Patrice Wendling

A recent ISCHEMIA trial substudy is under scrutiny from surgeons for a data discrepancy, rekindling concerns about reliance on the landmark trial data in the latest coronary revascularization guidelines.

As previously reported, the main ISCHEMIA findings showed no significant benefit for an initial strategy of percutaneous coronary intervention (PCI) or coronary bypass graft surgery (CABG) over medical therapy in patients with stable moderate to severe ischemic heart disease.

The 2021 substudy by Reynolds et al. showed that coronary artery disease (CAD) severity, classified using the modified Duke Prognostic Index score, predicted 4-year mortality and myocardial infarction in the trial, whereas ischemia severity did not.

Cardiac surgeons Joseph F. Sabik III, MD, and Faisal Bakaeen, MD, however, spotted that only 40 patients are in the Duke category 6 group (three-vessel severe stenosis of at least 70% or two-vessel severe stenosis with a proximal left anterior descending lesion) in Supplemental tables 1 and 2, whereas 659 are in the main paper.

In addition, the Supplemental tables list the following:

• 659 patients in Duke group 5, not 894 as in the paper.
• 894 patients in Duke group 4, not 743 as in the paper.
• 743 patients in Duke group 3, not 179 as in the paper.

The surgeons penned a letter to Circulation early in April flagging the discrepancies, but say it was rejected April 15 because it was submitted outside the journal’s 6-week window for letters. They posted a public comment on the Remarq research platform, as advised by Circulation’s editorial office, and reached out directly to the authors and ISCHEMIA leadership.

“They just keep saying it’s a simple formatting error. Well, if it is a simple formatting error, then fix it,” Dr. Sabik, chair of surgery at University Hospitals Cleveland Medical Center, said in an interview. “But here we are now, a month later, and they still haven’t published our letter. Why? We’re the ones who identified the problem.”

Dr. Sabik said the accuracy of the data has important implications because the recent AHA/ACC/SCAI coronary revascularization guidelines used the ISCHEMIA data to downgrade the CABG recommendation for complex multivessel disease from class 1 to class 2B. Patients with a Duke 6 score are also typically the ones referred for CABG by today’s heart teams.

Several surgical societies have contested the guidelines, questioning whether the ISCHEMIA patients are truly reflective of those seen in clinical practice and questioning the decision to treat PCI and surgery as equivalent strategies to decrease ischemic events.

Dr. Bakaeen, from the Cleveland Clinic, told this news organization they don’t want a public battle over the data like the one that befell the EXCEL trial, and that it’s entirely possible the investigators might have inadvertently upgraded all the Duke score assignments by 1.

A systematic error, however, is more plausible than a formatting error, he said, because Supplemental tables 1 and 2 correspond exactly to the Duke 1 to Duke 7 sequence, suggesting the tables are correct and that the error might have occurred downstream, including in the manuscript.

The numbers should be consistent across all the ISCHEMIA manuscripts, Dr. Bakaeen added, but currently “don’t add up,” even after adjustment for different denominators, and especially for participants with left main disease.

They hope that publication of their letter, he said, will convince the authors to publicly share the data for patients in each of the seven modified Duke categories.

Lead author of the ISCHEMIA substudy, Harmony Reynolds, MD, New York (N.Y.) University Langone Health, told this news organization via email that as a result of a “formatting error in the transfer of data from the statistical output file to a Word document, data in Supplemental tables 1 and 2 were incorrect.”

She explained that they planned to present six, not seven, rows for the Duke score in the tables, collapsing the first two categories of nonobstructive disease (Duke 1-2), as they were in all other tables and figures. However, the Supplemental tables had incorrect row headings and because the Word program is designed to fill all available rows, it inserted the data from the output file into a seven-row table shell, duplicating the values for row 1 in the last row for left main disease of at least 50%.

“The data were correctly presented in the main manuscript tables and figures and in the remainder of the supplement, with a total of 659 patients in the subset with modified Duke prognostic index category 6 on coronary CT angiography,” Dr. Reynolds said.

She noted that Circulation will issue a correction. In addition, “we are in the process of preparing the data for public sharing soon. The data will include the Duke prognostic score at all levels.”

Circulation editor-in-chief Joseph A. Hill, MD, PhD, chief of cardiology at UT Southwestern Medical Center, Dallas, declined to be interviewed but confirmed via email that Dr. Bakaeen and Dr. Sabik’s letter and the correction will be published the week of May 16.

As for the delay, he said, “I received their reach-out just over 1 week ago, and per protocol, we conducted an internal evaluation of their allegations, which took a bit of time.”
 

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

A recent ISCHEMIA trial substudy is under scrutiny from surgeons for a data discrepancy, rekindling concerns about reliance on the landmark trial data in the latest coronary revascularization guidelines.

As previously reported, the main ISCHEMIA findings showed no significant benefit for an initial strategy of percutaneous coronary intervention (PCI) or coronary bypass graft surgery (CABG) over medical therapy in patients with stable moderate to severe ischemic heart disease.

The 2021 substudy by Reynolds et al. showed that coronary artery disease (CAD) severity, classified using the modified Duke Prognostic Index score, predicted 4-year mortality and myocardial infarction in the trial, whereas ischemia severity did not.

Cardiac surgeons Joseph F. Sabik III, MD, and Faisal Bakaeen, MD, however, spotted that only 40 patients are in the Duke category 6 group (three-vessel severe stenosis of at least 70% or two-vessel severe stenosis with a proximal left anterior descending lesion) in Supplemental tables 1 and 2, whereas 659 are in the main paper.

In addition, the Supplemental tables list the following:

• 659 patients in Duke group 5, not 894 as in the paper.
• 894 patients in Duke group 4, not 743 as in the paper.
• 743 patients in Duke group 3, not 179 as in the paper.

The surgeons penned a letter to Circulation early in April flagging the discrepancies, but say it was rejected April 15 because it was submitted outside the journal’s 6-week window for letters. They posted a public comment on the Remarq research platform, as advised by Circulation’s editorial office, and reached out directly to the authors and ISCHEMIA leadership.

“They just keep saying it’s a simple formatting error. Well, if it is a simple formatting error, then fix it,” Dr. Sabik, chair of surgery at University Hospitals Cleveland Medical Center, said in an interview. “But here we are now, a month later, and they still haven’t published our letter. Why? We’re the ones who identified the problem.”

Dr. Sabik said the accuracy of the data has important implications because the recent AHA/ACC/SCAI coronary revascularization guidelines used the ISCHEMIA data to downgrade the CABG recommendation for complex multivessel disease from class 1 to class 2B. Patients with a Duke 6 score are also typically the ones referred for CABG by today’s heart teams.

Several surgical societies have contested the guidelines, questioning whether the ISCHEMIA patients are truly reflective of those seen in clinical practice and questioning the decision to treat PCI and surgery as equivalent strategies to decrease ischemic events.

Dr. Bakaeen, from the Cleveland Clinic, told this news organization they don’t want a public battle over the data like the one that befell the EXCEL trial, and that it’s entirely possible the investigators might have inadvertently upgraded all the Duke score assignments by 1.

A systematic error, however, is more plausible than a formatting error, he said, because Supplemental tables 1 and 2 correspond exactly to the Duke 1 to Duke 7 sequence, suggesting the tables are correct and that the error might have occurred downstream, including in the manuscript.

The numbers should be consistent across all the ISCHEMIA manuscripts, Dr. Bakaeen added, but currently “don’t add up,” even after adjustment for different denominators, and especially for participants with left main disease.

They hope that publication of their letter, he said, will convince the authors to publicly share the data for patients in each of the seven modified Duke categories.

Lead author of the ISCHEMIA substudy, Harmony Reynolds, MD, New York (N.Y.) University Langone Health, told this news organization via email that as a result of a “formatting error in the transfer of data from the statistical output file to a Word document, data in Supplemental tables 1 and 2 were incorrect.”

She explained that they planned to present six, not seven, rows for the Duke score in the tables, collapsing the first two categories of nonobstructive disease (Duke 1-2), as they were in all other tables and figures. However, the Supplemental tables had incorrect row headings and because the Word program is designed to fill all available rows, it inserted the data from the output file into a seven-row table shell, duplicating the values for row 1 in the last row for left main disease of at least 50%.

“The data were correctly presented in the main manuscript tables and figures and in the remainder of the supplement, with a total of 659 patients in the subset with modified Duke prognostic index category 6 on coronary CT angiography,” Dr. Reynolds said.

She noted that Circulation will issue a correction. In addition, “we are in the process of preparing the data for public sharing soon. The data will include the Duke prognostic score at all levels.”

Circulation editor-in-chief Joseph A. Hill, MD, PhD, chief of cardiology at UT Southwestern Medical Center, Dallas, declined to be interviewed but confirmed via email that Dr. Bakaeen and Dr. Sabik’s letter and the correction will be published the week of May 16.

As for the delay, he said, “I received their reach-out just over 1 week ago, and per protocol, we conducted an internal evaluation of their allegations, which took a bit of time.”
 

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

A recent ISCHEMIA trial substudy is under scrutiny from surgeons for a data discrepancy, rekindling concerns about reliance on the landmark trial data in the latest coronary revascularization guidelines.

As previously reported, the main ISCHEMIA findings showed no significant benefit for an initial strategy of percutaneous coronary intervention (PCI) or coronary bypass graft surgery (CABG) over medical therapy in patients with stable moderate to severe ischemic heart disease.

The 2021 substudy by Reynolds et al. showed that coronary artery disease (CAD) severity, classified using the modified Duke Prognostic Index score, predicted 4-year mortality and myocardial infarction in the trial, whereas ischemia severity did not.

Cardiac surgeons Joseph F. Sabik III, MD, and Faisal Bakaeen, MD, however, spotted that only 40 patients are in the Duke category 6 group (three-vessel severe stenosis of at least 70% or two-vessel severe stenosis with a proximal left anterior descending lesion) in Supplemental tables 1 and 2, whereas 659 are in the main paper.

In addition, the Supplemental tables list the following:

• 659 patients in Duke group 5, not 894 as in the paper.
• 894 patients in Duke group 4, not 743 as in the paper.
• 743 patients in Duke group 3, not 179 as in the paper.

The surgeons penned a letter to Circulation early in April flagging the discrepancies, but say it was rejected April 15 because it was submitted outside the journal’s 6-week window for letters. They posted a public comment on the Remarq research platform, as advised by Circulation’s editorial office, and reached out directly to the authors and ISCHEMIA leadership.

“They just keep saying it’s a simple formatting error. Well, if it is a simple formatting error, then fix it,” Dr. Sabik, chair of surgery at University Hospitals Cleveland Medical Center, said in an interview. “But here we are now, a month later, and they still haven’t published our letter. Why? We’re the ones who identified the problem.”

Dr. Sabik said the accuracy of the data has important implications because the recent AHA/ACC/SCAI coronary revascularization guidelines used the ISCHEMIA data to downgrade the CABG recommendation for complex multivessel disease from class 1 to class 2B. Patients with a Duke 6 score are also typically the ones referred for CABG by today’s heart teams.

Several surgical societies have contested the guidelines, questioning whether the ISCHEMIA patients are truly reflective of those seen in clinical practice and questioning the decision to treat PCI and surgery as equivalent strategies to decrease ischemic events.

Dr. Bakaeen, from the Cleveland Clinic, told this news organization they don’t want a public battle over the data like the one that befell the EXCEL trial, and that it’s entirely possible the investigators might have inadvertently upgraded all the Duke score assignments by 1.

A systematic error, however, is more plausible than a formatting error, he said, because Supplemental tables 1 and 2 correspond exactly to the Duke 1 to Duke 7 sequence, suggesting the tables are correct and that the error might have occurred downstream, including in the manuscript.

The numbers should be consistent across all the ISCHEMIA manuscripts, Dr. Bakaeen added, but currently “don’t add up,” even after adjustment for different denominators, and especially for participants with left main disease.

They hope that publication of their letter, he said, will convince the authors to publicly share the data for patients in each of the seven modified Duke categories.

Lead author of the ISCHEMIA substudy, Harmony Reynolds, MD, New York (N.Y.) University Langone Health, told this news organization via email that as a result of a “formatting error in the transfer of data from the statistical output file to a Word document, data in Supplemental tables 1 and 2 were incorrect.”

She explained that they planned to present six, not seven, rows for the Duke score in the tables, collapsing the first two categories of nonobstructive disease (Duke 1-2), as they were in all other tables and figures. However, the Supplemental tables had incorrect row headings and because the Word program is designed to fill all available rows, it inserted the data from the output file into a seven-row table shell, duplicating the values for row 1 in the last row for left main disease of at least 50%.

“The data were correctly presented in the main manuscript tables and figures and in the remainder of the supplement, with a total of 659 patients in the subset with modified Duke prognostic index category 6 on coronary CT angiography,” Dr. Reynolds said.

She noted that Circulation will issue a correction. In addition, “we are in the process of preparing the data for public sharing soon. The data will include the Duke prognostic score at all levels.”

Circulation editor-in-chief Joseph A. Hill, MD, PhD, chief of cardiology at UT Southwestern Medical Center, Dallas, declined to be interviewed but confirmed via email that Dr. Bakaeen and Dr. Sabik’s letter and the correction will be published the week of May 16.

As for the delay, he said, “I received their reach-out just over 1 week ago, and per protocol, we conducted an internal evaluation of their allegations, which took a bit of time.”
 

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

The U.S. Food and Drug Administration has approved the Onyx Frontier drug-eluting stent (DES) to treat patients with coronary artery disease, the device manufacturer, Medtronic, announced today.

The Onyx Frontier shares the same stent platform and clinical indications as the previous-generation Resolute Onyx zotarolimus-eluting stent, including the most recent approval for patients at high risk of bleeding who may benefit from just 1 month dual-antiplatelet therapy.

“Meaningful design changes, including increased catheter flexibility, an innovative dual-layer balloon technology and a lower crossing profile led to a 16% improvement in deliverability with Onyx Frontier vs. the previous generation Resolute Onyx DES,” Medtronic said in a news release.

Onyx Frontier also offers a broad size matrix to treat more patients, and joins the Resolute Onyx as the only 2-mm DES available in the United States, the company noted. The stent is available in 4.5- to 5-mm sizes that can be expanded to 6 mm, specifically designed to support extra-large vessels.

The Onyx Frontier DES is pending CE Mark in Europe.

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

The U.S. Food and Drug Administration has approved the Onyx Frontier drug-eluting stent (DES) to treat patients with coronary artery disease, the device manufacturer, Medtronic, announced today.

The Onyx Frontier shares the same stent platform and clinical indications as the previous-generation Resolute Onyx zotarolimus-eluting stent, including the most recent approval for patients at high risk of bleeding who may benefit from just 1 month dual-antiplatelet therapy.

“Meaningful design changes, including increased catheter flexibility, an innovative dual-layer balloon technology and a lower crossing profile led to a 16% improvement in deliverability with Onyx Frontier vs. the previous generation Resolute Onyx DES,” Medtronic said in a news release.

Onyx Frontier also offers a broad size matrix to treat more patients, and joins the Resolute Onyx as the only 2-mm DES available in the United States, the company noted. The stent is available in 4.5- to 5-mm sizes that can be expanded to 6 mm, specifically designed to support extra-large vessels.

The Onyx Frontier DES is pending CE Mark in Europe.

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

The U.S. Food and Drug Administration has approved the Onyx Frontier drug-eluting stent (DES) to treat patients with coronary artery disease, the device manufacturer, Medtronic, announced today.

The Onyx Frontier shares the same stent platform and clinical indications as the previous-generation Resolute Onyx zotarolimus-eluting stent, including the most recent approval for patients at high risk of bleeding who may benefit from just 1 month dual-antiplatelet therapy.

“Meaningful design changes, including increased catheter flexibility, an innovative dual-layer balloon technology and a lower crossing profile led to a 16% improvement in deliverability with Onyx Frontier vs. the previous generation Resolute Onyx DES,” Medtronic said in a news release.

Onyx Frontier also offers a broad size matrix to treat more patients, and joins the Resolute Onyx as the only 2-mm DES available in the United States, the company noted. The stent is available in 4.5- to 5-mm sizes that can be expanded to 6 mm, specifically designed to support extra-large vessels.

The Onyx Frontier DES is pending CE Mark in Europe.

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

A new study finds clinicians are shifting away from the U.S. Food and Drug Administration–approved combination of warfarin and aspirin after left atrial appendage occlusion (LAAO) with the Watchman device and that adverse events, particularly bleeding, are lower when aspirin is dropped.

Of 31,994 patients successfully implanted with the Watchman 2.5 device in the 3 years after its March 2015 approval, only 1 in 10 received the full postprocedure protocol studied in pivotal trials and codified into the FDA-device approval.

The protocol consisted of aspirin (81-325 mg) indefinitely and warfarin for 45 days. Following transesophageal echocardiography, patients were then maintained on warfarin and aspirin if there was a peridevice leak greater than 5 mm or switched to clopidogrel 75 mg for 6 months if a peridevice leak was ruled out or was 5 mm or less.

Based on the results, drawn from the National Cardiovascular Data Registry (NCDR) LAAO Registry, the most common discharge medications were warfarin and aspirin in 36.9% of patients, followed by a direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin alone (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (5%).

“There’s a little bit of practice leading the science in this space,” lead author James V. Freeman, MD, MPH, Yale School of Medicine, New Haven, Conn., told this news organization.

Patients who couldn’t tolerate long-term anticoagulation were excluded from the pivotal trials but are now the patients in whom the device is most often used, because of the Centers for Medicare & Medicaid reimbursement mandate for a relative or absolute contraindication to long-term anticoagulation, he noted.

