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Combining a new-generation oral anticoagulant with standard dual antiplatelet therapy to protect patients against ischemic events in the wake of an acute coronary syndrome (ACS) dramatically increases bleeding while providing no mortality benefit, according to a meta-analysis published on line September 24, 2012, ahead of print in Archives of Internal Medicine. In the absence of a net clinical benefit, the authors caution that triple therapy should not be prescribed for most ACS patients. 

Investigators led by András Komócsi, MD, PhD, of the University of Pécs (Pécs, Hungary), analyzed pooled data from 7 randomized, placebo-controlled clinical trials involving 31,286 patients with ACS. The trials, published between 2003 and 2011, evaluated the safety and efficacy of a novel oral factor Xa antagonist (rivaroxaban, apixaban, or darexaban) or direct thrombin inhibitor (dabigatran or ximelagatran) on top of antiplatelet therapy (primarily aspirin and clopidogrel).

Major Bleeding Threefold Higher with Triple Therapy 

Overall, use of a new-generation oral anticoagulant reduced composite ischemic events and modestly lowered the risk of MI and stent thrombosis. On the other hand, triple therapy was associated with no reduction in all-cause mortality and a threefold increased risk of major bleeding. There was no difference in net clinical benefit (sum of composite ischemic events and TIMI major bleeding events) compared with placebo (table 1).

Table 1. Risk of Events with Novel Oral Anticoagulant Plus Dual Therapy

Results of subgroup and sensitivity analyses were consistent with those of the overall study. In addition, no interaction was observed between net clinical benefit and the type or dose of anticoagulant studied.

The authors conclude that “the extremely high risk for bleeding complications offsets any ischemic benefits associated with the administration of new-generation oral anticoagulant agents to patients receiving antiplatelet therapy after an ACS, resulting in a neutral net clinical benefit.” Thus, they say, “unrestricted use” of such drugs cannot be recommended.

However, Dr. Komócsi and colleagues add, limited data suggest that such potent strategies may be beneficial in high-risk ACS subgroups, such as patients who require long-term anticoagulation to prevent thromboembolic complications due to atrial fibrillation, pulmonary embolism, or prosthetic heart valves.

Explaining Contradictory Results

In an accompanying editorial, Adrian Hernandez, MD, PhD, of the Cleveland Clinic (Cleveland, OH), observes that the findings of the meta-analysis were driven by 2 large phase 3 trials—APPRAISE-2 (n = 7,392) and ATLAS ACS-TIMI 51 (n = 15,526)—which yielded contradictory results. APPRAISE-2 was halted prematurely because of an increase in major bleeding with apixaban without a counterbalancing reduction in ischemic events, while ATLAS ACS-TIMI 51 showed a reduction in all-cause mortality and no increase in fatal bleeding with the lower of 2 doses of rivaroxaban (2.5 mg vs. 5 mg, both twice daily). 

According to Dr. Hernandez, the divergent results may be due in part to the older and sicker population treated in APPRAISE-2. Their pathology may have been less closely tied to thrombotic risk and they may therefore have been less responsive to anticoagulation, he explained.

Dr. Hernandez also noted that the trials in the meta-analysis did not address specific ACS subgroups. “[T]herefore, it is unknown whether the effects of [novel oral anticoagulants] differ among patients with unstable angina, ST-elevation MI, and non-ST-elevation MI.” And importantly, data are lacking on the use of such agents in ACS patients on more potent antiplatelet agents such as prasugrel or ticagrelor, or who undergo PCI. 

Dosing Intensity Matters 

In a telephone interview with TCTMD, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), faulted the meta-analysis for obscuring the fact that the effect of triple therapy in ACS patients appears to depend on the dosage of the newer oral anticoagulants.

“For example, in APPRAISE-2, the dose of apixaban [5 mg twice daily] was essentially full-dose anticoagulation,” he pointed out. “The distinction the authors didn’t make is that in ATLAS there were 2 different doses of anticoagulation studied, and both were lower than full dose. I don’t think it’s fair to combine all 3 of those dosing intensities because the results aren’t the same. What is lost by lumping all the data together is that with very low dose rivaroxaban in ATLAS, there was a significant mortality reduction.

“While that very low dose did increase bleeding, including intracranial bleeding—which is not trivial—I think when there’s reduction in all-cause mortality, that’s a therapy that potentially has value,” Dr. Bhatt concluded. On the other hand, as anticoagulation “moves up the dosing ladder, bleeding increases and ischemic and mortality benefits are lost,” he added. “So dosing intensity matters.”

Dr. Bhatt, who was involved in both the APPRAISE-2 and ATLAS ACS-TIMI 151 trials, said he doubted this meta-analysis would carry any weight with antithrombotic researchers. “The conclusions of [the 2 trials] are self-contained,” he said. “Adding them together doesn’t add anything.” 

Triple Therapy: One Drug Too Many 

On the other hand, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), found the study compelling. “As meta-analyses go, I think it’s very good,” he told TCTMD in a telephone interview. “And the results are quite consistent [across subanalyses].”

He did, however, question the authors’ implication that bleeding and ischemic events can be said to simply “offset” each other. They may be equal if both cause death, he noted, “but it doesn’t follow that a bleeding event, even a major one, is [always] as bad as a heart attack.” Moreover, “it is simplistic to suggest that mortality depends entirely on the degree of bleeding,” he asserted.

Dr. Brener acknowledged that triple therapy might yet be found to have a role in STEMI patients. But, he added, “the point of [a] meta-analysis is to take a more global approach and ask, Can we say that in general in ACS patients, adding a drug in a different antithrombotic class [to dual antiplatelet therapy] is beneficial or not? And to me [the authors] make a good case that the answer is no. Some subsets may benefit, and they need potentially to be investigated, but that doesn’t change the overall picture.”

Dr. Brener added that the current findings do not preclude a search for a better dual therapy to protect ACS patients without unacceptable bleeding risk—for example, aspirin with apixaban vs. aspirin with ticagrelor.

Study Details 

Use of PCI in the trials ranged from 8.3% to 74.6%, and rates of discontinuation of the trial drug were high (mean 26.4%, range 12.0%-44.0%). In addition, the duration of follow-up ranged from 3 months to 5 years.

 

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Sources:
1. Komócsi A, Vorobcsuk A, Kehl D, et al. Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome: Systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;Epub ahead of print.

2. Hernandez AV. No place for novel oral anticoagulants in current treatment of acute coronary syndromes. Arch Intern Med. 2012;Epub ahead of print.

 

 

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