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Heart rhythm data from wearables confounds EP practice
NATIONAL HARBOR, MD. – or other warnings that flagged a possible cardiac arrhythmia.
While the clinical community has yet to reach an evidence-based consensus on how to deal with this information, or even asymptomatic arrhythmias identified by more standard means, the American public is voting with their wrists. People seem to like collecting and reviewing readouts on their heart rhythm and other vital data, and then they often take their numbers to a physician, especially when their device suggests a possible problem.
“The whole paradigm of ordering a test only if you intend to act on the result has been flipped. People now get what they want directly, and our job is to guide them” after the fact. “You need to teach people what’s actionable and what’s not,” Mintu P. Turakhia, MD, said at the annual International AF Symposium.
“We’re in a situation where the ability of a sensor to detect things is separate from access to the health care system. They are no longer coupled; they are disjointed. People can create their own ICU in their house just by shopping online, but what do we do with this information, whether it’s an irregular heart rhythm or their whole genome?” asked Dr. Turakhia, executive director of the Center for Digital Health at Stanford (Calif.) University and director of cardiac electrophysiology at the VA Palo Alto (Calif.) Health Care System.
“The main challenge is people without a diagnosis who get a notification. How much monitoring should you do until you can say it was a false positive? We don’t know what to do, so we monitor them. People are trying to figure this out.” Dr. Turakhia said. Some people who seek out electrophysiologists this way “may not even have a primary care physician,” he noted.
The potential implications of widespread monitoring for heartbeat irregularities in the general public began to surface in a study that Dr. Turakhia helped run that collected wearable data from nearly 420,000 Americans. Results from the Apple Heart Study showed that, during a median 117 days of monitoring with a smart watch, 2,161 people (0.5%) received a report of an irregular pulse, which led to further investigations that eventually diagnosed atrial fibrillation (AFib) in 153 people of the 450 who underwent follow-up assessment (N Engl J Med. 2019 Nov 14;381[20]:1909-17). These results “raise questions” about the large number of people who underwent follow-up testing who did not have arrhythmia, Dr. Turakhia noted.
“The dissemination of wearables has been quite dramatic, and electrophysiologists end up owning this,” commented Jeremy N. Ruskin, MD, professor of medicine at Harvard Medical School and director emeritus of the cardiac arrhythmia service at Massachusetts General Hospital, both in Boston. “I get a ton of calls from people whom I wish never bought a smart watch, and they say ‘I have atrial fibrillation. What do I do?’ ”
To document the growth of this trend, Dr. Turakhia cited results from a survey he collaborated on, run by Stanford and Rock Health, that found a 33% ownership rate among American adults of a wearable device capable of collecting health data, and a 42% rate of people who tracked their health data with a device, app, journal, or log. Both of these rates more than doubled what a similar survey found in 2015.
The cardiac electrophysiology community took a first step toward addressing one aspect of this evolving situation. In early 2020, the Heart Rhythm Society and the Consumer Technology Association jointly issued a guidance document targeted at consumers that walks them through the kinds of information their wearable devices might collect and how to approach this information. The main message: If you have questions or concerns about your data, consult a clinician. What remains in short supply is guidance to clinicians on what to do when they see these patients.
“Until recently, device-detected AFib was the sole purview of electrophysiologists using implanted rhythm-monitoring devices. Now mobile and other devices raise issues [of asymptomatic AFib] for a much broader population,” noted Daniel E. Singer, MD, professor of medicine and epidemiology at Harvard and Massachusetts General Hospital. “The world of device-detected AFib now includes watches.”
Researchers have tried for years to better understand the stroke risk faced by patients with asymptomatic or subclinical AFib that’s detected by an implanted device, as in the ASSERT study of nearly 2,600 patients followed for a median of 2.5 years that found an increased stroke risk when the duration of individual, subclinical AFib episodes surpassed 24 hours (Eur Heart J. 2017 May 1;38[17]:1339-44). More recently, a study of AFib duration collected by implanted cardiac devices in nearly 22,000 Americans showed a relationship between stroke risk and both the duration of AFib episodes and the underlying risk of a person for stroke as measured by their CHA2DS2-VAScscore (Circulation. 2019 Nov 12;140[20]:1639-46). Just under 30% of patients in the study were diagnosed with AFib at entry.
The implications of asymptomatic episodes of AFib have so far been largely studied in people with an implanted cardiac device, which may have limited applicability to wearable users. In addition, the field has not yet fully sorted out the relationships between the duration of individual AFib episodes and overall AFib burden, and a person’s stroke risk and the window of time when the potential stroke-preventing benefits of anticoagulation outweigh its bleeding risk.
The results of trials now in progress that are examining the safety and efficacy of medical interventions designed to avert strokes in patients with asymptomatic AFib “will bear on the use of anticoagulants in a large group of patients,” including people with AFib detected by a wearable, Dr. Singer predicted.
The Apple Heart Study was sponsored Apple. Dr. Turakhia has received funding from Apple, and he has received honoraria or research funding from several other companies. Dr. Ruskin has been a consultant or adviser to several companies, is a steering committee member for Pfizer, and holds equity or options in Portola, Element Science, NewPace, Gilead, and InfoBionic. Dr. Singer has been a consultant and adviser to Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Merck, and Pfizer, and he has received research grants from Bristol-Myers Squibb.
NATIONAL HARBOR, MD. – or other warnings that flagged a possible cardiac arrhythmia.
While the clinical community has yet to reach an evidence-based consensus on how to deal with this information, or even asymptomatic arrhythmias identified by more standard means, the American public is voting with their wrists. People seem to like collecting and reviewing readouts on their heart rhythm and other vital data, and then they often take their numbers to a physician, especially when their device suggests a possible problem.
“The whole paradigm of ordering a test only if you intend to act on the result has been flipped. People now get what they want directly, and our job is to guide them” after the fact. “You need to teach people what’s actionable and what’s not,” Mintu P. Turakhia, MD, said at the annual International AF Symposium.
“We’re in a situation where the ability of a sensor to detect things is separate from access to the health care system. They are no longer coupled; they are disjointed. People can create their own ICU in their house just by shopping online, but what do we do with this information, whether it’s an irregular heart rhythm or their whole genome?” asked Dr. Turakhia, executive director of the Center for Digital Health at Stanford (Calif.) University and director of cardiac electrophysiology at the VA Palo Alto (Calif.) Health Care System.
“The main challenge is people without a diagnosis who get a notification. How much monitoring should you do until you can say it was a false positive? We don’t know what to do, so we monitor them. People are trying to figure this out.” Dr. Turakhia said. Some people who seek out electrophysiologists this way “may not even have a primary care physician,” he noted.
The potential implications of widespread monitoring for heartbeat irregularities in the general public began to surface in a study that Dr. Turakhia helped run that collected wearable data from nearly 420,000 Americans. Results from the Apple Heart Study showed that, during a median 117 days of monitoring with a smart watch, 2,161 people (0.5%) received a report of an irregular pulse, which led to further investigations that eventually diagnosed atrial fibrillation (AFib) in 153 people of the 450 who underwent follow-up assessment (N Engl J Med. 2019 Nov 14;381[20]:1909-17). These results “raise questions” about the large number of people who underwent follow-up testing who did not have arrhythmia, Dr. Turakhia noted.
“The dissemination of wearables has been quite dramatic, and electrophysiologists end up owning this,” commented Jeremy N. Ruskin, MD, professor of medicine at Harvard Medical School and director emeritus of the cardiac arrhythmia service at Massachusetts General Hospital, both in Boston. “I get a ton of calls from people whom I wish never bought a smart watch, and they say ‘I have atrial fibrillation. What do I do?’ ”
To document the growth of this trend, Dr. Turakhia cited results from a survey he collaborated on, run by Stanford and Rock Health, that found a 33% ownership rate among American adults of a wearable device capable of collecting health data, and a 42% rate of people who tracked their health data with a device, app, journal, or log. Both of these rates more than doubled what a similar survey found in 2015.
The cardiac electrophysiology community took a first step toward addressing one aspect of this evolving situation. In early 2020, the Heart Rhythm Society and the Consumer Technology Association jointly issued a guidance document targeted at consumers that walks them through the kinds of information their wearable devices might collect and how to approach this information. The main message: If you have questions or concerns about your data, consult a clinician. What remains in short supply is guidance to clinicians on what to do when they see these patients.
“Until recently, device-detected AFib was the sole purview of electrophysiologists using implanted rhythm-monitoring devices. Now mobile and other devices raise issues [of asymptomatic AFib] for a much broader population,” noted Daniel E. Singer, MD, professor of medicine and epidemiology at Harvard and Massachusetts General Hospital. “The world of device-detected AFib now includes watches.”
Researchers have tried for years to better understand the stroke risk faced by patients with asymptomatic or subclinical AFib that’s detected by an implanted device, as in the ASSERT study of nearly 2,600 patients followed for a median of 2.5 years that found an increased stroke risk when the duration of individual, subclinical AFib episodes surpassed 24 hours (Eur Heart J. 2017 May 1;38[17]:1339-44). More recently, a study of AFib duration collected by implanted cardiac devices in nearly 22,000 Americans showed a relationship between stroke risk and both the duration of AFib episodes and the underlying risk of a person for stroke as measured by their CHA2DS2-VAScscore (Circulation. 2019 Nov 12;140[20]:1639-46). Just under 30% of patients in the study were diagnosed with AFib at entry.
The implications of asymptomatic episodes of AFib have so far been largely studied in people with an implanted cardiac device, which may have limited applicability to wearable users. In addition, the field has not yet fully sorted out the relationships between the duration of individual AFib episodes and overall AFib burden, and a person’s stroke risk and the window of time when the potential stroke-preventing benefits of anticoagulation outweigh its bleeding risk.
The results of trials now in progress that are examining the safety and efficacy of medical interventions designed to avert strokes in patients with asymptomatic AFib “will bear on the use of anticoagulants in a large group of patients,” including people with AFib detected by a wearable, Dr. Singer predicted.
The Apple Heart Study was sponsored Apple. Dr. Turakhia has received funding from Apple, and he has received honoraria or research funding from several other companies. Dr. Ruskin has been a consultant or adviser to several companies, is a steering committee member for Pfizer, and holds equity or options in Portola, Element Science, NewPace, Gilead, and InfoBionic. Dr. Singer has been a consultant and adviser to Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Merck, and Pfizer, and he has received research grants from Bristol-Myers Squibb.
NATIONAL HARBOR, MD. – or other warnings that flagged a possible cardiac arrhythmia.
While the clinical community has yet to reach an evidence-based consensus on how to deal with this information, or even asymptomatic arrhythmias identified by more standard means, the American public is voting with their wrists. People seem to like collecting and reviewing readouts on their heart rhythm and other vital data, and then they often take their numbers to a physician, especially when their device suggests a possible problem.
“The whole paradigm of ordering a test only if you intend to act on the result has been flipped. People now get what they want directly, and our job is to guide them” after the fact. “You need to teach people what’s actionable and what’s not,” Mintu P. Turakhia, MD, said at the annual International AF Symposium.
“We’re in a situation where the ability of a sensor to detect things is separate from access to the health care system. They are no longer coupled; they are disjointed. People can create their own ICU in their house just by shopping online, but what do we do with this information, whether it’s an irregular heart rhythm or their whole genome?” asked Dr. Turakhia, executive director of the Center for Digital Health at Stanford (Calif.) University and director of cardiac electrophysiology at the VA Palo Alto (Calif.) Health Care System.
“The main challenge is people without a diagnosis who get a notification. How much monitoring should you do until you can say it was a false positive? We don’t know what to do, so we monitor them. People are trying to figure this out.” Dr. Turakhia said. Some people who seek out electrophysiologists this way “may not even have a primary care physician,” he noted.
The potential implications of widespread monitoring for heartbeat irregularities in the general public began to surface in a study that Dr. Turakhia helped run that collected wearable data from nearly 420,000 Americans. Results from the Apple Heart Study showed that, during a median 117 days of monitoring with a smart watch, 2,161 people (0.5%) received a report of an irregular pulse, which led to further investigations that eventually diagnosed atrial fibrillation (AFib) in 153 people of the 450 who underwent follow-up assessment (N Engl J Med. 2019 Nov 14;381[20]:1909-17). These results “raise questions” about the large number of people who underwent follow-up testing who did not have arrhythmia, Dr. Turakhia noted.
“The dissemination of wearables has been quite dramatic, and electrophysiologists end up owning this,” commented Jeremy N. Ruskin, MD, professor of medicine at Harvard Medical School and director emeritus of the cardiac arrhythmia service at Massachusetts General Hospital, both in Boston. “I get a ton of calls from people whom I wish never bought a smart watch, and they say ‘I have atrial fibrillation. What do I do?’ ”
To document the growth of this trend, Dr. Turakhia cited results from a survey he collaborated on, run by Stanford and Rock Health, that found a 33% ownership rate among American adults of a wearable device capable of collecting health data, and a 42% rate of people who tracked their health data with a device, app, journal, or log. Both of these rates more than doubled what a similar survey found in 2015.
The cardiac electrophysiology community took a first step toward addressing one aspect of this evolving situation. In early 2020, the Heart Rhythm Society and the Consumer Technology Association jointly issued a guidance document targeted at consumers that walks them through the kinds of information their wearable devices might collect and how to approach this information. The main message: If you have questions or concerns about your data, consult a clinician. What remains in short supply is guidance to clinicians on what to do when they see these patients.
“Until recently, device-detected AFib was the sole purview of electrophysiologists using implanted rhythm-monitoring devices. Now mobile and other devices raise issues [of asymptomatic AFib] for a much broader population,” noted Daniel E. Singer, MD, professor of medicine and epidemiology at Harvard and Massachusetts General Hospital. “The world of device-detected AFib now includes watches.”
Researchers have tried for years to better understand the stroke risk faced by patients with asymptomatic or subclinical AFib that’s detected by an implanted device, as in the ASSERT study of nearly 2,600 patients followed for a median of 2.5 years that found an increased stroke risk when the duration of individual, subclinical AFib episodes surpassed 24 hours (Eur Heart J. 2017 May 1;38[17]:1339-44). More recently, a study of AFib duration collected by implanted cardiac devices in nearly 22,000 Americans showed a relationship between stroke risk and both the duration of AFib episodes and the underlying risk of a person for stroke as measured by their CHA2DS2-VAScscore (Circulation. 2019 Nov 12;140[20]:1639-46). Just under 30% of patients in the study were diagnosed with AFib at entry.
The implications of asymptomatic episodes of AFib have so far been largely studied in people with an implanted cardiac device, which may have limited applicability to wearable users. In addition, the field has not yet fully sorted out the relationships between the duration of individual AFib episodes and overall AFib burden, and a person’s stroke risk and the window of time when the potential stroke-preventing benefits of anticoagulation outweigh its bleeding risk.
