French Study Unexpectedly Uncovers Role of Substance Use in Heart Attacks
From Canadian AIDS Treatment Information Exchange
Several years ago researchers working with a large observational database called DAD (with more than 33,000 HIV-positive people) announced that they had found a link between the use of the anti-HIV drug abacavir (Ziagen and in Kivexa, Epzicom and Trizivir) and an increased risk for heart attack. They also announced that they found a link between the use of the anti-HIV drug ddI (Videx EC, didanosine) and an increased risk for heart attack. Several other studies have not found this link with abacavir (and none have found a link with ddI), and so the initial findings from DAD have become deeply controversial for at least these and other reasons, as follows:
- Observational studies such as DAD are very good at finding associations but cannot by their design prove cause (taking a particular drug) and a resulting effect (heart attack).
- Abacavir has had a good overall track record of safety, so researchers were surprised by its association with heart attack.
- Cardiovascular events -- heart attacks and strokes -- can sometimes have related underlying causes, yet DAD found only an increased risk of heart attack but not stroke.
- It is possible that there were events or data in DAD that may have been overlooked which could, in theory, have biased researchers' interpretation of its analyses. For instance, DAD researchers announced last February that about 20% of people who had a heart attack while using abacavir had had a heart attack in the past. This finding might make it difficult to draw firm conclusions about the role of abacavir in heart attacks in these people.
- DAD researchers are unable to fully take into account factors such as preexisting kidney disease in all participants. This may affect their conclusions. What's more, DAD has not yet released findings on substance use by its participants, particularly substances that can stress the heart, such as cocaine, crystal meth and other stimulants. So it is possible that these factors could have biased the researchers' analyses. On the other hand, sometimes patients may be embarrassed or uncomfortable about disclosing the use of substances to their doctors, so it may not be possible to get this information.
Finally, at least two large databases, the French Hospital Database (with more than 77,000 HIV-positive people) and the Veterans Administration (almost 20,000 HIV-positive people), have not found an association between the use of abacavir and the development of heart attack or stroke. A recent analysis of Kaiser Permanente, a large database in northern California with records on more than 35,000 HIV-positive people, has found that the risk of heart attack and stroke has significantly decreased over time (1996 to 2008), falling to levels seen in HIV-negative people.
About the French Hospital Database
In 1989, doctors in France established the French Hospital Database (FHDB), which has collected health-related information on more than 77,000 HIV-positive people. Researchers working in HIV sought to assess rates of heart attacks among HIV-positive patients in France and looked at cases between the years 2000 and 2008. During this time they found 278 cases of heart attack, all of which were confirmed by a research cardiologist. These 278 cases occurred among more than 77,000 people, about 80% of whom were using HAART (personal communication, Dominique Costagliola, PhD).
Lead researcher Dominique Costagliola recently reanalyzed the FHDB's large dataset to find any links between the occurrence of a heart attack and any of the following anti-HIV drugs commonly called nukes:
- ABC (abacavir)
- AZT (zidovudine/Retrovir, and in Combivir and Trizivir)
- ddC (zalcitabine, Hivid)
- ddI (Videx EC, didanosine)
- d4T (stavudine, Zerit)
- 3TC (lamivudine, and in Combivir, Kivexa and Trizivir)
Overall, there was no statistically significant connection between the use of any of these nukes -- including abacavir -- and a heart attack.
It is important to note that French researchers made sure to take into account other conditions that are known to cause heart attacks and which could have biased their results and caused them to draw false conclusions, including these:
- higher-than-normal blood pressure
- smoking tobacco or having quit in the past three years
- family history of premature cardiovascular disease
- abnormal cholesterol levels
- use of cocaine or other illicit substances
- viral load
- CD4+ and CD8+ cell counts
The French researchers also took into account the use of the following anti-HIV medicines, in case they might have played a role in heart attacks observed in abacavir users.
