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Evidence builds for AFib ablation’s efficacy in heart failure
Roughly a third of patients with heart failure also have atrial fibrillation, a comorbid combination notorious for working synergistically to worsen a patient’s quality of life and life expectancy.
During the past year, radiofrequency catheter ablation of atrial fibrillation in patients with both conditions has gathered steam as a way to intervene in at least selected patients, driven by study results that featured attention-grabbing reductions in death and cardiovascular hospitalizations.
The evidence favoring catheter ablation of atrial fibrillation (AFib) in patients with heart failure, particularly patients with heart failure with reduced ejection fraction (HFrEF), ramped up in 2019, spurred largely by a subgroup analysis from the CABANA trial, the largest randomized comparison by far of AFib ablation with antiarrhythmic drug treatment with 2,204 patients.
The past few months also featured release of two meta-analyses that took the CABANA results into account plus findings from about a dozen earlier randomized studies. Both meta-analyses, as well as the heart failure analysis from CABANA, all point in one direction, as stated in the conclusion of one of the meta-analyses: “In patients with AFib, catheter ablation is associated with all-cause mortality benefit, compared with medical therapy, that is driven by patients with AFib and HFrEF. Catheter ablation is safe and reduces cardiovascular hospitalizations and recurrences of atrial arrhythmias” both in patients with paroxysmal and persistent AFib,” wrote Stavros Stavrakis, MD, and his associates in their systematic review of 18 randomized, controlled trials of catheter ablation of AFib in a total of 4,464 patients with or without heart failure (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: e007414).
Despite these new data and analyses, clinicians seem to have very mixed reactions. Some call for an upgraded recommendation by professional societies that would support more aggressive use of AFib ablation in heart failure patients, and the anecdotal impressions of people who manage these patients are that ablation procedures have recently increased. But others advise caution, and note that in their opinion the efficacy data remain preliminary; the procedure has safety, logistical, and economic concerns; and questions remain about the ability of all active ablation programs to consistently deliver the results seen in published trials.
The meta-analysis led by Dr. Stavrakis showed that catheter ablation of AFib cut all-cause mortality during follow-up by a statistically significant 31%, compared with medical therapy, in all patients regardless of their heart failure status. But in patients with HFrEF, the reduction was 48%, along with a 38% cut in cardiovascular hospitalizations. In contrast, patients without heart failure who underwent AFib ablation showed no significant change in their all-cause mortality, compared with medical management of these patients.
“Based both on our meta-analysis and the CABANA data, patients with AFib most likely to benefit from ablation are patients younger than 65 and those with heart failure,” summed up Dr. Stavrakis, a cardiac electrophysiologist at the Heart Rhythm Institute of the University of Oklahoma in Oklahoma City.
The second meta-analysis, which initially appeared in July, analyzed data from 11 randomized trials of catheter ablations compared with anti-arrhythmic medical therapy for rate or rhythm control with in a total of 3,598 patients who all had heart failure, again including the patients enrolled in the CABANA study. The results showed a significant 49% relative drop in all cause mortality with ablation compared with medical treatment, and a statistically significant 56% cut in hospitalizations, as well as a significant, nearly 7% average, absolute improvement in left ventricular ejection fraction, plus benefits for preventing arrhythmia recurrence and improving quality of life (Eur Heart J. 2019 Jul 11. doi: 10.1093/eurheartj/ehz443).
“The magnitude of the effect seen in the meta-analysis, a 49% reduction in total mortality and a 56% reduction in hospitalizations, is rather staggering, and is larger than typically quoted for other medical interventions or device therapy in heart failure. The treatment effect was uniform among studies, and entirely compatible with the changes in left ventricular function, exercise capacity, and heart failure symptoms. Therefore, although more data are desirable, there are already arguably sufficient data to understand a great deal regarding the impact of a fib ablation,” commented Ross J. Hunter, MRCP, a cardiac electrophysiologist at Barts Heart Centre in London, and his associates in an editorial about this meta-analysis (Eur Heart J. 2019 Oct 22. doi: 10.1093/eurheartj/ehz704).
The heart failure analysis of CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) itself also showed striking findings when first reported at the annual scientific sessions of the Heart Rhythm Society last May. In presentations he made at this meeting, Douglas L. Packer, MD, CABANA’s lead investigator, reported details of a prespecified subgroup analysis of the 778 patients enrolled in CABANA who had heart failure at baseline, slightly more than a third of the total study enrollment. This was more than double the number of patients identified as specifically having heart failure at entry in the initial publication of CABANA’s findings (JAMA. 2019 Mar 15;321[134]:1261-74). Comparison of the 378 patients with heart failure and randomized to undergo ablation with the 400 with heart failure randomized to medical treatment showed a 36% reduction in the study’s primary, composite endpoint relative to the control group in an intention-to-treat analysis, and a 43% relative cut in all-cause mortality during follow-up, Dr. Packer reported at the May meeting. (As of early November 2019, these results had not yet appeared in a published article.) In contrast, in the 1,422 CABANA patients randomized who did not have heart failure, ablation produced results for these endpoints that were similar to and not statistically different from the outcomes in patients treated medically, said Dr. Packer, a cardiac electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn.
The CABANA results added to what had been previously reported from two other landmark studies that documented incremental efficacy of AFib ablation compared with medical treatment in patients with heart failure: The AATAC (Ablation vs Amiodarone for Treatment of AFib in Patients With Congestive HF and an Implanted Device) study, which randomized 203 patients (Circulation. 2016 Apr 26;133[17]:1637-44), and CASTLE-AF (Catheter Ablation vs. Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) trial, which randomized 363 patients (N Engl J Med. 2018 Feb 1;378[5]:417-27). These three studies contributed the most patients and outcomes to the two recent meta-analyses.
“The CASTLE-AF and AATAC trials both showed improved cardiovascular outcomes with ablation in patients with heart failure and AFib. The meta-analysis [by Dr. Stavrakis and his associates] and CABANA subgroup analysis further support use of catheter ablation to improve the outcomes in these patients,” noted Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator.
“The CABANA trial was very important because it confirmed the safety of catheter ablation, and more importantly suggested that patients with heart failure may benefit the most [from AFib ablation]. The evidence is very strong to advocate ablation as first-line therapy for selected patients with heart failure. Perhaps the optimal patients are those with [New York Heart Association] class I-III or ambulatory class IV heart failure who are on optimized, guideline-directed medical therapy. We have enough data to make this a class I recommendation. The question that remains is whether this is a cost effective strategy. Because it lowers rehospitalization and death, I suspect it is,” said Luigi Di Biase, MD, lead investigator of AATAC, and director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine, both in New York.
Opinions differ on AFib ablation’s role
Despite this expansive assessment of the current status of AFib ablation for patients with heart failure from Dr. Di Biase and shared by others, another camp of cardiologists currently sees ablation as having more limited current utility, as recommended earlier this year by a guideline-update panel representing the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. The guideline update included this new recommendation for how to use AFib ablation in heart failure patients: “AF catheter ablation may be reasonable in selected patients with symptomatic AFib and heart failure with reduced left ventricular ejection fraction to potentially lower mortality rate and reduce hospitalization for heart failure,” a class IIb recommendation. (J Am Coll Cardiol. 2019 Jul 9;74[1]:104-32). The guideline’s text cited the findings from AATAC and CASTLE-AF, but qualified both studies as “relatively small” and with “highly selected patient populations.” The guideline also incorporated the CABANA results into its considerations (although they may not have had the full analysis in heart failure patients available during their deliberations), but cited the study’s main limitation: CABANA failed to show a statistically significant difference in the primary endpoint in its primary, intention-to-treat analysis, which meant that by the strict statistical criteria that trialists apply to study findings, all other endpoints analyzed using CABANA’s are merely “hypothesis generating” and not definitive.
Questions about the extent of patient selection required to see a clear clinical-endpoint benefit from AFib ablation in heart failure patients, as well as the flawed validity of the CABANA results for making unqualified practice recommendation are the main arguments advanced by experts who caution against broader and more routine ablations.
“The findings from the heart failure subgroup of CABANA are hypothesis generating rather than definitive. Even with the recent meta-analysis, uncertainty remains regarding the ability of catheter ablation to improve outcomes beyond reducing AFib-related symptoms,” commented Gregg Fonarow, MD, a heart failure physician and professor of medicine at the University of California, Los Angeles.
“CASTLE-HF had fewer than 100 deaths combined in both arms, which means very unstable results. We don’t know a lot of detail about the heart failure patients in CABANA, and overall we do not have much data from patients with heart failure with preserved ejection fraction [HFpEF],” said Javed Butler, MD, a heart failure physician and professor and chairman of medicine at the University of Mississippi in Jackson. Dr. Butler also voiced his concerns (shared by other heart failure specialists) about the safety of ablation in heart failure patients, noting that “many patients require multiple ablations; many burns result in scarring and can worsen atrial function. In short, ablation of AFib is probably good for selected patients, but to have a class 1 recommendation, we need much larger trials with well-phenotyped heart failure patients,” Dr. Butler said in an interview.
“The totality of data still captures a relatively small number of patients. CASTLE-HF took 8 years to enroll fewer than 400 patients, and the results showed some heterogeneity. Study patients were a decade younger than average HFrEF patients in the community, and thus the effectiveness and safety of catheter ablation in people with more comorbidity and frailty remains in question. Certain HFrEF patients may be less likely to benefit, such as those with amyloid cardiomyopathy. And with the increasing availability of other treatments for HFrEF such as sacubitril/valsartan, dapagliflozin, and MitraClip, it is less clear how catheter ablation would [benefit patients] on top of what is now current best therapy,” said Larry Allen, MD, a heart failure physician and professor of medicine at the University of Colorado in Aurora.
“With these limitations and the fact that catheter ablation is not a simple procedure, a large randomized, controlled trial of ablation, compared with no ablation, in a wide range of HFrEF patients on contemporary therapy would be welcome,” Dr. Allen said. “Given the prevalence of heart failure and AFib and the potential positive and negative implications of catheter ablation running such a trial seems critical for patients and for society.”
“For ablation of AFib in heart failure to become a class I recommendation there will need to be results from larger randomized studies,” summed up Dr. Stavrakis. The meta-analysis that he coauthored noted that “the benefits of catheter ablation for AFib in HFrEF patients have been consistently shown for over a decade now; however, the uptake of this procedure by clinicians in practice has been slow.”
Despite this history of reticence and ongoing caution about ablation, some cardiology experts see the indications for AFib ablation in heart failure steadily creeping forward, buoyed by a safety record that has more benign than ablation’s reputation suggests.
The CABANA results showed that “ablation is remarkably safe in the hands of experienced clinicians, with risks comparable to anti-arrhythmic drugs,” said Peter R. Kowey, MD, a specialist in treating AFib and professor of medicine at Thomas Jefferson University in Philadelphia, who made this assessment during a talk at an AFib meeting in early 2019. Dr. Kowey’s take on what the CABANA safety data showed contrasts with the impression of other cardiologists who are wary of perceived dangers from ablation.
“Ablation comes with a lot of morbidity and mortality. It’s not that the idea of ablation is wrong, but the ability to do it without a lot of adverse effects. ... We’re not quite there yet,” said Douglas L. Mann, MD, a heart failure physician and professor of medicine and chief of the cardiovascular division at Washington University in St. Louis.
“If I had a patient with HFrEF and AFib who was really sick, I’m not so sure I’d send them for ablation, which is not a simple procedure. The patients we tend to send for ablation are selected. Ablation is a big undertaking in patients who are already sick, and it’s expensive. I don’t think the data we have now will change the consensus view, but every heart failure physician is sending some patients for AFib ablation. People are turning to AFib ablation earlier than before. I think the consensus is that ablation is for symptoms or poor rate control, not for better outcomes,” said Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
However, this caution about safety and skepticism over efficacy may be dissipating as experience with ablation accumulates.
“CASTLE-AF and other data, including evidence for the apparent isolation of beta-blocker benefit to patients in sinus rhythm, have made me much more proactive about considering catheter ablation in my HFrEF patients. I think many other cardiologists have a similar view,” said Dr. Allen in an interview.
“A lot [of heart failure] patients are [being] referred for ablation, depending on the practice, setting, the local availability of electrophysiologists, and patient interest in ablation,” said Dr. Butler.
“We have no absolutely compelling data, but the data we have all point in the same direction. Like most, I am becoming convinced that AFib ablation in heart failure patients is a very valuable method for managing patients, but I can’t point to one study that was conclusive. Results from lots of studies show that it is likely, and when you add them all together it looks indisputable,” commented A. John Camm, MD, an atrial fibrillation specialist and professor of clinical cardiology at St. George’s University in London. “The findings put a responsibility on cardiologists to assess patients with heart failure for AFib. But there are nothing like enough resources to deal with all the patients who have heart failure who also have AFib.”
A rough estimate of just the U.S. volume of patients with heart failure and AFib is likely in the ball park of 2 million people (a third of the estimated 6 million American currently living with heart failure), and with the prevalence of each of these disorders rising precipitously (more than 5 million Americans have AFib) the confluence of the two should also show a steady increase. “It will take a major change in our concept of heart failure management to really address this. Potentially it would mean a large increase in the number of RF ablations of AFib, but the resources for that are not now present,” Dr. Camm said in an interview.
The attractions of catheter ablation also stand in contrast to the limitations of alternative treatments. Ablation is effective in a majority of patients for reducing AFib burden, both the frequency and duration of AFib episodes, and safety issues are mostly limited to the procedural and immediate postprocedural periods. The drugs available for trying to control AFib are beta-blockers, which provide rate control and can help prevent AFib onset, and rhythm-controlling anti-arrhythmic drugs like amiodarone, which have substantial limitations in both their ability to prevent arrhythmia recurrences as well as for safety.
“Most of the conventional antiarrhythmic drugs are contraindicated, frequently ineffective, or not well tolerated in patients with HFrEF. Catheter ablation of AFib provides an increasingly important option for rhythm control in these patients without using antiarrhythmic drugs,” Dr. Di Biase and his associates wrote in a recent review of AFib ablation in heart failure patients (Eur Heart J. 2019 Feb 21;40[8]:663-71).
“The guidelines that are controversial still make amiodarone a class I drug even though it’s been associated with serious side effects and has been shown in several heart failure trials to increase mortality. I can’t believe that ablation is a class IIb recommendation while a drug like amiodarone is a class I recommendation,” Dr. Di Biase said.
And although beta-blockers are a mainstay of heart failure treatment, once AFib becomes established they are less useful for maintaining sinus rhythm. “Beta-blockers provide effective rate control, but they can’t convert patients to sinus rhythm [once AFib begins], and there is no convincing evidence that patients on beta-blockers stay in sinus rhythm longer. You can’t just say: the patient is on a beta-blocker so I’ve done my best,” noted Dr. Jessup.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Stavrakis, Dr, Jessup, and Dr. Di Biase. Dr. Hunter has received research funding, educational grants, and speakers fees from Biosense Webster and Medtronic. Dr. Packer had received honoraria from Biotronik and MediaSphere Medical and research support from several companies. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis, he has received research funding from Abbott, ARCA biopharma, Boston Scientific, Gilead, and Johnson & Johnson, and he had a financial relationship with GlaxoSmithKline. Dr. Fonarow has been a consultant to Abbott, Amgen, Bayer, Janssen, and Novartis. Dr. Butler has been a consultant to several companies. Dr. Allen has been a consultant to Boston Scientific, Janssen, and Novartis. Dr. Kowey has been a consultant to several companies. Dr. Mann has been a consultant to Bristol-Myers Squibb, Corvia, and Novartis, and an adviser to miRagen. Dr. Camm has been a consultant to several companies.
This is part one of a two-part article.
Roughly a third of patients with heart failure also have atrial fibrillation, a comorbid combination notorious for working synergistically to worsen a patient’s quality of life and life expectancy.
During the past year, radiofrequency catheter ablation of atrial fibrillation in patients with both conditions has gathered steam as a way to intervene in at least selected patients, driven by study results that featured attention-grabbing reductions in death and cardiovascular hospitalizations.
The evidence favoring catheter ablation of atrial fibrillation (AFib) in patients with heart failure, particularly patients with heart failure with reduced ejection fraction (HFrEF), ramped up in 2019, spurred largely by a subgroup analysis from the CABANA trial, the largest randomized comparison by far of AFib ablation with antiarrhythmic drug treatment with 2,204 patients.