The results of trials now in progress that are examining the safety and efficacy of medical interventions designed to avert strokes in patients with asymptomatic AFib “will bear on the use of anticoagulants in a large group of patients,” including people with AFib detected by a wearable, Dr. Singer predicted.
The Apple Heart Study was sponsored Apple. Dr. Turakhia has received funding from Apple, and he has received honoraria or research funding from several other companies. Dr. Ruskin has been a consultant or adviser to several companies, is a steering committee member for Pfizer, and holds equity or options in Portola, Element Science, NewPace, Gilead, and InfoBionic. Dr. Singer has been a consultant and adviser to Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Merck, and Pfizer, and he has received research grants from Bristol-Myers Squibb.
REPORTING FROM THE AF SYMPOSIUM 2020
Walk test may predict complications after lung cancer surgery
Risk of cardiopulmonary complications increased nearly eightfold in patients with moderate lung function decreases who failed to walk 400 m or more, according to the study, which included data on 416 patients with non–small cell lung cancer (NSCLC) who underwent lobectomy.
This is believed to be the first large study evaluating the utility of the 6-minute walk test (6MWT) to predict postoperative cardiopulmonary complications in this surgical setting, according to researchers led by Hyun Lee, MD, of Hanyang University in Seoul, South Korea.
“Our findings suggest that 6-minute walk distance would provide additional information in lung cancer patients with moderately decreased lung function who plan to undergo surgical resection,” said Dr. Lee and coauthors of the study report, which appears in CHEST.
More specifically, the option of curative resection should be considered in those lung cancer patients with moderately decreased lung function but a longer 6-minute walk distance, they added.
Exercise testing is currently recommended to further stratify risk of postoperative complications among patient with moderately decreased lung function, according to the researchers. The 6-minute walk test might be a good tool to evaluate feasibility for moderate risk patients, according to one recent review. However, studies so far have been limited by small numbers of patients, and larger studies have not specifically looked at predicted postoperative lung function status, they said.
Accordingly, the researchers evaluated data from patients expected to undergo curative lung cancer surgery who were enrolled in a prospective cohort study in Korea. They were classified as low or moderate risk based on pulmonary function tests, and further classified into short distance (less than 400 m) and long distance (400 m or more) groups based on their performance on the 6-minute walk test.
Postoperative cardiopulmonary complications were seen in 42.9% of the moderate-risk, short-distance group, versus 14.4% of patients in the moderate-risk, long-distance group. In the low-risk patients, those complications were seen in 9.5% and 8.3% of those in the long and short distance groups.
Odds for postoperative cardiopulmonary complications were significantly increased in the moderate-risk, short-distance group, compared with the low-risk, long-distance group (adjusted odds ratio, 7.84; 95% confidence interval, 2.24-27.46).
By contrast, odds for complications were not significantly increased in the moderate-risk, long-distance group, nor in the low-risk, short-distance groups, investigators said.
Dr. Lee and coauthors said they had no conflicts of interest to disclose.
SOURCE: Lee H et al. CHEST. 2020. doi: 10.1016/j.chest.2019.12.039.
Risk of cardiopulmonary complications increased nearly eightfold in patients with moderate lung function decreases who failed to walk 400 m or more, according to the study, which included data on 416 patients with non–small cell lung cancer (NSCLC) who underwent lobectomy.
This is believed to be the first large study evaluating the utility of the 6-minute walk test (6MWT) to predict postoperative cardiopulmonary complications in this surgical setting, according to researchers led by Hyun Lee, MD, of Hanyang University in Seoul, South Korea.
“Our findings suggest that 6-minute walk distance would provide additional information in lung cancer patients with moderately decreased lung function who plan to undergo surgical resection,” said Dr. Lee and coauthors of the study report, which appears in CHEST.
More specifically, the option of curative resection should be considered in those lung cancer patients with moderately decreased lung function but a longer 6-minute walk distance, they added.
Exercise testing is currently recommended to further stratify risk of postoperative complications among patient with moderately decreased lung function, according to the researchers. The 6-minute walk test might be a good tool to evaluate feasibility for moderate risk patients, according to one recent review. However, studies so far have been limited by small numbers of patients, and larger studies have not specifically looked at predicted postoperative lung function status, they said.
Accordingly, the researchers evaluated data from patients expected to undergo curative lung cancer surgery who were enrolled in a prospective cohort study in Korea. They were classified as low or moderate risk based on pulmonary function tests, and further classified into short distance (less than 400 m) and long distance (400 m or more) groups based on their performance on the 6-minute walk test.
Postoperative cardiopulmonary complications were seen in 42.9% of the moderate-risk, short-distance group, versus 14.4% of patients in the moderate-risk, long-distance group. In the low-risk patients, those complications were seen in 9.5% and 8.3% of those in the long and short distance groups.
Odds for postoperative cardiopulmonary complications were significantly increased in the moderate-risk, short-distance group, compared with the low-risk, long-distance group (adjusted odds ratio, 7.84; 95% confidence interval, 2.24-27.46).
By contrast, odds for complications were not significantly increased in the moderate-risk, long-distance group, nor in the low-risk, short-distance groups, investigators said.
Dr. Lee and coauthors said they had no conflicts of interest to disclose.
SOURCE: Lee H et al. CHEST. 2020. doi: 10.1016/j.chest.2019.12.039.
Risk of cardiopulmonary complications increased nearly eightfold in patients with moderate lung function decreases who failed to walk 400 m or more, according to the study, which included data on 416 patients with non–small cell lung cancer (NSCLC) who underwent lobectomy.
This is believed to be the first large study evaluating the utility of the 6-minute walk test (6MWT) to predict postoperative cardiopulmonary complications in this surgical setting, according to researchers led by Hyun Lee, MD, of Hanyang University in Seoul, South Korea.
“Our findings suggest that 6-minute walk distance would provide additional information in lung cancer patients with moderately decreased lung function who plan to undergo surgical resection,” said Dr. Lee and coauthors of the study report, which appears in CHEST.
More specifically, the option of curative resection should be considered in those lung cancer patients with moderately decreased lung function but a longer 6-minute walk distance, they added.
Exercise testing is currently recommended to further stratify risk of postoperative complications among patient with moderately decreased lung function, according to the researchers. The 6-minute walk test might be a good tool to evaluate feasibility for moderate risk patients, according to one recent review. However, studies so far have been limited by small numbers of patients, and larger studies have not specifically looked at predicted postoperative lung function status, they said.
Accordingly, the researchers evaluated data from patients expected to undergo curative lung cancer surgery who were enrolled in a prospective cohort study in Korea. They were classified as low or moderate risk based on pulmonary function tests, and further classified into short distance (less than 400 m) and long distance (400 m or more) groups based on their performance on the 6-minute walk test.
Postoperative cardiopulmonary complications were seen in 42.9% of the moderate-risk, short-distance group, versus 14.4% of patients in the moderate-risk, long-distance group. In the low-risk patients, those complications were seen in 9.5% and 8.3% of those in the long and short distance groups.
Odds for postoperative cardiopulmonary complications were significantly increased in the moderate-risk, short-distance group, compared with the low-risk, long-distance group (adjusted odds ratio, 7.84; 95% confidence interval, 2.24-27.46).
By contrast, odds for complications were not significantly increased in the moderate-risk, long-distance group, nor in the low-risk, short-distance groups, investigators said.
Dr. Lee and coauthors said they had no conflicts of interest to disclose.
SOURCE: Lee H et al. CHEST. 2020. doi: 10.1016/j.chest.2019.12.039.
FROM CHEST
Nonculprit Lesion PCI Strategies in Patients With STEMI Without Cardiogenic Shock
Study Overview
Objective. To determine whether percutaneous coronary intervention (PCI) of a nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) reduces the risk of cardiovascular death or myocardial infarction.
Design. International, multicenter, randomized controlled trial blinded to outcome.
Setting and participants. Patients with STEMI who had multivessel coronary disease and had undergone successful PCI to the culprit lesion.
Intervention. A total of 4041 patients were randomly assigned to either PCI of angiographically significant nonculprit lesions or optimal medical therapy without further revascularization. Randomization was stratified according to intended timing of nonculprit lesion PCI (either during or after the index hospitalization).
Main outcome measures. The first co-primary endpoint was the composite of cardiovascular death or myocardial infarction (MI). The second co-primary endpoint was the composite of cardiovascular death, MI or ischemia-driven revascularization.
Main results. At a median follow-up of 3 years, the composite of cardiovascular death or MI occurred in 158 of the 2016 patients (7.8%) in the nonculprit PCI group and in 213 of the 2025 patients (10.5%) in the culprit-lesion-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.60-0.91; P = 0.004). The second co-primary endpoint occurred in 179 patients (8.9%) in the nonculprit PCI group and in 339 patients (16.7%) in the culprit-lesion-only group (hazard ratio, 0.51; 95% CI, 0.43-0.61; P < 0.001).
Conclusion. Among patients with STEMI and multivessel disease, those who underwent complete revascularization with nonculprit lesion PCI had lower rates of cardiovascular death or MI compared to patients with culprit-lesion-only revascularization.
Commentary
Patients presenting with STEMI often have multivessel disease.1 Although it is known that mortality can be reduced by early revascularization of the culprit vessel,2 whether the nonculprit vessel should be revascularized at the time of presentation with STEMI remains controversial.
Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI. Four trials (PRAMI, CvPRIT, DANAMI-PRIMULTI, and COMPARE ACUTE) investigated this clinical question with different designs, and all reported benefit of nonculprit vessel revascularization compared to a culprit-only strategy.3-6 However, the differences in the composite endpoints were mainly driven by the softer endpoints used in these trials, such as refractory angina and ischemia-driven revascularization, and none of these previous trials had adequate power to evaluate differences in hard outcomes, such as death or MI.
In this context, Mehta et al investigated whether achieving complete revascularization by performing PCI on nonculprit vessels would improve the composite of cardiovascular death or MI compared to the culprit-only strategy by conducting a well-designed randomized controlled study. At median follow-up of 3 years, patients who underwent nonculprit vessel PCI had a lower incidence of death or MI compared to those who received the culprit-only strategy (7.8% versus 10.5%). The second co-primary endpoint (composite of death, MI, or ischemia-driven revascularization) also occurred significantly less frequently in the nonculprit PCI group than in the culprit-only PCI group (8.9% versus 16.7%).
The current study has a number of strengths. First, this was a multicenter, international study, and a large number of patients were enrolled (> 4000), achieving adequate power to evaluate for the composite of death and MI. Second, the treatments the patients received reflect contemporary medical therapy and interventional practice: the third-generation thienopyridine ticagrelor, high-dose statins, and ACE inhibitors were prescribed at high rates, and radial access (> 80%) and current-generation drug-eluting stents were used at high rates as well. Third, all angiograms were reviewed by the core lab to evaluate for completeness of revascularization. Fourth, the trial mandated use of fractional flow reserve to assess lesion stenosis 50% to 69% before considering revascularization, ensuring that only ischemic or very-high-grade lesions were revascularized. Fifth, the crossover rate in each group was low compared to the previous studies (4.7% into the complete revascularization group, 3.9% into the lesion-only group). Finally, this study evaluated the timing of the nonculprit PCI. Randomization to each group was stratified according to the intended timing of the nonculprit PCI during the index hospitalization or after hospital discharge (within 45 days). They found that benefit was consistent regardless of when the nonculprit PCI was performed.
Although the COMPLETE study’s design has a number of strengths, it is important to note that patients enrolled in this trial represent a lower-risk STEMI population. Patients with complex anatomy likely were not included, as evidenced by a lower SYNTAX score (mean, 16). Furthermore, no patients who presented with STEMI complicated by cardiogenic shock were enrolled. In the recent CULPRIT SHOCK trial, which focused on patients who had multivessel disease, acute MI, and cardiogenic shock, patients who underwent the culprit-only strategy had a lower rate of death or renal replacement therapy, as compared to patients who underwent immediate complete revascularization.7 Therefore, whether the findings from the COMPLETE study can be extended to a sicker population requires further study.
In 2015, the results from the previous trials, such as PRAMI and CvPRIT, led to a focused update of US PCI guidelines.8 Recommendations for noninfarct-related artery PCI in hemodynamically stable patients presenting with acute MI were upgraded from class III to class IIb. The results from the COMPLETE trial will likely influence the future guidelines, with stronger recommendations toward complete revascularization in patients presenting with hemodynamically stable STEMI.
Applications for Clinical Practice
In patients presenting with hemodynamically stable STEMI, staged complete revascularization, including the nonculprit vessel, should be considered.
– Taishi Hirai, MD, University of Missouri, Columbia, MO, and John EA Blair, MD, University of Chicago Medical Center, Chicago, IL
1. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014;312:2019-2027.
2. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999;341:625-634.
3. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369:1115-1123.
4. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65:963-972.
5. Engstrom T, Kelbaek H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386:665-671.
6. Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med. 2017;376:1234-1244.
7. Thiele H, Akin I, Sandri M, et al. PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N Engl J Med. 2017;377:2419-2432.
8. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol. 2016;67:1235-1250.
Study Overview
Objective. To determine whether percutaneous coronary intervention (PCI) of a nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) reduces the risk of cardiovascular death or myocardial infarction.
Design. International, multicenter, randomized controlled trial blinded to outcome.
Setting and participants. Patients with STEMI who had multivessel coronary disease and had undergone successful PCI to the culprit lesion.
Intervention. A total of 4041 patients were randomly assigned to either PCI of angiographically significant nonculprit lesions or optimal medical therapy without further revascularization. Randomization was stratified according to intended timing of nonculprit lesion PCI (either during or after the index hospitalization).
Main outcome measures. The first co-primary endpoint was the composite of cardiovascular death or myocardial infarction (MI). The second co-primary endpoint was the composite of cardiovascular death, MI or ischemia-driven revascularization.
Main results. At a median follow-up of 3 years, the composite of cardiovascular death or MI occurred in 158 of the 2016 patients (7.8%) in the nonculprit PCI group and in 213 of the 2025 patients (10.5%) in the culprit-lesion-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.60-0.91; P = 0.004). The second co-primary endpoint occurred in 179 patients (8.9%) in the nonculprit PCI group and in 339 patients (16.7%) in the culprit-lesion-only group (hazard ratio, 0.51; 95% CI, 0.43-0.61; P < 0.001).
Conclusion. Among patients with STEMI and multivessel disease, those who underwent complete revascularization with nonculprit lesion PCI had lower rates of cardiovascular death or MI compared to patients with culprit-lesion-only revascularization.
