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BARCELONA -- Researchers here showed overall enthusiasm for factor XIa inhibitors, which have been shown to keep bleeding at bay when added to standard dual antiplatelet therapy, though there were only hints of efficacy in preventing ischemic events that emerged in preliminary trials presented at the European Society of Cardiology Congress.

PACIFIC AMI

In this phase II study, which was published simultaneously in , three doses of the novel factor XIa inhibitor asundexian -- 10 mg, 20 mg, and 50 mg daily -- reduced factor XIa activity in a dose-dependent manner by up to more than 90% in patients with recent acute MI, without significantly increasing bleeding, reported John Alexander, MD, MHS, of Duke University in Durham, North Carolina.

Among 1,600 patients who also received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor, the prespecified main safety outcome -- Bleeding Academic Research Consortium type 2, 3, or 5 bleeding -- occurred in 7.6% of patients receiving asundexian 10 mg, 8.1% of those receiving 20 mg, 10.5% of those receiving 50 mg, and 9.0% of those receiving placebo over a median follow-up of 368 days (pooled asundexian vs placebo: HR 0.98, 90% CI 0.71-1.35).

The primary efficacy outcome -- a composite of cardiovascular death, MI, stroke, or stent thrombosis -- occurred in 6.8%, 6.0%, 5.5%, and 5.5% of patients, respectively (pooled asundexian 20 and 50 mg vs placebo: HR 1.05, 90% CI 0.69-1.61).

At an ESC press conference, Alexander said bleeding episodes with asundexian at all doses -- including 50 mg -- were not statistically different than those seen in patients on dual antiplatelet therapy plus placebo. However, he also noted that there was no reduction in ischemic events with asundexian compared with placebo.

He suggested that the lack of efficacy might be due to the small numbers of events in the trial overall. "These results, together with existing genetic and preclinical evidence, suggest the further study of the factor XIa inhibitor asundexian in adequately-sized phase III studies as a potentially safer anticoagulant for patients following an acute myocardial infarction."

In an , Gregory Lip, MD, of the University of Liverpool in England, and colleagues wrote, "Despite revascularization and optimal secondary prevention, including dual antiplatelet medication, patients with acute coronary syndrome remain at risk of recurrent ischemic events, with up to 7% risk of recurrent myocardial infarction at 3 years."

"To address this residual risk, prior studies have investigated the benefit of increasing the intensity of antithrombotic medication, through the addition of an oral anticoagulant ... to antiplatelet therapy," he continued. "While studies have generally shown a significant reduction in ischemic events with this approach, it came at a significant cost of excess major hemorrhage."

"The phase II study is important," Lip added, "showing the apparent safety of asundexian in addition to dual antiplatelet therapy in acute coronary syndrome, although the lack of signal for reducing ischemic events is disappointing. However, the apparent safety yet the numerically fewer ischemic events seen with the 50 mg asundexian dose is encouraging and suggests the need to properly evaluate the potential ischemic benefit of this dose."

For this study, 400 patients were enrolled in each of the asundexian arms, and another 400 were enrolled in the placebo arm. Median age was 68 years, 23% were women, and 51% had ST-elevation MI.

PACIFIC-Stroke

In an exploratory analysis of this phase II study, there was no statistically significant difference in the primary endpoint of recurrent ischemic stroke and incident MRI-detected covert brain infarcts at 6 months between asundexian and placebo.

Among 362 outcomes in over 1,800 patients, 19.1% occurred in placebo patients, 18.9% occurred in patients who received asundexian 10 mg, 22% occurred in those who received 20 mg, and 20.1% occurred in those who received 50 mg, reported Ashkan Shoamanesh, MD, of the Population Health Research Institute in Hamilton, Canada.

There was no dose-dependent reduction of the primary efficacy outcome with asundexian (P=0.80) at 6 months, he noted.

The primary safety outcome was not significantly increased at 12 months with asundexian, occurring in 2.4% of patients assigned to placebo and 3.9% of those assigned to asundexian (HR 1.57, 90% CI 0.91-2.71).

In a secondary exploratory analysis, risk of recurrent ischemic stroke or transient ischemic attack was reduced in patients who received asundexian 50 mg compared with placebo (HR 0.64, 90% CI 0.41-0.98), with the largest reduction in those with extracranial or intracranial atherosclerotic plaque (HR 0.39, 90% CI 0.18-0.85).

This study included 1,808 patients across 196 sites in 23 countries. Average age was 67 years, and 34% were women.

AXIOMATIC-SSP

In another phase II randomized trial, treatment with the factor XIa inhibitor milvexian was shown to lower the risk of ischemic stroke compared with placebo in patients with a prior ischemic stroke or high-risk transient ischemic attack (TIA).

Among over 2,300 patients in the intention-to-treat population, milvexian numerically reduced the risk of clinical ischemic stroke (excluding covert brain infarction) at doses of 25 mg once daily, and 25 mg, 50 mg, and 100 mg twice daily, with an approximately 30% relative risk reduction with doses from 25 to 100 mg compared with placebo (placebo 5.5%, 25 mg once daily 4.6%, 25 mg twice daily 3.8%, 50 mg twice daily 4.0%, and 100 mg twice daily 3.5%), reported Mukul Sharma, MD, MSc, of the University of Ottawa in Ontario, Canada.

The 200 mg twice daily dose did not show a reduced risk compared with placebo (7.7%).

While the rate of the primary endpoint was numerically lower at the 50 mg and 100 mg twice daily doses, there was no apparent dose response, the researchers noted.

Overall, the incidence of major bleeding was low, while the rate of major bleeding for the 25 mg once daily and twice daily doses was similar to placebo, and a moderate increase was seen with the 50 mg twice daily and above doses, with no apparent dose response. There was no increase in severe bleeding versus placebo, and there was no fatal bleeding in any of the study arms.

For this study, Sharma and team included 2,366 patients from 367 sites in 27 countries. Median age was 71 years, and 64% were men.

In commenting on these studies, B. Hadley Wilson, MD, of the University of North Carolina School of Medicine in Charlotte, told MedPage Today that "up to now we have had vitamin K anticoagulants like warfarin and the newer oral anticoagulants in the past 5 years such as rivaroxaban [Xarelto], and those have all been shown to be helpful in patients after ischemic heart disease and acute myocardial infarction in terms of avoiding ischemic risk, but they had a significant downside of increasing bleeding risk."

"These new factor XIa inhibitors ... allow for hemostasis but not thrombosis. In the trials, when compared with placebo, there didn't appear to be any increase in bleeding risk, so these drugs look safe," he said.

"I think the fact that there was great safety indicates that this might be a promising therapy to add on to our treatment regimen post-myocardial infarction, if, in larger trials, we can show that not only does it not cause increased bleeding but actually does help with preventing ischemic events down the road," he added.

Bayer has announced that it will recruit patients for its phase III OCEANIC-AF study, which will investigate asundexian compared with apixaban (Eliquis) in patients with atrial fibrillation at risk for stroke. The studies are expected to enroll up to 30,000 patients in over 40 countries.