Conference Coverage

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

A version of this article first appeared on Medscape.com.

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

A version of this article first appeared on Medscape.com.

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

A version of this article first appeared on Medscape.com.

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

mzoler@mdedge.com
 

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

mzoler@mdedge.com
 

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

mzoler@mdedge.com
 

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

A version of this article first appeared on Medscape.com.

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

A version of this article first appeared on Medscape.com.

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

A version of this article first appeared on Medscape.com.

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

A version of this article first appeared on Medscape.com.

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

A version of this article first appeared on Medscape.com.

Patients with acute coronary syndromes who have been taking the antiplatelet medication, ticagrelor, and who need coronary artery bypass surgery (CABG) may be able to safely have the procedure earlier than typically recommended, a new randomized trial suggests.

The RAPID CABG trial found that early surgery 2-3 days after ticagrelor cessation was noninferior in incurring severe or massive perioperative bleeding, compared with waiting 5-7 days. There was also no significant difference in TIMI CABG or Bleeding Academic Research Consortium (BARC) type 4 or 5 bleeding.

Patients in the delayed group had a numerically higher number of ischemic events requiring earlier surgery and had a longer hospital stay.

The study was presented at the American Heart Association scientific sessions.

“RAPID CABG is the first and only randomized controlled trial evaluating the safety of early surgery in patients taking ticagrelor,” said lead investigator Derek So, MD.

Dr. So, a cardiologist at the University of Ottawa Heart Institute and a professor at the University of Ottawa, explained that ticagrelor is a first-line antiplatelet agent for patients with acute coronary syndromes (ACS), but around 10% of patients presenting with ACS require CABG surgery.

A major concern among patients requiring bypass surgery is perioperative bleeding, and it has been shown that patients undergoing urgent bypass within 24 hours of the last dose of ticagrelor have increased mortality. Accordingly, guidelines suggest a waiting period for patients not requiring urgent bypass surgery, Dr. So noted.

Current North American guidelines suggest a waiting period of at least 5 days after stopping ticagrelor before bypass surgery. In contrast, the updated European and Japanese guidelines suggest a waiting period of 3 days.

Dr. So noted that all of the guidelines are based on cohort studies and pharmacodynamic studies, with no randomized evidence. Pharmacodynamic studies have shown that at 48 hours after the last dose of ticagrelor, the level of platelet inhibition drops to the same levels seen with long-term treatment with clopidogrel, a weaker antiplatelet drug, and after 120 hours (5 days) the effect has completely worn off.

Dr. So concluded that these new results from the RAPID CABG trial “may influence future iterations of North American guidelines with reduced waiting prior to bypass surgery” for patients receiving ticagrelor, and “they could also strengthen the level of evidence in European and Asian guidelines.”

Designated discussant of the RAPID CABG trial, Roxana Mehran, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, said this was a “very important study,” being the only randomized trial to look at this issue to date.

Dr. Mehran noted that the results showed a similar number of major life-threatening bleeding events in the early and delayed groups and met the noninferiority endpoint, but she pointed out that the trial had a small sample size and a small number of events. “Therefore, larger trials are needed to verify these important and encouraging results.”

However, she concluded that these results should be considered in decisions about the timing of bypass surgery in patients receiving ticagrelor. “I will be changing my practice and sending patients earlier based on this data,” she said.

 RAPID CABG

RAPID CABG was a physician-initiated multicenter randomized study evaluating the safety of early surgery at 2-3 days after ticagrelor cessation, compared with a delay of 5-7 days among patients presenting with ACS who required nonemergency CABG surgery.

The study enrolled 143 patients with ACS who were receiving ticagrelor and needed CABG surgery. Patients with stenting for culprit lesions, those requiring urgent surgery (less than 24 hours after presentation), and those requiring valve surgery were excluded.   

Three patients declined surgery, and several others underwent surgery outside the assigned time window, so the results were based on the per protocol analysis of patients who actually had CABG in the assigned time window: 65 patients in the early CABG group and 58 in the delayed group.

The mean time from last ticagrelor dose to surgery was 3 days in the early group and 6 days in the delayed group.

Platelet reactivity on the VerifyNow test showed more residual antiplatelet activity in the early group, with P2Y12 reaction unit (PRU) levels of 200 (vs. 251 in the delayed group). This test measures the extent of platelet aggregation in the presence of P2Y12-inhibitor drugs, with lower PRU levels showing stronger antiplatelet effects.

The primary outcome of the study was severe or massive bleeding by Universal Definition of Perioperative Bleeding (UDPB) class 3 or 4. This is defined as a blood transfusions of more than 5 units of red blood cells or plasma within 24 hours of surgical closure, chest tube drainage of over 1,000 mL in the first 12 hours, and reoperation for bleeding.

Results showed that 4.6% of the early-surgery group had a primary outcome bleeding event, compared with 5.2% of the delayed surgery group, meeting the criteria for noninferiority (P = .0253 for noninferiority).

Individual components of the primary endpoint showed three class 3 (severe) bleeding events in both groups and no class 4 (massive) bleeding events in either group.  

In terms of other bleeding outcomes, TIMI CABG bleeding occurred in two patients (3.1%) in the early-surgery group vs. no patients in the delayed group; BARC 4 bleeding occurred in two patients (3.1%) in the early group versus none in the delayed group, and there were no BARC 5 bleeding events in either group.

In the intention-to-treat analysis, ischemic events before surgery occurred in six patients (8.7%) in the delayed group (one myocardial infarction, four cases of recurrent ischemia, and one ventricular tachycardia) versus none in the early group.

Cumulative 6-month ischemic events occurred in nine patients (13.0%) in the delayed group vs. four patients (5.6%) in the early group, the difference being driven by nonfatal MI and recurrent ischemia.  

There were no cardiovascular deaths in either group and one all-cause death in both groups.

Patients undergoing early surgery also had a shorter hospitalization, with a median length of stay of 9 days versus 12 days in the delayed group.

Larger trial needed

Commenting on the RAPID CABG study at an AHA press conference, Joanna Chikwe, MD, chair of the cardiac surgery department at Cedars-Sinai Medical Center, Los Angeles, said the results were in line with her practice.

“These results confirm what I already think is safe,” she said. “I’m comfortable going within 48 hours. But we individualize our approach, so it was helpful that the study investigators included platelet reactivity data. The interesting thing for me in this study was the number of adverse events in patients who waited longer.” 

Dr. Chikwe said her top-line message was that “Surgery looked incredibly safe; there was amazingly low mortality. And if a patient has an indication for surgery, waiting does not serve you well.”

However, she also cautioned that the trial was somewhat underpowered, with a small number of events that drove the primary outcome, leading to some uncertainty on the results.

“The RAPID trial was helpful, and although it confirms my practice, I think physicians may want to see a larger-powered trial to be convincingly compelled that they should change their practice,” Dr. Chikwe noted.  

