February 4, 2008

Abacavir, Didanosine Linked to Increased Heart Attack Risk

Abacavir—the active drug in Ziagen and a component of Epzicom and Trizivir—may double the risk of a heart attack in HIV-positive people currently using the drug, a potential concern for individuals with other major heart disease risk factors. The latest results from the international Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study, reported today at the 15th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, also found an increased heart attack risk associated with current use of didanosine (Videx EC) but not other drugs in the nucleoside reverse transcriptase inhibitor (NRTI) class, including zidovudine (Retrovir) and stavudine (Zerit).

While most research has focused on the role of protease inhibitors and the risk of cardiovascular disease, little data have been generated regarding the potential association between NRTIs—which are almost always used in HIV drug combinations—and heart attacks. Zidovudine and stavudine are two NRTIs that have been linked to higher lipid levels and insulin resistance, two risk factors for heart disease. However, there hasn’t been any research showing that these two agents actually increase the risk of a heart attack.

Hypothesizing that stavudine and zidovudine do increase this risk, the D:A:D investigators examined their suspicions by turning to the D:A:D cohort of more than 33,000 HIV-positive patients who have been followed over the past seven years at clinics based in Europe, Australia and North America. To ensure balanced reporting, the D:A:D researchers also looked at the heart attack risk among those who have used, or are currently taking, the NRTIs abacavir, didanosine, and lamivudine (Epivir)—none of which have been tied to problems known to increase the risk of cardiovascular disease.

Surprising the researchers, an increased risk of a heart attack was documented only in patients currently receiving abacavir and didanosine. Abacavir use was associated with a 90 percent increased risk of experiencing a heart attack. Didanosine use was associated with a 49 percent increased risk of a heart attack.

Additional analysis suggested that the increased risk with these two drugs could be confirmed only in people currently using abacavir or didanosine. An increased risk was not found among past users of abacavir or didanosine, regardless of how long they were on treatment with either NRTI, provided that they had been discontinued at least six months previously. According to the study authors, this finding suggests that the potential cardiovascular effects of abacavir and didanosine are reversible if the drugs are stopped.

Neither past nor present use of stavudine or zidovudine increased the risk of a heart attack.

A position statement released by D:A:D study organizers, published on its website to coincide with the presentation of the data at CROI, suggests that these results need to be interpreted carefully and stresses that the effect of abacavir and didanosine was most pronounced in patients with a high underlying cardiovascular risk due to other factors.

“In people who start abacavir or [didanosine] with a low risk based on other factors,” the authors of the position statement write, referring to those who are young, do not smoke, have no diabetes or high blood pressure, and normal cholesterol levels, “increasing the low risk by 90 percent still results in a low absolute risk of having a heart attack. However, in someone who starts off with a high risk of a heart attack based on other factors"—such as a cigarette smoker, who has a 2- to 3-fold greater risk of a heart attack, compared with the 1.90-fold increase associated with abacavir treatment—"increasing this existing high risk by 90 percent means that the additional effect from abacavir or [didanosine] will be more important.”

The D:A:D investigators did not offer a potential explanation for these "surprising and unexpected" findings. Additional research will be needed to explore the link between heart attacks and the use of abacavir or didanosine.

The authors of position statement also note that patients receiving abacavir or didanosine should consult with their health care providers to discuss whether a modification of their current drug regimen is appropriate.

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