Commentary
Patients presenting with STEMI often have multivessel disease.1 Although it is known that mortality can be reduced by early revascularization of the culprit vessel,2 whether the nonculprit vessel should be revascularized at the time of presentation with STEMI remains controversial.
Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI. Four trials (PRAMI, CvPRIT, DANAMI-PRIMULTI, and COMPARE ACUTE) investigated this clinical question with different designs, and all reported benefit of nonculprit vessel revascularization compared to a culprit-only strategy.3-6 However, the differences in the composite endpoints were mainly driven by the softer endpoints used in these trials, such as refractory angina and ischemia-driven revascularization, and none of these previous trials had adequate power to evaluate differences in hard outcomes, such as death or MI.
In this context, Mehta et al investigated whether achieving complete revascularization by performing PCI on nonculprit vessels would improve the composite of cardiovascular death or MI compared to the culprit-only strategy by conducting a well-designed randomized controlled study. At median follow-up of 3 years, patients who underwent nonculprit vessel PCI had a lower incidence of death or MI compared to those who received the culprit-only strategy (7.8% versus 10.5%). The second co-primary endpoint (composite of death, MI, or ischemia-driven revascularization) also occurred significantly less frequently in the nonculprit PCI group than in the culprit-only PCI group (8.9% versus 16.7%).
The current study has a number of strengths. First, this was a multicenter, international study, and a large number of patients were enrolled (> 4000), achieving adequate power to evaluate for the composite of death and MI. Second, the treatments the patients received reflect contemporary medical therapy and interventional practice: the third-generation thienopyridine ticagrelor, high-dose statins, and ACE inhibitors were prescribed at high rates, and radial access (> 80%) and current-generation drug-eluting stents were used at high rates as well. Third, all angiograms were reviewed by the core lab to evaluate for completeness of revascularization. Fourth, the trial mandated use of fractional flow reserve to assess lesion stenosis 50% to 69% before considering revascularization, ensuring that only ischemic or very-high-grade lesions were revascularized. Fifth, the crossover rate in each group was low compared to the previous studies (4.7% into the complete revascularization group, 3.9% into the lesion-only group). Finally, this study evaluated the timing of the nonculprit PCI. Randomization to each group was stratified according to the intended timing of the nonculprit PCI during the index hospitalization or after hospital discharge (within 45 days). They found that benefit was consistent regardless of when the nonculprit PCI was performed.
Although the COMPLETE study’s design has a number of strengths, it is important to note that patients enrolled in this trial represent a lower-risk STEMI population. Patients with complex anatomy likely were not included, as evidenced by a lower SYNTAX score (mean, 16). Furthermore, no patients who presented with STEMI complicated by cardiogenic shock were enrolled. In the recent CULPRIT SHOCK trial, which focused on patients who had multivessel disease, acute MI, and cardiogenic shock, patients who underwent the culprit-only strategy had a lower rate of death or renal replacement therapy, as compared to patients who underwent immediate complete revascularization.7 Therefore, whether the findings from the COMPLETE study can be extended to a sicker population requires further study.
In 2015, the results from the previous trials, such as PRAMI and CvPRIT, led to a focused update of US PCI guidelines.8 Recommendations for noninfarct-related artery PCI in hemodynamically stable patients presenting with acute MI were upgraded from class III to class IIb. The results from the COMPLETE trial will likely influence the future guidelines, with stronger recommendations toward complete revascularization in patients presenting with hemodynamically stable STEMI.
Applications for Clinical Practice
In patients presenting with hemodynamically stable STEMI, staged complete revascularization, including the nonculprit vessel, should be considered.
– Taishi Hirai, MD, University of Missouri, Columbia, MO, and John EA Blair, MD, University of Chicago Medical Center, Chicago, IL
Study Overview
Objective. To determine whether percutaneous coronary intervention (PCI) of a nonculprit lesion in patients with ST-segment elevation myocardial infarction (STEMI) reduces the risk of cardiovascular death or myocardial infarction.
Design. International, multicenter, randomized controlled trial blinded to outcome.
Setting and participants. Patients with STEMI who had multivessel coronary disease and had undergone successful PCI to the culprit lesion.
Intervention. A total of 4041 patients were randomly assigned to either PCI of angiographically significant nonculprit lesions or optimal medical therapy without further revascularization. Randomization was stratified according to intended timing of nonculprit lesion PCI (either during or after the index hospitalization).
Main outcome measures. The first co-primary endpoint was the composite of cardiovascular death or myocardial infarction (MI). The second co-primary endpoint was the composite of cardiovascular death, MI or ischemia-driven revascularization.
Main results. At a median follow-up of 3 years, the composite of cardiovascular death or MI occurred in 158 of the 2016 patients (7.8%) in the nonculprit PCI group and in 213 of the 2025 patients (10.5%) in the culprit-lesion-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.60-0.91; P = 0.004). The second co-primary endpoint occurred in 179 patients (8.9%) in the nonculprit PCI group and in 339 patients (16.7%) in the culprit-lesion-only group (hazard ratio, 0.51; 95% CI, 0.43-0.61; P < 0.001).
Conclusion. Among patients with STEMI and multivessel disease, those who underwent complete revascularization with nonculprit lesion PCI had lower rates of cardiovascular death or MI compared to patients with culprit-lesion-only revascularization.
Commentary
Patients presenting with STEMI often have multivessel disease.1 Although it is known that mortality can be reduced by early revascularization of the culprit vessel,2 whether the nonculprit vessel should be revascularized at the time of presentation with STEMI remains controversial.
Recently, multiple studies have reported the benefit of nonculprit vessel revascularization in patients presenting with hemodynamically stable STEMI. Four trials (PRAMI, CvPRIT, DANAMI-PRIMULTI, and COMPARE ACUTE) investigated this clinical question with different designs, and all reported benefit of nonculprit vessel revascularization compared to a culprit-only strategy.3-6 However, the differences in the composite endpoints were mainly driven by the softer endpoints used in these trials, such as refractory angina and ischemia-driven revascularization, and none of these previous trials had adequate power to evaluate differences in hard outcomes, such as death or MI.
In this context, Mehta et al investigated whether achieving complete revascularization by performing PCI on nonculprit vessels would improve the composite of cardiovascular death or MI compared to the culprit-only strategy by conducting a well-designed randomized controlled study. At median follow-up of 3 years, patients who underwent nonculprit vessel PCI had a lower incidence of death or MI compared to those who received the culprit-only strategy (7.8% versus 10.5%). The second co-primary endpoint (composite of death, MI, or ischemia-driven revascularization) also occurred significantly less frequently in the nonculprit PCI group than in the culprit-only PCI group (8.9% versus 16.7%).
The current study has a number of strengths. First, this was a multicenter, international study, and a large number of patients were enrolled (> 4000), achieving adequate power to evaluate for the composite of death and MI. Second, the treatments the patients received reflect contemporary medical therapy and interventional practice: the third-generation thienopyridine ticagrelor, high-dose statins, and ACE inhibitors were prescribed at high rates, and radial access (> 80%) and current-generation drug-eluting stents were used at high rates as well. Third, all angiograms were reviewed by the core lab to evaluate for completeness of revascularization. Fourth, the trial mandated use of fractional flow reserve to assess lesion stenosis 50% to 69% before considering revascularization, ensuring that only ischemic or very-high-grade lesions were revascularized. Fifth, the crossover rate in each group was low compared to the previous studies (4.7% into the complete revascularization group, 3.9% into the lesion-only group). Finally, this study evaluated the timing of the nonculprit PCI. Randomization to each group was stratified according to the intended timing of the nonculprit PCI during the index hospitalization or after hospital discharge (within 45 days). They found that benefit was consistent regardless of when the nonculprit PCI was performed.
Although the COMPLETE study’s design has a number of strengths, it is important to note that patients enrolled in this trial represent a lower-risk STEMI population. Patients with complex anatomy likely were not included, as evidenced by a lower SYNTAX score (mean, 16). Furthermore, no patients who presented with STEMI complicated by cardiogenic shock were enrolled. In the recent CULPRIT SHOCK trial, which focused on patients who had multivessel disease, acute MI, and cardiogenic shock, patients who underwent the culprit-only strategy had a lower rate of death or renal replacement therapy, as compared to patients who underwent immediate complete revascularization.7 Therefore, whether the findings from the COMPLETE study can be extended to a sicker population requires further study.
In 2015, the results from the previous trials, such as PRAMI and CvPRIT, led to a focused update of US PCI guidelines.8 Recommendations for noninfarct-related artery PCI in hemodynamically stable patients presenting with acute MI were upgraded from class III to class IIb. The results from the COMPLETE trial will likely influence the future guidelines, with stronger recommendations toward complete revascularization in patients presenting with hemodynamically stable STEMI.
Applications for Clinical Practice
In patients presenting with hemodynamically stable STEMI, staged complete revascularization, including the nonculprit vessel, should be considered.
– Taishi Hirai, MD, University of Missouri, Columbia, MO, and John EA Blair, MD, University of Chicago Medical Center, Chicago, IL
1. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014;312:2019-2027.
2. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999;341:625-634.
3. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369:1115-1123.
4. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65:963-972.
5. Engstrom T, Kelbaek H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386:665-671.
6. Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med. 2017;376:1234-1244.
7. Thiele H, Akin I, Sandri M, et al. PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N Engl J Med. 2017;377:2419-2432.
8. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol. 2016;67:1235-1250.
1. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014;312:2019-2027.
2. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999;341:625-634.
3. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013;369:1115-1123.
4. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015;65:963-972.
5. Engstrom T, Kelbaek H, Helqvist S, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015;386:665-671.
6. Smits PC, Abdel-Wahab M, Neumann FJ, et al. Fractional flow reserve-guided multivessel angioplasty in myocardial infarction. N Engl J Med. 2017;376:1234-1244.
7. Thiele H, Akin I, Sandri M, et al. PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N Engl J Med. 2017;377:2419-2432.
8. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol. 2016;67:1235-1250.
Expanded indication for leadless pacemaker triples eligible patients
The U.S. Food and Drug Administration’s approval of an expanded indication for a leadless pacemaker for patients “who may benefit from maintenance of atrioventricular synchrony” will make this technology potentially available to nearly half of the Americans who need a pacemaker, roughly triple the number of patients who have been candidates for a leadless pacemaker up to now.
“This approval was huge. The complication rate with leadless pacemakers has been 63% less than the rate using pacemakers with transvenous leads,” said Larry A. Chinitz, MD, a cardiac electrophysiologist and a coinvestigator on some of the studies that led to the new indication. By expanding the types of patients suitable for leadless pacing “we’ll achieve AV [atrioventricular] synchrony in more patients with fewer complications,” said Dr. Chinitz, professor of medicine and director of the Cardiac Electrophysiology and Heart Rhythm Center at NYU Langone Health in New York.
Because the device is both leadless and requires no pocket owing to its small size and placement in a patient’s right ventricle, it has implications for potentially broadening the population that could benefit from the device, he said in an interview. “When we started with this pacemaker, it was limited to elderly patients with persistent atrial fibrillation who needed only ventricular pacing, a very small group,” just under 15% of the universe of patients who need pacemakers. The broadened indication, for patients with high-grade AV block who also have atrial function, makes it possible to think of using this safer and easier-to-place device in patients who need infrequent pacing, and in patients with multiple comorbidities that give them an increased complication risk, he said. The new indication means “you’re treating a much broader patient population, doing it more safely, and creating the foundation for expanding this technology.”
The Micra AV pacemaker uses the same basic design as the previously approved Micra Transcatheter Pacing System, which came onto the U.S. market in 2016 and provides single-chamber pacing. An accelerometer on the device allows it to detect atrial motion and thereby synchronize ventricular and atrial contractions, which led to the new indication. Although the Micra AV device looks similar to the original single-chamber model, it has an entirely new circuitry that prolongs battery life during dual-chamber pacing as well as new software that incorporates the accelerometer data, explained Robert Kowal, MD, a cardiac electrophysiologist, and vice president of medical affairs and chief medical officer of cardiac rhythm and heart failure at Medtronic in Minneapolis. The battery of the Micra AV is designed to last about 15 years, Dr. Chinitz noted.
Results from two studies that Dr. Chinitz helped run established the safety and efficacy of the device for dual-chamber pacing. The MARVEL (Micra Atrial Tracking Using a Ventricular Accelerometer) study included 64 patients who completed the study at 12 worldwide centers, which produced an average 80% AV synchrony in 33 patients with high-degree AV block (The other patients in the study had predominantly intrinsic AV conduction; Heart Rhythm. 2018 Sep;15[9]:1363-71). The MARVEL 2 study included 75 patients with either second- or third-degree AV block at 12 worldwide centers and showed that AV synchrony increased from an average of 27% without two-chamber pacing to 89% with the dual-chamber function turned on, and with 95% of patients achieving at least 70% AV synchrony (JACC Clin Electrophysiol. 2020 Jan;6[1]:94-106).
The 2016 indication for single-chamber pacing included patients with “high-grade” AV bloc with or without atrial fibrillation, typically patients for whom dual-chamber pacemaker was not a great option because of the risks for complication but with the downside of limited AV synchrony, a limitation now mitigated by the option of mechanical synchronization, Dr. Kowal said. The AV device remains intended for patients with high-grade AV node block, which means patients with second- or third-degree block, he added in an interview. The estimated prevalence of third-degree AV block among U.S. adults is about 0.02%, which translates into about 50,000 people; the estimated prevalence of second-degree AV block is much less, about 10% of the third-degree prevalence.
Despite the substantial cut in complications by a leadless and pocketless pacemaker, “some patients may still benefit from a traditional dual-chamber pacemaker,” specifically active patients who might sometimes get their heart rates up with exercise to levels of about 150 beats/min or higher, Dr. Kowal said. That’s because currently the programing algorithms used to synchronize the ventricle and atrium become less reliable at heart rates above 105 beats/min, he explained. However, the ability for mechanical synchronization to keep up at higher heart rates should improve as additional data are collected that can refine the algorithms. It’s also unusual for most patients who are pacemaker candidates to reach heart rates this high, he said.
The MARVEL and MARVEL 2 studies were sponsored by Medtronic, the company that markets Micra pacemakers. Dr. Chinitz has received fees and fellowship support from Medtronic, and has also received fees from Abbott, Biosense Webster, Biotronik, and Pfizer, and he has also received fellowship support from Biotronik and Boston Scientific. Dr. Kowal is a Medtronic employee.
The U.S. Food and Drug Administration’s approval of an expanded indication for a leadless pacemaker for patients “who may benefit from maintenance of atrioventricular synchrony” will make this technology potentially available to nearly half of the Americans who need a pacemaker, roughly triple the number of patients who have been candidates for a leadless pacemaker up to now.
