BARCELONA – Researchers here show an overall enthusiasm for factor XIa inhibitors, which have been shown to prevent bleeding when added to standard dual antiplatelet therapy, although Only some signs of efficacy in preventing ischemic events emerged in preliminary trials presented at the European Society of Cardiology Congress.
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Phase II study at Circulation , three doses of novel factor XIa inhibitor asundexian — 10 mg, 20 Durham Duke University MD, Department of Medicine John Alexander reported a dose-dependent reduction in factor XIa activity of up to more than 90% in patients with recent acute myocardial infarction at 50 mg and 50 mg per day without a significant increase in bleeding. , North Carolina.
In 1,600 patients receiving concurrent aspirin plus P2Y12 inhibitor dual antiplatelet therapy, the prespecified primary safety outcome — Bleeding Academic Re at median follow-up, 2, 3 or type 5 combined bleeding – occurred in 7.6% of patients receiving asundexian 10 mg, 8.1% receiving 20 mg, 10.5% receiving 50 mg, and 9.0% receiving placebo for 368 days (combined asundexian vs placebo: HR 0.98, 90 %CI 0.71-1.35).
The primary efficacy outcome—cardiovascular death, myocardial infarction, stroke, or stent thrombosis—occurred in 6.8%, 6.0%, 5.5%, and 5.5% of patients, respectively (combined asundexian 20 and 50 mg vs placebo: HR 1.05, 90% CI 0.69-1.61).
In an ESC press release, Alexander said that at all doses, including 50 mg, bleeding events with asundexian versus those in patients receiving dual antiplatelet therapy plus placebo No statistical difference. However, he also noted that there was no reduction in ischemic events with asundexian compared with placebo.
He suggested that the lack of efficacy may be due to the low number of events across the trial. “These results, together with the available genetic and preclinical evidence, suggest that in a sufficiently large phase III study Further investigation of the factor XIa inhibitor asundexian as a potentially safer anticoagulant in patients following acute myocardial infarction.”
Gregory Lip, MD, University of Liverpool, England, and colleagues in an accompanying editorial Writes: “Despite revascularization and optimal secondary prevention, including dual antiplatelet agents, patients with acute coronary syndrome remain at risk for recurrent ischemic events, and risk of recurrent myocardial infarction within 3 years. Up to 7%.”
“To address this residual risk, previous studies have investigated the benefit of increasing the strength of antithrombotic drugs, by adding oral anticoagulants to antiplatelet therapy… …” he continued. “While studies generally show a significant reduction in ischemic events with this approach, it comes at the cost of massive bleeding.”
“Phase II studies are important,” added Lip , “Despite the disappointing lack of a signal to reduce ischemic events, the apparent safety profile of asendixin in addition to dual antiplatelet therapy in acute coronary syndromes has been disappointing. However, 50 mg asendexine The apparent safety and quantitatively fewer ischemic events are encouraging and suggest that the potential ischemic benefit of this dose needs to be properly assessed.”
In this study, each A total of 400 patients in the subcisternal brachial plexus participated, and another 400 participated in the placebo group. The median age was 68 years, 23% were female, and 51% had ST-segment elevation myocardial infarction.
in an exploratory analysis of this Phase II study There were no statistically significant differences between asundexian and placebo in the primary endpoint of recurrent ischemic stroke and MRI-detected occult cerebral infarction at 6 months.
Of 362 outcomes in more than 1,800 patients, 19.1% occurred in placebo patients, 18.9% in patients receiving asundexian 10 mg, and 22% in patients receiving 20 mg of patients, and 20.1% of those who received 50 mg reported that Ashkan Shoamanesh, MD, of the Hamilton Institute of Population Health, Canada. (P=0.80) at 6 months, he noted.
No significant increase in primary safety outcome asundexian at 12 months occurred in 2.4% of patients assigned to pl acebo and 3.9% of patients assigned to asundexian (HR 1.57 , 90% CI 0.91-2.71).
Reduced risk of recurrent ischemic stroke or transient ischemic attack compared with placebo in patients receiving asundexian 50 mg in secondary exploratory analysis (HR 0.64 , 90% CI 0.41-0.98), with the greatest reduction in extracranial or intracranial atherosclerotic plaques (HR 0.39, 90% CI 0.18-0.85).
This study included 1,808 patients at 196 sites in 23 countries. The average age was 67 years, and 34% were women.
In another phase II randomized trial, Compared with placebo, treatment with the factor XIa inhibitor milvexian reduced the risk of ischemic stroke in patients with prior ischemic stroke or high-risk transient ischemic attack (TIA).
In the intention-to-treat population of more than 2,300 patients, milvexian 25 mg once daily and 25 mg, 50 mg, and 100 mg twice daily, compared with placebo, 25 to 100 Relative risk reduction of approximately 30% for mg doses (5.5% for placebo, 4.6% for 25 mg once daily, 3.8% for 25 mg twice daily, 4.0% for 50 mg twice daily, and 3.5% for 100 mg twice daily), Canada Presentation by Mukul Sharma, MD, MS, University of Ottawa, Ontario.
The 200 mg twice daily dose did not show a reduced risk compared to placebo (7.7%).
While the primary endpoint was numerically lower at the 50 mg and 100 mg twice-daily doses, there was no apparent dose response, the investigators noted.
Overall, the primary endpoint had a lower rate of bleeding, while the rate of major bleeding was similar to placebo in the 25 mg once and twice daily dose groups and 50 mg twice daily and above There were moderate increases in the dose groups, but no apparent dose response. There was no increase in major bleeding compared with placebo, and there were no fatal bleeding in any of the study groups.
In this study, Sharma and team included 2,366 patients from 367 sites in 27 countries. The median age was 71 years, and 64% were male.
Commenting on the studies, B. Hadley Wilson, MD, of the University of North Carolina School of Medicine in Charlotte said MedPage Today said “So far, we have used vitamin K anticoagulants such as warfarin and newer oral anticoagulants in the past 5 years, such as rivaroxaban [Xarelto], and these have been Proven to be helpful in avoiding ischemic risk in patients with ischemic heart disease and after acute myocardial infarction, but they have the significant disadvantage of increasing bleeding risk.”
“These new Factor XIa inhibitors … stop bleeding, but don’t form blood clots. In trials, there doesn’t seem to be an increased risk of bleeding compared to placebo, so these drugs appear to be safe,” he said.
“I think the fact that there is a substantial safety profile suggests that, on a larger scale, this could be a promising therapy to add to our heart muscle In addition, we can show that not only does it not lead to increased bleeding, but it does help prevent future ischemic events,” he added.
Bayer announced that it will recruit patients for its Phase III OCEANIC-AF study, which will study asundexian versus apixaban (Eliquis) in patients with atrial fibrillation at risk for stroke. The studies are expected to enroll up to 30,000 patients in more than 40 countries.
Ed Susman is a freelance medical writer based in Fort Pierce, Florida, USA.
The PACIFIC trial was sponsored by Bayer and the AXIOMATIC-SSP was funded by the BMS-Janssen consortium.
Alexander discloses relationship with Artivion/CryoLife, Bayer, Bristol-Myers Squibb, CSL Behring, Ferring, Humacyte, XaTek, AbbVie, Akros, AtriCure, GlaxoSmithKline, Janssen, Pfizer, Portola , and Quantum Genomics.
The Lip report is not industry related.
Shoamanesh discloses relationship with Bayer AG.
Sharma discloses relationships with Bristol Myers Squibb, Bayer, AstraZeneca, Janssen, HLS Therapeutics and Alexion.
The Wilson report has no industry affiliation.