She added that clinical trials in cardiac surgery are driven by inherent challenges. “Cardiac surgery is not very common, and it is hard to recruit patients into these trials, so you are generally tied to a small number of patients, and you therefore have to be extremely thoughtful about the study design. It is almost a given that you will need to use surrogate endpoints, and the choice of the surrogate endpoint can determine which way the trial goes.”

The RAPID CABG study was funded by the Canadian Institutes of Health Research. Dr. So reports research support, consultancy, or speaker’s fees from AggreDyne, Roche Diagnostics, Fujimori Kogyo, and AstraZeneca Canada. Dr. Mehran reports that her institution has received significant trial funding from AstraZeneca (the manufacturer of ticagrelor).  

A version of this article first appeared on Medscape.com.

Tricuspid valve repair at the time of mitral valve surgery reduces tricuspid regurgitation progression, but at the cost of more than a fivefold increase in permanent pacemakers, results of a new Cardiothoracic Surgical Trials Network study show.

The results were presented during the opening late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

Tricuspid regurgitation (TR) is common among patients undergoing mitral valve surgery, and there’s broad agreement to intervene when a patient has severe TR. There’s uncertainty, however, about the management of moderate or less TR during mitral valve surgery, which is reflected in current guidelines on the basis of observational data, explained coprimary investigator James Gammie, MD, codirector and surgical director of the Johns Hopkins Heart and Vascular Institute, Baltimore. As a result, rates of concomitant tricuspid-mitral surgery range from 5% to 75% at various centers.

To help fill the gap, Dr. Gammie and colleagues screened 5,208 patients at 29 centers in the United States, Canada, and Germany undergoing surgery for degenerative mitral regurgitation, and randomly assigned 401 patients (75% male) to mitral valve surgery alone or with tricuspid annuloplasty.

Patients had either moderate TR (37%) or less than moderate TR with a dilated tricuspid annulus of at least 40 mm or at least 21 mm/m² indexed for body surface area. Importantly, there was a uniform surgical approach using undersized (26-30 mm) rigid nonplanar annuloplasty rings to repair the tricuspid valve, he said.

The study’s primary outcome of treatment failure at 2 years was defined as the composite of death, reoperation for TR, or progression of TR from baseline by 2 grades or severe TR.

The primary endpoint occurred in 10.2% of patients who underwent mitral valve surgery alone and 3.9% who underwent concomitant tricuspid annuloplasty (relative risk, 0.37; 95% confidence interval, 0.16-0.86; P = .02).

The endpoint was driven exclusively by less TR progression in the annuloplasty group, with no TR reoperations in either group, observed Dr. Gammie. At 2 years, just 0.6% of the annuloplasty group had severe TR, compared with 5.6% of the surgery-alone group.

The rate of permanent pacemaker implantations, however, jumped from 2.5% with surgery alone to 14.1% with concomitant tricuspid annuloplasty (rate ratio, 5.75; 95% CI, 2.27-14.60). More than half of pacemakers were placed during the first 2 days after surgery.

There was no between-group difference in 2-year rates of all-cause mortality, major adverse cardiac and cerebrovascular events, readmission, quality of life, or functional status.

Less than moderate TR

In a post hoc analysis stratified by baseline TR severity, treatment failure was significantly less common with surgery plus tricuspid annuloplasty among patients with moderate TR (4.5% vs. 18.1%) but not among those with less than moderate TR and tricuspid annular dilation (3.4% vs. 6.1%).

Although the trial was not powered for the subgroup analysis, “these results call into question the idea that less than moderate TR with annular dilation should be an indication for tricuspid valve repair,” Dr. Gammie told this news organization.

“I did not repair the tricuspid valve in the setting of less than moderate TR before the trial, and my practice won’t change; but it will be based on much better evidence,” he added. “Of course, long-term data from our trial will be of great interest.”

Discussant Joseph Woo, MD, chair of surgery at Stanford (Calif.) University, congratulated the authors on a “landmark trial” that addresses a highly relevant problem without a clear-cut indication.

In the 2020 AHA/American College of Cardiology heart valve disease guideline, tricuspid valve surgery is a class I recommendation when there’s severe TR (stages C and D) and left-sided valve surgery but a class IIa recommendation in patients with progressive TR (stage B) with an annular dilation of at least 40 mm.

“The interesting findings in this study include that moderate TR was only 37% of the enrolled patients, and only 97% of the patients with degenerative MR received a mitral valve repair,” Dr. Woo said. “This level of mitral valve repair is perhaps lower than what we might expect at these centers and lower, certainly, than what the AHA/ACC guidelines recommend for surgery on asymptomatic severe mitral regurgitation.”

Panelist Roxanna Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York said, “What I was struck by is that we, as clinicians, believe that if you fix the mitral valve, maybe the tricuspid regurgitation will improve. And it seems like that is not what’s happening, and I think that’s a big takeaway.”

Session comoderator Joanna Chikwe, MD, head of cardiac surgery at Cedars-Sinai Medical Center, Los Angeles, said, “I think we can all agree that severe tricuspid regurgitation is a disaster for patients, and I think the fact the trial is designed for an additional 5 years’ follow-up will hopefully give us some insights into the clinical impact of severe tricuspid regurgitation.”

For now, “a back of the envelope calculation suggests that, for every 20 patients with moderate tricuspid regurgitation who we repair the tricuspid valve in, we would prevent severe tricuspid valve regurgitation in 1 at the price of pacemakers in 2,” she said.

Dr. Chikwe said in an interview that “transcatheter tricuspid repair is increasingly helping these patients, but if you could avoid it with a technique that doesn’t cause incremental harm beyond, perhaps, the need for pacemakers, then this is helpful data that supports that approach.”

The pacemaker burden is not negligible, she said, but also not surprising to surgeons. “If you look at national practice of mitral-tricuspid surgery, it’s about 15% after that, and it’s simply because the conduction tissue is so close to the tricuspid annulus.”

Pacemaker implantation rates, like those for concomitant tricuspid-mitral surgery, are also highly variable, and in some single-center series only around 2%, Dr. Chikwe said. “So that suggests there are technical approaches that can minimize the pacemaker rate [such as] being extremely careful to avoid suture placement around the area of the conduction tissues.”

For some the trade-off between reduced TR progression and the risk of a permanent pacemaker is worth it. “But the fact that the trial didn’t show a difference in survival, a difference in symptoms or quality of life, might suggest that patients you anticipated were high risk for surgery or didn’t have a longer projected survival aren’t going to benefit from what is quite an aggressive surgical approach,” Dr. Chikwe said.

In an accompanying editorial, Dr. Chikwe and Mario Gaudino, MD, of Weill Cornell Medicine, New York, also point out that the “very dynamic nature of tricuspid regurgitation and wide variability in assessing tricuspid annular dilatation are additional compelling reasons to leave lesser regurgitation alone.”