Not surprisingly, 70% of patients in the registry had history of clinically relevant bleeding, the mean CHA2DS2-VASc score was 4.6, and mean HAS-BLED score was 3. At an average age of 76, they were also older, by years, than those in the clinical trials.

Secular trends at the time also saw the ascendancy of the DOACs relative to warfarin, observed Dr. Freeman. “So I think it’s pretty reasonable for physicians to be considering DOACs rather than warfarin in this context.”
 

Aspirin takes another hit

Results, published May 2 in the Journal of the American College of Cardiology, showed that any adverse event occurred at 45 days in 5.7% of patients discharged on warfarin and aspirin, 4% on warfarin alone, 5.2% on DOAC and aspirin, 3.8% on DOAC only, and 5.5% on DAPT.

Rates of any major adverse event were 4.4%, 3.3%, 4.3%, 3.1%, and 4.2% respectively, and for major bleeding were 3%, 1.8%, 2.8%, 1.7%, and 2.2% respectively. Although patients were similar across treatment groups, those treated with DAPT were slightly older and had more comorbidities, Dr. Freeman said.

In Cox frailty regression, the adjusted risk of any adverse event at 45 days was significantly lower when patients were discharged on warfarin alone (hazard ratio, 0.692; 95% confidence interval, 0.56-0.84) and a DOAC alone (HR, 0.731; 95% CI, 0.57-0.93), compared with warfarin and aspirin. There were no differences among the other groups.

The risk of any major adverse event was also significantly lower with warfarin alone (HR, 0.658; 95% CI, 0.53-0.80) and DOAC alone (HR, 0.767; 95% CI, 0.59-0.98).

At 6 months, rates of any adverse event (HR, 0.814; 95% CI, 0.72-0.93) and any major adverse event (HR, 0.840; 95% CI, 0.73-0.95) were significantly lower only in patients treated with warfarin alone.

“I think if there’s a take-home [message] here, it’s that for a lot of patients there’s good data now to suggest getting rid of the aspirin is a very reasonable thing to do,” Dr. Freeman said.

Further studies are needed in the space, but the results are consistent with those from transcatheter aortic valve replacement studies showing discharge on warfarin or DOAC anticoagulation alone reduces major adverse events without increasing thrombotic events, he said.

“I do think if there’s a strong indication for aspirin – someone has terrible coronary disease – there may be a role for using it,” Dr. Freeman said. But for a lot of these patients, anticoagulation alone without aspirin “may present a big opportunity to mitigate morbidity associated with this procedure.”

Dr. Freeman said he doesn’t expect the findings would be dramatically different with the second-generation Watchman FLX device but noted that randomized data will be forthcoming, as Boston Scientific changed the CHAMPION-AF trial protocol to include DOAC alone without aspirin.

Commenting for this news organization, Domenico Della Rocca, MD, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, said the study is a useful overview of post-LAAO therapies in a large population – but not surprising.

“Practice has changed over the years. More and more we are adopting and trusting the DOACs,” he said. “And, we are realizing that dual antiplatelet therapy is so aggressive and antiplatelet therapy alone maybe is not the best choice based on data on activation of coagulation.”

Commenting further, he said “I think it’s too early to suggest being too keen to completely drop aspirin,” noting that 20%-25% of patients have clopidogrel resistance and that the combination of two antiplatelets may be too aggressive a strategy for others.

Dr. Della Rocca and colleagues recently reported favorable long-term results with half-dose DOAC therapy after Watchman implantation and said the team is launching a randomized trial in more than 500 LAAO patients in the United States and Europe later this year. The trial will be comparing a DOAC-based strategy with low-dose apixaban long-term versus clopidogrel and aspirin initially and then switching to 100 mg aspirin long-term.

“We hope that in the next 2-3 years we will have some better answers, but at this point I would say that clopidogrel is kind of an obsolete strategy for appendage closure,” Dr. Della Rocca said.

In an accompanying editorial, David R. Holmes Jr., MD, Mayo Clinic, Rochester, Minn., says “the cornucopia of these specific strategies can be expected to change as practices evolve, as instructions for use broaden and, hopefully, with the results of well-done, scientifically performed trials. This current LAAO Registry report, however, serves as a useful benchmark.”

He cautioned that this is an observational cohort study and that unmeasured imbalances still may affect the ability to identify an unbiased treatment signal. The use of DAPT was also infrequent during the study and “conclusions based on this information are soft.”

The study was funded by the American College of Cardiology National Cardiovascular Data Registry (NCDR), and the National Heart, Lung, and Blood Institute (NHLBI) grants. Dr. Freeman has received salary support from the ACC NCDR and the NHLBI and has received consulting/advisory board fees from Boston Scientific, Medtronic, Janssen Pharmaceuticals, and Biosense Webster.

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

A new study finds clinicians are shifting away from the U.S. Food and Drug Administration–approved combination of warfarin and aspirin after left atrial appendage occlusion (LAAO) with the Watchman device and that adverse events, particularly bleeding, are lower when aspirin is dropped.

Of 31,994 patients successfully implanted with the Watchman 2.5 device in the 3 years after its March 2015 approval, only 1 in 10 received the full postprocedure protocol studied in pivotal trials and codified into the FDA-device approval.

The protocol consisted of aspirin (81-325 mg) indefinitely and warfarin for 45 days. Following transesophageal echocardiography, patients were then maintained on warfarin and aspirin if there was a peridevice leak greater than 5 mm or switched to clopidogrel 75 mg for 6 months if a peridevice leak was ruled out or was 5 mm or less.

Based on the results, drawn from the National Cardiovascular Data Registry (NCDR) LAAO Registry, the most common discharge medications were warfarin and aspirin in 36.9% of patients, followed by a direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin alone (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (5%).

“There’s a little bit of practice leading the science in this space,” lead author James V. Freeman, MD, MPH, Yale School of Medicine, New Haven, Conn., told this news organization.

Patients who couldn’t tolerate long-term anticoagulation were excluded from the pivotal trials but are now the patients in whom the device is most often used, because of the Centers for Medicare & Medicaid reimbursement mandate for a relative or absolute contraindication to long-term anticoagulation, he noted.

Not surprisingly, 70% of patients in the registry had history of clinically relevant bleeding, the mean CHA2DS2-VASc score was 4.6, and mean HAS-BLED score was 3. At an average age of 76, they were also older, by years, than those in the clinical trials.

Secular trends at the time also saw the ascendancy of the DOACs relative to warfarin, observed Dr. Freeman. “So I think it’s pretty reasonable for physicians to be considering DOACs rather than warfarin in this context.”
 

Aspirin takes another hit

Results, published May 2 in the Journal of the American College of Cardiology, showed that any adverse event occurred at 45 days in 5.7% of patients discharged on warfarin and aspirin, 4% on warfarin alone, 5.2% on DOAC and aspirin, 3.8% on DOAC only, and 5.5% on DAPT.

Rates of any major adverse event were 4.4%, 3.3%, 4.3%, 3.1%, and 4.2% respectively, and for major bleeding were 3%, 1.8%, 2.8%, 1.7%, and 2.2% respectively. Although patients were similar across treatment groups, those treated with DAPT were slightly older and had more comorbidities, Dr. Freeman said.

In Cox frailty regression, the adjusted risk of any adverse event at 45 days was significantly lower when patients were discharged on warfarin alone (hazard ratio, 0.692; 95% confidence interval, 0.56-0.84) and a DOAC alone (HR, 0.731; 95% CI, 0.57-0.93), compared with warfarin and aspirin. There were no differences among the other groups.

The risk of any major adverse event was also significantly lower with warfarin alone (HR, 0.658; 95% CI, 0.53-0.80) and DOAC alone (HR, 0.767; 95% CI, 0.59-0.98).

At 6 months, rates of any adverse event (HR, 0.814; 95% CI, 0.72-0.93) and any major adverse event (HR, 0.840; 95% CI, 0.73-0.95) were significantly lower only in patients treated with warfarin alone.

“I think if there’s a take-home [message] here, it’s that for a lot of patients there’s good data now to suggest getting rid of the aspirin is a very reasonable thing to do,” Dr. Freeman said.

Further studies are needed in the space, but the results are consistent with those from transcatheter aortic valve replacement studies showing discharge on warfarin or DOAC anticoagulation alone reduces major adverse events without increasing thrombotic events, he said.

“I do think if there’s a strong indication for aspirin – someone has terrible coronary disease – there may be a role for using it,” Dr. Freeman said. But for a lot of these patients, anticoagulation alone without aspirin “may present a big opportunity to mitigate morbidity associated with this procedure.”

Dr. Freeman said he doesn’t expect the findings would be dramatically different with the second-generation Watchman FLX device but noted that randomized data will be forthcoming, as Boston Scientific changed the CHAMPION-AF trial protocol to include DOAC alone without aspirin.

Commenting for this news organization, Domenico Della Rocca, MD, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, said the study is a useful overview of post-LAAO therapies in a large population – but not surprising.

“Practice has changed over the years. More and more we are adopting and trusting the DOACs,” he said. “And, we are realizing that dual antiplatelet therapy is so aggressive and antiplatelet therapy alone maybe is not the best choice based on data on activation of coagulation.”

Commenting further, he said “I think it’s too early to suggest being too keen to completely drop aspirin,” noting that 20%-25% of patients have clopidogrel resistance and that the combination of two antiplatelets may be too aggressive a strategy for others.

Dr. Della Rocca and colleagues recently reported favorable long-term results with half-dose DOAC therapy after Watchman implantation and said the team is launching a randomized trial in more than 500 LAAO patients in the United States and Europe later this year. The trial will be comparing a DOAC-based strategy with low-dose apixaban long-term versus clopidogrel and aspirin initially and then switching to 100 mg aspirin long-term.

“We hope that in the next 2-3 years we will have some better answers, but at this point I would say that clopidogrel is kind of an obsolete strategy for appendage closure,” Dr. Della Rocca said.

In an accompanying editorial, David R. Holmes Jr., MD, Mayo Clinic, Rochester, Minn., says “the cornucopia of these specific strategies can be expected to change as practices evolve, as instructions for use broaden and, hopefully, with the results of well-done, scientifically performed trials. This current LAAO Registry report, however, serves as a useful benchmark.”

He cautioned that this is an observational cohort study and that unmeasured imbalances still may affect the ability to identify an unbiased treatment signal. The use of DAPT was also infrequent during the study and “conclusions based on this information are soft.”

The study was funded by the American College of Cardiology National Cardiovascular Data Registry (NCDR), and the National Heart, Lung, and Blood Institute (NHLBI) grants. Dr. Freeman has received salary support from the ACC NCDR and the NHLBI and has received consulting/advisory board fees from Boston Scientific, Medtronic, Janssen Pharmaceuticals, and Biosense Webster.

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

A new study finds clinicians are shifting away from the U.S. Food and Drug Administration–approved combination of warfarin and aspirin after left atrial appendage occlusion (LAAO) with the Watchman device and that adverse events, particularly bleeding, are lower when aspirin is dropped.

Of 31,994 patients successfully implanted with the Watchman 2.5 device in the 3 years after its March 2015 approval, only 1 in 10 received the full postprocedure protocol studied in pivotal trials and codified into the FDA-device approval.

The protocol consisted of aspirin (81-325 mg) indefinitely and warfarin for 45 days. Following transesophageal echocardiography, patients were then maintained on warfarin and aspirin if there was a peridevice leak greater than 5 mm or switched to clopidogrel 75 mg for 6 months if a peridevice leak was ruled out or was 5 mm or less.

Based on the results, drawn from the National Cardiovascular Data Registry (NCDR) LAAO Registry, the most common discharge medications were warfarin and aspirin in 36.9% of patients, followed by a direct oral anticoagulant (DOAC) and aspirin (20.8%), warfarin alone (13.5%), DOAC only (12.3%), and dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (5%).

“There’s a little bit of practice leading the science in this space,” lead author James V. Freeman, MD, MPH, Yale School of Medicine, New Haven, Conn., told this news organization.

Patients who couldn’t tolerate long-term anticoagulation were excluded from the pivotal trials but are now the patients in whom the device is most often used, because of the Centers for Medicare & Medicaid reimbursement mandate for a relative or absolute contraindication to long-term anticoagulation, he noted.

Not surprisingly, 70% of patients in the registry had history of clinically relevant bleeding, the mean CHA2DS2-VASc score was 4.6, and mean HAS-BLED score was 3. At an average age of 76, they were also older, by years, than those in the clinical trials.

Secular trends at the time also saw the ascendancy of the DOACs relative to warfarin, observed Dr. Freeman. “So I think it’s pretty reasonable for physicians to be considering DOACs rather than warfarin in this context.”
 

Aspirin takes another hit

Results, published May 2 in the Journal of the American College of Cardiology, showed that any adverse event occurred at 45 days in 5.7% of patients discharged on warfarin and aspirin, 4% on warfarin alone, 5.2% on DOAC and aspirin, 3.8% on DOAC only, and 5.5% on DAPT.

Rates of any major adverse event were 4.4%, 3.3%, 4.3%, 3.1%, and 4.2% respectively, and for major bleeding were 3%, 1.8%, 2.8%, 1.7%, and 2.2% respectively. Although patients were similar across treatment groups, those treated with DAPT were slightly older and had more comorbidities, Dr. Freeman said.

In Cox frailty regression, the adjusted risk of any adverse event at 45 days was significantly lower when patients were discharged on warfarin alone (hazard ratio, 0.692; 95% confidence interval, 0.56-0.84) and a DOAC alone (HR, 0.731; 95% CI, 0.57-0.93), compared with warfarin and aspirin. There were no differences among the other groups.

The risk of any major adverse event was also significantly lower with warfarin alone (HR, 0.658; 95% CI, 0.53-0.80) and DOAC alone (HR, 0.767; 95% CI, 0.59-0.98).

At 6 months, rates of any adverse event (HR, 0.814; 95% CI, 0.72-0.93) and any major adverse event (HR, 0.840; 95% CI, 0.73-0.95) were significantly lower only in patients treated with warfarin alone.

“I think if there’s a take-home [message] here, it’s that for a lot of patients there’s good data now to suggest getting rid of the aspirin is a very reasonable thing to do,” Dr. Freeman said.

Further studies are needed in the space, but the results are consistent with those from transcatheter aortic valve replacement studies showing discharge on warfarin or DOAC anticoagulation alone reduces major adverse events without increasing thrombotic events, he said.

“I do think if there’s a strong indication for aspirin – someone has terrible coronary disease – there may be a role for using it,” Dr. Freeman said. But for a lot of these patients, anticoagulation alone without aspirin “may present a big opportunity to mitigate morbidity associated with this procedure.”

Dr. Freeman said he doesn’t expect the findings would be dramatically different with the second-generation Watchman FLX device but noted that randomized data will be forthcoming, as Boston Scientific changed the CHAMPION-AF trial protocol to include DOAC alone without aspirin.

Commenting for this news organization, Domenico Della Rocca, MD, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, said the study is a useful overview of post-LAAO therapies in a large population – but not surprising.

“Practice has changed over the years. More and more we are adopting and trusting the DOACs,” he said. “And, we are realizing that dual antiplatelet therapy is so aggressive and antiplatelet therapy alone maybe is not the best choice based on data on activation of coagulation.”

Commenting further, he said “I think it’s too early to suggest being too keen to completely drop aspirin,” noting that 20%-25% of patients have clopidogrel resistance and that the combination of two antiplatelets may be too aggressive a strategy for others.

Dr. Della Rocca and colleagues recently reported favorable long-term results with half-dose DOAC therapy after Watchman implantation and said the team is launching a randomized trial in more than 500 LAAO patients in the United States and Europe later this year. The trial will be comparing a DOAC-based strategy with low-dose apixaban long-term versus clopidogrel and aspirin initially and then switching to 100 mg aspirin long-term.

“We hope that in the next 2-3 years we will have some better answers, but at this point I would say that clopidogrel is kind of an obsolete strategy for appendage closure,” Dr. Della Rocca said.

In an accompanying editorial, David R. Holmes Jr., MD, Mayo Clinic, Rochester, Minn., says “the cornucopia of these specific strategies can be expected to change as practices evolve, as instructions for use broaden and, hopefully, with the results of well-done, scientifically performed trials. This current LAAO Registry report, however, serves as a useful benchmark.”

He cautioned that this is an observational cohort study and that unmeasured imbalances still may affect the ability to identify an unbiased treatment signal. The use of DAPT was also infrequent during the study and “conclusions based on this information are soft.”

The study was funded by the American College of Cardiology National Cardiovascular Data Registry (NCDR), and the National Heart, Lung, and Blood Institute (NHLBI) grants. Dr. Freeman has received salary support from the ACC NCDR and the NHLBI and has received consulting/advisory board fees from Boston Scientific, Medtronic, Janssen Pharmaceuticals, and Biosense Webster.

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

Topline results from the phase 3 DELIVER trial show dapagliflozin (Farxiga) significantly reduced the primary endpoint of cardiovascular death or worsening heart failure in patients with mildly reduced or preserved ejection fraction, AstraZeneca announced today.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor is not approved in this setting but is already approved for treatment of type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction.

“The results of DELIVER extend the benefit of dapagliflozin to the full spectrum of patients with heart failure,” principal investigator of the trial, Scott Solomon, MD, Harvard Medical School and Brigham and Women’s Hospital, Boston, said in the news release.

The safety and tolerability of dapagliflozin in the trial were consistent with its established safety profile, the company says.

The full trial results will be submitted for presentation at a forthcoming medical meeting, and regulatory submissions will be made in the coming months, it notes.

