Thrombosis

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Three or more weeks of oral anticoagulation (OAC) sometimes isn’t up to the job of clearing any potentially embolic left atrial (LA) thrombi before procedures like cardioversion or catheter ablation in patients with atrial fibrillation (AF). Such OAC-defiant LA thrombi aren’t common, nor are they rare enough to ignore, suggests a new meta-analysis that might also have identified features that predispose to them.

Such predictors of LA clots that persist despite OAC could potentially guide selective use of transesophageal echocardiography (TEE) instead of more routine policies to either use or not use TEE for thrombus rule-out before rhythm-control procedures, researchers propose.

Their prevalence was about 2.7% among the study’s more than 14,000 patients who received at least 3 weeks of OAC with either vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) before undergoing TEE.

But OAC-resistant LA thrombi were two- to four-times as common in patients with than without certain features, including AF other than paroxysmal and higher CHADS2 and CHA2DS2-VASc stroke risk-stratification scores.

“TEE imaging in select patients at an elevated risk of LA thrombus, despite anticoagulation status, may be a reasonable approach to minimize the risk of thromboembolic complications following cardioversion or catheter ablation,” propose the study’s authors, led by Antony Lurie, BMSC, Population Health Research Institute, Hamilton, Ont. Their report was published in the June 15 issue of the Journal of the American College of Cardiology.

Guidelines don’t encourage TEE before cardioversion in patients who have been on OAC for at least 3 weeks, the group notes, and policies on TEE use before AF ablation vary widely regardless of anticoagulation status.

The current study suggests that 3 weeks of OAC isn’t enough for a substantial number of patients, who might be put at thromboembolic risk if TEE were to be skipped before rhythm-control procedures.

Conversely, many patients unlikely to have LA thrombi get preprocedure TEE anyway. That can happen “irrespective of how long they’ve been anticoagulated, their pattern of atrial fibrillation, or their stroke risk,” senior author Jorge A. Wong, MD, MPH, Population Health Research Institute and McMaster University, Hamilton, Ont., told this news organization.

But “TEE is an invasive imaging modality, so it is associated with small element of risk.” The current study, Dr. Wong said, points to potential risk-stratification tools clinicians might use to guide more selective TEE screening.

“At sites where TEEs are done all the time for patients undergoing ablation, one could use several of these risk markers to perhaps tailor use of TEE in individuals,” Dr. Wong said. “For example, in people with paroxysmal atrial fibrillation, we found that the risk of left atrial appendage clot was approximately 1% or less.” Screening by TEE might reasonably be avoided in such patients.

“Fortunately, continued oral anticoagulation already yields low peri-procedural stroke rates,” observes an accompanying editorial from Paulus Kirchhof, MD, and Christoph Sinning, MD, from the University Heart & Vascular Center and German Centre of Cardiovascular Research, Hamburg.

“Based on this new analysis of existing data, a risk-based use of TEE imaging in anticoagulated patients could enable further improvement in the safe delivery of rhythm control interventions in patients with AF,” the editorialists agree.

The meta-analysis covered 10 prospective and 25 retrospective studies with a total of 14,653 patients that reported whether LA thrombus was present in patients with AF or atrial flutter (AFL) who underwent TEE after at least 3 weeks of VKA or DOAC therapy. Reports for 30 of the studies identified patients by rhythm-control procedure, and the remaining five didn’t specify TEE indications.

The weighted mean prevalence of LA thrombus at TEE was 2.73% (95% confidence interval, 1.95%-3.80%). The finding was not significantly changed in separate sensitivity analyses, the report says, including one limited to studies with low risk of bias and others excluding patients with valvular AF, interrupted OAC, heparin bridging, or subtherapeutic anticoagulation, respectively.

Patients treated with VKA and DOACs showed similar prevalences of LA thrombi, with means of 2.80% and 3.12%, respectively (P = .674). The prevalence was significantly higher in patients:

• with nonparoxysmal than with paroxysmal AF/AFL (4.81% vs. 1.03%; P < .001)
• undergoing cardioversion than ablation (5.55% vs. 1.65; P < .001)
• with CHA2DS2-VASc scores of at least 3 than with scores of 2 or less (6.31% vs. 1.06%; P < .001).

A limitation of the study, observe Dr. Kirchhof and Dr. Sinning, “is that all patients had a clinical indication for a TEE, which might be a selection bias. When a thrombus was found on TEE, clinical judgment led to postponing of the procedure,” thereby avoiding potential thromboembolism.

