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DAD study: 26% increased risk of stroke, angioplasty or bypass surgery for each year on HAART
Edwin J. Bernard, Friday, August 27, 2004
Incremental new data from the landmark DAD (Data collection on Adverse event of anti-HIV Drugs) trial, which last year reported a 26% increased risk in the frequency of heart attacks (myocardial infarctions, or MI) per year of antiretroviral drug exposure, has found that HAART also increases the risk of stroke and other cardiovascular or cerebrovascular events (CCVEs) by the same amount. The results appear in the September 3rd issue of the journal AIDS.

DAD is an observational study established to track long-term antiretroviral safety involving over 23,000 HIV-positive people in eleven cohorts in three continents. Their first findings, published in 2003, was that during over 36,165 person-years of follow-up, 126 people suffered a heart attack, or myocardial infarction (MI), 36 of which were fatal. The incidence of MI increased with additional years on combination antiretroviral therapy, resulting in a 26% increased risk of MI per year of drug exposure. However, overall, the frequency of reported MI remained low at 3.5 cases per 1,000 person-years of follow-up.

In this analysis, an additional 81 patients experienced at least once CCVE other than an MI.

The other CCVEs included in this analysis were:

  • Invasive cardiovascular procedure: a procedure in which the interior of the body is "invaded" either by catheters placed in large blood vessels, or by surgical or related procedures, for example coronary artery angioplasty (blockage removal) or bypass surgery. This was the first CCVE in 39 patients, and no-one died.

  • Stroke (a sudden disruption of the blood flow to the brain). This was the first CCVE in 38 patients, and nine were fatal.

  • Deaths from other CCVEs. Four patients died from a CCVE, having never previously experienced another cardio- or cerebrovascular event.

The incidence of first CCVE was 5.7 cases per 1,000 person-years of follow-up (95% confidence interval [CI] 5.0 - 6.5), and increased with longer exposure to antiretroviral therapy (p < 0.001). Given the range of events reported, this is still a relatively low frequency, and is not enough for the investigators to pin the blame on a particular class of antiretroviral.

To put this into perspective with the other, classic risk factors for CCVE, the authors examined the relative risk (RR) through multivariate analysis.

They were, in order of risk:

  • Previous history of CCVE (RR, 7.12; 95% CI 4.91 - 10.3; p < 0.001).

  • Male gender (RR, 1.82; 95% CI 1.10 - 3.00; p = 0.02).

  • Smoking (RR, 1.66; 95% CI 1.14 - 2.42; p = 0.008).

  • Family history of CCVE (RR, 1.62; 95% CI 1.05 - 2.50; p = 0.03).

  • Older age (RR per five years older, 1.42; 95% CI 1.32-1.52; p < 0.001).

  • Antiretroviral therapy (RR per year of exposure, 1.26; 95% CI 1.14-1.38; p < 0.001).

Additional analyses tested the association between CCVE and a number of metabolic and physiological causes.
Factors independently associated with the risk of CCVE, were, in order of relative risk:

  • Diabetes (RR, 2.22; 95% CI 1.46 - 3.37; p < 0.001).

  • High blood pressure (RR, 1.79; 95% CI 1.25 - 2.56; p = 0.001).

  • High triglycerides (RR, 1.30; 95% CI 1.12 - 1.51 per log2 higher; p = 0.006).

  • High cholesterol (RR, 1.11; 95% CI 1.03 - 1.19 per mM higher; p = 0.008).

The authors conclude that “the results of this study further support the hypothesis that [antiretroviral therapy] is associated with increased risk of atherosclerosis.” However, more follow-up of this cohort is necessary to determine whether the risk will continue to increase with the length of antiretroviral therapy. So far, their analysis shows that the risk increases each year during four years of follow-up, with a doubling of risk after four years of antiretroviral treatment compared to someone who has not taken antiretrovirals.

Importantly, the DAD study does not differentiate between different classes of antiretrovirals and their relative risk, since there have not been enough clinical endpoints for the investigators to be absoutely certain of the significance of their interpretations. These analyses are planned for the future.

Reference
The DAD Writing Committee. Cardio- and cerebrovascular events in HIV-infected persons. AIDS 18: 1811-1817, 2004.