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

Topline results from the phase 3 DELIVER trial show dapagliflozin (Farxiga) significantly reduced the primary endpoint of cardiovascular death or worsening heart failure in patients with mildly reduced or preserved ejection fraction, AstraZeneca announced today.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor is not approved in this setting but is already approved for treatment of type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction.

“The results of DELIVER extend the benefit of dapagliflozin to the full spectrum of patients with heart failure,” principal investigator of the trial, Scott Solomon, MD, Harvard Medical School and Brigham and Women’s Hospital, Boston, said in the news release.

The safety and tolerability of dapagliflozin in the trial were consistent with its established safety profile, the company says.

The full trial results will be submitted for presentation at a forthcoming medical meeting, and regulatory submissions will be made in the coming months, it notes.

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

Topline results from the phase 3 DELIVER trial show dapagliflozin (Farxiga) significantly reduced the primary endpoint of cardiovascular death or worsening heart failure in patients with mildly reduced or preserved ejection fraction, AstraZeneca announced today.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor is not approved in this setting but is already approved for treatment of type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction.

“The results of DELIVER extend the benefit of dapagliflozin to the full spectrum of patients with heart failure,” principal investigator of the trial, Scott Solomon, MD, Harvard Medical School and Brigham and Women’s Hospital, Boston, said in the news release.

The safety and tolerability of dapagliflozin in the trial were consistent with its established safety profile, the company says.

The full trial results will be submitted for presentation at a forthcoming medical meeting, and regulatory submissions will be made in the coming months, it notes.

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

New research suggests physicians face a Herculean task to get Americans with atherosclerotic cardiovascular disease (ASCVD) to take high-intensity statins, despite multiple professional guidelines giving the therapy their highest level recommendation.

Results from more 600,000 commercially insured patients with established ASCVD showed:

• Only one in five patients (22.5%) were taking a high-intensity statin.
• 27.6% were taking a low- or moderate-intensity statin.
• One-half (49.9%) were not taking any statin.

“It’s embarrassing,” senior author Christopher B. Granger, MD, Duke Clinical Research Institute, Durham, N.C., told this news organization. “It should be embarrassing for anybody in health care that we do such a terrible job with something so simple and effective.”

The results were published in the Journal of the American College of Cardiology.

Statins have been shown to reduce the risk for ASCVD events by about 30%, with an added 15% reduction with a high-intensity formulation. The class I recommendation for high-intensity statin use in ASCVD patients younger than 75 years in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines prompted a jump in prescriptions that plateaued by 2017.

A class II recommendation was added to the 2018 guideline update for high-intensity statins in adults older than 75 years with ASCVD. But underuse persists, despite falling prices with generic availability and initiatives to improve statin adoption, the authors noted.

“There are a lot of barriers for patients to statin use, including the misinformation on the Internet and elsewhere that statins have all kinds of side effects,” Dr. Granger said. “They have uncommon side effects, but when we look at it carefully, only about 10% of patients, even with statin intolerance, have true intolerance.”

Efforts are needed to better understand and address these barriers, particularly for younger and female patients, he noted.

In multivariate analyses, patients who were middle-aged (odds ratio, 2.66) or at least 75 years of age (OR, 2.09) were more than twice as likely as patients younger than 45 years to be on any statin.

Not surprisingly, women were 30% less likely than men to receive a statin (OR, 0.70), Dr. Granger said. A high Charlson comorbidity score (OR, 0.72) and peripheral artery disease (OR, 0.55) also reduced the odds of a statin prescription.

Among statin users, middle-aged (OR, 0.83) and older (OR, 0.44) patients were less likely to be on a high-intensity statin, as were women (OR, 0.68) and patients with peripheral artery disease (OR, 0.43).

Visiting a cardiologist in the previous 12 months, however, increased the odds a patient was on a high-intensity statin (OR, 1.21), as did the use of other LDL-cholesterol-lowering drugs (OR, 1.44).

“With no evidence of heterogeneity in efficacy by sex, ongoing work must not only address misperceptions and barriers to the prescription of high-intensity statins in women, but also further understand (and address) differences in tolerability, which may be related to sex-based variation in statin metabolism,” wrote the authors, led by Adam J. Nelson, MBBS, MBA, MPH, also from Duke.

The study involved 601,934 patients (mean age, 67.5 years) who had a diagnosis of ASCVD between Jan. 31, 2018, and an index date of Jan. 31, 2019, and were enrolled in the HealthCore Integrated Research Environment database.

Two-thirds (70.9%) of patients visited a cardiologist in the 12 months prior to the index date, and three-fourths (81.3%) visited a primary care provider.

Pharmacy claims for the 12 months after the index date showed 82.8% of high-intensity users at index achieved coverage for at least 75% of days. Those with the least adherence (< 50% of days covered) included younger patients, as well as those with chronic kidney disease or depression.

“We need implementation research. What are the tools and the methods that we can use to improve the proportion of patients who are having the life-saving benefits from statins?” Dr. Granger said.

He noted that the team has submitted a National Institutes of Health grant to try to use pharmacists, as a mechanism within the context of health systems and payer systems, to improve the appropriate use of statins in a randomized trial. “I think that’s a win.”

Salim S. Virani, MD, PhD, Baylor College of Medicine, and Michael DeBakey VA Medical Center, Houston, and colleagues point out in a related editorial that the rates of statin usage in the study are “considerably lower” than in other contemporary studies, where about 80% and 50% of ASCVD patients are receiving statins and high-intensity statins, respectively.

Possible explanations are the use of rule-out codes, a short medication fill window from the index date, or issues with medication capture, they said. “Nevertheless, the findings are largely consistent with other work highlighting low use of statin therapy.”

The editorialists said social media, statin-related adverse effects, and therapeutic inertia are key drivers of non–guideline-concordant statin use. Possible solutions include improving guideline dissemination, leveraging team-based care, using smart clinical decision-support tools at the point of care, and identifying trustworthy and easily understood sources of information for patients.

“We can only hope that the fate of statin therapy is not repeated with sodium-glucose cotranspoerter-2 inhibitors or glucagon-like peptide-1 receptor agonists in another 30 years, or worse yet, that continued gaps in statin therapy use in patients with ASCVD persist 30 years from now,” Dr. Virani and colleagues concluded.

A sliver of optimism?

A research letter by Colantonio et al. in the same issue of JACC points to some positive steps, at least among patients having a myocardial infarction (MI). It reported that the percentage of patients who received a high-intensity statin as their first statin prescription 30 days after MI jumped from 30.7% in the first quarter of 2011 to 78.6% in the fourth quarter of 2019.

Similar increases were reported by race/ethnicity, despite statin use previously shown to be lower among non-Hispanic Black patients with ASCVD. In each calendar year, however, high-intensity statin therapy was lower among patients older than 75 years and among women.

Dr. Granger disclosed ties with Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, Pfizer, AKROS, Apple, AstraZeneca, Daiichi Sankyo, Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, Novartis Pharmaceuticals, AbbVie, Bayer, Boston Scientific, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Virani disclosed ties with the Department of Veterans Affairs, the National Institutes of Health, the World Heart Federation, and the Jooma and Tahir Family, and the American College of Cardiology.

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

New research suggests physicians face a Herculean task to get Americans with atherosclerotic cardiovascular disease (ASCVD) to take high-intensity statins, despite multiple professional guidelines giving the therapy their highest level recommendation.

Results from more 600,000 commercially insured patients with established ASCVD showed:

• Only one in five patients (22.5%) were taking a high-intensity statin.
• 27.6% were taking a low- or moderate-intensity statin.
• One-half (49.9%) were not taking any statin.

“It’s embarrassing,” senior author Christopher B. Granger, MD, Duke Clinical Research Institute, Durham, N.C., told this news organization. “It should be embarrassing for anybody in health care that we do such a terrible job with something so simple and effective.”

The results were published in the Journal of the American College of Cardiology.

Statins have been shown to reduce the risk for ASCVD events by about 30%, with an added 15% reduction with a high-intensity formulation. The class I recommendation for high-intensity statin use in ASCVD patients younger than 75 years in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines prompted a jump in prescriptions that plateaued by 2017.

A class II recommendation was added to the 2018 guideline update for high-intensity statins in adults older than 75 years with ASCVD. But underuse persists, despite falling prices with generic availability and initiatives to improve statin adoption, the authors noted.

“There are a lot of barriers for patients to statin use, including the misinformation on the Internet and elsewhere that statins have all kinds of side effects,” Dr. Granger said. “They have uncommon side effects, but when we look at it carefully, only about 10% of patients, even with statin intolerance, have true intolerance.”

Efforts are needed to better understand and address these barriers, particularly for younger and female patients, he noted.

In multivariate analyses, patients who were middle-aged (odds ratio, 2.66) or at least 75 years of age (OR, 2.09) were more than twice as likely as patients younger than 45 years to be on any statin.

Not surprisingly, women were 30% less likely than men to receive a statin (OR, 0.70), Dr. Granger said. A high Charlson comorbidity score (OR, 0.72) and peripheral artery disease (OR, 0.55) also reduced the odds of a statin prescription.

Among statin users, middle-aged (OR, 0.83) and older (OR, 0.44) patients were less likely to be on a high-intensity statin, as were women (OR, 0.68) and patients with peripheral artery disease (OR, 0.43).

Visiting a cardiologist in the previous 12 months, however, increased the odds a patient was on a high-intensity statin (OR, 1.21), as did the use of other LDL-cholesterol-lowering drugs (OR, 1.44).

“With no evidence of heterogeneity in efficacy by sex, ongoing work must not only address misperceptions and barriers to the prescription of high-intensity statins in women, but also further understand (and address) differences in tolerability, which may be related to sex-based variation in statin metabolism,” wrote the authors, led by Adam J. Nelson, MBBS, MBA, MPH, also from Duke.

The study involved 601,934 patients (mean age, 67.5 years) who had a diagnosis of ASCVD between Jan. 31, 2018, and an index date of Jan. 31, 2019, and were enrolled in the HealthCore Integrated Research Environment database.

Two-thirds (70.9%) of patients visited a cardiologist in the 12 months prior to the index date, and three-fourths (81.3%) visited a primary care provider.

Pharmacy claims for the 12 months after the index date showed 82.8% of high-intensity users at index achieved coverage for at least 75% of days. Those with the least adherence (< 50% of days covered) included younger patients, as well as those with chronic kidney disease or depression.

“We need implementation research. What are the tools and the methods that we can use to improve the proportion of patients who are having the life-saving benefits from statins?” Dr. Granger said.

He noted that the team has submitted a National Institutes of Health grant to try to use pharmacists, as a mechanism within the context of health systems and payer systems, to improve the appropriate use of statins in a randomized trial. “I think that’s a win.”

Salim S. Virani, MD, PhD, Baylor College of Medicine, and Michael DeBakey VA Medical Center, Houston, and colleagues point out in a related editorial that the rates of statin usage in the study are “considerably lower” than in other contemporary studies, where about 80% and 50% of ASCVD patients are receiving statins and high-intensity statins, respectively.

Possible explanations are the use of rule-out codes, a short medication fill window from the index date, or issues with medication capture, they said. “Nevertheless, the findings are largely consistent with other work highlighting low use of statin therapy.”

The editorialists said social media, statin-related adverse effects, and therapeutic inertia are key drivers of non–guideline-concordant statin use. Possible solutions include improving guideline dissemination, leveraging team-based care, using smart clinical decision-support tools at the point of care, and identifying trustworthy and easily understood sources of information for patients.

“We can only hope that the fate of statin therapy is not repeated with sodium-glucose cotranspoerter-2 inhibitors or glucagon-like peptide-1 receptor agonists in another 30 years, or worse yet, that continued gaps in statin therapy use in patients with ASCVD persist 30 years from now,” Dr. Virani and colleagues concluded.

A sliver of optimism?

A research letter by Colantonio et al. in the same issue of JACC points to some positive steps, at least among patients having a myocardial infarction (MI). It reported that the percentage of patients who received a high-intensity statin as their first statin prescription 30 days after MI jumped from 30.7% in the first quarter of 2011 to 78.6% in the fourth quarter of 2019.

Similar increases were reported by race/ethnicity, despite statin use previously shown to be lower among non-Hispanic Black patients with ASCVD. In each calendar year, however, high-intensity statin therapy was lower among patients older than 75 years and among women.

Dr. Granger disclosed ties with Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, Pfizer, AKROS, Apple, AstraZeneca, Daiichi Sankyo, Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, Novartis Pharmaceuticals, AbbVie, Bayer, Boston Scientific, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Virani disclosed ties with the Department of Veterans Affairs, the National Institutes of Health, the World Heart Federation, and the Jooma and Tahir Family, and the American College of Cardiology.

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

New research suggests physicians face a Herculean task to get Americans with atherosclerotic cardiovascular disease (ASCVD) to take high-intensity statins, despite multiple professional guidelines giving the therapy their highest level recommendation.

Results from more 600,000 commercially insured patients with established ASCVD showed:

• Only one in five patients (22.5%) were taking a high-intensity statin.
• 27.6% were taking a low- or moderate-intensity statin.
• One-half (49.9%) were not taking any statin.

“It’s embarrassing,” senior author Christopher B. Granger, MD, Duke Clinical Research Institute, Durham, N.C., told this news organization. “It should be embarrassing for anybody in health care that we do such a terrible job with something so simple and effective.”

The results were published in the Journal of the American College of Cardiology.

Statins have been shown to reduce the risk for ASCVD events by about 30%, with an added 15% reduction with a high-intensity formulation. The class I recommendation for high-intensity statin use in ASCVD patients younger than 75 years in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines prompted a jump in prescriptions that plateaued by 2017.

A class II recommendation was added to the 2018 guideline update for high-intensity statins in adults older than 75 years with ASCVD. But underuse persists, despite falling prices with generic availability and initiatives to improve statin adoption, the authors noted.

“There are a lot of barriers for patients to statin use, including the misinformation on the Internet and elsewhere that statins have all kinds of side effects,” Dr. Granger said. “They have uncommon side effects, but when we look at it carefully, only about 10% of patients, even with statin intolerance, have true intolerance.”

Efforts are needed to better understand and address these barriers, particularly for younger and female patients, he noted.

In multivariate analyses, patients who were middle-aged (odds ratio, 2.66) or at least 75 years of age (OR, 2.09) were more than twice as likely as patients younger than 45 years to be on any statin.

Not surprisingly, women were 30% less likely than men to receive a statin (OR, 0.70), Dr. Granger said. A high Charlson comorbidity score (OR, 0.72) and peripheral artery disease (OR, 0.55) also reduced the odds of a statin prescription.

Among statin users, middle-aged (OR, 0.83) and older (OR, 0.44) patients were less likely to be on a high-intensity statin, as were women (OR, 0.68) and patients with peripheral artery disease (OR, 0.43).

Visiting a cardiologist in the previous 12 months, however, increased the odds a patient was on a high-intensity statin (OR, 1.21), as did the use of other LDL-cholesterol-lowering drugs (OR, 1.44).

“With no evidence of heterogeneity in efficacy by sex, ongoing work must not only address misperceptions and barriers to the prescription of high-intensity statins in women, but also further understand (and address) differences in tolerability, which may be related to sex-based variation in statin metabolism,” wrote the authors, led by Adam J. Nelson, MBBS, MBA, MPH, also from Duke.

The study involved 601,934 patients (mean age, 67.5 years) who had a diagnosis of ASCVD between Jan. 31, 2018, and an index date of Jan. 31, 2019, and were enrolled in the HealthCore Integrated Research Environment database.

Two-thirds (70.9%) of patients visited a cardiologist in the 12 months prior to the index date, and three-fourths (81.3%) visited a primary care provider.

Pharmacy claims for the 12 months after the index date showed 82.8% of high-intensity users at index achieved coverage for at least 75% of days. Those with the least adherence (< 50% of days covered) included younger patients, as well as those with chronic kidney disease or depression.

“We need implementation research. What are the tools and the methods that we can use to improve the proportion of patients who are having the life-saving benefits from statins?” Dr. Granger said.

He noted that the team has submitted a National Institutes of Health grant to try to use pharmacists, as a mechanism within the context of health systems and payer systems, to improve the appropriate use of statins in a randomized trial. “I think that’s a win.”

Salim S. Virani, MD, PhD, Baylor College of Medicine, and Michael DeBakey VA Medical Center, Houston, and colleagues point out in a related editorial that the rates of statin usage in the study are “considerably lower” than in other contemporary studies, where about 80% and 50% of ASCVD patients are receiving statins and high-intensity statins, respectively.

Possible explanations are the use of rule-out codes, a short medication fill window from the index date, or issues with medication capture, they said. “Nevertheless, the findings are largely consistent with other work highlighting low use of statin therapy.”

The editorialists said social media, statin-related adverse effects, and therapeutic inertia are key drivers of non–guideline-concordant statin use. Possible solutions include improving guideline dissemination, leveraging team-based care, using smart clinical decision-support tools at the point of care, and identifying trustworthy and easily understood sources of information for patients.

“We can only hope that the fate of statin therapy is not repeated with sodium-glucose cotranspoerter-2 inhibitors or glucagon-like peptide-1 receptor agonists in another 30 years, or worse yet, that continued gaps in statin therapy use in patients with ASCVD persist 30 years from now,” Dr. Virani and colleagues concluded.

A sliver of optimism?

A research letter by Colantonio et al. in the same issue of JACC points to some positive steps, at least among patients having a myocardial infarction (MI). It reported that the percentage of patients who received a high-intensity statin as their first statin prescription 30 days after MI jumped from 30.7% in the first quarter of 2011 to 78.6% in the fourth quarter of 2019.

