Dose-Ranging Study of Novel Anticoagulant Promising

September 05, 2008

September 5, 2008 (Munich, Germany) — The addition of a novel factor Xa inhibitor to antiplatelet therapy resulted in a dose-dependent increase in bleeding, but there was also a trend toward a reduction in clinically relevant ischemic events, a new study has shown. Investigators say the drug, known as apixaban, is promising as an adjunct to aspirin or dual antiplatelet therapy in patients with a recent acute coronary syndrome.

"Patients after acute coronary syndrome continue to have recurrent events," lead investigator Dr John Alexander (Duke Clinical Research Institute, Durham, NC) told heartwire . "Everybody is happy with how effective aspirin and clopidogrel are, but if you look at event curves, they're all going up.

"We know that with warfarin and, to some extent, direct thrombin inhibitors like ximelagatran, more potent anticoagulation can reduce those events, but, as with all effective anticoagulants, they increase bleeding."

The phase 2 apixaban study, known as APPRAISE-1, was presented this week at the European Society of Cardiology Congress 2008.

Bleeding and Efficacy Trading Off

Apixaban is direct, selective inhibitor of factor Xa, one of the proteins involved in the clotting process. The study included 1715 patients with a recent acute coronary syndrome (<7 days) and was designed to test different doses of apixaban on top of standard antiplatelet therapies. An interim analysis of data showed an excess of major and minor bleeding at the highest doses--10 mg twice daily and 20 mg once daily--of apixaban, and these doses were discontinued.

Overall, 317 patients were randomized to apixaban 2.5 mg twice daily, 318 patients to apixaban 10 mg daily, and 611 patients to placebo. The rate of major bleeding, defined by the International Society of Thrombosis and Hemostasis (ISTH), plus clinically relevant nonmajor bleeding, was highest in those treated with the 10-mg dose of apixaban. In addition to the bleeding risks, investigators observed a trend in the reduction of ischemic events, with the 10-mg dose of apixaban having the lowest incidence of cardiovascular death, MI, or stroke.

"Phase 2 studies often don't have these nice dose-response signals," said Alexander. "We got lucky here in seeing a signal on safety and efficacy, and that is very useful for studying doses in phase 3 studies."

ISTH Major or Clinically Relevant Nonmajor Bleeding

Dose Hazard Ratio (95% CI)*
Apixaban 10 mg once daily 2.45 (1.31–4.61)
Apixaban 2.5 mg twice daily 1.78 (0.91–3.38)

*Compared with placebo

Ischemic events: Cardiovascular death, MI, or stroke

Dose Hazard Ratio (95% CI)
Apixaban 10 mg once daily 0.61 (0.35–1.04)
Apixaban 2.5 mg twice daily 0.73 (0.44–1.19)

*Compared with placebo

Alexander said the study used the ISTH definition of major bleeding plus clinically relevant nonmajor bleeding because it is encompasses nearly any bleeding that requires medical intervention, a sensitive marker that allowed investigators to distinguish the differing risks among the different doses. There were lower bleeding rates with different definitions, but there still appearedto be a net clinical benefit depending on the definition used.

Investigators left the use of clopidogrel prior to randomization up to the discretion of the attending clinicians, with about 75% of patients being treated with aspirin and clopidogrel. ISTH major and clinical relevant nonmajor bleeding was increased more among patients taking clopidogrel compared with patients not taking clopidogrel. Alexander noted that most of these clopidogrel patients underwent PCI and were younger and more likely to be male and enrolled in a North American or Western European center.

There are ongoing phase 3 studies investigating the role of factor Xa inhibitors in patients with atrial fibrillation, although one study has already missed its primary end point. Bristol-Myers Squibb and Pfizer, the companies that license and market apixaban together, released the results of the ADVANCE-1 trial last week, a study that tested whether apixaban was statistically noninferior to enoxaparin for the prevention of asymptomatic deep vein thrombosis, pulmonary embolism, and death by any cause in patients undergoing knee-replacement surgery. The drug failed to meet statistical criteria for noninferiority when compared with enoxaparin.

Alexander announced research support from Bristol-Myers Squibb, Medicure, Medtronic Japan, Millennium, the National Institutes of Health , Regado Biosciences, and Schering-Plough Pharmaceuticals and consulting fees from Adolor, Daiichi Sankyo, Medicure, the National Institutes of Health, and Novartis.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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