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No Association of Abacavir Use with Myocardial Infarction: Findings of an FDA Meta-analysis
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JAIDS Journal of Acquired Immune Deficiency Syndromes: POST ACCEPTANCE, 28 August 2012
Ding, Xiao PhD; Andraca-Carrera, Eugenio PhD; Cooper, Charles MD; Miele, Peter MD; Kornegay, Cynthia PhD; Soukup, Mat PhD; Marcus, Kendall MD
Meetings at Which Data were Presented in Part:
18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, Boston, MA
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 (RCT) and a pooled analysis by GlaxoSmithKline, however, do not support this association. To better estimate the effect of abacavir use on risk of MI, the U.S. Food and Drug Administration (FDA) conducted a trial-level meta-analysis of RCTs in which abacavir use was randomized as part of a combined antiretroviral regimen.
Methods: From a literature search conducted among four databases, 26 RCTs were selected that met the following criteria: conducted in adults, sample size greater 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, 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, 22 [0.46%] non-ABC), with no significant difference noted between the two groups (risk difference 0.008% with 95% CI [-0.26%, 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 abacavir 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.1 As a result of declines in AIDS-related mortality, as well as 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 the majority of deaths among HIV-infected persons receiving cART.2,3 While traditional cardiovascular risk factors contribute to MI risk in HIV-infected persons as in the general population, the risk of myocardial infarction (MI) in HIV-infected persons on cART appears to be significantly higher.4-6 Both HIV infection itself and cART may contribute independently to this increased cardiovascular risk.7
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.8,9 Unexpectedly, the D:A:D study also reported an increased risk of MI associated with current or recent (within six 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 to other antiretroviral drugs.10
Because the D:A:D data are observational, other researchers have sought to replicate the ABC association using independent datasets. The findings have been conflicting. Several observational studies appear to support the results of the D:A:D study.11.,12 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.13 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.14 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 ten 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 three allowed ABC as background medication. Similarly, a recent analysis of data from six RCTs of initial cART regimens in the AIDS Clinical Trials Group (ACTG) found no significant association between recent ABC use and risk of MI.15 Since 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 three of the six 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 U.S. 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.
Results
As shown in Figure 1, a total of 26 randomized controlled clinical trials were included in the meta-analysis. These trials are listed in Table 2. The FDA procured subject level data from all 16 GSK trials and five academic trials, but was unable to get any data for six other academic trials, as shown in Table 1. The five ACTG trials provided trial level data following the FDA data request. Within this 26 trial data base, 5028 subjects were randomized to ABC-containing cART regimens and 4840 subjects were randomized to non-ABC cART regimens. The mean follow-up for the 26 trials was 719 person-years with a minimum of 42.2 person-years and a maximum of 1257.3 person-years. This resulted in an average duration of follow-up of 1.62 person-years for each subject with a minimum of 0.49 person-years per subject (COL30305) and a maximum of 4.72 personyears per subject (ACTG 372A).
Baseline subject characteristics were not provided to the FDA for any of the 26 trials. If available, these data were obtained from publications. Table 3 depicts a summary of baseline subject characteristics grouped by trial sponsor (GSK, ACTG, other academic). As shown in the table, important baseline covariates including gender, age, body mass index (BMI), CD4 count, and HIV viral load are comparable between the ABC group and the non-ABC group.
Of the 9868 subjects included in the analysis, a total of 46 (0.47%) MI events were reported, including 24 (0.48%) MI events from subjects randomized to an ABC-containing regimen and 22 (0.46%) MI events from subjects randomized to a non-ABC regimen. Table 4 depicts a summary of overall results as well as results by trial sponsor (GSK, ACTG, other academic). Overall, no statistically significant difference in MI events was detected between subjects receiving ABC-containing regimens and non-ABC regimens: risk difference=0.008% with a 95% CI of (-0.26%, 0.27%) and a corresponding odds ratio of 1.02 with 95% CI (0.56, 1.84). Separate analyses by the trial sponsors (GSK, ACTG, and other academic) also did not show statistically significant difference in the MI risk between the ABC-treated subjects and the non-ABC treated subjects. Figure 2 depicts a forest plot of the 26 trials sorted by average duration of follow-up (longest duration at the top to shortest duration at the bottom). No trends regarding total person-years of follow-up were seen in the meta-analysis. No single trial showed a statistically significant increased risk of developing MI between subjects treated with ABC and subjects treated with non-ABC regimens.
Alternative Analyses
In the previous section, results based on Mantel-Haenszel (M-H) risk difference and Mantel-Haenszel odds ratio are presented. The M-H risk difference method uses information from all the trials, including those with zero events; in contrast, the M-H odds ratio method excludes trials without events. Based on the exact and efficient inference procedure, the risk difference between ABC containing regimen and non-ABC regimen is 0.03%, with a 95% CI of ( 0.44%, 0.50%).27 This result is consistent with the primary result based on the M-H risk difference. This method also utilizes data from trials with zero events. Similar to many exact approaches, this exact risk difference tends to provide conservative confidence intervals.
In the pre-specified statistical analysis plan, fixed effect models were chosen over a random effect model because of the small number of events expected. In order to evaluate the heterogeneity in the data, the CochranÕs Q statistic and the I2 statistic were calculated based on all the trials with at least one event. The Q statistic was 20.51 and the corresponding p-value for test of heterogeneity was 0.75, suggesting that no statistically significant heterogeneity was found. Similarly, the I2 statistic was 0.17, suggesting that only 17% of the between-trial variation was due to heterogeneity rather than to random chance. Therefore, the choice of fixed effects model is appropriate in this meta-analysis. However, a random effects model that incorporates trials with zero events, the modified D-L method, yielded a risk difference of 0.0003% with a 95% CI of (-0.26%, 0.26%).28, 29 The result is very similar to the primary results based on a fixed effect model (the M-H risk difference).