Similar increases were reported by race/ethnicity, despite statin use previously shown to be lower among non-Hispanic Black patients with ASCVD. In each calendar year, however, high-intensity statin therapy was lower among patients older than 75 years and among women.

Dr. Granger disclosed ties with Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, Pfizer, AKROS, Apple, AstraZeneca, Daiichi Sankyo, Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, Novartis Pharmaceuticals, AbbVie, Bayer, Boston Scientific, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Virani disclosed ties with the Department of Veterans Affairs, the National Institutes of Health, the World Heart Federation, and the Jooma and Tahir Family, and the American College of Cardiology.

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

The Society for Cardiovascular Angiography and Interventions (SCAI) has issued the first statement on best practices for percutaneous axillary arterial access and training.

The position statement helps fill a gap amid increasing use of transaxillary access as an alternative to the femoral route for large-bore transcatheter aortic valve replacement (TAVR), endovascular aortic repair (EVAR), and mechanical circulatory support.

“The need for alternative access has increased as we are using more and more TAVR for our elderly population, and EVAR has also increased,” writing committee chair Arnold H. Seto, MD, Long Beach VA Health Care System (California) said in an interview. “There’s also a set of patients who require balloon pumps for a prolonged period, and people were using balloon pumps from the axillary approach, which were not custom-designed for that purpose.”

He noted that the evidence base leans heavily on case reports and case series, and that they were approached for guidance by a vendor developing a balloon pump specific to axillary access. “So that helped spur all of us to get together and decide to write up something on this topic, which was developing, but was certainly picking up steam rapidly.”

The statement was published in the Journal of the Society for Cardiovascular Angiography and Interventions, and it reflects the consensus of experts in heart failure, interventional cardiology and radiology, and cardiothoracic and vascular surgery. It reviews anatomic considerations and risks for percutaneous axillary access and suggests techniques for insertion, closure, and complication management.

Although the femoral artery is the most frequent access site for percutaneous large-bore procedures, the document notes that this approach may be limited in 13%-20% of patients because of prior surgeries or severe aortoiliac and/or iliofemoral atherosclerotic disease, tortuosity, or calcification.

“Absolutely, the femoral should be the predominant access site,” Dr. Seto said. Whenever there is a compromised femoral artery, “the axillary artery, which is rarely involved with atherosclerosis, makes for the most optimal alternative access. Other forms of alternative access, including transcaval and transcarotid, are possible but have their own issues and difficulties.”

Axillary access has traditionally been done through an open surgical approach, which allows for direct puncture, primary arterial repair, or placement of a sidearm conduit. Percutaneous transaxillary access avoids a surgical incision and general anesthesia and, theoretically, reduces the risk of infection, he said. It also allows for better mobility for patients, for example, who may have a balloon pump in place for weeks or even a month when waiting for a bridge to transplant.

In terms of technique, key recommendations include:

• Gaining access preferably through the left axillary
• Inserting the needle directly through the pectoralis minor into the second segment of the axillary artery
• Using a shallow-needle angle of 25-30 degrees to improve access success and decrease sheath malformation, kinking, bleeding, or vessel perforation
• Using micropuncture needles to minimize trauma to adjacent tissues
• Abducting the patient’s arm to 45-90 degrees to reduce tortuosity
• Using angiographic and ultrasound techniques to optimize vascular access

The latter point was the one area of debate among the writing committee, Dr. Seto observed. “That is one of the controversies: Should we make ultrasound mandatory? ... Everybody agreed that it can be quite useful and was likely to be useful because of its success in every other access area,” he said. “But in the absence of randomized evidence, we couldn’t make it mandatory or a strong recommendation. We just had to make it one of several options for the operator.”

The document highlights the need for familiarity with potential axillary artery complications and their management, noting that the axillary is more fragile than the femoral artery and, thus, potentially more prone to complications during instrumentation.

Data from the ARMS study in 102 patients undergoing transaxillary access for mechanical hemodynamic support reported 17 procedural complications, including 10 minor access site bleeding events, one stroke, and one pseudoaneurysm. A small study of 25 complex EVAR procedures reported a perioperative access complication rate of 8%, including one axillary artery dissection and one stenosis.

“Despite the brachial plexus being around there, there’s actually rare reports of neurologic injury and certainly none that have been permanent,” Dr. Seto said. “Also, stroke risk is probably more related to your device size and type of device rather than the approach itself.”

A significant amount of the paper is also devoted to training and privileging suggestions with an emphasis on a multidisciplinary team. The writing group recommends graduate medical education programs develop training curricula in percutaneous axillary artery access.

Those already in practice should participate in a formal training program that focuses on axillary artery anatomy, training in large bore access and closure devices, and didactic training in imaging modalities as applied to the axillary artery. Training can occur hands-on or using online simulations.

They also recommend outlining the potential need or role for proctoring and call for ongoing formal professional monitoring programs to evaluate operator outcomes using local or registry data.

“From a privileging standpoint, it was important for hospitals to be equally fair, regardless of the specialty that a requesting practitioner came from,” Dr. Seto said. “In other words, treat the vascular surgeons and interventional cardiologists and radiologists equally in terms of who has the privilege to do transaxillary access.”

The SCAI position statement has been endorsed by the American College of Cardiology, the Heart Failure Society of America, the Society of Interventional Radiology, and the Vascular & Endovascular Surgery Society.

Dr. Seto reported receiving honoraria from Getinge prior to initiation of the document. Disclosures for the rest of the writing group are available with the original article.

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

The Society for Cardiovascular Angiography and Interventions (SCAI) has issued the first statement on best practices for percutaneous axillary arterial access and training.

The position statement helps fill a gap amid increasing use of transaxillary access as an alternative to the femoral route for large-bore transcatheter aortic valve replacement (TAVR), endovascular aortic repair (EVAR), and mechanical circulatory support.

“The need for alternative access has increased as we are using more and more TAVR for our elderly population, and EVAR has also increased,” writing committee chair Arnold H. Seto, MD, Long Beach VA Health Care System (California) said in an interview. “There’s also a set of patients who require balloon pumps for a prolonged period, and people were using balloon pumps from the axillary approach, which were not custom-designed for that purpose.”

He noted that the evidence base leans heavily on case reports and case series, and that they were approached for guidance by a vendor developing a balloon pump specific to axillary access. “So that helped spur all of us to get together and decide to write up something on this topic, which was developing, but was certainly picking up steam rapidly.”

The statement was published in the Journal of the Society for Cardiovascular Angiography and Interventions, and it reflects the consensus of experts in heart failure, interventional cardiology and radiology, and cardiothoracic and vascular surgery. It reviews anatomic considerations and risks for percutaneous axillary access and suggests techniques for insertion, closure, and complication management.

Although the femoral artery is the most frequent access site for percutaneous large-bore procedures, the document notes that this approach may be limited in 13%-20% of patients because of prior surgeries or severe aortoiliac and/or iliofemoral atherosclerotic disease, tortuosity, or calcification.

“Absolutely, the femoral should be the predominant access site,” Dr. Seto said. Whenever there is a compromised femoral artery, “the axillary artery, which is rarely involved with atherosclerosis, makes for the most optimal alternative access. Other forms of alternative access, including transcaval and transcarotid, are possible but have their own issues and difficulties.”

Axillary access has traditionally been done through an open surgical approach, which allows for direct puncture, primary arterial repair, or placement of a sidearm conduit. Percutaneous transaxillary access avoids a surgical incision and general anesthesia and, theoretically, reduces the risk of infection, he said. It also allows for better mobility for patients, for example, who may have a balloon pump in place for weeks or even a month when waiting for a bridge to transplant.

In terms of technique, key recommendations include:

• Gaining access preferably through the left axillary
• Inserting the needle directly through the pectoralis minor into the second segment of the axillary artery
• Using a shallow-needle angle of 25-30 degrees to improve access success and decrease sheath malformation, kinking, bleeding, or vessel perforation
• Using micropuncture needles to minimize trauma to adjacent tissues
• Abducting the patient’s arm to 45-90 degrees to reduce tortuosity
• Using angiographic and ultrasound techniques to optimize vascular access

The latter point was the one area of debate among the writing committee, Dr. Seto observed. “That is one of the controversies: Should we make ultrasound mandatory? ... Everybody agreed that it can be quite useful and was likely to be useful because of its success in every other access area,” he said. “But in the absence of randomized evidence, we couldn’t make it mandatory or a strong recommendation. We just had to make it one of several options for the operator.”

The document highlights the need for familiarity with potential axillary artery complications and their management, noting that the axillary is more fragile than the femoral artery and, thus, potentially more prone to complications during instrumentation.

Data from the ARMS study in 102 patients undergoing transaxillary access for mechanical hemodynamic support reported 17 procedural complications, including 10 minor access site bleeding events, one stroke, and one pseudoaneurysm. A small study of 25 complex EVAR procedures reported a perioperative access complication rate of 8%, including one axillary artery dissection and one stenosis.

“Despite the brachial plexus being around there, there’s actually rare reports of neurologic injury and certainly none that have been permanent,” Dr. Seto said. “Also, stroke risk is probably more related to your device size and type of device rather than the approach itself.”

A significant amount of the paper is also devoted to training and privileging suggestions with an emphasis on a multidisciplinary team. The writing group recommends graduate medical education programs develop training curricula in percutaneous axillary artery access.

Those already in practice should participate in a formal training program that focuses on axillary artery anatomy, training in large bore access and closure devices, and didactic training in imaging modalities as applied to the axillary artery. Training can occur hands-on or using online simulations.

They also recommend outlining the potential need or role for proctoring and call for ongoing formal professional monitoring programs to evaluate operator outcomes using local or registry data.

“From a privileging standpoint, it was important for hospitals to be equally fair, regardless of the specialty that a requesting practitioner came from,” Dr. Seto said. “In other words, treat the vascular surgeons and interventional cardiologists and radiologists equally in terms of who has the privilege to do transaxillary access.”

The SCAI position statement has been endorsed by the American College of Cardiology, the Heart Failure Society of America, the Society of Interventional Radiology, and the Vascular & Endovascular Surgery Society.

Dr. Seto reported receiving honoraria from Getinge prior to initiation of the document. Disclosures for the rest of the writing group are available with the original article.

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

The Society for Cardiovascular Angiography and Interventions (SCAI) has issued the first statement on best practices for percutaneous axillary arterial access and training.

The position statement helps fill a gap amid increasing use of transaxillary access as an alternative to the femoral route for large-bore transcatheter aortic valve replacement (TAVR), endovascular aortic repair (EVAR), and mechanical circulatory support.

“The need for alternative access has increased as we are using more and more TAVR for our elderly population, and EVAR has also increased,” writing committee chair Arnold H. Seto, MD, Long Beach VA Health Care System (California) said in an interview. “There’s also a set of patients who require balloon pumps for a prolonged period, and people were using balloon pumps from the axillary approach, which were not custom-designed for that purpose.”

He noted that the evidence base leans heavily on case reports and case series, and that they were approached for guidance by a vendor developing a balloon pump specific to axillary access. “So that helped spur all of us to get together and decide to write up something on this topic, which was developing, but was certainly picking up steam rapidly.”

The statement was published in the Journal of the Society for Cardiovascular Angiography and Interventions, and it reflects the consensus of experts in heart failure, interventional cardiology and radiology, and cardiothoracic and vascular surgery. It reviews anatomic considerations and risks for percutaneous axillary access and suggests techniques for insertion, closure, and complication management.

Although the femoral artery is the most frequent access site for percutaneous large-bore procedures, the document notes that this approach may be limited in 13%-20% of patients because of prior surgeries or severe aortoiliac and/or iliofemoral atherosclerotic disease, tortuosity, or calcification.

“Absolutely, the femoral should be the predominant access site,” Dr. Seto said. Whenever there is a compromised femoral artery, “the axillary artery, which is rarely involved with atherosclerosis, makes for the most optimal alternative access. Other forms of alternative access, including transcaval and transcarotid, are possible but have their own issues and difficulties.”

Axillary access has traditionally been done through an open surgical approach, which allows for direct puncture, primary arterial repair, or placement of a sidearm conduit. Percutaneous transaxillary access avoids a surgical incision and general anesthesia and, theoretically, reduces the risk of infection, he said. It also allows for better mobility for patients, for example, who may have a balloon pump in place for weeks or even a month when waiting for a bridge to transplant.

In terms of technique, key recommendations include:

• Gaining access preferably through the left axillary
• Inserting the needle directly through the pectoralis minor into the second segment of the axillary artery
• Using a shallow-needle angle of 25-30 degrees to improve access success and decrease sheath malformation, kinking, bleeding, or vessel perforation
• Using micropuncture needles to minimize trauma to adjacent tissues
• Abducting the patient’s arm to 45-90 degrees to reduce tortuosity
• Using angiographic and ultrasound techniques to optimize vascular access

The latter point was the one area of debate among the writing committee, Dr. Seto observed. “That is one of the controversies: Should we make ultrasound mandatory? ... Everybody agreed that it can be quite useful and was likely to be useful because of its success in every other access area,” he said. “But in the absence of randomized evidence, we couldn’t make it mandatory or a strong recommendation. We just had to make it one of several options for the operator.”

The document highlights the need for familiarity with potential axillary artery complications and their management, noting that the axillary is more fragile than the femoral artery and, thus, potentially more prone to complications during instrumentation.

Data from the ARMS study in 102 patients undergoing transaxillary access for mechanical hemodynamic support reported 17 procedural complications, including 10 minor access site bleeding events, one stroke, and one pseudoaneurysm. A small study of 25 complex EVAR procedures reported a perioperative access complication rate of 8%, including one axillary artery dissection and one stenosis.

“Despite the brachial plexus being around there, there’s actually rare reports of neurologic injury and certainly none that have been permanent,” Dr. Seto said. “Also, stroke risk is probably more related to your device size and type of device rather than the approach itself.”

A significant amount of the paper is also devoted to training and privileging suggestions with an emphasis on a multidisciplinary team. The writing group recommends graduate medical education programs develop training curricula in percutaneous axillary artery access.

Those already in practice should participate in a formal training program that focuses on axillary artery anatomy, training in large bore access and closure devices, and didactic training in imaging modalities as applied to the axillary artery. Training can occur hands-on or using online simulations.

They also recommend outlining the potential need or role for proctoring and call for ongoing formal professional monitoring programs to evaluate operator outcomes using local or registry data.

“From a privileging standpoint, it was important for hospitals to be equally fair, regardless of the specialty that a requesting practitioner came from,” Dr. Seto said. “In other words, treat the vascular surgeons and interventional cardiologists and radiologists equally in terms of who has the privilege to do transaxillary access.”

The SCAI position statement has been endorsed by the American College of Cardiology, the Heart Failure Society of America, the Society of Interventional Radiology, and the Vascular & Endovascular Surgery Society.

Dr. Seto reported receiving honoraria from Getinge prior to initiation of the document. Disclosures for the rest of the writing group are available with the original article.

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

Although lipoprotein(a) is causally related to coronary artery disease and aortic valve stenosis – two known risk factors for atrial fibrillation (AFib) – evidence linking Lp(a) to a causal role in the development of AFib has been lukewarm at best.

A recent Mendelian randomization study showed only a nominally significant effect of Lp(a) on AFib, whereas an ARIC substudy showed high levels of Lp(a) to be associated with elevated ischemic stroke risk but not incident AFib.

A new study that adds the heft of Mendelian randomization to large observational and genetic analyses, however, implicates Lp(a) as a potential causal mediator of AFib, independent of its known effects on atherosclerotic cardiovascular disease (ASCVD).

“Why this is exciting is because it shows that Lp(a) has effects beyond the arteries and beyond the aortic valve, and that provides two things,” senior author Guillaume Paré, MD, MSc, Population Health Research Institute, Hamilton, Ontario, told this news organization.

“First, it provides a potential means to decrease the risk, because there are all these Lp(a) inhibitors in development,” he said. “But I think the other thing is that it just points to a new pathway that leads to atrial fibrillation development that could potentially be targeted with other drugs when it’s better understood. We don’t pretend that we understand the biology there, but it opens this possibility.”

The results were published in the Journal of the American College of Cardiology.

Using data from 435,579 participants in the UK Biobank, the researchers identified 20,432 cases of incident AFib over a median of 11 years of follow-up. They also constructed a genetic risk score for Lp(a) using genetic variants within 500 kb of the LPA gene.

After common AFib risk factors were controlled for, results showed a 3% increased risk for incident AFib per 50 nmol/L increase in Lp(a) at enrollment (hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

A Mendelian randomization analysis showed a similar association between genetically predicted Lp(a) and AFib (odds ratio, 1.03; 95% CI, 1.02-1.05).

To replicate the results, the investigators performed separate Mendelian randomization analyses using publicly available genome-wide association study (GWAS) statistics from the largest GWAS of AFib involving more than 1 million participants and from the FinnGen cohort involving more than 114,000 Finnish residents.

The analyses showed a 3% increase in risk for AFib in the genome-wide study (OR, 1.03; 95% CI, 1.02-1.05) and an 8% increase in risk in the Finnish study (OR, 1.08; 95% CI, 1.04-1.12) per 50 nmol/L increase in Lp(a).

There was no evidence that the effect of observed or genetically predicted Lp(a) was modified by prevalent ischemic heart disease or aortic stenosis.

Further, MR analyses revealed no risk effect of low-density-lipoprotein cholesterol or triglycerides on AFib.

Notably, only 39% of Lp(a) was mediated through ASCVD, suggesting that Lp(a) partly influences AFib independent of its known effect on ASCVD.

