Except in emergency or specific high-risk surgery, or for extremely fragile high-risk patients, we anticipate a successful outcome from noncardiac surgery. The skills and tools of our anesthesiology colleagues have advanced to the point that severe intraoperative and immediate postoperative complications are rare.

Preoperative risk assessment and perioperative medical management in large medical centers are now largely done by hospital-based physicians with interest and expertise in this subspecialty, and are integrated into the care of the surgical patient. This has likely contributed to improved patient outcomes. Yet postoperative cardiovascular events still cause significant morbidity (although they generally occur in less than 10% of patients).

The entity of perioperative myocardial infarction (MI) has an interesting history. We have recognized for several decades that its presentation is often different than the usually diagnosed MI: perioperative MI is often painless and may manifest as unexplained sinus tachycardia, subtle changes in mental status, or mild dyspnea. These symptoms, if they occurred while the patient was at home, would often be mild enough that the patient would not seek immediate medical attention. Autopsy studies suggested that many of these MIs result from a different pathophysiology than the garden variety MI; plaque rupture with or without secondary thrombosis may be less common than myocardial injury resulting from an imbalance between cardiac demand and blood flow. Studies initially suggested that postoperative MI occurred many days after the surgery. But as tests to diagnose myocyte injury became more sensitive (electrocardiography, creatine kinase, creatine kinase MB, and now troponin), it was recognized that cardiac injury actually occurred very soon after or even during surgery.

With the advent of highly sensitive and fairly specific troponin assays, it seems that perioperative cardiac injury is extremely common, perhaps occurring in up to 20% of patients (if we include patients at high risk based on traditional criteria). This has led to the newly described entity of “myocardial injury after noncardiac surgery” (MINS). MINS patients, diagnosed by troponin elevations, usually are asymptomatic, and many do not meet criteria for any type of MI. But strikingly, as discussed in this issue of the Journal by Horr et al, simply having a postoperative troponin elevation predicts an increased risk of clinical cardiovascular events and a decreased 30-day survival rate.

Adding postoperative troponin measurement to the usual preoperative screening protocol significantly increases our ability to predict delayed cardiovascular events and mortality. As pointed out by Cohn in his accompanying editorial, the benefit, if any, of screening low-risk patients remains to be defined. But an even more important issue, as commented upon in both papers, is what to do when an elevated troponin is detected in a postoperative patient who is otherwise doing perfectly well. Given our current knowledge of the pathophysiology of postoperative MI and the still overall low mortality, it seems unreasonable to immediately take all of these patients to the catheterization suite. Yet with current knowledge of the prognostic significance of troponin elevation, this can’t be ignored. Should all patients receive immediate high-intensity statin therapy, antiplatelet therapy if safe in the specific perioperative setting, and postdischarge physiologic stress studies, or should we “just” take it as a potential high-impact teaching moment and advise patients of their increased cardiovascular risk and offer our usual heart-healthy admonitions?

The confirmed observation that postoperative troponin elevation predicts morbidity and mortality over the subsequent 30 days, and perhaps even longer, has triggered the start of several interventional trials. The results of these will, hopefully, help us to further improve perioperative outcomes.

Except in emergency or specific high-risk surgery, or for extremely fragile high-risk patients, we anticipate a successful outcome from noncardiac surgery. The skills and tools of our anesthesiology colleagues have advanced to the point that severe intraoperative and immediate postoperative complications are rare.

Preoperative risk assessment and perioperative medical management in large medical centers are now largely done by hospital-based physicians with interest and expertise in this subspecialty, and are integrated into the care of the surgical patient. This has likely contributed to improved patient outcomes. Yet postoperative cardiovascular events still cause significant morbidity (although they generally occur in less than 10% of patients).

The entity of perioperative myocardial infarction (MI) has an interesting history. We have recognized for several decades that its presentation is often different than the usually diagnosed MI: perioperative MI is often painless and may manifest as unexplained sinus tachycardia, subtle changes in mental status, or mild dyspnea. These symptoms, if they occurred while the patient was at home, would often be mild enough that the patient would not seek immediate medical attention. Autopsy studies suggested that many of these MIs result from a different pathophysiology than the garden variety MI; plaque rupture with or without secondary thrombosis may be less common than myocardial injury resulting from an imbalance between cardiac demand and blood flow. Studies initially suggested that postoperative MI occurred many days after the surgery. But as tests to diagnose myocyte injury became more sensitive (electrocardiography, creatine kinase, creatine kinase MB, and now troponin), it was recognized that cardiac injury actually occurred very soon after or even during surgery.

With the advent of highly sensitive and fairly specific troponin assays, it seems that perioperative cardiac injury is extremely common, perhaps occurring in up to 20% of patients (if we include patients at high risk based on traditional criteria). This has led to the newly described entity of “myocardial injury after noncardiac surgery” (MINS). MINS patients, diagnosed by troponin elevations, usually are asymptomatic, and many do not meet criteria for any type of MI. But strikingly, as discussed in this issue of the Journal by Horr et al, simply having a postoperative troponin elevation predicts an increased risk of clinical cardiovascular events and a decreased 30-day survival rate.

Adding postoperative troponin measurement to the usual preoperative screening protocol significantly increases our ability to predict delayed cardiovascular events and mortality. As pointed out by Cohn in his accompanying editorial, the benefit, if any, of screening low-risk patients remains to be defined. But an even more important issue, as commented upon in both papers, is what to do when an elevated troponin is detected in a postoperative patient who is otherwise doing perfectly well. Given our current knowledge of the pathophysiology of postoperative MI and the still overall low mortality, it seems unreasonable to immediately take all of these patients to the catheterization suite. Yet with current knowledge of the prognostic significance of troponin elevation, this can’t be ignored. Should all patients receive immediate high-intensity statin therapy, antiplatelet therapy if safe in the specific perioperative setting, and postdischarge physiologic stress studies, or should we “just” take it as a potential high-impact teaching moment and advise patients of their increased cardiovascular risk and offer our usual heart-healthy admonitions?

The confirmed observation that postoperative troponin elevation predicts morbidity and mortality over the subsequent 30 days, and perhaps even longer, has triggered the start of several interventional trials. The results of these will, hopefully, help us to further improve perioperative outcomes.

Except in emergency or specific high-risk surgery, or for extremely fragile high-risk patients, we anticipate a successful outcome from noncardiac surgery. The skills and tools of our anesthesiology colleagues have advanced to the point that severe intraoperative and immediate postoperative complications are rare.

Preoperative risk assessment and perioperative medical management in large medical centers are now largely done by hospital-based physicians with interest and expertise in this subspecialty, and are integrated into the care of the surgical patient. This has likely contributed to improved patient outcomes. Yet postoperative cardiovascular events still cause significant morbidity (although they generally occur in less than 10% of patients).

The entity of perioperative myocardial infarction (MI) has an interesting history. We have recognized for several decades that its presentation is often different than the usually diagnosed MI: perioperative MI is often painless and may manifest as unexplained sinus tachycardia, subtle changes in mental status, or mild dyspnea. These symptoms, if they occurred while the patient was at home, would often be mild enough that the patient would not seek immediate medical attention. Autopsy studies suggested that many of these MIs result from a different pathophysiology than the garden variety MI; plaque rupture with or without secondary thrombosis may be less common than myocardial injury resulting from an imbalance between cardiac demand and blood flow. Studies initially suggested that postoperative MI occurred many days after the surgery. But as tests to diagnose myocyte injury became more sensitive (electrocardiography, creatine kinase, creatine kinase MB, and now troponin), it was recognized that cardiac injury actually occurred very soon after or even during surgery.

With the advent of highly sensitive and fairly specific troponin assays, it seems that perioperative cardiac injury is extremely common, perhaps occurring in up to 20% of patients (if we include patients at high risk based on traditional criteria). This has led to the newly described entity of “myocardial injury after noncardiac surgery” (MINS). MINS patients, diagnosed by troponin elevations, usually are asymptomatic, and many do not meet criteria for any type of MI. But strikingly, as discussed in this issue of the Journal by Horr et al, simply having a postoperative troponin elevation predicts an increased risk of clinical cardiovascular events and a decreased 30-day survival rate.

Adding postoperative troponin measurement to the usual preoperative screening protocol significantly increases our ability to predict delayed cardiovascular events and mortality. As pointed out by Cohn in his accompanying editorial, the benefit, if any, of screening low-risk patients remains to be defined. But an even more important issue, as commented upon in both papers, is what to do when an elevated troponin is detected in a postoperative patient who is otherwise doing perfectly well. Given our current knowledge of the pathophysiology of postoperative MI and the still overall low mortality, it seems unreasonable to immediately take all of these patients to the catheterization suite. Yet with current knowledge of the prognostic significance of troponin elevation, this can’t be ignored. Should all patients receive immediate high-intensity statin therapy, antiplatelet therapy if safe in the specific perioperative setting, and postdischarge physiologic stress studies, or should we “just” take it as a potential high-impact teaching moment and advise patients of their increased cardiovascular risk and offer our usual heart-healthy admonitions?

The confirmed observation that postoperative troponin elevation predicts morbidity and mortality over the subsequent 30 days, and perhaps even longer, has triggered the start of several interventional trials. The results of these will, hopefully, help us to further improve perioperative outcomes.

A major goal of perioperative medicine is to prevent, detect, and treat postoperative complications—in particular, cardiovascular complications. In the Perioperative Ischemic Evaluation (POISE) study,¹ the 30-day mortality rate was four times higher in patients who had a perioperative myocardial infarction (MI) than in those who did not.¹ Yet fewer than half of patients who have a postoperative MI have ischemic symptoms, suggesting that routine monitoring of cardiac biomarkers could detect these events and allow early intervention.

See related article

From 10% to 20% of patients have troponin elevations after noncardiac surgery.² But until recently, many of these elevations were thought to be of minor importance and were ignored unless the patient met diagnostic criteria for MI. A new entity called MINS (myocardial injury after noncardiac surgery)³ was defined as a troponin level exceeding the upper limit of normal with or without ischemic symptoms or electrocardiographic changes and excluding noncardiac causes such as stroke, sepsis, and pulmonary embolism. Because elevations of troponin at any level have been associated with increased 30-day mortality rates, the question of the value of routine screening of asymptomatic postoperative patients for troponin elevation has been raised.

In this issue of Cleveland Clinic Journal of Medicine, Horr et al⁴ review the controversy of postoperative screening using troponin measurement and propose an algorithm for management.

QUESTIONS TO CONSIDER

Before recommending screening asymptomatic patients for troponin elevation, we need to consider a number of questions:

• Which patients should be screened?
• How should troponin elevations be treated?
• Would casting a wider net improve outcomes?
• What are the possible harms of troponin screening?

The bottom line is, will postoperative troponin screening change management and result in improved outcomes?

WHICH PATIENTS SHOULD BE SCREENED?

Why routine screening may be indicated

Elevated or even just detectable troponin levels are associated with adverse outcomes. A systematic review and meta-analysis of 3,318 patients² demonstrated that high troponin levels after noncardiac surgery were independently associated with a risk of death three times higher than in patients with normal troponin levels.

In the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁵ troponin T was measured in 15,133 patients after surgery. The overall mortality rate was 1.9%, and the higher the peak troponin T level the higher the risk of death.

Postoperative troponin elevations are linked to bad outcomes, but should we screen everyone?In a single-center Canadian retrospective cohort analysis of 51,701 consecutive patients by Beattie et al,⁶ the peak postoperative level of troponin I improved the ability of a multivariable model to predict the risk of death. As in the VISION study, the mortality rate rose with the troponin level.⁶

In a study by van Waes et al⁷ in 2,232 consecutive noncardiac surgery patients over age 60 at intermediate to high risk, the all-cause mortality rate was 3%, and troponin I was elevated in 19% of patients. As in VISION and the Canadian retrospective study, the mortality rate increased with the troponin level.

Why routine screening may not help

In VISION,⁵ the probability of detecting myocardial injury was three times higher if patients were screened for 3 days after surgery than if they were tested only if clinical signs or symptoms indicated it.

However, in deciding whether to screen troponin levels in postoperative patients, we must take into account the patient’s clinical risk as well as the risk of the surgical procedure. Troponin elevation in low-risk patients is associated with a low mortality rate, and troponin elevations often are secondary to causes other than myocardial ischemia. In the study by van Waes et al,⁷ the association was stronger with all-cause mortality than with myocardial infarction, and in VISION⁵ there were more nonvascular deaths than vascular deaths, suggesting that troponin elevation is a nonspecific marker of adverse events.

Beattie et al⁶ found that the probability that a patient’s postoperative troponin level would be elevated increased as the patient’s clinical risk increased, but the yield was very low and the mortality rate was less than 1% in patients in risk classes 1 through 3 (of a possible 5 classes). In risk class 4, troponin I was elevated in 21.8%, and the mortality rate was 2.5%; in risk class 5 troponin I was elevated in 18.6%, and the mortality rate was 11.9%. Analyzing the data according to the type of surgery, mortality rates were highest in patients undergoing vascular surgery, neurosurgery, general surgery, and thoracic procedures, with all-cause mortality rates ranging from 2.6% to 5.2%.⁶

Screening should depend on risk

If postoperative troponin screening is to be recommended, it should not be routine for all patients but should be restricted to those with high clinical risk and those undergoing high-risk surgical procedures.

Rodseth and Devereaux⁸ recommended routine postoperative troponin measurement not only after vascular surgery, but also after high-risk surgery (general, neurosurgery, emergency surgery), as well as in patients over age 65 and patients with established atherosclerotic disease or risk factors for it. However, I believe this latter group may not be at high enough risk to justify routine screening.

Beattie et al⁶ advocated limiting postoperative troponin screening to patients with at least a moderate risk of MI and also suggested an international consensus conference to define criteria for postoperative MI, populations who should have routine postoperative screening, and consensus on treatment of patients with troponin elevations but not meeting the criteria for MI. Without this consensus on treatment, it is unclear if protocols for universal postoperative screening would improve outcomes.

