Value of New Anticoagulants in Acute Coronary Syndrome Still Unclear

Value-Based Care in Cardiometabolic Health May 2012, Vol 1, No 1 - Acute Coronary Syndrome
Wayne Kuznar

Chicago, IL—The new oral anticoagulants rivaroxaban (Xarelto), dabigatran (Pradaxa), and the yet-to-be-approved apixaban (Eliquis) have been shown to be superior to warfarin (Coumadin) in preventing stroke in patients with atrial fibrillation (AF). However, the jury is still out on their value in patients with acute coronary syndrome (ACS), and the safety profiles of these agents have not been fully elucidated, said William Dager, PharmD, Clinical Professor of Pharmacy, University of California School of Pharmacy, San Francisco, and Clinical Professor of Pharmacy, University of California-Davis School of Medicine, at the 2012 American College of Cardiology meeting.

Issues remain about reversing the anticoagulant effects of the new drugs in cases of life-threatening bleeding and appropriate monitoring of their activity.

Most of the data with rivaroxaban, dabigatran, and apixaban have been collected in the setting of AF. Both riv - aroxaban and the 150-mg dosage of dabigatran were shown to reduce the risk for stroke and systemic embolism with lower rates of intracerebral hemorrhage (ICH) compared with warfarin in large, randomized clinical trials of patients with AF.

In the ROCKET-AF trial of rivaroxaban, there was an increase in the incidence of stroke in the rivaroxaban arm during the posttrial transition to open-label warfarin. Apixaban has produced favorable outcomes (prevention of stroke or systemic embolism) compared with aspirin and warfarin in separate trials in patients with AF.

Consider Renal Function When Dosing

Both dabigatran and rivaroxaban require dosing that is sensitive to renal function, said Dr Dager. The standard approved dosage of rivaroxaban for stroke prevention in patients with nonvalvular AF is 20 mg daily, but in patients with renal impairment—creatinine clearance (CrCl) in the range of 30 mL/min to 49 mL/min—the dosage should be reduced to 15 mg once daily. Riv aroxaban’s use should be avoided in patients with CrCl <15 mL/min.

“The way renal failure is calculated is one thing you have to consider,” said Dr Dager. “In the trials, we used the Cockcroft-Gault, using ideal total body weight to do renal assess ments; that was for both dabigatran and rivaroxaban.”

The ACS Setting In the setting of ACS, dabigatran was associated with an excess of acute myocardial infarction (MI) of approximately 0.2% compared with warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. However, further analysis of the RE-LY data showed a nonsignificant increase in the risk for MI with dabigatran, irrespective of risk factors.

A review of 7 clinical trials conducted with dabigatran in various settings uncovered a consistently significant increased risk for MI or ACS with dabigatran against various controls.

There was no significant difference between dabigatran and warfarin in the rates of ACS in clinical trials conducted in patients with deep-vein thrombosis.

With bleeding issues unresolved, rivaroxaban cannot yet be considered an option in the long-term management of ACS, said Dr Dager. In low-risk patients with recent ACS, rivaroxaban added to aspirin, with or without clopidogrel, was associated with a significant reduction in the occurrence of major adverse cardiovascular events compared with placebo, but it increased the rates of major bleeding and ICH, without an increase in fatal bleeding.

APPRAISE-2A (Apixaban for Prevention of Acute Ischemic Events 2), a clinical trial of apixaban in patients with ACS, was stopped early because of a significant increase in major bleeding and ICH in the apixaban group.

Vorapaxar, a protease-activated receptor 1 antagonist, was not effective in reducing the risk of adverse thrombotic events in addition to standard antiplatelet therapy in patients with non–ST-segment elevation ACS, while increasing bleeding risk.

Can They Be Reversed?

A potential drawback to the use of the new anticoagulants is the so-far lack of an effective agent to reverse their anticoagulant effects in the presence of life-threatening bleeding. Prothrombin complex concentrates (PCCs) have been studied in rats and humans with varying success.

There are encouraging signs that activated PCC (aPCC) may work in this regard. The effect of dabigatran was successfully reversed with the use of 25 U/kg of aPCC (factor VIII inhibitor bypass activity) in 1 patient with a trans - septal perforation who lost 4 L of blood during cardiac ablation, said Dr Dager.

Is Monitoring Needed?

Although routine monitoring is not recommended for the new anticoagulants, their activity may need to be measured in certain situations. An elevated thrombin time may indicate the presence of dabigatran, and a chromogenic anti–factor Xa can indicate the presence of rivaroxaban, Dr Dager noted.

Quantitative tests are not readily available for assessing the intensity of anticoagulation effects with either agent. A chromogenic ecarin clotting time–driven dabigatran level has been developed but requires further study.

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