“Thus, the paper cannot demonstrate that presence of a thrombus on TEE is related to peri-procedural ischemic stroke,” they write.

The literature puts the risk for stroke or systemic embolism at well under 1% for patients anticoagulated with either VKA or DOACs for at least 3 weeks prior to cardioversion, in contrast to the nearly 3% prevalence of LA appendage thrombus by TEE in the current analysis, Dr. Wong observed.

“So we’re seeing a lot more left atrial appendage thrombus than we would see stroke,” but there wasn’t a way to determine whether that increases the stroke risk, he agreed.Dr. Wong, Dr. Lurie, and the other authors report no relevant conflicts. Dr. Kirchhof discloses receiving partial support “from several drug and device companies active in atrial fibrillation” and to being listed as inventor on two AF-related patents held by the University of Birmingham. Dr. Sinning reports no relevant relationships. 

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

Three or more weeks of oral anticoagulation (OAC) sometimes isn’t up to the job of clearing any potentially embolic left atrial (LA) thrombi before procedures like cardioversion or catheter ablation in patients with atrial fibrillation (AF). Such OAC-defiant LA thrombi aren’t common, nor are they rare enough to ignore, suggests a new meta-analysis that might also have identified features that predispose to them.

Such predictors of LA clots that persist despite OAC could potentially guide selective use of transesophageal echocardiography (TEE) instead of more routine policies to either use or not use TEE for thrombus rule-out before rhythm-control procedures, researchers propose.

Their prevalence was about 2.7% among the study’s more than 14,000 patients who received at least 3 weeks of OAC with either vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) before undergoing TEE.

But OAC-resistant LA thrombi were two- to four-times as common in patients with than without certain features, including AF other than paroxysmal and higher CHADS2 and CHA2DS2-VASc stroke risk-stratification scores.

“TEE imaging in select patients at an elevated risk of LA thrombus, despite anticoagulation status, may be a reasonable approach to minimize the risk of thromboembolic complications following cardioversion or catheter ablation,” propose the study’s authors, led by Antony Lurie, BMSC, Population Health Research Institute, Hamilton, Ont. Their report was published in the June 15 issue of the Journal of the American College of Cardiology.

Guidelines don’t encourage TEE before cardioversion in patients who have been on OAC for at least 3 weeks, the group notes, and policies on TEE use before AF ablation vary widely regardless of anticoagulation status.

The current study suggests that 3 weeks of OAC isn’t enough for a substantial number of patients, who might be put at thromboembolic risk if TEE were to be skipped before rhythm-control procedures.

Conversely, many patients unlikely to have LA thrombi get preprocedure TEE anyway. That can happen “irrespective of how long they’ve been anticoagulated, their pattern of atrial fibrillation, or their stroke risk,” senior author Jorge A. Wong, MD, MPH, Population Health Research Institute and McMaster University, Hamilton, Ont., told this news organization.

But “TEE is an invasive imaging modality, so it is associated with small element of risk.” The current study, Dr. Wong said, points to potential risk-stratification tools clinicians might use to guide more selective TEE screening.

“At sites where TEEs are done all the time for patients undergoing ablation, one could use several of these risk markers to perhaps tailor use of TEE in individuals,” Dr. Wong said. “For example, in people with paroxysmal atrial fibrillation, we found that the risk of left atrial appendage clot was approximately 1% or less.” Screening by TEE might reasonably be avoided in such patients.

“Fortunately, continued oral anticoagulation already yields low peri-procedural stroke rates,” observes an accompanying editorial from Paulus Kirchhof, MD, and Christoph Sinning, MD, from the University Heart & Vascular Center and German Centre of Cardiovascular Research, Hamburg.

“Based on this new analysis of existing data, a risk-based use of TEE imaging in anticoagulated patients could enable further improvement in the safe delivery of rhythm control interventions in patients with AF,” the editorialists agree.

The meta-analysis covered 10 prospective and 25 retrospective studies with a total of 14,653 patients that reported whether LA thrombus was present in patients with AF or atrial flutter (AFL) who underwent TEE after at least 3 weeks of VKA or DOAC therapy. Reports for 30 of the studies identified patients by rhythm-control procedure, and the remaining five didn’t specify TEE indications.

The weighted mean prevalence of LA thrombus at TEE was 2.73% (95% confidence interval, 1.95%-3.80%). The finding was not significantly changed in separate sensitivity analyses, the report says, including one limited to studies with low risk of bias and others excluding patients with valvular AF, interrupted OAC, heparin bridging, or subtherapeutic anticoagulation, respectively.