- atazanavir (Reyataz)
- ritonavir (Norvir and in Kaletra)
- tipranvir (Aptivus)
- FTC (emtricitabine, Emtriva)
Researchers found that the use of these particular medicines had no significant effect.
A Lot of Cardio Risk Factors
The French researchers found that out of 278 abacavir users who had a heart attack, only five had no risk factors for cardiovascular disease (CVD). This means that 98% of abacavir users who had a heart attack had at least one risk factor for cardiovascular disease. Indeed, a large proportion (nearly 40%) of the 278 people had three or more risk factors for CVD.
The Role of HIV
Other studies have found that having HIV infection appears to be a risk factor for CVD. Among the 278 abacavir users who developed a heart attack, 56% had a detectable viral load. This could have played a role in the development of heart attack.
Going beyond previous analyses, French researchers specifically checked for the use of cocaine and other substances or behaviours, such as injecting drug use, in abacavir users who had a heart attack. Cocaine, which can be snorted or injected, is a stimulant and can stress the heart. Because injection drug use is one of the means by which HIV is transmitted, it is not surprising that some HIV-positive people use cocaine and other illicit drugs.
To find out if these drugs played a role in some of the heart attacks seen in some abacavir users, the FHDB did another analysis. When the researchers took into account the use of cocaine or other illicit substances among people who were prescribed abacavir, again they found no link between the use of abacavir and heart attacks. Furthermore, the researchers found that many of the people who used cocaine and other illicit drugs also had traditional CVD risk factors. Perhaps their use of cocaine in the setting of other CVD risk factors might have greatly increased their risk for having a heart attack.
In conclusion, Dr. Costagliola noted that traditional risk factors (high cholesterol, blood pressure and so on) in concert with cocaine and injection drug use are "very strong risk factors for [heart attack] in HIV-1 infected patients."
Therefore, based on the most recent analysis of the large French Hospital Database, particularly taking into account the use of cocaine and other illicit substances, it seems that exposure to abacavir is not statistically linked to the development of a heart attack.
However, doctors caring for HIV positive patients who use cocaine or stimulants or inject illicit substances may wish to avoid the use of abacavir in this population.
This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.NEXT ARTICLE
- Costagliola D. The current debate on abacavir; risks and relationship between HIV viremia and cardiovascular events. In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 19-22, 2009, Cape Town, South Africa. Abstract MOAB201.
- Lundgren J, Reiss P, Worm S, et al. Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI and NRTI drug classes: The D:A:D study. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal, Canada. Abstract 44LB.
- Hurley L, Leyden W, Xu L, et al. Updated surveillance of cardiovascular event rates among HIV-infected and HIV-uninfected Californians, 1996 to 2008. In: Program and abstracts of the 16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal, Canada. Abstract 710.
- Martinez E, Larousse M, Perez I, et al. No evidence for recent abacavir/lamivudine use in promoting inflammation, endothelial dysfunction, hypercoagulability, or insulin resistance in virologically suppressed HIV-infected patients: a sub-study of the BICOMBO randomized clinical trial (ISRCTN61891868). In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town, South Africa. Abstract MOAB203.
- Bedimo R, Westfall A, Dreschler H, et al. Abacavir use and risk of acute myocardial infarction and cerebrovascular disease in the HAART era. In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town, South Africa. Abstract MOAB202.
- Fichtenbaum CJ. Metabolic abnormalities associated with HIV infection and antiretrovirals. Current Infectious Disease Reports. 2009 Jan;11(1):84-92.
- Martin A, Bloch M, Amin J, et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96-week trial. Clinical Infectious Diseases. 2009; in press.
- Reiss P. The art of managing human immunodeficiency virus infection: a balancing act. Clinical Infectious Diseases. 2009; in press.
- Seaberg EC, Sharrett AR, Hodis HN, et al. Duration of HIV infection is associated with carotid artery stiffness. In: Program and abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town, South Africa. Abstract MOAB204.