Tag Archives: rivaroxaban

Prevent Atherothrombotic Events? It’s Complicated

When researchers reported earlier this week at the American College of Cardiology’s annual meeting results from the TRA 2P-TIMI 50 trial, which tested a novel anticoagulant drug, vorapaxar, for preventing cardiovascular death, myocardial infarction (MI), and stroke in stable patients with cardiovascular disease, the results showed a questionable balance between benefit and bleeding risk that only looked good if you squinted and confined the analysis to patients with just a history of MI, no history of stroke, a body weight of at least 60 kg, and, ideally, those who were younger than 75 years old. Even within this pared-down universe, experts differed on whether vorapaxar had an unequivocal net benefit after taking into account the bleeding risk it caused.

But if vorapaxar someday gets FDA approval and appears on the U.S. market, physicians will face the tricky calculus of how to use it compared with the other new, potent antithrombotic drugs.

blood clot/courtesy Janice Carr; Public Health Image Library

Looking at vorapaxar’s performance in patients with stable cardiovascular disease, it was hard not to recall last November’s report on the ATLAS ACS 2-TIMI 51 trial, which tested adding a 2.5 mg b.i.d. dosage of another new anticoagulant drug, rivaroxaban, in acute coronary syndrome (ACS) patients also treated with aspirin and clopidogrel. In ATLAS, adding this small dose of rivaroxaban led to benefit and a bleeding risk that was strikingly similar to the pattern seen with vorapaxar in TRA 2P.  Rivaroxaban on top of aspirin and clopidogrel produced an absolute, 1.6% cut in the combined rate of cardiovascular death, MI, or stroke while boosting the rate of major bleeds by an absolute 1.2%, and the rate of intracranial bleeds by 0.2%. The new vorapaxar results showed that in the best-case subgroup, adding the drug to aspirin and clopidogrel cut cardiovascular death, MI, or stroke by an absolute 1.9%, while boosting major bleeds by 1.0% and intracranial hemorrhage by 0.2%.

A big difference in the two analyses was that the benefits and risk seen with 2.5 mg rivaroxaban was in the entire study population of 5,100 patients, with no need to resort to subgroup analyses. The vorapaxar result was in about 9,500 patients, roughly 70% of all patients enrolled in the trial. Another big difference was the major impact of rivaroxaban was on cutting cardiovascular deaths. Vorapaxar’s main effect was to lower nonfatal MIs. It cut cardiovascular deaths too, but not as well as low-dose rivaroxaban.

Many experts whom I spoke with at the meeting seemed confident that low-dose rivaroxaban is on track for FDA approval later this year for treating ACS patients. Whether Merck, the company developing vorapaxar, will seek FDA approval for its drug in stable patients based on the TRA 2P data remains to be seen.

But while rivaroxaban won’t receive labeling for treating non-ACS patients, all that separates an ACS patient and a patient who is stable but with a history of prior MI is time; in fact, just a few weeks or months. The point at which an acute ACS patient becomes a stable, post-MI patient is pretty murky. Would anyone consider treating a stable, post-ACS patient with low-dose rivaroxaban? The labeling probably won’t cover it, but will the temptation be there? And the what-ifs don’t stop there.

Both the low-dose rivaroxaban study and the vorapaxar study used aspirin and clopidogrel as standard, background treatment. But U.S. physicians are increasingly switching from clopidogrel to the newer, more potent antiplatelet drugs already on the market, prasugrel and ticagrelor, several experts told me at ACC. Putting a patient on prasugrel or ticagrelor plus aspirin will likely preclude any thought of also adding rivaroxaban, not to mention vorapaxar. These combinations have not been tested, and given the bleeding risks that these drugs pose individually, the idea of using them in combination is downright scary.

After several years when clopidogrel plus aspirin reigned alone as the top treatment for preventing atherothrombotic events, the last few years brought a flurry of new agents. How these drugs compare and relate to each other, and how they are optimally used alone or in combination, will take several more years to sort out.

—Mitchel Zoler (on Twitter @mitchelzoler)


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Filed under Blognosis, Cardiovascular Medicine, IMNG, Internal Medicine, Internal Medicine News

Safety and Efficacy First

From the meeting of the FDA Cardiovascular and Renal Drugs Advisory Committee, Adelphi, Md. 

Like cost-effectiveness, convenience is on the list of topics that cannot be taken into account when a Food and Drug Administration advisory panel decides whether or not to recommend approval of a drug. But for the oral anticoagulant rivaroxaban, under review for the prevention of deep vein thromboses and pulmonary emboli in patients who have had hip or knee replacement surgery, the topic was hard to avoid during extensive discussion of the drug’s risks and benefits. That’s because, if approved, rivaroxaban would be the first oral anticoagulant to become available since warfarin was approved over 40 years ago. And unlike warfarin, rivaroxaban is not titrated and patients on the drug do not need regular blood draws to check INR.

Panel members commented that if approved rivaroxaban could help improve compliance with the American College of Chest Physicians and American Academy of Orthopedic Surgeon guidelines for prophylaxis of DVT and PE after hip and knee surgery, and that having an oral option would be a significant advantage.

But Dr. Richard Pazdur, director of the FDA office of oncology drug products, reminded panelists that safety and efficacy of a drug should come first, then convenience can be discussed. “It’s not about convenience, it’s about safety and efficacy that has to be demonstrated first, then a discussion of convenience can be entertained,” he said. If convenience was considered over uncertainty over safety, the FDA would “simply approve more convenient toxic placebos.”

Most of the panel supported approval, despite reservations about more cases of excess bleeding and elevated liver enzymes in patients treated with the drug in trials than in patients on enoxaparin. But they agreed that the benefits exceeded those potential risks, and recommended that the potential for severe hepatotoxicity be followed closely.

Panel members also expressed concern that once the drug becomes available, clinicians would prescribe it off-label for periods longer than the short-term use studied in the trials (35 days after hip surgery and 14 days after a hip replacement).

The FDA’s deadline for an approval decision is May 28 and approval is likely, since the FDA usually follows the advice of its advisory panels.

Pharma giant Johnson & Johnson also is studying rivaroxaban for indications that will be treated for extended periods of time (including acute coronary syndromes and secondary prevention of DVT/PE) and those studies are expected to provide more useful data about the potential hepatoxicity issue.

—Elizabeth Mechcatie
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Filed under Cardiovascular Medicine, Hospital and Critical Care Medicine, Orthopedic Surgery, Surgery