“This approval was huge. The complication rate with leadless pacemakers has been 63% less than the rate using pacemakers with transvenous leads,” said Larry A. Chinitz, MD, a cardiac electrophysiologist and a coinvestigator on some of the studies that led to the new indication. By expanding the types of patients suitable for leadless pacing “we’ll achieve AV [atrioventricular] synchrony in more patients with fewer complications,” said Dr. Chinitz, professor of medicine and director of the Cardiac Electrophysiology and Heart Rhythm Center at NYU Langone Health in New York.
Because the device is both leadless and requires no pocket owing to its small size and placement in a patient’s right ventricle, it has implications for potentially broadening the population that could benefit from the device, he said in an interview. “When we started with this pacemaker, it was limited to elderly patients with persistent atrial fibrillation who needed only ventricular pacing, a very small group,” just under 15% of the universe of patients who need pacemakers. The broadened indication, for patients with high-grade AV block who also have atrial function, makes it possible to think of using this safer and easier-to-place device in patients who need infrequent pacing, and in patients with multiple comorbidities that give them an increased complication risk, he said. The new indication means “you’re treating a much broader patient population, doing it more safely, and creating the foundation for expanding this technology.”
The Micra AV pacemaker uses the same basic design as the previously approved Micra Transcatheter Pacing System, which came onto the U.S. market in 2016 and provides single-chamber pacing. An accelerometer on the device allows it to detect atrial motion and thereby synchronize ventricular and atrial contractions, which led to the new indication. Although the Micra AV device looks similar to the original single-chamber model, it has an entirely new circuitry that prolongs battery life during dual-chamber pacing as well as new software that incorporates the accelerometer data, explained Robert Kowal, MD, a cardiac electrophysiologist, and vice president of medical affairs and chief medical officer of cardiac rhythm and heart failure at Medtronic in Minneapolis. The battery of the Micra AV is designed to last about 15 years, Dr. Chinitz noted.
Results from two studies that Dr. Chinitz helped run established the safety and efficacy of the device for dual-chamber pacing. The MARVEL (Micra Atrial Tracking Using a Ventricular Accelerometer) study included 64 patients who completed the study at 12 worldwide centers, which produced an average 80% AV synchrony in 33 patients with high-degree AV block (The other patients in the study had predominantly intrinsic AV conduction; Heart Rhythm. 2018 Sep;15[9]:1363-71). The MARVEL 2 study included 75 patients with either second- or third-degree AV block at 12 worldwide centers and showed that AV synchrony increased from an average of 27% without two-chamber pacing to 89% with the dual-chamber function turned on, and with 95% of patients achieving at least 70% AV synchrony (JACC Clin Electrophysiol. 2020 Jan;6[1]:94-106).
The 2016 indication for single-chamber pacing included patients with “high-grade” AV bloc with or without atrial fibrillation, typically patients for whom dual-chamber pacemaker was not a great option because of the risks for complication but with the downside of limited AV synchrony, a limitation now mitigated by the option of mechanical synchronization, Dr. Kowal said. The AV device remains intended for patients with high-grade AV node block, which means patients with second- or third-degree block, he added in an interview. The estimated prevalence of third-degree AV block among U.S. adults is about 0.02%, which translates into about 50,000 people; the estimated prevalence of second-degree AV block is much less, about 10% of the third-degree prevalence.
Despite the substantial cut in complications by a leadless and pocketless pacemaker, “some patients may still benefit from a traditional dual-chamber pacemaker,” specifically active patients who might sometimes get their heart rates up with exercise to levels of about 150 beats/min or higher, Dr. Kowal said. That’s because currently the programing algorithms used to synchronize the ventricle and atrium become less reliable at heart rates above 105 beats/min, he explained. However, the ability for mechanical synchronization to keep up at higher heart rates should improve as additional data are collected that can refine the algorithms. It’s also unusual for most patients who are pacemaker candidates to reach heart rates this high, he said.
The MARVEL and MARVEL 2 studies were sponsored by Medtronic, the company that markets Micra pacemakers. Dr. Chinitz has received fees and fellowship support from Medtronic, and has also received fees from Abbott, Biosense Webster, Biotronik, and Pfizer, and he has also received fellowship support from Biotronik and Boston Scientific. Dr. Kowal is a Medtronic employee.
The U.S. Food and Drug Administration’s approval of an expanded indication for a leadless pacemaker for patients “who may benefit from maintenance of atrioventricular synchrony” will make this technology potentially available to nearly half of the Americans who need a pacemaker, roughly triple the number of patients who have been candidates for a leadless pacemaker up to now.
“This approval was huge. The complication rate with leadless pacemakers has been 63% less than the rate using pacemakers with transvenous leads,” said Larry A. Chinitz, MD, a cardiac electrophysiologist and a coinvestigator on some of the studies that led to the new indication. By expanding the types of patients suitable for leadless pacing “we’ll achieve AV [atrioventricular] synchrony in more patients with fewer complications,” said Dr. Chinitz, professor of medicine and director of the Cardiac Electrophysiology and Heart Rhythm Center at NYU Langone Health in New York.
Because the device is both leadless and requires no pocket owing to its small size and placement in a patient’s right ventricle, it has implications for potentially broadening the population that could benefit from the device, he said in an interview. “When we started with this pacemaker, it was limited to elderly patients with persistent atrial fibrillation who needed only ventricular pacing, a very small group,” just under 15% of the universe of patients who need pacemakers. The broadened indication, for patients with high-grade AV block who also have atrial function, makes it possible to think of using this safer and easier-to-place device in patients who need infrequent pacing, and in patients with multiple comorbidities that give them an increased complication risk, he said. The new indication means “you’re treating a much broader patient population, doing it more safely, and creating the foundation for expanding this technology.”
The Micra AV pacemaker uses the same basic design as the previously approved Micra Transcatheter Pacing System, which came onto the U.S. market in 2016 and provides single-chamber pacing. An accelerometer on the device allows it to detect atrial motion and thereby synchronize ventricular and atrial contractions, which led to the new indication. Although the Micra AV device looks similar to the original single-chamber model, it has an entirely new circuitry that prolongs battery life during dual-chamber pacing as well as new software that incorporates the accelerometer data, explained Robert Kowal, MD, a cardiac electrophysiologist, and vice president of medical affairs and chief medical officer of cardiac rhythm and heart failure at Medtronic in Minneapolis. The battery of the Micra AV is designed to last about 15 years, Dr. Chinitz noted.
Results from two studies that Dr. Chinitz helped run established the safety and efficacy of the device for dual-chamber pacing. The MARVEL (Micra Atrial Tracking Using a Ventricular Accelerometer) study included 64 patients who completed the study at 12 worldwide centers, which produced an average 80% AV synchrony in 33 patients with high-degree AV block (The other patients in the study had predominantly intrinsic AV conduction; Heart Rhythm. 2018 Sep;15[9]:1363-71). The MARVEL 2 study included 75 patients with either second- or third-degree AV block at 12 worldwide centers and showed that AV synchrony increased from an average of 27% without two-chamber pacing to 89% with the dual-chamber function turned on, and with 95% of patients achieving at least 70% AV synchrony (JACC Clin Electrophysiol. 2020 Jan;6[1]:94-106).
The 2016 indication for single-chamber pacing included patients with “high-grade” AV bloc with or without atrial fibrillation, typically patients for whom dual-chamber pacemaker was not a great option because of the risks for complication but with the downside of limited AV synchrony, a limitation now mitigated by the option of mechanical synchronization, Dr. Kowal said. The AV device remains intended for patients with high-grade AV node block, which means patients with second- or third-degree block, he added in an interview. The estimated prevalence of third-degree AV block among U.S. adults is about 0.02%, which translates into about 50,000 people; the estimated prevalence of second-degree AV block is much less, about 10% of the third-degree prevalence.
Despite the substantial cut in complications by a leadless and pocketless pacemaker, “some patients may still benefit from a traditional dual-chamber pacemaker,” specifically active patients who might sometimes get their heart rates up with exercise to levels of about 150 beats/min or higher, Dr. Kowal said. That’s because currently the programing algorithms used to synchronize the ventricle and atrium become less reliable at heart rates above 105 beats/min, he explained. However, the ability for mechanical synchronization to keep up at higher heart rates should improve as additional data are collected that can refine the algorithms. It’s also unusual for most patients who are pacemaker candidates to reach heart rates this high, he said.
The MARVEL and MARVEL 2 studies were sponsored by Medtronic, the company that markets Micra pacemakers. Dr. Chinitz has received fees and fellowship support from Medtronic, and has also received fees from Abbott, Biosense Webster, Biotronik, and Pfizer, and he has also received fellowship support from Biotronik and Boston Scientific. Dr. Kowal is a Medtronic employee.
Silent ischemia isn’t what it used to be
SNOWMASS, COLO. – The concept that silent myocardial ischemia is clinically detrimental has fallen by the wayside, and routine screening for this phenomenon can no longer be recommended, Patrick T. O’Gara, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
What a difference a decade or 2 can make.
“Think about where we were 25 years ago, when we worried about people who had transient ST-segment depression without angina on Holter monitoring. We would wig out, chase them down the street, try to tackle them and load them up with medications and think about balloon [percutaneous transluminal coronary angioplasty]. And now we’re at the point where it doesn’t seem to help with respect to quality of life, let alone death or myocardial infarction,” observed Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.
The end of the line for the now-discredited notion that silent ischemia carries clinical significance approaching that of ischemia plus angina pectoris was the landmark ISCHEMIA trial, reported in November 2019 at the annual scientific sessions of the American Heart Association. This randomized trial asked the question: Is there any high-risk subgroup of patients with stable ischemic heart disease not involving the left main coronary artery for whom a strategy of routine revascularization improves hard outcomes in the current era of highly effective, guideline-directed medical therapy?
The answer turned out to be no. At 5 years of follow-up of 5,179 randomized patients with baseline stable coronary artery disease (CAD) and rigorously determined baseline moderate or severe ischemia affecting more than 10% of the myocardium, there was no difference between patients randomized to routine revascularization plus optimal medical therapy versus those on optimal medical therapy alone in the primary combined outcome of cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina.
Of note, 35% of participants in the ISCHEMIA trial had moderate or severe silent ischemia. Like those who had angina, they achieved no additional benefit from a strategy of routine revascularization in terms of the primary outcome. ISCHEMIA participants with angina did show significant and durable improvements in quality of life and angina control with routine revascularization; however, those with silent ischemia showed little or no such improvement with an invasive strategy.
That being said, Dr. O’Gara added that he supports the ISCHEMIA investigators’ efforts to obtain funding from the National Institutes of Health for another 5 years or so of follow-up in order to determine whether revascularization actually does lead to improvement in the hard outcomes.
“Remember, in the STICH trial it took 10 years to show superiority of CABG [coronary artery bypass surgery] versus medical therapy to treat ischemic cardiomyopathy [N Engl J Med 2016; 374:1511-20]. My own view is that it’s too premature to throw the baby out with the bathwater. I think shared decision making is still very important, and I think, for many of our patients, relief of angina and improved quality of life are legitimate reasons in a low-risk situation with a good interventionalist to proceed,” he said.
Dr. O’Gara traced the history of medical thinking about silent ischemia. The notion that silent ischemia carried a clinical significance comparable with ischemia with angina gained wide credence more than 30 years ago, when investigators from the National Institutes of Health–sponsored Coronary Artery Surgery Study registry reported: “Patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death – except in the three-vessel CAD subgroup, where the risk is greater in silent ischemia” (Am J Cardiol. 1988 Dec 1;62[17]:1155-8).
“This was a very important observation and led to many, many recommendations about screening and making sure that you took the expression of ST-segment depression on exercise treadmill testing pretty seriously, even if your patient did not have angina,” Dr. O’Gara recalled.
The prevailing wisdom that silent ischemia was detrimental took a hit in the Detection of Ischemia in Asymptomatic Diabetics (DIAC) trial. DIAC was conducted at a time when it had become clear that type 2 diabetes was a condition associated with increased cardiovascular risk, and that various methods of imaging were more accurate than treadmill exercise testing for the detection of underlying CAD. But when 1,123 DIAC participants with type 2 diabetes were randomized to screening with adenosine-stress radionuclide myocardial perfusion imaging or not and prospectively followed for roughly 5 years, it turned out there was no between-group difference in cardiac death or MI (JAMA. 2009 Apr 15;301[15]:1547-55).
“This pretty much put the lid on going out of one’s way to do routine screening of this nature in persons with diabetes who were considered to be at higher than average risk for the development of coronary disease,” the cardiologist commented.
Another fissure in the idea that silent ischemia was worth searching for and treating came from CLARIFY, an observational international registry of more than 20,000 individuals with stable CAD, roughly 12% of whom had silent ischemia, a figure in line with the prevalence reported in other studies. The 2-year rate of cardiovascular death or MI in the group with silent ischemia didn’t differ from the rate in patients with neither angina nor provocable ischemia. In contrast, rates of cardiovascular death or MI were significantly higher in the groups with angina but no ischemia or angina with ischemia (JAMA Intern Med. 2014 Oct;174[10]:1651-9).
“There’s something about the expression of angina that’s a very key clinical marker,” Dr. O’Gara observed.
He noted that just a few months before the ISCHEMIA trial results were released, a report from the far-smaller, randomized second Medicine, Angioplasty, or Surgery Study “threw cold water” on the notion that stress-induced ischemia in patients with multivessel CAD is a bad thing. Over 10 years of follow-up, the risk of major adverse cardiovascular events or deterioration in left ventricular function was identical in patients with or without baseline ischemia on stress testing performed after percutaneous coronary intervention, CABG surgery, or initiation of medical therapy (JAMA Intern Med. 2019 Jul 22. doi: 10.1001/jamainternmed.2019.2227).
What the guidelines say
The 6-year-old U.S. guidelines on the diagnosis and management of patients with stable ischemic heart disease are clearly out of date on the topic of silent ischemia (Circulation. 2014 Nov 4;130[19]:1749-67). The recommendations are based on expert opinion formed prior to the massive amount of new evidence that has since become available. For example, the current guidelines state as a class IIa, level of evidence C recommendation that exercise or pharmacologic stress can be useful for follow-up assessment at 2-year or greater intervals in patients with stable ischemic heart disease with prior evidence of silent ischemia.
“This is a very weak recommendation. The class of recommendation says it would be reasonable, but in the absence of an evidence base and in light of newer information, I’m not sure that it approaches even a class IIa level of recommendation,” according to Dr. O’Gara.
The 2019 European Society of Cardiology guidelines on chronic coronary syndromes are similarly weak on silent ischemia. The European guidelines state that patients with diabetes or chronic kidney disease may have a higher burden of silent ischemia, might be at higher risk for atherosclerotic cardiovascular disease events, and that periodic ECGs and functional testing every 3-5 years might be considered.
