No Association of Abacavir Use With Myocardial Infarction
No Association of Abacavir Use With Myocardial Infarction
Background: Several studies have reported an association between abacavir (ABC) exposure and increased risk of myocardial infarction (MI) among HIV-infected individuals. Randomized controlled trials (RCTs) and a pooled analysis by GlaxoSmithKline, however, do not support this association. To better estimate the effect of ABC use on risk of MI, the US Food and Drug Administration (FDA) conducted a trial-level meta-analysis of RCTs in which ABC use was randomized as part of a combined antiretroviral regimen.
Methods: From a literature search conducted among 4 databases, 26 RCTs were selected that met the following criteria: conducted in adults, sample size more than 50 subjects, status completed, not a pharmacokinetic trial, and not conducted in Africa. The Mantel–Haenszel method, with risk difference and 95% confidence interval, was used for the primary analysis, along with additional alternative analyses, based on FDA-requested adverse event reports of MI provided by each investigator.
Results: The 26 RCTs were conducted from 1996 to 2010, and included 9868 subjects (5028 ABC and 4840 non-ABC). Mean follow-up was 1.43 person-years in the ABC group and 1.49 person-years in the non-ABC group. Forty-six (0.47%) MI events were reported [24 (0.48%) ABC and 22 (0.46%) non-ABC], with no significant difference noted between the 2 groups (risk difference of 0.008% with 95% confidence interval: -0.26% to 0.27%).
Conclusions: To the best of our knowledge, our study represents the largest trial-level meta-analysis to date of clinical trials in which ABC use was randomized. Our analysis found no association between ABC use and MI risk.
Combination antiretroviral therapy (cART) has dramatically decreased the morbidity and mortality associated with HIV infection and has led to prolonged survival overall. As a result of declines in AIDS-related mortality and the increasing age of the HIV-infected population, non-AIDS causes of death such as cardiovascular disease (CVD), viral hepatitis, and malignancy now account for most deaths among HIV-infected persons receiving cART. Although traditional cardiovascular risk factors contribute to myocardial infarction (MI) risk in HIV-infected persons as in the general population, the risk of MI in HIV-infected persons on cART seems to be significantly higher. Both HIV infection itself and cART may contribute independently to this increased cardiovascular risk.
The Data Collection of Adverse events of Anti-HIV Drugs (D:A:D) study, a large, prospective, observational study with an international cohort of 33,347 HIV-1–infected individuals, was initiated to explore the association between cART and risk of MI. The D:A:D study has reported a 26% increase in the relative risk of MI per year of exposure to cART in general, and a 16% increase with the protease inhibitor drug class. Unexpectedly, the D:A:D study also reported an increased risk of MI associated with current or recent (within 6 months) use of abacavir (ABC) [relative risk 1.9, 95% confidence interval (CI): 1.47 to 2.45, P = 0.0001] and didanosine (relative risk 1.49, 95% CI: 1.14 to 1.95, P = 0.003) after a median follow-up of 5.1 years as compared with other antiretroviral drugs.
Because the D:A:D data are observational, other researchers have sought to replicate the ABC association using independent data sets. The findings have been conflicting. Several observational studies seem to support the results of the D:A:D study. Also, the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, a randomized clinical trial (RCT) evaluating treatment strategy, found an association between ABC and increased risk of CVD. On the other hand, analysis of pooled data from 52 GlaxoSmithKline (GSK) sponsored clinical trials with at least 24 weeks of cART found no excess risk of MI with ABC therapy. Among the GSK sponsored trials, 36 were RCTs: 12 randomized with respect to ABC therapy, 14 randomized with respect to other antiretrovirals and used ABC as a background medication, and 10 permitted ABC as a background medication or did not include ABC at all. Sixteen GSK trials were single-arm trials: 13 included ABC as a component of cART and 3 allowed ABC as background medication. Similarly, a recent analysis of data from 6 RCTs of initial cART regimens in the AIDS Clinical Trials Group (ACTG) found no significant association between recent ABC use and risk of MI. Because the pooled analysis of GSK data did not stratify by trial, it cannot be considered a proper meta-analysis. The ACTG pooled analysis has the important limitation that only 3 of the 6 trials included in the analysis had a randomized ABC arm.
Given the conflicting results from the observational studies, the SMART trial, and pooled analyses by GSK and ACTG, the US Food and Drug Administration (FDA) set out to conduct a meta-analysis of RCTs in which ABC use was randomized as part of cART to estimate the effect of ABC use on the risk of MI. The meta-analysis of RCTs was undertaken to reduce potential biases that may not be controlled for in analyses of observational studies and to preserve randomization within a trial, which was not accounted for in the GSK and ACTG analyses.
