No Place for New Anticoagulants in ACS, Says New Review

September 25, 2012 (Pécs, Hungary) — New oral anticoagulant agents have no net clinical benefit when given to patients with acute coronary syndrome (ACS) who are already receiving antiplatelet therapy, a new meta-analysis has concluded [1].
"ACS patients are a very delicate population. There is a small benefit when oral anticoagulants are added to dual antiplatelet therapy, but such administration results in an unacceptably high rate of bleeding," lead author of the meta-analysis, Dr András Komócsi (University of Pécs, Hungary), told heartwire . Komócsi and colleagues report their findings online September 24, 2012 in the Archives of Internal Medicine.

There is a small benefit when oral anticoagulants are added to dual antiplatelet therapy but such administration results in an unacceptably high rate of bleeding.

In an accompanying editorial [2], Dr Adrian V Hernandez (Cleveland Clinic, OH) largely agrees. "The benefit is largely canceled by the harm; therefore, the routine use of newer oral anticoagulants among patients with ACS is unwarranted," he observes.
The newer anticoagulant agents include the factor Xa inhibitors rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim). While these new drugs have all shown good results as an alternative to warfarin in patients with atrial fibrillation (AF) and are licensed for use in venous thromboembolism (VTE), their use in patients with ACS has been fraught with difficulty, because in this situation they are added to several other anticlotting agents, so the bleeding risk is very high.
The first phase 3 trial of one of these agents in ACS (the APPRAISE-2 trial with apixaban) was stopped early because of bleeding, but a later trial, ATLAS ACS 2 TIMI 51, appeared to have demonstrated success in this indication with rivaroxaban. But the US FDA has failed to clear rivaroxaban for the additional indication of ACS after its Cardiovascular and Renal Drugs Advisory Committee voted against recommending approval, based on concerns about missing data from the trial. So the fate of these agents in the ACS indication remains in limbo, for the time being.
New Oral Anticoagulants Associated With Threefold Increased Risk of Major Bleeding
Komócsi and colleagues identified seven prospective randomized placebo-controlled studies that evaluated the effects of factor Xa or direct thrombin inhibitors in just over 31 000 patients receiving antiplatelet therapy after an ACS, published between January 2000 and December 2011. Five were dose-finding trials, in which the primary outcome was safety, and two were large phase 3 trials--APPRAISE-2 and ATLAS-ACS 2 TIMI 51.
Based on the pooled results, the use of new oral anticoagulants in patients taking antiplatelets after ACS was associated with a "dramatic" threefold increased risk of major bleeding, the researchers note (odds ratio 3.03; p<0.001).
Significant, although moderate, reductions in the risk for stent thrombosis or composite ischemic events were observed, with no significant benefit on overall mortality. For the net clinical benefit, treatment with the new oral anticoagulants "provided no advantage over placebo (odds ratio 0.98; p=0.57)," they observe.
"The inhibition of the coagulation system is already somehow pushed to the limit in these patients, and we have to be very conscious about this delicate balance of bleeding and ischemic events," Komócsi commented to heartwire .
In his editorial, Hernandez discusses some of the limitations of the new review, including the use of death as an end point rather than cardiovascular death, and the fact that Komócsi et al provided only relative risk reductions, not absolute ones. Nevertheless, he observes, "The conclusions of the meta-analysis seem to be robust."
Could New Anticoagulants Be Beneficial in Subpopulations of ACS Patients?
Hernandez goes on to wonder, however, whether the new oral anticoagulants might be useful for specific populations of patients with ACS and says trials are needed to evaluate the use of these agents in such subgroups.
"It is unknown whether the effects of [new oral anticoagulants] differ among patients with unstable angina, ST-elevation myocardial infarction [STEMI], and non-STEMI," he observes. Also, "no data are available to date on the use of [new oral anticoagulants] in patients with ACS taking prasugrel [Effient, Daiichi Sankyo/Lilly] or ticagrelor [Brilinta, AstraZeneca] undergoing percutaneous coronary interventions [PCIs] or having indications for anticoagulation (eg, cancer, mitral stenosis, mechanical prosthetic valves, or prior stroke without AF)."
Komócsi believes by far the biggest subgroup that might benefit from the new oral anticoagulants comprises ACS patients who also have AF, noting that AF patients were excluded from the pivotal trials included in his meta-analysis. This group constitutes about 9% to 11% of ACS patients, he estimates.
Other subpopulations that might also benefit include those with prosthetic valves and those who have had a prior pulmonary embolism who then go on to develop ACS, he says, noting however that these are "much smaller populations."
Komócsi reports receiving lecture fees from DSI/Lilly. Disclosures for the coauthors are listed in the paper. Hernandez reports no conflicts of interest.source medscape