For these reasons, the 2014 joint guidelines of the American College of Cardiology and American Heart Association⁹ (ACC/AHA) stated that the benefit of postoperative screening of troponin levels in patients with a high perioperative risk of MI but no signs or symptoms of myocardial ischemia or MI is “uncertain in the absence of established risks and benefits of a defined management strategy.” This recommendation was given a class IIb rating (may be considered) and level of evidence B (usefulness or efficacy less well established). On the other hand, the guidelines recommend measuring troponin levels if signs or symptoms suggest myocardial ischemia or MI (class I recommendation, level of evidence A) but state there is no benefit in routine screening of unselected patients without signs or symptoms of ischemia (class III recommendation, level of evidence B).

HOW SHOULD ELEVATIONS BE TREATED?

Lacking evidence, we can only speculate whether troponin screening helps or harmsBecause a troponin elevation in a patient without signs or symptoms of ischemia does not predict a specific type of death, physicians need to treat patients individually. Perioperative ischemia and inflammation could lead to injury of other organs, and death could result from multiorgan injury rather than from myocardial injury. Treating these troponin elevations in the same way we treat MI—ie, with antiplatelet therapy and anticoagulation—may result in increased bleeding or unnecessary cardiac catheterization, and starting beta-blockers in the perioperative period may be harmful. Because it is unclear how to manage these patients, cardiac medications have not routinely been given in previous studies.

POISE provided some evidence that patients with postoperative MI who were given aspirin and a statin did better.¹ And the results of a smaller study¹⁰ suggested that intensification of drug therapy (aspirin, statin, beta-blocker, angiotensin-converting enzyme inhibitor) in patients with postoperative troponin I elevations was associated with improved outcomes at 1 year. If the bleeding risk is low, I believe that there is potential benefit in prescribing aspirin and statins for these patients.

CASTING A WIDER NET

Further complicating matters in the near future is the issue of using fifth-generation high-sensitivity troponin T assays. The European Society of Cardiology guidelines¹¹ are somewhat more liberal than the ACC/AHA guidelines, stating that measuring high-sensitivity troponin after surgery “may be considered in high-risk patients to improve risk stratification.” This is a class IIB recommendation, level of evidence B.

With fifth-generation high-sensitivity troponin assays, troponin may be elevated in as many as 20% of patients preoperatively and 40% postoperatively, significantly increasing the number of patients said to have a complication. Besides potentially subjecting these patients to unproven treatments, such results would give the false impression that hospitals and surgeons using the screening tools actually had higher complication rates than those that did not screen.

POSSIBLE HARMS OF SCREENING

Elevated postoperative troponin may identify patients at higher risk of any adverse event but not specifically of cardiac-specific events. In an editorial, Beckman¹² stated that routine measurement of troponin “is more likely to cause harm than to provide benefit and should not be used as a screening modality” because of the lack of a proven beneficial treatment strategy, because of the possible harm from applying the standard treatment for type 1 MI, and because it could divert attention from a true cause of an adverse event to a false one—ie, from a nonvascular condition to MI.¹¹

There is clearly a need for clinical trials to determine which treatment, if any, can improve outcomes in these patients, and several trials have been started. But until we have evidence, we can only speculate as to whether screening postoperative patients for troponin elevation is beneficial or detrimental.

A major goal of perioperative medicine is to prevent, detect, and treat postoperative complications—in particular, cardiovascular complications. In the Perioperative Ischemic Evaluation (POISE) study,¹ the 30-day mortality rate was four times higher in patients who had a perioperative myocardial infarction (MI) than in those who did not.¹ Yet fewer than half of patients who have a postoperative MI have ischemic symptoms, suggesting that routine monitoring of cardiac biomarkers could detect these events and allow early intervention.

See related article

From 10% to 20% of patients have troponin elevations after noncardiac surgery.² But until recently, many of these elevations were thought to be of minor importance and were ignored unless the patient met diagnostic criteria for MI. A new entity called MINS (myocardial injury after noncardiac surgery)³ was defined as a troponin level exceeding the upper limit of normal with or without ischemic symptoms or electrocardiographic changes and excluding noncardiac causes such as stroke, sepsis, and pulmonary embolism. Because elevations of troponin at any level have been associated with increased 30-day mortality rates, the question of the value of routine screening of asymptomatic postoperative patients for troponin elevation has been raised.

In this issue of Cleveland Clinic Journal of Medicine, Horr et al⁴ review the controversy of postoperative screening using troponin measurement and propose an algorithm for management.

QUESTIONS TO CONSIDER

Before recommending screening asymptomatic patients for troponin elevation, we need to consider a number of questions:

• Which patients should be screened?
• How should troponin elevations be treated?
• Would casting a wider net improve outcomes?
• What are the possible harms of troponin screening?

The bottom line is, will postoperative troponin screening change management and result in improved outcomes?

WHICH PATIENTS SHOULD BE SCREENED?

Why routine screening may be indicated

Elevated or even just detectable troponin levels are associated with adverse outcomes. A systematic review and meta-analysis of 3,318 patients² demonstrated that high troponin levels after noncardiac surgery were independently associated with a risk of death three times higher than in patients with normal troponin levels.

In the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁵ troponin T was measured in 15,133 patients after surgery. The overall mortality rate was 1.9%, and the higher the peak troponin T level the higher the risk of death.

Postoperative troponin elevations are linked to bad outcomes, but should we screen everyone?In a single-center Canadian retrospective cohort analysis of 51,701 consecutive patients by Beattie et al,⁶ the peak postoperative level of troponin I improved the ability of a multivariable model to predict the risk of death. As in the VISION study, the mortality rate rose with the troponin level.⁶

In a study by van Waes et al⁷ in 2,232 consecutive noncardiac surgery patients over age 60 at intermediate to high risk, the all-cause mortality rate was 3%, and troponin I was elevated in 19% of patients. As in VISION and the Canadian retrospective study, the mortality rate increased with the troponin level.

Why routine screening may not help

In VISION,⁵ the probability of detecting myocardial injury was three times higher if patients were screened for 3 days after surgery than if they were tested only if clinical signs or symptoms indicated it.

However, in deciding whether to screen troponin levels in postoperative patients, we must take into account the patient’s clinical risk as well as the risk of the surgical procedure. Troponin elevation in low-risk patients is associated with a low mortality rate, and troponin elevations often are secondary to causes other than myocardial ischemia. In the study by van Waes et al,⁷ the association was stronger with all-cause mortality than with myocardial infarction, and in VISION⁵ there were more nonvascular deaths than vascular deaths, suggesting that troponin elevation is a nonspecific marker of adverse events.

Beattie et al⁶ found that the probability that a patient’s postoperative troponin level would be elevated increased as the patient’s clinical risk increased, but the yield was very low and the mortality rate was less than 1% in patients in risk classes 1 through 3 (of a possible 5 classes). In risk class 4, troponin I was elevated in 21.8%, and the mortality rate was 2.5%; in risk class 5 troponin I was elevated in 18.6%, and the mortality rate was 11.9%. Analyzing the data according to the type of surgery, mortality rates were highest in patients undergoing vascular surgery, neurosurgery, general surgery, and thoracic procedures, with all-cause mortality rates ranging from 2.6% to 5.2%.⁶

Screening should depend on risk

If postoperative troponin screening is to be recommended, it should not be routine for all patients but should be restricted to those with high clinical risk and those undergoing high-risk surgical procedures.

Rodseth and Devereaux⁸ recommended routine postoperative troponin measurement not only after vascular surgery, but also after high-risk surgery (general, neurosurgery, emergency surgery), as well as in patients over age 65 and patients with established atherosclerotic disease or risk factors for it. However, I believe this latter group may not be at high enough risk to justify routine screening.

Beattie et al⁶ advocated limiting postoperative troponin screening to patients with at least a moderate risk of MI and also suggested an international consensus conference to define criteria for postoperative MI, populations who should have routine postoperative screening, and consensus on treatment of patients with troponin elevations but not meeting the criteria for MI. Without this consensus on treatment, it is unclear if protocols for universal postoperative screening would improve outcomes.

For these reasons, the 2014 joint guidelines of the American College of Cardiology and American Heart Association⁹ (ACC/AHA) stated that the benefit of postoperative screening of troponin levels in patients with a high perioperative risk of MI but no signs or symptoms of myocardial ischemia or MI is “uncertain in the absence of established risks and benefits of a defined management strategy.” This recommendation was given a class IIb rating (may be considered) and level of evidence B (usefulness or efficacy less well established). On the other hand, the guidelines recommend measuring troponin levels if signs or symptoms suggest myocardial ischemia or MI (class I recommendation, level of evidence A) but state there is no benefit in routine screening of unselected patients without signs or symptoms of ischemia (class III recommendation, level of evidence B).

HOW SHOULD ELEVATIONS BE TREATED?

Lacking evidence, we can only speculate whether troponin screening helps or harmsBecause a troponin elevation in a patient without signs or symptoms of ischemia does not predict a specific type of death, physicians need to treat patients individually. Perioperative ischemia and inflammation could lead to injury of other organs, and death could result from multiorgan injury rather than from myocardial injury. Treating these troponin elevations in the same way we treat MI—ie, with antiplatelet therapy and anticoagulation—may result in increased bleeding or unnecessary cardiac catheterization, and starting beta-blockers in the perioperative period may be harmful. Because it is unclear how to manage these patients, cardiac medications have not routinely been given in previous studies.

POISE provided some evidence that patients with postoperative MI who were given aspirin and a statin did better.¹ And the results of a smaller study¹⁰ suggested that intensification of drug therapy (aspirin, statin, beta-blocker, angiotensin-converting enzyme inhibitor) in patients with postoperative troponin I elevations was associated with improved outcomes at 1 year. If the bleeding risk is low, I believe that there is potential benefit in prescribing aspirin and statins for these patients.

CASTING A WIDER NET

Further complicating matters in the near future is the issue of using fifth-generation high-sensitivity troponin T assays. The European Society of Cardiology guidelines¹¹ are somewhat more liberal than the ACC/AHA guidelines, stating that measuring high-sensitivity troponin after surgery “may be considered in high-risk patients to improve risk stratification.” This is a class IIB recommendation, level of evidence B.

With fifth-generation high-sensitivity troponin assays, troponin may be elevated in as many as 20% of patients preoperatively and 40% postoperatively, significantly increasing the number of patients said to have a complication. Besides potentially subjecting these patients to unproven treatments, such results would give the false impression that hospitals and surgeons using the screening tools actually had higher complication rates than those that did not screen.

POSSIBLE HARMS OF SCREENING

Elevated postoperative troponin may identify patients at higher risk of any adverse event but not specifically of cardiac-specific events. In an editorial, Beckman¹² stated that routine measurement of troponin “is more likely to cause harm than to provide benefit and should not be used as a screening modality” because of the lack of a proven beneficial treatment strategy, because of the possible harm from applying the standard treatment for type 1 MI, and because it could divert attention from a true cause of an adverse event to a false one—ie, from a nonvascular condition to MI.¹¹

There is clearly a need for clinical trials to determine which treatment, if any, can improve outcomes in these patients, and several trials have been started. But until we have evidence, we can only speculate as to whether screening postoperative patients for troponin elevation is beneficial or detrimental.

A major goal of perioperative medicine is to prevent, detect, and treat postoperative complications—in particular, cardiovascular complications. In the Perioperative Ischemic Evaluation (POISE) study,¹ the 30-day mortality rate was four times higher in patients who had a perioperative myocardial infarction (MI) than in those who did not.¹ Yet fewer than half of patients who have a postoperative MI have ischemic symptoms, suggesting that routine monitoring of cardiac biomarkers could detect these events and allow early intervention.

See related article

From 10% to 20% of patients have troponin elevations after noncardiac surgery.² But until recently, many of these elevations were thought to be of minor importance and were ignored unless the patient met diagnostic criteria for MI. A new entity called MINS (myocardial injury after noncardiac surgery)³ was defined as a troponin level exceeding the upper limit of normal with or without ischemic symptoms or electrocardiographic changes and excluding noncardiac causes such as stroke, sepsis, and pulmonary embolism. Because elevations of troponin at any level have been associated with increased 30-day mortality rates, the question of the value of routine screening of asymptomatic postoperative patients for troponin elevation has been raised.

In this issue of Cleveland Clinic Journal of Medicine, Horr et al⁴ review the controversy of postoperative screening using troponin measurement and propose an algorithm for management.

QUESTIONS TO CONSIDER

Before recommending screening asymptomatic patients for troponin elevation, we need to consider a number of questions:

• Which patients should be screened?
• How should troponin elevations be treated?
• Would casting a wider net improve outcomes?
• What are the possible harms of troponin screening?

The bottom line is, will postoperative troponin screening change management and result in improved outcomes?

WHICH PATIENTS SHOULD BE SCREENED?

Why routine screening may be indicated

Elevated or even just detectable troponin levels are associated with adverse outcomes. A systematic review and meta-analysis of 3,318 patients² demonstrated that high troponin levels after noncardiac surgery were independently associated with a risk of death three times higher than in patients with normal troponin levels.

In the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study,⁵ troponin T was measured in 15,133 patients after surgery. The overall mortality rate was 1.9%, and the higher the peak troponin T level the higher the risk of death.

Postoperative troponin elevations are linked to bad outcomes, but should we screen everyone?In a single-center Canadian retrospective cohort analysis of 51,701 consecutive patients by Beattie et al,⁶ the peak postoperative level of troponin I improved the ability of a multivariable model to predict the risk of death. As in the VISION study, the mortality rate rose with the troponin level.⁶

In a study by van Waes et al⁷ in 2,232 consecutive noncardiac surgery patients over age 60 at intermediate to high risk, the all-cause mortality rate was 3%, and troponin I was elevated in 19% of patients. As in VISION and the Canadian retrospective study, the mortality rate increased with the troponin level.

Why routine screening may not help

In VISION,⁵ the probability of detecting myocardial injury was three times higher if patients were screened for 3 days after surgery than if they were tested only if clinical signs or symptoms indicated it.

