Bleeding With New Oral Anticoagulants Depends on Clinical Setting

Shelley Wood

November 21, 2013

DALLAS, TX — A new meta-analysis addressing bleeding risks with the novel oral anticoagulants concludes that there is very little difference between the new drugs but that bleeding risks associated with the new agents vary substantially based on their indication for use.

Dr Partha Sardar (New York Medical College, NY) presented the new analysis on the final day of the American Heart Association 2013 Scientific Sessions . The analysis was based on 48 randomized clinical trials testing dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals), apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), edoxaban (Lixiana, Daiichi-Sankyo), or darexaban (Astellas) in the settings of thromboprophylaxis after hip or knee surgery or in medically ill patients;  treatment of venous thromboembolism (VTE), pulmonary embolism (PE), atrial fibrillation (AF), or acute coronary syndrome (ACS); or extended treatment of VTE.

"To find out which newer agent is better, we did some indirect comparison analyses, and those did not show that any particular one of the newer agents had a certain advantage compared with other oral anticoagulants. But these were indirect analyses, so we can only take this as hypothesis generating."

Dr Partha Sardar

Of note, in patients undergoing hip surgery, patients with ACS, and medically ill patients being treated for thromboprophylaxis, the newer drugs were linked with significantly higher risks of bleeding than the comparator agents in the studies in question.

To zero in on the most appropriate dose, Sardar and colleagues used the approved dosages, or, in phase 2 trials, the doses that were subsequently tested in phase 3 studies. Relevant trials were selected after a comprehensive literature review.

In all, 141 932 patients were included in the analysis. Hip-surgery studies (12) were the most common, followed by AF studies (10), knee-surgery studies (nine), VTE/PE studies (six), and ACS studies (six), with extended VTE and medically ill patients making up the remainder.

As a group, the new oral anticoagulants caused significantly less major bleeding compared with vitamin-K antagonists (relative risk 0.82, 95% CI 0.69–0.96), with no differences between drug type.

But while no differences in bleeding were seen between the newer agents and comparators (vitamin-K antagonists or low-molecular-weight heparin, depending on the trial) for the treatment of AF and extended treatment of VTE, significant bleeding differences—both lower and higher—were seen in other settings.

Relative Risk of Bleeding Associated With the New Oral Anticoagulants

Indication Relative Risk 95% CI
Hip surgery 1.43 1.02–1.99
ACS 3.27 2.30–4.66
Medically ill thromboprophylaxis 2.79 1.69–4.60
VTE/PE 0.64 0.47–0.89

Specific new oral anticoagulants stood out in particular settings (of note, not all agents have been tested in all settings). For example, rivaroxaban was associated with significant reductions in major bleeding in the setting of acute VTE/PE, but a four-times-higher risk of major bleeding in the setting of ACS and a nearly threefold higher risk of bleeding in the setting of acutely ill patients. Apixaban was associated with a statistically significant 2.58 relative risk of increased major bleeding in the setting of ACS.

The key, Sardar told heartwire , is to consider whether to use the newer or older drugs based on the setting. "Clearly, the bleeding risk is changing with the various indications of use, and we need to pay attention to the indication of use, rather than worrying about which new drug to choose. Most new drugs seem similar, based on the evidence we have so far, but we need to be much more concerned about when we are giving these drugs in the setting of ACS and hip surgery, while they are much safer in the setting of VTE."

Commenting on the study for heartwire , Dr Lori Mosca (Columbia University, Medical Center, NY) observed that it's important to see that none of the new agents appears to be acting markedly different from the others in terms of bleeding risk but stressed that this information comes from a highly selected, randomized clinical trial population. "It is reassuring that the new drugs actually show very positive profiles in terms of similar bleeding complications; however, I think it is very important that we keep in mind as we roll out these new drugs into very diverse populations and settings that we may see differences. For that, we need surveillance systems that actually monitor both the benefits and potential complications of these drugs among diverse populations of patients."

Sardar had no conflicts of interest.

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