Julia Grapsa, MD, PhD, Kings College and tricuspid service lead at Guys and St. Thomas NHS, London, also pointed to the need for longer-term follow-up but said increased use of imaging markers is also needed to help pinpoint TR progression in these patients. “For the moment, the results should remind imagers and clinicians to refer patients earlier.”

“As a valvular heart physician, I see more and more patients coming in with significant severe tricuspid regurgitation post–mitral valve surgery and because of the time that’s passed, there’s dysfunction of the right heart, the left heart, and it’s very hard to suggest an operation because they’re at high risk,” she said. “So we’re discussing with these patients whether to do an intervention or medical management.”

“Now, with this study, and the pending longer follow-up by the authors, I’m optimistic that the class II recommendation will be class I in order to help our patients treat tricuspid regurgitation earlier than late,” said Dr. Grapsa, who is also editor-in-chief of JACC: Case Reports.

The study was funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research. Dr. Gammie reports a consultant/stockholder relationship with Edwards Lifesciences. Dr. Grapsa reports no conflicts of interest. Dr. Chikwe reports that as coprincipal investigator/study director of NCT 05051033 (an NHLBI-sponsored Cardiothoracic Surgical Trials Network trial), she collaborates with several of the study authors.
 

A version of this article first appeared on Medscape.com.

Tricuspid valve repair at the time of mitral valve surgery reduces tricuspid regurgitation progression, but at the cost of more than a fivefold increase in permanent pacemakers, results of a new Cardiothoracic Surgical Trials Network study show.

The results were presented during the opening late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

Tricuspid regurgitation (TR) is common among patients undergoing mitral valve surgery, and there’s broad agreement to intervene when a patient has severe TR. There’s uncertainty, however, about the management of moderate or less TR during mitral valve surgery, which is reflected in current guidelines on the basis of observational data, explained coprimary investigator James Gammie, MD, codirector and surgical director of the Johns Hopkins Heart and Vascular Institute, Baltimore. As a result, rates of concomitant tricuspid-mitral surgery range from 5% to 75% at various centers.

To help fill the gap, Dr. Gammie and colleagues screened 5,208 patients at 29 centers in the United States, Canada, and Germany undergoing surgery for degenerative mitral regurgitation, and randomly assigned 401 patients (75% male) to mitral valve surgery alone or with tricuspid annuloplasty.

Patients had either moderate TR (37%) or less than moderate TR with a dilated tricuspid annulus of at least 40 mm or at least 21 mm/m² indexed for body surface area. Importantly, there was a uniform surgical approach using undersized (26-30 mm) rigid nonplanar annuloplasty rings to repair the tricuspid valve, he said.

The study’s primary outcome of treatment failure at 2 years was defined as the composite of death, reoperation for TR, or progression of TR from baseline by 2 grades or severe TR.

The primary endpoint occurred in 10.2% of patients who underwent mitral valve surgery alone and 3.9% who underwent concomitant tricuspid annuloplasty (relative risk, 0.37; 95% confidence interval, 0.16-0.86; P = .02).

The endpoint was driven exclusively by less TR progression in the annuloplasty group, with no TR reoperations in either group, observed Dr. Gammie. At 2 years, just 0.6% of the annuloplasty group had severe TR, compared with 5.6% of the surgery-alone group.

The rate of permanent pacemaker implantations, however, jumped from 2.5% with surgery alone to 14.1% with concomitant tricuspid annuloplasty (rate ratio, 5.75; 95% CI, 2.27-14.60). More than half of pacemakers were placed during the first 2 days after surgery.

There was no between-group difference in 2-year rates of all-cause mortality, major adverse cardiac and cerebrovascular events, readmission, quality of life, or functional status.

Less than moderate TR

In a post hoc analysis stratified by baseline TR severity, treatment failure was significantly less common with surgery plus tricuspid annuloplasty among patients with moderate TR (4.5% vs. 18.1%) but not among those with less than moderate TR and tricuspid annular dilation (3.4% vs. 6.1%).

Although the trial was not powered for the subgroup analysis, “these results call into question the idea that less than moderate TR with annular dilation should be an indication for tricuspid valve repair,” Dr. Gammie told this news organization.

“I did not repair the tricuspid valve in the setting of less than moderate TR before the trial, and my practice won’t change; but it will be based on much better evidence,” he added. “Of course, long-term data from our trial will be of great interest.”

Discussant Joseph Woo, MD, chair of surgery at Stanford (Calif.) University, congratulated the authors on a “landmark trial” that addresses a highly relevant problem without a clear-cut indication.

In the 2020 AHA/American College of Cardiology heart valve disease guideline, tricuspid valve surgery is a class I recommendation when there’s severe TR (stages C and D) and left-sided valve surgery but a class IIa recommendation in patients with progressive TR (stage B) with an annular dilation of at least 40 mm.

“The interesting findings in this study include that moderate TR was only 37% of the enrolled patients, and only 97% of the patients with degenerative MR received a mitral valve repair,” Dr. Woo said. “This level of mitral valve repair is perhaps lower than what we might expect at these centers and lower, certainly, than what the AHA/ACC guidelines recommend for surgery on asymptomatic severe mitral regurgitation.”

Panelist Roxanna Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York said, “What I was struck by is that we, as clinicians, believe that if you fix the mitral valve, maybe the tricuspid regurgitation will improve. And it seems like that is not what’s happening, and I think that’s a big takeaway.”

Session comoderator Joanna Chikwe, MD, head of cardiac surgery at Cedars-Sinai Medical Center, Los Angeles, said, “I think we can all agree that severe tricuspid regurgitation is a disaster for patients, and I think the fact the trial is designed for an additional 5 years’ follow-up will hopefully give us some insights into the clinical impact of severe tricuspid regurgitation.”

For now, “a back of the envelope calculation suggests that, for every 20 patients with moderate tricuspid regurgitation who we repair the tricuspid valve in, we would prevent severe tricuspid valve regurgitation in 1 at the price of pacemakers in 2,” she said.

Dr. Chikwe said in an interview that “transcatheter tricuspid repair is increasingly helping these patients, but if you could avoid it with a technique that doesn’t cause incremental harm beyond, perhaps, the need for pacemakers, then this is helpful data that supports that approach.”

The pacemaker burden is not negligible, she said, but also not surprising to surgeons. “If you look at national practice of mitral-tricuspid surgery, it’s about 15% after that, and it’s simply because the conduction tissue is so close to the tricuspid annulus.”

Pacemaker implantation rates, like those for concomitant tricuspid-mitral surgery, are also highly variable, and in some single-center series only around 2%, Dr. Chikwe said. “So that suggests there are technical approaches that can minimize the pacemaker rate [such as] being extremely careful to avoid suture placement around the area of the conduction tissues.”

For some the trade-off between reduced TR progression and the risk of a permanent pacemaker is worth it. “But the fact that the trial didn’t show a difference in survival, a difference in symptoms or quality of life, might suggest that patients you anticipated were high risk for surgery or didn’t have a longer projected survival aren’t going to benefit from what is quite an aggressive surgical approach,” Dr. Chikwe said.