Patients treated with VKA and DOACs showed similar prevalences of LA thrombi, with means of 2.80% and 3.12%, respectively (P = .674). The prevalence was significantly higher in patients:

• with nonparoxysmal than with paroxysmal AF/AFL (4.81% vs. 1.03%; P < .001)
• undergoing cardioversion than ablation (5.55% vs. 1.65; P < .001)
• with CHA2DS2-VASc scores of at least 3 than with scores of 2 or less (6.31% vs. 1.06%; P < .001).

A limitation of the study, observe Dr. Kirchhof and Dr. Sinning, “is that all patients had a clinical indication for a TEE, which might be a selection bias. When a thrombus was found on TEE, clinical judgment led to postponing of the procedure,” thereby avoiding potential thromboembolism.

“Thus, the paper cannot demonstrate that presence of a thrombus on TEE is related to peri-procedural ischemic stroke,” they write.

The literature puts the risk for stroke or systemic embolism at well under 1% for patients anticoagulated with either VKA or DOACs for at least 3 weeks prior to cardioversion, in contrast to the nearly 3% prevalence of LA appendage thrombus by TEE in the current analysis, Dr. Wong observed.

“So we’re seeing a lot more left atrial appendage thrombus than we would see stroke,” but there wasn’t a way to determine whether that increases the stroke risk, he agreed.Dr. Wong, Dr. Lurie, and the other authors report no relevant conflicts. Dr. Kirchhof discloses receiving partial support “from several drug and device companies active in atrial fibrillation” and to being listed as inventor on two AF-related patents held by the University of Birmingham. Dr. Sinning reports no relevant relationships. 

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

Three or more weeks of oral anticoagulation (OAC) sometimes isn’t up to the job of clearing any potentially embolic left atrial (LA) thrombi before procedures like cardioversion or catheter ablation in patients with atrial fibrillation (AF). Such OAC-defiant LA thrombi aren’t common, nor are they rare enough to ignore, suggests a new meta-analysis that might also have identified features that predispose to them.

Such predictors of LA clots that persist despite OAC could potentially guide selective use of transesophageal echocardiography (TEE) instead of more routine policies to either use or not use TEE for thrombus rule-out before rhythm-control procedures, researchers propose.

Their prevalence was about 2.7% among the study’s more than 14,000 patients who received at least 3 weeks of OAC with either vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) before undergoing TEE.

But OAC-resistant LA thrombi were two- to four-times as common in patients with than without certain features, including AF other than paroxysmal and higher CHADS2 and CHA2DS2-VASc stroke risk-stratification scores.

“TEE imaging in select patients at an elevated risk of LA thrombus, despite anticoagulation status, may be a reasonable approach to minimize the risk of thromboembolic complications following cardioversion or catheter ablation,” propose the study’s authors, led by Antony Lurie, BMSC, Population Health Research Institute, Hamilton, Ont. Their report was published in the June 15 issue of the Journal of the American College of Cardiology.

Guidelines don’t encourage TEE before cardioversion in patients who have been on OAC for at least 3 weeks, the group notes, and policies on TEE use before AF ablation vary widely regardless of anticoagulation status.

The current study suggests that 3 weeks of OAC isn’t enough for a substantial number of patients, who might be put at thromboembolic risk if TEE were to be skipped before rhythm-control procedures.

Conversely, many patients unlikely to have LA thrombi get preprocedure TEE anyway. That can happen “irrespective of how long they’ve been anticoagulated, their pattern of atrial fibrillation, or their stroke risk,” senior author Jorge A. Wong, MD, MPH, Population Health Research Institute and McMaster University, Hamilton, Ont., told this news organization.

But “TEE is an invasive imaging modality, so it is associated with small element of risk.” The current study, Dr. Wong said, points to potential risk-stratification tools clinicians might use to guide more selective TEE screening.

“At sites where TEEs are done all the time for patients undergoing ablation, one could use several of these risk markers to perhaps tailor use of TEE in individuals,” Dr. Wong said. “For example, in people with paroxysmal atrial fibrillation, we found that the risk of left atrial appendage clot was approximately 1% or less.” Screening by TEE might reasonably be avoided in such patients.

“Fortunately, continued oral anticoagulation already yields low peri-procedural stroke rates,” observes an accompanying editorial from Paulus Kirchhof, MD, and Christoph Sinning, MD, from the University Heart & Vascular Center and German Centre of Cardiovascular Research, Hamburg.