However, in deciding whether to screen troponin levels in postoperative patients, we must take into account the patient’s clinical risk as well as the risk of the surgical procedure. Troponin elevation in low-risk patients is associated with a low mortality rate, and troponin elevations often are secondary to causes other than myocardial ischemia. In the study by van Waes et al,⁷ the association was stronger with all-cause mortality than with myocardial infarction, and in VISION⁵ there were more nonvascular deaths than vascular deaths, suggesting that troponin elevation is a nonspecific marker of adverse events.

Beattie et al⁶ found that the probability that a patient’s postoperative troponin level would be elevated increased as the patient’s clinical risk increased, but the yield was very low and the mortality rate was less than 1% in patients in risk classes 1 through 3 (of a possible 5 classes). In risk class 4, troponin I was elevated in 21.8%, and the mortality rate was 2.5%; in risk class 5 troponin I was elevated in 18.6%, and the mortality rate was 11.9%. Analyzing the data according to the type of surgery, mortality rates were highest in patients undergoing vascular surgery, neurosurgery, general surgery, and thoracic procedures, with all-cause mortality rates ranging from 2.6% to 5.2%.⁶

Screening should depend on risk

If postoperative troponin screening is to be recommended, it should not be routine for all patients but should be restricted to those with high clinical risk and those undergoing high-risk surgical procedures.

Rodseth and Devereaux⁸ recommended routine postoperative troponin measurement not only after vascular surgery, but also after high-risk surgery (general, neurosurgery, emergency surgery), as well as in patients over age 65 and patients with established atherosclerotic disease or risk factors for it. However, I believe this latter group may not be at high enough risk to justify routine screening.

Beattie et al⁶ advocated limiting postoperative troponin screening to patients with at least a moderate risk of MI and also suggested an international consensus conference to define criteria for postoperative MI, populations who should have routine postoperative screening, and consensus on treatment of patients with troponin elevations but not meeting the criteria for MI. Without this consensus on treatment, it is unclear if protocols for universal postoperative screening would improve outcomes.

For these reasons, the 2014 joint guidelines of the American College of Cardiology and American Heart Association⁹ (ACC/AHA) stated that the benefit of postoperative screening of troponin levels in patients with a high perioperative risk of MI but no signs or symptoms of myocardial ischemia or MI is “uncertain in the absence of established risks and benefits of a defined management strategy.” This recommendation was given a class IIb rating (may be considered) and level of evidence B (usefulness or efficacy less well established). On the other hand, the guidelines recommend measuring troponin levels if signs or symptoms suggest myocardial ischemia or MI (class I recommendation, level of evidence A) but state there is no benefit in routine screening of unselected patients without signs or symptoms of ischemia (class III recommendation, level of evidence B).

HOW SHOULD ELEVATIONS BE TREATED?

Lacking evidence, we can only speculate whether troponin screening helps or harmsBecause a troponin elevation in a patient without signs or symptoms of ischemia does not predict a specific type of death, physicians need to treat patients individually. Perioperative ischemia and inflammation could lead to injury of other organs, and death could result from multiorgan injury rather than from myocardial injury. Treating these troponin elevations in the same way we treat MI—ie, with antiplatelet therapy and anticoagulation—may result in increased bleeding or unnecessary cardiac catheterization, and starting beta-blockers in the perioperative period may be harmful. Because it is unclear how to manage these patients, cardiac medications have not routinely been given in previous studies.

POISE provided some evidence that patients with postoperative MI who were given aspirin and a statin did better.¹ And the results of a smaller study¹⁰ suggested that intensification of drug therapy (aspirin, statin, beta-blocker, angiotensin-converting enzyme inhibitor) in patients with postoperative troponin I elevations was associated with improved outcomes at 1 year. If the bleeding risk is low, I believe that there is potential benefit in prescribing aspirin and statins for these patients.

CASTING A WIDER NET

Further complicating matters in the near future is the issue of using fifth-generation high-sensitivity troponin T assays. The European Society of Cardiology guidelines¹¹ are somewhat more liberal than the ACC/AHA guidelines, stating that measuring high-sensitivity troponin after surgery “may be considered in high-risk patients to improve risk stratification.” This is a class IIB recommendation, level of evidence B.

With fifth-generation high-sensitivity troponin assays, troponin may be elevated in as many as 20% of patients preoperatively and 40% postoperatively, significantly increasing the number of patients said to have a complication. Besides potentially subjecting these patients to unproven treatments, such results would give the false impression that hospitals and surgeons using the screening tools actually had higher complication rates than those that did not screen.

POSSIBLE HARMS OF SCREENING

Elevated postoperative troponin may identify patients at higher risk of any adverse event but not specifically of cardiac-specific events. In an editorial, Beckman¹² stated that routine measurement of troponin “is more likely to cause harm than to provide benefit and should not be used as a screening modality” because of the lack of a proven beneficial treatment strategy, because of the possible harm from applying the standard treatment for type 1 MI, and because it could divert attention from a true cause of an adverse event to a false one—ie, from a nonvascular condition to MI.¹¹

There is clearly a need for clinical trials to determine which treatment, if any, can improve outcomes in these patients, and several trials have been started. But until we have evidence, we can only speculate as to whether screening postoperative patients for troponin elevation is beneficial or detrimental.

More than 200 million patients undergo noncardiac surgery each year, and the volume is increasing.¹ Cardiovascular complications are a major cause of morbidity and mortality in the perioperative period.

See related editorial

Before the advent of modern cardiac biomarkers, an estimated 2% to 3% of all patients undergoing noncardiac surgery had a major adverse cardiac event.² However, more recent studies suggest that 5% to 25% of patients have troponin elevations after noncardiac surgery, depending on the patient population,^3–6 and many are asymptomatic, suggesting that many patients are sustaining undetected myocardial injury. Those who suffer a myocardial infarction or myocardial injury have elevated morbidity and mortality rates, not only perioperatively, but also at 30 days and even at up to 1 year.^3–5,7–11

Yet there are almost no data on how best to manage these patients; the available guidelines, therefore, do not provide sufficient recommendations for clinical practice.

To address the lack of guidelines, we examine the incidence and proposed mechanisms of myocardial injury after noncardiac surgery, suggest an approach to identifying patients at risk, recommend treatment strategies, and consider future directions.

CARDIAC BIOMARKERS

When cardiac cellular injury from ischemia, direct trauma, or other cause disrupts the cell membrane, intracellular contents enter the extracellular space, including the blood stream. If the myocyte damage is extensive enough, biochemical assays can detect these substances.

Reprinted from Kumar A, et al. Acute coronary syndromes: diagnosis and management,part I. Mayo Clin Proc 2009; 84:917–938, with permission from Elsevier.

Troponin, creatine kinase, myoglobin, and lactate dehydrogenase are common biomarkers of necrosis that, when detected in the plasma, may indicate cardiac injury. Each can be detected at varying times after cardiac injury (Figure 1).¹²

Cardiac troponins I and T

Of the biomarkers, cardiac troponin I and cardiac troponin T are now the most widely used and are the most specific for myocyte injury.

Troponins are proteins that regulate the calcium-induced interaction between myosin and actin that results in muscle contraction. Troponin is a complex consisting of three subunits: troponin C, troponin I, and troponin T. The cardiac troponin I and T isoforms are distinct from those found in skeletal muscle, making them specific for myocyte injury, and they are currently the recommended markers for diagnosing acute myocardial infarction.¹³

The troponin immunoassays currently available are not standardized among laboratories and point-of-care methods, and thus, levels cannot be compared across testing centers.¹⁴ Each assay has unique performance characteristics, but guidelines recommend using the 99th percentile value from a normal reference population for a given assay to define whether myocardial injury is present.¹³

Troponin elevation has prognostic value in patients presenting with acute coronary syndromes,^15–18 and the degree of elevation correlates with infarct size.^19–21

Controversy exists as to whether troponin and other biomarkers are released only after myocardial necrosis or after reversible injury as well. Using newer, highly sensitive assays, troponin elevations have been detected after short periods of ischemia during stress testing^22,23 and in patients with stable angina,²⁴ suggesting that reversible cardiac stress and injury can lead to troponin release. This mechanism may play an important role during the myocardial injury that can occur in patients undergoing noncardiac surgery.

MYOCARDIAL INFARCTION vs MYOCARDIAL INJURY

In 2000, the Joint Task Force of the European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and World Heart Federation revised the criteria for the diagnosis of myocardial infarction created by the World Health Organization in 1979. The definition was revised again in 2007 and once more in 2012 to create the third universal definition of myocardial infarction.

Acute myocardial infarction

Acute myocardial infarction is defined as evidence of myocardial necrosis in a setting of myocardial ischemia, not related to causes such as trauma or pulmonary embolism, with a rise or a fall (or a rise and a fall) of cardiac biomarkers (at least one value being above the 99th percentile in the reference population) and any of the following:

• Symptoms of ischemia
• New ST-segment changes or new left bundle branch block
• Pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new regional wall-motion abnormality
• Intracoronary thrombus by angiography or autopsy.¹³

Myocardial injury after noncardiac surgery

Studies^10,11 have shown that many patients undergoing noncardiac surgery have evidence of cardiac biomarker release but do not meet the universal definition of myocardial infarction.

The Perioperative Ischemic Evaluation (POISE) trial¹⁰ reported that 415 (5%) of its patients met the definition of myocardial infarction, of whom only about 35% had symptoms of ischemia. Another 697 patients (8.3%) had isolated elevations in biomarkers without meeting the definition of myocardial infarction.

The VISION study¹¹ (Vascular Events in Noncardiac Surgery Patients Cohort Evaluation) prospectively screened more than 15,000 patients in several countries for troponin elevation during the first 3 postoperative days and for ischemic symptoms and features. Of the patients screened, approximately 1,200 (8%) had troponin elevations, with fewer than half fulfilling the criteria for myocardial infarction.

In another study, van Waes et al⁶ prospectively screened 2,232 patients ages 60 and older undergoing intermediate- to high-risk noncardiac surgery. Troponin levels were elevated in 19% of the patients, but only 10 of these patients met the universal definition of myocardial infarction.

In all of these studies, patients with isolated elevation in myocardial biomarkers had worse short-term and long-term outcomes than those without. These observations led to a proposed definition of “myocardial injury after noncardiac surgery” that is broader than that of myocardial infarction and requires only elevation of cardiac biomarkers judged to be due to myocardial ischemia (ie, not from another obvious cause such as pulmonary embolism or myocarditis).³

FIVE TYPES OF MYOCARDIAL INFARCTION

The Joint Task Force¹³ categorizes myocardial infarction into five distinct types:

• Type 1—due to plaque rupture
• Type 2—due to imbalance between oxygen supply and demand
• Type 3—sudden cardiac death
• Type 4a—associated with percutaneous coronary intervention
• Type 4b—associated with stent thrombosis
• Type 5—associated with coronary artery bypass surgery.

Types 1 and 2 have both been implicated in perioperative myocardial infarction and injury. Patient characteristics and the physiologic response to surgical and anesthetic stressors likely contribute to the development of myocardial infarction and injury after noncardiac surgery.

Plaque rupture as a cause of postoperative myocardial infarction

The mechanism of type 1 myocardial infarction—plaque rupture or erosion leading to thrombosis and infarction—plays a significant role in most cases of acute coronary syndromes. Its role in perioperative and postoperative myocardial infarction or injury, however, is less clear.

In an autopsy study of 26 patients who died of myocardial infarction after noncardiac surgery, plaque rupture was evident in 12 (46%).²⁵ A prospective angiographic study of 120 patients with acute coronary syndromes after noncardiac surgery found that nearly 50% had evidence of plaque rupture.²⁶

Higher levels of catecholamines, cortisol,^27,28 platelet reactivity,²⁹ procoagulant factors,³⁰ and coronary artery shear stress³¹ are all present in the postoperative period and may contribute to an increased propensity for plaque rupture or erosion. Whether plaque rupture is present in patients who have isolated troponin elevation but do not meet the criteria for myocardial infarction has not been investigated.

Oxygen supply-demand imbalance during and after surgery

Oxygen supply-demand imbalance (the mechanism in type 2 myocardial infarction) leading to myocyte stress, ischemia, and subsequent infarction is likely common in the perioperative and postoperative periods. As previously discussed, this imbalance may be present with or without symptoms.

Oxygen demand may increase in this period as a result of tachycardia³² caused by bleeding, pain, and catecholamines or increased wall stress from hypertension due to vasoconstriction or pain.³³ Oxygen supply can be decreased secondary to tachycardia, anemia,³⁴ hypotension, hypoxemia, hypercarbia, intravascular fluid shifts (bleeding or volume overload), or coronary vasoconstriction.^33,35

These mechanisms of myocardial injury, infarction, or both can occur with or without underlying significant obstructive coronary artery disease. However, severe coronary artery disease is more common in those who have had a perioperative myocardial infarction.³⁶

POSTOPERATIVE TROPONIN ELEVATION CARRIES A WORSE PROGNOSIS

Patients who suffer a myocardial infarction after noncardiac surgery have worse short- and long-term outcomes than their counterparts.^{4,5,7, 8,10,33} In the POISE trial,¹⁰ the 30-day mortality rate was 11.6% in those who had had a perioperative myocardial infarction, compared with 2.2% in those who did not (P < .001). The patients who had had a myocardial infarction were also more likely to have nonfatal cardiac arrest, coronary revascularization, and congestive heart failure.

Myocardial injury not fulfilling the criteria for myocardial infarction after noncardiac surgery is also associated with worse short-term and long-term outcomes.^{3,6,10,11,37,38} POISE patients with isolated elevations in cardiac biomarkers had a higher 30-day risk of coronary revascularization and nonfatal arrest.¹⁰ In the VISION trial, an elevation in troponin was the strongest predictor of death within 30 days after noncardiac surgery. This analysis also showed that the higher the peak troponin value, the greater the risk of death and the shorter the median time until death.¹¹

A meta-analysis of 14 studies in 3,139 patients found that elevated troponin after noncardiac surgery was an independent predictor of death within 1 year (odds ratio [OR] 6.7, 95% confidence interval [CI] 4.1–10.9) and beyond 1 year (OR 1.8, 95% CI 1.4–2.3).³⁷

SHOULD SCREENING BE ROUTINE AFTER NONCARDIAC SURGERY?