The past few months also featured release of two meta-analyses that took the CABANA results into account plus findings from about a dozen earlier randomized studies. Both meta-analyses, as well as the heart failure analysis from CABANA, all point in one direction, as stated in the conclusion of one of the meta-analyses: “In patients with AFib, catheter ablation is associated with all-cause mortality benefit, compared with medical therapy, that is driven by patients with AFib and HFrEF. Catheter ablation is safe and reduces cardiovascular hospitalizations and recurrences of atrial arrhythmias” both in patients with paroxysmal and persistent AFib,” wrote Stavros Stavrakis, MD, and his associates in their systematic review of 18 randomized, controlled trials of catheter ablation of AFib in a total of 4,464 patients with or without heart failure (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: e007414).
Despite these new data and analyses, clinicians seem to have very mixed reactions. Some call for an upgraded recommendation by professional societies that would support more aggressive use of AFib ablation in heart failure patients, and the anecdotal impressions of people who manage these patients are that ablation procedures have recently increased. But others advise caution, and note that in their opinion the efficacy data remain preliminary; the procedure has safety, logistical, and economic concerns; and questions remain about the ability of all active ablation programs to consistently deliver the results seen in published trials.
The meta-analysis led by Dr. Stavrakis showed that catheter ablation of AFib cut all-cause mortality during follow-up by a statistically significant 31%, compared with medical therapy, in all patients regardless of their heart failure status. But in patients with HFrEF, the reduction was 48%, along with a 38% cut in cardiovascular hospitalizations. In contrast, patients without heart failure who underwent AFib ablation showed no significant change in their all-cause mortality, compared with medical management of these patients.
“Based both on our meta-analysis and the CABANA data, patients with AFib most likely to benefit from ablation are patients younger than 65 and those with heart failure,” summed up Dr. Stavrakis, a cardiac electrophysiologist at the Heart Rhythm Institute of the University of Oklahoma in Oklahoma City.
The second meta-analysis, which initially appeared in July, analyzed data from 11 randomized trials of catheter ablations compared with anti-arrhythmic medical therapy for rate or rhythm control with in a total of 3,598 patients who all had heart failure, again including the patients enrolled in the CABANA study. The results showed a significant 49% relative drop in all cause mortality with ablation compared with medical treatment, and a statistically significant 56% cut in hospitalizations, as well as a significant, nearly 7% average, absolute improvement in left ventricular ejection fraction, plus benefits for preventing arrhythmia recurrence and improving quality of life (Eur Heart J. 2019 Jul 11. doi: 10.1093/eurheartj/ehz443).
“The magnitude of the effect seen in the meta-analysis, a 49% reduction in total mortality and a 56% reduction in hospitalizations, is rather staggering, and is larger than typically quoted for other medical interventions or device therapy in heart failure. The treatment effect was uniform among studies, and entirely compatible with the changes in left ventricular function, exercise capacity, and heart failure symptoms. Therefore, although more data are desirable, there are already arguably sufficient data to understand a great deal regarding the impact of a fib ablation,” commented Ross J. Hunter, MRCP, a cardiac electrophysiologist at Barts Heart Centre in London, and his associates in an editorial about this meta-analysis (Eur Heart J. 2019 Oct 22. doi: 10.1093/eurheartj/ehz704).
The heart failure analysis of CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) itself also showed striking findings when first reported at the annual scientific sessions of the Heart Rhythm Society last May. In presentations he made at this meeting, Douglas L. Packer, MD, CABANA’s lead investigator, reported details of a prespecified subgroup analysis of the 778 patients enrolled in CABANA who had heart failure at baseline, slightly more than a third of the total study enrollment. This was more than double the number of patients identified as specifically having heart failure at entry in the initial publication of CABANA’s findings (JAMA. 2019 Mar 15;321[134]:1261-74). Comparison of the 378 patients with heart failure and randomized to undergo ablation with the 400 with heart failure randomized to medical treatment showed a 36% reduction in the study’s primary, composite endpoint relative to the control group in an intention-to-treat analysis, and a 43% relative cut in all-cause mortality during follow-up, Dr. Packer reported at the May meeting. (As of early November 2019, these results had not yet appeared in a published article.) In contrast, in the 1,422 CABANA patients randomized who did not have heart failure, ablation produced results for these endpoints that were similar to and not statistically different from the outcomes in patients treated medically, said Dr. Packer, a cardiac electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn.
The CABANA results added to what had been previously reported from two other landmark studies that documented incremental efficacy of AFib ablation compared with medical treatment in patients with heart failure: The AATAC (Ablation vs Amiodarone for Treatment of AFib in Patients With Congestive HF and an Implanted Device) study, which randomized 203 patients (Circulation. 2016 Apr 26;133[17]:1637-44), and CASTLE-AF (Catheter Ablation vs. Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) trial, which randomized 363 patients (N Engl J Med. 2018 Feb 1;378[5]:417-27). These three studies contributed the most patients and outcomes to the two recent meta-analyses.
“The CASTLE-AF and AATAC trials both showed improved cardiovascular outcomes with ablation in patients with heart failure and AFib. The meta-analysis [by Dr. Stavrakis and his associates] and CABANA subgroup analysis further support use of catheter ablation to improve the outcomes in these patients,” noted Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator.
“The CABANA trial was very important because it confirmed the safety of catheter ablation, and more importantly suggested that patients with heart failure may benefit the most [from AFib ablation]. The evidence is very strong to advocate ablation as first-line therapy for selected patients with heart failure. Perhaps the optimal patients are those with [New York Heart Association] class I-III or ambulatory class IV heart failure who are on optimized, guideline-directed medical therapy. We have enough data to make this a class I recommendation. The question that remains is whether this is a cost effective strategy. Because it lowers rehospitalization and death, I suspect it is,” said Luigi Di Biase, MD, lead investigator of AATAC, and director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine, both in New York.
Opinions differ on AFib ablation’s role
Despite this expansive assessment of the current status of AFib ablation for patients with heart failure from Dr. Di Biase and shared by others, another camp of cardiologists currently sees ablation as having more limited current utility, as recommended earlier this year by a guideline-update panel representing the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. The guideline update included this new recommendation for how to use AFib ablation in heart failure patients: “AF catheter ablation may be reasonable in selected patients with symptomatic AFib and heart failure with reduced left ventricular ejection fraction to potentially lower mortality rate and reduce hospitalization for heart failure,” a class IIb recommendation. (J Am Coll Cardiol. 2019 Jul 9;74[1]:104-32). The guideline’s text cited the findings from AATAC and CASTLE-AF, but qualified both studies as “relatively small” and with “highly selected patient populations.” The guideline also incorporated the CABANA results into its considerations (although they may not have had the full analysis in heart failure patients available during their deliberations), but cited the study’s main limitation: CABANA failed to show a statistically significant difference in the primary endpoint in its primary, intention-to-treat analysis, which meant that by the strict statistical criteria that trialists apply to study findings, all other endpoints analyzed using CABANA’s are merely “hypothesis generating” and not definitive.
Questions about the extent of patient selection required to see a clear clinical-endpoint benefit from AFib ablation in heart failure patients, as well as the flawed validity of the CABANA results for making unqualified practice recommendation are the main arguments advanced by experts who caution against broader and more routine ablations.
“The findings from the heart failure subgroup of CABANA are hypothesis generating rather than definitive. Even with the recent meta-analysis, uncertainty remains regarding the ability of catheter ablation to improve outcomes beyond reducing AFib-related symptoms,” commented Gregg Fonarow, MD, a heart failure physician and professor of medicine at the University of California, Los Angeles.
“CASTLE-HF had fewer than 100 deaths combined in both arms, which means very unstable results. We don’t know a lot of detail about the heart failure patients in CABANA, and overall we do not have much data from patients with heart failure with preserved ejection fraction [HFpEF],” said Javed Butler, MD, a heart failure physician and professor and chairman of medicine at the University of Mississippi in Jackson. Dr. Butler also voiced his concerns (shared by other heart failure specialists) about the safety of ablation in heart failure patients, noting that “many patients require multiple ablations; many burns result in scarring and can worsen atrial function. In short, ablation of AFib is probably good for selected patients, but to have a class 1 recommendation, we need much larger trials with well-phenotyped heart failure patients,” Dr. Butler said in an interview.
“The totality of data still captures a relatively small number of patients. CASTLE-HF took 8 years to enroll fewer than 400 patients, and the results showed some heterogeneity. Study patients were a decade younger than average HFrEF patients in the community, and thus the effectiveness and safety of catheter ablation in people with more comorbidity and frailty remains in question. Certain HFrEF patients may be less likely to benefit, such as those with amyloid cardiomyopathy. And with the increasing availability of other treatments for HFrEF such as sacubitril/valsartan, dapagliflozin, and MitraClip, it is less clear how catheter ablation would [benefit patients] on top of what is now current best therapy,” said Larry Allen, MD, a heart failure physician and professor of medicine at the University of Colorado in Aurora.
“With these limitations and the fact that catheter ablation is not a simple procedure, a large randomized, controlled trial of ablation, compared with no ablation, in a wide range of HFrEF patients on contemporary therapy would be welcome,” Dr. Allen said. “Given the prevalence of heart failure and AFib and the potential positive and negative implications of catheter ablation running such a trial seems critical for patients and for society.”
“For ablation of AFib in heart failure to become a class I recommendation there will need to be results from larger randomized studies,” summed up Dr. Stavrakis. The meta-analysis that he coauthored noted that “the benefits of catheter ablation for AFib in HFrEF patients have been consistently shown for over a decade now; however, the uptake of this procedure by clinicians in practice has been slow.”
Despite this history of reticence and ongoing caution about ablation, some cardiology experts see the indications for AFib ablation in heart failure steadily creeping forward, buoyed by a safety record that has more benign than ablation’s reputation suggests.
The CABANA results showed that “ablation is remarkably safe in the hands of experienced clinicians, with risks comparable to anti-arrhythmic drugs,” said Peter R. Kowey, MD, a specialist in treating AFib and professor of medicine at Thomas Jefferson University in Philadelphia, who made this assessment during a talk at an AFib meeting in early 2019. Dr. Kowey’s take on what the CABANA safety data showed contrasts with the impression of other cardiologists who are wary of perceived dangers from ablation.
“Ablation comes with a lot of morbidity and mortality. It’s not that the idea of ablation is wrong, but the ability to do it without a lot of adverse effects. ... We’re not quite there yet,” said Douglas L. Mann, MD, a heart failure physician and professor of medicine and chief of the cardiovascular division at Washington University in St. Louis.
“If I had a patient with HFrEF and AFib who was really sick, I’m not so sure I’d send them for ablation, which is not a simple procedure. The patients we tend to send for ablation are selected. Ablation is a big undertaking in patients who are already sick, and it’s expensive. I don’t think the data we have now will change the consensus view, but every heart failure physician is sending some patients for AFib ablation. People are turning to AFib ablation earlier than before. I think the consensus is that ablation is for symptoms or poor rate control, not for better outcomes,” said Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
However, this caution about safety and skepticism over efficacy may be dissipating as experience with ablation accumulates.
“CASTLE-AF and other data, including evidence for the apparent isolation of beta-blocker benefit to patients in sinus rhythm, have made me much more proactive about considering catheter ablation in my HFrEF patients. I think many other cardiologists have a similar view,” said Dr. Allen in an interview.
“A lot [of heart failure] patients are [being] referred for ablation, depending on the practice, setting, the local availability of electrophysiologists, and patient interest in ablation,” said Dr. Butler.
“We have no absolutely compelling data, but the data we have all point in the same direction. Like most, I am becoming convinced that AFib ablation in heart failure patients is a very valuable method for managing patients, but I can’t point to one study that was conclusive. Results from lots of studies show that it is likely, and when you add them all together it looks indisputable,” commented A. John Camm, MD, an atrial fibrillation specialist and professor of clinical cardiology at St. George’s University in London. “The findings put a responsibility on cardiologists to assess patients with heart failure for AFib. But there are nothing like enough resources to deal with all the patients who have heart failure who also have AFib.”
A rough estimate of just the U.S. volume of patients with heart failure and AFib is likely in the ball park of 2 million people (a third of the estimated 6 million American currently living with heart failure), and with the prevalence of each of these disorders rising precipitously (more than 5 million Americans have AFib) the confluence of the two should also show a steady increase. “It will take a major change in our concept of heart failure management to really address this. Potentially it would mean a large increase in the number of RF ablations of AFib, but the resources for that are not now present,” Dr. Camm said in an interview.
The attractions of catheter ablation also stand in contrast to the limitations of alternative treatments. Ablation is effective in a majority of patients for reducing AFib burden, both the frequency and duration of AFib episodes, and safety issues are mostly limited to the procedural and immediate postprocedural periods. The drugs available for trying to control AFib are beta-blockers, which provide rate control and can help prevent AFib onset, and rhythm-controlling anti-arrhythmic drugs like amiodarone, which have substantial limitations in both their ability to prevent arrhythmia recurrences as well as for safety.
“Most of the conventional antiarrhythmic drugs are contraindicated, frequently ineffective, or not well tolerated in patients with HFrEF. Catheter ablation of AFib provides an increasingly important option for rhythm control in these patients without using antiarrhythmic drugs,” Dr. Di Biase and his associates wrote in a recent review of AFib ablation in heart failure patients (Eur Heart J. 2019 Feb 21;40[8]:663-71).
“The guidelines that are controversial still make amiodarone a class I drug even though it’s been associated with serious side effects and has been shown in several heart failure trials to increase mortality. I can’t believe that ablation is a class IIb recommendation while a drug like amiodarone is a class I recommendation,” Dr. Di Biase said.
And although beta-blockers are a mainstay of heart failure treatment, once AFib becomes established they are less useful for maintaining sinus rhythm. “Beta-blockers provide effective rate control, but they can’t convert patients to sinus rhythm [once AFib begins], and there is no convincing evidence that patients on beta-blockers stay in sinus rhythm longer. You can’t just say: the patient is on a beta-blocker so I’ve done my best,” noted Dr. Jessup.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Stavrakis, Dr, Jessup, and Dr. Di Biase. Dr. Hunter has received research funding, educational grants, and speakers fees from Biosense Webster and Medtronic. Dr. Packer had received honoraria from Biotronik and MediaSphere Medical and research support from several companies. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis, he has received research funding from Abbott, ARCA biopharma, Boston Scientific, Gilead, and Johnson & Johnson, and he had a financial relationship with GlaxoSmithKline. Dr. Fonarow has been a consultant to Abbott, Amgen, Bayer, Janssen, and Novartis. Dr. Butler has been a consultant to several companies. Dr. Allen has been a consultant to Boston Scientific, Janssen, and Novartis. Dr. Kowey has been a consultant to several companies. Dr. Mann has been a consultant to Bristol-Myers Squibb, Corvia, and Novartis, and an adviser to miRagen. Dr. Camm has been a consultant to several companies.
This is part one of a two-part article.
Roughly a third of patients with heart failure also have atrial fibrillation, a comorbid combination notorious for working synergistically to worsen a patient’s quality of life and life expectancy.
During the past year, radiofrequency catheter ablation of atrial fibrillation in patients with both conditions has gathered steam as a way to intervene in at least selected patients, driven by study results that featured attention-grabbing reductions in death and cardiovascular hospitalizations.
The evidence favoring catheter ablation of atrial fibrillation (AFib) in patients with heart failure, particularly patients with heart failure with reduced ejection fraction (HFrEF), ramped up in 2019, spurred largely by a subgroup analysis from the CABANA trial, the largest randomized comparison by far of AFib ablation with antiarrhythmic drug treatment with 2,204 patients.
The past few months also featured release of two meta-analyses that took the CABANA results into account plus findings from about a dozen earlier randomized studies. Both meta-analyses, as well as the heart failure analysis from CABANA, all point in one direction, as stated in the conclusion of one of the meta-analyses: “In patients with AFib, catheter ablation is associated with all-cause mortality benefit, compared with medical therapy, that is driven by patients with AFib and HFrEF. Catheter ablation is safe and reduces cardiovascular hospitalizations and recurrences of atrial arrhythmias” both in patients with paroxysmal and persistent AFib,” wrote Stavros Stavrakis, MD, and his associates in their systematic review of 18 randomized, controlled trials of catheter ablation of AFib in a total of 4,464 patients with or without heart failure (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: e007414).
Despite these new data and analyses, clinicians seem to have very mixed reactions. Some call for an upgraded recommendation by professional societies that would support more aggressive use of AFib ablation in heart failure patients, and the anecdotal impressions of people who manage these patients are that ablation procedures have recently increased. But others advise caution, and note that in their opinion the efficacy data remain preliminary; the procedure has safety, logistical, and economic concerns; and questions remain about the ability of all active ablation programs to consistently deliver the results seen in published trials.