“Based on this new analysis of existing data, a risk-based use of TEE imaging in anticoagulated patients could enable further improvement in the safe delivery of rhythm control interventions in patients with AF,” the editorialists agree.

The meta-analysis covered 10 prospective and 25 retrospective studies with a total of 14,653 patients that reported whether LA thrombus was present in patients with AF or atrial flutter (AFL) who underwent TEE after at least 3 weeks of VKA or DOAC therapy. Reports for 30 of the studies identified patients by rhythm-control procedure, and the remaining five didn’t specify TEE indications.

The weighted mean prevalence of LA thrombus at TEE was 2.73% (95% confidence interval, 1.95%-3.80%). The finding was not significantly changed in separate sensitivity analyses, the report says, including one limited to studies with low risk of bias and others excluding patients with valvular AF, interrupted OAC, heparin bridging, or subtherapeutic anticoagulation, respectively.

Patients treated with VKA and DOACs showed similar prevalences of LA thrombi, with means of 2.80% and 3.12%, respectively (P = .674). The prevalence was significantly higher in patients:

• with nonparoxysmal than with paroxysmal AF/AFL (4.81% vs. 1.03%; P < .001)
• undergoing cardioversion than ablation (5.55% vs. 1.65; P < .001)
• with CHA2DS2-VASc scores of at least 3 than with scores of 2 or less (6.31% vs. 1.06%; P < .001).

A limitation of the study, observe Dr. Kirchhof and Dr. Sinning, “is that all patients had a clinical indication for a TEE, which might be a selection bias. When a thrombus was found on TEE, clinical judgment led to postponing of the procedure,” thereby avoiding potential thromboembolism.

“Thus, the paper cannot demonstrate that presence of a thrombus on TEE is related to peri-procedural ischemic stroke,” they write.

The literature puts the risk for stroke or systemic embolism at well under 1% for patients anticoagulated with either VKA or DOACs for at least 3 weeks prior to cardioversion, in contrast to the nearly 3% prevalence of LA appendage thrombus by TEE in the current analysis, Dr. Wong observed.

“So we’re seeing a lot more left atrial appendage thrombus than we would see stroke,” but there wasn’t a way to determine whether that increases the stroke risk, he agreed.Dr. Wong, Dr. Lurie, and the other authors report no relevant conflicts. Dr. Kirchhof discloses receiving partial support “from several drug and device companies active in atrial fibrillation” and to being listed as inventor on two AF-related patents held by the University of Birmingham. Dr. Sinning reports no relevant relationships. 

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

[email protected]

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

[email protected]

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

[email protected]

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

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

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

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

A new analysis from the TWILIGHT study has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men.

But there were some interesting observations in the analysis suggesting possible additional benefits of this strategy for women.

“These data support the use of ticagrelor monotherapy in women and men, and importantly show that the absolute risk reduction of bleeding was higher in women, as their bleeding rates were higher,” senior author Roxana Mehran, MD, the Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“These data also support the need for prospective dual antiplatelet therapy deescalation studies in women,” Dr. Mehran added.

The main results of the TWILIGHT study showed that after a short period of dual antiplatelet therapy, a strategy of ticagrelor monotherapy, compared with continued dual therapy led to reduced bleeding without an increase in ischemic events among patients at high risk for bleeding or ischemic events after PCI.

The new gender-based analysis was presented by Birgit Vogel, MD, on May 15 at the annual scientific sessions of the American College of Cardiology. It was also published online in JAMA Cardiology to coincide with the ACC presentation.

Dr. Vogel, also from Wiener Cardiovascular Institute, explained that the current analysis was undertaken to investigate whether the TWILIGHT results varied in relation to sex, given that women are believed to have an increased risk for bleeding after PCI, compared with men.

“The current analysis showed that, while women did have a higher bleeding risk, compared to men, this was no longer significant after adjustment for baseline characteristics; and ischemic events were similar between the two sexes,” she reported.

“Results showed that withdrawing aspirin while continuing ticagrelor after 3 months of dual antiplatelet therapy was associated with a reduction in bleeding and preserved ischemic benefits in both women and men,” she added.

The TWILIGHT trial randomized 7,119 patients at high risk of ischemic or bleeding events who had undergone successful PCI with at least one drug-eluting stent and had completed 3 months of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open-label ticagrelor.

The main results showed that the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 1 year was almost halved with ticagrelor monotherapy, occurring in 4% of these patients, compared with 7.1% of the ticagrelor/aspirin group (hazard ratio, 0.56). Ischemic events were similar in the two groups.