Since patients suffering myocardial infarction or injury after noncardiac surgery have a worse prognosis, many experts advocate routinely screening all high-risk patients and those undergoing moderate- to high-risk surgery. Many tools exist to determine which patients undergoing noncardiac surgery are at high risk of cardiac complications.

The revised Goldman Cardiac Risk Index is commonly used and well validated. Variables in this index that predict major cardiac complications are:

• High-risk surgery (vascular surgery, orthopedic surgery, and intraperitoneal or intrathoracic surgery)
• History of ischemic heart disease
• History of congestive heart failure
• History of cerebrovascular disease
• Diabetes requiring insulin therapy
• Chronic kidney disease with a creatinine > 2.0 mg/dL.

The more of these variables that are present, the higher the risk of perioperative cardiac events^2,4:

• No risk factors: 0.4% risk (95% CI 0.1–0.8)
• One risk factor: 1.0% risk (95% CI 0.5–1.4)
• Two risk factors: 2.4% risk (95% CI 1.3–3.5)
• Three or more risk factors: 5.4% risk (95% CI 2.7–7.9).

Current guidelines from the American College of Cardiology and the American Heart Association give a class I recommendation (the highest) for measuring troponin levels after noncardiac surgery in patients who have symptoms or signs suggesting myocardial ischemia. They give a class IIb recommendation (usefulness is less well established) for screening those at high risk but without symptoms or signs of ischemia, despite the previously cited evidence that patients with troponin elevation are at increased risk. The IIb recommendation is due to a lack of validated treatment strategies to modify and attenuate the recognized risk with troponin elevation in this setting.³⁹

LITTLE EVIDENCE TO GUIDE TREATMENT

In current practice, internists and cardiologists are often asked to consult on patients with troponin elevations noted after noncardiac surgery. Although published and ongoing studies examine strategies to prevent cardiovascular events during noncardiac surgery, we lack data on managing the cases of myocardial infarction and injury that actually occur after noncardiac surgery.

When managing a patient who has a troponin elevation after surgery, many clinical factors must be weighed, including hemodynamic and clinical stability and risk of bleeding. Confronted with ST-segment elevation myocardial infarction or high-risk non–ST-segment elevation myocardial infarction, most clinicians would favor an early invasive reperfusion strategy in accordance with guidelines on managing acute coronary syndrome. Fibrinolytic drugs for ST-segment elevation myocardial infarction are likely to be contraindicated in the postoperative period because they pose an unacceptable risk of bleeding.

Guideline-directed medical therapies for those suffering perioperative myocardial infarction may lower the risk of future cardiovascular events, as suggested by a retrospective study of 66 patients diagnosed with perioperative myocardial infarction after vascular surgery.⁴⁰ Those in whom medical therapy for coronary artery disease was not intensified—defined as adding or increasing the dose of antiplatelet agent, statin, beta-blocker, or angiotensin-converting enzyme inhibitor—had higher rates of cardiovascular events at 12 months (hazard ratio [HR] 2.80, 95% CI 1.05–24.2).⁴⁰

In those with asymptomatic myocardial infarction or isolated elevation in cardiac biomarkers, no treatment strategies have been assessed prospectively or in randomized trials. However, statins and aspirin have been suggested as providing some benefit. In a substudy of the POISE trial, the use of aspirin was associated with a 46% reduction in the 30-day mortality rate in those suffering a perioperative myocardial infarction, and statins were associated with a 76% reduction.¹⁰ In a single-center retrospective analysis of 337 patients undergoing moderate- to high-risk vascular surgery, statin therapy was associated with a lower 1-year mortality  rate (OR 0.63, 95% CI 0.40–0.98).³⁸

We propose a treatment algorithm for patients identified as having cardiovascular events after noncardiac surgery (Figure 2), based on current evidence and guidelines. Ultimately, treatment decisions should be tailored to the individual patient. Discussion of the risks and benefits of therapeutic options should include the patient and surgeon.

Ongoing and future trials

Ongoing and future trials are aimed at addressing definitive treatment strategies in this patient population.

The MANAGE trial (Management of Myocardial Injury After Non-cardiac Surgery Trial) is randomizing patients suffering myocardial injury after noncardiac surgery to receive either dabigatran and omeprazole or placebo to assess the efficacy of these agents in preventing major adverse cardiac events and the safety of anticoagulation (ClinicalTrials.gov Identifier: NCT01661101).

The INTREPID trial (Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-Cardiac Surgery) will assess the efficacy and safety of ticagrelor treatment compared with aspirin in a similar population (ClinicalTrial.gov Identifier: NCT02291419). The trial will enroll approximately 1,000 patients identified as having a postoperative troponin elevation more than two times the upper limit of normal of the assay during the index hospitalization (Figure 3). Enrollment was to have begun in mid-2015.

More than 200 million patients undergo noncardiac surgery each year, and the volume is increasing.¹ Cardiovascular complications are a major cause of morbidity and mortality in the perioperative period.

See related editorial

Before the advent of modern cardiac biomarkers, an estimated 2% to 3% of all patients undergoing noncardiac surgery had a major adverse cardiac event.² However, more recent studies suggest that 5% to 25% of patients have troponin elevations after noncardiac surgery, depending on the patient population,^3–6 and many are asymptomatic, suggesting that many patients are sustaining undetected myocardial injury. Those who suffer a myocardial infarction or myocardial injury have elevated morbidity and mortality rates, not only perioperatively, but also at 30 days and even at up to 1 year.^3–5,7–11

Yet there are almost no data on how best to manage these patients; the available guidelines, therefore, do not provide sufficient recommendations for clinical practice.

To address the lack of guidelines, we examine the incidence and proposed mechanisms of myocardial injury after noncardiac surgery, suggest an approach to identifying patients at risk, recommend treatment strategies, and consider future directions.

CARDIAC BIOMARKERS

When cardiac cellular injury from ischemia, direct trauma, or other cause disrupts the cell membrane, intracellular contents enter the extracellular space, including the blood stream. If the myocyte damage is extensive enough, biochemical assays can detect these substances.

Reprinted from Kumar A, et al. Acute coronary syndromes: diagnosis and management,part I. Mayo Clin Proc 2009; 84:917–938, with permission from Elsevier.

Troponin, creatine kinase, myoglobin, and lactate dehydrogenase are common biomarkers of necrosis that, when detected in the plasma, may indicate cardiac injury. Each can be detected at varying times after cardiac injury (Figure 1).¹²

Cardiac troponins I and T

Of the biomarkers, cardiac troponin I and cardiac troponin T are now the most widely used and are the most specific for myocyte injury.

Troponins are proteins that regulate the calcium-induced interaction between myosin and actin that results in muscle contraction. Troponin is a complex consisting of three subunits: troponin C, troponin I, and troponin T. The cardiac troponin I and T isoforms are distinct from those found in skeletal muscle, making them specific for myocyte injury, and they are currently the recommended markers for diagnosing acute myocardial infarction.¹³

The troponin immunoassays currently available are not standardized among laboratories and point-of-care methods, and thus, levels cannot be compared across testing centers.¹⁴ Each assay has unique performance characteristics, but guidelines recommend using the 99th percentile value from a normal reference population for a given assay to define whether myocardial injury is present.¹³

Troponin elevation has prognostic value in patients presenting with acute coronary syndromes,^15–18 and the degree of elevation correlates with infarct size.^19–21

Controversy exists as to whether troponin and other biomarkers are released only after myocardial necrosis or after reversible injury as well. Using newer, highly sensitive assays, troponin elevations have been detected after short periods of ischemia during stress testing^22,23 and in patients with stable angina,²⁴ suggesting that reversible cardiac stress and injury can lead to troponin release. This mechanism may play an important role during the myocardial injury that can occur in patients undergoing noncardiac surgery.

MYOCARDIAL INFARCTION vs MYOCARDIAL INJURY

In 2000, the Joint Task Force of the European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and World Heart Federation revised the criteria for the diagnosis of myocardial infarction created by the World Health Organization in 1979. The definition was revised again in 2007 and once more in 2012 to create the third universal definition of myocardial infarction.

Acute myocardial infarction

Acute myocardial infarction is defined as evidence of myocardial necrosis in a setting of myocardial ischemia, not related to causes such as trauma or pulmonary embolism, with a rise or a fall (or a rise and a fall) of cardiac biomarkers (at least one value being above the 99th percentile in the reference population) and any of the following:

• Symptoms of ischemia
• New ST-segment changes or new left bundle branch block
• Pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new regional wall-motion abnormality
• Intracoronary thrombus by angiography or autopsy.¹³

Myocardial injury after noncardiac surgery

Studies^10,11 have shown that many patients undergoing noncardiac surgery have evidence of cardiac biomarker release but do not meet the universal definition of myocardial infarction.

The Perioperative Ischemic Evaluation (POISE) trial¹⁰ reported that 415 (5%) of its patients met the definition of myocardial infarction, of whom only about 35% had symptoms of ischemia. Another 697 patients (8.3%) had isolated elevations in biomarkers without meeting the definition of myocardial infarction.

The VISION study¹¹ (Vascular Events in Noncardiac Surgery Patients Cohort Evaluation) prospectively screened more than 15,000 patients in several countries for troponin elevation during the first 3 postoperative days and for ischemic symptoms and features. Of the patients screened, approximately 1,200 (8%) had troponin elevations, with fewer than half fulfilling the criteria for myocardial infarction.

In another study, van Waes et al⁶ prospectively screened 2,232 patients ages 60 and older undergoing intermediate- to high-risk noncardiac surgery. Troponin levels were elevated in 19% of the patients, but only 10 of these patients met the universal definition of myocardial infarction.

In all of these studies, patients with isolated elevation in myocardial biomarkers had worse short-term and long-term outcomes than those without. These observations led to a proposed definition of “myocardial injury after noncardiac surgery” that is broader than that of myocardial infarction and requires only elevation of cardiac biomarkers judged to be due to myocardial ischemia (ie, not from another obvious cause such as pulmonary embolism or myocarditis).³

FIVE TYPES OF MYOCARDIAL INFARCTION

The Joint Task Force¹³ categorizes myocardial infarction into five distinct types:

• Type 1—due to plaque rupture
• Type 2—due to imbalance between oxygen supply and demand
• Type 3—sudden cardiac death
• Type 4a—associated with percutaneous coronary intervention
• Type 4b—associated with stent thrombosis
• Type 5—associated with coronary artery bypass surgery.

Types 1 and 2 have both been implicated in perioperative myocardial infarction and injury. Patient characteristics and the physiologic response to surgical and anesthetic stressors likely contribute to the development of myocardial infarction and injury after noncardiac surgery.

Plaque rupture as a cause of postoperative myocardial infarction

The mechanism of type 1 myocardial infarction—plaque rupture or erosion leading to thrombosis and infarction—plays a significant role in most cases of acute coronary syndromes. Its role in perioperative and postoperative myocardial infarction or injury, however, is less clear.

In an autopsy study of 26 patients who died of myocardial infarction after noncardiac surgery, plaque rupture was evident in 12 (46%).²⁵ A prospective angiographic study of 120 patients with acute coronary syndromes after noncardiac surgery found that nearly 50% had evidence of plaque rupture.²⁶

Higher levels of catecholamines, cortisol,^27,28 platelet reactivity,²⁹ procoagulant factors,³⁰ and coronary artery shear stress³¹ are all present in the postoperative period and may contribute to an increased propensity for plaque rupture or erosion. Whether plaque rupture is present in patients who have isolated troponin elevation but do not meet the criteria for myocardial infarction has not been investigated.

Oxygen supply-demand imbalance during and after surgery

Oxygen supply-demand imbalance (the mechanism in type 2 myocardial infarction) leading to myocyte stress, ischemia, and subsequent infarction is likely common in the perioperative and postoperative periods. As previously discussed, this imbalance may be present with or without symptoms.

Oxygen demand may increase in this period as a result of tachycardia³² caused by bleeding, pain, and catecholamines or increased wall stress from hypertension due to vasoconstriction or pain.³³ Oxygen supply can be decreased secondary to tachycardia, anemia,³⁴ hypotension, hypoxemia, hypercarbia, intravascular fluid shifts (bleeding or volume overload), or coronary vasoconstriction.^33,35

These mechanisms of myocardial injury, infarction, or both can occur with or without underlying significant obstructive coronary artery disease. However, severe coronary artery disease is more common in those who have had a perioperative myocardial infarction.³⁶

POSTOPERATIVE TROPONIN ELEVATION CARRIES A WORSE PROGNOSIS

Patients who suffer a myocardial infarction after noncardiac surgery have worse short- and long-term outcomes than their counterparts.^{4,5,7, 8,10,33} In the POISE trial,¹⁰ the 30-day mortality rate was 11.6% in those who had had a perioperative myocardial infarction, compared with 2.2% in those who did not (P < .001). The patients who had had a myocardial infarction were also more likely to have nonfatal cardiac arrest, coronary revascularization, and congestive heart failure.

Myocardial injury not fulfilling the criteria for myocardial infarction after noncardiac surgery is also associated with worse short-term and long-term outcomes.^{3,6,10,11,37,38} POISE patients with isolated elevations in cardiac biomarkers had a higher 30-day risk of coronary revascularization and nonfatal arrest.¹⁰ In the VISION trial, an elevation in troponin was the strongest predictor of death within 30 days after noncardiac surgery. This analysis also showed that the higher the peak troponin value, the greater the risk of death and the shorter the median time until death.¹¹

A meta-analysis of 14 studies in 3,139 patients found that elevated troponin after noncardiac surgery was an independent predictor of death within 1 year (odds ratio [OR] 6.7, 95% confidence interval [CI] 4.1–10.9) and beyond 1 year (OR 1.8, 95% CI 1.4–2.3).³⁷

SHOULD SCREENING BE ROUTINE AFTER NONCARDIAC SURGERY?

Since patients suffering myocardial infarction or injury after noncardiac surgery have a worse prognosis, many experts advocate routinely screening all high-risk patients and those undergoing moderate- to high-risk surgery. Many tools exist to determine which patients undergoing noncardiac surgery are at high risk of cardiac complications.