The meta-analysis led by Dr. Stavrakis showed that catheter ablation of AFib cut all-cause mortality during follow-up by a statistically significant 31%, compared with medical therapy, in all patients regardless of their heart failure status. But in patients with HFrEF, the reduction was 48%, along with a 38% cut in cardiovascular hospitalizations. In contrast, patients without heart failure who underwent AFib ablation showed no significant change in their all-cause mortality, compared with medical management of these patients.
“Based both on our meta-analysis and the CABANA data, patients with AFib most likely to benefit from ablation are patients younger than 65 and those with heart failure,” summed up Dr. Stavrakis, a cardiac electrophysiologist at the Heart Rhythm Institute of the University of Oklahoma in Oklahoma City.
The second meta-analysis, which initially appeared in July, analyzed data from 11 randomized trials of catheter ablations compared with anti-arrhythmic medical therapy for rate or rhythm control with in a total of 3,598 patients who all had heart failure, again including the patients enrolled in the CABANA study. The results showed a significant 49% relative drop in all cause mortality with ablation compared with medical treatment, and a statistically significant 56% cut in hospitalizations, as well as a significant, nearly 7% average, absolute improvement in left ventricular ejection fraction, plus benefits for preventing arrhythmia recurrence and improving quality of life (Eur Heart J. 2019 Jul 11. doi: 10.1093/eurheartj/ehz443).
“The magnitude of the effect seen in the meta-analysis, a 49% reduction in total mortality and a 56% reduction in hospitalizations, is rather staggering, and is larger than typically quoted for other medical interventions or device therapy in heart failure. The treatment effect was uniform among studies, and entirely compatible with the changes in left ventricular function, exercise capacity, and heart failure symptoms. Therefore, although more data are desirable, there are already arguably sufficient data to understand a great deal regarding the impact of a fib ablation,” commented Ross J. Hunter, MRCP, a cardiac electrophysiologist at Barts Heart Centre in London, and his associates in an editorial about this meta-analysis (Eur Heart J. 2019 Oct 22. doi: 10.1093/eurheartj/ehz704).
The heart failure analysis of CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) itself also showed striking findings when first reported at the annual scientific sessions of the Heart Rhythm Society last May. In presentations he made at this meeting, Douglas L. Packer, MD, CABANA’s lead investigator, reported details of a prespecified subgroup analysis of the 778 patients enrolled in CABANA who had heart failure at baseline, slightly more than a third of the total study enrollment. This was more than double the number of patients identified as specifically having heart failure at entry in the initial publication of CABANA’s findings (JAMA. 2019 Mar 15;321[134]:1261-74). Comparison of the 378 patients with heart failure and randomized to undergo ablation with the 400 with heart failure randomized to medical treatment showed a 36% reduction in the study’s primary, composite endpoint relative to the control group in an intention-to-treat analysis, and a 43% relative cut in all-cause mortality during follow-up, Dr. Packer reported at the May meeting. (As of early November 2019, these results had not yet appeared in a published article.) In contrast, in the 1,422 CABANA patients randomized who did not have heart failure, ablation produced results for these endpoints that were similar to and not statistically different from the outcomes in patients treated medically, said Dr. Packer, a cardiac electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn.
The CABANA results added to what had been previously reported from two other landmark studies that documented incremental efficacy of AFib ablation compared with medical treatment in patients with heart failure: The AATAC (Ablation vs Amiodarone for Treatment of AFib in Patients With Congestive HF and an Implanted Device) study, which randomized 203 patients (Circulation. 2016 Apr 26;133[17]:1637-44), and CASTLE-AF (Catheter Ablation vs. Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) trial, which randomized 363 patients (N Engl J Med. 2018 Feb 1;378[5]:417-27). These three studies contributed the most patients and outcomes to the two recent meta-analyses.
“The CASTLE-AF and AATAC trials both showed improved cardiovascular outcomes with ablation in patients with heart failure and AFib. The meta-analysis [by Dr. Stavrakis and his associates] and CABANA subgroup analysis further support use of catheter ablation to improve the outcomes in these patients,” noted Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator.
“The CABANA trial was very important because it confirmed the safety of catheter ablation, and more importantly suggested that patients with heart failure may benefit the most [from AFib ablation]. The evidence is very strong to advocate ablation as first-line therapy for selected patients with heart failure. Perhaps the optimal patients are those with [New York Heart Association] class I-III or ambulatory class IV heart failure who are on optimized, guideline-directed medical therapy. We have enough data to make this a class I recommendation. The question that remains is whether this is a cost effective strategy. Because it lowers rehospitalization and death, I suspect it is,” said Luigi Di Biase, MD, lead investigator of AATAC, and director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine, both in New York.
Opinions differ on AFib ablation’s role
Despite this expansive assessment of the current status of AFib ablation for patients with heart failure from Dr. Di Biase and shared by others, another camp of cardiologists currently sees ablation as having more limited current utility, as recommended earlier this year by a guideline-update panel representing the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. The guideline update included this new recommendation for how to use AFib ablation in heart failure patients: “AF catheter ablation may be reasonable in selected patients with symptomatic AFib and heart failure with reduced left ventricular ejection fraction to potentially lower mortality rate and reduce hospitalization for heart failure,” a class IIb recommendation. (J Am Coll Cardiol. 2019 Jul 9;74[1]:104-32). The guideline’s text cited the findings from AATAC and CASTLE-AF, but qualified both studies as “relatively small” and with “highly selected patient populations.” The guideline also incorporated the CABANA results into its considerations (although they may not have had the full analysis in heart failure patients available during their deliberations), but cited the study’s main limitation: CABANA failed to show a statistically significant difference in the primary endpoint in its primary, intention-to-treat analysis, which meant that by the strict statistical criteria that trialists apply to study findings, all other endpoints analyzed using CABANA’s are merely “hypothesis generating” and not definitive.
Questions about the extent of patient selection required to see a clear clinical-endpoint benefit from AFib ablation in heart failure patients, as well as the flawed validity of the CABANA results for making unqualified practice recommendation are the main arguments advanced by experts who caution against broader and more routine ablations.
“The findings from the heart failure subgroup of CABANA are hypothesis generating rather than definitive. Even with the recent meta-analysis, uncertainty remains regarding the ability of catheter ablation to improve outcomes beyond reducing AFib-related symptoms,” commented Gregg Fonarow, MD, a heart failure physician and professor of medicine at the University of California, Los Angeles.
“CASTLE-HF had fewer than 100 deaths combined in both arms, which means very unstable results. We don’t know a lot of detail about the heart failure patients in CABANA, and overall we do not have much data from patients with heart failure with preserved ejection fraction [HFpEF],” said Javed Butler, MD, a heart failure physician and professor and chairman of medicine at the University of Mississippi in Jackson. Dr. Butler also voiced his concerns (shared by other heart failure specialists) about the safety of ablation in heart failure patients, noting that “many patients require multiple ablations; many burns result in scarring and can worsen atrial function. In short, ablation of AFib is probably good for selected patients, but to have a class 1 recommendation, we need much larger trials with well-phenotyped heart failure patients,” Dr. Butler said in an interview.
“The totality of data still captures a relatively small number of patients. CASTLE-HF took 8 years to enroll fewer than 400 patients, and the results showed some heterogeneity. Study patients were a decade younger than average HFrEF patients in the community, and thus the effectiveness and safety of catheter ablation in people with more comorbidity and frailty remains in question. Certain HFrEF patients may be less likely to benefit, such as those with amyloid cardiomyopathy. And with the increasing availability of other treatments for HFrEF such as sacubitril/valsartan, dapagliflozin, and MitraClip, it is less clear how catheter ablation would [benefit patients] on top of what is now current best therapy,” said Larry Allen, MD, a heart failure physician and professor of medicine at the University of Colorado in Aurora.
“With these limitations and the fact that catheter ablation is not a simple procedure, a large randomized, controlled trial of ablation, compared with no ablation, in a wide range of HFrEF patients on contemporary therapy would be welcome,” Dr. Allen said. “Given the prevalence of heart failure and AFib and the potential positive and negative implications of catheter ablation running such a trial seems critical for patients and for society.”
“For ablation of AFib in heart failure to become a class I recommendation there will need to be results from larger randomized studies,” summed up Dr. Stavrakis. The meta-analysis that he coauthored noted that “the benefits of catheter ablation for AFib in HFrEF patients have been consistently shown for over a decade now; however, the uptake of this procedure by clinicians in practice has been slow.”
Despite this history of reticence and ongoing caution about ablation, some cardiology experts see the indications for AFib ablation in heart failure steadily creeping forward, buoyed by a safety record that has more benign than ablation’s reputation suggests.
The CABANA results showed that “ablation is remarkably safe in the hands of experienced clinicians, with risks comparable to anti-arrhythmic drugs,” said Peter R. Kowey, MD, a specialist in treating AFib and professor of medicine at Thomas Jefferson University in Philadelphia, who made this assessment during a talk at an AFib meeting in early 2019. Dr. Kowey’s take on what the CABANA safety data showed contrasts with the impression of other cardiologists who are wary of perceived dangers from ablation.
“Ablation comes with a lot of morbidity and mortality. It’s not that the idea of ablation is wrong, but the ability to do it without a lot of adverse effects. ... We’re not quite there yet,” said Douglas L. Mann, MD, a heart failure physician and professor of medicine and chief of the cardiovascular division at Washington University in St. Louis.
“If I had a patient with HFrEF and AFib who was really sick, I’m not so sure I’d send them for ablation, which is not a simple procedure. The patients we tend to send for ablation are selected. Ablation is a big undertaking in patients who are already sick, and it’s expensive. I don’t think the data we have now will change the consensus view, but every heart failure physician is sending some patients for AFib ablation. People are turning to AFib ablation earlier than before. I think the consensus is that ablation is for symptoms or poor rate control, not for better outcomes,” said Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
However, this caution about safety and skepticism over efficacy may be dissipating as experience with ablation accumulates.
“CASTLE-AF and other data, including evidence for the apparent isolation of beta-blocker benefit to patients in sinus rhythm, have made me much more proactive about considering catheter ablation in my HFrEF patients. I think many other cardiologists have a similar view,” said Dr. Allen in an interview.
“A lot [of heart failure] patients are [being] referred for ablation, depending on the practice, setting, the local availability of electrophysiologists, and patient interest in ablation,” said Dr. Butler.
“We have no absolutely compelling data, but the data we have all point in the same direction. Like most, I am becoming convinced that AFib ablation in heart failure patients is a very valuable method for managing patients, but I can’t point to one study that was conclusive. Results from lots of studies show that it is likely, and when you add them all together it looks indisputable,” commented A. John Camm, MD, an atrial fibrillation specialist and professor of clinical cardiology at St. George’s University in London. “The findings put a responsibility on cardiologists to assess patients with heart failure for AFib. But there are nothing like enough resources to deal with all the patients who have heart failure who also have AFib.”
A rough estimate of just the U.S. volume of patients with heart failure and AFib is likely in the ball park of 2 million people (a third of the estimated 6 million American currently living with heart failure), and with the prevalence of each of these disorders rising precipitously (more than 5 million Americans have AFib) the confluence of the two should also show a steady increase. “It will take a major change in our concept of heart failure management to really address this. Potentially it would mean a large increase in the number of RF ablations of AFib, but the resources for that are not now present,” Dr. Camm said in an interview.
The attractions of catheter ablation also stand in contrast to the limitations of alternative treatments. Ablation is effective in a majority of patients for reducing AFib burden, both the frequency and duration of AFib episodes, and safety issues are mostly limited to the procedural and immediate postprocedural periods. The drugs available for trying to control AFib are beta-blockers, which provide rate control and can help prevent AFib onset, and rhythm-controlling anti-arrhythmic drugs like amiodarone, which have substantial limitations in both their ability to prevent arrhythmia recurrences as well as for safety.
“Most of the conventional antiarrhythmic drugs are contraindicated, frequently ineffective, or not well tolerated in patients with HFrEF. Catheter ablation of AFib provides an increasingly important option for rhythm control in these patients without using antiarrhythmic drugs,” Dr. Di Biase and his associates wrote in a recent review of AFib ablation in heart failure patients (Eur Heart J. 2019 Feb 21;40[8]:663-71).
“The guidelines that are controversial still make amiodarone a class I drug even though it’s been associated with serious side effects and has been shown in several heart failure trials to increase mortality. I can’t believe that ablation is a class IIb recommendation while a drug like amiodarone is a class I recommendation,” Dr. Di Biase said.
And although beta-blockers are a mainstay of heart failure treatment, once AFib becomes established they are less useful for maintaining sinus rhythm. “Beta-blockers provide effective rate control, but they can’t convert patients to sinus rhythm [once AFib begins], and there is no convincing evidence that patients on beta-blockers stay in sinus rhythm longer. You can’t just say: the patient is on a beta-blocker so I’ve done my best,” noted Dr. Jessup.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Stavrakis, Dr, Jessup, and Dr. Di Biase. Dr. Hunter has received research funding, educational grants, and speakers fees from Biosense Webster and Medtronic. Dr. Packer had received honoraria from Biotronik and MediaSphere Medical and research support from several companies. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis, he has received research funding from Abbott, ARCA biopharma, Boston Scientific, Gilead, and Johnson & Johnson, and he had a financial relationship with GlaxoSmithKline. Dr. Fonarow has been a consultant to Abbott, Amgen, Bayer, Janssen, and Novartis. Dr. Butler has been a consultant to several companies. Dr. Allen has been a consultant to Boston Scientific, Janssen, and Novartis. Dr. Kowey has been a consultant to several companies. Dr. Mann has been a consultant to Bristol-Myers Squibb, Corvia, and Novartis, and an adviser to miRagen. Dr. Camm has been a consultant to several companies.
This is part one of a two-part article.
ATTEST: AFib ablation slows progression to persistence
PARIS – Radiofrequency catheter ablation of atrial fibrillation is not only a more definitive rhythm control treatment than antiarrhythmic drugs, but it’s also much more effective at slowing progression of AFib from paroxysmal to persistent, according to results from a randomized trial in 255 patients.
The multicenter study, ATTEST, randomized patients with paroxysmal AFib to radiofrequency catheter ablation or medical management and found that, during up to 3 years of follow-up, ablation cut the incidence of progression to persistent AFib by 89%, compared with medically managed patients, a statistically significant difference that documented a previously unappreciated benefit of catheter ablation: the ability to slow AFib progression, Karl-Heinz Kuck, MD, said at the annual congress of the European Society of Cardiology.
“This was never looked at before.” Assessing progression to persistent AFib is “a new endpoint for ablation” and an important one because progression from paroxysmal to persistent AFib has been associated with increased mortality, increased strokes, and increased hospitalizations,” said Dr. Kuck, a professor and cardiologist at the Asklepios Clinic St. Georg in Hamburg, Germany. If the findings are confirmed, “it may introduce a new indication for catheter ablation” in patients with paroxysmal AFib, Dr. Kuck said in an interview.
ATTEST (Atrial Fibrillation Progression Trial) enrolled patients at 30 sites worldwide who were at least 60 years old, had been diagnosed with paroxysmal AFib for at least 2 years, had at least two AFib episodes within 6 months of enrollment, and had not fully responded to one or two rhythm- or rate-control drugs. The 255 patients enrolled averaged 68 years of age, 58% were women, their median duration of AFib was slightly greater than 4 years, and on average patients had six to seven episodes during the prior 6 months. Enrollment into the study stopped sooner than planned because of slow recruitment, which topped out at 79% of the goal. Enrolled patients underwent weekly screening by transtelephonic monitoring for an AFib episode of at least 30 seconds during 3-9 months after entry, and then they had monthly screening. Patients positive for AFib on screening underwent a week of daily transtelephonic monitoring to determine whether their AFib persisted. The study’s primary endpoint was development of an AFib episode that lasted at least 7 days or for at least 2 days followed by cardioversion, which the investigators defined as persistent AFib.
The results showed that after 1 year development of persistent AFib occurred in 1% of the 128 patients assigned to receive ablation (102 actually underwent ablation) and in 7% of 127 patients assigned to drug management, with 123 patients who followed the treatment protocol. After 2 years of follow-up, the cumulative rate of progression to persistent AFib was 2% after ablation and 12% with medical treatment, and after 3 years, the respective rates of progression were 2% and 18%. The between-group differences were statistically significant at all three follow-up intervals, Dr. Kuck reported. Analysis of only patients who followed their assigned protocol showed similar results, as did an analysis that used the definition of persistent AFib advanced by the Heart Rhythm Society in 2017 (Heart Rhythm. 2017 Oct;14[10]:e275-e444).
