Abacavir and ddl Linked to Increased MI Risk
In a surprising finding from the DAD Study, recent use of abacavir or ddI was associated with increased risk for myocardial infarction.
At this year's Retrovirus Conference, investigators from the DAD Study reported an unexpected association between recent use of abacavir or ddI and increased risk for myocardial infarction (MI; ACC Mar 10 2008). Based on this finding, the FDA recently issued an "early communication," stating that it will be investigating the safety of these two drugs. Now, the DAD results have been published in The Lancet, along with a letter from the maker of abacavir (GlaxoSmithKline [GSK]).
The DAD analysis involved 33,347 HIV-infected patients from 11 cohorts and focused on cumulative, past, and recent (within the previous 6 months) use of five NRTIs: AZT, ddI, d4T, 3TC, and abacavir. Statistical adjustments were made for cardiovascular risk factors that were not likely to be affected by antiretroviral therapy and for cohort, calendar year, and use of other antiretrovirals. During nearly 158,000 person-years of follow-up, 517 study participants had verified MIs. No association was seen relative to the use of AZT or d4T; one model noted a weak association with recent 3TC use (relative risk, 1.69; P=0.04). Recent use of ddI and abacavir were each significantly associated with increased MI risk (RRs, 1.49 [P=0.003] and 1.90 [P=0.0001], respectively). This excess risk was greatest in patients already deemed most likely to develop heart disease in the next decade, but, even after adjustment for that factor, the higher MI risk due to ddI and abacavir use persisted. No association was seen with cumulative use of these drugs or with use more than 6 months in the past.
In accompanying correspondence, GSK investigators summarized data from 54 GSK-sponsored studies with 24 to 48 weeks of follow-up. They reported no increase in MI risk among 9639 patients who received abacavir, compared with 5044 patients who did not.
The GSK analysis suffers from short observation times, a mixture of study designs, a small number of MIs (11), and a lack of standard clinical verification of MIs. (The FDA has stated that the results of both this analysis and a similar one from the maker of ddI are inconclusive.) As noted by editorialists and the DAD investigators, the association between ddI or abacavir use and MI risk in the DAD Study was unexpected, and the underlying biological mechanism is unclear. Furthermore, we do not yet know whether testing for HLA B*5701 before prescribing abacavir would influence any link between use of the drug and MI risk, because such testing was not yet standard practice during the time periods covered in these analyses. Notably, no comparable data are available yet regarding the safety of tenofovir or FTC, the former being the major alternative to abacavir.
The increased MI risk previously seen with PI use in the DAD Study (ACC Jan 1 2004 and Apr 25 2007) has not been a major deterrent to using boosted PIs when indicated. Whether the same will be true with abacavir remains to be seen. For now, use of abacavir among patients at higher risk for MI should be carefully considered in light of the DAD data. For those at moderate to low risk for MI, abacavir use remains reasonable, with continued focus on reducing other cardiovascular risk factors, such as smoking.
— Keith Henry, MD
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In a surprising finding from the DAD Study, recent use of abacavir or ddI was associated with increased risk for myocardial infarction.
At this year's Retrovirus Conference, investigators from the DAD Study reported an unexpected association between recent use of abacavir or ddI and increased risk for myocardial infarction (MI; ACC Mar 10 2008). Based on this finding, the FDA recently issued an "early communication," stating that it will be investigating the safety of these two drugs. Now, the DAD results have been published in The Lancet, along with a letter from the maker of abacavir (GlaxoSmithKline [GSK]).
The DAD analysis involved 33,347 HIV-infected patients from 11 cohorts and focused on cumulative, past, and recent (within the previous 6 months) use of five NRTIs: AZT, ddI, d4T, 3TC, and abacavir. Statistical adjustments were made for cardiovascular risk factors that were not likely to be affected by antiretroviral therapy and for cohort, calendar year, and use of other antiretrovirals. During nearly 158,000 person-years of follow-up, 517 study participants had verified MIs. No association was seen relative to the use of AZT or d4T; one model noted a weak association with recent 3TC use (relative risk, 1.69; P=0.04). Recent use of ddI and abacavir were each significantly associated with increased MI risk (RRs, 1.49 [P=0.003] and 1.90 [P=0.0001], respectively). This excess risk was greatest in patients already deemed most likely to develop heart disease in the next decade, but, even after adjustment for that factor, the higher MI risk due to ddI and abacavir use persisted. No association was seen with cumulative use of these drugs or with use more than 6 months in the past.
In accompanying correspondence, GSK investigators summarized data from 54 GSK-sponsored studies with 24 to 48 weeks of follow-up. They reported no increase in MI risk among 9639 patients who received abacavir, compared with 5044 patients who did not.
The GSK analysis suffers from short observation times, a mixture of study designs, a small number of MIs (11), and a lack of standard clinical verification of MIs. (The FDA has stated that the results of both this analysis and a similar one from the maker of ddI are inconclusive.) As noted by editorialists and the DAD investigators, the association between ddI or abacavir use and MI risk in the DAD Study was unexpected, and the underlying biological mechanism is unclear. Furthermore, we do not yet know whether testing for HLA B*5701 before prescribing abacavir would influence any link between use of the drug and MI risk, because such testing was not yet standard practice during the time periods covered in these analyses. Notably, no comparable data are available yet regarding the safety of tenofovir or FTC, the former being the major alternative to abacavir.
The increased MI risk previously seen with PI use in the DAD Study (ACC Jan 1 2004 and Apr 25 2007) has not been a major deterrent to using boosted PIs when indicated. Whether the same will be true with abacavir remains to be seen. For now, use of abacavir among patients at higher risk for MI should be carefully considered in light of the DAD data. For those at moderate to low risk for MI, abacavir use remains reasonable, with continued focus on reducing other cardiovascular risk factors, such as smoking.
— Keith Henry, MD
CLICK HERE for AIDS Clinical Care subscription information.
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