A US Food and Drug Administration (FDA) analysis of 26 trials comparing Ziagen (abacavir) to other drugs found no evidence that this antiretroviral raises the risk of myocardial infarction (heart attack).1 Ziagen is part of the two-drug combination Epzicom or Kivexa and the three-drug combination Trizivir.
Earlier, a large study of people taking antiretrovirals2 and analysis of SMART trial results3 suggested that Ziagen does raise the risk of heart attack and other heart disease. But the FDA study contradicts that finding. For people with HIV and physicians unsure about how to interpret all these findings, the FDA offers some advice, summarized below in What the results mean for you.
The DAD Study Group analyzed the impact of current or recent nucleosides in 33,347 people taking antiretrovirals.2 Using standard statistical methods, the DAD researchers found no associations between the heart attack rate and total or recent use of Retrovir (zidovudine), Zerit (stavudine), or Epivir (lamivudine). But in an analysis that accounted for 10-year risk of heart disease, recent use of Ziagen raised the heart attack risk 89%, and recent use of Videx (didanosine) raised the risk 49%.
The SMART trial randomized HIV-positive people to take antiretrovirals continuously or to interrupt treatment according to their CD4 count. Analysis of heart disease rates in these people determined that recent Ziagen use almost doubled the risk of major heart disease (heart attack, stroke, or surgery for coronary artery disease).3
Partly because of the DAD and SMART results, experts who write antiretroviral guidelines in the United States removed Ziagen from the list of drugs recommended for a first antiretroviral combination. But several other studies found no link between Ziagen and heart disease. And safety data collected by Ziagen's maker saw no hint that Ziagen makes heart disease more likely. The FDA decided the issue is important enough to examine in a different way -- by comparing heart attack rates in people who took Ziagen in randomized trials with rates in people who did not take Ziagen in those trials.
How the study worked. FDA researchers reviewed four databases to find randomized trials (that is, trials in which study participants are assigned by chance to one treatment or another). The trials selected for analysis had to meet five requirements: (1) patients were adults, (2) at least 50 people were studied, (3) the trial was completed, (4) the trial was not planned mainly to measure antiretroviral levels in people, and (5) the trial did not take place in Africa.
The FDA team used standard statistical methods to determine whether heart attack rates differed in people taking antiretroviral combinations including Ziagen versus people taking combinations not including Ziagen.
What the study found. The FDA found 26 trials to analyze. Sixteen trials were conducted by GlaxoSmith- Kline, the company that makes Ziagen. Five trials were run by the US AIDS Clinical Trials Group (ACTG). And five trials were run by physicians at university medical centers. Together, the studies included 5028 people taking Ziagen and 4840 taking combinations not including Ziagen. Average follow-up (patient monitoring time) in these studies was 719 person-years, or an average 1.6 years for each person. The FDA relied on heart attack reports noted by the original researchers; they did not analyze these findings further to confirm that all these people had heart attacks.
About 80% of people in these trials were men, and their ages averaged about 40 years. CD4 counts when trials began averaged 360 in the GlaxoSmithKline trials, 236 in the ACTG trials, and 252 in the university trials. The FDA rated overall heart attack risk in these people as "moderate" (0.45%).
The main analysis found no difference in heart attack rate between people taking Ziagen and people not taking Ziagen in these studies. When the FDA team looked only at trials run by Ziagen's maker, they also found no difference in heart attack rate with and without Ziagen. The same was true for the ACTG trials and the university trials. No single trial analyzed had evidence that Ziagen raises the risk of heart attack. The FDA performed further analyses to determine the statistical power of their study to detect a heart attack difference between people taking versus not taking Ziagen. Note 4 in the References summarizes these technical details.
What the results mean for you. The FDA researchers concluded that their findings "raise significant uncertainty about the likelihood of [a Ziagen-heart attack] association."
It is important to understand that the FDA study analyzed trials that were not planned to figure the risk of heart attack or any heart disease in people taking Ziagen or non-Ziagen combinations. One of two earlier studies that did find a higher heart attack risk with Ziagen is a cohort study.2 In this type of study, researchers monitor many health changes in antiretroviral-treated people over time, but those people are not randomly assigned to take one set of antiretrovirals or another. As a result, it is possible that factors not included in the analysis may explain why a higher proportion of people taking Ziagen had heart attacks.
An advantage of this kind of cohort study is that it includes a much larger number of people than an analysis of randomized trials. There were 33,347 people in the DAD cohort study and 157,912 person-years of observation.2 In contrast, there were 9868 people in the FDA study and an average of 719 person-years of observation in each of the 26 trials analyzed.1 Also, average age in the FDA study was 40 compared with 49 in the cohort study, which means people in the FDA study would be less likely to have heart attacks because they were younger. However, statistical analysis by the FDA researchers convinced them that their results make it highly unlikely that Ziagen raises the heart attack risk in these 26 trials.4 In a statement about this study, the FDA said "healthcare professionals should continue to prescribe [Ziagen] according to the professional label. Patients should not stop taking their [Ziagen] without first talking to their healthcare professional."5 The FDA also advised people with HIV to discuss any questions or concerns about Ziagen with their physician.
As people with HIV grow older thanks to effective antiretroviral therapy, heart attacks and other heart disease pose a growing threat. The two preceding articles in this issue of HIV Treatment Alerts! review studies that identify factors that raise the risk of heart disease in people with HIV. It is important to realize that several recent studies, including the original SMART trial,6 found that antiretroviral therapy lowers the risk of heart disease when all antiretrovirals are considered together. Interrupting antiretroviral therapy in the SMART trial raised the risk of major heart disease. Fear of heart disease is certainly not a reason to stop antiretroviral therapy or to delay starting. However, many people with HIV have heart attack risk factors that can be avoided or changed (see box).
Heart Attack Risk Factors That Can Be Avoided or Changed
Source: US National Library of Medicine, National Institutes of Health. www.nlm.nih.gov/medlineplus/ency/article/000195.htm. Accesed March 6, 2011. Illustration from the National Library of Medicine.
- High blood pressure
- Too much fat in your diet
- Unhealthy cholesterol levels, especially high LDL ("bad") cholesterol and low HDL ("good") cholesterol
- Chronic kidney disease
- Ding X, Andraca-Carrera E, Cooper C, et al. 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.
- 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. www.ncbi.nlm.nih.gov/pmc/articles/PMC2688660/?tool=pubmed. Accessed March 6, 2011.
- 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. www.ncbi.nlm.nih.gov/pmc/articles/PMC2644883/?tool=pubmed. Accessed March 6, 2011.
- "Based on our [statistical] simulations, the power of our study to exclude a relative risk of 1.8 with the observed myocardial infarction background risk (0.45%) was 0.62; however, lack of power does not explain the observed risk difference of 0.008% with a 95% confidence interval of (-0.26%, 0.27%). The simulation to assess the power demonstrates that our study had a probability of 0.95 to find a risk difference greater than 0.1%. Our study's finding is very unlikely if the true risk of [Ziagen] is 1.8 or higher at the observed background myocardial infarction risk (0.45%)."
- FDA Drug Safety Communication. Safety review update of abacavir: no statistically significant association seen between myocardial infarction and [abacavir]. March 1, 2011. www.fda.gov/Drugs/DrugSafety/ucm245164.htm. Accessed March 10, 2011.
- Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296. www.nejm.org/doi/full/10.1056/NEJMoa062360. Accessed March 6, 2011.