In an accompanying editorial, Dr. Chikwe and Mario Gaudino, MD, of Weill Cornell Medicine, New York, also point out that the “very dynamic nature of tricuspid regurgitation and wide variability in assessing tricuspid annular dilatation are additional compelling reasons to leave lesser regurgitation alone.”

Julia Grapsa, MD, PhD, Kings College and tricuspid service lead at Guys and St. Thomas NHS, London, also pointed to the need for longer-term follow-up but said increased use of imaging markers is also needed to help pinpoint TR progression in these patients. “For the moment, the results should remind imagers and clinicians to refer patients earlier.”

“As a valvular heart physician, I see more and more patients coming in with significant severe tricuspid regurgitation post–mitral valve surgery and because of the time that’s passed, there’s dysfunction of the right heart, the left heart, and it’s very hard to suggest an operation because they’re at high risk,” she said. “So we’re discussing with these patients whether to do an intervention or medical management.”

“Now, with this study, and the pending longer follow-up by the authors, I’m optimistic that the class II recommendation will be class I in order to help our patients treat tricuspid regurgitation earlier than late,” said Dr. Grapsa, who is also editor-in-chief of JACC: Case Reports.

The study was funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research. Dr. Gammie reports a consultant/stockholder relationship with Edwards Lifesciences. Dr. Grapsa reports no conflicts of interest. Dr. Chikwe reports that as coprincipal investigator/study director of NCT 05051033 (an NHLBI-sponsored Cardiothoracic Surgical Trials Network trial), she collaborates with several of the study authors.
 

A version of this article first appeared on Medscape.com.

Tricuspid valve repair at the time of mitral valve surgery reduces tricuspid regurgitation progression, but at the cost of more than a fivefold increase in permanent pacemakers, results of a new Cardiothoracic Surgical Trials Network study show.

The results were presented during the opening late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.

Tricuspid regurgitation (TR) is common among patients undergoing mitral valve surgery, and there’s broad agreement to intervene when a patient has severe TR. There’s uncertainty, however, about the management of moderate or less TR during mitral valve surgery, which is reflected in current guidelines on the basis of observational data, explained coprimary investigator James Gammie, MD, codirector and surgical director of the Johns Hopkins Heart and Vascular Institute, Baltimore. As a result, rates of concomitant tricuspid-mitral surgery range from 5% to 75% at various centers.

To help fill the gap, Dr. Gammie and colleagues screened 5,208 patients at 29 centers in the United States, Canada, and Germany undergoing surgery for degenerative mitral regurgitation, and randomly assigned 401 patients (75% male) to mitral valve surgery alone or with tricuspid annuloplasty.

Patients had either moderate TR (37%) or less than moderate TR with a dilated tricuspid annulus of at least 40 mm or at least 21 mm/m² indexed for body surface area. Importantly, there was a uniform surgical approach using undersized (26-30 mm) rigid nonplanar annuloplasty rings to repair the tricuspid valve, he said.

The study’s primary outcome of treatment failure at 2 years was defined as the composite of death, reoperation for TR, or progression of TR from baseline by 2 grades or severe TR.

The primary endpoint occurred in 10.2% of patients who underwent mitral valve surgery alone and 3.9% who underwent concomitant tricuspid annuloplasty (relative risk, 0.37; 95% confidence interval, 0.16-0.86; P = .02).

The endpoint was driven exclusively by less TR progression in the annuloplasty group, with no TR reoperations in either group, observed Dr. Gammie. At 2 years, just 0.6% of the annuloplasty group had severe TR, compared with 5.6% of the surgery-alone group.

The rate of permanent pacemaker implantations, however, jumped from 2.5% with surgery alone to 14.1% with concomitant tricuspid annuloplasty (rate ratio, 5.75; 95% CI, 2.27-14.60). More than half of pacemakers were placed during the first 2 days after surgery.

There was no between-group difference in 2-year rates of all-cause mortality, major adverse cardiac and cerebrovascular events, readmission, quality of life, or functional status.

Less than moderate TR

In a post hoc analysis stratified by baseline TR severity, treatment failure was significantly less common with surgery plus tricuspid annuloplasty among patients with moderate TR (4.5% vs. 18.1%) but not among those with less than moderate TR and tricuspid annular dilation (3.4% vs. 6.1%).

Although the trial was not powered for the subgroup analysis, “these results call into question the idea that less than moderate TR with annular dilation should be an indication for tricuspid valve repair,” Dr. Gammie told this news organization.

“I did not repair the tricuspid valve in the setting of less than moderate TR before the trial, and my practice won’t change; but it will be based on much better evidence,” he added. “Of course, long-term data from our trial will be of great interest.”

Discussant Joseph Woo, MD, chair of surgery at Stanford (Calif.) University, congratulated the authors on a “landmark trial” that addresses a highly relevant problem without a clear-cut indication.

In the 2020 AHA/American College of Cardiology heart valve disease guideline, tricuspid valve surgery is a class I recommendation when there’s severe TR (stages C and D) and left-sided valve surgery but a class IIa recommendation in patients with progressive TR (stage B) with an annular dilation of at least 40 mm.

“The interesting findings in this study include that moderate TR was only 37% of the enrolled patients, and only 97% of the patients with degenerative MR received a mitral valve repair,” Dr. Woo said. “This level of mitral valve repair is perhaps lower than what we might expect at these centers and lower, certainly, than what the AHA/ACC guidelines recommend for surgery on asymptomatic severe mitral regurgitation.”

Panelist Roxanna Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York said, “What I was struck by is that we, as clinicians, believe that if you fix the mitral valve, maybe the tricuspid regurgitation will improve. And it seems like that is not what’s happening, and I think that’s a big takeaway.”

Session comoderator Joanna Chikwe, MD, head of cardiac surgery at Cedars-Sinai Medical Center, Los Angeles, said, “I think we can all agree that severe tricuspid regurgitation is a disaster for patients, and I think the fact the trial is designed for an additional 5 years’ follow-up will hopefully give us some insights into the clinical impact of severe tricuspid regurgitation.”

For now, “a back of the envelope calculation suggests that, for every 20 patients with moderate tricuspid regurgitation who we repair the tricuspid valve in, we would prevent severe tricuspid valve regurgitation in 1 at the price of pacemakers in 2,” she said.

Dr. Chikwe said in an interview that “transcatheter tricuspid repair is increasingly helping these patients, but if you could avoid it with a technique that doesn’t cause incremental harm beyond, perhaps, the need for pacemakers, then this is helpful data that supports that approach.”

The pacemaker burden is not negligible, she said, but also not surprising to surgeons. “If you look at national practice of mitral-tricuspid surgery, it’s about 15% after that, and it’s simply because the conduction tissue is so close to the tricuspid annulus.”

Pacemaker implantation rates, like those for concomitant tricuspid-mitral surgery, are also highly variable, and in some single-center series only around 2%, Dr. Chikwe said. “So that suggests there are technical approaches that can minimize the pacemaker rate [such as] being extremely careful to avoid suture placement around the area of the conduction tissues.”