The advantage of ablation for deferring progression was consistent in all subgroups analyzed, with no signal of interaction by age, sex, or other subgroup definitions. The rate of serious adverse events was “low,” occurring in 12% of the ablated patients and in 5% of controls. The need for two or more ablations was also “low,” Dr Kuck said, with 17% of patients requiring a second procedure. The results additionally showed that ablation also led to a lower rate of any AFib recurrence, regardless of whether or not it met the definition of persistent AFib. Any AFib recurrence occurred in 57% of the ablated patients and in 85% of those managed medically during 3 years of follow-up, a statistically significant difference.
Although the mechanism by which ablation slowed AFib progression is not known, Dr. Kuck suggested that it may relate to a reduction in the frequency and duration of AFib recurrences. “I believe that AFib burden is the key. If AFib episodes last a few days, then the likelihood of progressing to episodes that last 7 days is much higher than when an episode only lasts a few minutes,” he explained. “We’re opening a new perspective that looks beyond managing AFib symptoms” using ablation.
ATTEST was funded by Biosense Webster, a company that markets catheter ablation devices. Dr. Kuck has been a consultant to Biosense Webster, as well as to Abbott, Boston Scientific, Edwards, and Medtronic.
The ATTEST design and results are important because the study’s findings provide a good complement to the previously reported outcomes from the CASTLE-AF study, which randomized 363 patients with mostly persistent AFib (and heart failure) to catheter ablation of the AFib or medical management. The CASTLE-HF results showed that ablation was much more effective for reducing death from any cause and heart failure hospitalizations (N Engl J Med. 2018 Feb 1;378[5]:417-27). In other words, catheter ablation was the superior treatment for persistent AFib, the type of AFib diagnosed in about two-thirds of the patients enrolled in CASTLE-AF.
Thorsten Lewalter, MD, an arrhythmia specialist and professor at Peter Osypka Heart Center in Munich, made these comments in an interview. He has received personal fees from Abbott, Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, and Pfizer.
The ATTEST design and results are important because the study’s findings provide a good complement to the previously reported outcomes from the CASTLE-AF study, which randomized 363 patients with mostly persistent AFib (and heart failure) to catheter ablation of the AFib or medical management. The CASTLE-HF results showed that ablation was much more effective for reducing death from any cause and heart failure hospitalizations (N Engl J Med. 2018 Feb 1;378[5]:417-27). In other words, catheter ablation was the superior treatment for persistent AFib, the type of AFib diagnosed in about two-thirds of the patients enrolled in CASTLE-AF.
Thorsten Lewalter, MD, an arrhythmia specialist and professor at Peter Osypka Heart Center in Munich, made these comments in an interview. He has received personal fees from Abbott, Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, and Pfizer.
The ATTEST design and results are important because the study’s findings provide a good complement to the previously reported outcomes from the CASTLE-AF study, which randomized 363 patients with mostly persistent AFib (and heart failure) to catheter ablation of the AFib or medical management. The CASTLE-HF results showed that ablation was much more effective for reducing death from any cause and heart failure hospitalizations (N Engl J Med. 2018 Feb 1;378[5]:417-27). In other words, catheter ablation was the superior treatment for persistent AFib, the type of AFib diagnosed in about two-thirds of the patients enrolled in CASTLE-AF.
Thorsten Lewalter, MD, an arrhythmia specialist and professor at Peter Osypka Heart Center in Munich, made these comments in an interview. He has received personal fees from Abbott, Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, and Pfizer.
PARIS – Radiofrequency catheter ablation of atrial fibrillation is not only a more definitive rhythm control treatment than antiarrhythmic drugs, but it’s also much more effective at slowing progression of AFib from paroxysmal to persistent, according to results from a randomized trial in 255 patients.
The multicenter study, ATTEST, randomized patients with paroxysmal AFib to radiofrequency catheter ablation or medical management and found that, during up to 3 years of follow-up, ablation cut the incidence of progression to persistent AFib by 89%, compared with medically managed patients, a statistically significant difference that documented a previously unappreciated benefit of catheter ablation: the ability to slow AFib progression, Karl-Heinz Kuck, MD, said at the annual congress of the European Society of Cardiology.
“This was never looked at before.” Assessing progression to persistent AFib is “a new endpoint for ablation” and an important one because progression from paroxysmal to persistent AFib has been associated with increased mortality, increased strokes, and increased hospitalizations,” said Dr. Kuck, a professor and cardiologist at the Asklepios Clinic St. Georg in Hamburg, Germany. If the findings are confirmed, “it may introduce a new indication for catheter ablation” in patients with paroxysmal AFib, Dr. Kuck said in an interview.
ATTEST (Atrial Fibrillation Progression Trial) enrolled patients at 30 sites worldwide who were at least 60 years old, had been diagnosed with paroxysmal AFib for at least 2 years, had at least two AFib episodes within 6 months of enrollment, and had not fully responded to one or two rhythm- or rate-control drugs. The 255 patients enrolled averaged 68 years of age, 58% were women, their median duration of AFib was slightly greater than 4 years, and on average patients had six to seven episodes during the prior 6 months. Enrollment into the study stopped sooner than planned because of slow recruitment, which topped out at 79% of the goal. Enrolled patients underwent weekly screening by transtelephonic monitoring for an AFib episode of at least 30 seconds during 3-9 months after entry, and then they had monthly screening. Patients positive for AFib on screening underwent a week of daily transtelephonic monitoring to determine whether their AFib persisted. The study’s primary endpoint was development of an AFib episode that lasted at least 7 days or for at least 2 days followed by cardioversion, which the investigators defined as persistent AFib.
The results showed that after 1 year development of persistent AFib occurred in 1% of the 128 patients assigned to receive ablation (102 actually underwent ablation) and in 7% of 127 patients assigned to drug management, with 123 patients who followed the treatment protocol. After 2 years of follow-up, the cumulative rate of progression to persistent AFib was 2% after ablation and 12% with medical treatment, and after 3 years, the respective rates of progression were 2% and 18%. The between-group differences were statistically significant at all three follow-up intervals, Dr. Kuck reported. Analysis of only patients who followed their assigned protocol showed similar results, as did an analysis that used the definition of persistent AFib advanced by the Heart Rhythm Society in 2017 (Heart Rhythm. 2017 Oct;14[10]:e275-e444).
The advantage of ablation for deferring progression was consistent in all subgroups analyzed, with no signal of interaction by age, sex, or other subgroup definitions. The rate of serious adverse events was “low,” occurring in 12% of the ablated patients and in 5% of controls. The need for two or more ablations was also “low,” Dr Kuck said, with 17% of patients requiring a second procedure. The results additionally showed that ablation also led to a lower rate of any AFib recurrence, regardless of whether or not it met the definition of persistent AFib. Any AFib recurrence occurred in 57% of the ablated patients and in 85% of those managed medically during 3 years of follow-up, a statistically significant difference.
Although the mechanism by which ablation slowed AFib progression is not known, Dr. Kuck suggested that it may relate to a reduction in the frequency and duration of AFib recurrences. “I believe that AFib burden is the key. If AFib episodes last a few days, then the likelihood of progressing to episodes that last 7 days is much higher than when an episode only lasts a few minutes,” he explained. “We’re opening a new perspective that looks beyond managing AFib symptoms” using ablation.
ATTEST was funded by Biosense Webster, a company that markets catheter ablation devices. Dr. Kuck has been a consultant to Biosense Webster, as well as to Abbott, Boston Scientific, Edwards, and Medtronic.
PARIS – Radiofrequency catheter ablation of atrial fibrillation is not only a more definitive rhythm control treatment than antiarrhythmic drugs, but it’s also much more effective at slowing progression of AFib from paroxysmal to persistent, according to results from a randomized trial in 255 patients.
The multicenter study, ATTEST, randomized patients with paroxysmal AFib to radiofrequency catheter ablation or medical management and found that, during up to 3 years of follow-up, ablation cut the incidence of progression to persistent AFib by 89%, compared with medically managed patients, a statistically significant difference that documented a previously unappreciated benefit of catheter ablation: the ability to slow AFib progression, Karl-Heinz Kuck, MD, said at the annual congress of the European Society of Cardiology.
“This was never looked at before.” Assessing progression to persistent AFib is “a new endpoint for ablation” and an important one because progression from paroxysmal to persistent AFib has been associated with increased mortality, increased strokes, and increased hospitalizations,” said Dr. Kuck, a professor and cardiologist at the Asklepios Clinic St. Georg in Hamburg, Germany. If the findings are confirmed, “it may introduce a new indication for catheter ablation” in patients with paroxysmal AFib, Dr. Kuck said in an interview.
ATTEST (Atrial Fibrillation Progression Trial) enrolled patients at 30 sites worldwide who were at least 60 years old, had been diagnosed with paroxysmal AFib for at least 2 years, had at least two AFib episodes within 6 months of enrollment, and had not fully responded to one or two rhythm- or rate-control drugs. The 255 patients enrolled averaged 68 years of age, 58% were women, their median duration of AFib was slightly greater than 4 years, and on average patients had six to seven episodes during the prior 6 months. Enrollment into the study stopped sooner than planned because of slow recruitment, which topped out at 79% of the goal. Enrolled patients underwent weekly screening by transtelephonic monitoring for an AFib episode of at least 30 seconds during 3-9 months after entry, and then they had monthly screening. Patients positive for AFib on screening underwent a week of daily transtelephonic monitoring to determine whether their AFib persisted. The study’s primary endpoint was development of an AFib episode that lasted at least 7 days or for at least 2 days followed by cardioversion, which the investigators defined as persistent AFib.
The results showed that after 1 year development of persistent AFib occurred in 1% of the 128 patients assigned to receive ablation (102 actually underwent ablation) and in 7% of 127 patients assigned to drug management, with 123 patients who followed the treatment protocol. After 2 years of follow-up, the cumulative rate of progression to persistent AFib was 2% after ablation and 12% with medical treatment, and after 3 years, the respective rates of progression were 2% and 18%. The between-group differences were statistically significant at all three follow-up intervals, Dr. Kuck reported. Analysis of only patients who followed their assigned protocol showed similar results, as did an analysis that used the definition of persistent AFib advanced by the Heart Rhythm Society in 2017 (Heart Rhythm. 2017 Oct;14[10]:e275-e444).
The advantage of ablation for deferring progression was consistent in all subgroups analyzed, with no signal of interaction by age, sex, or other subgroup definitions. The rate of serious adverse events was “low,” occurring in 12% of the ablated patients and in 5% of controls. The need for two or more ablations was also “low,” Dr Kuck said, with 17% of patients requiring a second procedure. The results additionally showed that ablation also led to a lower rate of any AFib recurrence, regardless of whether or not it met the definition of persistent AFib. Any AFib recurrence occurred in 57% of the ablated patients and in 85% of those managed medically during 3 years of follow-up, a statistically significant difference.
Although the mechanism by which ablation slowed AFib progression is not known, Dr. Kuck suggested that it may relate to a reduction in the frequency and duration of AFib recurrences. “I believe that AFib burden is the key. If AFib episodes last a few days, then the likelihood of progressing to episodes that last 7 days is much higher than when an episode only lasts a few minutes,” he explained. “We’re opening a new perspective that looks beyond managing AFib symptoms” using ablation.
ATTEST was funded by Biosense Webster, a company that markets catheter ablation devices. Dr. Kuck has been a consultant to Biosense Webster, as well as to Abbott, Boston Scientific, Edwards, and Medtronic.
REPORTING FROM THE ESC 2019 CONGRESS
Getting high heightens stroke, arrhythmia risks
Stoners, beware: , and people with cannabis use disorder are at a 50% greater risk of being hospitalized for arrhythmias, according to new research presented at the American Heart Association Scientific Sessions 2019.
An analysis of pooled data on nearly 44,000 participants in a cross-sectional survey showed that, among the 13.6% who reported using marijuana within the last 30 days, the adjusted odds ratio for young-onset stroke (aged 18-44 years), compared with non-users, was 2.75, reported Tarang Parekh, MBBS, a health policy researcher of George Mason University in Fairfax, Va., and colleagues.
In a separate study, a retrospective analysis of national inpatient data showed that people diagnosed with cannabis use disorder – a pathological pattern of impaired control, social impairment, risky behavior or physiological adaptation similar in nature to alcoholism – had a 47%-52% increased likelihood of hospitalization for an arrhythmia, reported Rikinkumar S. Patel, MD, a psychiatry resident at Griffin Memorial Hospital in Norman, Okla.
“As these [cannabis] products become increasingly used across the country, getting clearer, scientifically rigorous data is going to be important as we try to understand the overall health effects of cannabis,” said AHA President Robert Harrington, MD, of Stanford (Calif.) University in a statement.
Currently, use of both medical and recreational marijuana is fully legal in 11 U.S. states and the District of Columbia. Medical marijuana is legal with recreational use decriminalized (or penalties reduced) in 28 other states, and totally illegal in 11 other states, according to employee screening firm DISA Global Solutions.
Stroke study
In an oral presentation with simultaneous publication in the AHA journal Stroke, Dr. Parekh and colleagues presented an analysis of pooled data from the Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative cross-sectional survey collected by the Centers for Disease Control and Prevention in 2016 and 2017.
They looked at baseline sociodemographic data and created multivariable logistic regression models with state fixed effects to determine whether marijuana use within the last 30 days was associated with young-onset stroke.
They identified 43,860 participants representing a weighted sample of 35.5 million Americans. Of the sample, 63.3% were male, and 13.6 % of all participants reported using marijuana in the last 30 days.
They found in an unadjusted model that marijuana users had an odds ratio for stroke, compared with nonusers, of 1.59 (P less than.1), and in a model adjusted for demographic factors (gender, race, ethnicity, and education) the OR increased to 1.76 (P less than .05).
When they threw risk behavior into the model (physical activity, body mass index, heavy drinking, and cigarette smoking), they saw that the OR for stroke shot up to 2.75 (P less than .01).
“Physicians should ask patients if they use cannabis and counsel them about its potential stroke risk as part of regular doctor visits,” Dr. Parekh said in a statement.
Arrhythmias study
Based on recent studies suggesting that cannabis use may trigger cardiovascular events, Dr. Patel and colleagues studied whether cannabis use disorder may be related to arrhythmias, approaching the question through hospital records.
“The effects of using cannabis are seen within 15 minutes and last for around 3 hours. At lower doses, it is linked to a rapid heartbeat. At higher doses, it is linked to a too-slow heartbeat,” he said in a statement.
Dr. Patel and colleagues conducted a retrospective analysis of the Nationwide Inpatient Sample from 2010-2014, a period during which medical marijuana became legal in several states and recreational marijuana became legal in Colorado and Washington. The sample is a database maintained by the Healthcare Cost and Utilization Project of the U.S. Office of Disease Prevention and Health Promotion.
They identified 570,557 patients aged 15-54 years with a primary diagnosis of arrhythmia, and compared them with a sample of 67,662,082 patients hospitalized with no arrhythmia diagnosed during the same period.
They found a 2.6% incidence of cannabis use disorder among patients hospitalized for arrhythmias. Patients with cannabis use disorder tended to be younger (15- to 24-years-old; OR, 4.23), male (OR, 1.70) and African American (OR, 2.70).
In regression analysis adjusted for demographics and comorbidities, cannabis use disorder was associated with higher odds of arrhythmia hospitalization in young patients, at 1.28 times among 15- to 24-year-olds (95% confidence interval, 1.229-1.346) and 1.52 times for 25- to 34-year-olds (95% CI, 1.469-1.578).
“As medical and recreational cannabis is legalized in many states, it is important to know the difference between therapeutic cannabis dosing for medical purposes and the consequences of cannabis abuse. We urgently need additional research to understand these issues,” Dr. Patel said.
“It’s not proving that there’s a direct link, but it’s raising a suggestion in an observational analysis that [this] indeed might be the case. What that means for clinicians is that, if you’re seeing a patient who is presenting with a symptomatic arrhythmia, adding cannabis usage to your list of questions as you begin to try to understand possible precipitating factors for this arrhythmia seems to be a reasonable thing to do,” Dr. Harrington commented.
Stoners, beware: , and people with cannabis use disorder are at a 50% greater risk of being hospitalized for arrhythmias, according to new research presented at the American Heart Association Scientific Sessions 2019.
An analysis of pooled data on nearly 44,000 participants in a cross-sectional survey showed that, among the 13.6% who reported using marijuana within the last 30 days, the adjusted odds ratio for young-onset stroke (aged 18-44 years), compared with non-users, was 2.75, reported Tarang Parekh, MBBS, a health policy researcher of George Mason University in Fairfax, Va., and colleagues.
