Indirect comparison of new anticoagulants provides insight into how the drugs compare

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According to a new study published in the Journal of American College of Cardiology, an indirect comparison of the new anticoagulants indicates that there are “no profound significant differences” in efficacy between apixaban (Eliquis, Pfizer and Bristol-Myers Squibb) and both does of dabigatran (Pradaxa, Boehringer Ingelheim) and Rivaroxaban (Xarelto, Bayer).

Gregory Lip, University of Birmingham, Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK, and others reported that head-to-head trials of the new anticoagulants for stroke prevention in patients with atrial fibrillation would require “huge number of patients to achieve statistical power for non-inferiority and may not be viable options in the near future.”

They added that, as an alternative to direct comparisons, an indirect comparison of the published trials of the drugs using a common comparator (ie, how the anticoagulants compare with warfarin) could be used instead. Lip et al wrote: “The aim of the present study was to perform an indirect comparison analysis of apixaban against dabigatran etexilate (two doses) and rivaroxaban as well as rivaroxaban against dabigatran etexilate (two doses) for their relative efficacy and safety against each other.”

Using the Bucher method to analysis the data, which Lip et al stated was the “preferred method for indirect comparison, superior to informal methods, as comparison of confidence intervals”, they found that dabigatran 150mg was associated with a significantly lower risk of stroke and systemic embolism (by 26%), less haemorrhagic stroke (by 56%), and non-disabling stroke (by 40%) compared with rivaroxaban. However, there were no differences between dabigatran 110mg and rivaroxaban nor were there any differences between both doses of dabigatran and apixaban. Additionally, there were no differences between apixaban and rivaroxaban in terms of efficacy.

Reviewing the safety endpoints, Lip et al found that apixaban had significantly lower rates of major bleeding than dabigatran 150mg (by 26%) and rivaroxaban (by 34%), but the investigators did not identify any significant differences in safety endpoints between apixaban and dabigatran 110mg.

Lip et al did acknowledge that there are a “number of constraints and limitations related to the method used for an indirect comparison analysis” but added: “this is still considered a reasonable statistical tool to qualify a comparison of effects that have not yet been investigated head to head.”

In an accompanying editorial, Christopher Cannon (Cardiovascular Division, Brigham and Women’s Hospital, Boston, USA) and Payal Kohli (Division of Cardiology, University of California, San Francisco, USA) wrote that “extreme caution” was needed when indirect comparisons were used. As an example of the problems of indirect comparisons, he reported that an indirect comparison of fibrinolytic agents found significant differences but a direct comparison did not. They added that the results of Lip et al‘s study were confusing because they reported that dabigatran 150mg was associated with a significantly lower risk of stroke and systemic embolism than rivaroxaban but also reported that there were no significant differences between apixaban and dabigatran (both doses) or rivaroxaban. Cannon et al wrote: “These conflicting results lend support to the conclusion that such methods for indirect comparisons may not be the most accurate due to several sources of confounding.” He added that Lip et al‘s data should not be used for the clinical care of patients and said: “Instead, we would turn to direct evidence from trials and the indications put forth by the FDA to select the right appropriate agent, at the dose tested, for use in the patient population studied within the trial.”

Lip told Cardiac Rhythm News: “Our indirect comparison study does have some limitations but the main message is that there are many similarities in efficacy between the new oral anticoagulants for stroke prevention in atrial fibrillation. However, there may be some major bleeding differences. Only a head-to-head direct comparison of the different new drugs would fully answer the questions of efficacy/safety differences between the new drugs.”

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