Abstract and Introduction
Abstract
Background: Several studies have reported an association between abacavir (ABC) exposure and increased risk of myocardial infarction (MI) among HIV-infected individuals. Randomized controlled trials (RCTs) and a pooled analysis by GlaxoSmithKline, however, do not support this association. To better estimate the effect of ABC use on risk of MI, the US Food and Drug Administration (FDA) conducted a trial-level meta-analysis of RCTs in which ABC use was randomized as part of a combined antiretroviral regimen.
Methods: From a literature search conducted among 4 databases, 26 RCTs were selected that met the following criteria: conducted in adults, sample size more than 50 subjects, status completed, not a pharmacokinetic trial, and not conducted in Africa. The Mantel–Haenszel method, with risk difference and 95% confidence interval, was used for the primary analysis, along with additional alternative analyses, based on FDA-requested adverse event reports of MI provided by each investigator.
Results: The 26 RCTs were conducted from 1996 to 2010, and included 9868 subjects (5028 ABC and 4840 non-ABC). Mean follow-up was 1.43 person-years in the ABC group and 1.49 person-years in the non-ABC group. Forty-six (0.47%) MI events were reported [24 (0.48%) ABC and 22 (0.46%) non-ABC], with no significant difference noted between the 2 groups (risk difference of 0.008% with 95% confidence interval: -0.26% to 0.27%).
Conclusions: To the best of our knowledge, our study represents the largest trial-level meta-analysis to date of clinical trials in which ABC use was randomized. Our analysis found no association between ABC use and MI risk.
Introduction
Combination antiretroviral therapy (cART) has dramatically decreased the morbidity and mortality associated with HIV infection and has led to prolonged survival overall. As a result of declines in AIDS-related mortality and the increasing age of the HIV-infected population, non-AIDS causes of death such as cardiovascular disease (CVD), viral hepatitis, and malignancy now account for most deaths among HIV-infected persons receiving cART. Although traditional cardiovascular risk factors contribute to myocardial infarction (MI) risk in HIV-infected persons as in the general population, the risk of MI in HIV-infected persons on cART seems to be significantly higher. Both HIV infection itself and cART may contribute independently to this increased cardiovascular risk.
The Data Collection of Adverse events of Anti-HIV Drugs (D:A:D) study, a large, prospective, observational study with an international cohort of 33,347 HIV-1–infected individuals, was initiated to explore the association between cART and risk of MI. The D:A:D study has reported a 26% increase in the relative risk of MI per year of exposure to cART in general, and a 16% increase with the protease inhibitor drug class. Unexpectedly, the D:A:D study also reported an increased risk of MI associated with current or recent (within 6 months) use of abacavir (ABC) [relative risk 1.9, 95% confidence interval (CI): 1.47 to 2.45, P = 0.0001] and didanosine (relative risk 1.49, 95% CI: 1.14 to 1.95, P = 0.003) after a median follow-up of 5.1 years as compared with other antiretroviral drugs.
Because the D:A:D data are observational, other researchers have sought to replicate the ABC association using independent data sets. The findings have been conflicting. Several observational studies seem to support the results of the D:A:D study. Also, the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, a randomized clinical trial (RCT) evaluating treatment strategy, found an association between ABC and increased risk of CVD. On the other hand, analysis of pooled data from 52 GlaxoSmithKline (GSK) sponsored clinical trials with at least 24 weeks of cART found no excess risk of MI with ABC therapy. Among the GSK sponsored trials, 36 were RCTs: 12 randomized with respect to ABC therapy, 14 randomized with respect to other antiretrovirals and used ABC as a background medication, and 10 permitted ABC as a background medication or did not include ABC at all. Sixteen GSK trials were single-arm trials: 13 included ABC as a component of cART and 3 allowed ABC as background medication. Similarly, a recent analysis of data from 6 RCTs of initial cART regimens in the AIDS Clinical Trials Group (ACTG) found no significant association between recent ABC use and risk of MI. Because the pooled analysis of GSK data did not stratify by trial, it cannot be considered a proper meta-analysis. The ACTG pooled analysis has the important limitation that only 3 of the 6 trials included in the analysis had a randomized ABC arm.
Given the conflicting results from the observational studies, the SMART trial, and pooled analyses by GSK and ACTG, the US Food and Drug Administration (FDA) set out to conduct a meta-analysis of RCTs in which ABC use was randomized as part of cART to estimate the effect of ABC use on the risk of MI. The meta-analysis of RCTs was undertaken to reduce potential biases that may not be controlled for in analyses of observational studies and to preserve randomization within a trial, which was not accounted for in the GSK and ACTG analyses.