In a separate study, a retrospective analysis of national inpatient data showed that people diagnosed with cannabis use disorder – a pathological pattern of impaired control, social impairment, risky behavior or physiological adaptation similar in nature to alcoholism – had a 47%-52% increased likelihood of hospitalization for an arrhythmia, reported Rikinkumar S. Patel, MD, a psychiatry resident at Griffin Memorial Hospital in Norman, Okla.
“As these [cannabis] products become increasingly used across the country, getting clearer, scientifically rigorous data is going to be important as we try to understand the overall health effects of cannabis,” said AHA President Robert Harrington, MD, of Stanford (Calif.) University in a statement.
Currently, use of both medical and recreational marijuana is fully legal in 11 U.S. states and the District of Columbia. Medical marijuana is legal with recreational use decriminalized (or penalties reduced) in 28 other states, and totally illegal in 11 other states, according to employee screening firm DISA Global Solutions.
Stroke study
In an oral presentation with simultaneous publication in the AHA journal Stroke, Dr. Parekh and colleagues presented an analysis of pooled data from the Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative cross-sectional survey collected by the Centers for Disease Control and Prevention in 2016 and 2017.
They looked at baseline sociodemographic data and created multivariable logistic regression models with state fixed effects to determine whether marijuana use within the last 30 days was associated with young-onset stroke.
They identified 43,860 participants representing a weighted sample of 35.5 million Americans. Of the sample, 63.3% were male, and 13.6 % of all participants reported using marijuana in the last 30 days.
They found in an unadjusted model that marijuana users had an odds ratio for stroke, compared with nonusers, of 1.59 (P less than.1), and in a model adjusted for demographic factors (gender, race, ethnicity, and education) the OR increased to 1.76 (P less than .05).
When they threw risk behavior into the model (physical activity, body mass index, heavy drinking, and cigarette smoking), they saw that the OR for stroke shot up to 2.75 (P less than .01).
“Physicians should ask patients if they use cannabis and counsel them about its potential stroke risk as part of regular doctor visits,” Dr. Parekh said in a statement.
Arrhythmias study
Based on recent studies suggesting that cannabis use may trigger cardiovascular events, Dr. Patel and colleagues studied whether cannabis use disorder may be related to arrhythmias, approaching the question through hospital records.
“The effects of using cannabis are seen within 15 minutes and last for around 3 hours. At lower doses, it is linked to a rapid heartbeat. At higher doses, it is linked to a too-slow heartbeat,” he said in a statement.
Dr. Patel and colleagues conducted a retrospective analysis of the Nationwide Inpatient Sample from 2010-2014, a period during which medical marijuana became legal in several states and recreational marijuana became legal in Colorado and Washington. The sample is a database maintained by the Healthcare Cost and Utilization Project of the U.S. Office of Disease Prevention and Health Promotion.
They identified 570,557 patients aged 15-54 years with a primary diagnosis of arrhythmia, and compared them with a sample of 67,662,082 patients hospitalized with no arrhythmia diagnosed during the same period.
They found a 2.6% incidence of cannabis use disorder among patients hospitalized for arrhythmias. Patients with cannabis use disorder tended to be younger (15- to 24-years-old; OR, 4.23), male (OR, 1.70) and African American (OR, 2.70).
In regression analysis adjusted for demographics and comorbidities, cannabis use disorder was associated with higher odds of arrhythmia hospitalization in young patients, at 1.28 times among 15- to 24-year-olds (95% confidence interval, 1.229-1.346) and 1.52 times for 25- to 34-year-olds (95% CI, 1.469-1.578).
“As medical and recreational cannabis is legalized in many states, it is important to know the difference between therapeutic cannabis dosing for medical purposes and the consequences of cannabis abuse. We urgently need additional research to understand these issues,” Dr. Patel said.
“It’s not proving that there’s a direct link, but it’s raising a suggestion in an observational analysis that [this] indeed might be the case. What that means for clinicians is that, if you’re seeing a patient who is presenting with a symptomatic arrhythmia, adding cannabis usage to your list of questions as you begin to try to understand possible precipitating factors for this arrhythmia seems to be a reasonable thing to do,” Dr. Harrington commented.
Stoners, beware: , and people with cannabis use disorder are at a 50% greater risk of being hospitalized for arrhythmias, according to new research presented at the American Heart Association Scientific Sessions 2019.
An analysis of pooled data on nearly 44,000 participants in a cross-sectional survey showed that, among the 13.6% who reported using marijuana within the last 30 days, the adjusted odds ratio for young-onset stroke (aged 18-44 years), compared with non-users, was 2.75, reported Tarang Parekh, MBBS, a health policy researcher of George Mason University in Fairfax, Va., and colleagues.
In a separate study, a retrospective analysis of national inpatient data showed that people diagnosed with cannabis use disorder – a pathological pattern of impaired control, social impairment, risky behavior or physiological adaptation similar in nature to alcoholism – had a 47%-52% increased likelihood of hospitalization for an arrhythmia, reported Rikinkumar S. Patel, MD, a psychiatry resident at Griffin Memorial Hospital in Norman, Okla.
“As these [cannabis] products become increasingly used across the country, getting clearer, scientifically rigorous data is going to be important as we try to understand the overall health effects of cannabis,” said AHA President Robert Harrington, MD, of Stanford (Calif.) University in a statement.
Currently, use of both medical and recreational marijuana is fully legal in 11 U.S. states and the District of Columbia. Medical marijuana is legal with recreational use decriminalized (or penalties reduced) in 28 other states, and totally illegal in 11 other states, according to employee screening firm DISA Global Solutions.
Stroke study
In an oral presentation with simultaneous publication in the AHA journal Stroke, Dr. Parekh and colleagues presented an analysis of pooled data from the Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative cross-sectional survey collected by the Centers for Disease Control and Prevention in 2016 and 2017.
They looked at baseline sociodemographic data and created multivariable logistic regression models with state fixed effects to determine whether marijuana use within the last 30 days was associated with young-onset stroke.
They identified 43,860 participants representing a weighted sample of 35.5 million Americans. Of the sample, 63.3% were male, and 13.6 % of all participants reported using marijuana in the last 30 days.
They found in an unadjusted model that marijuana users had an odds ratio for stroke, compared with nonusers, of 1.59 (P less than.1), and in a model adjusted for demographic factors (gender, race, ethnicity, and education) the OR increased to 1.76 (P less than .05).
When they threw risk behavior into the model (physical activity, body mass index, heavy drinking, and cigarette smoking), they saw that the OR for stroke shot up to 2.75 (P less than .01).
“Physicians should ask patients if they use cannabis and counsel them about its potential stroke risk as part of regular doctor visits,” Dr. Parekh said in a statement.
Arrhythmias study
Based on recent studies suggesting that cannabis use may trigger cardiovascular events, Dr. Patel and colleagues studied whether cannabis use disorder may be related to arrhythmias, approaching the question through hospital records.
“The effects of using cannabis are seen within 15 minutes and last for around 3 hours. At lower doses, it is linked to a rapid heartbeat. At higher doses, it is linked to a too-slow heartbeat,” he said in a statement.
Dr. Patel and colleagues conducted a retrospective analysis of the Nationwide Inpatient Sample from 2010-2014, a period during which medical marijuana became legal in several states and recreational marijuana became legal in Colorado and Washington. The sample is a database maintained by the Healthcare Cost and Utilization Project of the U.S. Office of Disease Prevention and Health Promotion.
They identified 570,557 patients aged 15-54 years with a primary diagnosis of arrhythmia, and compared them with a sample of 67,662,082 patients hospitalized with no arrhythmia diagnosed during the same period.
They found a 2.6% incidence of cannabis use disorder among patients hospitalized for arrhythmias. Patients with cannabis use disorder tended to be younger (15- to 24-years-old; OR, 4.23), male (OR, 1.70) and African American (OR, 2.70).
In regression analysis adjusted for demographics and comorbidities, cannabis use disorder was associated with higher odds of arrhythmia hospitalization in young patients, at 1.28 times among 15- to 24-year-olds (95% confidence interval, 1.229-1.346) and 1.52 times for 25- to 34-year-olds (95% CI, 1.469-1.578).
“As medical and recreational cannabis is legalized in many states, it is important to know the difference between therapeutic cannabis dosing for medical purposes and the consequences of cannabis abuse. We urgently need additional research to understand these issues,” Dr. Patel said.
“It’s not proving that there’s a direct link, but it’s raising a suggestion in an observational analysis that [this] indeed might be the case. What that means for clinicians is that, if you’re seeing a patient who is presenting with a symptomatic arrhythmia, adding cannabis usage to your list of questions as you begin to try to understand possible precipitating factors for this arrhythmia seems to be a reasonable thing to do,” Dr. Harrington commented.
REPORTING FROM AHA 2019
Patients frequently drive too soon after ICD implantation
PARIS – Fewer than half of commercial drivers who received implantable cardioverter-defibrillators (ICDs) recalled being told they should never drive professionally again, according to a recent Danish survey. Further, about a third of patients overall reported that they began driving soon after they received an ICD, during the period when guidelines recommend refraining from driving.
“These devices, they save lives – so what’s not to like?” lead investigator Jenny Bjerre, MD, asked at the annual congress of the European Society of Cardiology. “Well, if you are a patient qualifying for an ICD, you also automatically qualify for some driving restrictions.” These are put in place because of the concern for an arrhythmia causing a loss of consciousness behind the wheel, she said.
A European consensus statement calls for a 3-month driving moratorium when an ICD is implanted for secondary prevention or after an appropriate ICD shock, and a 4-week restriction when an ICD is placed for primary prevention. All these restrictions apply to personal driver’s licenses; anyone with an ICD is permanently restricted from commercial driving according to the consensus statement, said Dr. Bjerre, of the University Hospital, Copenhagen.
“As you can imagine, these restrictions are not that popular with the patients,” she said. She related the story of a patient, a taxi driver who had returned to a full range of physically taxing activities after his ICD implantation, but whose livelihood had been taken away from him.
Dr. Bjerre said she sought to understand the perspective of this patient, who said, “Sometimes I wish I hadn’t been resuscitated!” She saw that the loss of freedom and a meaningful occupation had profoundly affected the daily life of this patient, and she became curious about adherence to driving restrictions in patients with ICDs.
Using the nationwide Danish medical record database, Dr. Bjerre and her colleagues looked at a nationwide cohort of ICD patients to see they remembered hearing about restrictions on personal and commercial driving activities after ICD implantation. They also investigated adherence to restrictions, and sought to identify what factors were associated with nonadherence.
The questionnaire developed by Dr. Bjerre and her colleagues was made available to the ICD cohort both electronically and in a paper version. Questionnaires received were linked with a variety of nationwide registries through each participant’s unique national identification number, she explained. They obtained information about comorbidities, pharmacotherapies, and socioeconomic status. Not only did this linkage give more precise and complete data than would a questionnaire alone, but it also allowed the investigators to see how responders differed from nonresponders – important in questionnaire research, said Dr. Bjerre.
The investigators were able to locate and distribute questionnaires to a total of 3,913 living adults who had received first-time ICDs during the 3-year study period. In the end, even after excluding 31 responses for missing data, 2,741 responses were used for analysis – a response rate of over 70%.
The median age of respondents was 67, and 83% were male. About half – 46% – of respondents had an ICD implanted for primary prevention. Compared with those who did respond, said Dr. Bjerre, the nonresponders “were younger, sicker, more likely to be female, had lower socioeconomic status, and were less likely to be on guideline-directed therapy.”
Over 90% of respondents held a private driver’s license at the time of their ICD implantation, and just 7% were actively using a commercial license prior to implantation. Participants had a variety of commercial driving occupations, including driving trucks, buses, and taxis.
“Only 43% of primary prevention patients and 64% of secondary prevention patients stated that they had been informed about any driving restrictions,” said Dr. Bjerre. The figure was slightly better for patients after an ICD shock was delivered – 72% of these patients recalled hearing about driving restrictions.
“Among professional drivers – who are never supposed to drive again – only 45% said they had been informed about any professional driving restrictions,” she added.
What did patients report about their actual driving behaviors? Of patients receiving an ICD for primary prevention, 34% resumed driving within one week of ICD implantation. For those receiving an ICD for secondary prevention and those who had received an appropriate ICD shock, 43% and 30%, respectively, began driving before the recommended 3 months had elapsed.
The driving behavior of those with commercial licenses didn’t differ from the cohort as a whole: 35% of this group had resumed commercial driving.
In all the study’s subgroups, nonadherence to driving restrictions was more likely if the participant didn’t recall having been informed of the restrictions, with an odds ratio (OR) of 3.34 for nonadherence. However, noted Dr. Bjerre, at least 20% of patients in all subgroups who said they’d been told not to drive still resumed driving in contravention of restrictions. “So it seems that information can’t explain everything,” she said.
Additional predictors of nonadherence included male sex, with an OR of 1.53, being the only driver in the household (OR 1.29), and being at least 60 years old (OR, 1.20). Those receiving an ICD for secondary prevention had an OR of 2.20 for nonadherence, as well.
The study had a large cohort of real-life ICD patients and the response rate was high, said Dr. Bjerre. However, there was a risk of recall bias; additionally, nonresponders differed from responders, limiting full generalizability of the data. Finally, she observed that participants may have given the answers they thought were socially desirable.
“I want to get back to our friend the taxi driver,” who was adherent to restrictions, but who kept wanting to know what the actual chances were that he’d harm someone if he resumed driving. Realizing she couldn’t give him a very precise answer, Dr. Bjerre concluded, “I do think we owe it to our patients to provide more evidence on the absolute risk of traffic accidents in these patients.”
Dr. Bjerre reported that she had no conflicts of interest.
PARIS – Fewer than half of commercial drivers who received implantable cardioverter-defibrillators (ICDs) recalled being told they should never drive professionally again, according to a recent Danish survey. Further, about a third of patients overall reported that they began driving soon after they received an ICD, during the period when guidelines recommend refraining from driving.
“These devices, they save lives – so what’s not to like?” lead investigator Jenny Bjerre, MD, asked at the annual congress of the European Society of Cardiology. “Well, if you are a patient qualifying for an ICD, you also automatically qualify for some driving restrictions.” These are put in place because of the concern for an arrhythmia causing a loss of consciousness behind the wheel, she said.
A European consensus statement calls for a 3-month driving moratorium when an ICD is implanted for secondary prevention or after an appropriate ICD shock, and a 4-week restriction when an ICD is placed for primary prevention. All these restrictions apply to personal driver’s licenses; anyone with an ICD is permanently restricted from commercial driving according to the consensus statement, said Dr. Bjerre, of the University Hospital, Copenhagen.
“As you can imagine, these restrictions are not that popular with the patients,” she said. She related the story of a patient, a taxi driver who had returned to a full range of physically taxing activities after his ICD implantation, but whose livelihood had been taken away from him.
Dr. Bjerre said she sought to understand the perspective of this patient, who said, “Sometimes I wish I hadn’t been resuscitated!” She saw that the loss of freedom and a meaningful occupation had profoundly affected the daily life of this patient, and she became curious about adherence to driving restrictions in patients with ICDs.
Using the nationwide Danish medical record database, Dr. Bjerre and her colleagues looked at a nationwide cohort of ICD patients to see they remembered hearing about restrictions on personal and commercial driving activities after ICD implantation. They also investigated adherence to restrictions, and sought to identify what factors were associated with nonadherence.
The questionnaire developed by Dr. Bjerre and her colleagues was made available to the ICD cohort both electronically and in a paper version. Questionnaires received were linked with a variety of nationwide registries through each participant’s unique national identification number, she explained. They obtained information about comorbidities, pharmacotherapies, and socioeconomic status. Not only did this linkage give more precise and complete data than would a questionnaire alone, but it also allowed the investigators to see how responders differed from nonresponders – important in questionnaire research, said Dr. Bjerre.
The investigators were able to locate and distribute questionnaires to a total of 3,913 living adults who had received first-time ICDs during the 3-year study period. In the end, even after excluding 31 responses for missing data, 2,741 responses were used for analysis – a response rate of over 70%.
The median age of respondents was 67, and 83% were male. About half – 46% – of respondents had an ICD implanted for primary prevention. Compared with those who did respond, said Dr. Bjerre, the nonresponders “were younger, sicker, more likely to be female, had lower socioeconomic status, and were less likely to be on guideline-directed therapy.”
Over 90% of respondents held a private driver’s license at the time of their ICD implantation, and just 7% were actively using a commercial license prior to implantation. Participants had a variety of commercial driving occupations, including driving trucks, buses, and taxis.