“Obviously there’s a lot of leeway there in how you wish to interpret that,” Dr. O’Gara said. “And this did not rise to the level where they’d put it in the table of recommendations, but it’s simply included as part of the explanatory text.”
What’s coming next in stable ischemic heart disease
“Nowadays all the rage has to do with coronary microvascular dysfunction,” according to Dr. O’Gara. “I think all of the research interest currently is focused on the coronary microcirculation as perhaps the next frontier in our understanding of why it is that ischemia can occur in the absence of epicardial coronary disease.”
He highly recommended a review article entitled: “Reappraisal of Ischemic Heart Disease,” in which an international trio of prominent cardiologists asserted that coronary microvascular dysfunction not only plays a pivotal pathogenic role in angina pectoris, but also in a phenomenon known as microvascular angina – that is, angina in the absence of obstructive CAD. Microvascular angina may explain the roughly one-third of patients who experience acute coronary syndrome without epicardial coronary artery stenosis or thrombosis. The authors delved into the structural and functional mechanisms underlying coronary microvascular dysfunction, while noting that effective treatment of this common phenomenon remains a major unmet need (Circulation. 2018 Oct 2;138[14]:1463-80).
Dr. O’Gara reported receiving funding from the National Heart, Lung, and Blood Institute; from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial; from Edwards Lifesciences for the ongoing EARLY TAVR trial; and from Medtrace Pharma, a Danish company developing an innovative form of PET diagnostic imaging.
SNOWMASS, COLO. – The concept that silent myocardial ischemia is clinically detrimental has fallen by the wayside, and routine screening for this phenomenon can no longer be recommended, Patrick T. O’Gara, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
What a difference a decade or 2 can make.
“Think about where we were 25 years ago, when we worried about people who had transient ST-segment depression without angina on Holter monitoring. We would wig out, chase them down the street, try to tackle them and load them up with medications and think about balloon [percutaneous transluminal coronary angioplasty]. And now we’re at the point where it doesn’t seem to help with respect to quality of life, let alone death or myocardial infarction,” observed Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.
The end of the line for the now-discredited notion that silent ischemia carries clinical significance approaching that of ischemia plus angina pectoris was the landmark ISCHEMIA trial, reported in November 2019 at the annual scientific sessions of the American Heart Association. This randomized trial asked the question: Is there any high-risk subgroup of patients with stable ischemic heart disease not involving the left main coronary artery for whom a strategy of routine revascularization improves hard outcomes in the current era of highly effective, guideline-directed medical therapy?
The answer turned out to be no. At 5 years of follow-up of 5,179 randomized patients with baseline stable coronary artery disease (CAD) and rigorously determined baseline moderate or severe ischemia affecting more than 10% of the myocardium, there was no difference between patients randomized to routine revascularization plus optimal medical therapy versus those on optimal medical therapy alone in the primary combined outcome of cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina.
Of note, 35% of participants in the ISCHEMIA trial had moderate or severe silent ischemia. Like those who had angina, they achieved no additional benefit from a strategy of routine revascularization in terms of the primary outcome. ISCHEMIA participants with angina did show significant and durable improvements in quality of life and angina control with routine revascularization; however, those with silent ischemia showed little or no such improvement with an invasive strategy.
That being said, Dr. O’Gara added that he supports the ISCHEMIA investigators’ efforts to obtain funding from the National Institutes of Health for another 5 years or so of follow-up in order to determine whether revascularization actually does lead to improvement in the hard outcomes.
“Remember, in the STICH trial it took 10 years to show superiority of CABG [coronary artery bypass surgery] versus medical therapy to treat ischemic cardiomyopathy [N Engl J Med 2016; 374:1511-20]. My own view is that it’s too premature to throw the baby out with the bathwater. I think shared decision making is still very important, and I think, for many of our patients, relief of angina and improved quality of life are legitimate reasons in a low-risk situation with a good interventionalist to proceed,” he said.
Dr. O’Gara traced the history of medical thinking about silent ischemia. The notion that silent ischemia carried a clinical significance comparable with ischemia with angina gained wide credence more than 30 years ago, when investigators from the National Institutes of Health–sponsored Coronary Artery Surgery Study registry reported: “Patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death – except in the three-vessel CAD subgroup, where the risk is greater in silent ischemia” (Am J Cardiol. 1988 Dec 1;62[17]:1155-8).
“This was a very important observation and led to many, many recommendations about screening and making sure that you took the expression of ST-segment depression on exercise treadmill testing pretty seriously, even if your patient did not have angina,” Dr. O’Gara recalled.
The prevailing wisdom that silent ischemia was detrimental took a hit in the Detection of Ischemia in Asymptomatic Diabetics (DIAC) trial. DIAC was conducted at a time when it had become clear that type 2 diabetes was a condition associated with increased cardiovascular risk, and that various methods of imaging were more accurate than treadmill exercise testing for the detection of underlying CAD. But when 1,123 DIAC participants with type 2 diabetes were randomized to screening with adenosine-stress radionuclide myocardial perfusion imaging or not and prospectively followed for roughly 5 years, it turned out there was no between-group difference in cardiac death or MI (JAMA. 2009 Apr 15;301[15]:1547-55).
“This pretty much put the lid on going out of one’s way to do routine screening of this nature in persons with diabetes who were considered to be at higher than average risk for the development of coronary disease,” the cardiologist commented.
Another fissure in the idea that silent ischemia was worth searching for and treating came from CLARIFY, an observational international registry of more than 20,000 individuals with stable CAD, roughly 12% of whom had silent ischemia, a figure in line with the prevalence reported in other studies. The 2-year rate of cardiovascular death or MI in the group with silent ischemia didn’t differ from the rate in patients with neither angina nor provocable ischemia. In contrast, rates of cardiovascular death or MI were significantly higher in the groups with angina but no ischemia or angina with ischemia (JAMA Intern Med. 2014 Oct;174[10]:1651-9).
“There’s something about the expression of angina that’s a very key clinical marker,” Dr. O’Gara observed.
He noted that just a few months before the ISCHEMIA trial results were released, a report from the far-smaller, randomized second Medicine, Angioplasty, or Surgery Study “threw cold water” on the notion that stress-induced ischemia in patients with multivessel CAD is a bad thing. Over 10 years of follow-up, the risk of major adverse cardiovascular events or deterioration in left ventricular function was identical in patients with or without baseline ischemia on stress testing performed after percutaneous coronary intervention, CABG surgery, or initiation of medical therapy (JAMA Intern Med. 2019 Jul 22. doi: 10.1001/jamainternmed.2019.2227).
What the guidelines say
The 6-year-old U.S. guidelines on the diagnosis and management of patients with stable ischemic heart disease are clearly out of date on the topic of silent ischemia (Circulation. 2014 Nov 4;130[19]:1749-67). The recommendations are based on expert opinion formed prior to the massive amount of new evidence that has since become available. For example, the current guidelines state as a class IIa, level of evidence C recommendation that exercise or pharmacologic stress can be useful for follow-up assessment at 2-year or greater intervals in patients with stable ischemic heart disease with prior evidence of silent ischemia.
“This is a very weak recommendation. The class of recommendation says it would be reasonable, but in the absence of an evidence base and in light of newer information, I’m not sure that it approaches even a class IIa level of recommendation,” according to Dr. O’Gara.
The 2019 European Society of Cardiology guidelines on chronic coronary syndromes are similarly weak on silent ischemia. The European guidelines state that patients with diabetes or chronic kidney disease may have a higher burden of silent ischemia, might be at higher risk for atherosclerotic cardiovascular disease events, and that periodic ECGs and functional testing every 3-5 years might be considered.
“Obviously there’s a lot of leeway there in how you wish to interpret that,” Dr. O’Gara said. “And this did not rise to the level where they’d put it in the table of recommendations, but it’s simply included as part of the explanatory text.”
What’s coming next in stable ischemic heart disease
“Nowadays all the rage has to do with coronary microvascular dysfunction,” according to Dr. O’Gara. “I think all of the research interest currently is focused on the coronary microcirculation as perhaps the next frontier in our understanding of why it is that ischemia can occur in the absence of epicardial coronary disease.”
He highly recommended a review article entitled: “Reappraisal of Ischemic Heart Disease,” in which an international trio of prominent cardiologists asserted that coronary microvascular dysfunction not only plays a pivotal pathogenic role in angina pectoris, but also in a phenomenon known as microvascular angina – that is, angina in the absence of obstructive CAD. Microvascular angina may explain the roughly one-third of patients who experience acute coronary syndrome without epicardial coronary artery stenosis or thrombosis. The authors delved into the structural and functional mechanisms underlying coronary microvascular dysfunction, while noting that effective treatment of this common phenomenon remains a major unmet need (Circulation. 2018 Oct 2;138[14]:1463-80).
Dr. O’Gara reported receiving funding from the National Heart, Lung, and Blood Institute; from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial; from Edwards Lifesciences for the ongoing EARLY TAVR trial; and from Medtrace Pharma, a Danish company developing an innovative form of PET diagnostic imaging.
SNOWMASS, COLO. – The concept that silent myocardial ischemia is clinically detrimental has fallen by the wayside, and routine screening for this phenomenon can no longer be recommended, Patrick T. O’Gara, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
What a difference a decade or 2 can make.
“Think about where we were 25 years ago, when we worried about people who had transient ST-segment depression without angina on Holter monitoring. We would wig out, chase them down the street, try to tackle them and load them up with medications and think about balloon [percutaneous transluminal coronary angioplasty]. And now we’re at the point where it doesn’t seem to help with respect to quality of life, let alone death or myocardial infarction,” observed Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.
The end of the line for the now-discredited notion that silent ischemia carries clinical significance approaching that of ischemia plus angina pectoris was the landmark ISCHEMIA trial, reported in November 2019 at the annual scientific sessions of the American Heart Association. This randomized trial asked the question: Is there any high-risk subgroup of patients with stable ischemic heart disease not involving the left main coronary artery for whom a strategy of routine revascularization improves hard outcomes in the current era of highly effective, guideline-directed medical therapy?
The answer turned out to be no. At 5 years of follow-up of 5,179 randomized patients with baseline stable coronary artery disease (CAD) and rigorously determined baseline moderate or severe ischemia affecting more than 10% of the myocardium, there was no difference between patients randomized to routine revascularization plus optimal medical therapy versus those on optimal medical therapy alone in the primary combined outcome of cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina.
Of note, 35% of participants in the ISCHEMIA trial had moderate or severe silent ischemia. Like those who had angina, they achieved no additional benefit from a strategy of routine revascularization in terms of the primary outcome. ISCHEMIA participants with angina did show significant and durable improvements in quality of life and angina control with routine revascularization; however, those with silent ischemia showed little or no such improvement with an invasive strategy.
That being said, Dr. O’Gara added that he supports the ISCHEMIA investigators’ efforts to obtain funding from the National Institutes of Health for another 5 years or so of follow-up in order to determine whether revascularization actually does lead to improvement in the hard outcomes.
“Remember, in the STICH trial it took 10 years to show superiority of CABG [coronary artery bypass surgery] versus medical therapy to treat ischemic cardiomyopathy [N Engl J Med 2016; 374:1511-20]. My own view is that it’s too premature to throw the baby out with the bathwater. I think shared decision making is still very important, and I think, for many of our patients, relief of angina and improved quality of life are legitimate reasons in a low-risk situation with a good interventionalist to proceed,” he said.
Dr. O’Gara traced the history of medical thinking about silent ischemia. The notion that silent ischemia carried a clinical significance comparable with ischemia with angina gained wide credence more than 30 years ago, when investigators from the National Institutes of Health–sponsored Coronary Artery Surgery Study registry reported: “Patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death – except in the three-vessel CAD subgroup, where the risk is greater in silent ischemia” (Am J Cardiol. 1988 Dec 1;62[17]:1155-8).
“This was a very important observation and led to many, many recommendations about screening and making sure that you took the expression of ST-segment depression on exercise treadmill testing pretty seriously, even if your patient did not have angina,” Dr. O’Gara recalled.
The prevailing wisdom that silent ischemia was detrimental took a hit in the Detection of Ischemia in Asymptomatic Diabetics (DIAC) trial. DIAC was conducted at a time when it had become clear that type 2 diabetes was a condition associated with increased cardiovascular risk, and that various methods of imaging were more accurate than treadmill exercise testing for the detection of underlying CAD. But when 1,123 DIAC participants with type 2 diabetes were randomized to screening with adenosine-stress radionuclide myocardial perfusion imaging or not and prospectively followed for roughly 5 years, it turned out there was no between-group difference in cardiac death or MI (JAMA. 2009 Apr 15;301[15]:1547-55).
“This pretty much put the lid on going out of one’s way to do routine screening of this nature in persons with diabetes who were considered to be at higher than average risk for the development of coronary disease,” the cardiologist commented.
Another fissure in the idea that silent ischemia was worth searching for and treating came from CLARIFY, an observational international registry of more than 20,000 individuals with stable CAD, roughly 12% of whom had silent ischemia, a figure in line with the prevalence reported in other studies. The 2-year rate of cardiovascular death or MI in the group with silent ischemia didn’t differ from the rate in patients with neither angina nor provocable ischemia. In contrast, rates of cardiovascular death or MI were significantly higher in the groups with angina but no ischemia or angina with ischemia (JAMA Intern Med. 2014 Oct;174[10]:1651-9).
“There’s something about the expression of angina that’s a very key clinical marker,” Dr. O’Gara observed.
He noted that just a few months before the ISCHEMIA trial results were released, a report from the far-smaller, randomized second Medicine, Angioplasty, or Surgery Study “threw cold water” on the notion that stress-induced ischemia in patients with multivessel CAD is a bad thing. Over 10 years of follow-up, the risk of major adverse cardiovascular events or deterioration in left ventricular function was identical in patients with or without baseline ischemia on stress testing performed after percutaneous coronary intervention, CABG surgery, or initiation of medical therapy (JAMA Intern Med. 2019 Jul 22. doi: 10.1001/jamainternmed.2019.2227).
What the guidelines say
The 6-year-old U.S. guidelines on the diagnosis and management of patients with stable ischemic heart disease are clearly out of date on the topic of silent ischemia (Circulation. 2014 Nov 4;130[19]:1749-67). The recommendations are based on expert opinion formed prior to the massive amount of new evidence that has since become available. For example, the current guidelines state as a class IIa, level of evidence C recommendation that exercise or pharmacologic stress can be useful for follow-up assessment at 2-year or greater intervals in patients with stable ischemic heart disease with prior evidence of silent ischemia.