For some the trade-off between reduced TR progression and the risk of a permanent pacemaker is worth it. “But the fact that the trial didn’t show a difference in survival, a difference in symptoms or quality of life, might suggest that patients you anticipated were high risk for surgery or didn’t have a longer projected survival aren’t going to benefit from what is quite an aggressive surgical approach,” Dr. Chikwe said.

In an accompanying editorial, Dr. Chikwe and Mario Gaudino, MD, of Weill Cornell Medicine, New York, also point out that the “very dynamic nature of tricuspid regurgitation and wide variability in assessing tricuspid annular dilatation are additional compelling reasons to leave lesser regurgitation alone.”

Julia Grapsa, MD, PhD, Kings College and tricuspid service lead at Guys and St. Thomas NHS, London, also pointed to the need for longer-term follow-up but said increased use of imaging markers is also needed to help pinpoint TR progression in these patients. “For the moment, the results should remind imagers and clinicians to refer patients earlier.”

“As a valvular heart physician, I see more and more patients coming in with significant severe tricuspid regurgitation post–mitral valve surgery and because of the time that’s passed, there’s dysfunction of the right heart, the left heart, and it’s very hard to suggest an operation because they’re at high risk,” she said. “So we’re discussing with these patients whether to do an intervention or medical management.”

“Now, with this study, and the pending longer follow-up by the authors, I’m optimistic that the class II recommendation will be class I in order to help our patients treat tricuspid regurgitation earlier than late,” said Dr. Grapsa, who is also editor-in-chief of JACC: Case Reports.

The study was funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research. Dr. Gammie reports a consultant/stockholder relationship with Edwards Lifesciences. Dr. Grapsa reports no conflicts of interest. Dr. Chikwe reports that as coprincipal investigator/study director of NCT 05051033 (an NHLBI-sponsored Cardiothoracic Surgical Trials Network trial), she collaborates with several of the study authors.
 

A version of this article first appeared on Medscape.com.

A novel, stent-shaped device that provides external buttressing to saphenous vein grafts placed during coronary artery bypass surgery was safe, but failed to improve 12-month patency of vein grafts, in a prospective study with 224 patients.

Despite the neutral result, “we are cautiously optimistic” about the prospects for the device to reduce the risk for failure of coronary vein grafts caused by intimal hyperplasia of the internal lining of the vein graft that leads to graft occlusion, said John D. Puskas, MD, lead investigator of the study, who reported the results at the American Heart Association scientific sessions.

In the trial, called VEST, each buttressed vein graft was compared with a similar, unbuttressed graft in the same patient. Perhaps the biggest issue faced by the study was the unexpectedly high 42% rate of vein-graft occlusion or diffuse disease seen in the studied grafts 12 months after placement. This rate included both the vein grafts placed within the external buttressing device and control vein grafts that underwent the same postharvest preparation but weren’t placed within an external sheath, which is formed from woven cobalt chromium wire.

Dr. Puskas attributed this high failure rate to the need to remove all adventitia tissue and fat from the harvested saphenous vein segments before grafting, a step required to allow the vein conduit to fit inside the wire sheath. The potential exists to further optimize this step, he said in an interview.

“I was very surprised by the low 12-month patency rates” in both treatment arms of the study, commented Joanna Chikwe, MD, chair of cardiac surgery at Cedars-Sinai Medical Center in Los Angeles.

External scaffold to counter blood pressure

The concept behind the external buttressing sheath is that the walls of saphenous vein grafts are not structured to accommodate arterial blood pressure, and over time this pressure produces accelerated atherosclerotic changes and premature occlusion and graft failure. The external support is supposed to impede vein wall dilatation, reduce irregularities of the inner lumen surface, and improve hemodynamics and shear stress.

The VEST trial ran at 14 U.S. and 3 Canadian centers and enrolled 224 patients scheduled for coronary artery bypass grafting with planned use of at least two saphenous vein grafts, along with an internal mammary artery graft for the left anterior descending coronary artery. The patients averaged 66 years of age, 21% were women, and 51% had diabetes.

All patients successfully underwent their surgery, with 203 returning after 12 months for their primary follow-up examination by intravascular ultrasound. However, because of the high rate of vein occlusion or development of diffuse intragraft disease, successful intravascular ultrasound (IVUS) examination of both vein grafts occurred in only 113 patients.

The IVUS examinations showed that the study’s primary endpoint, the intimal hyperplasia area in all 224 patients who received vein grafts, averaged 5.11 mm² in the grafts placed within the wire sleeve and 5.79 mm² for control grafts not placed in the wire sheath, a difference that fell short of significance (P = .072). However, in a sensitivity analysis that focused on only the 113 patients who had both vein grafts successfully assayed by IVUS, the average area of intimal hyperplasia was 4.58 mm² in the grafts within a wire sheath and 5.12 mm² in the control grafts, a significant difference (P = .043).

The combined rate of major adverse cardiovascular events after 12 months was 7%, including a 2% mortality rate, a 3% stroke rate, and 3% rate of Mis, outcomes that suggested “no safety signals,” said Dr. Puskas, chair of cardiovascular surgery at Mount Sinai St. Luke’s in New York.

Although a large body of evidence has shown the superiority of arterial grafts for long-term graft patency, vein grafts have many advantages that have maintained them as the most widely used conduits worldwide for coronary artery bypass surgery, Dr. Puskas said.

Saphenous vein segments are readily available from patients and easy to harvest; they nicely conform to the coronary arteries that require bypass, rarely leak, are easy to work with, and can successfully hold stitches. Surgeons performing coronary artery bypass are unlikely to abandon vein grafts anytime soon, which makes improving the performance of vein grafts a priority, Dr. Puskas said.

The study was sponsored by Vascular Graft Solutions, the company developing the venous graft external support. Dr. Puskas and Dr. Chikwe had no disclosures related to the study.

mzoler@mdedge.com
 

A novel, stent-shaped device that provides external buttressing to saphenous vein grafts placed during coronary artery bypass surgery was safe, but failed to improve 12-month patency of vein grafts, in a prospective study with 224 patients.

Despite the neutral result, “we are cautiously optimistic” about the prospects for the device to reduce the risk for failure of coronary vein grafts caused by intimal hyperplasia of the internal lining of the vein graft that leads to graft occlusion, said John D. Puskas, MD, lead investigator of the study, who reported the results at the American Heart Association scientific sessions.

In the trial, called VEST, each buttressed vein graft was compared with a similar, unbuttressed graft in the same patient. Perhaps the biggest issue faced by the study was the unexpectedly high 42% rate of vein-graft occlusion or diffuse disease seen in the studied grafts 12 months after placement. This rate included both the vein grafts placed within the external buttressing device and control vein grafts that underwent the same postharvest preparation but weren’t placed within an external sheath, which is formed from woven cobalt chromium wire.