“Only 43% of primary prevention patients and 64% of secondary prevention patients stated that they had been informed about any driving restrictions,” said Dr. Bjerre. The figure was slightly better for patients after an ICD shock was delivered – 72% of these patients recalled hearing about driving restrictions.
“Among professional drivers – who are never supposed to drive again – only 45% said they had been informed about any professional driving restrictions,” she added.
What did patients report about their actual driving behaviors? Of patients receiving an ICD for primary prevention, 34% resumed driving within one week of ICD implantation. For those receiving an ICD for secondary prevention and those who had received an appropriate ICD shock, 43% and 30%, respectively, began driving before the recommended 3 months had elapsed.
The driving behavior of those with commercial licenses didn’t differ from the cohort as a whole: 35% of this group had resumed commercial driving.
In all the study’s subgroups, nonadherence to driving restrictions was more likely if the participant didn’t recall having been informed of the restrictions, with an odds ratio (OR) of 3.34 for nonadherence. However, noted Dr. Bjerre, at least 20% of patients in all subgroups who said they’d been told not to drive still resumed driving in contravention of restrictions. “So it seems that information can’t explain everything,” she said.
Additional predictors of nonadherence included male sex, with an OR of 1.53, being the only driver in the household (OR 1.29), and being at least 60 years old (OR, 1.20). Those receiving an ICD for secondary prevention had an OR of 2.20 for nonadherence, as well.
The study had a large cohort of real-life ICD patients and the response rate was high, said Dr. Bjerre. However, there was a risk of recall bias; additionally, nonresponders differed from responders, limiting full generalizability of the data. Finally, she observed that participants may have given the answers they thought were socially desirable.
“I want to get back to our friend the taxi driver,” who was adherent to restrictions, but who kept wanting to know what the actual chances were that he’d harm someone if he resumed driving. Realizing she couldn’t give him a very precise answer, Dr. Bjerre concluded, “I do think we owe it to our patients to provide more evidence on the absolute risk of traffic accidents in these patients.”
Dr. Bjerre reported that she had no conflicts of interest.
PARIS – Fewer than half of commercial drivers who received implantable cardioverter-defibrillators (ICDs) recalled being told they should never drive professionally again, according to a recent Danish survey. Further, about a third of patients overall reported that they began driving soon after they received an ICD, during the period when guidelines recommend refraining from driving.
“These devices, they save lives – so what’s not to like?” lead investigator Jenny Bjerre, MD, asked at the annual congress of the European Society of Cardiology. “Well, if you are a patient qualifying for an ICD, you also automatically qualify for some driving restrictions.” These are put in place because of the concern for an arrhythmia causing a loss of consciousness behind the wheel, she said.
A European consensus statement calls for a 3-month driving moratorium when an ICD is implanted for secondary prevention or after an appropriate ICD shock, and a 4-week restriction when an ICD is placed for primary prevention. All these restrictions apply to personal driver’s licenses; anyone with an ICD is permanently restricted from commercial driving according to the consensus statement, said Dr. Bjerre, of the University Hospital, Copenhagen.
“As you can imagine, these restrictions are not that popular with the patients,” she said. She related the story of a patient, a taxi driver who had returned to a full range of physically taxing activities after his ICD implantation, but whose livelihood had been taken away from him.
Dr. Bjerre said she sought to understand the perspective of this patient, who said, “Sometimes I wish I hadn’t been resuscitated!” She saw that the loss of freedom and a meaningful occupation had profoundly affected the daily life of this patient, and she became curious about adherence to driving restrictions in patients with ICDs.
Using the nationwide Danish medical record database, Dr. Bjerre and her colleagues looked at a nationwide cohort of ICD patients to see they remembered hearing about restrictions on personal and commercial driving activities after ICD implantation. They also investigated adherence to restrictions, and sought to identify what factors were associated with nonadherence.
The questionnaire developed by Dr. Bjerre and her colleagues was made available to the ICD cohort both electronically and in a paper version. Questionnaires received were linked with a variety of nationwide registries through each participant’s unique national identification number, she explained. They obtained information about comorbidities, pharmacotherapies, and socioeconomic status. Not only did this linkage give more precise and complete data than would a questionnaire alone, but it also allowed the investigators to see how responders differed from nonresponders – important in questionnaire research, said Dr. Bjerre.
The investigators were able to locate and distribute questionnaires to a total of 3,913 living adults who had received first-time ICDs during the 3-year study period. In the end, even after excluding 31 responses for missing data, 2,741 responses were used for analysis – a response rate of over 70%.
The median age of respondents was 67, and 83% were male. About half – 46% – of respondents had an ICD implanted for primary prevention. Compared with those who did respond, said Dr. Bjerre, the nonresponders “were younger, sicker, more likely to be female, had lower socioeconomic status, and were less likely to be on guideline-directed therapy.”
Over 90% of respondents held a private driver’s license at the time of their ICD implantation, and just 7% were actively using a commercial license prior to implantation. Participants had a variety of commercial driving occupations, including driving trucks, buses, and taxis.
“Only 43% of primary prevention patients and 64% of secondary prevention patients stated that they had been informed about any driving restrictions,” said Dr. Bjerre. The figure was slightly better for patients after an ICD shock was delivered – 72% of these patients recalled hearing about driving restrictions.
“Among professional drivers – who are never supposed to drive again – only 45% said they had been informed about any professional driving restrictions,” she added.
What did patients report about their actual driving behaviors? Of patients receiving an ICD for primary prevention, 34% resumed driving within one week of ICD implantation. For those receiving an ICD for secondary prevention and those who had received an appropriate ICD shock, 43% and 30%, respectively, began driving before the recommended 3 months had elapsed.
The driving behavior of those with commercial licenses didn’t differ from the cohort as a whole: 35% of this group had resumed commercial driving.
In all the study’s subgroups, nonadherence to driving restrictions was more likely if the participant didn’t recall having been informed of the restrictions, with an odds ratio (OR) of 3.34 for nonadherence. However, noted Dr. Bjerre, at least 20% of patients in all subgroups who said they’d been told not to drive still resumed driving in contravention of restrictions. “So it seems that information can’t explain everything,” she said.
Additional predictors of nonadherence included male sex, with an OR of 1.53, being the only driver in the household (OR 1.29), and being at least 60 years old (OR, 1.20). Those receiving an ICD for secondary prevention had an OR of 2.20 for nonadherence, as well.
The study had a large cohort of real-life ICD patients and the response rate was high, said Dr. Bjerre. However, there was a risk of recall bias; additionally, nonresponders differed from responders, limiting full generalizability of the data. Finally, she observed that participants may have given the answers they thought were socially desirable.
“I want to get back to our friend the taxi driver,” who was adherent to restrictions, but who kept wanting to know what the actual chances were that he’d harm someone if he resumed driving. Realizing she couldn’t give him a very precise answer, Dr. Bjerre concluded, “I do think we owe it to our patients to provide more evidence on the absolute risk of traffic accidents in these patients.”
Dr. Bjerre reported that she had no conflicts of interest.
REPORTING FROM ESC CONGRESS 2019
Native Americans appear to be at increased risk for AFib
Over 4 years, atrial fibrillation (AFib) developed significantly more often in a group of Native Americans men than it did among other racial and ethnic groups, a large longitudinal cohort study has found.
The overall incidence among Native Americans was 7.49 per 1,000 person-years – significantly higher than the incidence in a comparator cohort of black, white, Asian, and Hispanic men, Gregory M. Marcus, MD, of the University of California, San Francisco, and colleagues wrote in a research letter published in Circulation.
“We were surprised to find that American Indians experienced a higher risk of atrial fibrillation, compared to every other racial and ethnic group,” Dr. Marcus said in a press release that accompanied the study. “Understanding the mechanisms and factors by which American Indians experience this higher risk may help investigators better understand the fundamental causes of atrial fibrillation that prove useful to everyone at risk for AFib, regardless of their race or ethnicity.”
The team plumbed the Healthcare Cost and Utilization Project (HCUP) California state databases for information on more than 16 million cases of AFib that occurred during 2005-2011. Native Americans comprised just 0.6% of the cohort. Most of the patients (57.2%) were white; 8% were black, 25.6% Hispanic, and 8.6% Asian. After targeting only new-onset cases, there were 344,469 incident AFib episodes over a median follow-up of 4.1 years.
The overall incidence of AFib in Native Americans was 7.49 per 1,000 person-years, significantly higher than the 6.89 per 1000 person-years observed in the rest of the cohort ( P less than .0001). The difference remained significant even after the team controlled for age, sex, income, and heart and other diseases. Nor was it altered by a sensitivity analysis that controlled for place of presentation and patients who were aged at least 35 years with at least two encounters with medical facilities.
In an interaction analysis, the increased risk appeared to be driven by higher rates of diabetes and chronic kidney disease, the authors wrote.
“This may suggest that the presence of these two processes contributes some pathophysiology related to AF[ib] risk that may be similar to the heightened risk inherent among American Indians,” they wrote. “It is also important to note that there was no evidence of any other statistically significant interactions despite the inclusion of millions of patients.”
Supporting data for these associations were not included in the research letter.
The authors noted some limitations of their study. Race or ethnicity were self-reported and could not be independently confirmed, so there was no way to tease out the effects in multiracial patients. Also, the database didn’t record outpatient encounters, which might result in some selection bias.
“Last, because this was an observational study, these results should not be interpreted as evidence of causal effect,” they noted.
“In conclusion, we observed that American Indians had a higher risk of atrial fibrillation, compared with all other racial and ethnic group. The heightened risk … in American Indians persisted after multivariable adjustment for known conventional confounders and mediators, suggesting that an unidentified characteristic, including possible genetic or environmental factors, may be responsible,” the investigators wrote.
The HCUP database is supported by the Agency for Healthcare Research and Quality. Dr. Marcus reported receiving research support from Jawbone, Medtronic, Eight, and Baylis Medical, and is a consultant for and holds equity in InCarda Therapeutics. The other authors reported no conflicts of interest.
SOURCE: Marcus GM et al. Circulation. 2019 Oct 21. doi:10.1161/CIRCULATIONAHA.119.042882.
Over 4 years, atrial fibrillation (AFib) developed significantly more often in a group of Native Americans men than it did among other racial and ethnic groups, a large longitudinal cohort study has found.
The overall incidence among Native Americans was 7.49 per 1,000 person-years – significantly higher than the incidence in a comparator cohort of black, white, Asian, and Hispanic men, Gregory M. Marcus, MD, of the University of California, San Francisco, and colleagues wrote in a research letter published in Circulation.
“We were surprised to find that American Indians experienced a higher risk of atrial fibrillation, compared to every other racial and ethnic group,” Dr. Marcus said in a press release that accompanied the study. “Understanding the mechanisms and factors by which American Indians experience this higher risk may help investigators better understand the fundamental causes of atrial fibrillation that prove useful to everyone at risk for AFib, regardless of their race or ethnicity.”
The team plumbed the Healthcare Cost and Utilization Project (HCUP) California state databases for information on more than 16 million cases of AFib that occurred during 2005-2011. Native Americans comprised just 0.6% of the cohort. Most of the patients (57.2%) were white; 8% were black, 25.6% Hispanic, and 8.6% Asian. After targeting only new-onset cases, there were 344,469 incident AFib episodes over a median follow-up of 4.1 years.
The overall incidence of AFib in Native Americans was 7.49 per 1,000 person-years, significantly higher than the 6.89 per 1000 person-years observed in the rest of the cohort ( P less than .0001). The difference remained significant even after the team controlled for age, sex, income, and heart and other diseases. Nor was it altered by a sensitivity analysis that controlled for place of presentation and patients who were aged at least 35 years with at least two encounters with medical facilities.
In an interaction analysis, the increased risk appeared to be driven by higher rates of diabetes and chronic kidney disease, the authors wrote.
“This may suggest that the presence of these two processes contributes some pathophysiology related to AF[ib] risk that may be similar to the heightened risk inherent among American Indians,” they wrote. “It is also important to note that there was no evidence of any other statistically significant interactions despite the inclusion of millions of patients.”
Supporting data for these associations were not included in the research letter.
The authors noted some limitations of their study. Race or ethnicity were self-reported and could not be independently confirmed, so there was no way to tease out the effects in multiracial patients. Also, the database didn’t record outpatient encounters, which might result in some selection bias.
“Last, because this was an observational study, these results should not be interpreted as evidence of causal effect,” they noted.
“In conclusion, we observed that American Indians had a higher risk of atrial fibrillation, compared with all other racial and ethnic group. The heightened risk … in American Indians persisted after multivariable adjustment for known conventional confounders and mediators, suggesting that an unidentified characteristic, including possible genetic or environmental factors, may be responsible,” the investigators wrote.
The HCUP database is supported by the Agency for Healthcare Research and Quality. Dr. Marcus reported receiving research support from Jawbone, Medtronic, Eight, and Baylis Medical, and is a consultant for and holds equity in InCarda Therapeutics. The other authors reported no conflicts of interest.
SOURCE: Marcus GM et al. Circulation. 2019 Oct 21. doi:10.1161/CIRCULATIONAHA.119.042882.
Over 4 years, atrial fibrillation (AFib) developed significantly more often in a group of Native Americans men than it did among other racial and ethnic groups, a large longitudinal cohort study has found.
The overall incidence among Native Americans was 7.49 per 1,000 person-years – significantly higher than the incidence in a comparator cohort of black, white, Asian, and Hispanic men, Gregory M. Marcus, MD, of the University of California, San Francisco, and colleagues wrote in a research letter published in Circulation.
“We were surprised to find that American Indians experienced a higher risk of atrial fibrillation, compared to every other racial and ethnic group,” Dr. Marcus said in a press release that accompanied the study. “Understanding the mechanisms and factors by which American Indians experience this higher risk may help investigators better understand the fundamental causes of atrial fibrillation that prove useful to everyone at risk for AFib, regardless of their race or ethnicity.”
The team plumbed the Healthcare Cost and Utilization Project (HCUP) California state databases for information on more than 16 million cases of AFib that occurred during 2005-2011. Native Americans comprised just 0.6% of the cohort. Most of the patients (57.2%) were white; 8% were black, 25.6% Hispanic, and 8.6% Asian. After targeting only new-onset cases, there were 344,469 incident AFib episodes over a median follow-up of 4.1 years.
The overall incidence of AFib in Native Americans was 7.49 per 1,000 person-years, significantly higher than the 6.89 per 1000 person-years observed in the rest of the cohort ( P less than .0001). The difference remained significant even after the team controlled for age, sex, income, and heart and other diseases. Nor was it altered by a sensitivity analysis that controlled for place of presentation and patients who were aged at least 35 years with at least two encounters with medical facilities.
In an interaction analysis, the increased risk appeared to be driven by higher rates of diabetes and chronic kidney disease, the authors wrote.
“This may suggest that the presence of these two processes contributes some pathophysiology related to AF[ib] risk that may be similar to the heightened risk inherent among American Indians,” they wrote. “It is also important to note that there was no evidence of any other statistically significant interactions despite the inclusion of millions of patients.”
Supporting data for these associations were not included in the research letter.
The authors noted some limitations of their study. Race or ethnicity were self-reported and could not be independently confirmed, so there was no way to tease out the effects in multiracial patients. Also, the database didn’t record outpatient encounters, which might result in some selection bias.
“Last, because this was an observational study, these results should not be interpreted as evidence of causal effect,” they noted.
“In conclusion, we observed that American Indians had a higher risk of atrial fibrillation, compared with all other racial and ethnic group. The heightened risk … in American Indians persisted after multivariable adjustment for known conventional confounders and mediators, suggesting that an unidentified characteristic, including possible genetic or environmental factors, may be responsible,” the investigators wrote.
The HCUP database is supported by the Agency for Healthcare Research and Quality. Dr. Marcus reported receiving research support from Jawbone, Medtronic, Eight, and Baylis Medical, and is a consultant for and holds equity in InCarda Therapeutics. The other authors reported no conflicts of interest.
SOURCE: Marcus GM et al. Circulation. 2019 Oct 21. doi:10.1161/CIRCULATIONAHA.119.042882.
FROM CIRCULATION
Regular drinking a greater AFib risk than binge drinking
Regular low-level alcohol consumption may be a bigger risk factor for new-onset atrial fibrillation than binge drinking, according to a paper published online in EP Europace.
Alcohol consumption is known to have a dose-dependent association with the risk of new-onset atrial fibrillation (AFib), but the mechanism underlying this association was not clear, according to Yun Gi Kim, MD, from the Seoul National University (South Korea), and coauthors.
They analyzed data from the Korean National Health Insurance Service database for 9,776,956 individuals without atrial fibrillation at baseline, including health survey information about their alcohol consumption.