“This is a very weak recommendation. The class of recommendation says it would be reasonable, but in the absence of an evidence base and in light of newer information, I’m not sure that it approaches even a class IIa level of recommendation,” according to Dr. O’Gara.
The 2019 European Society of Cardiology guidelines on chronic coronary syndromes are similarly weak on silent ischemia. The European guidelines state that patients with diabetes or chronic kidney disease may have a higher burden of silent ischemia, might be at higher risk for atherosclerotic cardiovascular disease events, and that periodic ECGs and functional testing every 3-5 years might be considered.
“Obviously there’s a lot of leeway there in how you wish to interpret that,” Dr. O’Gara said. “And this did not rise to the level where they’d put it in the table of recommendations, but it’s simply included as part of the explanatory text.”
What’s coming next in stable ischemic heart disease
“Nowadays all the rage has to do with coronary microvascular dysfunction,” according to Dr. O’Gara. “I think all of the research interest currently is focused on the coronary microcirculation as perhaps the next frontier in our understanding of why it is that ischemia can occur in the absence of epicardial coronary disease.”
He highly recommended a review article entitled: “Reappraisal of Ischemic Heart Disease,” in which an international trio of prominent cardiologists asserted that coronary microvascular dysfunction not only plays a pivotal pathogenic role in angina pectoris, but also in a phenomenon known as microvascular angina – that is, angina in the absence of obstructive CAD. Microvascular angina may explain the roughly one-third of patients who experience acute coronary syndrome without epicardial coronary artery stenosis or thrombosis. The authors delved into the structural and functional mechanisms underlying coronary microvascular dysfunction, while noting that effective treatment of this common phenomenon remains a major unmet need (Circulation. 2018 Oct 2;138[14]:1463-80).
Dr. O’Gara reported receiving funding from the National Heart, Lung, and Blood Institute; from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial; from Edwards Lifesciences for the ongoing EARLY TAVR trial; and from Medtrace Pharma, a Danish company developing an innovative form of PET diagnostic imaging.
EXPERT ANALYSIS FROM ACC SNOWMASS 2020
What 2019’s top five CAD trials tell us
SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.
“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’ll remind you that, when we go back to the early stent days, observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
AUGUSTUS
For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.
“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.
In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).
A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.
“And we should really be avoiding DAPT,” Dr. Bell added.
How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?
“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
SMART-CHOICE and STOPDAPT-2
These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.
Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).
“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
COLCOT
This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.
“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.
Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.
“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.
These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
COMPLETE
This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).
The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.
“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
EXCEL
Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.
The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.
“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.
PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.
He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”
Dr. Bell reported having no financial conflicts regarding his presentation.
SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.
“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’ll remind you that, when we go back to the early stent days, observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
AUGUSTUS
For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.
“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.
In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).
A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.
“And we should really be avoiding DAPT,” Dr. Bell added.
How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?
“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
SMART-CHOICE and STOPDAPT-2
These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.
Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).
“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
COLCOT
This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.
“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.
Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.
“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.
These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
COMPLETE
This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).
The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.
“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
EXCEL
Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.
The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.
“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.
PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.
He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”
Dr. Bell reported having no financial conflicts regarding his presentation.
SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.
“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
“I’ll remind you that, when we go back to the early stent days, observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.
Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
AUGUSTUS
For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.
“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.
In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).
Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).
A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.
“And we should really be avoiding DAPT,” Dr. Bell added.
How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?
“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
SMART-CHOICE and STOPDAPT-2
These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.
Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).
“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
COLCOT
This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.
“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.
Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.
“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.
These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
COMPLETE
This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).
The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.
“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
EXCEL
Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.
The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.
“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.
PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.
He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”
Dr. Bell reported having no financial conflicts regarding his presentation.
REPORTING FROM ACC SNOWMASS 2020
Routine heart disease screening not recommended
Opioid deaths boost donor heart supply
SNOWMASS, COLO. – The tragic opioid epidemic has “one small bright spot”: an expanding pool of eligible donor hearts for transplantation, Akshay S. Desai, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
For decades, the annual volume of heart transplantations performed in the U.S. was static because of the huge mismatch between donor organ supply and demand. But heart transplant volume has increased steadily in the last few years – a result of the opioid epidemic.
Data from the U.S. Organ Procurement and Transplantation Network show that the proportion of donor hearts obtained from individuals who died from drug intoxication climbed from a mere 1.5% in 1999 to 17.6% in 2017, the most recent year for which data are available. Meanwhile, the size of the heart transplant waiting list, which rose year after year in 2009-2015, has since declined (N Engl J Med. 2019 Feb 7;380[6]:597-9).
“What’s amazing is that, even though these patients might have historically been considered high risk in general, the organs recovered from these patients – and particularly the hearts – don’t seem to be any worse in terms of allograft survival than the organs recovered from patients who died from other causes, which are the traditional sources, like blunt head trauma, gunshot wounds, or stroke, that lead to brain death. In general, these organs are useful and do quite well,” according to Dr. Desai, medical director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, Boston.
He highlighted several other recent developments in the field of cardiac transplantation that promise to further expand the donor heart pool, including acceptance of hepatitis C–infected donors and organ donation after circulatory rather than brain death. Dr. Desai also drew attention to the unintended perverse consequences of a recent redesign of the U.S. donor heart allocation system and discussed the impressive improvement in clinical outcomes with mechanical circulatory support. He noted that, while relatively few cardiologists practice in the highly specialized centers where heart transplants take place, virtually all cardiologists are affected by advances in heart transplantation since hundreds of thousands of the estimated 7 million Americans with heart failure have advanced disease.
Heart transplantation, he emphasized, is becoming increasingly complex. Recipients are on average older, sicker, and have more comorbidities than in times past. As a result, there is greater need for dual organ transplants: heart/lung, heart/liver, or heart/kidney. Plus, more patients come to transplantation after prior cardiac surgery for implantation of a ventricular assist device, so sensitization to blood products is a growing issue. And, of course, the pool of transplant candidates has expanded.
“We’re now forced to take patients previously considered to have contraindications to transplant; for example, diabetes was a contraindication to transplant in the early years, but now it’s the rule in 35%-40% of our patients who present with advanced heart failure,” the cardiologist noted.
Transplants from HCV-infected donors to uninfected recipients
Hearts and lungs from donors with hepatitis C viremia were traditionally deemed unsuitable for transplant. That’s all changed in the current era of highly effective direct-acting antiviral agents for the treatment of HCV infection.
In the DONATE HCV trial, Dr. Desai’s colleagues at Brigham and Women’s Hospital showed that giving HCV-uninfected recipients of hearts or lungs from HCV-viremic donors a shortened 4-week course of treatment with sofosbuvir-velpatasvir (Epclusa) beginning within a few hours after transplantation uniformly blocked viral replication. Six months after transplantation, none of the study participants had a detectable HCV viral load, and all had excellent graft function (N Engl J Med. 2019 Apr 25;380[17]:1606-17).
“This is effective prevention of HCV infection by aggressive upfront therapy,” Dr. Desai explained. “We can now take organs from HCV-viremic patients and use them in solid organ transplantation. This has led to a skyrocketing increase in donors with HCV infection, and those donations have helped us clear the waiting list.”
Donation after circulatory death
Australian transplant physicians have pioneered the use of donor hearts obtained after circulatory death in individuals with devastating neurologic injury who didn’t quite meet the criteria for brain death, which is the traditional prerequisite. In the new scenario, withdrawal of life-supporting therapy is followed by circulatory death, then the donor heart is procured and preserved via extracorporeal perfusion until transplantation.
The Australians report excellent outcomes, with rates of overall survival and rejection episodes similar to outcomes from brain-dead donors (J Am Coll Cardiol. 2019 Apr 2;73[12]:1447-59). The first U.S. heart transplant involving donation after circulatory death took place at Duke University in Durham, North Carolina. A multicenter U.S. clinical trial of this practice is underway.
If the results are positive and the practice of donation after circulatory death becomes widely implemented, the U.S. heart donor pool could increase by 30%.
Recent overhaul of donor heart allocation system may have backfired
The U.S. donor heart allocation system was redesigned in the fall of 2018 in an effort to reduce waiting times. One of the biggest changes involved breaking down the category with the highest urgency status into three new subcategories based upon sickness. Now, the highest-urgency category is for patients in cardiogenic shock who are supported by extracorporeal membrane oxygenation (ECMO) or other temporary mechanical circulatory support devices.
But an analysis of United Network for Organ Sharing (UNOS) data suggests this change has unintended adverse consequences for clinical outcomes.
Indeed, the investigators reported that the use of ECMO support is fourfold greater in the new system, the use of durable left ventricular assist devices (LVADs) as a bridge to transplant is down, and outcomes are worse. The 180-day rate of freedom from death or retransplantation was 77.9%, down significantly from 93.4% in the former system. In a multivariate analysis, patients transplanted in the new system had an adjusted 2.1-fold increased risk of death or retransplantation (J Heart Lung Transplant. 2020 Jan;39[1]:1-4).
“When you create a new listing system, you create new incentives, and people start to manage patients differently,” Dr. Desai observed. “Increasingly now, the path direct to transplant is through temporary mechanical circulatory support rather than durable mechanical circulatory support. Is that a good idea? We don’t know, but if you look at the best data, those on ECMO or percutaneous VADs have the worst outcomes. So the question of whether we should take the sickest of sick patients directly to transplant as a standard strategy has come under scrutiny.”
Improved durable LVAD technology brings impressive clinical outcomes
Results of the landmark MOMENTUM 3 randomized trial showed that 2-year clinical outcomes with the magnetically levitated centrifugal-flow HeartMate 3 LVAD now rival those of percutaneous mitral valve repair using the MitraClip device. Two-year all-cause mortality in the LVAD recipients was 22% versus 29.1% with the MitraClip in the COAPT trial and 34.9% in the MITRA-FR trial. The HeartMate 3 reduces the hemocompatibility issues that plagued earlier-generation durable LVADs, with resultant lower rates of pump thrombosis, stroke, and GI bleeding. Indeed, the outcomes in MOMENTUM 3 were so good – and so similar – with the HeartMate 3, regardless of whether the intended treatment goal was as a bridge to transplant or as lifelong destination therapy, that the investigators have recently proposed doing away with those distinctions.
“It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure,” according to the investigators (JAMA Cardiol. 2020 Jan 15. doi: 10.1001/jamacardio.2019.5323).
The next step forward in LVAD technology is already on the horizon: a fully implantable device that eliminates the transcutaneous drive-line for the power supply, which is prone to infection and diminishes overall quality of life. This investigational device utilizes wireless coplanar energy transfer, with a coil ring placed around the lung and fixed to the chest wall. The implanted battery provides more than 6 hours of power without a recharge (J Heart Lung Transplant. 2019 Apr;38[4]:339-43).
“The first LVAD patient has gone swimming in Kazakhstan,” according to Dr. Desai.
Myocardial recovery in LVAD recipients remains elusive
The initial hope for LVADs was that they would not only be able to serve as a bridge to transplantation or as lifetime therapy, but that the prolonged unloading of the ventricle would enable potent medical therapy to rescue myocardial function so that the device could eventually be explanted. That does happen, but only rarely. In a large registry study, myocardial recovery occurred in only about 1% of patients on mechanical circulatory support. Attempts to enhance the process by add-on stem cell therapy have thus far been ineffective.
“For the moment, recovery is still a hope, not a reality,” the cardiologist said.
He reported serving as a consultant to more than a dozen pharmaceutical or medical device companies and receiving research grants from Alnylam, AstraZeneca, Bayer Healthcare, MyoKardia, and Novartis.
bjancin@mdedge.com
SNOWMASS, COLO. – The tragic opioid epidemic has “one small bright spot”: an expanding pool of eligible donor hearts for transplantation, Akshay S. Desai, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
For decades, the annual volume of heart transplantations performed in the U.S. was static because of the huge mismatch between donor organ supply and demand. But heart transplant volume has increased steadily in the last few years – a result of the opioid epidemic.
Data from the U.S. Organ Procurement and Transplantation Network show that the proportion of donor hearts obtained from individuals who died from drug intoxication climbed from a mere 1.5% in 1999 to 17.6% in 2017, the most recent year for which data are available. Meanwhile, the size of the heart transplant waiting list, which rose year after year in 2009-2015, has since declined (N Engl J Med. 2019 Feb 7;380[6]:597-9).
“What’s amazing is that, even though these patients might have historically been considered high risk in general, the organs recovered from these patients – and particularly the hearts – don’t seem to be any worse in terms of allograft survival than the organs recovered from patients who died from other causes, which are the traditional sources, like blunt head trauma, gunshot wounds, or stroke, that lead to brain death. In general, these organs are useful and do quite well,” according to Dr. Desai, medical director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, Boston.
He highlighted several other recent developments in the field of cardiac transplantation that promise to further expand the donor heart pool, including acceptance of hepatitis C–infected donors and organ donation after circulatory rather than brain death. Dr. Desai also drew attention to the unintended perverse consequences of a recent redesign of the U.S. donor heart allocation system and discussed the impressive improvement in clinical outcomes with mechanical circulatory support. He noted that, while relatively few cardiologists practice in the highly specialized centers where heart transplants take place, virtually all cardiologists are affected by advances in heart transplantation since hundreds of thousands of the estimated 7 million Americans with heart failure have advanced disease.
Heart transplantation, he emphasized, is becoming increasingly complex. Recipients are on average older, sicker, and have more comorbidities than in times past. As a result, there is greater need for dual organ transplants: heart/lung, heart/liver, or heart/kidney. Plus, more patients come to transplantation after prior cardiac surgery for implantation of a ventricular assist device, so sensitization to blood products is a growing issue. And, of course, the pool of transplant candidates has expanded.
“We’re now forced to take patients previously considered to have contraindications to transplant; for example, diabetes was a contraindication to transplant in the early years, but now it’s the rule in 35%-40% of our patients who present with advanced heart failure,” the cardiologist noted.
Transplants from HCV-infected donors to uninfected recipients
Hearts and lungs from donors with hepatitis C viremia were traditionally deemed unsuitable for transplant. That’s all changed in the current era of highly effective direct-acting antiviral agents for the treatment of HCV infection.
In the DONATE HCV trial, Dr. Desai’s colleagues at Brigham and Women’s Hospital showed that giving HCV-uninfected recipients of hearts or lungs from HCV-viremic donors a shortened 4-week course of treatment with sofosbuvir-velpatasvir (Epclusa) beginning within a few hours after transplantation uniformly blocked viral replication. Six months after transplantation, none of the study participants had a detectable HCV viral load, and all had excellent graft function (N Engl J Med. 2019 Apr 25;380[17]:1606-17).