The revised Goldman Cardiac Risk Index is commonly used and well validated. Variables in this index that predict major cardiac complications are:

• High-risk surgery (vascular surgery, orthopedic surgery, and intraperitoneal or intrathoracic surgery)
• History of ischemic heart disease
• History of congestive heart failure
• History of cerebrovascular disease
• Diabetes requiring insulin therapy
• Chronic kidney disease with a creatinine > 2.0 mg/dL.

The more of these variables that are present, the higher the risk of perioperative cardiac events^2,4:

• No risk factors: 0.4% risk (95% CI 0.1–0.8)
• One risk factor: 1.0% risk (95% CI 0.5–1.4)
• Two risk factors: 2.4% risk (95% CI 1.3–3.5)
• Three or more risk factors: 5.4% risk (95% CI 2.7–7.9).

Current guidelines from the American College of Cardiology and the American Heart Association give a class I recommendation (the highest) for measuring troponin levels after noncardiac surgery in patients who have symptoms or signs suggesting myocardial ischemia. They give a class IIb recommendation (usefulness is less well established) for screening those at high risk but without symptoms or signs of ischemia, despite the previously cited evidence that patients with troponin elevation are at increased risk. The IIb recommendation is due to a lack of validated treatment strategies to modify and attenuate the recognized risk with troponin elevation in this setting.³⁹

LITTLE EVIDENCE TO GUIDE TREATMENT

In current practice, internists and cardiologists are often asked to consult on patients with troponin elevations noted after noncardiac surgery. Although published and ongoing studies examine strategies to prevent cardiovascular events during noncardiac surgery, we lack data on managing the cases of myocardial infarction and injury that actually occur after noncardiac surgery.

When managing a patient who has a troponin elevation after surgery, many clinical factors must be weighed, including hemodynamic and clinical stability and risk of bleeding. Confronted with ST-segment elevation myocardial infarction or high-risk non–ST-segment elevation myocardial infarction, most clinicians would favor an early invasive reperfusion strategy in accordance with guidelines on managing acute coronary syndrome. Fibrinolytic drugs for ST-segment elevation myocardial infarction are likely to be contraindicated in the postoperative period because they pose an unacceptable risk of bleeding.

Guideline-directed medical therapies for those suffering perioperative myocardial infarction may lower the risk of future cardiovascular events, as suggested by a retrospective study of 66 patients diagnosed with perioperative myocardial infarction after vascular surgery.⁴⁰ Those in whom medical therapy for coronary artery disease was not intensified—defined as adding or increasing the dose of antiplatelet agent, statin, beta-blocker, or angiotensin-converting enzyme inhibitor—had higher rates of cardiovascular events at 12 months (hazard ratio [HR] 2.80, 95% CI 1.05–24.2).⁴⁰

In those with asymptomatic myocardial infarction or isolated elevation in cardiac biomarkers, no treatment strategies have been assessed prospectively or in randomized trials. However, statins and aspirin have been suggested as providing some benefit. In a substudy of the POISE trial, the use of aspirin was associated with a 46% reduction in the 30-day mortality rate in those suffering a perioperative myocardial infarction, and statins were associated with a 76% reduction.¹⁰ In a single-center retrospective analysis of 337 patients undergoing moderate- to high-risk vascular surgery, statin therapy was associated with a lower 1-year mortality  rate (OR 0.63, 95% CI 0.40–0.98).³⁸

We propose a treatment algorithm for patients identified as having cardiovascular events after noncardiac surgery (Figure 2), based on current evidence and guidelines. Ultimately, treatment decisions should be tailored to the individual patient. Discussion of the risks and benefits of therapeutic options should include the patient and surgeon.

Ongoing and future trials

Ongoing and future trials are aimed at addressing definitive treatment strategies in this patient population.

The MANAGE trial (Management of Myocardial Injury After Non-cardiac Surgery Trial) is randomizing patients suffering myocardial injury after noncardiac surgery to receive either dabigatran and omeprazole or placebo to assess the efficacy of these agents in preventing major adverse cardiac events and the safety of anticoagulation (ClinicalTrials.gov Identifier: NCT01661101).

The INTREPID trial (Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-Cardiac Surgery) will assess the efficacy and safety of ticagrelor treatment compared with aspirin in a similar population (ClinicalTrial.gov Identifier: NCT02291419). The trial will enroll approximately 1,000 patients identified as having a postoperative troponin elevation more than two times the upper limit of normal of the assay during the index hospitalization (Figure 3). Enrollment was to have begun in mid-2015.

More than 200 million patients undergo noncardiac surgery each year, and the volume is increasing.¹ Cardiovascular complications are a major cause of morbidity and mortality in the perioperative period.

See related editorial

Before the advent of modern cardiac biomarkers, an estimated 2% to 3% of all patients undergoing noncardiac surgery had a major adverse cardiac event.² However, more recent studies suggest that 5% to 25% of patients have troponin elevations after noncardiac surgery, depending on the patient population,^3–6 and many are asymptomatic, suggesting that many patients are sustaining undetected myocardial injury. Those who suffer a myocardial infarction or myocardial injury have elevated morbidity and mortality rates, not only perioperatively, but also at 30 days and even at up to 1 year.^3–5,7–11

Yet there are almost no data on how best to manage these patients; the available guidelines, therefore, do not provide sufficient recommendations for clinical practice.

To address the lack of guidelines, we examine the incidence and proposed mechanisms of myocardial injury after noncardiac surgery, suggest an approach to identifying patients at risk, recommend treatment strategies, and consider future directions.

CARDIAC BIOMARKERS

When cardiac cellular injury from ischemia, direct trauma, or other cause disrupts the cell membrane, intracellular contents enter the extracellular space, including the blood stream. If the myocyte damage is extensive enough, biochemical assays can detect these substances.

Reprinted from Kumar A, et al. Acute coronary syndromes: diagnosis and management,part I. Mayo Clin Proc 2009; 84:917–938, with permission from Elsevier.

Troponin, creatine kinase, myoglobin, and lactate dehydrogenase are common biomarkers of necrosis that, when detected in the plasma, may indicate cardiac injury. Each can be detected at varying times after cardiac injury (Figure 1).¹²

Cardiac troponins I and T

Of the biomarkers, cardiac troponin I and cardiac troponin T are now the most widely used and are the most specific for myocyte injury.

Troponins are proteins that regulate the calcium-induced interaction between myosin and actin that results in muscle contraction. Troponin is a complex consisting of three subunits: troponin C, troponin I, and troponin T. The cardiac troponin I and T isoforms are distinct from those found in skeletal muscle, making them specific for myocyte injury, and they are currently the recommended markers for diagnosing acute myocardial infarction.¹³

The troponin immunoassays currently available are not standardized among laboratories and point-of-care methods, and thus, levels cannot be compared across testing centers.¹⁴ Each assay has unique performance characteristics, but guidelines recommend using the 99th percentile value from a normal reference population for a given assay to define whether myocardial injury is present.¹³

Troponin elevation has prognostic value in patients presenting with acute coronary syndromes,^15–18 and the degree of elevation correlates with infarct size.^19–21

Controversy exists as to whether troponin and other biomarkers are released only after myocardial necrosis or after reversible injury as well. Using newer, highly sensitive assays, troponin elevations have been detected after short periods of ischemia during stress testing^22,23 and in patients with stable angina,²⁴ suggesting that reversible cardiac stress and injury can lead to troponin release. This mechanism may play an important role during the myocardial injury that can occur in patients undergoing noncardiac surgery.

MYOCARDIAL INFARCTION vs MYOCARDIAL INJURY

In 2000, the Joint Task Force of the European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and World Heart Federation revised the criteria for the diagnosis of myocardial infarction created by the World Health Organization in 1979. The definition was revised again in 2007 and once more in 2012 to create the third universal definition of myocardial infarction.

Acute myocardial infarction

Acute myocardial infarction is defined as evidence of myocardial necrosis in a setting of myocardial ischemia, not related to causes such as trauma or pulmonary embolism, with a rise or a fall (or a rise and a fall) of cardiac biomarkers (at least one value being above the 99th percentile in the reference population) and any of the following:

• Symptoms of ischemia
• New ST-segment changes or new left bundle branch block
• Pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new regional wall-motion abnormality
• Intracoronary thrombus by angiography or autopsy.¹³

Myocardial injury after noncardiac surgery

Studies^10,11 have shown that many patients undergoing noncardiac surgery have evidence of cardiac biomarker release but do not meet the universal definition of myocardial infarction.

The Perioperative Ischemic Evaluation (POISE) trial¹⁰ reported that 415 (5%) of its patients met the definition of myocardial infarction, of whom only about 35% had symptoms of ischemia. Another 697 patients (8.3%) had isolated elevations in biomarkers without meeting the definition of myocardial infarction.

The VISION study¹¹ (Vascular Events in Noncardiac Surgery Patients Cohort Evaluation) prospectively screened more than 15,000 patients in several countries for troponin elevation during the first 3 postoperative days and for ischemic symptoms and features. Of the patients screened, approximately 1,200 (8%) had troponin elevations, with fewer than half fulfilling the criteria for myocardial infarction.

In another study, van Waes et al⁶ prospectively screened 2,232 patients ages 60 and older undergoing intermediate- to high-risk noncardiac surgery. Troponin levels were elevated in 19% of the patients, but only 10 of these patients met the universal definition of myocardial infarction.

In all of these studies, patients with isolated elevation in myocardial biomarkers had worse short-term and long-term outcomes than those without. These observations led to a proposed definition of “myocardial injury after noncardiac surgery” that is broader than that of myocardial infarction and requires only elevation of cardiac biomarkers judged to be due to myocardial ischemia (ie, not from another obvious cause such as pulmonary embolism or myocarditis).³

FIVE TYPES OF MYOCARDIAL INFARCTION

The Joint Task Force¹³ categorizes myocardial infarction into five distinct types:

• Type 1—due to plaque rupture
• Type 2—due to imbalance between oxygen supply and demand
• Type 3—sudden cardiac death
• Type 4a—associated with percutaneous coronary intervention
• Type 4b—associated with stent thrombosis
• Type 5—associated with coronary artery bypass surgery.

Types 1 and 2 have both been implicated in perioperative myocardial infarction and injury. Patient characteristics and the physiologic response to surgical and anesthetic stressors likely contribute to the development of myocardial infarction and injury after noncardiac surgery.

Plaque rupture as a cause of postoperative myocardial infarction

The mechanism of type 1 myocardial infarction—plaque rupture or erosion leading to thrombosis and infarction—plays a significant role in most cases of acute coronary syndromes. Its role in perioperative and postoperative myocardial infarction or injury, however, is less clear.

In an autopsy study of 26 patients who died of myocardial infarction after noncardiac surgery, plaque rupture was evident in 12 (46%).²⁵ A prospective angiographic study of 120 patients with acute coronary syndromes after noncardiac surgery found that nearly 50% had evidence of plaque rupture.²⁶

Higher levels of catecholamines, cortisol,^27,28 platelet reactivity,²⁹ procoagulant factors,³⁰ and coronary artery shear stress³¹ are all present in the postoperative period and may contribute to an increased propensity for plaque rupture or erosion. Whether plaque rupture is present in patients who have isolated troponin elevation but do not meet the criteria for myocardial infarction has not been investigated.

Oxygen supply-demand imbalance during and after surgery

Oxygen supply-demand imbalance (the mechanism in type 2 myocardial infarction) leading to myocyte stress, ischemia, and subsequent infarction is likely common in the perioperative and postoperative periods. As previously discussed, this imbalance may be present with or without symptoms.

Oxygen demand may increase in this period as a result of tachycardia³² caused by bleeding, pain, and catecholamines or increased wall stress from hypertension due to vasoconstriction or pain.³³ Oxygen supply can be decreased secondary to tachycardia, anemia,³⁴ hypotension, hypoxemia, hypercarbia, intravascular fluid shifts (bleeding or volume overload), or coronary vasoconstriction.^33,35

These mechanisms of myocardial injury, infarction, or both can occur with or without underlying significant obstructive coronary artery disease. However, severe coronary artery disease is more common in those who have had a perioperative myocardial infarction.³⁶

POSTOPERATIVE TROPONIN ELEVATION CARRIES A WORSE PROGNOSIS

Patients who suffer a myocardial infarction after noncardiac surgery have worse short- and long-term outcomes than their counterparts.^{4,5,7, 8,10,33} In the POISE trial,¹⁰ the 30-day mortality rate was 11.6% in those who had had a perioperative myocardial infarction, compared with 2.2% in those who did not (P < .001). The patients who had had a myocardial infarction were also more likely to have nonfatal cardiac arrest, coronary revascularization, and congestive heart failure.

Myocardial injury not fulfilling the criteria for myocardial infarction after noncardiac surgery is also associated with worse short-term and long-term outcomes.^{3,6,10,11,37,38} POISE patients with isolated elevations in cardiac biomarkers had a higher 30-day risk of coronary revascularization and nonfatal arrest.¹⁰ In the VISION trial, an elevation in troponin was the strongest predictor of death within 30 days after noncardiac surgery. This analysis also showed that the higher the peak troponin value, the greater the risk of death and the shorter the median time until death.¹¹

A meta-analysis of 14 studies in 3,139 patients found that elevated troponin after noncardiac surgery was an independent predictor of death within 1 year (odds ratio [OR] 6.7, 95% confidence interval [CI] 4.1–10.9) and beyond 1 year (OR 1.8, 95% CI 1.4–2.3).³⁷

SHOULD SCREENING BE ROUTINE AFTER NONCARDIAC SURGERY?

Since patients suffering myocardial infarction or injury after noncardiac surgery have a worse prognosis, many experts advocate routinely screening all high-risk patients and those undergoing moderate- to high-risk surgery. Many tools exist to determine which patients undergoing noncardiac surgery are at high risk of cardiac complications.

The revised Goldman Cardiac Risk Index is commonly used and well validated. Variables in this index that predict major cardiac complications are:

• High-risk surgery (vascular surgery, orthopedic surgery, and intraperitoneal or intrathoracic surgery)
• History of ischemic heart disease
• History of congestive heart failure
• History of cerebrovascular disease
• Diabetes requiring insulin therapy
• Chronic kidney disease with a creatinine > 2.0 mg/dL.

