By Feb 1, 2007, 33 347 patients had been followed up for a total of 157 912 person-years (median 5.1 [IQR 3.2-6.5] years per person) over which time 517 patients had a myocardial infarction (event rate 3.3 [95% CI 3.0-3.6] per 1000 person-years). Of these patients, 284 (55%) were white and 304 (59%) had a homosexual risk for HIV infection. 509 individuals who had a myocardial infarction had been exposed to antiretroviral therapy, 59 of whom were off therapy at the time of their myocardial infarction. At the last test before diagnosis of myocardial infection, median CD4 cell count was 420 (range 1-1686) cells per μL; median nadir CD4 cell count was 130 (0-1020) cells per μL. 262 (51%) of these patients had a viral load of less than 50 copies per mL at the last reading before diagnosis of myocardial infarction.
Patients who had a myocardial infarction were older, more often were men and current smokers, and more often had a family history of cardiovascular disease, or were more likely to have been diagnosed with diabetes mellitus, hypertension, lipodystrophy, or dyslipidaemia than were individuals who did not have such an event (). More patients who had a myocardial infarction had a high or moderate predicted 10-year risk of coronary heart disease than did those who did not have a myocardial infarction (). When analyses were restricted to only those with sufficient data to calculate risk, 120 (33%) patients who had a myocardial infarction were at high risk and 134 (37%) were at moderate risk compared with only 1308 (6%) and 4161 (18%) patients who had not had a myocardial infarction, respectively. 29629 (90%) patients who not had a myocardial infarction had been exposed to antiretroviral therapy.
Characteristics of patients at the time of their first myocardial infarction during follow-up (or at last D:A:D follow-up visit for those who did not have a myocardial infarction)
In a regression model that incorporated cumulative exposure to each NRTI, there were no significant associations between the development of myocardial infarction and exposure to zidovudine, stavudine, or lamivudine (; model 1). However, longer duration of exposure to didanosine and abacavir was associated with an increased rate of myocardial infarction (; model 1). Initial analyses of the associations with use of didanosine and abacavir revealed that the rate of myocardial infarction increased rapidly after first use of each drug and remained high thereafter compared with patients not taking these drugs (data not shown).
Rates of myocardial infarction by exposure to various NRTIs
The rate of myocardial infarction was significantly increased with recent use of didanosine or abacavir (; model 2). The rate of myocardial infarction was 49% greater in patients who had recently used didanosine and 90% greater in those who had recently used abacavir than in those who had never used or who last used these drugs more than 6 months previously (; model 2). After adjustment for recent use of didanosine and abacavir, no evidence remained of an increased risk associated with increasing exposure to each drug (; model 2). By contrast, there were no significant associations with recent or cumulative use of other NRTIs.
There were no associations between the rate of myocardial infarction and past exposure to any of the NRTIs when we incorporated covariates for past use of each drug (; model 3); recent use of didanosine and abacavir remained significantly associated with an increased rate of myocardial infarction. In this model the comparator group consisted of patients who had never used the drug in question. Recent use of lamivudine was also associated with an increased rate of myocardial infarction (; model 3).
Additional sensitivity analyses resulted in consistent findings, even after exclusion of follow-up time and events in the first 2 months after starting abacavir and after consideration of cumulative exposure to each NRTI as a categorical rather than continuous variable (data not shown). In each case, recent—but not cumulative—exposure to didanosine or abacavir was most strongly associated with the development of myocardial infarction. There was no evidence of an interaction between recent and cumulative exposure (data not shown). Our analyses did not reveal any significant interaction between recent use of didanosine or abacavir and recent use of either the PI or NNRTI class of drugs, and results were unchanged when analyses additionally controlled for recent use of each PI (as opposed to cumulative exposure only; data not shown).
The characteristics of patients at the time of myocardial infarction were similar in those recently exposed to didanosine, those recently exposed to abacavir, and those who were antiretroviral-experienced but had not recently been exposed to either drug (). In particular, there was no evidence that the classification of myocardial infarction differed, or that myocardial infarctions were more likely to be fatal in any one group.
