Dabigatran MI Risk Is Oral DTI Class Effect in Meta-analysis
Dabigatran MI Risk Is Oral DTI Class Effect in Meta-analysis
OMAHA, NE — Treatment with oral direct thrombin inhibitors, including dabigatran etexilate (Pradaxa, Boehringer Ingelheim), appears to raise the risk of MI, according to a pair of meta-analyses published recently in the American Journal of Cardiology.
The findings likely explain the small elevated MI risk associated with dabigatran in the RE-LY trial, refute suggestions that it reflected a protective effect from the warfarin comparator, and extend the risk to all oral direct thrombin inhibitors, conclude the authors, led by Dr Ramin Artang (University of Nebraska Medical Center, Omaha).
The group's paper expands on their prior meta-analysis that concluded much the same things based on trials available at the time and only two oral direct thrombin inhibitors, not the three discussed by the new report, as covered by heartwire.
"Many, but not all, studies of direct thrombin inhibitors, ximelagatran included, have shown this imbalance in MI frequency, so the meta-analysis is not a surprise," according to Dr Peter Kowey (Jefferson Medical College, Philadelphia, PA), who wasn't involved in the current study. The elevated MI frequency hasn't been explained, he told heartwire in an email, but "I wouldn’t doubt that it is a class effect."
Artang et al's first meta-analysis focused on 39 357 patients in 11 trials comparing an oral direct thrombin inhibitor with warfarin for any indication. They included four trials of dabigatran in atrial fibrillation, venous thromboembolism (VTE), or patients with mechanical valves; three trials of the discontinued ximelagatran in atrial fibrillation, VTE, or thromboprophylaxis; and two of the investigational AZD0837 (AstraZeneca). Most of the studies did not prospectively define MI or other acute coronary syndromes.
The odds ratio (OR) for MI was:
There was no increased MI risk for AZD0837 vs warfarin across two trials (OR 1.17, 95% CI 0.17–7.94; p=0.87).
"To our knowledge, this is the first analysis to extend the findings of an increased risk of MI with dabigatran to other oral thrombin inhibitors," the group writes.
Their second meta-analysis included eight atrial-fibrillation trials with a total of 69 615 patients that reported MI rates in comparisons of warfarin with other antithrombotic regimens, including factor Xa inhibitors, direct thrombin inhibitors, aspirin, and clopidogrel.
The OR for MI was 1.06 (95% CI 0.85–1.34; p=0.59) for warfarin vs comparators.
That warfarin wasn’t associated with more MIs in those trials suggests that the MI risk seen for oral direct thrombin inhibitors in the first meta-analysis "is likely due to a class effect of oral direct thrombin inhibitors and not due to a protective effect of warfarin."
Kowey said, "Just because [the elevation in MIs] has not been seen with other anticoagulants does not refute the theory that it is because direct thrombin inhibitors provide less ischemia protection than warfarin in patients at risk. Therefore, I would not conclude that it is a prothrombotic effect. Nevertheless, it can and should be a factor in the intelligent choice of anticoagulant for patients who may have antecedent coronary artery disease."
The authors had no disclosures. Kowey recently disclosed consulting for Sanofi, Boehringer Ingelheim, Merck, AstraZeneca, Johnson & Johnson, and Daiichi Sankyo and being on the speaker's bureau for Sanofi, Boehringer Ingelheim, and Johnson & Johnson.
OMAHA, NE — Treatment with oral direct thrombin inhibitors, including dabigatran etexilate (Pradaxa, Boehringer Ingelheim), appears to raise the risk of MI, according to a pair of meta-analyses published recently in the American Journal of Cardiology.
The findings likely explain the small elevated MI risk associated with dabigatran in the RE-LY trial, refute suggestions that it reflected a protective effect from the warfarin comparator, and extend the risk to all oral direct thrombin inhibitors, conclude the authors, led by Dr Ramin Artang (University of Nebraska Medical Center, Omaha).
The group's paper expands on their prior meta-analysis that concluded much the same things based on trials available at the time and only two oral direct thrombin inhibitors, not the three discussed by the new report, as covered by heartwire.
"Many, but not all, studies of direct thrombin inhibitors, ximelagatran included, have shown this imbalance in MI frequency, so the meta-analysis is not a surprise," according to Dr Peter Kowey (Jefferson Medical College, Philadelphia, PA), who wasn't involved in the current study. The elevated MI frequency hasn't been explained, he told heartwire in an email, but "I wouldn’t doubt that it is a class effect."
Artang et al's first meta-analysis focused on 39 357 patients in 11 trials comparing an oral direct thrombin inhibitor with warfarin for any indication. They included four trials of dabigatran in atrial fibrillation, venous thromboembolism (VTE), or patients with mechanical valves; three trials of the discontinued ximelagatran in atrial fibrillation, VTE, or thromboprophylaxis; and two of the investigational AZD0837 (AstraZeneca). Most of the studies did not prospectively define MI or other acute coronary syndromes.
The odds ratio (OR) for MI was:
1.35 (95% CI 1.10–1.66; p=0.005) for oral direct thrombin inhibitors vs warfarin across all 11 trials.
1.41 (95%CI 1.09–1.83; p=0.009) for dabigatran vs warfarin in four trials.
1.23 (95% CI 0.86–1.76; p=0.25) for ximelagatran vs warfarin across five trials.
3.46 (95% CI 1.25–9.57; p=0.017) for ximelagatran vs warfarin for only the two trials of acute VTE or VTE prophylaxis.
There was no increased MI risk for AZD0837 vs warfarin across two trials (OR 1.17, 95% CI 0.17–7.94; p=0.87).
"To our knowledge, this is the first analysis to extend the findings of an increased risk of MI with dabigatran to other oral thrombin inhibitors," the group writes.
Their second meta-analysis included eight atrial-fibrillation trials with a total of 69 615 patients that reported MI rates in comparisons of warfarin with other antithrombotic regimens, including factor Xa inhibitors, direct thrombin inhibitors, aspirin, and clopidogrel.
The OR for MI was 1.06 (95% CI 0.85–1.34; p=0.59) for warfarin vs comparators.
That warfarin wasn’t associated with more MIs in those trials suggests that the MI risk seen for oral direct thrombin inhibitors in the first meta-analysis "is likely due to a class effect of oral direct thrombin inhibitors and not due to a protective effect of warfarin."
Kowey said, "Just because [the elevation in MIs] has not been seen with other anticoagulants does not refute the theory that it is because direct thrombin inhibitors provide less ischemia protection than warfarin in patients at risk. Therefore, I would not conclude that it is a prothrombotic effect. Nevertheless, it can and should be a factor in the intelligent choice of anticoagulant for patients who may have antecedent coronary artery disease."
The authors had no disclosures. Kowey recently disclosed consulting for Sanofi, Boehringer Ingelheim, Merck, AstraZeneca, Johnson & Johnson, and Daiichi Sankyo and being on the speaker's bureau for Sanofi, Boehringer Ingelheim, and Johnson & Johnson.
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