Dr. Puskas attributed this high failure rate to the need to remove all adventitia tissue and fat from the harvested saphenous vein segments before grafting, a step required to allow the vein conduit to fit inside the wire sheath. The potential exists to further optimize this step, he said in an interview.

“I was very surprised by the low 12-month patency rates” in both treatment arms of the study, commented Joanna Chikwe, MD, chair of cardiac surgery at Cedars-Sinai Medical Center in Los Angeles.

External scaffold to counter blood pressure

The concept behind the external buttressing sheath is that the walls of saphenous vein grafts are not structured to accommodate arterial blood pressure, and over time this pressure produces accelerated atherosclerotic changes and premature occlusion and graft failure. The external support is supposed to impede vein wall dilatation, reduce irregularities of the inner lumen surface, and improve hemodynamics and shear stress.

The VEST trial ran at 14 U.S. and 3 Canadian centers and enrolled 224 patients scheduled for coronary artery bypass grafting with planned use of at least two saphenous vein grafts, along with an internal mammary artery graft for the left anterior descending coronary artery. The patients averaged 66 years of age, 21% were women, and 51% had diabetes.

All patients successfully underwent their surgery, with 203 returning after 12 months for their primary follow-up examination by intravascular ultrasound. However, because of the high rate of vein occlusion or development of diffuse intragraft disease, successful intravascular ultrasound (IVUS) examination of both vein grafts occurred in only 113 patients.

The IVUS examinations showed that the study’s primary endpoint, the intimal hyperplasia area in all 224 patients who received vein grafts, averaged 5.11 mm² in the grafts placed within the wire sleeve and 5.79 mm² for control grafts not placed in the wire sheath, a difference that fell short of significance (P = .072). However, in a sensitivity analysis that focused on only the 113 patients who had both vein grafts successfully assayed by IVUS, the average area of intimal hyperplasia was 4.58 mm² in the grafts within a wire sheath and 5.12 mm² in the control grafts, a significant difference (P = .043).

The combined rate of major adverse cardiovascular events after 12 months was 7%, including a 2% mortality rate, a 3% stroke rate, and 3% rate of Mis, outcomes that suggested “no safety signals,” said Dr. Puskas, chair of cardiovascular surgery at Mount Sinai St. Luke’s in New York.

Although a large body of evidence has shown the superiority of arterial grafts for long-term graft patency, vein grafts have many advantages that have maintained them as the most widely used conduits worldwide for coronary artery bypass surgery, Dr. Puskas said.

Saphenous vein segments are readily available from patients and easy to harvest; they nicely conform to the coronary arteries that require bypass, rarely leak, are easy to work with, and can successfully hold stitches. Surgeons performing coronary artery bypass are unlikely to abandon vein grafts anytime soon, which makes improving the performance of vein grafts a priority, Dr. Puskas said.

The study was sponsored by Vascular Graft Solutions, the company developing the venous graft external support. Dr. Puskas and Dr. Chikwe had no disclosures related to the study.

mzoler@mdedge.com
 

A novel, stent-shaped device that provides external buttressing to saphenous vein grafts placed during coronary artery bypass surgery was safe, but failed to improve 12-month patency of vein grafts, in a prospective study with 224 patients.

Despite the neutral result, “we are cautiously optimistic” about the prospects for the device to reduce the risk for failure of coronary vein grafts caused by intimal hyperplasia of the internal lining of the vein graft that leads to graft occlusion, said John D. Puskas, MD, lead investigator of the study, who reported the results at the American Heart Association scientific sessions.

In the trial, called VEST, each buttressed vein graft was compared with a similar, unbuttressed graft in the same patient. Perhaps the biggest issue faced by the study was the unexpectedly high 42% rate of vein-graft occlusion or diffuse disease seen in the studied grafts 12 months after placement. This rate included both the vein grafts placed within the external buttressing device and control vein grafts that underwent the same postharvest preparation but weren’t placed within an external sheath, which is formed from woven cobalt chromium wire.

Dr. Puskas attributed this high failure rate to the need to remove all adventitia tissue and fat from the harvested saphenous vein segments before grafting, a step required to allow the vein conduit to fit inside the wire sheath. The potential exists to further optimize this step, he said in an interview.

“I was very surprised by the low 12-month patency rates” in both treatment arms of the study, commented Joanna Chikwe, MD, chair of cardiac surgery at Cedars-Sinai Medical Center in Los Angeles.

External scaffold to counter blood pressure

The concept behind the external buttressing sheath is that the walls of saphenous vein grafts are not structured to accommodate arterial blood pressure, and over time this pressure produces accelerated atherosclerotic changes and premature occlusion and graft failure. The external support is supposed to impede vein wall dilatation, reduce irregularities of the inner lumen surface, and improve hemodynamics and shear stress.

The VEST trial ran at 14 U.S. and 3 Canadian centers and enrolled 224 patients scheduled for coronary artery bypass grafting with planned use of at least two saphenous vein grafts, along with an internal mammary artery graft for the left anterior descending coronary artery. The patients averaged 66 years of age, 21% were women, and 51% had diabetes.

All patients successfully underwent their surgery, with 203 returning after 12 months for their primary follow-up examination by intravascular ultrasound. However, because of the high rate of vein occlusion or development of diffuse intragraft disease, successful intravascular ultrasound (IVUS) examination of both vein grafts occurred in only 113 patients.

The IVUS examinations showed that the study’s primary endpoint, the intimal hyperplasia area in all 224 patients who received vein grafts, averaged 5.11 mm² in the grafts placed within the wire sleeve and 5.79 mm² for control grafts not placed in the wire sheath, a difference that fell short of significance (P = .072). However, in a sensitivity analysis that focused on only the 113 patients who had both vein grafts successfully assayed by IVUS, the average area of intimal hyperplasia was 4.58 mm² in the grafts within a wire sheath and 5.12 mm² in the control grafts, a significant difference (P = .043).

The combined rate of major adverse cardiovascular events after 12 months was 7%, including a 2% mortality rate, a 3% stroke rate, and 3% rate of Mis, outcomes that suggested “no safety signals,” said Dr. Puskas, chair of cardiovascular surgery at Mount Sinai St. Luke’s in New York.

Although a large body of evidence has shown the superiority of arterial grafts for long-term graft patency, vein grafts have many advantages that have maintained them as the most widely used conduits worldwide for coronary artery bypass surgery, Dr. Puskas said.

Saphenous vein segments are readily available from patients and easy to harvest; they nicely conform to the coronary arteries that require bypass, rarely leak, are easy to work with, and can successfully hold stitches. Surgeons performing coronary artery bypass are unlikely to abandon vein grafts anytime soon, which makes improving the performance of vein grafts a priority, Dr. Puskas said.