“This is effective prevention of HCV infection by aggressive upfront therapy,” Dr. Desai explained. “We can now take organs from HCV-viremic patients and use them in solid organ transplantation. This has led to a skyrocketing increase in donors with HCV infection, and those donations have helped us clear the waiting list.”
Donation after circulatory death
Australian transplant physicians have pioneered the use of donor hearts obtained after circulatory death in individuals with devastating neurologic injury who didn’t quite meet the criteria for brain death, which is the traditional prerequisite. In the new scenario, withdrawal of life-supporting therapy is followed by circulatory death, then the donor heart is procured and preserved via extracorporeal perfusion until transplantation.
The Australians report excellent outcomes, with rates of overall survival and rejection episodes similar to outcomes from brain-dead donors (J Am Coll Cardiol. 2019 Apr 2;73[12]:1447-59). The first U.S. heart transplant involving donation after circulatory death took place at Duke University in Durham, North Carolina. A multicenter U.S. clinical trial of this practice is underway.
If the results are positive and the practice of donation after circulatory death becomes widely implemented, the U.S. heart donor pool could increase by 30%.
Recent overhaul of donor heart allocation system may have backfired
The U.S. donor heart allocation system was redesigned in the fall of 2018 in an effort to reduce waiting times. One of the biggest changes involved breaking down the category with the highest urgency status into three new subcategories based upon sickness. Now, the highest-urgency category is for patients in cardiogenic shock who are supported by extracorporeal membrane oxygenation (ECMO) or other temporary mechanical circulatory support devices.
But an analysis of United Network for Organ Sharing (UNOS) data suggests this change has unintended adverse consequences for clinical outcomes.
Indeed, the investigators reported that the use of ECMO support is fourfold greater in the new system, the use of durable left ventricular assist devices (LVADs) as a bridge to transplant is down, and outcomes are worse. The 180-day rate of freedom from death or retransplantation was 77.9%, down significantly from 93.4% in the former system. In a multivariate analysis, patients transplanted in the new system had an adjusted 2.1-fold increased risk of death or retransplantation (J Heart Lung Transplant. 2020 Jan;39[1]:1-4).
“When you create a new listing system, you create new incentives, and people start to manage patients differently,” Dr. Desai observed. “Increasingly now, the path direct to transplant is through temporary mechanical circulatory support rather than durable mechanical circulatory support. Is that a good idea? We don’t know, but if you look at the best data, those on ECMO or percutaneous VADs have the worst outcomes. So the question of whether we should take the sickest of sick patients directly to transplant as a standard strategy has come under scrutiny.”
Improved durable LVAD technology brings impressive clinical outcomes
Results of the landmark MOMENTUM 3 randomized trial showed that 2-year clinical outcomes with the magnetically levitated centrifugal-flow HeartMate 3 LVAD now rival those of percutaneous mitral valve repair using the MitraClip device. Two-year all-cause mortality in the LVAD recipients was 22% versus 29.1% with the MitraClip in the COAPT trial and 34.9% in the MITRA-FR trial. The HeartMate 3 reduces the hemocompatibility issues that plagued earlier-generation durable LVADs, with resultant lower rates of pump thrombosis, stroke, and GI bleeding. Indeed, the outcomes in MOMENTUM 3 were so good – and so similar – with the HeartMate 3, regardless of whether the intended treatment goal was as a bridge to transplant or as lifelong destination therapy, that the investigators have recently proposed doing away with those distinctions.
“It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure,” according to the investigators (JAMA Cardiol. 2020 Jan 15. doi: 10.1001/jamacardio.2019.5323).
The next step forward in LVAD technology is already on the horizon: a fully implantable device that eliminates the transcutaneous drive-line for the power supply, which is prone to infection and diminishes overall quality of life. This investigational device utilizes wireless coplanar energy transfer, with a coil ring placed around the lung and fixed to the chest wall. The implanted battery provides more than 6 hours of power without a recharge (J Heart Lung Transplant. 2019 Apr;38[4]:339-43).
“The first LVAD patient has gone swimming in Kazakhstan,” according to Dr. Desai.
Myocardial recovery in LVAD recipients remains elusive
The initial hope for LVADs was that they would not only be able to serve as a bridge to transplantation or as lifetime therapy, but that the prolonged unloading of the ventricle would enable potent medical therapy to rescue myocardial function so that the device could eventually be explanted. That does happen, but only rarely. In a large registry study, myocardial recovery occurred in only about 1% of patients on mechanical circulatory support. Attempts to enhance the process by add-on stem cell therapy have thus far been ineffective.
“For the moment, recovery is still a hope, not a reality,” the cardiologist said.
He reported serving as a consultant to more than a dozen pharmaceutical or medical device companies and receiving research grants from Alnylam, AstraZeneca, Bayer Healthcare, MyoKardia, and Novartis.
bjancin@mdedge.com
SNOWMASS, COLO. – The tragic opioid epidemic has “one small bright spot”: an expanding pool of eligible donor hearts for transplantation, Akshay S. Desai, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
For decades, the annual volume of heart transplantations performed in the U.S. was static because of the huge mismatch between donor organ supply and demand. But heart transplant volume has increased steadily in the last few years – a result of the opioid epidemic.
Data from the U.S. Organ Procurement and Transplantation Network show that the proportion of donor hearts obtained from individuals who died from drug intoxication climbed from a mere 1.5% in 1999 to 17.6% in 2017, the most recent year for which data are available. Meanwhile, the size of the heart transplant waiting list, which rose year after year in 2009-2015, has since declined (N Engl J Med. 2019 Feb 7;380[6]:597-9).
“What’s amazing is that, even though these patients might have historically been considered high risk in general, the organs recovered from these patients – and particularly the hearts – don’t seem to be any worse in terms of allograft survival than the organs recovered from patients who died from other causes, which are the traditional sources, like blunt head trauma, gunshot wounds, or stroke, that lead to brain death. In general, these organs are useful and do quite well,” according to Dr. Desai, medical director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, Boston.
He highlighted several other recent developments in the field of cardiac transplantation that promise to further expand the donor heart pool, including acceptance of hepatitis C–infected donors and organ donation after circulatory rather than brain death. Dr. Desai also drew attention to the unintended perverse consequences of a recent redesign of the U.S. donor heart allocation system and discussed the impressive improvement in clinical outcomes with mechanical circulatory support. He noted that, while relatively few cardiologists practice in the highly specialized centers where heart transplants take place, virtually all cardiologists are affected by advances in heart transplantation since hundreds of thousands of the estimated 7 million Americans with heart failure have advanced disease.
Heart transplantation, he emphasized, is becoming increasingly complex. Recipients are on average older, sicker, and have more comorbidities than in times past. As a result, there is greater need for dual organ transplants: heart/lung, heart/liver, or heart/kidney. Plus, more patients come to transplantation after prior cardiac surgery for implantation of a ventricular assist device, so sensitization to blood products is a growing issue. And, of course, the pool of transplant candidates has expanded.
“We’re now forced to take patients previously considered to have contraindications to transplant; for example, diabetes was a contraindication to transplant in the early years, but now it’s the rule in 35%-40% of our patients who present with advanced heart failure,” the cardiologist noted.
Transplants from HCV-infected donors to uninfected recipients
Hearts and lungs from donors with hepatitis C viremia were traditionally deemed unsuitable for transplant. That’s all changed in the current era of highly effective direct-acting antiviral agents for the treatment of HCV infection.
In the DONATE HCV trial, Dr. Desai’s colleagues at Brigham and Women’s Hospital showed that giving HCV-uninfected recipients of hearts or lungs from HCV-viremic donors a shortened 4-week course of treatment with sofosbuvir-velpatasvir (Epclusa) beginning within a few hours after transplantation uniformly blocked viral replication. Six months after transplantation, none of the study participants had a detectable HCV viral load, and all had excellent graft function (N Engl J Med. 2019 Apr 25;380[17]:1606-17).
“This is effective prevention of HCV infection by aggressive upfront therapy,” Dr. Desai explained. “We can now take organs from HCV-viremic patients and use them in solid organ transplantation. This has led to a skyrocketing increase in donors with HCV infection, and those donations have helped us clear the waiting list.”
Donation after circulatory death
Australian transplant physicians have pioneered the use of donor hearts obtained after circulatory death in individuals with devastating neurologic injury who didn’t quite meet the criteria for brain death, which is the traditional prerequisite. In the new scenario, withdrawal of life-supporting therapy is followed by circulatory death, then the donor heart is procured and preserved via extracorporeal perfusion until transplantation.
The Australians report excellent outcomes, with rates of overall survival and rejection episodes similar to outcomes from brain-dead donors (J Am Coll Cardiol. 2019 Apr 2;73[12]:1447-59). The first U.S. heart transplant involving donation after circulatory death took place at Duke University in Durham, North Carolina. A multicenter U.S. clinical trial of this practice is underway.
If the results are positive and the practice of donation after circulatory death becomes widely implemented, the U.S. heart donor pool could increase by 30%.
Recent overhaul of donor heart allocation system may have backfired
The U.S. donor heart allocation system was redesigned in the fall of 2018 in an effort to reduce waiting times. One of the biggest changes involved breaking down the category with the highest urgency status into three new subcategories based upon sickness. Now, the highest-urgency category is for patients in cardiogenic shock who are supported by extracorporeal membrane oxygenation (ECMO) or other temporary mechanical circulatory support devices.
But an analysis of United Network for Organ Sharing (UNOS) data suggests this change has unintended adverse consequences for clinical outcomes.
Indeed, the investigators reported that the use of ECMO support is fourfold greater in the new system, the use of durable left ventricular assist devices (LVADs) as a bridge to transplant is down, and outcomes are worse. The 180-day rate of freedom from death or retransplantation was 77.9%, down significantly from 93.4% in the former system. In a multivariate analysis, patients transplanted in the new system had an adjusted 2.1-fold increased risk of death or retransplantation (J Heart Lung Transplant. 2020 Jan;39[1]:1-4).
“When you create a new listing system, you create new incentives, and people start to manage patients differently,” Dr. Desai observed. “Increasingly now, the path direct to transplant is through temporary mechanical circulatory support rather than durable mechanical circulatory support. Is that a good idea? We don’t know, but if you look at the best data, those on ECMO or percutaneous VADs have the worst outcomes. So the question of whether we should take the sickest of sick patients directly to transplant as a standard strategy has come under scrutiny.”
Improved durable LVAD technology brings impressive clinical outcomes
Results of the landmark MOMENTUM 3 randomized trial showed that 2-year clinical outcomes with the magnetically levitated centrifugal-flow HeartMate 3 LVAD now rival those of percutaneous mitral valve repair using the MitraClip device. Two-year all-cause mortality in the LVAD recipients was 22% versus 29.1% with the MitraClip in the COAPT trial and 34.9% in the MITRA-FR trial. The HeartMate 3 reduces the hemocompatibility issues that plagued earlier-generation durable LVADs, with resultant lower rates of pump thrombosis, stroke, and GI bleeding. Indeed, the outcomes in MOMENTUM 3 were so good – and so similar – with the HeartMate 3, regardless of whether the intended treatment goal was as a bridge to transplant or as lifelong destination therapy, that the investigators have recently proposed doing away with those distinctions.
“It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure,” according to the investigators (JAMA Cardiol. 2020 Jan 15. doi: 10.1001/jamacardio.2019.5323).
The next step forward in LVAD technology is already on the horizon: a fully implantable device that eliminates the transcutaneous drive-line for the power supply, which is prone to infection and diminishes overall quality of life. This investigational device utilizes wireless coplanar energy transfer, with a coil ring placed around the lung and fixed to the chest wall. The implanted battery provides more than 6 hours of power without a recharge (J Heart Lung Transplant. 2019 Apr;38[4]:339-43).
“The first LVAD patient has gone swimming in Kazakhstan,” according to Dr. Desai.
Myocardial recovery in LVAD recipients remains elusive
The initial hope for LVADs was that they would not only be able to serve as a bridge to transplantation or as lifetime therapy, but that the prolonged unloading of the ventricle would enable potent medical therapy to rescue myocardial function so that the device could eventually be explanted. That does happen, but only rarely. In a large registry study, myocardial recovery occurred in only about 1% of patients on mechanical circulatory support. Attempts to enhance the process by add-on stem cell therapy have thus far been ineffective.
“For the moment, recovery is still a hope, not a reality,” the cardiologist said.
He reported serving as a consultant to more than a dozen pharmaceutical or medical device companies and receiving research grants from Alnylam, AstraZeneca, Bayer Healthcare, MyoKardia, and Novartis.
bjancin@mdedge.com
EXPERT ANALYSIS FROM ACC SNOWMASS 2020
Vigilance safely keeps AFib patients off anticoagulants post ablation
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.
This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.
Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.
“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.
Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).
This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.
Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.
“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.
Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.
REPORTING FROM THE AF SYMPOSIUM 2020
Catheter cryoablation effective for persistent AFib in pivotal trial
NATIONAL HARBOR, MD. – , setting the stage for the device to become the first to receive U.S. labeling for catheter ablation in this atrial fibrillation population.
The Arctic Front Advance cryoballoon, used on 165 patients with persistent atrial fibrillation (AFib) enrolled in the trial, produced a 55% rate of treatment success, including freedom from recurrent AFib during 12 months of follow-up, and produced one prespecified serious adverse event in the primary safety endpoint.
Both results easily surpassed the prespecified performance goals set by negotiation with the FDA, Hugh Calkins, MD, said at the annual International AF Symposium. The trial design included no control group and instead assessed safety and efficacy against prespecified standards set by the regulatory agency.
The cryoballoon “showed excellent performance. I don’t see how this could possibly be turned down by the FDA,” said Dr. Calkins, professor of medicine and director of the cardiac arrhythmia service at Johns Hopkins Medicine in Baltimore.
Cardiac electrophysiologists have for years routinely performed catheter ablation procedures on patients with persistent AFib even though the devices, based on ablation by radiofrequency or by chilling, have been labeled for use only in treating patients with paroxysmal AFib. Although this off-label use has not resulted in any problems with health insurance coverage, Dr. Calkins said, it has kept manufacturers from marketing their ablation devices for use in persistent AFib patients.
If the reported data result in labeling for the tested cryoballoon for persistant AFib patients, “it will have a big impact,” he predicted. “People have used cryoballoons for ablating persistent AFib for years, but this would put more fuel in the fire, both the [very positive] safety and efficacy data, and getting an FDA label, which is worth a lot,” he said in an interview.
But Dr. Calkins stopped short of anticipating that the results would convince operators experienced and focused on performing radiofrequency ablation to switch to cryo devices for treating persistent AFib patients. “People are pretty stuck in their ways,” he noted, and reports are expected soon from pivotal trials that are now testing various radiofrequency devices, as well as other types of cryo devices, in persistent AFib patients, so the range of device options labeled for this population may soon grow even more.
