September 24th, 2012

‘Dramatic’ Increase in Bleeding Accompanies Addition of Oral Anticoagulant Therapy in ACS

The newer oral anticoagulants may help reduce ischemic events after an acute coronary syndrome (ACS), but only at the cost of a “dramatic” increase in bleeding complications, according to a new meta-analysis published in the Archives of Internal Medicine.

Hungarian researchers performed a systematic review and meta-analysis of seven trials in which 31,286 ACS patients were randomized to placebo or a new oral anticoagulant, either an anti-Xa or direct thrombin inhibitor. All patients also received antiplatelet therapy. Here are the odds ratios for bleeding events and important clinical endpoints with the newer agents:

  • TIMI major bleeding events: OR 3.03 (2.20-4.16)
  • Overall mortality: OR 0.90 (0.76-1.06)
  • Composite ischemic events: OR 0.86 (0.79-0.94)
  • Stent thrombosis (definite or probable): OR 0.73 (0.54-0.98)

“These results suggest that the unrestricted use of new-generation oral anticoagulant agents as an adjunct to dual antiplatelet therapy after an ACS cannot be recommended,” the authors concluded. However, they left open the possibility that the newer oral anticoagulants may be beneficial in the 6%-21% of ACS patients who require long-term anticoagulation for atrial fibrillation and other conditions.

In an accompanying comment, Adrian Hernandez writes that “the conclusions of the meta-analysis seem to be robust.” He points out that the large differences in the relative risk of bleeding and clinical events found in the meta-analysis translate into smaller differences in absolute risk. Nevertheless, he writes, “the benefit is largely canceled by the harm; therefore, the routine use of [novel oral anticoagulants] among patients with ACS is unwarranted.”

2 Responses to “‘Dramatic’ Increase in Bleeding Accompanies Addition of Oral Anticoagulant Therapy in ACS”

  1. Thomas Benzoni, DO says:

    Ok, I will confess I’m just the EM doc keeping your patient alive at 0200. Help me understand something about these new drugs.

    You don’t have to adjust doses; great, no calculators needed because we’re not smart enough and don’t have computers.
    You don’t have to measure levels; I.e., you can’t measure effect. This one defeats me as to why it’s an advantage.
    You can’t reverse it. Now this I really don’t get; I can’t find any advantage here.

    Maybe a few more patients don’t get rare disease related outcomes…few indeed.

    I do understand the effects of costing more, like 100X more/month. More patients won’t buy it, which could be a good thing for them!

  2. Judith Andersen, AB, MD says:

    Without having read either the meta-analysis or the details of the individual studies included in the analysis, I should probably not comment. Still, having had a substantial experience with both rivaroxaban and dabigatran, in a variety of clinical settings, including post-coronary interventions, I think that the devil is in the details. The meta-analysis indicates that cardiac outcomes are better and the comparisons –with regard to cardiac and bleeding outcomes — are to placebo– not to other anticoagulant agents such as enoxaparin and fondaparinux– often used in post-intervention settings in which “hypercoagulability” with potential stent closure is anticipated. Timing of administration is also an issue– having not read the studies, I cannot address this, but issues that contribute to post-procedure hemostasis, such as adequate Vitamin K intake, become important when no Vitamin K antagonist is used.

    With regard to Dr Benzoni’s concerns, I would venture to say that “you do need to adjust doses” based upon the indication for the antithrombotic agent: “prophylaxis” and “treatment” doses are not identical, and the amounts of either rivaroxaban or dabigatran used for stroke prevention in atrial fibrillation are not necessarily those employed in either primary or secondary prevention of coronary thrombosis or other thrombotic disorders. With regard to the cost of the new agents, and the freedom they provide to patients with atrial fibrillation or orthopedic surgery prophylaxis, Dr Benzoni might be a bit more open-minded. Not having to have an INR tested biweekly and not having to restrict diet or worry about drug-drug interactions are powerful inducements for most patients, and the cost of both drugs, although greater than the cost of generic warfarin, is not excessive compared to that of other cardiac agents. Irreversibility of drug effect is only an issue with dabigatran and even then only a 12 hr issue; rivaroxaban can be reversed readily with 3 – 5 component prothrombin complex concentrates. And you can measure the effects, if your institution will provide the testing methods (e.g.,for rivaroxaban, a calibrated drug-specific prothrombin time), a strategy that many institutions are embarking upon, chiefly for patients with renal dysfunction in whom calculation of drug half-life is critical for efficacy and safety. Few drugs are without issues — but let’s not throw out the baby with the bathwater.