Patients who started abacavir or didanosine for the first time while under follow-up in D:A:D generally had worse cardiovascular risk profiles than did those who started the other NRTIs for the first time: 1119 (27%) of 4076 patients first starting abacavir and 383 (22%) of 1731 first starting didanosine had moderate or high predicted 10-year risk of coronary heart disease compared with 414 (19%) of 2177, 139 (19%) of 741, and 474 (19%) of 2546 patients first starting zidovudine, stavudine, and lamivudine, respectively. When we analysed all patients who started or switched to each NRTI (including those who restarted these drugs) during follow-up, the differences between the groups remained but were less marked: 1651 (26%) of 6266 patients starting or switching to abacavir and 1081 (24%) of 4486 patients starting or switching to didanosine had a moderate or high predicted 10-year risk of coronary heart disease compared with 1611 (22%) of 7461, 607 (23%) of 2650, and 2627 (22%) of 12 085 patients starting or switching to zidovudine, stavudine or lamivudine, respectively.
shows the characteristics of patients under follow-up with recent use of each NRTI, compared with those without recent use; the webtable describes concomitant use of other antiretroviral drugs as well as treatment history. Patients with recent exposure to abacavir were more likely to be men, older, and to have diabetes, hypertension, dyslipidaemia, or a personal or family history of cardiovascular disease than those with no recent exposure to abacavir, but were less likely to be smokers or to have a high body-mass index. Patients with recent exposure to didanosine did not differ greatly from those without recent exposure to this drug. For other NRTIs there was generally little difference between those with and without recent use, although most drugs (with the exception of zidovudine) seemed to be associated with diabetes and dyslipidaemia to some degree.
Characteristics of patients under follow-up* with recent exposure to each NRTI
shows the observed rates of myocardial infarction stratified by predicted 10-year risk of coronary heart disease as well as by recent exposure to didanosine or abacavir. In those who had no recent use of didanosine, rates of myocardial infarction were 1.3, 6.0, and 19.4 events per 1000 person-years in those with low, moderate, and high predicted risk of coronary heart disease, respectively. In those who had recently used the drug, rates were higher, with 1.8, 7.7, and 23.1 events per 1000 patient-years for those with low, moderate, and high risk of coronary heart disease. In the same categories of risk, rates of myocardial infarction were 1.0, 5.9, and 15.9 events per 1000 patient-years in those with no recent abacavir use, but 2.9, 7.7, and 32.5 events per 1000 patient-years in those with recent use of abacavir.
Rates of myocardial infarction, stratified by predicted 10-year risk of coronary heart disease, and recent use of either (A) didanosine or (B) abacavir
After incorporation of the predicted 10-year risk of coronary heart disease into the main regression model of cumulative and recent exposure to NRTIs, the rate of myocardial infarction was increased both in those with moderate and in those with high 10-year risk of coronary heart disease, compared with those with a low 10-year risk (relative rate 2.19, 95% CI 1.64-2.92 [p=0.0001] for those with moderate risk; 3.22, 2.27-4.57 [p=0.0001] for those with high risk). After adjustment for the predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained significantly associated with increased rates of myocardial infarction (relative rate 1.49, 1.14-1.95 [p=0.004] for didanosine; 1.89, 1.47-2.45 [p=0.0001] for abacavir compared with those who had never received or who had only past exposure to the drugs). There was no significant interaction between predicted 10-year risk of coronary heart disease and recent use of didanosine (p=0.36 for test of interaction between moderate/high risk and recent use of drug). However, there was a significant interaction between the predicted 10-year risk of coronary heart disease and recent use of abacavir (p=0.04 for test of interation between moderate/high risk and recent use of drug). In relative terms, the effect of recent use of abacavir was stronger in those with lower underlying risk of coronary heart disease, although the absolute difference was greater in those at higher risk of coronary heart disease.
shows the association with recent use of each drug before and after adjustment for the latest CD4 cell count, viral load, lipid and glucose measurements, blood pressure, and the presence or absence of diabetes and lipodystrophy. Adjustment for these measurements had little effect on either estimate. Further adjustment for the actual use of lipid-lowering or anti-hypertensive medication did not modify our estimates.
Relative rate associated with recent use of (A) didanosine and (B) abacavir, before and after adjustment for latest measures of response to combination antiretroviral therapy and metabolic measurements
Recent use of didanosine and abacavir was associated with the composite endpoint of myocardial infarction, cardiovascular death, or invasive cardiovascular procedure; by contrast, there was no association between cumulative exposure to didanosine and abacavir and this endpoint after adjustment for recent use of the drugs (). No association was found between exposure to either drug (either cumulative or recent use) and stroke, although confidence intervals were wider because of the smaller number of patients with this endpoint ().
Exposure to NRTIs and risk of first myocardial infarction, cardiovascular death, or invasive cardiovascular procedure, and of risk of possible or definite stroke*