“To me, the eureka moment is when we repeated the same analysis for LDL cholesterol and it had absolutely no association with AFib,” Dr. Paré said. “Because up to that point, there was always this lingering doubt that, well, it’s because of coronary artery disease, and that’s logical. But the signal is completely flat with LDL, and we see this strong signal with Lp(a).”

Another ‘red flag’

Erin D. Michos, MD, MHS, senior author of the ARIC substudy and associate director of preventive cardiology at Johns Hopkins School of Medicine, Baltimore, said the findings are “another red flag that lipoprotein(a) is a marker we need to pay attention to and potentially needs treatment.”

“The fact that it was Mendelian randomization does suggest that there’s a causal role,” she said. “I think the relationship is relatively modest compared to its known risk for stroke, ASCVD, coronary disease, and aortic stenosis, ... which may be why we didn’t see it in the ARIC cohort with 12,000 participants. You needed to have a million participants and 60,000 cases to see an effect here.”

Dr. Michos said she hopes the findings encourage increased testing, particularly with multiple potential treatments currently in the pipeline. She pointed out that the researchers estimated that the experimental antisense agent pelacarsen, which lowers Lp(a) by about 80%, would translate into about an 8% reduction in AFib risk, or “the same effect as 2 kg of weight loss or a 5 mm Hg reduction in blood pressure, which we do think are meaningful.”

Adding to this point in an accompanying editorial, Daniel Seung Kim, MD, PhD, and Abha Khandelwal, MD, MS, Stanford University School of Medicine, California, say that “moreover, reduction of Lp(a) levels would have multifactorial effects on CAD, cerebrovascular/peripheral artery disease, and AS risk.

“Therefore, approaches to reduce Lp(a) should be prioritized to further reduce the morbidity and mortality of a rapidly aging population,” they write.

The editorialists also join the researchers in calling for inclusion of AFib as a secondary outcome in ongoing Lp(a) trials, in addition to cerebrovascular disease and peripheral vascular disease.
 

Unanswered questions

As to what’s driving the risk effect of Lp(a), first author Pedrum Mohammadi-Shemirani, PhD, also from the Population Health Research Institute, explained that in aortic stenosis, “mechanical stress increases endothelial permeability, allowing Lp(a) to infiltrate valvular tissue and induce gene expression that results in microcalcifications and cell death.”

“So, in theory, a similar sort of mechanism could be at play in atrial tissue that may lead to damage and the electrical remodeling that causes atrial fibrillation,” he told this news organization.

Dr. Mohammadi-Shemirani also noted that Lp(a) has proinflammatory properties, but added that any potential mechanisms are “speculative and require further research to disentangle.”

Dr. Paré and colleagues say follow-up studies are also warranted, noting that generalizability of the results may be limited because AFib cases were found using electronic health records in the population-scale cohorts and because few UK Biobank participants were of non-European ancestry and Lp(a) levels vary among ethnic groups.

Another limitation is that the number of kringle IV type 2 domain repeats within the LPA gene, the largest contributor to genetic variation in Lp(a), could not be directly measured. Still, 71.4% of the variation in Lp(a) was explained using the genetic risk score alone, they say.

Dr. Paré holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. Dr. Mohammadi-Shemirani is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institute of Health Research. Dr. Michos reports consulting for Novartis and serving on advisory boards for Novartis, AstraZeneca, Bayer, and Boehringer Ingelheim. Dr. Kim reports grant support from the National Institutes of Health and the American Heart Association. Dr. Khandelwal serves on the advisory board of Amgen and has received funding from Novartis CTQJ and Akcea.

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

Although lipoprotein(a) is causally related to coronary artery disease and aortic valve stenosis – two known risk factors for atrial fibrillation (AFib) – evidence linking Lp(a) to a causal role in the development of AFib has been lukewarm at best.

A recent Mendelian randomization study showed only a nominally significant effect of Lp(a) on AFib, whereas an ARIC substudy showed high levels of Lp(a) to be associated with elevated ischemic stroke risk but not incident AFib.

A new study that adds the heft of Mendelian randomization to large observational and genetic analyses, however, implicates Lp(a) as a potential causal mediator of AFib, independent of its known effects on atherosclerotic cardiovascular disease (ASCVD).

“Why this is exciting is because it shows that Lp(a) has effects beyond the arteries and beyond the aortic valve, and that provides two things,” senior author Guillaume Paré, MD, MSc, Population Health Research Institute, Hamilton, Ontario, told this news organization.

“First, it provides a potential means to decrease the risk, because there are all these Lp(a) inhibitors in development,” he said. “But I think the other thing is that it just points to a new pathway that leads to atrial fibrillation development that could potentially be targeted with other drugs when it’s better understood. We don’t pretend that we understand the biology there, but it opens this possibility.”

The results were published in the Journal of the American College of Cardiology.

Using data from 435,579 participants in the UK Biobank, the researchers identified 20,432 cases of incident AFib over a median of 11 years of follow-up. They also constructed a genetic risk score for Lp(a) using genetic variants within 500 kb of the LPA gene.

After common AFib risk factors were controlled for, results showed a 3% increased risk for incident AFib per 50 nmol/L increase in Lp(a) at enrollment (hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

A Mendelian randomization analysis showed a similar association between genetically predicted Lp(a) and AFib (odds ratio, 1.03; 95% CI, 1.02-1.05).

To replicate the results, the investigators performed separate Mendelian randomization analyses using publicly available genome-wide association study (GWAS) statistics from the largest GWAS of AFib involving more than 1 million participants and from the FinnGen cohort involving more than 114,000 Finnish residents.

The analyses showed a 3% increase in risk for AFib in the genome-wide study (OR, 1.03; 95% CI, 1.02-1.05) and an 8% increase in risk in the Finnish study (OR, 1.08; 95% CI, 1.04-1.12) per 50 nmol/L increase in Lp(a).

There was no evidence that the effect of observed or genetically predicted Lp(a) was modified by prevalent ischemic heart disease or aortic stenosis.

Further, MR analyses revealed no risk effect of low-density-lipoprotein cholesterol or triglycerides on AFib.

Notably, only 39% of Lp(a) was mediated through ASCVD, suggesting that Lp(a) partly influences AFib independent of its known effect on ASCVD.

“To me, the eureka moment is when we repeated the same analysis for LDL cholesterol and it had absolutely no association with AFib,” Dr. Paré said. “Because up to that point, there was always this lingering doubt that, well, it’s because of coronary artery disease, and that’s logical. But the signal is completely flat with LDL, and we see this strong signal with Lp(a).”

Another ‘red flag’

Erin D. Michos, MD, MHS, senior author of the ARIC substudy and associate director of preventive cardiology at Johns Hopkins School of Medicine, Baltimore, said the findings are “another red flag that lipoprotein(a) is a marker we need to pay attention to and potentially needs treatment.”

“The fact that it was Mendelian randomization does suggest that there’s a causal role,” she said. “I think the relationship is relatively modest compared to its known risk for stroke, ASCVD, coronary disease, and aortic stenosis, ... which may be why we didn’t see it in the ARIC cohort with 12,000 participants. You needed to have a million participants and 60,000 cases to see an effect here.”

Dr. Michos said she hopes the findings encourage increased testing, particularly with multiple potential treatments currently in the pipeline. She pointed out that the researchers estimated that the experimental antisense agent pelacarsen, which lowers Lp(a) by about 80%, would translate into about an 8% reduction in AFib risk, or “the same effect as 2 kg of weight loss or a 5 mm Hg reduction in blood pressure, which we do think are meaningful.”

Adding to this point in an accompanying editorial, Daniel Seung Kim, MD, PhD, and Abha Khandelwal, MD, MS, Stanford University School of Medicine, California, say that “moreover, reduction of Lp(a) levels would have multifactorial effects on CAD, cerebrovascular/peripheral artery disease, and AS risk.

“Therefore, approaches to reduce Lp(a) should be prioritized to further reduce the morbidity and mortality of a rapidly aging population,” they write.

The editorialists also join the researchers in calling for inclusion of AFib as a secondary outcome in ongoing Lp(a) trials, in addition to cerebrovascular disease and peripheral vascular disease.
 

Unanswered questions

As to what’s driving the risk effect of Lp(a), first author Pedrum Mohammadi-Shemirani, PhD, also from the Population Health Research Institute, explained that in aortic stenosis, “mechanical stress increases endothelial permeability, allowing Lp(a) to infiltrate valvular tissue and induce gene expression that results in microcalcifications and cell death.”

“So, in theory, a similar sort of mechanism could be at play in atrial tissue that may lead to damage and the electrical remodeling that causes atrial fibrillation,” he told this news organization.

Dr. Mohammadi-Shemirani also noted that Lp(a) has proinflammatory properties, but added that any potential mechanisms are “speculative and require further research to disentangle.”

Dr. Paré and colleagues say follow-up studies are also warranted, noting that generalizability of the results may be limited because AFib cases were found using electronic health records in the population-scale cohorts and because few UK Biobank participants were of non-European ancestry and Lp(a) levels vary among ethnic groups.

Another limitation is that the number of kringle IV type 2 domain repeats within the LPA gene, the largest contributor to genetic variation in Lp(a), could not be directly measured. Still, 71.4% of the variation in Lp(a) was explained using the genetic risk score alone, they say.

Dr. Paré holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. Dr. Mohammadi-Shemirani is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institute of Health Research. Dr. Michos reports consulting for Novartis and serving on advisory boards for Novartis, AstraZeneca, Bayer, and Boehringer Ingelheim. Dr. Kim reports grant support from the National Institutes of Health and the American Heart Association. Dr. Khandelwal serves on the advisory board of Amgen and has received funding from Novartis CTQJ and Akcea.

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

Although lipoprotein(a) is causally related to coronary artery disease and aortic valve stenosis – two known risk factors for atrial fibrillation (AFib) – evidence linking Lp(a) to a causal role in the development of AFib has been lukewarm at best.

A recent Mendelian randomization study showed only a nominally significant effect of Lp(a) on AFib, whereas an ARIC substudy showed high levels of Lp(a) to be associated with elevated ischemic stroke risk but not incident AFib.

A new study that adds the heft of Mendelian randomization to large observational and genetic analyses, however, implicates Lp(a) as a potential causal mediator of AFib, independent of its known effects on atherosclerotic cardiovascular disease (ASCVD).

“Why this is exciting is because it shows that Lp(a) has effects beyond the arteries and beyond the aortic valve, and that provides two things,” senior author Guillaume Paré, MD, MSc, Population Health Research Institute, Hamilton, Ontario, told this news organization.

“First, it provides a potential means to decrease the risk, because there are all these Lp(a) inhibitors in development,” he said. “But I think the other thing is that it just points to a new pathway that leads to atrial fibrillation development that could potentially be targeted with other drugs when it’s better understood. We don’t pretend that we understand the biology there, but it opens this possibility.”

The results were published in the Journal of the American College of Cardiology.

Using data from 435,579 participants in the UK Biobank, the researchers identified 20,432 cases of incident AFib over a median of 11 years of follow-up. They also constructed a genetic risk score for Lp(a) using genetic variants within 500 kb of the LPA gene.

After common AFib risk factors were controlled for, results showed a 3% increased risk for incident AFib per 50 nmol/L increase in Lp(a) at enrollment (hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

A Mendelian randomization analysis showed a similar association between genetically predicted Lp(a) and AFib (odds ratio, 1.03; 95% CI, 1.02-1.05).

To replicate the results, the investigators performed separate Mendelian randomization analyses using publicly available genome-wide association study (GWAS) statistics from the largest GWAS of AFib involving more than 1 million participants and from the FinnGen cohort involving more than 114,000 Finnish residents.

The analyses showed a 3% increase in risk for AFib in the genome-wide study (OR, 1.03; 95% CI, 1.02-1.05) and an 8% increase in risk in the Finnish study (OR, 1.08; 95% CI, 1.04-1.12) per 50 nmol/L increase in Lp(a).

There was no evidence that the effect of observed or genetically predicted Lp(a) was modified by prevalent ischemic heart disease or aortic stenosis.

Further, MR analyses revealed no risk effect of low-density-lipoprotein cholesterol or triglycerides on AFib.

Notably, only 39% of Lp(a) was mediated through ASCVD, suggesting that Lp(a) partly influences AFib independent of its known effect on ASCVD.

“To me, the eureka moment is when we repeated the same analysis for LDL cholesterol and it had absolutely no association with AFib,” Dr. Paré said. “Because up to that point, there was always this lingering doubt that, well, it’s because of coronary artery disease, and that’s logical. But the signal is completely flat with LDL, and we see this strong signal with Lp(a).”

Another ‘red flag’

Erin D. Michos, MD, MHS, senior author of the ARIC substudy and associate director of preventive cardiology at Johns Hopkins School of Medicine, Baltimore, said the findings are “another red flag that lipoprotein(a) is a marker we need to pay attention to and potentially needs treatment.”

“The fact that it was Mendelian randomization does suggest that there’s a causal role,” she said. “I think the relationship is relatively modest compared to its known risk for stroke, ASCVD, coronary disease, and aortic stenosis, ... which may be why we didn’t see it in the ARIC cohort with 12,000 participants. You needed to have a million participants and 60,000 cases to see an effect here.”

Dr. Michos said she hopes the findings encourage increased testing, particularly with multiple potential treatments currently in the pipeline. She pointed out that the researchers estimated that the experimental antisense agent pelacarsen, which lowers Lp(a) by about 80%, would translate into about an 8% reduction in AFib risk, or “the same effect as 2 kg of weight loss or a 5 mm Hg reduction in blood pressure, which we do think are meaningful.”

Adding to this point in an accompanying editorial, Daniel Seung Kim, MD, PhD, and Abha Khandelwal, MD, MS, Stanford University School of Medicine, California, say that “moreover, reduction of Lp(a) levels would have multifactorial effects on CAD, cerebrovascular/peripheral artery disease, and AS risk.

“Therefore, approaches to reduce Lp(a) should be prioritized to further reduce the morbidity and mortality of a rapidly aging population,” they write.

The editorialists also join the researchers in calling for inclusion of AFib as a secondary outcome in ongoing Lp(a) trials, in addition to cerebrovascular disease and peripheral vascular disease.
 

Unanswered questions

As to what’s driving the risk effect of Lp(a), first author Pedrum Mohammadi-Shemirani, PhD, also from the Population Health Research Institute, explained that in aortic stenosis, “mechanical stress increases endothelial permeability, allowing Lp(a) to infiltrate valvular tissue and induce gene expression that results in microcalcifications and cell death.”

“So, in theory, a similar sort of mechanism could be at play in atrial tissue that may lead to damage and the electrical remodeling that causes atrial fibrillation,” he told this news organization.

Dr. Mohammadi-Shemirani also noted that Lp(a) has proinflammatory properties, but added that any potential mechanisms are “speculative and require further research to disentangle.”

Dr. Paré and colleagues say follow-up studies are also warranted, noting that generalizability of the results may be limited because AFib cases were found using electronic health records in the population-scale cohorts and because few UK Biobank participants were of non-European ancestry and Lp(a) levels vary among ethnic groups.

Another limitation is that the number of kringle IV type 2 domain repeats within the LPA gene, the largest contributor to genetic variation in Lp(a), could not be directly measured. Still, 71.4% of the variation in Lp(a) was explained using the genetic risk score alone, they say.

Dr. Paré holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. Dr. Mohammadi-Shemirani is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institute of Health Research. Dr. Michos reports consulting for Novartis and serving on advisory boards for Novartis, AstraZeneca, Bayer, and Boehringer Ingelheim. Dr. Kim reports grant support from the National Institutes of Health and the American Heart Association. Dr. Khandelwal serves on the advisory board of Amgen and has received funding from Novartis CTQJ and Akcea.

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

Radiofrequency renal denervation provided progressive reductions in blood pressure at 3 years in patients on antihypertensive medication, but this did not translate into fewer antihypertensive drugs, new results from the SPYRAL HTN-ON MED trial show.

At 36 months, 24-hour ambulatory systolic and diastolic blood pressures were 10.0 mm Hg (P = .003) and 5.9 mm Hg (P = .005) lower, respectively, in patients who underwent renal denervation with Medtronic’s Symplicity Spyral radiofrequency catheter, compared with patients treated with a sham procedure.

The number of antihypertensive drugs, however, increased in both groups from an average of two at baseline and 6 months to three at 3 years (P = .76).

Based on the number of drugs, class, and dose, medication burden increased significantly in the sham group at 12 months (6.5 vs. 4.9; P = .04) and trended higher at 3 years (10.3 vs. 7.6; P = .26).

The procedure appeared safe, with no renal safety events in the denervation group and only three safety events overall at 36 months. One cardiovascular death occurred 693 days after a sham procedure and one patient had a hypertensive crisis and stroke 427 days after renal denervation and was discharged in stable condition, according to results published in The Lancet.

“Given the long-term safety and efficacy of renal denervation, it may provide an alternative adjunctive treatment modality in the management of hypertension,” Felix Mahfoud, MD, Saarland University Hospital, Homburg, Germany, said during a presentation of the study at the recent American College of Cardiology (ACC) 2022 Scientific Session.

Ted Bosworth/MDedge News

Sham-controlled evidence

As previously reported, significant BP reductions at 6 months in SPYRAL HTN-ON provided proof of concept and helped revive enthusiasm for the procedure after failing to meet the primary endpoint in the SYMPLICITY HTN-3 trial. Results from the Global SYMPLICITY Registry have shown benefits out to 3 years, but sham-controlled data have been lacking.

The trial enrolled 80 patients with an office systolic BP of 150-180 mm Hg and diastolic of 90 mm Hg or greater and 24-hour ambulatory systolic BP of 140-170 mm Hg, who were on up to three antihypertensive medications.

