNP) or BNP preoperatively to improve risk prediction in 3 groups (strong recommendation; moderate-quality evidence):

• Patients ages 65 and older
• Patients ages 45 to 64 with significant cardiovascular disease
• Patients with an RCRI score of 1 or more.

This differs from the American guidelines, which did not recommend measuring preoperative biomarkers but did acknowledge that they may provide incremental value. The American College of Cardiology/American Heart Association authors felt that there were no data to suggest that targeting these biomarkers for treatment and intervention would reduce postoperative risk. The European guidelines did not recommend routinely using biomarkers, but stated that they may be considered in high-risk patients (who have a functional capacity ≤ 4 metabolic equivalents or an RCRI score > 1 undergoing vascular surgery, or > 2 undergoing nonvascular surgery).

Stress testing deemphasized. The Canadian guidelines recommended biomarker testing rather than noninvasive tests to enhance risk assessment based on cost, potential delays in surgery, and absence of evidence of an overall absolute net improvement in risk reclassification. This contrasts with the American and European guidelines and algorithms, which recommended pharmacologic stress testing in patients at elevated risk with poor functional capacity undergoing intermediate- to high-risk surgery if the results would change how they are managed.

Postoperative monitoring. The Canadian guidelines recommended that if patients have an NT-proBNP level higher than 300 mg/L or a BNP level higher than 92 mg/L, they should receive  postoperative monitoring with electrocardiography in the postanesthesia care unit and daily troponin measurements for 48 to 72 hours. The American guidelines recommended postoperative electrocardiography and troponin measurement only for patients suspected of having myocardial ischemia, and the European guidelines said postoperative biomarkers may be considered in patients at high risk.

Physician judgment needed

While guidelines and risk calculators are potentially helpful in risk assessment, the lack of consensus and the conflicting recommendations force the physician to weigh the evidence and make individual decisions based on his or her interpretation of the data.

Until there are studies directly comparing the various risk calculators, physicians will most likely use the RCRI, which is simple and has been externally validated, in conjunction with the American guidelines.

At this time, it is unclear how biomarkers should be used—preoperatively, postoperatively, or both—because there are no studies demonstrating that management strategies based on the results lead to better outcomes. We do not believe that biomarker testing will be accepted in lieu of stress testing by our surgery, anesthesiology, or cardiology colleagues, but going forward, it will probably be used more frequently postoperatively, particularly in patients at moderate to high risk.

WHAT IS THE APPROPRIATE TIMING FOR SURGERY AFTER PCI?

A 2014 American College of Cardiology/American Heart Association guideline recommended delaying noncardiac surgery for 1 month after percutaneous coronary intervention (PCI) with bare-metal stents and 1 year after PCI with drug-eluting stents.¹⁵ The guideline suggested that surgery may be performed 6 months after drug-eluting stent placement if the risks of delaying surgery outweigh the risk of thrombosis.¹⁵

The primary rationale behind these timeframes was to provide dual antiplatelet therapy for a minimally acceptable duration before temporary interruption for a procedure. These recommendations were influenced largely by observational studies of first-generation devices, which are no longer used. Studies of newer-generation stents have suggested that the risk of stent thrombosis reaches a plateau considerably earlier than 6 to 12 months after PCI.

2016 Revised guideline on dual antiplatelet therapy

Although not separately delineated in the recommendations, risk factors for stent thrombosis that should influence the decision include smoking, multivessel coronary artery disease, and suboptimally controlled diabetes mellitus or hyperlipidemia.¹⁷ The presence of such stent thrombosis risk factors should be factored into the decision about proceeding with surgery within 3 to 6 months after drug-eluting stent placement.

Holcomb et al: Higher postoperative risk after PCI for myocardial infarction

Another important consideration is the indication for which PCI was performed. In a recent study, Holcomb et al¹⁶ found an association between postoperative major adverse cardiac events and PCI for myocardial infarction (MI) that was independent of stent type.

Compared with patients who underwent PCI not associated with acute coronary syndrome, the odds ratios and 95% confidence intervals (CIs) for major adverse cardiac events in those who underwent PCI for MI were:

• 5.25 (4.08–6.75) in the first 3 months
• 2.45 (1.80–3.35) in months 3 to 6
• 2.50 (1.90–3.28) in months 6 to 12.