Overall, 51.3% of the study population were classified as nondrinkers, 32.1% were mild drinkers – defined as up to 105 g of alcohol consumed per week – 9.7% were moderate drinkers consuming 105-210 g/week, and 6.9% were heavy drinkers consuming 210 g or more per week.
The analysis revealed that heavy drinkers had the highest risk for new-onset AFib – 21.5% higher than mild drinkers – while nondrinkers had an 8.6% higher risk and moderate drinkers had a 7.7% higher risk, compared with mild drinkers.
It also showed an association between the number of drinking sessions per week and the development of new-onset atrial fibrillation. Individuals who only drank once per week had the lowest risk of AFib while those who drank every day had the highest.
“Although weekly alcohol intake was associated with the risk of new-onset [AFib], such association was lost when drinking frequency was included in the multivariate model,” the authors wrote.
They found a significant inverse relationship between the amount of alcohol consumed per drinking session, and the risk of new-onset AFib, such that individuals who consumed low amounts of alcohol per session had a higher risk, and the risk decreased as higher amounts were consumed.
“Regardless of whether weekly alcohol intake exceeded 210 g, the frequency of drinking was significantly associated with risk of new-onset [AFib],” they reported. “Patients who drink everyday represented the highest-risk group and those who drink once per week were the lowest-risk group for new-onset [AFib] in this investigation, respectively.”
The authors speculated that if alcohol consumption can trigger AFib, then multiple drinking episodes per week, regardless of amount, might trigger more episodes of AFib and potentially lead to the development of overt, new-onset disease. They also suggested that frequent drinking could lead to regular sleep disturbance, which might also contribute to the link with atrial fibrillation.
The study was supported by Korea University, Korea University Anam Hospital, Republic of Korea, the National Research Foundation of Korea, the Ministry of Education and the Ministry of Science, ICT, and Future Planning. No conflicts of interest were declared.
SOURCE: Kim YG et al. EP Europace. 2019 Oct 17. doi: 10.1093/europace/euz256.
Regular low-level alcohol consumption may be a bigger risk factor for new-onset atrial fibrillation than binge drinking, according to a paper published online in EP Europace.
Alcohol consumption is known to have a dose-dependent association with the risk of new-onset atrial fibrillation (AFib), but the mechanism underlying this association was not clear, according to Yun Gi Kim, MD, from the Seoul National University (South Korea), and coauthors.
They analyzed data from the Korean National Health Insurance Service database for 9,776,956 individuals without atrial fibrillation at baseline, including health survey information about their alcohol consumption.
Overall, 51.3% of the study population were classified as nondrinkers, 32.1% were mild drinkers – defined as up to 105 g of alcohol consumed per week – 9.7% were moderate drinkers consuming 105-210 g/week, and 6.9% were heavy drinkers consuming 210 g or more per week.
The analysis revealed that heavy drinkers had the highest risk for new-onset AFib – 21.5% higher than mild drinkers – while nondrinkers had an 8.6% higher risk and moderate drinkers had a 7.7% higher risk, compared with mild drinkers.
It also showed an association between the number of drinking sessions per week and the development of new-onset atrial fibrillation. Individuals who only drank once per week had the lowest risk of AFib while those who drank every day had the highest.
“Although weekly alcohol intake was associated with the risk of new-onset [AFib], such association was lost when drinking frequency was included in the multivariate model,” the authors wrote.
They found a significant inverse relationship between the amount of alcohol consumed per drinking session, and the risk of new-onset AFib, such that individuals who consumed low amounts of alcohol per session had a higher risk, and the risk decreased as higher amounts were consumed.
“Regardless of whether weekly alcohol intake exceeded 210 g, the frequency of drinking was significantly associated with risk of new-onset [AFib],” they reported. “Patients who drink everyday represented the highest-risk group and those who drink once per week were the lowest-risk group for new-onset [AFib] in this investigation, respectively.”
The authors speculated that if alcohol consumption can trigger AFib, then multiple drinking episodes per week, regardless of amount, might trigger more episodes of AFib and potentially lead to the development of overt, new-onset disease. They also suggested that frequent drinking could lead to regular sleep disturbance, which might also contribute to the link with atrial fibrillation.
The study was supported by Korea University, Korea University Anam Hospital, Republic of Korea, the National Research Foundation of Korea, the Ministry of Education and the Ministry of Science, ICT, and Future Planning. No conflicts of interest were declared.
SOURCE: Kim YG et al. EP Europace. 2019 Oct 17. doi: 10.1093/europace/euz256.
Regular low-level alcohol consumption may be a bigger risk factor for new-onset atrial fibrillation than binge drinking, according to a paper published online in EP Europace.
Alcohol consumption is known to have a dose-dependent association with the risk of new-onset atrial fibrillation (AFib), but the mechanism underlying this association was not clear, according to Yun Gi Kim, MD, from the Seoul National University (South Korea), and coauthors.
They analyzed data from the Korean National Health Insurance Service database for 9,776,956 individuals without atrial fibrillation at baseline, including health survey information about their alcohol consumption.
Overall, 51.3% of the study population were classified as nondrinkers, 32.1% were mild drinkers – defined as up to 105 g of alcohol consumed per week – 9.7% were moderate drinkers consuming 105-210 g/week, and 6.9% were heavy drinkers consuming 210 g or more per week.
The analysis revealed that heavy drinkers had the highest risk for new-onset AFib – 21.5% higher than mild drinkers – while nondrinkers had an 8.6% higher risk and moderate drinkers had a 7.7% higher risk, compared with mild drinkers.
It also showed an association between the number of drinking sessions per week and the development of new-onset atrial fibrillation. Individuals who only drank once per week had the lowest risk of AFib while those who drank every day had the highest.
“Although weekly alcohol intake was associated with the risk of new-onset [AFib], such association was lost when drinking frequency was included in the multivariate model,” the authors wrote.
They found a significant inverse relationship between the amount of alcohol consumed per drinking session, and the risk of new-onset AFib, such that individuals who consumed low amounts of alcohol per session had a higher risk, and the risk decreased as higher amounts were consumed.
“Regardless of whether weekly alcohol intake exceeded 210 g, the frequency of drinking was significantly associated with risk of new-onset [AFib],” they reported. “Patients who drink everyday represented the highest-risk group and those who drink once per week were the lowest-risk group for new-onset [AFib] in this investigation, respectively.”
The authors speculated that if alcohol consumption can trigger AFib, then multiple drinking episodes per week, regardless of amount, might trigger more episodes of AFib and potentially lead to the development of overt, new-onset disease. They also suggested that frequent drinking could lead to regular sleep disturbance, which might also contribute to the link with atrial fibrillation.
The study was supported by Korea University, Korea University Anam Hospital, Republic of Korea, the National Research Foundation of Korea, the Ministry of Education and the Ministry of Science, ICT, and Future Planning. No conflicts of interest were declared.
SOURCE: Kim YG et al. EP Europace. 2019 Oct 17. doi: 10.1093/europace/euz256.
FROM EP EUROPACE
AF risk is elevated after early-stage breast cancer diagnosis
Women with early-stage breast cancer are at elevated risk for atrial fibrillation (AF) short term and, to a lesser extent, long term, finds a large Canadian cohort study. Risk was higher for those who had received chemotherapy but not tied to specific cardiotoxic drugs or drug classes.
“Cardiovascular disease is a particularly pertinent clinical concern for women diagnosed with early-stage breast cancer,” note the investigators, led by Husam Abdel-Qadir, MD, PhD, FRCPC, Cardiology Clinic, Women’s College Hospital, Toronto. “Many early-stage breast cancer survivors are older than 65 years and have hypertension, diabetes, or left ventricular dysfunction. Accordingly, a diagnosis of AF would translate to a clinically relevant stroke risk for many early-stage breast cancer survivors.”
The investigators undertook a population-based retrospective cohort study of women in the province of Ontario with stage I-III breast cancer diagnosed between April 2007 and December 2016, matching them 1:3 to cancer-free control women on birth year and receipt of breast imaging.
An initial analysis, based on 95,539 breast cancer patients and 217,456 cancer-free controls, showed that the former and latter groups did not differ significantly on the prevalence of preexisting AF (5.3% vs. 5.2%; P = .21), according to results reported in JAMA Network Open.
Main analyses excluded women with preexisting AF, leaving 68,113 breast cancer patients and 204,330 cancer-free controls having a mean follow-up of 5.7 years. Both groups had a mean age of 60 years at baseline, and prevalences of cardiovascular comorbidities were similar. Within the breast cancer group, 50.4% had left-sided disease; overall, 53.2% received chemotherapy and 71.7% received radiation therapy.
At 10 years after diagnosis, breast cancer patients had a small but significant increase in AF incidence relative to control peers (7.4% vs. 6.8%; P less than .001). When the investigators looked at specific time periods, survivors had a significantly elevated AF risk in year 1 postdiagnosis (hazard ratio, 2.16) and after year 5 postdiagnosis (hazard ratio, 1.20), but not during years 2 through 5.
Analyses beginning 1 year after diagnosis showed a slightly smaller but still significant elevation of AF incidence for the breast cancer group at 9 years of follow-up (10 years after diagnosis) (7.0% vs. 6.5%; P less than .001).
Among breast cancer patients, those who received chemotherapy had a higher risk of AF than those who did not (adjusted hazard ratio, 1.23); however, this elevation of risk was not specifically tied to receipt of anthracyclines or trastuzumab (Herceptin) versus other chemotherapy. Risk was not elevated for those who received radiation therapy.
“Our study findings suggest that a diagnosis of early-stage breast cancer may be associated with a small increase in the risk of AF compared with that for cancer-free women,” Dr. Abdel-Qadir and coinvestigators noted. “Since the absolute risk is small, this finding does not warrant routine surveillance but rather should prompt consideration of AF in the differential diagnosis for women with compatible symptoms.
“The early and late periods of increased AF risk in early-stage breast cancer survivors warrant focused research to better understand the underlying causes and subsequent implications,” they concluded.
Dr. Abdel-Qadir reported receiving grants from the Canadian Cardiovascular Society during the conduct of the study, speaker fees from Amgen, and an honorarium for clinical events adjudication committee membership from the Canadian Vigour Centre for a study funded by AstraZeneca. The study was funded by the Canadian Cardiovascular Society Atrial Fibrillation Research Award.
SOURCE: Abdel-Qadir H et al. JAMA Netw Open. 2019 Sep 4;2(9):e1911838.
Women with early-stage breast cancer are at elevated risk for atrial fibrillation (AF) short term and, to a lesser extent, long term, finds a large Canadian cohort study. Risk was higher for those who had received chemotherapy but not tied to specific cardiotoxic drugs or drug classes.
“Cardiovascular disease is a particularly pertinent clinical concern for women diagnosed with early-stage breast cancer,” note the investigators, led by Husam Abdel-Qadir, MD, PhD, FRCPC, Cardiology Clinic, Women’s College Hospital, Toronto. “Many early-stage breast cancer survivors are older than 65 years and have hypertension, diabetes, or left ventricular dysfunction. Accordingly, a diagnosis of AF would translate to a clinically relevant stroke risk for many early-stage breast cancer survivors.”
The investigators undertook a population-based retrospective cohort study of women in the province of Ontario with stage I-III breast cancer diagnosed between April 2007 and December 2016, matching them 1:3 to cancer-free control women on birth year and receipt of breast imaging.
An initial analysis, based on 95,539 breast cancer patients and 217,456 cancer-free controls, showed that the former and latter groups did not differ significantly on the prevalence of preexisting AF (5.3% vs. 5.2%; P = .21), according to results reported in JAMA Network Open.
Main analyses excluded women with preexisting AF, leaving 68,113 breast cancer patients and 204,330 cancer-free controls having a mean follow-up of 5.7 years. Both groups had a mean age of 60 years at baseline, and prevalences of cardiovascular comorbidities were similar. Within the breast cancer group, 50.4% had left-sided disease; overall, 53.2% received chemotherapy and 71.7% received radiation therapy.
At 10 years after diagnosis, breast cancer patients had a small but significant increase in AF incidence relative to control peers (7.4% vs. 6.8%; P less than .001). When the investigators looked at specific time periods, survivors had a significantly elevated AF risk in year 1 postdiagnosis (hazard ratio, 2.16) and after year 5 postdiagnosis (hazard ratio, 1.20), but not during years 2 through 5.
Analyses beginning 1 year after diagnosis showed a slightly smaller but still significant elevation of AF incidence for the breast cancer group at 9 years of follow-up (10 years after diagnosis) (7.0% vs. 6.5%; P less than .001).
Among breast cancer patients, those who received chemotherapy had a higher risk of AF than those who did not (adjusted hazard ratio, 1.23); however, this elevation of risk was not specifically tied to receipt of anthracyclines or trastuzumab (Herceptin) versus other chemotherapy. Risk was not elevated for those who received radiation therapy.
“Our study findings suggest that a diagnosis of early-stage breast cancer may be associated with a small increase in the risk of AF compared with that for cancer-free women,” Dr. Abdel-Qadir and coinvestigators noted. “Since the absolute risk is small, this finding does not warrant routine surveillance but rather should prompt consideration of AF in the differential diagnosis for women with compatible symptoms.
“The early and late periods of increased AF risk in early-stage breast cancer survivors warrant focused research to better understand the underlying causes and subsequent implications,” they concluded.
Dr. Abdel-Qadir reported receiving grants from the Canadian Cardiovascular Society during the conduct of the study, speaker fees from Amgen, and an honorarium for clinical events adjudication committee membership from the Canadian Vigour Centre for a study funded by AstraZeneca. The study was funded by the Canadian Cardiovascular Society Atrial Fibrillation Research Award.
SOURCE: Abdel-Qadir H et al. JAMA Netw Open. 2019 Sep 4;2(9):e1911838.
Women with early-stage breast cancer are at elevated risk for atrial fibrillation (AF) short term and, to a lesser extent, long term, finds a large Canadian cohort study. Risk was higher for those who had received chemotherapy but not tied to specific cardiotoxic drugs or drug classes.
“Cardiovascular disease is a particularly pertinent clinical concern for women diagnosed with early-stage breast cancer,” note the investigators, led by Husam Abdel-Qadir, MD, PhD, FRCPC, Cardiology Clinic, Women’s College Hospital, Toronto. “Many early-stage breast cancer survivors are older than 65 years and have hypertension, diabetes, or left ventricular dysfunction. Accordingly, a diagnosis of AF would translate to a clinically relevant stroke risk for many early-stage breast cancer survivors.”
The investigators undertook a population-based retrospective cohort study of women in the province of Ontario with stage I-III breast cancer diagnosed between April 2007 and December 2016, matching them 1:3 to cancer-free control women on birth year and receipt of breast imaging.
An initial analysis, based on 95,539 breast cancer patients and 217,456 cancer-free controls, showed that the former and latter groups did not differ significantly on the prevalence of preexisting AF (5.3% vs. 5.2%; P = .21), according to results reported in JAMA Network Open.
Main analyses excluded women with preexisting AF, leaving 68,113 breast cancer patients and 204,330 cancer-free controls having a mean follow-up of 5.7 years. Both groups had a mean age of 60 years at baseline, and prevalences of cardiovascular comorbidities were similar. Within the breast cancer group, 50.4% had left-sided disease; overall, 53.2% received chemotherapy and 71.7% received radiation therapy.
At 10 years after diagnosis, breast cancer patients had a small but significant increase in AF incidence relative to control peers (7.4% vs. 6.8%; P less than .001). When the investigators looked at specific time periods, survivors had a significantly elevated AF risk in year 1 postdiagnosis (hazard ratio, 2.16) and after year 5 postdiagnosis (hazard ratio, 1.20), but not during years 2 through 5.
Analyses beginning 1 year after diagnosis showed a slightly smaller but still significant elevation of AF incidence for the breast cancer group at 9 years of follow-up (10 years after diagnosis) (7.0% vs. 6.5%; P less than .001).
Among breast cancer patients, those who received chemotherapy had a higher risk of AF than those who did not (adjusted hazard ratio, 1.23); however, this elevation of risk was not specifically tied to receipt of anthracyclines or trastuzumab (Herceptin) versus other chemotherapy. Risk was not elevated for those who received radiation therapy.
“Our study findings suggest that a diagnosis of early-stage breast cancer may be associated with a small increase in the risk of AF compared with that for cancer-free women,” Dr. Abdel-Qadir and coinvestigators noted. “Since the absolute risk is small, this finding does not warrant routine surveillance but rather should prompt consideration of AF in the differential diagnosis for women with compatible symptoms.