Medication changes were allowed beginning at 6 months; patients and physicians were unblinded at 12 months. Between 24 and 36 months, 13 patients assigned to the sham procedure crossed over to denervation treatment. Medication adherence at 3 years was 77% in the denervation group versus 93% in the sham group.

At 3 years, the renal denervation group had significantly greater reductions from baseline in several ambulatory BP measures, compared with the sham group, including: 24-hour systolic (10.0 mm Hg), morning systolic (11.0 mm Hg), daytime systolic (8.9 mm Hg), and night-time systolic (11.8 mm Hg).

Renal denervation led to an 8.2 mm Hg greater fall in office systolic BP, but this failed to reach statistical significance (P = .07).

Almost twice as many patients in the denervation group achieved a 24-hour systolic BP less than 140 mm Hg than in the sham group (83.3%, vs. 43.8%; P = .002), Dr. Mahfoud reported.

“Although renal denervation appears to effectively lower blood pressure, participants in the renal denervation group did not quite reach guideline-recommended blood pressure thresholds,” Harini Sarathy, MD, University of California, San Francisco, and Liann Abu Salman, MD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, point out in an accompanying editorial. “This result could have been due to a degree of physician inertia or differential prescribing of blood pressure medications for the intervention group, compared with the sham control group, wherein physicians might have considered renal denervation to be the fourth antihypertensive medication.”

The editorialists also note that nearly a third of the sham group (13 of 42) underwent renal denervation. “The differentially missing BP readings at 24 months for the sham group are a cause for concern, although the absence of any meaningful differences in results after imputation is somewhat reassuring.”

A 10 mm Hg reduction in BP after 36 months would be expected to translate to a significant reduction in cardiovascular outcomes, they say. The sustained reductions in several systolic readings also speak to the “always-on distinctiveness” that renal denervation proponents claim.

“In the stark absence of novel antihypertensive drug development, renal denervation is seemingly poised to be an effective supplement, if not an alternative, to complex antihypertensive regimens with frequent dosing schedules,” they conclude. “We look forward to results of the Expansion trial in providing more definitive answers regarding whether this translates to meaningful protection from target organ damage.”

Dr. Mahfoud observed that BP control worsened during the COVID-19 pandemic, which may have impacted BP results, but that in-person follow-up visits were still performed. Other limitations are a lack of information on patients’ exercise, diet, and smoking habits and that blood and urine testing assessed medication adherence at discrete time points, but adherence over an extended period of time is uncertain.

Dr. Mahfoud reports research grants from Deutsche Forschungsgemeinschaft and Deutsche Gesellschaft für Kardiologie and scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, Merck, and ReCor Medical. The study was funded by Medtronic. Dr. Sarathy and Dr. Salman report no relevant financial relationships.

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

Radiofrequency renal denervation provided progressive reductions in blood pressure at 3 years in patients on antihypertensive medication, but this did not translate into fewer antihypertensive drugs, new results from the SPYRAL HTN-ON MED trial show.

At 36 months, 24-hour ambulatory systolic and diastolic blood pressures were 10.0 mm Hg (P = .003) and 5.9 mm Hg (P = .005) lower, respectively, in patients who underwent renal denervation with Medtronic’s Symplicity Spyral radiofrequency catheter, compared with patients treated with a sham procedure.

The number of antihypertensive drugs, however, increased in both groups from an average of two at baseline and 6 months to three at 3 years (P = .76).

Based on the number of drugs, class, and dose, medication burden increased significantly in the sham group at 12 months (6.5 vs. 4.9; P = .04) and trended higher at 3 years (10.3 vs. 7.6; P = .26).

The procedure appeared safe, with no renal safety events in the denervation group and only three safety events overall at 36 months. One cardiovascular death occurred 693 days after a sham procedure and one patient had a hypertensive crisis and stroke 427 days after renal denervation and was discharged in stable condition, according to results published in The Lancet.

“Given the long-term safety and efficacy of renal denervation, it may provide an alternative adjunctive treatment modality in the management of hypertension,” Felix Mahfoud, MD, Saarland University Hospital, Homburg, Germany, said during a presentation of the study at the recent American College of Cardiology (ACC) 2022 Scientific Session.

Ted Bosworth/MDedge News

Sham-controlled evidence

As previously reported, significant BP reductions at 6 months in SPYRAL HTN-ON provided proof of concept and helped revive enthusiasm for the procedure after failing to meet the primary endpoint in the SYMPLICITY HTN-3 trial. Results from the Global SYMPLICITY Registry have shown benefits out to 3 years, but sham-controlled data have been lacking.

The trial enrolled 80 patients with an office systolic BP of 150-180 mm Hg and diastolic of 90 mm Hg or greater and 24-hour ambulatory systolic BP of 140-170 mm Hg, who were on up to three antihypertensive medications.

Medication changes were allowed beginning at 6 months; patients and physicians were unblinded at 12 months. Between 24 and 36 months, 13 patients assigned to the sham procedure crossed over to denervation treatment. Medication adherence at 3 years was 77% in the denervation group versus 93% in the sham group.

At 3 years, the renal denervation group had significantly greater reductions from baseline in several ambulatory BP measures, compared with the sham group, including: 24-hour systolic (10.0 mm Hg), morning systolic (11.0 mm Hg), daytime systolic (8.9 mm Hg), and night-time systolic (11.8 mm Hg).

Renal denervation led to an 8.2 mm Hg greater fall in office systolic BP, but this failed to reach statistical significance (P = .07).

Almost twice as many patients in the denervation group achieved a 24-hour systolic BP less than 140 mm Hg than in the sham group (83.3%, vs. 43.8%; P = .002), Dr. Mahfoud reported.

“Although renal denervation appears to effectively lower blood pressure, participants in the renal denervation group did not quite reach guideline-recommended blood pressure thresholds,” Harini Sarathy, MD, University of California, San Francisco, and Liann Abu Salman, MD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, point out in an accompanying editorial. “This result could have been due to a degree of physician inertia or differential prescribing of blood pressure medications for the intervention group, compared with the sham control group, wherein physicians might have considered renal denervation to be the fourth antihypertensive medication.”

The editorialists also note that nearly a third of the sham group (13 of 42) underwent renal denervation. “The differentially missing BP readings at 24 months for the sham group are a cause for concern, although the absence of any meaningful differences in results after imputation is somewhat reassuring.”

A 10 mm Hg reduction in BP after 36 months would be expected to translate to a significant reduction in cardiovascular outcomes, they say. The sustained reductions in several systolic readings also speak to the “always-on distinctiveness” that renal denervation proponents claim.

“In the stark absence of novel antihypertensive drug development, renal denervation is seemingly poised to be an effective supplement, if not an alternative, to complex antihypertensive regimens with frequent dosing schedules,” they conclude. “We look forward to results of the Expansion trial in providing more definitive answers regarding whether this translates to meaningful protection from target organ damage.”

Dr. Mahfoud observed that BP control worsened during the COVID-19 pandemic, which may have impacted BP results, but that in-person follow-up visits were still performed. Other limitations are a lack of information on patients’ exercise, diet, and smoking habits and that blood and urine testing assessed medication adherence at discrete time points, but adherence over an extended period of time is uncertain.

Dr. Mahfoud reports research grants from Deutsche Forschungsgemeinschaft and Deutsche Gesellschaft für Kardiologie and scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, Merck, and ReCor Medical. The study was funded by Medtronic. Dr. Sarathy and Dr. Salman report no relevant financial relationships.

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

Radiofrequency renal denervation provided progressive reductions in blood pressure at 3 years in patients on antihypertensive medication, but this did not translate into fewer antihypertensive drugs, new results from the SPYRAL HTN-ON MED trial show.

At 36 months, 24-hour ambulatory systolic and diastolic blood pressures were 10.0 mm Hg (P = .003) and 5.9 mm Hg (P = .005) lower, respectively, in patients who underwent renal denervation with Medtronic’s Symplicity Spyral radiofrequency catheter, compared with patients treated with a sham procedure.

The number of antihypertensive drugs, however, increased in both groups from an average of two at baseline and 6 months to three at 3 years (P = .76).

Based on the number of drugs, class, and dose, medication burden increased significantly in the sham group at 12 months (6.5 vs. 4.9; P = .04) and trended higher at 3 years (10.3 vs. 7.6; P = .26).

The procedure appeared safe, with no renal safety events in the denervation group and only three safety events overall at 36 months. One cardiovascular death occurred 693 days after a sham procedure and one patient had a hypertensive crisis and stroke 427 days after renal denervation and was discharged in stable condition, according to results published in The Lancet.

“Given the long-term safety and efficacy of renal denervation, it may provide an alternative adjunctive treatment modality in the management of hypertension,” Felix Mahfoud, MD, Saarland University Hospital, Homburg, Germany, said during a presentation of the study at the recent American College of Cardiology (ACC) 2022 Scientific Session.

Ted Bosworth/MDedge News

Sham-controlled evidence

As previously reported, significant BP reductions at 6 months in SPYRAL HTN-ON provided proof of concept and helped revive enthusiasm for the procedure after failing to meet the primary endpoint in the SYMPLICITY HTN-3 trial. Results from the Global SYMPLICITY Registry have shown benefits out to 3 years, but sham-controlled data have been lacking.

The trial enrolled 80 patients with an office systolic BP of 150-180 mm Hg and diastolic of 90 mm Hg or greater and 24-hour ambulatory systolic BP of 140-170 mm Hg, who were on up to three antihypertensive medications.

Medication changes were allowed beginning at 6 months; patients and physicians were unblinded at 12 months. Between 24 and 36 months, 13 patients assigned to the sham procedure crossed over to denervation treatment. Medication adherence at 3 years was 77% in the denervation group versus 93% in the sham group.

At 3 years, the renal denervation group had significantly greater reductions from baseline in several ambulatory BP measures, compared with the sham group, including: 24-hour systolic (10.0 mm Hg), morning systolic (11.0 mm Hg), daytime systolic (8.9 mm Hg), and night-time systolic (11.8 mm Hg).

Renal denervation led to an 8.2 mm Hg greater fall in office systolic BP, but this failed to reach statistical significance (P = .07).

Almost twice as many patients in the denervation group achieved a 24-hour systolic BP less than 140 mm Hg than in the sham group (83.3%, vs. 43.8%; P = .002), Dr. Mahfoud reported.

“Although renal denervation appears to effectively lower blood pressure, participants in the renal denervation group did not quite reach guideline-recommended blood pressure thresholds,” Harini Sarathy, MD, University of California, San Francisco, and Liann Abu Salman, MD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, point out in an accompanying editorial. “This result could have been due to a degree of physician inertia or differential prescribing of blood pressure medications for the intervention group, compared with the sham control group, wherein physicians might have considered renal denervation to be the fourth antihypertensive medication.”

The editorialists also note that nearly a third of the sham group (13 of 42) underwent renal denervation. “The differentially missing BP readings at 24 months for the sham group are a cause for concern, although the absence of any meaningful differences in results after imputation is somewhat reassuring.”

A 10 mm Hg reduction in BP after 36 months would be expected to translate to a significant reduction in cardiovascular outcomes, they say. The sustained reductions in several systolic readings also speak to the “always-on distinctiveness” that renal denervation proponents claim.

“In the stark absence of novel antihypertensive drug development, renal denervation is seemingly poised to be an effective supplement, if not an alternative, to complex antihypertensive regimens with frequent dosing schedules,” they conclude. “We look forward to results of the Expansion trial in providing more definitive answers regarding whether this translates to meaningful protection from target organ damage.”

Dr. Mahfoud observed that BP control worsened during the COVID-19 pandemic, which may have impacted BP results, but that in-person follow-up visits were still performed. Other limitations are a lack of information on patients’ exercise, diet, and smoking habits and that blood and urine testing assessed medication adherence at discrete time points, but adherence over an extended period of time is uncertain.

Dr. Mahfoud reports research grants from Deutsche Forschungsgemeinschaft and Deutsche Gesellschaft für Kardiologie and scientific support and speaker honoraria from Bayer, Boehringer Ingelheim, Medtronic, Merck, and ReCor Medical. The study was funded by Medtronic. Dr. Sarathy and Dr. Salman report no relevant financial relationships.

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

The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.

Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45-60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.

Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-and 600-mg doses.

In addition, for participants receiving the two highest doses, apolipoprotein B (apo B) was reduced was 21% and 24%, respectively, and LDL cholesterol (LDL-C), by 21% and 26%, respectively.

“The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD [atherosclerotic cardiovascular disease] or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted,” said principal investigator Steven E. Nissen, MD, Cleveland Clinic.

The results were presented in a late-breaking clinical trial session at the annual scientific sessions of the American College of Cardiology and published simultaneously in JAMA.

Elevated Lp(a) is a powerful genetic risk factor for ASCVD and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).

SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.
 

Testing vacuum

Dr. Nissen said in an interview that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.

“Someone comes in with an MI in their 40s and we measure it and it’s 100, 150 [mg/dL], clearly abnormal, and often these patients don’t have a lot of other risk factors,” Dr. Nissen said. “So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it.”

During a media briefing, ACC 2022 program cochair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won’t be reimbursed because they don’t understand it.

“What Dr. Nissen is telling you: It should be measured in everyone at least once, we all believe that, but it hasn’t made it into the major guidelines,” she added. “I think what we’re going to have to do is have the guidelines mandate it and the insurers will follow.”

Guidelines currently list elevated Lp(a) as a “risk-enhancing factor,” which can help with at least recommending LDL-C treatment in patients with borderline risk and a sky-high Lp(a), noted Dr. Nissen. “But we need to go beyond that.”
 

Safety analyses

The first-in-human APOLLO trial evaluated 32 adults without known ASCVD and an Lp(a) concentration greater than 150 nmol/L (approximately 60 mg/dL) who received one of the four doses of SLN360 or placebo subcutaneously. Participants were monitored in a research unit for the first 24 hours and then followed periodically for up to 150 days. At baseline, their median Lp(a) level was 224 nmol/L, mean apo B level was 85 mg/dL, and mean LDL-C level was 108 mg/dL.

Treatment-emergent adverse events were generally mild, mostly grade 1 injection site reactions (83% at 30 mg, 100% at 100 mg, 67% at 300 mg, and 33% at 600 mg) and headache (33%, 17%, 0%, and 83%).

At the highest dose, C-reactive protein was increased in four patients and neutrophil counts in three. ALT and AST levels were elevated three times above the upper limit of normal in one patient at the lowest dose.

One participant in the lowest-dose group experienced two serious adverse events unrelated to SLN360 at day 45 after receiving a SARS-Co-V-2 vaccine.

Dr. Nissen noted that safety cannot be comprehensively assessed in a trial of this duration or size and that follow-up has been extended to 1 year in the two highest-dose groups.

Enrollment continues in the multiple-ascending dose portion of the study in patients with high Lp(a) and a history of stable ASCVD. A phase 2 study of SLN360 is also planned for the second half of 2022, pending regulatory discussions.
 

But will it reduce ASCVD events?

Study discussant Vera Bittner, MD, MSPH, University of Alabama at Birmingham, said that the development of Lp(a)-specific lowering agents has been a “holy grail” for years and congratulated the authors on a successful trial demonstrating very robust Lp(a) lowering.

She asked Dr. Nissen about the observation in proprotein convertase subtilisin/kexin type 9 inhibitor trials that absolute Lp(a) lowering is greater at higher baseline levels.

Dr. Nissen said this kind of analysis wasn’t possible because of the small sample size but “because these agents so effectively degrade messenger RNA, it’s very likely we will see robust suppression of plasma levels virtually regardless of the baseline level.”

Dr. Bittner also questioned if “LDL-C declined because of the cholesterol content in the lipoprotein(a) or is there some additional effect on LDL particles themselves?”

“It’s a really terrific question that will ultimately need to be answered,” Dr. Nissen replied. “There’s some controversy about the extent to which suppressing lipoprotein(a) will reduce LDL because the assays for LDL are measuring the LDL that’s in lipoprotein(a) and the LDL that is not. ... I think it’s probably a bystander effect, but it may also contribute to efficacy from a morbidity and mortality point of view, which is why we measured it.”

Dr. Bittner also called out the elevation in C-reactive protein and leukocytosis, which has not been seen in other siRNA studies. Dr. Nissen said the increases in C-reactive protein occurred in the first few days after administration and were gone after a week or so. “I don’t see it as a long-term limitation.”

In an accompanying editorial, Brian Ference, MD, MPhil, MSc, University of Cambridge (England), suggests that because circulating Lp(a) particles can progressively become trapped within the artery wall over time, it’s unlikely that lowering Lp(a) for only a few years starting later in life will eliminate the effect of lifelong exposure to Lp(a) and may only cut cardiovascular event risk by about 10%-15%.

He called for continued safety and efficacy evaluation of SLN360 and olpasiran, a similar siRNA agent in early development, and said further insights into whether large absolute reductions in Lp(a) can reduce the risk for major cardiovascular events will come from cardiovascular trials, such as the ongoing phase 3 Lp(a)HORIZON trial. It follows strong phase 2 results with the antisense agent AKCEA-APO(a)-LRx and has Dr. Nissen pulling double duty as study chair.

The study was funded by Silence Therapeutics. Dr. Nissen reported consulting for many pharmaceutical companies, which are directed to pay any renumeration directly to charity. Dr. Bittner reported consultant fees or honoraria from Pfizer; other from AstraZeneca, DalCor, Esperion, and Sanofi-Aventis; and research/research grants from Amgen and Novartis. Dr. Ference reported financial ties to Merck, Novartis, Amgen, Pfizer, Esperion Therapeutics, and numerous other companies.

