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GlaxoSmithKline Meta-analysis Does Not Show Elevated Cardiovascular Risk Associated with Use of Abacavir

Since the 2008 Conference on Retroviruses and Opportunistic Infections, researchers have presented conflicting findings concerning the association between use of abacavir (Ziagen, also in the Epzicom and Trizivir combination pills) and increased risk of cardiovascular events.

As reported in the May 1, 2009 Journal of Acquired Immune Deficiency Syndromes, an analysis of more than 50 clinical trials conducted by abacavir manufacturer GlaxoSmithKline (GSK) did not find an increase in heart attacks or other cardiovascular events.

At CROI 2008, researchers with the large D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study reported that recent use of abacavir was associated with an unexpected 90% increase in the risk of myocardial infarction (MI), with the increase being most pronounced in individuals with underlying cardiovascular risk factors and diminishing after the drug was discontinued.

Similarly, at the International AIDS Conference the following summer, investigators with the large SMART treatment interruption trial reported that abacavir was associated with an increased risk of MI, stroke, and other cardiovascular events, as well as elevated levels of certain biomarkers of inflammation.

After the D:A:D results were first reported, GSK researchers performed an analysis of the company's past clinical studies to see if they could find a similar "signal" linking abacavir and cardiovascular disease. Results were first reported in part at the 2008 International AIDS Conference.

Using the GSK HIV Data Repository, the investigators compiled data from 52 company-sponsored clinical trials, encompassing all phases of drug development, in which adult participants received at least 24 weeks of combination antiretroviral therapy (2 pediatric studies were excluded from the analysis); 36 of these studies were randomized, including 12 trials in which 3263 patients were randomly assigned to receive abacavir versus a control drug or placebo.

In total, these trials included 9502 HIV positive adults who received abacavir (accounting for 7641 person-years [PY] of follow-up) and 4672 patients who did not take the drug (accounting for 4267 PY). About 60% were treatment-experienced, while 40% were treatment-naive. Overall, most participant (82%) were men, the median age was 37 years, and 10% had a prior AIDS diagnosis; in studies with available race/ethnicity data, 58% were white, 24% were black, and 14% were Hispanic.

The researchers searched adverse event reports for terms related to coronary artery disease (CAD), including coronary artery atherosclerosis or occlusion, myocardial ischemia or infarction, acute MI, angina pectoris, and unstable angina. In addition, they reviewed all fatal adverse events due to any cause.

Results

• Baseline demographics and HIV disease characteristics -- including lipid and glucose levels -- were similar in abacavir recipients and patients not exposed to abacavir.
• MI rates were statistically similar for patients exposed to abacavir and those who did not take the drug (intent-to-treat, switch included):
  • Abacavir: 16 MIs; 0.168%; 2.09 per 1000 PY.
  • Non-abacavir: 11 MIs, 0.235%; 2.57 per 1000 PY.
• Results were consistent when the analysis was restricted to the 12 trials in which participants were randomized to receive abacavir or a control drug/placebo:
  • Abacavir: 4 MIs; 2.15 per 1000 PY;
  • Non-abacavir: 7 MIs; 4.10 per 1000 PY.

"In this pooled summary, we observed few MI events overall and no excess risk of MI with abacavir therapy," the investigators stated.

"It is unclear why results from this data set seem discrepant to the [D:A:D] data set, particularly, as the non-abacavir MI event rate is similar," they added. "Further data are needed to evaluate any association between abacavir and increased risk of MI."

In their discussion, the researchers acknowledged that the total number of study participants may have been too small -- and the follow-up periods too short (typically 24 or 48 weeks) -- to detect an increase in cardiovascular events.

Furthermore, given what was known at the time the studies were designed, they typically did not collect data about cardiovascular risk factors such as blood lipid levels or biomarkers such as C-reactive protein, and did not employ HLA-B*5701 screening for abacavir hypersensitivity.

"Our initial intention was to supplement the descriptive data summaries presented in this article with a more sophisticated multivariate analysis, adjusting for available baseline cardiovascular risk factors," the authors wrote. "However, given the relatively small number of CAD and MI events observed and missing baseline CAD risk factor data for many individuals, this additional work was not viable."

"Whether abacavir has a role in coronary heart disease risk needs further clarification and understanding; however, it is clear that combination antiretroviral therapy overwhelmingly provides substantial survival benefit to patients with HIV," they concluded. "As with all medications, physicians and patients must weigh the risks of HIV disease against the overall benefits and risks of the antiretroviral medicines available."

GlaxoSmithKline Infectious Disease Medicine Development Center, Research Triangle Park, NC; GlaxoSmithKline Global Clinical Safety and Pharmacovigilance and Infectious Disease Medicine Development Center, Middlesex, UK; GlaxoSmithKline Worldwide Epidemiology, Upper Providence, PA.

5/19/09

Reference

CH Brothers, JE Hernandez, AG Cutrell, and others. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. Journal of Acquired Immune Deficiency Syndromes 51(1): 20-28. May 1, 2009.