The STOP Persistent AF trial ran at 25 sites in the United States, Canada, and Japan during March 2017-August 2019, and included 165 adults with symptomatic, persistent AFib who had not responded to at least one antiarrhythmic drug and had a history of AFib episodes lasting at least 7 days but with no episodes persisting for 6 months or longer. The study excluded patients with prior ablation or left atrial surgery, a recent cerebrovascular event, substantially reduced left ventricular function, or substantial left atrial enlargement.
The enrolled patients were an average 65 years of age and 70% were men. Patients had been diagnosed with paroxysmal AFib an average of 5 years before study entry and with persistent AFib a little over 6 months before entry. The most recent AFib episode of enrolled patients averaged about 60 days, on average they had been unsuccessfully treated with just over one antiarrhythmic drug, and on average they had previously undergone about two cardioversions, after which their arrhythmia recurred.
The primary efficacy endpoint – a 55% rate of acute procedural success plus freedom from AFib recurrence during the 9 months following a 90-day blanking period immediately after ablation plus no added or increased antiarrhythmic drugs – significantly exceeded the prespecified performance goal of a 40% rate, Dr. Calkins reported. The study used the standard measure of recurrence as any 30-second or longer AFib episode detected during a weekly ECG telemonitoring session or during 48-hour ambulatory ECG monitoring at 6- and 12-month follow-ups or during in-office 12-lead ECG assessment at 3-, 6-, and 12-month follow-up. Twelve-month follow-up occurred for 145 of the enrolled patients.
The only prespecified primary safety event was one episode of cardiac perforation, which occurred during a repeat procedure. This rate of one safety event among 165 patients (0.6%) fell well within the prespecified safety performance goal of no more than 13%. In addition to this perforation, five additional serious adverse events (3%) occurred that were attributable to the cryoballoon treatment, including two cases of vascular pseudoaneurysm, one puncture-site hematoma, one case of pericarditis, and one episode of atrial tachycardia. Four additional serious adverse events occurred that were attributable to the ablation procedure (one acute cardiac failure, one postprocedure ileus, one respiratory failure, and one urinary tract infection), for an overall serious event rate of 5%.
During follow-up, 13% of patients had a repeat ablation procedure, following an initial ablation limited to pulmonary-vein isolation (PVI). The overall rate of 1-year efficacy, including the relatively low rate of need for redo ablation, “are an impressive endorsement of a PVI-only strategy” for initial ablation, Dr. Calkins said. “I’m a strong believer in PVI only for the first ablation for both paroxysmal and persistent AFib.”
He also noted that the 30-second threshold for scoring recurrent arrhythmia episodes following the 90-day blanking period after ablation was a very conservative measure of treatment failure, but it continues to define recurrence in this and many other current AFib ablation studies because it is the historical criteria for measuring ablation success or failure. It is especially important to maintain this criteria in a study that relied on prespecified performance criteria rather than a control arm for judging efficacy, Dr. Calkins said.
The study also included three quality-of-life measures. Patient scores on the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire rose by an average of nearly 26 points from baseline to 12 months, a statistically significant and clinically meaningful increase. Scores on both the physical and mental domains of the Short Form-12 (SF-12) improved from baseline by an average of about five points on each subscale, also statistically significant and clinically meaningful changes. Patients also reported statistically significant and in some cases substantial reductions in the prevalence rates of each of five different AFib symptoms: dizziness, dyspnea, fatigue, palpitations, and rapid heartbeat.
The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.
NATIONAL HARBOR, MD. – , setting the stage for the device to become the first to receive U.S. labeling for catheter ablation in this atrial fibrillation population.
The Arctic Front Advance cryoballoon, used on 165 patients with persistent atrial fibrillation (AFib) enrolled in the trial, produced a 55% rate of treatment success, including freedom from recurrent AFib during 12 months of follow-up, and produced one prespecified serious adverse event in the primary safety endpoint.
Both results easily surpassed the prespecified performance goals set by negotiation with the FDA, Hugh Calkins, MD, said at the annual International AF Symposium. The trial design included no control group and instead assessed safety and efficacy against prespecified standards set by the regulatory agency.
The cryoballoon “showed excellent performance. I don’t see how this could possibly be turned down by the FDA,” said Dr. Calkins, professor of medicine and director of the cardiac arrhythmia service at Johns Hopkins Medicine in Baltimore.
Cardiac electrophysiologists have for years routinely performed catheter ablation procedures on patients with persistent AFib even though the devices, based on ablation by radiofrequency or by chilling, have been labeled for use only in treating patients with paroxysmal AFib. Although this off-label use has not resulted in any problems with health insurance coverage, Dr. Calkins said, it has kept manufacturers from marketing their ablation devices for use in persistent AFib patients.
If the reported data result in labeling for the tested cryoballoon for persistant AFib patients, “it will have a big impact,” he predicted. “People have used cryoballoons for ablating persistent AFib for years, but this would put more fuel in the fire, both the [very positive] safety and efficacy data, and getting an FDA label, which is worth a lot,” he said in an interview.
But Dr. Calkins stopped short of anticipating that the results would convince operators experienced and focused on performing radiofrequency ablation to switch to cryo devices for treating persistent AFib patients. “People are pretty stuck in their ways,” he noted, and reports are expected soon from pivotal trials that are now testing various radiofrequency devices, as well as other types of cryo devices, in persistent AFib patients, so the range of device options labeled for this population may soon grow even more.
The STOP Persistent AF trial ran at 25 sites in the United States, Canada, and Japan during March 2017-August 2019, and included 165 adults with symptomatic, persistent AFib who had not responded to at least one antiarrhythmic drug and had a history of AFib episodes lasting at least 7 days but with no episodes persisting for 6 months or longer. The study excluded patients with prior ablation or left atrial surgery, a recent cerebrovascular event, substantially reduced left ventricular function, or substantial left atrial enlargement.
The enrolled patients were an average 65 years of age and 70% were men. Patients had been diagnosed with paroxysmal AFib an average of 5 years before study entry and with persistent AFib a little over 6 months before entry. The most recent AFib episode of enrolled patients averaged about 60 days, on average they had been unsuccessfully treated with just over one antiarrhythmic drug, and on average they had previously undergone about two cardioversions, after which their arrhythmia recurred.
The primary efficacy endpoint – a 55% rate of acute procedural success plus freedom from AFib recurrence during the 9 months following a 90-day blanking period immediately after ablation plus no added or increased antiarrhythmic drugs – significantly exceeded the prespecified performance goal of a 40% rate, Dr. Calkins reported. The study used the standard measure of recurrence as any 30-second or longer AFib episode detected during a weekly ECG telemonitoring session or during 48-hour ambulatory ECG monitoring at 6- and 12-month follow-ups or during in-office 12-lead ECG assessment at 3-, 6-, and 12-month follow-up. Twelve-month follow-up occurred for 145 of the enrolled patients.
The only prespecified primary safety event was one episode of cardiac perforation, which occurred during a repeat procedure. This rate of one safety event among 165 patients (0.6%) fell well within the prespecified safety performance goal of no more than 13%. In addition to this perforation, five additional serious adverse events (3%) occurred that were attributable to the cryoballoon treatment, including two cases of vascular pseudoaneurysm, one puncture-site hematoma, one case of pericarditis, and one episode of atrial tachycardia. Four additional serious adverse events occurred that were attributable to the ablation procedure (one acute cardiac failure, one postprocedure ileus, one respiratory failure, and one urinary tract infection), for an overall serious event rate of 5%.
During follow-up, 13% of patients had a repeat ablation procedure, following an initial ablation limited to pulmonary-vein isolation (PVI). The overall rate of 1-year efficacy, including the relatively low rate of need for redo ablation, “are an impressive endorsement of a PVI-only strategy” for initial ablation, Dr. Calkins said. “I’m a strong believer in PVI only for the first ablation for both paroxysmal and persistent AFib.”
He also noted that the 30-second threshold for scoring recurrent arrhythmia episodes following the 90-day blanking period after ablation was a very conservative measure of treatment failure, but it continues to define recurrence in this and many other current AFib ablation studies because it is the historical criteria for measuring ablation success or failure. It is especially important to maintain this criteria in a study that relied on prespecified performance criteria rather than a control arm for judging efficacy, Dr. Calkins said.
The study also included three quality-of-life measures. Patient scores on the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire rose by an average of nearly 26 points from baseline to 12 months, a statistically significant and clinically meaningful increase. Scores on both the physical and mental domains of the Short Form-12 (SF-12) improved from baseline by an average of about five points on each subscale, also statistically significant and clinically meaningful changes. Patients also reported statistically significant and in some cases substantial reductions in the prevalence rates of each of five different AFib symptoms: dizziness, dyspnea, fatigue, palpitations, and rapid heartbeat.
The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.
NATIONAL HARBOR, MD. – , setting the stage for the device to become the first to receive U.S. labeling for catheter ablation in this atrial fibrillation population.
The Arctic Front Advance cryoballoon, used on 165 patients with persistent atrial fibrillation (AFib) enrolled in the trial, produced a 55% rate of treatment success, including freedom from recurrent AFib during 12 months of follow-up, and produced one prespecified serious adverse event in the primary safety endpoint.
Both results easily surpassed the prespecified performance goals set by negotiation with the FDA, Hugh Calkins, MD, said at the annual International AF Symposium. The trial design included no control group and instead assessed safety and efficacy against prespecified standards set by the regulatory agency.
The cryoballoon “showed excellent performance. I don’t see how this could possibly be turned down by the FDA,” said Dr. Calkins, professor of medicine and director of the cardiac arrhythmia service at Johns Hopkins Medicine in Baltimore.
Cardiac electrophysiologists have for years routinely performed catheter ablation procedures on patients with persistent AFib even though the devices, based on ablation by radiofrequency or by chilling, have been labeled for use only in treating patients with paroxysmal AFib. Although this off-label use has not resulted in any problems with health insurance coverage, Dr. Calkins said, it has kept manufacturers from marketing their ablation devices for use in persistent AFib patients.
If the reported data result in labeling for the tested cryoballoon for persistant AFib patients, “it will have a big impact,” he predicted. “People have used cryoballoons for ablating persistent AFib for years, but this would put more fuel in the fire, both the [very positive] safety and efficacy data, and getting an FDA label, which is worth a lot,” he said in an interview.
But Dr. Calkins stopped short of anticipating that the results would convince operators experienced and focused on performing radiofrequency ablation to switch to cryo devices for treating persistent AFib patients. “People are pretty stuck in their ways,” he noted, and reports are expected soon from pivotal trials that are now testing various radiofrequency devices, as well as other types of cryo devices, in persistent AFib patients, so the range of device options labeled for this population may soon grow even more.
The STOP Persistent AF trial ran at 25 sites in the United States, Canada, and Japan during March 2017-August 2019, and included 165 adults with symptomatic, persistent AFib who had not responded to at least one antiarrhythmic drug and had a history of AFib episodes lasting at least 7 days but with no episodes persisting for 6 months or longer. The study excluded patients with prior ablation or left atrial surgery, a recent cerebrovascular event, substantially reduced left ventricular function, or substantial left atrial enlargement.
The enrolled patients were an average 65 years of age and 70% were men. Patients had been diagnosed with paroxysmal AFib an average of 5 years before study entry and with persistent AFib a little over 6 months before entry. The most recent AFib episode of enrolled patients averaged about 60 days, on average they had been unsuccessfully treated with just over one antiarrhythmic drug, and on average they had previously undergone about two cardioversions, after which their arrhythmia recurred.
The primary efficacy endpoint – a 55% rate of acute procedural success plus freedom from AFib recurrence during the 9 months following a 90-day blanking period immediately after ablation plus no added or increased antiarrhythmic drugs – significantly exceeded the prespecified performance goal of a 40% rate, Dr. Calkins reported. The study used the standard measure of recurrence as any 30-second or longer AFib episode detected during a weekly ECG telemonitoring session or during 48-hour ambulatory ECG monitoring at 6- and 12-month follow-ups or during in-office 12-lead ECG assessment at 3-, 6-, and 12-month follow-up. Twelve-month follow-up occurred for 145 of the enrolled patients.
The only prespecified primary safety event was one episode of cardiac perforation, which occurred during a repeat procedure. This rate of one safety event among 165 patients (0.6%) fell well within the prespecified safety performance goal of no more than 13%. In addition to this perforation, five additional serious adverse events (3%) occurred that were attributable to the cryoballoon treatment, including two cases of vascular pseudoaneurysm, one puncture-site hematoma, one case of pericarditis, and one episode of atrial tachycardia. Four additional serious adverse events occurred that were attributable to the ablation procedure (one acute cardiac failure, one postprocedure ileus, one respiratory failure, and one urinary tract infection), for an overall serious event rate of 5%.
During follow-up, 13% of patients had a repeat ablation procedure, following an initial ablation limited to pulmonary-vein isolation (PVI). The overall rate of 1-year efficacy, including the relatively low rate of need for redo ablation, “are an impressive endorsement of a PVI-only strategy” for initial ablation, Dr. Calkins said. “I’m a strong believer in PVI only for the first ablation for both paroxysmal and persistent AFib.”
He also noted that the 30-second threshold for scoring recurrent arrhythmia episodes following the 90-day blanking period after ablation was a very conservative measure of treatment failure, but it continues to define recurrence in this and many other current AFib ablation studies because it is the historical criteria for measuring ablation success or failure. It is especially important to maintain this criteria in a study that relied on prespecified performance criteria rather than a control arm for judging efficacy, Dr. Calkins said.
The study also included three quality-of-life measures. Patient scores on the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire rose by an average of nearly 26 points from baseline to 12 months, a statistically significant and clinically meaningful increase. Scores on both the physical and mental domains of the Short Form-12 (SF-12) improved from baseline by an average of about five points on each subscale, also statistically significant and clinically meaningful changes. Patients also reported statistically significant and in some cases substantial reductions in the prevalence rates of each of five different AFib symptoms: dizziness, dyspnea, fatigue, palpitations, and rapid heartbeat.
The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.
REPORTING FROM THE AF SYMPOSIUM 2020
Key clinical point: Catheter ablation using a cryoballoon was safe and effective for patients with persistent atrial fibrillation in a pivotal trial.
Major finding: The rate of freedom from treatment failure after 12 months was 55%, significantly exceeding the prespecified performance goal of 40%.
Study details: A multicenter, international study with 165 enrolled patients.
Disclosures: The study was funded by Medtronic, the company that markets the tested cryoballoon (Arctic Front Advance). Dr. Calkins has been a consultant to and has received honoraria from Medtronic, as well as from Abbott, AtriCure, Boehringer Ingelheim, Boston Scientific, and Johnson & Johnson.