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

The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.

Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45-60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.

Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-and 600-mg doses.

In addition, for participants receiving the two highest doses, apolipoprotein B (apo B) was reduced was 21% and 24%, respectively, and LDL cholesterol (LDL-C), by 21% and 26%, respectively.

“The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD [atherosclerotic cardiovascular disease] or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted,” said principal investigator Steven E. Nissen, MD, Cleveland Clinic.

The results were presented in a late-breaking clinical trial session at the annual scientific sessions of the American College of Cardiology and published simultaneously in JAMA.

Elevated Lp(a) is a powerful genetic risk factor for ASCVD and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).

SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.
 

Testing vacuum

Dr. Nissen said in an interview that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.

“Someone comes in with an MI in their 40s and we measure it and it’s 100, 150 [mg/dL], clearly abnormal, and often these patients don’t have a lot of other risk factors,” Dr. Nissen said. “So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it.”

During a media briefing, ACC 2022 program cochair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won’t be reimbursed because they don’t understand it.

“What Dr. Nissen is telling you: It should be measured in everyone at least once, we all believe that, but it hasn’t made it into the major guidelines,” she added. “I think what we’re going to have to do is have the guidelines mandate it and the insurers will follow.”

Guidelines currently list elevated Lp(a) as a “risk-enhancing factor,” which can help with at least recommending LDL-C treatment in patients with borderline risk and a sky-high Lp(a), noted Dr. Nissen. “But we need to go beyond that.”
 

Safety analyses

The first-in-human APOLLO trial evaluated 32 adults without known ASCVD and an Lp(a) concentration greater than 150 nmol/L (approximately 60 mg/dL) who received one of the four doses of SLN360 or placebo subcutaneously. Participants were monitored in a research unit for the first 24 hours and then followed periodically for up to 150 days. At baseline, their median Lp(a) level was 224 nmol/L, mean apo B level was 85 mg/dL, and mean LDL-C level was 108 mg/dL.

Treatment-emergent adverse events were generally mild, mostly grade 1 injection site reactions (83% at 30 mg, 100% at 100 mg, 67% at 300 mg, and 33% at 600 mg) and headache (33%, 17%, 0%, and 83%).

At the highest dose, C-reactive protein was increased in four patients and neutrophil counts in three. ALT and AST levels were elevated three times above the upper limit of normal in one patient at the lowest dose.

One participant in the lowest-dose group experienced two serious adverse events unrelated to SLN360 at day 45 after receiving a SARS-Co-V-2 vaccine.

Dr. Nissen noted that safety cannot be comprehensively assessed in a trial of this duration or size and that follow-up has been extended to 1 year in the two highest-dose groups.

Enrollment continues in the multiple-ascending dose portion of the study in patients with high Lp(a) and a history of stable ASCVD. A phase 2 study of SLN360 is also planned for the second half of 2022, pending regulatory discussions.
 

But will it reduce ASCVD events?

Study discussant Vera Bittner, MD, MSPH, University of Alabama at Birmingham, said that the development of Lp(a)-specific lowering agents has been a “holy grail” for years and congratulated the authors on a successful trial demonstrating very robust Lp(a) lowering.

She asked Dr. Nissen about the observation in proprotein convertase subtilisin/kexin type 9 inhibitor trials that absolute Lp(a) lowering is greater at higher baseline levels.

Dr. Nissen said this kind of analysis wasn’t possible because of the small sample size but “because these agents so effectively degrade messenger RNA, it’s very likely we will see robust suppression of plasma levels virtually regardless of the baseline level.”

Dr. Bittner also questioned if “LDL-C declined because of the cholesterol content in the lipoprotein(a) or is there some additional effect on LDL particles themselves?”

“It’s a really terrific question that will ultimately need to be answered,” Dr. Nissen replied. “There’s some controversy about the extent to which suppressing lipoprotein(a) will reduce LDL because the assays for LDL are measuring the LDL that’s in lipoprotein(a) and the LDL that is not. ... I think it’s probably a bystander effect, but it may also contribute to efficacy from a morbidity and mortality point of view, which is why we measured it.”

Dr. Bittner also called out the elevation in C-reactive protein and leukocytosis, which has not been seen in other siRNA studies. Dr. Nissen said the increases in C-reactive protein occurred in the first few days after administration and were gone after a week or so. “I don’t see it as a long-term limitation.”

In an accompanying editorial, Brian Ference, MD, MPhil, MSc, University of Cambridge (England), suggests that because circulating Lp(a) particles can progressively become trapped within the artery wall over time, it’s unlikely that lowering Lp(a) for only a few years starting later in life will eliminate the effect of lifelong exposure to Lp(a) and may only cut cardiovascular event risk by about 10%-15%.

He called for continued safety and efficacy evaluation of SLN360 and olpasiran, a similar siRNA agent in early development, and said further insights into whether large absolute reductions in Lp(a) can reduce the risk for major cardiovascular events will come from cardiovascular trials, such as the ongoing phase 3 Lp(a)HORIZON trial. It follows strong phase 2 results with the antisense agent AKCEA-APO(a)-LRx and has Dr. Nissen pulling double duty as study chair.

The study was funded by Silence Therapeutics. Dr. Nissen reported consulting for many pharmaceutical companies, which are directed to pay any renumeration directly to charity. Dr. Bittner reported consultant fees or honoraria from Pfizer; other from AstraZeneca, DalCor, Esperion, and Sanofi-Aventis; and research/research grants from Amgen and Novartis. Dr. Ference reported financial ties to Merck, Novartis, Amgen, Pfizer, Esperion Therapeutics, and numerous other companies.

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

The short interfering RNA (siRNA) agent SLN360 was well tolerated and lowered lipoprotein(a) by up to 98% in volunteers without cardiovascular disease but with elevated Lp(a) in the small dose-ranging APOLLO trial.

Following a single subcutaneous dose of SLN360 (Silence Therapeutics), there was a dose-dependent reduction in Lp(a) plasma levels by a median of 46%, 86%, 96%, and 98% at about 45-60 days with 30-mg, 100-mg, 300-mg, and 600-mg doses, respectively.

Lp(a) levels at 150 days were 70% and 81% below baseline with the 300-and 600-mg doses.

In addition, for participants receiving the two highest doses, apolipoprotein B (apo B) was reduced was 21% and 24%, respectively, and LDL cholesterol (LDL-C), by 21% and 26%, respectively.

“The development of therapies targeting messenger RNA has made possible significant lowering of lipoprotein(a). Whether these reductions can impact on the incidence of ASCVD [atherosclerotic cardiovascular disease] or prevent progression of aortic stenosis remains to be determined but, we think, that optimism is warranted,” said principal investigator Steven E. Nissen, MD, Cleveland Clinic.

The results were presented in a late-breaking clinical trial session at the annual scientific sessions of the American College of Cardiology and published simultaneously in JAMA.

Elevated Lp(a) is a powerful genetic risk factor for ASCVD and aortic stenosis, which affects some 64 million Americans and 1.4 billion people globally. Although several experimental agents are under investigation, no currently approved drugs selectively lower Lp(a).

SLN360 is designed to lower Lp(a) production by using RNA interference to silence messenger RNA transcribed from the LPA gene in liver cells.
 

Testing vacuum

Dr. Nissen said in an interview that one of the big takeaways from the study is the need for greater testing of Lp(a). Automatic assays are available in almost every hospital, but two-unit systems (nmol/L and mg/dL) are used and thresholds for accelerated risk vary. The Cleveland Clinic currently tests all patients in its cardiac critical care unit and its prevention clinic.

“Someone comes in with an MI in their 40s and we measure it and it’s 100, 150 [mg/dL], clearly abnormal, and often these patients don’t have a lot of other risk factors,” Dr. Nissen said. “So the explanation very likely for their premature disease is this risk factor. We now have to educate everybody about the importance of getting it tested and finding out about it.”

During a media briefing, ACC 2022 program cochair Pamela B. Morris, MD, Medical University of South Carolina, Charleston, said testing for Lp(a) is not well reimbursed by insurance providers and that her patients will often cancel the test after learning it won’t be reimbursed because they don’t understand it.

“What Dr. Nissen is telling you: It should be measured in everyone at least once, we all believe that, but it hasn’t made it into the major guidelines,” she added. “I think what we’re going to have to do is have the guidelines mandate it and the insurers will follow.”

Guidelines currently list elevated Lp(a) as a “risk-enhancing factor,” which can help with at least recommending LDL-C treatment in patients with borderline risk and a sky-high Lp(a), noted Dr. Nissen. “But we need to go beyond that.”
 

Safety analyses

The first-in-human APOLLO trial evaluated 32 adults without known ASCVD and an Lp(a) concentration greater than 150 nmol/L (approximately 60 mg/dL) who received one of the four doses of SLN360 or placebo subcutaneously. Participants were monitored in a research unit for the first 24 hours and then followed periodically for up to 150 days. At baseline, their median Lp(a) level was 224 nmol/L, mean apo B level was 85 mg/dL, and mean LDL-C level was 108 mg/dL.

Treatment-emergent adverse events were generally mild, mostly grade 1 injection site reactions (83% at 30 mg, 100% at 100 mg, 67% at 300 mg, and 33% at 600 mg) and headache (33%, 17%, 0%, and 83%).

At the highest dose, C-reactive protein was increased in four patients and neutrophil counts in three. ALT and AST levels were elevated three times above the upper limit of normal in one patient at the lowest dose.

One participant in the lowest-dose group experienced two serious adverse events unrelated to SLN360 at day 45 after receiving a SARS-Co-V-2 vaccine.

Dr. Nissen noted that safety cannot be comprehensively assessed in a trial of this duration or size and that follow-up has been extended to 1 year in the two highest-dose groups.

Enrollment continues in the multiple-ascending dose portion of the study in patients with high Lp(a) and a history of stable ASCVD. A phase 2 study of SLN360 is also planned for the second half of 2022, pending regulatory discussions.
 

But will it reduce ASCVD events?

Study discussant Vera Bittner, MD, MSPH, University of Alabama at Birmingham, said that the development of Lp(a)-specific lowering agents has been a “holy grail” for years and congratulated the authors on a successful trial demonstrating very robust Lp(a) lowering.

She asked Dr. Nissen about the observation in proprotein convertase subtilisin/kexin type 9 inhibitor trials that absolute Lp(a) lowering is greater at higher baseline levels.

Dr. Nissen said this kind of analysis wasn’t possible because of the small sample size but “because these agents so effectively degrade messenger RNA, it’s very likely we will see robust suppression of plasma levels virtually regardless of the baseline level.”

Dr. Bittner also questioned if “LDL-C declined because of the cholesterol content in the lipoprotein(a) or is there some additional effect on LDL particles themselves?”

“It’s a really terrific question that will ultimately need to be answered,” Dr. Nissen replied. “There’s some controversy about the extent to which suppressing lipoprotein(a) will reduce LDL because the assays for LDL are measuring the LDL that’s in lipoprotein(a) and the LDL that is not. ... I think it’s probably a bystander effect, but it may also contribute to efficacy from a morbidity and mortality point of view, which is why we measured it.”

Dr. Bittner also called out the elevation in C-reactive protein and leukocytosis, which has not been seen in other siRNA studies. Dr. Nissen said the increases in C-reactive protein occurred in the first few days after administration and were gone after a week or so. “I don’t see it as a long-term limitation.”

In an accompanying editorial, Brian Ference, MD, MPhil, MSc, University of Cambridge (England), suggests that because circulating Lp(a) particles can progressively become trapped within the artery wall over time, it’s unlikely that lowering Lp(a) for only a few years starting later in life will eliminate the effect of lifelong exposure to Lp(a) and may only cut cardiovascular event risk by about 10%-15%.

He called for continued safety and efficacy evaluation of SLN360 and olpasiran, a similar siRNA agent in early development, and said further insights into whether large absolute reductions in Lp(a) can reduce the risk for major cardiovascular events will come from cardiovascular trials, such as the ongoing phase 3 Lp(a)HORIZON trial. It follows strong phase 2 results with the antisense agent AKCEA-APO(a)-LRx and has Dr. Nissen pulling double duty as study chair.

The study was funded by Silence Therapeutics. Dr. Nissen reported consulting for many pharmaceutical companies, which are directed to pay any renumeration directly to charity. Dr. Bittner reported consultant fees or honoraria from Pfizer; other from AstraZeneca, DalCor, Esperion, and Sanofi-Aventis; and research/research grants from Amgen and Novartis. Dr. Ference reported financial ties to Merck, Novartis, Amgen, Pfizer, Esperion Therapeutics, and numerous other companies.

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

The antifibrinolytic tranexamic acid (TXA) reduced serious bleeding without a significant effect on major vascular outcomes in patients undergoing noncardiac surgery at risk for these complications in the POISE-3 trial.

TXA cut the primary efficacy outcome of life-threatening, major, and critical organ bleeding at 30 days by 24% compared with placebo (9.1% vs. 11.7%; hazard ratio [HR], 0.76; P < .0001).

The primary safety outcome of myocardial injury after noncardiac surgery (MINS), nonhemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism (VTE) at 30 days occurred in 14.2% vs.. 13.9% of patients, respectively (HR, 1.023). This failed, however, to meet the study›s threshold to prove TXA noninferior to placebo (one-sided P = .044).

There was no increased risk for death or stroke with TXA, according to results published April 2 in the New England Journal of Medicine.

Principal investigator P.J. Devereaux, MD, PhD, Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada, pointed out that there is only a 4.4% probability that the composite vascular outcome hazard ratio was above the noninferiority margin and that just 10 events separated the two groups (649 vs.. 639).

“Healthcare providers and patients will have to weigh a clear beneficial reduction in the composite bleeding outcome, which is an absolute difference of 2.7%, a result that was highly statistically significant, versus a low probability of a small increase in risk of the composite vascular endpoint, with an absolute difference of 0.3%,” a nonsignificant result, Dr. Devereaux said during the formal presentation of the results at the hybrid annual scientific sessions of the American College of Cardiology.

The findings, he said, should also be put in the context that 300 million adults have a major surgery each year worldwide and most don’t receive TXA. At the same time, there’s an annual global shortage of 30 million blood product units, and surgical bleeding accounts for up to 40% of all transfusions.

“POISE-3 identifies that use of TXA could avoid upwards of 8 million bleeding events resulting in transfusion on an annual basis, indicating potential for large public health and clinical benefit if TXA become standard practice in noncardiac surgery,” Dr. Devereaux said during the late-breaking trial session.

TXA is indicated for heavy menstrual bleeding and hemophilia and has been used in cardiac surgery, but it is increasingly being used in noncardiac surgeries. As previously reported, POISE showed that the beta-blocker metoprolol lowered the risk for myocardial infarction (MI) but increased the risk for severe stroke and overall death, whereas in POISE-2, perioperative low-dose aspirin lowered the risk for MI but was linked to more major bleeding.

The cumulative data have not shown an increased risk for thrombotic events in other settings, Dr. Devereaux told this news organization.

“I’m a cardiologist, and I think that we’ve been guilty at times of always only focusing on the thrombotic side of the equation and ignoring that bleeding is a very important aspect of the circulatory system,” he said. “And I think this shows for the first time clear unequivocal evidence that there’s a cheap, very encouraging, safe way to prevent this.”

“An important point is that if you can give tranexamic acid and prevent bleeding in your cardiac patients having noncardiac surgery, then you can prevent the delay of reinitiating their anticoagulants and their antiplatelets after surgery and getting them back on the medications that are important for them to prevent their cardiovascular event,” Dr. Devereaux added.

Discussant Michael J. Mack, MD, commented that TXA, widely used in cardiac surgery, is an old, inexpensive drug that “should be more widely used in noncardiac surgery.” Dr. Mack, from Baylor Scott & White Health, Dallas, added that he would limit it to major noncardiac surgery.

International trial

PeriOperative ISchemic Evaluation-3 (POISE-3) investigators at 114 hospitals in 22 countries (including countries in North and South America, Europe, and Africa; Russia; India; and Australia) randomly assigned 9,535 patients, aged 45 years or older, with or at risk for cardiovascular and bleeding complications to receive a TXA 1-g intravenous bolus or placebo at the start and end of inpatient noncardiac surgery.

Patients taking at least one long-term antihypertensive medication were also randomly assigned to a perioperative hypotension- or hypertension-avoidance strategy, which differ in the use of antihypertensives on the morning of surgery and the first 2 days after surgery, and in the target mean arterial pressure during surgery. Results from these cohorts will be presented in a separate session on April 4.

The study had planned to enroll 10,000 patients but was stopped early by the steering committee because of financial constraints resulting from slow enrollment during the pandemic. The decision was made without knowledge of the trial results but with knowledge that aggregate composite bleeding and vascular outcomes were higher than originally estimated, Dr. Devereaux noted.

Among all participants, the mean age was 70 years, 56% were male, almost a third had coronary artery disease, 15% had peripheral artery disease, and 8% had a prior stroke. About 80% were undergoing major surgery. Adherence to the study medications was 96.3% in both groups.

Secondary bleeding outcomes were lower in the TXA and placebo groups, including bleeding independently associated with mortality after surgery (8.7% vs. 11.3%), life-threatening bleeding (1.6% vs. 1.7%), major bleeding (7.6% vs. 10.4%), and critical organ bleeding (0.3% vs. 0.4%).

Importantly, the TXA group had significantly lower rates of International Society on Thrombosis and Haemostasis major bleeding (6.6% vs. 8.7%; P = .0001) and the need for transfusion of 1 or more units of packed red blood cells (9.4% vs. 12.0%; P <.0001), Dr. Devereaux noted.