The study was sponsored by Vascular Graft Solutions, the company developing the venous graft external support. Dr. Puskas and Dr. Chikwe had no disclosures related to the study.

mzoler@mdedge.com
 

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In large-vessel occlusion stroke, results of a randomized trial failed to show noninferiority of direct mechanical thrombectomy using the Solitaire device to the combination of intravenous (IV) thrombolysis plus mechanical thrombectomy.

In the prospective, multicenter trial, the rate of good functional outcome was 57% for patients who underwent direct thrombectomy and 65% among patients who received IV thrombolysis before undergoing thrombectomy. This result failed to demonstrate noninferiority of direct mechanical thrombectomy compared to combination therapy, the researchers conclude.

“Good outcome was high in both treatment arms, with the point estimate in favor of the bridging cohort,” said lead investigator Urs Fischer, MD, co-chair of the stroke center at Inselspital, Bern University Hospital, Switzerland, during his presentation. “Postinterventional reperfusion was very high in both treatment arms and higher in patients with bridging thrombolysis, compared to direct mechanical thrombectomy.”

The findings were presented at the 13th World Stroke Congress (WSC) 2021.
 

Two views of thrombolysis

The value of bridging thrombolysis for patients who undergo mechanical thrombectomy is a matter of debate. One argument is that, for patients with large-vessel occlusion, IV thrombolysis may improve reperfusion before and after thrombectomy and yield better clinical outcomes. The opposing argument is that bridging thrombolysis may increase the risk for distal emboli, delay mechanical thrombectomy, and increase the rate of hemorrhage.

The researchers conducted the SWIFT DIRECT trial to investigate this question. They enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery.

The trial was conducted at 48 sites in seven European countries and Canada. The investigators randomly assigned patients to receive IV alteplase (0.9 mg/kg) plus mechanical thrombectomy with the Solitaire device or to receive direct mechanical thrombectomy with the same device. Treatment was open label, but the assessment of endpoints was blinded.

Investigators assigned 423 patients to treatment, and 408 were included in the full analysis set. Of this group, 201 participants received direct mechanical thrombectomy, and 207 received IV thrombolysis plus thrombectomy. There were three crossovers in each treatment arm.

The primary outcome was functional independence, defined as a Modified Rankin Scale (mRS) score of 0-2, at 90 days. Secondary outcomes included mortality at 90 days, mRS shift, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, successful reperfusion, and symptomatic and asymptomatic intracranial hemorrhage (ICH).
 

Noninferiority not demonstrated

At baseline, patient characteristics were well balanced between the treatment groups. The median age of the patients was 72 years, and about 50% of participants were women. The median NIHSS score was 17 in both arms.

Approximately 57% of patients who underwent direct thrombectomy and 65% of those who received IV thrombolysis plus thrombectomy were functionally independent at 90 days, the primary outcome.

In addition, the researchers found no difference in mRS shift, mortality at 90 days, or change in NIHSS score at 24 hours. Postinterventional reperfusion was very high in both arms and was higher in patients who received IV tissue plasminogen activator, compared with those who received direct mechanical thrombectomy, said Dr. Fischer.

The rate of successful postinterventional reperfusion, however, was higher among patients who received thrombolysis than among those who underwent direct thrombectomy. The rate of symptomatic ICH was 1.5% in the direct thrombectomy group and 4.9% in the thrombolysis-plus-thrombectomy group.
 

New endpoints needed?

The investigators used noninferiority margins of 12%. “This question about the noninferiority margins, that’s a very tricky and difficult one in randomized clinical trials,” said Dr. Fischer. The investigators defined their margin using the 2015 HERMES data because no trials had yet compared direct mechanical thrombectomy and bridging thrombolysis at the time.

The researchers are performing a pooled analysis of all the trials that compared bridging thrombolysis with direct mechanical thrombectomy. “We are therefore looking at several margins, and I think this is the way we should look at these noninferiority margins,” said Dr. Fischer. “There’s not a clear-cut level which you can define.”

Enrollment in the trial was well balanced with respect to gender, which is not always the case in stroke studies, said Kevin Sheth, MD, professor of neurology and neurosurgery at Yale School of Medicine, New Haven, Conn., who commented on the study for this news organization.

The findings indicate that the likelihood of there being a difference between groups on this question is low, said Dr. Sheth. Both groups had large-vessel occlusion, both received thrombectomy, and both achieved reperfusion. But the higher rate of successful reperfusion in the bridging cohort was not reflected in any of the clinical endpoints that the investigators examined.

Observing a difference in this context will require very large trials or different endpoints that are more responsive to the intervention, said Dr. Sheth. “This is going to be a challenge for not just this but for any neuroprotection trial in the future,” he said.

The study was supported by Medtronic. Dr. Fischer has served as a consultant for Medtronic, Stryker, and CSL Behring. Dr. Sheth has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In large-vessel occlusion stroke, results of a randomized trial failed to show noninferiority of direct mechanical thrombectomy using the Solitaire device to the combination of intravenous (IV) thrombolysis plus mechanical thrombectomy.

In the prospective, multicenter trial, the rate of good functional outcome was 57% for patients who underwent direct thrombectomy and 65% among patients who received IV thrombolysis before undergoing thrombectomy. This result failed to demonstrate noninferiority of direct mechanical thrombectomy compared to combination therapy, the researchers conclude.

“Good outcome was high in both treatment arms, with the point estimate in favor of the bridging cohort,” said lead investigator Urs Fischer, MD, co-chair of the stroke center at Inselspital, Bern University Hospital, Switzerland, during his presentation. “Postinterventional reperfusion was very high in both treatment arms and higher in patients with bridging thrombolysis, compared to direct mechanical thrombectomy.”

The findings were presented at the 13th World Stroke Congress (WSC) 2021.
 

Two views of thrombolysis

The value of bridging thrombolysis for patients who undergo mechanical thrombectomy is a matter of debate. One argument is that, for patients with large-vessel occlusion, IV thrombolysis may improve reperfusion before and after thrombectomy and yield better clinical outcomes. The opposing argument is that bridging thrombolysis may increase the risk for distal emboli, delay mechanical thrombectomy, and increase the rate of hemorrhage.

The researchers conducted the SWIFT DIRECT trial to investigate this question. They enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery.

The trial was conducted at 48 sites in seven European countries and Canada. The investigators randomly assigned patients to receive IV alteplase (0.9 mg/kg) plus mechanical thrombectomy with the Solitaire device or to receive direct mechanical thrombectomy with the same device. Treatment was open label, but the assessment of endpoints was blinded.

Investigators assigned 423 patients to treatment, and 408 were included in the full analysis set. Of this group, 201 participants received direct mechanical thrombectomy, and 207 received IV thrombolysis plus thrombectomy. There were three crossovers in each treatment arm.

The primary outcome was functional independence, defined as a Modified Rankin Scale (mRS) score of 0-2, at 90 days. Secondary outcomes included mortality at 90 days, mRS shift, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, successful reperfusion, and symptomatic and asymptomatic intracranial hemorrhage (ICH).
 