The current analysis focused on whether these effects varied in relation to sex.

Dr. Vogel noted that women made up 23.9% of the study population, were older than the men, and were more likely to have diabetes, chronic kidney disease, anemia and hypertension, while the men were more likely to be current smokers. Men had a higher incidence of coronary heart disease history, while women were more likely to have an ACS indication for PCI.

Unadjusted results showed a higher rate of BARC 2, 3, or 5 bleeding at 1 year in women (6.8%) versus men (5.2%), giving an HR of 1.32 (95% CI, 1.06-1.64).

But after adjustment for baseline characteristics, this became nonsignificant (HR, 1.20; 95% CI, 0.95-1.52).

Dr. Vogel pointed out that the most severe type of bleeding (BARC 3 and 5) was not attenuated as much by adjustment for baseline characteristics, with the HR reducing from 1.57 to 1.49.

The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics.

In terms of the two treatment groups, BARC 2, 3, or 5 bleeding was reduced to a similar extent with ticagrelor monotherapy in both men and women. This endpoint decreased from 8.6% in women on dual-antiplatelet therapy to 5.0% in women on ticagrelor alone (adjusted HR, 0.62) and from 6.6% to 3.7% in men (aHR, 0.57). But she noted that the absolute risk reduction in bleeding was greater in women (3.6%) versus men (2.9%).

“If we have a relative risk reduction in bleeding with early withdrawal of aspirin that is similar between the sexes but an overall higher risk of bleeding in women, that results in a greater absolute risk reduction,” Dr. Vogel commented.

The primary ischemic endpoint of death/MI/stroke was not increased in the ticagrelor group vs the dual antiplatelet group in either men (aHR, 1.06) or women (aHR, 1.04).
 

Greater reduction in mortality in women?

However, Dr. Vogel reported that there was a suggestion of a greater reduction in all-cause mortality with ticagrelor monotherapy in women versus men. “We found a significant interaction for treatment effect and sex for all-cause mortality, a prespecified endpoint, which was significantly lower in women treated with ticagrelor monotherapy, compared to dual antiplatelet therapy, but this was not the case in men.”

However, this observation was based on few events and should not be considered definitive, she added.

Dr. Vogel noted that the analysis had the limitations of the study not being powered to show differences in men versus women, and the results are only applicable to the population studied who were at high risk of bleeding post PCI.

Commenting on the study at the ACC session, Jacqueline Tamis-Holland, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, described the presentation as “very interesting.”

“We know that women notoriously have higher bleeding risk than men, but this particular study did not show a difference in bleeding risk after adjusting for other confounding variables,” she said.

“In fact, one would think that the relative benefit of a treatment designed to decrease bleeding would be more favorable to women, but this analysis didn’t show that,” she added.

Dr. Vogel replied that the HR of the most serious type of bleeding (BARC 3 and 5) in women versus men was only reduced minimally after adjustment for baseline characteristics, “which still makes us think that there are additional factors that might be important and contribute to an increased risk for bleeding and especially more serous types of bleeding in women.”

She pointed out that, while there was a similar risk reduction in bleeding in women and men, there was a potential mortality benefit in women. “The question is whether this mortality benefit is due to reduced bleeding that might be greater in women than men, and the reality is we don’t have a lot of data on that.”

Dr. Vogel added: “We know about the relationship between bleeding and mortality very well but the impact of sex on this is really not well investigated. It would be worth investigating this further to come up with bleeding reduction strategies for women because this is a really important issue.”

This work was supported by an investigator-initiated grant from AstraZeneca. Dr. Mehran reported grants and personal fees (paid to the institution) from Abbott, Abiomed, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Chiesi, Concept Medical Research, Medtronic, Novartis and DSI Research; grants from Applied Therapeutics, AstraZeneca, Cerecor, CSL Behring, OrbusNeich, and Zoll; personal fees from Boston Scientific, California Institute for Regenerative Medicine, Cine-Med Research, Janssen Scientific Affairs, ACC, and WebMD; personal fees paid to the institution from CardiaWave, Duke University, and Idorsia Pharmaceuticals; serving as a consultant or committee or advisory board member for Society for Cardiovascular Angiography and Interventions, the American Medical Association, and Regeneron Pharmaceuticals; and owning stock in ControlRad, Elixir Medical, and STEL outside the submitted work. Dr. Vogel disclosed no relevant financial relationships.

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

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

[email protected]

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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