The more of these variables that are present, the higher the risk of perioperative cardiac events^2,4:

• No risk factors: 0.4% risk (95% CI 0.1–0.8)
• One risk factor: 1.0% risk (95% CI 0.5–1.4)
• Two risk factors: 2.4% risk (95% CI 1.3–3.5)
• Three or more risk factors: 5.4% risk (95% CI 2.7–7.9).

Current guidelines from the American College of Cardiology and the American Heart Association give a class I recommendation (the highest) for measuring troponin levels after noncardiac surgery in patients who have symptoms or signs suggesting myocardial ischemia. They give a class IIb recommendation (usefulness is less well established) for screening those at high risk but without symptoms or signs of ischemia, despite the previously cited evidence that patients with troponin elevation are at increased risk. The IIb recommendation is due to a lack of validated treatment strategies to modify and attenuate the recognized risk with troponin elevation in this setting.³⁹

LITTLE EVIDENCE TO GUIDE TREATMENT

In current practice, internists and cardiologists are often asked to consult on patients with troponin elevations noted after noncardiac surgery. Although published and ongoing studies examine strategies to prevent cardiovascular events during noncardiac surgery, we lack data on managing the cases of myocardial infarction and injury that actually occur after noncardiac surgery.

When managing a patient who has a troponin elevation after surgery, many clinical factors must be weighed, including hemodynamic and clinical stability and risk of bleeding. Confronted with ST-segment elevation myocardial infarction or high-risk non–ST-segment elevation myocardial infarction, most clinicians would favor an early invasive reperfusion strategy in accordance with guidelines on managing acute coronary syndrome. Fibrinolytic drugs for ST-segment elevation myocardial infarction are likely to be contraindicated in the postoperative period because they pose an unacceptable risk of bleeding.

Guideline-directed medical therapies for those suffering perioperative myocardial infarction may lower the risk of future cardiovascular events, as suggested by a retrospective study of 66 patients diagnosed with perioperative myocardial infarction after vascular surgery.⁴⁰ Those in whom medical therapy for coronary artery disease was not intensified—defined as adding or increasing the dose of antiplatelet agent, statin, beta-blocker, or angiotensin-converting enzyme inhibitor—had higher rates of cardiovascular events at 12 months (hazard ratio [HR] 2.80, 95% CI 1.05–24.2).⁴⁰

In those with asymptomatic myocardial infarction or isolated elevation in cardiac biomarkers, no treatment strategies have been assessed prospectively or in randomized trials. However, statins and aspirin have been suggested as providing some benefit. In a substudy of the POISE trial, the use of aspirin was associated with a 46% reduction in the 30-day mortality rate in those suffering a perioperative myocardial infarction, and statins were associated with a 76% reduction.¹⁰ In a single-center retrospective analysis of 337 patients undergoing moderate- to high-risk vascular surgery, statin therapy was associated with a lower 1-year mortality  rate (OR 0.63, 95% CI 0.40–0.98).³⁸

We propose a treatment algorithm for patients identified as having cardiovascular events after noncardiac surgery (Figure 2), based on current evidence and guidelines. Ultimately, treatment decisions should be tailored to the individual patient. Discussion of the risks and benefits of therapeutic options should include the patient and surgeon.

Ongoing and future trials

Ongoing and future trials are aimed at addressing definitive treatment strategies in this patient population.

The MANAGE trial (Management of Myocardial Injury After Non-cardiac Surgery Trial) is randomizing patients suffering myocardial injury after noncardiac surgery to receive either dabigatran and omeprazole or placebo to assess the efficacy of these agents in preventing major adverse cardiac events and the safety of anticoagulation (ClinicalTrials.gov Identifier: NCT01661101).

The INTREPID trial (Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-Cardiac Surgery) will assess the efficacy and safety of ticagrelor treatment compared with aspirin in a similar population (ClinicalTrial.gov Identifier: NCT02291419). The trial will enroll approximately 1,000 patients identified as having a postoperative troponin elevation more than two times the upper limit of normal of the assay during the index hospitalization (Figure 3). Enrollment was to have begun in mid-2015.

Click here for a partial list of common questions and assumptions that individuals who are newly diagnosed with epilepsy or seizures may have.

Click here for a partial list of common questions and assumptions that individuals who are newly diagnosed with epilepsy or seizures may have.

Click here for a partial list of common questions and assumptions that individuals who are newly diagnosed with epilepsy or seizures may have.

LONDON – Aldosterone blockade with oral spironolactone showed a disappointing lack of clinical benefit when initiated in the first hours after an acute MI without heart failure in the large, randomized ALBATROSS trial.

ALBATROSS did, however, flash a silver lining under one wing: A whopping 80% reduction in 6-month mortality in a prespecified subgroup analysis restricted to the 1,229 participants with ST-elevation MI, Dr. Gilles Montalescot reported at the annual congress of the European Society of Cardiology.

Bruce Jancin/Frontline Medical News

Although this finding is intriguing, hypothesis-generating, and definitely warrants a confirmatory study, he continued, mortality was nevertheless merely a secondary endpoint in ALBATROSS (Aldosterone Lethal Effects Blockade in Acute Myocardial Infarction Treated With or Without Reperfusion to Improve Outcome and Survival at Six Months Follow-up).

In contrast, the primary composite outcome was negative, so the takeaway message is clear: “The results of the ALBATROSS study do not warrant the extension of aldosterone blockade to MI patients without heart failure,” said Dr. Montalescot, professor of cardiology at the University of Paris.

ALBATROSS was a multicenter French trial that randomly assigned 1,603 acute MI patients to standard therapy alone or with added mineralocorticoid antagonist therapy started within the first 2 days of their coronary event. Often the aldosterone antagonist was begun in the ambulance en route to the hospital.

The primary endpoint was a composite of death, resuscitated cardiac arrest, ventricular fibrillation or tachycardia, heart failure, or an indication for an implantable cardioverter defibrillator. There were 194 such events, and they occurred at a similar rate in the patients who got 25 mg/day of spironolactone and those who did not.

The rationale for ALBATROSS was sound, according to the cardiologist. Aldosterone is a stress hormone released in acute MI. It has deleterious cardiac effects, including arrhythmias, heart failure, and a dose-dependent increase in mortality, so it makes good sense to block it as soon as possible in MI patients. In the EPHESUS trial, the aldosterone antagonist eplerenone, when started 3-14 days post MI in patients with early heart failure, significantly reduced mortality (N Engl J Med. 2003 Apr 3;348[14]:1309-2), with the bulk of the benefit occurring in patients in whom the drug was started 3-7 days post MI.

Last year, Dr. Montalescot and his coinvestigators published the REMINDER study, in which 1,012 ST-elevation MI (STEMI) patients without heart failure were randomized to eplerenone or placebo within the first 24 hours. The study showed a significant reduction in levels of brain natriuretic peptide or N-terminal pro-BNP in the eplerenone arm (Eur Heart J. 2014 Sep 7;35[34]:2295-302), but that’s not a clinical endpoint. ALBATROSS was the first study to look at the clinical impact of commencing mineralocorticoid antagonist therapy prior to day 3 post MI.

Discussant Dr. John McMurray, professor of cardiology at the University of Glasgow, said that ALBATROSS was simply underpowered and thus leaves unanswered the clinically important question of whether early initiation of aldosterone blockade post MI in patients without heart failure confers clinical benefit. The investigators projected a total of 269 events in the composite endpoint but got only 194 because the study participants were so well treated and contemporary medical and interventional therapies are quite effective.

He dismissed the sharp reduction seen in 6-month mortality with spironolactone in the STEMI patients as “just implausible – we don’t know of any treatments in medicine that reduce mortality by 80%.”

Noting that there were only 28 deaths in the study, Dr. McMurray asserted that “a subgroup analysis on such a small number of events is never going to give you a reliable result.” Moreover, he added, “subgroup analysis is even more treacherous when the overall trial is underpowered.”

Dr. Montalescot replied that, while he considers the signal of a mortality benefit for aldosterone blockade in STEMI patients worthy of pursuit in a large randomized trial, the prospects for mounting such a study are poor. The medications are now available as generics, so there is no commercial incentive. The French Ministry of Health, which funded ALBATROSS, isn’t prepared to back a follow-up study. The best hope is that eventually one of the pharmaceutical companies developing third-generation aldosterone antagonists, now in phase II studies, will become interested, he said.

Dr. Montalescot said that, while he receives research grants and consulting fees from numerous pharmaceutical companies, these commercial relationships aren’t relevant to the government-funded ALBATROSS trial.

[email protected]

LONDON – Aldosterone blockade with oral spironolactone showed a disappointing lack of clinical benefit when initiated in the first hours after an acute MI without heart failure in the large, randomized ALBATROSS trial.

ALBATROSS did, however, flash a silver lining under one wing: A whopping 80% reduction in 6-month mortality in a prespecified subgroup analysis restricted to the 1,229 participants with ST-elevation MI, Dr. Gilles Montalescot reported at the annual congress of the European Society of Cardiology.

Bruce Jancin/Frontline Medical News

Although this finding is intriguing, hypothesis-generating, and definitely warrants a confirmatory study, he continued, mortality was nevertheless merely a secondary endpoint in ALBATROSS (Aldosterone Lethal Effects Blockade in Acute Myocardial Infarction Treated With or Without Reperfusion to Improve Outcome and Survival at Six Months Follow-up).

In contrast, the primary composite outcome was negative, so the takeaway message is clear: “The results of the ALBATROSS study do not warrant the extension of aldosterone blockade to MI patients without heart failure,” said Dr. Montalescot, professor of cardiology at the University of Paris.

ALBATROSS was a multicenter French trial that randomly assigned 1,603 acute MI patients to standard therapy alone or with added mineralocorticoid antagonist therapy started within the first 2 days of their coronary event. Often the aldosterone antagonist was begun in the ambulance en route to the hospital.

The primary endpoint was a composite of death, resuscitated cardiac arrest, ventricular fibrillation or tachycardia, heart failure, or an indication for an implantable cardioverter defibrillator. There were 194 such events, and they occurred at a similar rate in the patients who got 25 mg/day of spironolactone and those who did not.

The rationale for ALBATROSS was sound, according to the cardiologist. Aldosterone is a stress hormone released in acute MI. It has deleterious cardiac effects, including arrhythmias, heart failure, and a dose-dependent increase in mortality, so it makes good sense to block it as soon as possible in MI patients. In the EPHESUS trial, the aldosterone antagonist eplerenone, when started 3-14 days post MI in patients with early heart failure, significantly reduced mortality (N Engl J Med. 2003 Apr 3;348[14]:1309-2), with the bulk of the benefit occurring in patients in whom the drug was started 3-7 days post MI.

Last year, Dr. Montalescot and his coinvestigators published the REMINDER study, in which 1,012 ST-elevation MI (STEMI) patients without heart failure were randomized to eplerenone or placebo within the first 24 hours. The study showed a significant reduction in levels of brain natriuretic peptide or N-terminal pro-BNP in the eplerenone arm (Eur Heart J. 2014 Sep 7;35[34]:2295-302), but that’s not a clinical endpoint. ALBATROSS was the first study to look at the clinical impact of commencing mineralocorticoid antagonist therapy prior to day 3 post MI.

Discussant Dr. John McMurray, professor of cardiology at the University of Glasgow, said that ALBATROSS was simply underpowered and thus leaves unanswered the clinically important question of whether early initiation of aldosterone blockade post MI in patients without heart failure confers clinical benefit. The investigators projected a total of 269 events in the composite endpoint but got only 194 because the study participants were so well treated and contemporary medical and interventional therapies are quite effective.

He dismissed the sharp reduction seen in 6-month mortality with spironolactone in the STEMI patients as “just implausible – we don’t know of any treatments in medicine that reduce mortality by 80%.”

Noting that there were only 28 deaths in the study, Dr. McMurray asserted that “a subgroup analysis on such a small number of events is never going to give you a reliable result.” Moreover, he added, “subgroup analysis is even more treacherous when the overall trial is underpowered.”

Dr. Montalescot replied that, while he considers the signal of a mortality benefit for aldosterone blockade in STEMI patients worthy of pursuit in a large randomized trial, the prospects for mounting such a study are poor. The medications are now available as generics, so there is no commercial incentive. The French Ministry of Health, which funded ALBATROSS, isn’t prepared to back a follow-up study. The best hope is that eventually one of the pharmaceutical companies developing third-generation aldosterone antagonists, now in phase II studies, will become interested, he said.

Dr. Montalescot said that, while he receives research grants and consulting fees from numerous pharmaceutical companies, these commercial relationships aren’t relevant to the government-funded ALBATROSS trial.

[email protected]

LONDON – Aldosterone blockade with oral spironolactone showed a disappointing lack of clinical benefit when initiated in the first hours after an acute MI without heart failure in the large, randomized ALBATROSS trial.

ALBATROSS did, however, flash a silver lining under one wing: A whopping 80% reduction in 6-month mortality in a prespecified subgroup analysis restricted to the 1,229 participants with ST-elevation MI, Dr. Gilles Montalescot reported at the annual congress of the European Society of Cardiology.

Bruce Jancin/Frontline Medical News

Although this finding is intriguing, hypothesis-generating, and definitely warrants a confirmatory study, he continued, mortality was nevertheless merely a secondary endpoint in ALBATROSS (Aldosterone Lethal Effects Blockade in Acute Myocardial Infarction Treated With or Without Reperfusion to Improve Outcome and Survival at Six Months Follow-up).

In contrast, the primary composite outcome was negative, so the takeaway message is clear: “The results of the ALBATROSS study do not warrant the extension of aldosterone blockade to MI patients without heart failure,” said Dr. Montalescot, professor of cardiology at the University of Paris.

ALBATROSS was a multicenter French trial that randomly assigned 1,603 acute MI patients to standard therapy alone or with added mineralocorticoid antagonist therapy started within the first 2 days of their coronary event. Often the aldosterone antagonist was begun in the ambulance en route to the hospital.