Stratified odds ratios based on the exact method and the Peto method were also conducted as alternative analyses. The stratified odds ratio based on the exact method was 1.02 with 95% CI (0.54, 1.92), and the Peto stratified odds ratio was 1.02 with 95% CI (0.56, 1.83). These results are consistent with the primary analysis based on the Mantel-Haenszel odds ratio. Note that trials with zero events do not contribute to any of the analyses based on odds ratios.
Duration of Follow-up
If a differential duration of follow-up were to exist between the ABC and non-ABC groups (for example, ABC subjects might have tended to drop out of a trial earlier than non-ABC subjects), the results of this meta-analysis might be biased. As shown in Table 5, for all 21 trials with available information, the average duration of follow-up was similar between the ABC and the non-ABC groups. Overall, the average duration of follow-up was 1.43 years for the ABC group and 1.49 years for the non-ABC group.
As shown in Table 5, the duration of follow-up was well balanced between the ABC and non-ABC groups within each trial. The duration, however, varied noticeably across the different trials. The interpretation of the risk difference in a trial-level meta-analysis is challenging when trials have different durations. In our meta-analysis, though, results were consistent regardless of the measure of risk; i.e., the risk difference or odds ratio.
Discussion
Recent observational studies have suggested increase in risk of MI for patients with current or recent exposure to abacavir. Because residual confounding is not completely controllable in observational studies and because of concerns of multiple testing, we conducted a meta-analysis with a pre-specified primary endpoint and statistical analysis plan of prospective, controlled trials in which abacavir use was randomized and in which MI risk was moderate (0.45%).
Through a process of literature search, trial identification, and data acquisition, the FDA conducted a meta-analysis based on 26 RCTs in which ABC was randomized as part of cART to estimate the effect of ABC use on MI risk. We originally intended to obtain subject level data for each trial in order to conduct a subject level meta-analysis that utilized a consistent definition of MI, as this would provide a greater level of evidence than a trial-level meta-analysis. However, subject level data were not procured for the five ACTG trials, thereby not allowing a subject level meta-analysis. Realizing that a trial level meta-analysis has some limitations as discussed below, we felt that obtaining key trial characteristics, such as a pre-specification of the primary safety endpoint, MI, and a statistical analysis plan, would provide meaningful information for the research question of interest.
Based upon our trial-level meta-analysis, no statistically significant association between the use of ABC and increased risk of developing MI was found. The Mantel-Haenszel risk difference between ABC-containing cART regimens and non-ABC cART regimens was 0.008% with a 95% CI of (-0.26%, 0.27%). The Mantel-Haenszel odds ratio of ABC compared with non-ABC was 1.02 with a 95% CI of (0.56, 1.84). These results were robust to various alternative analyses.
The major strengths of our meta-analysis are the minimization or elimination of confounding and selection bias through maintaining the abacavir randomization within each trial and preserving the study level randomization. In addition, our analysis was based upon the pre-specification of a single hypothesis that does not have the weakness of multiple testing associated with it.
One weakness in our analysis is that MI events were not adjudicated and were reported as part of adverse event reporting in clinical trials. In our analysis, MI was based upon an FDA request to the trial sponsor/investigator and not on events reported in the literature. In addition, protocols were provided for the majority of studies to confirm event ascertainment similarities. While such steps were meant to limit errors in event ascertainment, absent a consistent and thorough adjudication process from all trials we were left to rely on event ascertainment as reported by trial investigators.
Another weakness of our meta-analysis is that it is based upon trial level information and not subject level information because we were not able to procure the subject level data for all trials included in our meta-analysis. A subject level analysis with adjudicated event ascertainment would be considered the highest standard in the assessment of MI risk with abacavir use. This would allow, for example, an assessment of the timing of events, assessments of data quality, application of consistent methods for event determination, and assessments of informative censoring. Given these limitations, it is still worth noting that discontinuation rates were low overall in these HIV trials, minimizing the possible effects of informative censoring.
One potential limitation associated with the use of clinical trial data relates to the possibility that subjects enrolled in these clinical trials may be at decreased risk of MI relative to the general population due to various exclusion criteria. This could lessen the likelihood of finding a positive association with MI. However, recent observational studies involving French and Kaiser-Permanente health record databases demonstrate a risk of MI amongst HIV-infected patients that is similar to that seen in our study.30, 31
Furthermore, in the D:A:D study, the relative risk for MI was constant within all risk groups with current use of abacavir. If this is true, our studyÕs ability to identify a risk difference observed between abacavir and non-abacavir randomized subjects should not have been impacted by the particular magnitude of MI risk inherent to the subjects in our study. While several limitations are noted with our trial-level meta-analysis, to our knowledge this represents the largest trial-level meta-analysis to date of clinical trials in which abacavir use was randomized. When taken together with the results from other publications, our meta-analysis raises questions about an association between MI and ABC use, re-affirming that a clear determination of MI risk remains uncertain. For a more certain understanding of the cardiovascular safety profile of abacavir use, an appropriately powered randomized clinical trial with a pre-specified analysis plan and adjudicated primary CVD endpoints would need to be conducted.
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