Noninferiority not demonstrated

At baseline, patient characteristics were well balanced between the treatment groups. The median age of the patients was 72 years, and about 50% of participants were women. The median NIHSS score was 17 in both arms.

Approximately 57% of patients who underwent direct thrombectomy and 65% of those who received IV thrombolysis plus thrombectomy were functionally independent at 90 days, the primary outcome.

In addition, the researchers found no difference in mRS shift, mortality at 90 days, or change in NIHSS score at 24 hours. Postinterventional reperfusion was very high in both arms and was higher in patients who received IV tissue plasminogen activator, compared with those who received direct mechanical thrombectomy, said Dr. Fischer.

The rate of successful postinterventional reperfusion, however, was higher among patients who received thrombolysis than among those who underwent direct thrombectomy. The rate of symptomatic ICH was 1.5% in the direct thrombectomy group and 4.9% in the thrombolysis-plus-thrombectomy group.
 

New endpoints needed?

The investigators used noninferiority margins of 12%. “This question about the noninferiority margins, that’s a very tricky and difficult one in randomized clinical trials,” said Dr. Fischer. The investigators defined their margin using the 2015 HERMES data because no trials had yet compared direct mechanical thrombectomy and bridging thrombolysis at the time.

The researchers are performing a pooled analysis of all the trials that compared bridging thrombolysis with direct mechanical thrombectomy. “We are therefore looking at several margins, and I think this is the way we should look at these noninferiority margins,” said Dr. Fischer. “There’s not a clear-cut level which you can define.”

Enrollment in the trial was well balanced with respect to gender, which is not always the case in stroke studies, said Kevin Sheth, MD, professor of neurology and neurosurgery at Yale School of Medicine, New Haven, Conn., who commented on the study for this news organization.

The findings indicate that the likelihood of there being a difference between groups on this question is low, said Dr. Sheth. Both groups had large-vessel occlusion, both received thrombectomy, and both achieved reperfusion. But the higher rate of successful reperfusion in the bridging cohort was not reflected in any of the clinical endpoints that the investigators examined.

Observing a difference in this context will require very large trials or different endpoints that are more responsive to the intervention, said Dr. Sheth. “This is going to be a challenge for not just this but for any neuroprotection trial in the future,” he said.

The study was supported by Medtronic. Dr. Fischer has served as a consultant for Medtronic, Stryker, and CSL Behring. Dr. Sheth has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In large-vessel occlusion stroke, results of a randomized trial failed to show noninferiority of direct mechanical thrombectomy using the Solitaire device to the combination of intravenous (IV) thrombolysis plus mechanical thrombectomy.

In the prospective, multicenter trial, the rate of good functional outcome was 57% for patients who underwent direct thrombectomy and 65% among patients who received IV thrombolysis before undergoing thrombectomy. This result failed to demonstrate noninferiority of direct mechanical thrombectomy compared to combination therapy, the researchers conclude.

“Good outcome was high in both treatment arms, with the point estimate in favor of the bridging cohort,” said lead investigator Urs Fischer, MD, co-chair of the stroke center at Inselspital, Bern University Hospital, Switzerland, during his presentation. “Postinterventional reperfusion was very high in both treatment arms and higher in patients with bridging thrombolysis, compared to direct mechanical thrombectomy.”

The findings were presented at the 13th World Stroke Congress (WSC) 2021.
 

Two views of thrombolysis

The value of bridging thrombolysis for patients who undergo mechanical thrombectomy is a matter of debate. One argument is that, for patients with large-vessel occlusion, IV thrombolysis may improve reperfusion before and after thrombectomy and yield better clinical outcomes. The opposing argument is that bridging thrombolysis may increase the risk for distal emboli, delay mechanical thrombectomy, and increase the rate of hemorrhage.

The researchers conducted the SWIFT DIRECT trial to investigate this question. They enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery.

The trial was conducted at 48 sites in seven European countries and Canada. The investigators randomly assigned patients to receive IV alteplase (0.9 mg/kg) plus mechanical thrombectomy with the Solitaire device or to receive direct mechanical thrombectomy with the same device. Treatment was open label, but the assessment of endpoints was blinded.

Investigators assigned 423 patients to treatment, and 408 were included in the full analysis set. Of this group, 201 participants received direct mechanical thrombectomy, and 207 received IV thrombolysis plus thrombectomy. There were three crossovers in each treatment arm.

The primary outcome was functional independence, defined as a Modified Rankin Scale (mRS) score of 0-2, at 90 days. Secondary outcomes included mortality at 90 days, mRS shift, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, successful reperfusion, and symptomatic and asymptomatic intracranial hemorrhage (ICH).
 

Noninferiority not demonstrated

At baseline, patient characteristics were well balanced between the treatment groups. The median age of the patients was 72 years, and about 50% of participants were women. The median NIHSS score was 17 in both arms.

Approximately 57% of patients who underwent direct thrombectomy and 65% of those who received IV thrombolysis plus thrombectomy were functionally independent at 90 days, the primary outcome.

In addition, the researchers found no difference in mRS shift, mortality at 90 days, or change in NIHSS score at 24 hours. Postinterventional reperfusion was very high in both arms and was higher in patients who received IV tissue plasminogen activator, compared with those who received direct mechanical thrombectomy, said Dr. Fischer.

The rate of successful postinterventional reperfusion, however, was higher among patients who received thrombolysis than among those who underwent direct thrombectomy. The rate of symptomatic ICH was 1.5% in the direct thrombectomy group and 4.9% in the thrombolysis-plus-thrombectomy group.
 

New endpoints needed?

The investigators used noninferiority margins of 12%. “This question about the noninferiority margins, that’s a very tricky and difficult one in randomized clinical trials,” said Dr. Fischer. The investigators defined their margin using the 2015 HERMES data because no trials had yet compared direct mechanical thrombectomy and bridging thrombolysis at the time.

The researchers are performing a pooled analysis of all the trials that compared bridging thrombolysis with direct mechanical thrombectomy. “We are therefore looking at several margins, and I think this is the way we should look at these noninferiority margins,” said Dr. Fischer. “There’s not a clear-cut level which you can define.”

Enrollment in the trial was well balanced with respect to gender, which is not always the case in stroke studies, said Kevin Sheth, MD, professor of neurology and neurosurgery at Yale School of Medicine, New Haven, Conn., who commented on the study for this news organization.

The findings indicate that the likelihood of there being a difference between groups on this question is low, said Dr. Sheth. Both groups had large-vessel occlusion, both received thrombectomy, and both achieved reperfusion. But the higher rate of successful reperfusion in the bridging cohort was not reflected in any of the clinical endpoints that the investigators examined.

Observing a difference in this context will require very large trials or different endpoints that are more responsive to the intervention, said Dr. Sheth. “This is going to be a challenge for not just this but for any neuroprotection trial in the future,” he said.

The study was supported by Medtronic. Dr. Fischer has served as a consultant for Medtronic, Stryker, and CSL Behring. Dr. Sheth has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.