The primary endpoint was a composite of death, resuscitated cardiac arrest, ventricular fibrillation or tachycardia, heart failure, or an indication for an implantable cardioverter defibrillator. There were 194 such events, and they occurred at a similar rate in the patients who got 25 mg/day of spironolactone and those who did not.

The rationale for ALBATROSS was sound, according to the cardiologist. Aldosterone is a stress hormone released in acute MI. It has deleterious cardiac effects, including arrhythmias, heart failure, and a dose-dependent increase in mortality, so it makes good sense to block it as soon as possible in MI patients. In the EPHESUS trial, the aldosterone antagonist eplerenone, when started 3-14 days post MI in patients with early heart failure, significantly reduced mortality (N Engl J Med. 2003 Apr 3;348[14]:1309-2), with the bulk of the benefit occurring in patients in whom the drug was started 3-7 days post MI.

Last year, Dr. Montalescot and his coinvestigators published the REMINDER study, in which 1,012 ST-elevation MI (STEMI) patients without heart failure were randomized to eplerenone or placebo within the first 24 hours. The study showed a significant reduction in levels of brain natriuretic peptide or N-terminal pro-BNP in the eplerenone arm (Eur Heart J. 2014 Sep 7;35[34]:2295-302), but that’s not a clinical endpoint. ALBATROSS was the first study to look at the clinical impact of commencing mineralocorticoid antagonist therapy prior to day 3 post MI.

Discussant Dr. John McMurray, professor of cardiology at the University of Glasgow, said that ALBATROSS was simply underpowered and thus leaves unanswered the clinically important question of whether early initiation of aldosterone blockade post MI in patients without heart failure confers clinical benefit. The investigators projected a total of 269 events in the composite endpoint but got only 194 because the study participants were so well treated and contemporary medical and interventional therapies are quite effective.

He dismissed the sharp reduction seen in 6-month mortality with spironolactone in the STEMI patients as “just implausible – we don’t know of any treatments in medicine that reduce mortality by 80%.”

Noting that there were only 28 deaths in the study, Dr. McMurray asserted that “a subgroup analysis on such a small number of events is never going to give you a reliable result.” Moreover, he added, “subgroup analysis is even more treacherous when the overall trial is underpowered.”

Dr. Montalescot replied that, while he considers the signal of a mortality benefit for aldosterone blockade in STEMI patients worthy of pursuit in a large randomized trial, the prospects for mounting such a study are poor. The medications are now available as generics, so there is no commercial incentive. The French Ministry of Health, which funded ALBATROSS, isn’t prepared to back a follow-up study. The best hope is that eventually one of the pharmaceutical companies developing third-generation aldosterone antagonists, now in phase II studies, will become interested, he said.

Dr. Montalescot said that, while he receives research grants and consulting fees from numerous pharmaceutical companies, these commercial relationships aren’t relevant to the government-funded ALBATROSS trial.

[email protected]

Click here to learn about tips for reducing falls in seniors with epilepsy.

Click here to learn about tips for reducing falls in seniors with epilepsy.

Click here to learn about tips for reducing falls in seniors with epilepsy.

LONDON—Results of a large study suggest that watching television for prolonged periods may increase a person’s risk of fatal pulmonary embolism (PE).

The study, which included more than 86,000 subjects, showed that watching an average of 5 or more hours of TV per day was associated with more than twice the risk of fatal PE as watching less than 2.5 hours daily.

And the risk was higher among younger subjects than older ones.

Toru Shirakawa, of Osaka University in Japan, presented this research at the ESC Congress 2015 (abstract P2686*).

“We showed that prolonged television viewing may be a risky behavior for death from pulmonary embolism,” Shirakawa said. “Leg immobility during television viewing may, in part, explain the finding. Public awareness of the risk of pulmonary embolism from lengthy leg immobility is essential.”

For this research, Shirakawa and his colleagues evaluated 86,024 individuals—36,007 men and 50,017 women ages 40 to 79—who were participating in the Japanese Collaborative Cohort Study.

The subjects completed a self-administered questionnaire that included information about average time spent watching TV each day. They were followed for a median of 18.4 years until 2009. Mortality from PE was determined from death certificates.

Subjects were divided into 3 groups according to the amount of TV they watched per day: less than 2.5 hours, 2.5 to 4.9 hours, and 5 or more hours.

The researchers calculated the risk of death from PE according to the amount of TV watched after adjusting for subjects’ age at baseline, gender, history of hypertension, history of diabetes, smoking status, drinking status, body mass index, walking and sports habits, and menopausal status.

During the follow-up period, there were 59 deaths from PE. And the multiavariate analysis revealed a link between extended TV viewing and fatal PE.

Compared to subjects who tended to watch less than 2.5 hours of TV per day, those who watched an average of 2.5 to 4.9 hours had an increased risk of fatal PE (hazard ratio [HR]=1.59). And the risk was greater among subjects whose average TV viewing time was more than 5 hours per day (HR=2.36).

Among subjects ages 40 to 59, the association between prolonged TV watching and fatal PE was more prominent.

Watching 2.5 to 4.9 hours of TV a day more than tripled the risk of fatal PE when compared to watching less than 2.5 hours (HR=3.24). And watching TV for more than 5 hours a day was associated with a more than 6-fold greater risk of fatal PE than watching less than 2.5 hours (HR=6.49).

Because prolonged leg immobility may explain these findings, Shirakawa and his colleagues recommend taking simple steps to prevent PE while watching TV for extended periods.

“[T]ake a break, stand up, and walk around during the television viewing,” he said. “Drinking water for preventing dehydration is also important.”

Shirakawa also noted that other media-based activities involving prolonged sitting may pose a risk of fatal PE.

“In this era of information technology, use of other visual-based media devices, such as personal computers or smartphones, is popular,” he said.

“Prolonged computer gaming has been associated with death from pulmonary embolism, but, to our knowledge, a relationship with prolonged smartphone use has not yet been reported. More research is needed to assess the risks of prolonged use of new technologies on pulmonary embolism morbidity and mortality.”

*Information in the abstract differs from that presented at the meeting.

LONDON—Results of a large study suggest that watching television for prolonged periods may increase a person’s risk of fatal pulmonary embolism (PE).

The study, which included more than 86,000 subjects, showed that watching an average of 5 or more hours of TV per day was associated with more than twice the risk of fatal PE as watching less than 2.5 hours daily.

And the risk was higher among younger subjects than older ones.

Toru Shirakawa, of Osaka University in Japan, presented this research at the ESC Congress 2015 (abstract P2686*).

“We showed that prolonged television viewing may be a risky behavior for death from pulmonary embolism,” Shirakawa said. “Leg immobility during television viewing may, in part, explain the finding. Public awareness of the risk of pulmonary embolism from lengthy leg immobility is essential.”

For this research, Shirakawa and his colleagues evaluated 86,024 individuals—36,007 men and 50,017 women ages 40 to 79—who were participating in the Japanese Collaborative Cohort Study.

The subjects completed a self-administered questionnaire that included information about average time spent watching TV each day. They were followed for a median of 18.4 years until 2009. Mortality from PE was determined from death certificates.

Subjects were divided into 3 groups according to the amount of TV they watched per day: less than 2.5 hours, 2.5 to 4.9 hours, and 5 or more hours.

The researchers calculated the risk of death from PE according to the amount of TV watched after adjusting for subjects’ age at baseline, gender, history of hypertension, history of diabetes, smoking status, drinking status, body mass index, walking and sports habits, and menopausal status.

During the follow-up period, there were 59 deaths from PE. And the multiavariate analysis revealed a link between extended TV viewing and fatal PE.

Compared to subjects who tended to watch less than 2.5 hours of TV per day, those who watched an average of 2.5 to 4.9 hours had an increased risk of fatal PE (hazard ratio [HR]=1.59). And the risk was greater among subjects whose average TV viewing time was more than 5 hours per day (HR=2.36).

Among subjects ages 40 to 59, the association between prolonged TV watching and fatal PE was more prominent.

Watching 2.5 to 4.9 hours of TV a day more than tripled the risk of fatal PE when compared to watching less than 2.5 hours (HR=3.24). And watching TV for more than 5 hours a day was associated with a more than 6-fold greater risk of fatal PE than watching less than 2.5 hours (HR=6.49).

Because prolonged leg immobility may explain these findings, Shirakawa and his colleagues recommend taking simple steps to prevent PE while watching TV for extended periods.

“[T]ake a break, stand up, and walk around during the television viewing,” he said. “Drinking water for preventing dehydration is also important.”

Shirakawa also noted that other media-based activities involving prolonged sitting may pose a risk of fatal PE.

“In this era of information technology, use of other visual-based media devices, such as personal computers or smartphones, is popular,” he said.

“Prolonged computer gaming has been associated with death from pulmonary embolism, but, to our knowledge, a relationship with prolonged smartphone use has not yet been reported. More research is needed to assess the risks of prolonged use of new technologies on pulmonary embolism morbidity and mortality.”

*Information in the abstract differs from that presented at the meeting.

LONDON—Results of a large study suggest that watching television for prolonged periods may increase a person’s risk of fatal pulmonary embolism (PE).

The study, which included more than 86,000 subjects, showed that watching an average of 5 or more hours of TV per day was associated with more than twice the risk of fatal PE as watching less than 2.5 hours daily.

And the risk was higher among younger subjects than older ones.

Toru Shirakawa, of Osaka University in Japan, presented this research at the ESC Congress 2015 (abstract P2686*).

“We showed that prolonged television viewing may be a risky behavior for death from pulmonary embolism,” Shirakawa said. “Leg immobility during television viewing may, in part, explain the finding. Public awareness of the risk of pulmonary embolism from lengthy leg immobility is essential.”

For this research, Shirakawa and his colleagues evaluated 86,024 individuals—36,007 men and 50,017 women ages 40 to 79—who were participating in the Japanese Collaborative Cohort Study.

The subjects completed a self-administered questionnaire that included information about average time spent watching TV each day. They were followed for a median of 18.4 years until 2009. Mortality from PE was determined from death certificates.

Subjects were divided into 3 groups according to the amount of TV they watched per day: less than 2.5 hours, 2.5 to 4.9 hours, and 5 or more hours.

The researchers calculated the risk of death from PE according to the amount of TV watched after adjusting for subjects’ age at baseline, gender, history of hypertension, history of diabetes, smoking status, drinking status, body mass index, walking and sports habits, and menopausal status.

During the follow-up period, there were 59 deaths from PE. And the multiavariate analysis revealed a link between extended TV viewing and fatal PE.

Compared to subjects who tended to watch less than 2.5 hours of TV per day, those who watched an average of 2.5 to 4.9 hours had an increased risk of fatal PE (hazard ratio [HR]=1.59). And the risk was greater among subjects whose average TV viewing time was more than 5 hours per day (HR=2.36).

Among subjects ages 40 to 59, the association between prolonged TV watching and fatal PE was more prominent.

Watching 2.5 to 4.9 hours of TV a day more than tripled the risk of fatal PE when compared to watching less than 2.5 hours (HR=3.24). And watching TV for more than 5 hours a day was associated with a more than 6-fold greater risk of fatal PE than watching less than 2.5 hours (HR=6.49).

Because prolonged leg immobility may explain these findings, Shirakawa and his colleagues recommend taking simple steps to prevent PE while watching TV for extended periods.

“[T]ake a break, stand up, and walk around during the television viewing,” he said. “Drinking water for preventing dehydration is also important.”

Shirakawa also noted that other media-based activities involving prolonged sitting may pose a risk of fatal PE.

“In this era of information technology, use of other visual-based media devices, such as personal computers or smartphones, is popular,” he said.

“Prolonged computer gaming has been associated with death from pulmonary embolism, but, to our knowledge, a relationship with prolonged smartphone use has not yet been reported. More research is needed to assess the risks of prolonged use of new technologies on pulmonary embolism morbidity and mortality.”

*Information in the abstract differs from that presented at the meeting.

Apixaban (Eliquis)

Photo courtesy of Pfizer

and Bristol-Myers Squibb

LONDON—An educational program designed to improve adherence to the anticoagulant apixaban proved ineffective in a phase 4 trial of patients with atrial fibrillation (AF).

But that’s because adherence was high whether patients completed the program or not.

This suggests current measures used to inform patients about apixaban may be sufficient to ensure treatment adherence, researchers said.

They presented these findings at the ESC Congress 2015 (abstract 2191).

The research, known as the AEGEAN trial, was sponsored by Bristol-Myers Squibb, the company co-developing apixaban (Eliquis) with Pfizer.

“We used the best possible tools for the educational program, including the usual staff and procedures of the anticoagulation clinics, and all of this was useless,” said study investigator Gilles Montalescot, MD, PhD, of Hospitalier Universitaire Pitié-Salpêtrière in Paris, France.

“However, the trial showed very good adherence to apixaban, leaving little room for improvement with an educational program, suggesting one more advantage of prescribing non-vitamin K antagonists (VKAs) over VKAs in that there is apparently no need for additional education and information.”

Dr Montalescot and his colleagues conducted this study in 1162 AF patients receiving apixaban as stroke prophylaxis.

Roughly half of the patients (n=579) completed an educational program promoting treatment adherence, and the other half (n=583) received the usual information about their disease and the treatment.

The educational program included a patient information booklet explaining AF and anticoagulant treatment for stroke prevention, reminder tools (eg, a key ring and mobile phone alerts), and access to a virtual clinic utilizing staff from existing VKA monitoring clinics.

The researchers assessed differences between the 2 patient groups with regard to treatment adherence (defined as continuous, twice-daily dosing, with an occasional missed dose allowed) and treatment persistence (defined as absence of discontinuation for 30 consecutive days) over a 6-month observational period.

Adherence/persistence was measured using an electronic device that holds a blister pack of medication and records each time the pack is removed.

The researchers found no additional value of the educational program for either outcome.

At 24 weeks, the adherence rate was 88.5% in the control group and 88.3% in the education group (P=0.89). Treatment persistence rates were 90.5% and 91.1%, respectively (P=0.76).

For the second part of this study, the researchers are investigating long-term treatment adherence and the value of an educational program beyond 6 months.

“Future studies may want to test more aggressive and more costly educational programs,” Dr Montalescot noted. “But, in the meantime, the adherence and persistence rates we measured are quite reassuring with the common practice and usual mode of prescription of this medication.”