“The early and late periods of increased AF risk in early-stage breast cancer survivors warrant focused research to better understand the underlying causes and subsequent implications,” they concluded.
Dr. Abdel-Qadir reported receiving grants from the Canadian Cardiovascular Society during the conduct of the study, speaker fees from Amgen, and an honorarium for clinical events adjudication committee membership from the Canadian Vigour Centre for a study funded by AstraZeneca. The study was funded by the Canadian Cardiovascular Society Atrial Fibrillation Research Award.
SOURCE: Abdel-Qadir H et al. JAMA Netw Open. 2019 Sep 4;2(9):e1911838.
FROM JAMA NETWORK OPEN
Dual therapy best for AFib with ACS no matter the treatment strategy
SAN FRANCISCO – Anticoagulation with apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have an acute coronary syndrome, compared with regimens that include vitamin K antagonists, aspirin, or both.
The findings come from a prespecified analysis of data from the AUGUSTUS trial presented by Stephan Windecker, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting.
“This study adds very important information [to the notion] that triple therapy in the setting of atrial fibrillation and PCI [percutaneous coronary intervention] is really not the way to go,” Ori Ben-Yehuda, MD, FACC, executive director of the Cardiovascular Research Foundation’s Clinical Trials Center, said during a media briefing.
In the recent multicenter AUGUSTUS trial, Dr. Windecker, of the department of cardiology at Bern University Hospital, Switzerland, and colleagues found that among 4,614 patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, apixaban without aspirin resulted in less bleeding, fewer hospitalizations, and no significant differences in ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both (N Engl J Med. 2019;380:1509-24). For this prespecified analysis, the researchers used a 2×2 factorial design to compare apixaban with VKA and aspirin with placebo in the AUGUSTUS trial participants with ACS treated medically (group 1; 1,097 patients, or 24%), those with ACS treated with PCI (group 2; 1,714 patients, or 37%), and those undergoing elective PCI (group 3; 1,784 patients, or 39%). The outcomes of interest were bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in the study participants. This marks the only trial in the field that included patients with ACS managed medically, Dr. Windecker said.
At baseline, the median age of patients was 71 years, 30% were female, 36% had diabetes, and 45% had heart failure. Patients managed medically were younger (a median age of 70) and more frequently female; 57% presented with heart failure. The groups had identical CHA2DS2VASc scores (4), and very similar HAS-BLED scores (2 in groups 1 and 2, and 3 in group 3).
Apixaban compared with VKA showed lower International Society on Thrombosis and Haemostasis–defined major or clinically relevant nonmajor bleeding among patients in group 1 (HR, 0.44), group 2 (HR, 0.68), and group 3 (HR, 0.82) (P for interaction = .052). Apixaban compared with VKA reduced death or hospitalization among patients in group 1 (HR, 0.71), group 2 (HR 0.88), and group 3 (HR, 0.87) (P for interaction = .345). Compared with VKA, apixaban resulted in a similar effect on death and ischemic events among patients in all three treatment groups (P for interaction = .356).
Compared with placebo, aspirin had a higher rate of bleeding among patients in group 1 (HR, 1.49), group 2 (HR, 2.02) and group 3 (HR, 1.91) (P for interaction = .479). For the same comparison, there was no difference in outcomes among the three groups for the composite of death or hospitalization and death and ischemic events.
“The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups,” Dr. Windecker said. The reasons why patients received medical therapy remain unclear, “because it was at the physician’s discretion as to whether they were treated medically or underwent PCI,” he said. “The proportion very much reflects our clinical practice, where 20%-25% of patients are treated medically. What was surprising for me is that I would have anticipated there would be more elderly patients with comorbidities, but I did anticipate that there would be more female patients (in this subgroup).”
Robert A. Harrington, MD, an interventional cardiologist at Stanford (Calif.) University who served on the Data Safety and Monitoring Board for the trial, noted that the patients with atrial fibrillation represent 7%-10% of all ACS patients, “so it’s a big population,” he said. “What’s been disappointing is that none of the trials have been big enough to uncouple the bleeding vs. ischemic issue. We don’t know the answer for how long do you need the triple therapy versus when you can switch to the double therapy.”
Dr. Windecker said that the optimal duration of short-term aspirin remains unclear in this patient population. “Whether there is a benefit of giving aspirin for 2 weeks or 4 weeks remains unanswered,” he said. “Triple therapy is not the way to go, but we need to fine-tune, and probably individualize, which patients may benefit from a certain duration of aspirin.”
The study results were published online at the time of presentation (Circulation 2019 Sep 26. doi: 10.1161/CIRCULATIONAHA.119.043308.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer Inc. Dr. Windecker reported having received institutional research and educational grants to Bern University Hospital from Abbott, Amgen, Bayer, BMS, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. His coauthors reported having numerous financial ties to the pharmaceutical and device industries.
SOURCE: Windecker S. TCT 2019, Late-Breaking Trials 1 session.
SAN FRANCISCO – Anticoagulation with apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have an acute coronary syndrome, compared with regimens that include vitamin K antagonists, aspirin, or both.
The findings come from a prespecified analysis of data from the AUGUSTUS trial presented by Stephan Windecker, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting.
“This study adds very important information [to the notion] that triple therapy in the setting of atrial fibrillation and PCI [percutaneous coronary intervention] is really not the way to go,” Ori Ben-Yehuda, MD, FACC, executive director of the Cardiovascular Research Foundation’s Clinical Trials Center, said during a media briefing.
In the recent multicenter AUGUSTUS trial, Dr. Windecker, of the department of cardiology at Bern University Hospital, Switzerland, and colleagues found that among 4,614 patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, apixaban without aspirin resulted in less bleeding, fewer hospitalizations, and no significant differences in ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both (N Engl J Med. 2019;380:1509-24). For this prespecified analysis, the researchers used a 2×2 factorial design to compare apixaban with VKA and aspirin with placebo in the AUGUSTUS trial participants with ACS treated medically (group 1; 1,097 patients, or 24%), those with ACS treated with PCI (group 2; 1,714 patients, or 37%), and those undergoing elective PCI (group 3; 1,784 patients, or 39%). The outcomes of interest were bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in the study participants. This marks the only trial in the field that included patients with ACS managed medically, Dr. Windecker said.
At baseline, the median age of patients was 71 years, 30% were female, 36% had diabetes, and 45% had heart failure. Patients managed medically were younger (a median age of 70) and more frequently female; 57% presented with heart failure. The groups had identical CHA2DS2VASc scores (4), and very similar HAS-BLED scores (2 in groups 1 and 2, and 3 in group 3).
Apixaban compared with VKA showed lower International Society on Thrombosis and Haemostasis–defined major or clinically relevant nonmajor bleeding among patients in group 1 (HR, 0.44), group 2 (HR, 0.68), and group 3 (HR, 0.82) (P for interaction = .052). Apixaban compared with VKA reduced death or hospitalization among patients in group 1 (HR, 0.71), group 2 (HR 0.88), and group 3 (HR, 0.87) (P for interaction = .345). Compared with VKA, apixaban resulted in a similar effect on death and ischemic events among patients in all three treatment groups (P for interaction = .356).
Compared with placebo, aspirin had a higher rate of bleeding among patients in group 1 (HR, 1.49), group 2 (HR, 2.02) and group 3 (HR, 1.91) (P for interaction = .479). For the same comparison, there was no difference in outcomes among the three groups for the composite of death or hospitalization and death and ischemic events.
“The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups,” Dr. Windecker said. The reasons why patients received medical therapy remain unclear, “because it was at the physician’s discretion as to whether they were treated medically or underwent PCI,” he said. “The proportion very much reflects our clinical practice, where 20%-25% of patients are treated medically. What was surprising for me is that I would have anticipated there would be more elderly patients with comorbidities, but I did anticipate that there would be more female patients (in this subgroup).”
Robert A. Harrington, MD, an interventional cardiologist at Stanford (Calif.) University who served on the Data Safety and Monitoring Board for the trial, noted that the patients with atrial fibrillation represent 7%-10% of all ACS patients, “so it’s a big population,” he said. “What’s been disappointing is that none of the trials have been big enough to uncouple the bleeding vs. ischemic issue. We don’t know the answer for how long do you need the triple therapy versus when you can switch to the double therapy.”
Dr. Windecker said that the optimal duration of short-term aspirin remains unclear in this patient population. “Whether there is a benefit of giving aspirin for 2 weeks or 4 weeks remains unanswered,” he said. “Triple therapy is not the way to go, but we need to fine-tune, and probably individualize, which patients may benefit from a certain duration of aspirin.”
The study results were published online at the time of presentation (Circulation 2019 Sep 26. doi: 10.1161/CIRCULATIONAHA.119.043308.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer Inc. Dr. Windecker reported having received institutional research and educational grants to Bern University Hospital from Abbott, Amgen, Bayer, BMS, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. His coauthors reported having numerous financial ties to the pharmaceutical and device industries.
SOURCE: Windecker S. TCT 2019, Late-Breaking Trials 1 session.
SAN FRANCISCO – Anticoagulation with apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have an acute coronary syndrome, compared with regimens that include vitamin K antagonists, aspirin, or both.
The findings come from a prespecified analysis of data from the AUGUSTUS trial presented by Stephan Windecker, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting.
“This study adds very important information [to the notion] that triple therapy in the setting of atrial fibrillation and PCI [percutaneous coronary intervention] is really not the way to go,” Ori Ben-Yehuda, MD, FACC, executive director of the Cardiovascular Research Foundation’s Clinical Trials Center, said during a media briefing.
In the recent multicenter AUGUSTUS trial, Dr. Windecker, of the department of cardiology at Bern University Hospital, Switzerland, and colleagues found that among 4,614 patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, apixaban without aspirin resulted in less bleeding, fewer hospitalizations, and no significant differences in ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both (N Engl J Med. 2019;380:1509-24). For this prespecified analysis, the researchers used a 2×2 factorial design to compare apixaban with VKA and aspirin with placebo in the AUGUSTUS trial participants with ACS treated medically (group 1; 1,097 patients, or 24%), those with ACS treated with PCI (group 2; 1,714 patients, or 37%), and those undergoing elective PCI (group 3; 1,784 patients, or 39%). The outcomes of interest were bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in the study participants. This marks the only trial in the field that included patients with ACS managed medically, Dr. Windecker said.
At baseline, the median age of patients was 71 years, 30% were female, 36% had diabetes, and 45% had heart failure. Patients managed medically were younger (a median age of 70) and more frequently female; 57% presented with heart failure. The groups had identical CHA2DS2VASc scores (4), and very similar HAS-BLED scores (2 in groups 1 and 2, and 3 in group 3).
Apixaban compared with VKA showed lower International Society on Thrombosis and Haemostasis–defined major or clinically relevant nonmajor bleeding among patients in group 1 (HR, 0.44), group 2 (HR, 0.68), and group 3 (HR, 0.82) (P for interaction = .052). Apixaban compared with VKA reduced death or hospitalization among patients in group 1 (HR, 0.71), group 2 (HR 0.88), and group 3 (HR, 0.87) (P for interaction = .345). Compared with VKA, apixaban resulted in a similar effect on death and ischemic events among patients in all three treatment groups (P for interaction = .356).
Compared with placebo, aspirin had a higher rate of bleeding among patients in group 1 (HR, 1.49), group 2 (HR, 2.02) and group 3 (HR, 1.91) (P for interaction = .479). For the same comparison, there was no difference in outcomes among the three groups for the composite of death or hospitalization and death and ischemic events.
“The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups,” Dr. Windecker said. The reasons why patients received medical therapy remain unclear, “because it was at the physician’s discretion as to whether they were treated medically or underwent PCI,” he said. “The proportion very much reflects our clinical practice, where 20%-25% of patients are treated medically. What was surprising for me is that I would have anticipated there would be more elderly patients with comorbidities, but I did anticipate that there would be more female patients (in this subgroup).”
Robert A. Harrington, MD, an interventional cardiologist at Stanford (Calif.) University who served on the Data Safety and Monitoring Board for the trial, noted that the patients with atrial fibrillation represent 7%-10% of all ACS patients, “so it’s a big population,” he said. “What’s been disappointing is that none of the trials have been big enough to uncouple the bleeding vs. ischemic issue. We don’t know the answer for how long do you need the triple therapy versus when you can switch to the double therapy.”
Dr. Windecker said that the optimal duration of short-term aspirin remains unclear in this patient population. “Whether there is a benefit of giving aspirin for 2 weeks or 4 weeks remains unanswered,” he said. “Triple therapy is not the way to go, but we need to fine-tune, and probably individualize, which patients may benefit from a certain duration of aspirin.”
The study results were published online at the time of presentation (Circulation 2019 Sep 26. doi: 10.1161/CIRCULATIONAHA.119.043308.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer Inc. Dr. Windecker reported having received institutional research and educational grants to Bern University Hospital from Abbott, Amgen, Bayer, BMS, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. His coauthors reported having numerous financial ties to the pharmaceutical and device industries.
SOURCE: Windecker S. TCT 2019, Late-Breaking Trials 1 session.
AT TCT 2019
Rivaroxaban bests combo therapy in post-PCI AFib
PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.
The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.
Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”
The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.
Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.
The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.
Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).
The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.
On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.
Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.
These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).
Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.
Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.
Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.
The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.
Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”
Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.
Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.
However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.
Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.
In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.
The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.
Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.
“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”
Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.
Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).
The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.
SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.
PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.
The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.
Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”
The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.
Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.
The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.
Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).
The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.
On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.
Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.
These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).
Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.
Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.
Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.
The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.
Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”
Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.
Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.
However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.
Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.
In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.
The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.
Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.
“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”
Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.
Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).
The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.
SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.
PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.
The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.
Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”
The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.
Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.
The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.
Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).
The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.
On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.
Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.
These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).
Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.
Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.
Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.
The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.
Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”
Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.
Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.
However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.
Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.
In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.
The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.
Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.
“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”
Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.
Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).
The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.
SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.
AT THE ESC CONGRESS 2019
Dapagliflozin given Fast Track status for HF therapy
The decision is based on results from two phase 3 trials – DAPA-HF and DELIVER – that assessed dapagliflozin in patients with HFrEF and HFpEF, respectively.
Dapagliflozin, an oral, once-daily sodium-glucose transporter 2 inhibitor, was first approved as monotherapy and as part of combination therapy for the improvement of glycemic control in adults with type 2 diabetes. It was also granted Fast Track designation in August 2019 as a therapy for chronic renal disease, both to slow progression of renal failure and to prevent cardiovascular and renal death.
“Heart failure affects approximately 64 million people worldwide, and about half will die within 5 years of diagnosis,” Mene Pangalos, executive vice president of biopharmaceuticals research and development, said in the AstraZeneca press release. “This Fast Track designation for Farxiga brings us closer to fulfilling our ambition to help prevent, treat and cure heart failure, and we look forward to working with the FDA to explore Farxiga as a potential new treatment option for heart failure patients.”
The decision is based on results from two phase 3 trials – DAPA-HF and DELIVER – that assessed dapagliflozin in patients with HFrEF and HFpEF, respectively.
Dapagliflozin, an oral, once-daily sodium-glucose transporter 2 inhibitor, was first approved as monotherapy and as part of combination therapy for the improvement of glycemic control in adults with type 2 diabetes. It was also granted Fast Track designation in August 2019 as a therapy for chronic renal disease, both to slow progression of renal failure and to prevent cardiovascular and renal death.
“Heart failure affects approximately 64 million people worldwide, and about half will die within 5 years of diagnosis,” Mene Pangalos, executive vice president of biopharmaceuticals research and development, said in the AstraZeneca press release. “This Fast Track designation for Farxiga brings us closer to fulfilling our ambition to help prevent, treat and cure heart failure, and we look forward to working with the FDA to explore Farxiga as a potential new treatment option for heart failure patients.”
The decision is based on results from two phase 3 trials – DAPA-HF and DELIVER – that assessed dapagliflozin in patients with HFrEF and HFpEF, respectively.
Dapagliflozin, an oral, once-daily sodium-glucose transporter 2 inhibitor, was first approved as monotherapy and as part of combination therapy for the improvement of glycemic control in adults with type 2 diabetes. It was also granted Fast Track designation in August 2019 as a therapy for chronic renal disease, both to slow progression of renal failure and to prevent cardiovascular and renal death.
“Heart failure affects approximately 64 million people worldwide, and about half will die within 5 years of diagnosis,” Mene Pangalos, executive vice president of biopharmaceuticals research and development, said in the AstraZeneca press release. “This Fast Track designation for Farxiga brings us closer to fulfilling our ambition to help prevent, treat and cure heart failure, and we look forward to working with the FDA to explore Farxiga as a potential new treatment option for heart failure patients.”