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AMPLIFY: Apixaban beat warfarin on safety in acute VTE

Major finding: Major bleeds occurred in 0.6% of patients on apixaban and 1.8% of patients on warfarin, with similar efficacy.

Data source: The AMPLIFY study, which randomized 5,400 patients with acute venous thromboembolism to treatment with apixaban or enoxaparin followed by warfarin for 6 months.

Disclosures: The trial was sponsored by Pfizer and Bristol-Myers Squibb, which market apixaban (Eliquis). Dr. Agnelli disclosed ties to Pfizer, Boehringer Ingelheim, Sanofi, Daiichi Sankyo, and Bayer. Dr. Rosendaal said that he had no disclosures.

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Shifting from warfarin requires thought and planning

The new anticoagulant era for patients with acute venous thromboembolism began late last year, when the Food and Drug Administration gave rivaroxaban this new labeled indication. Each physician who enters this new era, by opting to prescribe rivaroxaban instead of warfarin, needs to carefully think through which types of patients the evidence supports treating.

Clinicians who manage patients with acute venous thromboembolism (VTE) need to decide how to bring rivaroxaban into their practices, and eventually they will need to make similar decisions about dabigatran and apixaban once those drugs receive an acute VTE indication.


Dr. Mary Cushman

A few weeks after rivaroxaban’s approval for acute VTE, I got together with my colleagues at the University of Vermont in Burlington who manage these patients to draw up a framework for how we’ll decide which patients should be treated with rivaroxaban and which ones we should still treat with warfarin. I included the six main elements of that framework in an editorial I wrote about the AMPLIFY results reported by Dr. Agnelli (N. Engl. J. Med. 2013;doi:10.1056/nejme1307413).

One factor we urged clinicians to keep in mind was that the new-anticoagulant trials use selected patients. For example, the AMPLIFY trial excluded patients with provoked VTE because they are usually not treated for 6 months, the treatment duration studied in the trial. The new drugs are not suitable for every patient; patients on dialysis shouldn’t get them because these agents all involve renal clearance. Very old patients, those aged beyond 80 years, are an uncertain group because the trials have so far included few such patients, but on the other hand, eliminating the need for regular anticoagulation monitoring may make the new drugs more suitable for some elderly patients. Patients with cancer are another uncertain subgroup because of their low representation in the trials. My colleagues and I have for the time being decided not to use rivaroxaban on cancer patients with acute VTE because we judged the current evidence base too limited.

Rivaroxaban, apixaban, and dabigatran each have their own unique list of drug interactions and contraindications. None of them has as many caveats as warfarin, but it’s still essential to be familiar with each drug’s label and which clinical situations to avoid.

Another issue is how likely a patient will be to adhere to the prescribed regimen. A limitation of the new drugs is their short half-life. A patient just needs to miss a couple of doses and the anticoagulation effect starts to fade. In contrast, warfarin’s effect lingers much longer; a patient on a stable warfarin regimen can go several days without treatment before the international normalized ratio begins to fall out of the target range. Plus, patients on the new drugs provide physicians with no compliance feedback from monitoring results. That means patients should only be started on a new oral anticoagulant if they understand this limitation and the need for commitment to full compliance. There are also issues of cost and insurance coverage with the new drugs. Some patients have insurers that require preapproval for treatment of VTE with rivaroxaban, but then the payers deny the preapproval when we request it.

Warfarin has been the top anticoagulant for the past 60 years, much longer than my entire career in medicine. Physicians now face the challenge of applying the results from carefully controlled studies of the new anticoagulants – where selected cohorts of patients received their care from a small number of anticoagulation management experts – to a much broader and more diverse spectrum of patients in a variety of clinical settings. How exactly that gets done needs careful consideration.

Dr. Mary Cushman is a hematologist and professor of medicine at the University of Vermont in Burlington. She made these comments in an interview. She said that she had no disclosures.


 

AT THE 2013 ISTH CONGRESS

AMSTERDAM – In patients with acute venous thromboembolism, 6 months of treatment with the oral-anticoagulant apixaban was as effective as was standard therapy with subcutaneous enoxaparin for a week followed by oral warfarin, and apixaban caused significantly fewer major bleeding complications in a randomized, multicenter trial with more than 5,000 patients.

But in addition to apixaban’s sterling individual performance in this pivotal trial, which seems to clear the way for the drug to eventually receive a labeled indication for acute venous thromboembolism, the results also appeared to further anoint the new, oral anticoagulant roster of dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) as the thrombotic-disease troika to be reckoned with, the newcomers whose time has come.

Dr. Giancarlo Agnelli

Ever since rivaroxaban became the first of the trio to gain acute VTE labeling, last November, physicians who manage patients with acute VTE had to wrestle with the question of how to integrate this option into their practices. The new findings on apixaban suggest that physicians will soon have to think about deciding between rivaroxaban and apixaban for this indication. And since recent results from other major trials also established dabigatran as the equal of warfarin for efficacy when treating acute VTE patients and with superior safety, dabigatran’s entry into acute VTE management seems imminent (N. Engl. J. Med. 2013;368:709-18).

Propelling this new anticoagulant era are the indications of efficacy that’s equivalent with heparin, but safer, and with far easier drug delivery as the need for anticoagulation clinics and regular measurement of international normalized ratio (INR) is eliminated by all three new drugs.

"An oral regimen without laboratory monitoring will simplify therapy," Dr. Giancarlo Agnelli noted when he presented the new apixaban findings at the congress of the International Society on Thrombosis and Haemostasis. Concurrently with his report at the meeting, the results were published online (N. Engl. J. Med. 2013;doi:10.1056/nejmoa1302507).

"I think the argument is overwhelming" to use one of the new drugs instead of warfarin. "They are oral drugs where you do not need a blood draw every 2 or 3 weeks, they are a lot easier to use, and they are at least as good as warfarin and at least as safe," said Dr. Frits R. Rosendaal, professor of clinical epidemiology in hemostasis and thrombosis at Leiden (The Netherlands) University.

The Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial randomized 5,400 acute VTE patients at 358 centers in 28 countries. Patients received either apixaban starting with a 10-mg b.i.d. dosage for 7 days, followed by a dosage of 5 mg b.i.d. for 6 months, or enoxaparin at a dosage of 1 mg/kg every 12 hours for a median of 7 days followed by warfarin for 6 months with a target INR of 2.0-3.0.

The study’s primary efficacy endpoint was the combined rate of recurrent, symptomatic VTE or death related to VTE. This occurred in 59 of 2,609 patients (2.3%) who received apixaban, and in 71 of 2,635 (2.7%) patients who received enoxaparin followed by warfarin. These results met the study’s prespecified criterion for apixaban’s noninferiority to standard treatment reported Dr. Agnelli, professor of medicine at the University of Perugia, Italy.

Major bleeding events occurred in 15 of 2,676 (0.6%) patients on apixaban and in 49 of 2,689 (1.8%) patients on enoxaparin and warfarin, a statistically significant difference. A composite safety outcome of major bleeds plus clinically relevant nonmajor bleeds occurred in 4.3% of the apixaban patients and in 9.7% of the patients on standard therapy, a statistically significant difference. Aside from bleeding events, the rates of all other adverse events were similar in the two treatment arms.

The trial was sponsored by Pfizer and Bristol-Myers Squibb, which market apixaban (Eliquis). Dr. Agnelli disclosed ties to Pfizer, Boehringer Ingelheim, Sanofi, Daiichi Sankyo, and Bayer. Dr. Rosendaal said that he had no disclosures.

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