Apixaban (Eliquis)

Photo courtesy of Pfizer

and Bristol-Myers Squibb

LONDON—An educational program designed to improve adherence to the anticoagulant apixaban proved ineffective in a phase 4 trial of patients with atrial fibrillation (AF).

But that’s because adherence was high whether patients completed the program or not.

This suggests current measures used to inform patients about apixaban may be sufficient to ensure treatment adherence, researchers said.

They presented these findings at the ESC Congress 2015 (abstract 2191).

The research, known as the AEGEAN trial, was sponsored by Bristol-Myers Squibb, the company co-developing apixaban (Eliquis) with Pfizer.

“We used the best possible tools for the educational program, including the usual staff and procedures of the anticoagulation clinics, and all of this was useless,” said study investigator Gilles Montalescot, MD, PhD, of Hospitalier Universitaire Pitié-Salpêtrière in Paris, France.

“However, the trial showed very good adherence to apixaban, leaving little room for improvement with an educational program, suggesting one more advantage of prescribing non-vitamin K antagonists (VKAs) over VKAs in that there is apparently no need for additional education and information.”

Dr Montalescot and his colleagues conducted this study in 1162 AF patients receiving apixaban as stroke prophylaxis.

Roughly half of the patients (n=579) completed an educational program promoting treatment adherence, and the other half (n=583) received the usual information about their disease and the treatment.

The educational program included a patient information booklet explaining AF and anticoagulant treatment for stroke prevention, reminder tools (eg, a key ring and mobile phone alerts), and access to a virtual clinic utilizing staff from existing VKA monitoring clinics.

The researchers assessed differences between the 2 patient groups with regard to treatment adherence (defined as continuous, twice-daily dosing, with an occasional missed dose allowed) and treatment persistence (defined as absence of discontinuation for 30 consecutive days) over a 6-month observational period.

Adherence/persistence was measured using an electronic device that holds a blister pack of medication and records each time the pack is removed.

The researchers found no additional value of the educational program for either outcome.

At 24 weeks, the adherence rate was 88.5% in the control group and 88.3% in the education group (P=0.89). Treatment persistence rates were 90.5% and 91.1%, respectively (P=0.76).

For the second part of this study, the researchers are investigating long-term treatment adherence and the value of an educational program beyond 6 months.

“Future studies may want to test more aggressive and more costly educational programs,” Dr Montalescot noted. “But, in the meantime, the adherence and persistence rates we measured are quite reassuring with the common practice and usual mode of prescription of this medication.”

Apixaban (Eliquis)

Photo courtesy of Pfizer

and Bristol-Myers Squibb

LONDON—An educational program designed to improve adherence to the anticoagulant apixaban proved ineffective in a phase 4 trial of patients with atrial fibrillation (AF).

But that’s because adherence was high whether patients completed the program or not.

This suggests current measures used to inform patients about apixaban may be sufficient to ensure treatment adherence, researchers said.

They presented these findings at the ESC Congress 2015 (abstract 2191).

The research, known as the AEGEAN trial, was sponsored by Bristol-Myers Squibb, the company co-developing apixaban (Eliquis) with Pfizer.

“We used the best possible tools for the educational program, including the usual staff and procedures of the anticoagulation clinics, and all of this was useless,” said study investigator Gilles Montalescot, MD, PhD, of Hospitalier Universitaire Pitié-Salpêtrière in Paris, France.

“However, the trial showed very good adherence to apixaban, leaving little room for improvement with an educational program, suggesting one more advantage of prescribing non-vitamin K antagonists (VKAs) over VKAs in that there is apparently no need for additional education and information.”

Dr Montalescot and his colleagues conducted this study in 1162 AF patients receiving apixaban as stroke prophylaxis.

Roughly half of the patients (n=579) completed an educational program promoting treatment adherence, and the other half (n=583) received the usual information about their disease and the treatment.

The educational program included a patient information booklet explaining AF and anticoagulant treatment for stroke prevention, reminder tools (eg, a key ring and mobile phone alerts), and access to a virtual clinic utilizing staff from existing VKA monitoring clinics.

The researchers assessed differences between the 2 patient groups with regard to treatment adherence (defined as continuous, twice-daily dosing, with an occasional missed dose allowed) and treatment persistence (defined as absence of discontinuation for 30 consecutive days) over a 6-month observational period.

Adherence/persistence was measured using an electronic device that holds a blister pack of medication and records each time the pack is removed.

The researchers found no additional value of the educational program for either outcome.

At 24 weeks, the adherence rate was 88.5% in the control group and 88.3% in the education group (P=0.89). Treatment persistence rates were 90.5% and 91.1%, respectively (P=0.76).

For the second part of this study, the researchers are investigating long-term treatment adherence and the value of an educational program beyond 6 months.

“Future studies may want to test more aggressive and more costly educational programs,” Dr Montalescot noted. “But, in the meantime, the adherence and persistence rates we measured are quite reassuring with the common practice and usual mode of prescription of this medication.”

NEW YORK – Evidence is mounting that early intervention in the menopausal transition could help forestall some of the skin aging associated with estrogen decline.

Estrogen supplementation and collagen stimulation both seem effective in preserving the integrity of a woman’s skin as levels of the hormone decrease, Dr. Diane Madfes said at the American Academy of Dermatology summer meeting.

Type 3 collagen decreases by up to 50% within a few years of menopause, said Dr. Madfes, a dermatologist in New York. This is directly related to a loss of estrogen receptor beta in the dermal matrix, which promotes collagen formation.

“There is a theory – the timing hypothesis – that we have a window of opportunity to intervene. If we can stimulate the collagen before the receptors go down, maybe we can have a beneficial effect on skin.”

Any method of collagen stimulation should work, she said: laser resurfacing, microneedling, or radiofrequency. “We are very good about being able to stimulate collagen. The method doesn’t matter as much as the timing. The important thing is to intervene early. If you see your patients starting to sag, see a loss of elasticity, that is the time to intervene. Get at the collagen while it’s still receptive.”

Estrogen exerts a plethora of antiaging, skin-preserving effects. “We know that a decrease in estrogen is related to telomere shortening. Estrogen protects against oxidative damage. It signals keratinocytes through IGF-1,” she said.

The hormone also protects skin’s water-binding qualities by promoting mucopolysaccharides, sebum production, barrier function, and hyaluronic acid. It may even play a role in protecting against ultraviolet light. Estrogen downregulation affects healing by inhibiting the proliferation of keratinocytes and the proliferation and migration of fibroblasts.

All these add up to rapid skin aging after estrogen levels drop.

“The visible effects of aging on women’s skin are not so much related to her chronological age as to the years after menopause,” Dr. Madfes said – a finding that is particularly illustrated in young women with surgical menopause and those with breast cancer who take tamoxifen. The observation seems to suggest that early intervention with estrogen might help prevent at least some of the signs of aging.

The ongoing KEEPS trial (Kronos Early Estrogen Prevention Study) may shed some light on the issue. KEEPS has randomized 729 women aged 42-58 years to oral or transdermal estrogen; the primary endpoint is rate of atherosclerosis. But an ancillary study is looking at the effect of estrogen on skin wrinkles and skin rigidity.

The substudy is based on positive findings of a 1996 study, which found evidence for facial application of topical estrogen designed for vulvar use. After 6 months, elasticity and firmness significantly improved. Skin moisture increased, as did type 3 collagen and collagen fibers.

Some women do use topical estrogens on their faces. “It seems to promote skin thickening and tightening,“ Dr. Madfes said, although a recent editorial suggested that using the product anywhere but on the genitals can cause estrogen-mediated side effects in both children and pets.

But recommending estrogen is fraught with controversy. Large studies have come to conflicting conclusions about its benefit and safety. And prescribing estrogen is not really within a dermatologist’s purview.

“It’s not for us to suggest that women go on hormone therapy. But we can explain these things and ask if she is taking it, or if she’s talked to her gynecologist about it.”

Dr. Madfes has no financial disclosures to report.

[email protected]

On Twitter @Alz_Gal

NEW YORK – Evidence is mounting that early intervention in the menopausal transition could help forestall some of the skin aging associated with estrogen decline.

Estrogen supplementation and collagen stimulation both seem effective in preserving the integrity of a woman’s skin as levels of the hormone decrease, Dr. Diane Madfes said at the American Academy of Dermatology summer meeting.

Type 3 collagen decreases by up to 50% within a few years of menopause, said Dr. Madfes, a dermatologist in New York. This is directly related to a loss of estrogen receptor beta in the dermal matrix, which promotes collagen formation.

“There is a theory – the timing hypothesis – that we have a window of opportunity to intervene. If we can stimulate the collagen before the receptors go down, maybe we can have a beneficial effect on skin.”

Any method of collagen stimulation should work, she said: laser resurfacing, microneedling, or radiofrequency. “We are very good about being able to stimulate collagen. The method doesn’t matter as much as the timing. The important thing is to intervene early. If you see your patients starting to sag, see a loss of elasticity, that is the time to intervene. Get at the collagen while it’s still receptive.”

Estrogen exerts a plethora of antiaging, skin-preserving effects. “We know that a decrease in estrogen is related to telomere shortening. Estrogen protects against oxidative damage. It signals keratinocytes through IGF-1,” she said.

The hormone also protects skin’s water-binding qualities by promoting mucopolysaccharides, sebum production, barrier function, and hyaluronic acid. It may even play a role in protecting against ultraviolet light. Estrogen downregulation affects healing by inhibiting the proliferation of keratinocytes and the proliferation and migration of fibroblasts.

All these add up to rapid skin aging after estrogen levels drop.

“The visible effects of aging on women’s skin are not so much related to her chronological age as to the years after menopause,” Dr. Madfes said – a finding that is particularly illustrated in young women with surgical menopause and those with breast cancer who take tamoxifen. The observation seems to suggest that early intervention with estrogen might help prevent at least some of the signs of aging.

The ongoing KEEPS trial (Kronos Early Estrogen Prevention Study) may shed some light on the issue. KEEPS has randomized 729 women aged 42-58 years to oral or transdermal estrogen; the primary endpoint is rate of atherosclerosis. But an ancillary study is looking at the effect of estrogen on skin wrinkles and skin rigidity.

The substudy is based on positive findings of a 1996 study, which found evidence for facial application of topical estrogen designed for vulvar use. After 6 months, elasticity and firmness significantly improved. Skin moisture increased, as did type 3 collagen and collagen fibers.

Some women do use topical estrogens on their faces. “It seems to promote skin thickening and tightening,“ Dr. Madfes said, although a recent editorial suggested that using the product anywhere but on the genitals can cause estrogen-mediated side effects in both children and pets.

But recommending estrogen is fraught with controversy. Large studies have come to conflicting conclusions about its benefit and safety. And prescribing estrogen is not really within a dermatologist’s purview.

“It’s not for us to suggest that women go on hormone therapy. But we can explain these things and ask if she is taking it, or if she’s talked to her gynecologist about it.”

Dr. Madfes has no financial disclosures to report.

[email protected]

On Twitter @Alz_Gal

NEW YORK – Evidence is mounting that early intervention in the menopausal transition could help forestall some of the skin aging associated with estrogen decline.

Estrogen supplementation and collagen stimulation both seem effective in preserving the integrity of a woman’s skin as levels of the hormone decrease, Dr. Diane Madfes said at the American Academy of Dermatology summer meeting.

Type 3 collagen decreases by up to 50% within a few years of menopause, said Dr. Madfes, a dermatologist in New York. This is directly related to a loss of estrogen receptor beta in the dermal matrix, which promotes collagen formation.

“There is a theory – the timing hypothesis – that we have a window of opportunity to intervene. If we can stimulate the collagen before the receptors go down, maybe we can have a beneficial effect on skin.”

Any method of collagen stimulation should work, she said: laser resurfacing, microneedling, or radiofrequency. “We are very good about being able to stimulate collagen. The method doesn’t matter as much as the timing. The important thing is to intervene early. If you see your patients starting to sag, see a loss of elasticity, that is the time to intervene. Get at the collagen while it’s still receptive.”

Estrogen exerts a plethora of antiaging, skin-preserving effects. “We know that a decrease in estrogen is related to telomere shortening. Estrogen protects against oxidative damage. It signals keratinocytes through IGF-1,” she said.

The hormone also protects skin’s water-binding qualities by promoting mucopolysaccharides, sebum production, barrier function, and hyaluronic acid. It may even play a role in protecting against ultraviolet light. Estrogen downregulation affects healing by inhibiting the proliferation of keratinocytes and the proliferation and migration of fibroblasts.

All these add up to rapid skin aging after estrogen levels drop.

“The visible effects of aging on women’s skin are not so much related to her chronological age as to the years after menopause,” Dr. Madfes said – a finding that is particularly illustrated in young women with surgical menopause and those with breast cancer who take tamoxifen. The observation seems to suggest that early intervention with estrogen might help prevent at least some of the signs of aging.

The ongoing KEEPS trial (Kronos Early Estrogen Prevention Study) may shed some light on the issue. KEEPS has randomized 729 women aged 42-58 years to oral or transdermal estrogen; the primary endpoint is rate of atherosclerosis. But an ancillary study is looking at the effect of estrogen on skin wrinkles and skin rigidity.

The substudy is based on positive findings of a 1996 study, which found evidence for facial application of topical estrogen designed for vulvar use. After 6 months, elasticity and firmness significantly improved. Skin moisture increased, as did type 3 collagen and collagen fibers.

Some women do use topical estrogens on their faces. “It seems to promote skin thickening and tightening,“ Dr. Madfes said, although a recent editorial suggested that using the product anywhere but on the genitals can cause estrogen-mediated side effects in both children and pets.

But recommending estrogen is fraught with controversy. Large studies have come to conflicting conclusions about its benefit and safety. And prescribing estrogen is not really within a dermatologist’s purview.

“It’s not for us to suggest that women go on hormone therapy. But we can explain these things and ask if she is taking it, or if she’s talked to her gynecologist about it.”

Dr. Madfes has no financial disclosures to report.

[email protected]

On Twitter @Alz_Gal

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?