FDA panel rejects rivaroxaban again for acute coronary syndrome

SILVER SPRING, MD. – Collection of missing data and additional analyses from a large study on rivaroxaban failed to convince a Food and Drug Administration advisory panel to recommend approval of the anticoagulant drug for acute coronary syndrome.

At a meeting Jan. 16, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 10 to 0, with 1 abstention, that the factor Xa inhibitor rivaroxaban (Xarelto) should not be approved as a treatment for acute coronary syndromes (ACS). Rivaroxaban maker Janssen Pharmaceuticals had proposed an indication to reduce the risk of thrombotic cardiovascular events in patients with ACS, based on the results of the ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) trial.

That study compared two doses of rivaroxaban (2.5 mg twice a day, the proposed dose, and 5 mg twice a day) plus standard antiplatelet therapy (aspirin and a thienopyridine) to placebo plus standard therapy in more than 15,000 people with recent ACS. The primary endpoint – the risk of a composite of cardiovascular death, MI, or stroke – was significantly reduced (P = .039) by 15% among patients on the 2.5-mg twice-daily dose, compared with patients on placebo. The difference was primarily driven by a reduction in cardiovascular deaths among rivaroxaban patients.

But in May 2012, the FDA panel voted 4 to 6 against approval of rivaroxaban for the ACS indication, citing safety concerns and the large amount of missing data from the study. In June 2012, the FDA declined to approve the indication, and the agency refused again in March 2013, after Janssen provided more information. The company disputed the decision and continued to pursue approval. Janssen submitted new analyses and proposed that treatment be limited to 90 days.

At the Jan. 16 advisory committee meeting, panel members commended the study investigators and Janssen for that new work. But they still voted against approval, noting that the missing data remained a problem, the P value for the primary endpoint was not low enough to support approval based on a single trial, and concerns continued about bleeding risk.

The additional work “didn’t really add in a substantial way to the primary endpoint analysis,” explained advisory panel member Dr. Philip Sager. Overall, the study “wasn’t robust enough in terms of statistical significance to be considered as a positive study,” added Dr. Sager, chair of the scientific programs committee at the Cardiac Safety Research Consortium, San Francisco.

The FDA has approved rivaroxaban for several indications, including reduction of the risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, and prevention of deep vein thrombosis after hip or knee replacement surgery.

Janssen will work with the FDA to address the questions raised at the meeting, according to a statement issued by the Johnson & Johnson subsidiary.

In May 2013, European Union drug regulators approved an ACS indication for rivaroxaban, to prevent atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an ACS in adults with elevated cardiac biomarkers, at a dose of 2.5 mg twice a day, co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.

The FDA usually follows the recommendations of its advisory panels. Advisory panel members have been cleared of potential conflicts related to the meeting topic. Occasionally, a panelist is given a waiver, but no waivers were given at this meeting.

 

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Mild coronary artery disease is gender blind

CHICAGO – Men and women may not really be all that different when it comes to mild coronary artery disease.

A prospective, multinational registry analysis found that 1.2% of women and 1.1% of men with mild, nonobstructive coronary artery disease on coronary CT angiography experience a major adverse cardiovascular event, either heart attack or death, each year.

For those free of coronary artery disease (CAD), the event rate was 0.3% for both sexes, Dr. Jonathon A. Leipsic reported at the annual meeting of the Radiological Society of North America.

Women’s heart disease is typically viewed as different from men’s heart disease, in part because of women’s unique presenting symptomatology. Studies such as the Women’sHealth Initiative have also reported that women with nonspecific or atypical chest pain have a twofold greater risk for nonfatal MI.

Importantly, all prior data has been reliant on invasive coronary angiography for anatomical coronary assessment, observed Dr. Leipsic, codirector of advanced cardiac imaging, Providence Health Care Heart Center at St. Paul’s Hospital, Vancouver, B.C.

The current analysis, however, used data from the prospective CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry, which tracks roughly 28,000 individuals in North America, Europe, and Asia who have undergone coronary CT angiography.

The results represent a major shift in thinking, Dr. Leipsic said in an interview.

“What we realize is that CT identifies mild disease in the wall in a way that the invasive angiogram does not,” he said. “So suddenly, when you say you have a normal invasive angiogram, there may still be mild disease in the arteries, whereas when you have a normal CT in a woman, our data would suggest that those women do very well, even if they have symptoms.”

Dr. Leipsic and his associates identified 18,158 patients in the CONFIRM registry with no disease or mild CAD with less than 50% stenosis. Propensity matching for risk factors, chest pain, and extent of disease left 11,462 patients.

Their average age was 55 years, 34% were asymptomatic, 45% had hypertension, 12% were diabetic, and 18% were current smokers.

Of these, 37 had an MI; 120 died; and 7 had an MI and died (1.4%).

The annual major adverse cardiovascular event (MACE) rate was 0.6% overall, and was significantly different between patients with a normal CT and those with nonobstructive disease (0.3% vs. 1.1%), Dr. Leipsic said.

“This mild disease we see on CT is not just incidental,” he said during a press briefing at the meeting. “It actually identifies patients who are at increased risk of having a heart attack and dying, with an increased risk of 1.84 for the overall cohort (P = .001).”

Notably, 3-year MACE-free survival was similar among men and women without coronary plaque on CT as well as those with non-obstructive disease.

Dr. Leipsic commented that detractors of the data have argued that the analysis failed to focus on women at the greatest risk – those with atypical symptoms. A further sub-analysis, however, based on the presence or absence of symptoms and the type of symptoms (nonanginal chest pain, atypical angina, and typical angina), once again “found that men and women behave similarly,” he said.

Event rates were lower in men and women with normal CT scans and elevated in both sexes in the setting of nonobstructive disease, “regardless of the nature of chest pain and even in the absence of chest pain,” he noted.

Press briefing moderator Dr. Candice Johnstone of the Medical College of Wisconsin, Milwaukee, said in an interview, “Observational studies have limits, but at the same time, I think it may be a paradigm shift, in that it may be a new tool in our toolbox for people at lower risk of heart disease to avoid an invasive procedure.”

Dr. Leipsic reported financial relationships with several entities including GE Healthcare, HeartFlow, Edwards LifeSciences, and TC3.

 

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Picture courtesy of www.cdc.gov