In terms of secondary vascular outcomes, there were no significant differences between the TXA and placebo groups in rates of MINS (12.8% vs. 12.6%), MINS not fulfilling definition of MI (both 11.5%), MI (1.4% vs. 1.1%), and the net risk-benefit outcome (a composite of vascular death and nonfatal life-threatening, major, or critical organ bleeding, MINS, stroke, peripheral arterial thrombosis, and symptomatic proximal VTE; 20.7% vs. 21.9%).

The two groups had similar rates of all-cause (1.1% vs. 1.2%) and vascular (0.5% vs. 0.6%) mortality.

There also were no significant differences in other tertiary outcomes, such as acute kidney injury (14.1% vs. 13.7%), rehospitalization for vascular reasons (1.8% vs. 1.6%), or seizures (0.2% vs. <0.1%). The latter has been a concern, with the risk reported to increase with higher doses.

Subgroup analyses

Preplanned subgroup analyses showed a benefit for TXA over placebo for the primary efficacy outcome in orthopedic and nonorthopedic surgery and in patients with hemoglobin level below 120 g/L or 120 g/L or higher, with an estimated glomerular filtration rate less than 45 mL/min/1.73 m ²  or 45 mL/min/1.73 m ²  or higher, or with an N-terminal pro– B-type natriuretic peptide level below 200 ng/L or 200 ng/L or higher.

For the primary safety outcome, the benefit favored placebo but the interaction was not statistically significant for any of the four subgroups.

A post hoc subgroup analysis also showed similar results across the major categories of surgery, including general, vascular, urologic, and gynecologic, Dr. Devereaux told this news organization.

Although TXA is commonly used in orthopedic procedures, Dr. Devereaux noted, in other types of surgeries, “it’s not used at all.” But because TXA “is so cheap, and we can apply it to a broad population, even at an economic level it looks like it’s a winner to give to almost all patients having noncardiac surgery.”

The team also recently published a risk prediction tool that can help estimate a patient’s baseline risk for bleeding.

“So just using a model, which will bring together the patient’s type of surgery and their risk factors, you can look to see, okay, this is enough risk of bleeding, I’m just going to give tranexamic acid,” he said. “We will also be doing economic analyses because blood is also not cheap.”

The study was funded by the Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and the Research Grant Council (Hong Kong). Dr. Devereaux reports research/research grants from Abbott Diagnostics, Philips Healthcare, Roche Diagnostics, and Siemens. Dr. Mack reports receiving research grants from Abbott Vascular, Edwards Lifesciences, and Medtronic.

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

The antifibrinolytic tranexamic acid (TXA) reduced serious bleeding without a significant effect on major vascular outcomes in patients undergoing noncardiac surgery at risk for these complications in the POISE-3 trial.

TXA cut the primary efficacy outcome of life-threatening, major, and critical organ bleeding at 30 days by 24% compared with placebo (9.1% vs. 11.7%; hazard ratio [HR], 0.76; P < .0001).

The primary safety outcome of myocardial injury after noncardiac surgery (MINS), nonhemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism (VTE) at 30 days occurred in 14.2% vs.. 13.9% of patients, respectively (HR, 1.023). This failed, however, to meet the study›s threshold to prove TXA noninferior to placebo (one-sided P = .044).

There was no increased risk for death or stroke with TXA, according to results published April 2 in the New England Journal of Medicine.

Principal investigator P.J. Devereaux, MD, PhD, Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada, pointed out that there is only a 4.4% probability that the composite vascular outcome hazard ratio was above the noninferiority margin and that just 10 events separated the two groups (649 vs.. 639).

“Healthcare providers and patients will have to weigh a clear beneficial reduction in the composite bleeding outcome, which is an absolute difference of 2.7%, a result that was highly statistically significant, versus a low probability of a small increase in risk of the composite vascular endpoint, with an absolute difference of 0.3%,” a nonsignificant result, Dr. Devereaux said during the formal presentation of the results at the hybrid annual scientific sessions of the American College of Cardiology.

The findings, he said, should also be put in the context that 300 million adults have a major surgery each year worldwide and most don’t receive TXA. At the same time, there’s an annual global shortage of 30 million blood product units, and surgical bleeding accounts for up to 40% of all transfusions.

“POISE-3 identifies that use of TXA could avoid upwards of 8 million bleeding events resulting in transfusion on an annual basis, indicating potential for large public health and clinical benefit if TXA become standard practice in noncardiac surgery,” Dr. Devereaux said during the late-breaking trial session.

TXA is indicated for heavy menstrual bleeding and hemophilia and has been used in cardiac surgery, but it is increasingly being used in noncardiac surgeries. As previously reported, POISE showed that the beta-blocker metoprolol lowered the risk for myocardial infarction (MI) but increased the risk for severe stroke and overall death, whereas in POISE-2, perioperative low-dose aspirin lowered the risk for MI but was linked to more major bleeding.

The cumulative data have not shown an increased risk for thrombotic events in other settings, Dr. Devereaux told this news organization.

“I’m a cardiologist, and I think that we’ve been guilty at times of always only focusing on the thrombotic side of the equation and ignoring that bleeding is a very important aspect of the circulatory system,” he said. “And I think this shows for the first time clear unequivocal evidence that there’s a cheap, very encouraging, safe way to prevent this.”

“An important point is that if you can give tranexamic acid and prevent bleeding in your cardiac patients having noncardiac surgery, then you can prevent the delay of reinitiating their anticoagulants and their antiplatelets after surgery and getting them back on the medications that are important for them to prevent their cardiovascular event,” Dr. Devereaux added.

Discussant Michael J. Mack, MD, commented that TXA, widely used in cardiac surgery, is an old, inexpensive drug that “should be more widely used in noncardiac surgery.” Dr. Mack, from Baylor Scott & White Health, Dallas, added that he would limit it to major noncardiac surgery.

International trial

PeriOperative ISchemic Evaluation-3 (POISE-3) investigators at 114 hospitals in 22 countries (including countries in North and South America, Europe, and Africa; Russia; India; and Australia) randomly assigned 9,535 patients, aged 45 years or older, with or at risk for cardiovascular and bleeding complications to receive a TXA 1-g intravenous bolus or placebo at the start and end of inpatient noncardiac surgery.

Patients taking at least one long-term antihypertensive medication were also randomly assigned to a perioperative hypotension- or hypertension-avoidance strategy, which differ in the use of antihypertensives on the morning of surgery and the first 2 days after surgery, and in the target mean arterial pressure during surgery. Results from these cohorts will be presented in a separate session on April 4.

The study had planned to enroll 10,000 patients but was stopped early by the steering committee because of financial constraints resulting from slow enrollment during the pandemic. The decision was made without knowledge of the trial results but with knowledge that aggregate composite bleeding and vascular outcomes were higher than originally estimated, Dr. Devereaux noted.

Among all participants, the mean age was 70 years, 56% were male, almost a third had coronary artery disease, 15% had peripheral artery disease, and 8% had a prior stroke. About 80% were undergoing major surgery. Adherence to the study medications was 96.3% in both groups.

Secondary bleeding outcomes were lower in the TXA and placebo groups, including bleeding independently associated with mortality after surgery (8.7% vs. 11.3%), life-threatening bleeding (1.6% vs. 1.7%), major bleeding (7.6% vs. 10.4%), and critical organ bleeding (0.3% vs. 0.4%).

Importantly, the TXA group had significantly lower rates of International Society on Thrombosis and Haemostasis major bleeding (6.6% vs. 8.7%; P = .0001) and the need for transfusion of 1 or more units of packed red blood cells (9.4% vs. 12.0%; P <.0001), Dr. Devereaux noted.

In terms of secondary vascular outcomes, there were no significant differences between the TXA and placebo groups in rates of MINS (12.8% vs. 12.6%), MINS not fulfilling definition of MI (both 11.5%), MI (1.4% vs. 1.1%), and the net risk-benefit outcome (a composite of vascular death and nonfatal life-threatening, major, or critical organ bleeding, MINS, stroke, peripheral arterial thrombosis, and symptomatic proximal VTE; 20.7% vs. 21.9%).

The two groups had similar rates of all-cause (1.1% vs. 1.2%) and vascular (0.5% vs. 0.6%) mortality.

There also were no significant differences in other tertiary outcomes, such as acute kidney injury (14.1% vs. 13.7%), rehospitalization for vascular reasons (1.8% vs. 1.6%), or seizures (0.2% vs. <0.1%). The latter has been a concern, with the risk reported to increase with higher doses.

Subgroup analyses

Preplanned subgroup analyses showed a benefit for TXA over placebo for the primary efficacy outcome in orthopedic and nonorthopedic surgery and in patients with hemoglobin level below 120 g/L or 120 g/L or higher, with an estimated glomerular filtration rate less than 45 mL/min/1.73 m ²  or 45 mL/min/1.73 m ²  or higher, or with an N-terminal pro– B-type natriuretic peptide level below 200 ng/L or 200 ng/L or higher.

For the primary safety outcome, the benefit favored placebo but the interaction was not statistically significant for any of the four subgroups.

A post hoc subgroup analysis also showed similar results across the major categories of surgery, including general, vascular, urologic, and gynecologic, Dr. Devereaux told this news organization.

Although TXA is commonly used in orthopedic procedures, Dr. Devereaux noted, in other types of surgeries, “it’s not used at all.” But because TXA “is so cheap, and we can apply it to a broad population, even at an economic level it looks like it’s a winner to give to almost all patients having noncardiac surgery.”

The team also recently published a risk prediction tool that can help estimate a patient’s baseline risk for bleeding.

“So just using a model, which will bring together the patient’s type of surgery and their risk factors, you can look to see, okay, this is enough risk of bleeding, I’m just going to give tranexamic acid,” he said. “We will also be doing economic analyses because blood is also not cheap.”

The study was funded by the Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and the Research Grant Council (Hong Kong). Dr. Devereaux reports research/research grants from Abbott Diagnostics, Philips Healthcare, Roche Diagnostics, and Siemens. Dr. Mack reports receiving research grants from Abbott Vascular, Edwards Lifesciences, and Medtronic.

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

The antifibrinolytic tranexamic acid (TXA) reduced serious bleeding without a significant effect on major vascular outcomes in patients undergoing noncardiac surgery at risk for these complications in the POISE-3 trial.

TXA cut the primary efficacy outcome of life-threatening, major, and critical organ bleeding at 30 days by 24% compared with placebo (9.1% vs. 11.7%; hazard ratio [HR], 0.76; P < .0001).

The primary safety outcome of myocardial injury after noncardiac surgery (MINS), nonhemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism (VTE) at 30 days occurred in 14.2% vs.. 13.9% of patients, respectively (HR, 1.023). This failed, however, to meet the study›s threshold to prove TXA noninferior to placebo (one-sided P = .044).

There was no increased risk for death or stroke with TXA, according to results published April 2 in the New England Journal of Medicine.

Principal investigator P.J. Devereaux, MD, PhD, Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada, pointed out that there is only a 4.4% probability that the composite vascular outcome hazard ratio was above the noninferiority margin and that just 10 events separated the two groups (649 vs.. 639).

“Healthcare providers and patients will have to weigh a clear beneficial reduction in the composite bleeding outcome, which is an absolute difference of 2.7%, a result that was highly statistically significant, versus a low probability of a small increase in risk of the composite vascular endpoint, with an absolute difference of 0.3%,” a nonsignificant result, Dr. Devereaux said during the formal presentation of the results at the hybrid annual scientific sessions of the American College of Cardiology.

The findings, he said, should also be put in the context that 300 million adults have a major surgery each year worldwide and most don’t receive TXA. At the same time, there’s an annual global shortage of 30 million blood product units, and surgical bleeding accounts for up to 40% of all transfusions.

“POISE-3 identifies that use of TXA could avoid upwards of 8 million bleeding events resulting in transfusion on an annual basis, indicating potential for large public health and clinical benefit if TXA become standard practice in noncardiac surgery,” Dr. Devereaux said during the late-breaking trial session.

TXA is indicated for heavy menstrual bleeding and hemophilia and has been used in cardiac surgery, but it is increasingly being used in noncardiac surgeries. As previously reported, POISE showed that the beta-blocker metoprolol lowered the risk for myocardial infarction (MI) but increased the risk for severe stroke and overall death, whereas in POISE-2, perioperative low-dose aspirin lowered the risk for MI but was linked to more major bleeding.

The cumulative data have not shown an increased risk for thrombotic events in other settings, Dr. Devereaux told this news organization.

“I’m a cardiologist, and I think that we’ve been guilty at times of always only focusing on the thrombotic side of the equation and ignoring that bleeding is a very important aspect of the circulatory system,” he said. “And I think this shows for the first time clear unequivocal evidence that there’s a cheap, very encouraging, safe way to prevent this.”

“An important point is that if you can give tranexamic acid and prevent bleeding in your cardiac patients having noncardiac surgery, then you can prevent the delay of reinitiating their anticoagulants and their antiplatelets after surgery and getting them back on the medications that are important for them to prevent their cardiovascular event,” Dr. Devereaux added.

Discussant Michael J. Mack, MD, commented that TXA, widely used in cardiac surgery, is an old, inexpensive drug that “should be more widely used in noncardiac surgery.” Dr. Mack, from Baylor Scott & White Health, Dallas, added that he would limit it to major noncardiac surgery.

International trial

PeriOperative ISchemic Evaluation-3 (POISE-3) investigators at 114 hospitals in 22 countries (including countries in North and South America, Europe, and Africa; Russia; India; and Australia) randomly assigned 9,535 patients, aged 45 years or older, with or at risk for cardiovascular and bleeding complications to receive a TXA 1-g intravenous bolus or placebo at the start and end of inpatient noncardiac surgery.

Patients taking at least one long-term antihypertensive medication were also randomly assigned to a perioperative hypotension- or hypertension-avoidance strategy, which differ in the use of antihypertensives on the morning of surgery and the first 2 days after surgery, and in the target mean arterial pressure during surgery. Results from these cohorts will be presented in a separate session on April 4.

The study had planned to enroll 10,000 patients but was stopped early by the steering committee because of financial constraints resulting from slow enrollment during the pandemic. The decision was made without knowledge of the trial results but with knowledge that aggregate composite bleeding and vascular outcomes were higher than originally estimated, Dr. Devereaux noted.

Among all participants, the mean age was 70 years, 56% were male, almost a third had coronary artery disease, 15% had peripheral artery disease, and 8% had a prior stroke. About 80% were undergoing major surgery. Adherence to the study medications was 96.3% in both groups.

Secondary bleeding outcomes were lower in the TXA and placebo groups, including bleeding independently associated with mortality after surgery (8.7% vs. 11.3%), life-threatening bleeding (1.6% vs. 1.7%), major bleeding (7.6% vs. 10.4%), and critical organ bleeding (0.3% vs. 0.4%).

Importantly, the TXA group had significantly lower rates of International Society on Thrombosis and Haemostasis major bleeding (6.6% vs. 8.7%; P = .0001) and the need for transfusion of 1 or more units of packed red blood cells (9.4% vs. 12.0%; P <.0001), Dr. Devereaux noted.

In terms of secondary vascular outcomes, there were no significant differences between the TXA and placebo groups in rates of MINS (12.8% vs. 12.6%), MINS not fulfilling definition of MI (both 11.5%), MI (1.4% vs. 1.1%), and the net risk-benefit outcome (a composite of vascular death and nonfatal life-threatening, major, or critical organ bleeding, MINS, stroke, peripheral arterial thrombosis, and symptomatic proximal VTE; 20.7% vs. 21.9%).

The two groups had similar rates of all-cause (1.1% vs. 1.2%) and vascular (0.5% vs. 0.6%) mortality.

There also were no significant differences in other tertiary outcomes, such as acute kidney injury (14.1% vs. 13.7%), rehospitalization for vascular reasons (1.8% vs. 1.6%), or seizures (0.2% vs. <0.1%). The latter has been a concern, with the risk reported to increase with higher doses.

Subgroup analyses

Preplanned subgroup analyses showed a benefit for TXA over placebo for the primary efficacy outcome in orthopedic and nonorthopedic surgery and in patients with hemoglobin level below 120 g/L or 120 g/L or higher, with an estimated glomerular filtration rate less than 45 mL/min/1.73 m ²  or 45 mL/min/1.73 m ²  or higher, or with an N-terminal pro– B-type natriuretic peptide level below 200 ng/L or 200 ng/L or higher.

For the primary safety outcome, the benefit favored placebo but the interaction was not statistically significant for any of the four subgroups.

A post hoc subgroup analysis also showed similar results across the major categories of surgery, including general, vascular, urologic, and gynecologic, Dr. Devereaux told this news organization.

Although TXA is commonly used in orthopedic procedures, Dr. Devereaux noted, in other types of surgeries, “it’s not used at all.” But because TXA “is so cheap, and we can apply it to a broad population, even at an economic level it looks like it’s a winner to give to almost all patients having noncardiac surgery.”

The team also recently published a risk prediction tool that can help estimate a patient’s baseline risk for bleeding.

“So just using a model, which will bring together the patient’s type of surgery and their risk factors, you can look to see, okay, this is enough risk of bleeding, I’m just going to give tranexamic acid,” he said. “We will also be doing economic analyses because blood is also not cheap.”

The study was funded by the Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and the Research Grant Council (Hong Kong). Dr. Devereaux reports research/research grants from Abbott Diagnostics, Philips Healthcare, Roche Diagnostics, and Siemens. Dr. Mack reports receiving research grants from Abbott Vascular, Edwards Lifesciences, and Medtronic.

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