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FDA Trial Meta-Analysis Does Not See Higher MI Risk With Abacavir
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Analyzing results of 26 randomized trials involving abacavir, the FDA found no evidence suggesting that use of this nucleoside raises the risk of myocardial infarction (MI) [1].
The D:A:D cohort study [2] and analysis of SMART treatment interruption trial data [3] found that current or recent abacavir independently raises the MI risk. Partly as a result of those findings, US Department of Health and Human Services guideline writers removed abacavir from its place as a recommended first-line nucleoside. But other cohort studies and trials, and analysis of the GlaxoSmithKline safety database, failed to find a higher MI risk with abacavir.
In an attempt to resolve this discrepancy, FDA investigators searched the medical literature for all clinical trials that randomized some participants to abacavir [1]. They analyzed randomized trials because confounding cannot be eliminated from cohort studies. Included trials had to be conducted in adults, had to include more than 50 participants, had to be completed, and could not be a pharmacokinetic study or a study conducted in Africa. The FDA team compared outcomes in abacavir and nonabacavir treatment arms.
Twenty-six trials conducted from 1996 through 2010 met selection criteria, including 16 trials by GlaxoSmithKline, five AIDS Clinical Trials Group (ACTG) studies, and five trials from academic centers. These trials randomized 5028 people to abacavir-containing regimens and 4840 to nonabacavir regimens. Follow-up time averaged 1.62 person-years for each study participant and did not differ between abacavir and nonabacavir groups. The FDA depended upon investigators' reports of MI and other outcomes.
MI risk did not differ significantly between the combined abacavir arms and the combined nonabacavir arms, with a risk difference of 0.008% (95% confidence interval -0.26% to +0.27%). Separate analyses of data from GlaxoSmithKline trials, ACTG trials, and academic trials also failed to show an MI risk difference between abacavir and nonabacavir arms. No single trial analyzed found an MI risk difference between treatment groups, and risk difference did not vary by length of follow-up.
Simulations to assess statistical power showed that the FDA meta-analysis had a probability of 0.95 to find a risk difference greater than 0.1%. The FDA team noted that their primary finding "is very unlikely if the true risk of [MI with] abacavir is 1.8 or higher at the observed background MI risk (0.45%)."
The FDA investigators believe their results "raise significant uncertainty about the likelihood of an abacavir-MI association." Definitive determination of MI risk with this nucleoside, they added, would require a randomized trial with primary cardiovascular outcomes.
References
1. Ding X, Andraca-Carrera E, Cooper C, Miele P, Kornegay P, Soukup M, Marcus K. No association of myocardial infarction with ABC use: an FDA meta-analysis. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 808.
2. D:A:D Study Group, Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371:1417-1426.
3. Strategies for Management of Anti-Retroviral Therapy/INSIGHT; DAD Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22:F17-F24.
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