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DAD: An Updated Analysis of Heart Attack Risk

February 2010

Some HIV-positive people can have more traditional risk factors for cardiovascular disease than HIV-negative people, including one or more of the following:

  • smoking tobacco
  • abnormal cholesterol levels
  • injecting illicit drugs such as cocaine, crystal meth or heroin

A large database called DAD has collected health information on just over 33,000 HIV-positive people living on several continents. DAD regularly analyses its data to find associations between the medicines people take and possible side effects.

The latest report from DAD focuses on the association between heart attacks and the use of particular anti-HIV drugs.


Understanding Risk

Before discussing the latest analysis from the DAD study, it might be helpful to review how researchers talk about risk.

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Normally, when we speak about risk, we mean overall (or absolute) risk, which tells us the probability that a certain event (such as a heart attack) will happen over a given period of time. Generally speaking, the overall risk of a heart attack in people living with HIV is quite low. Overall, about 2% of 33,000 people in the DAD study developed a heart attack; so in the DAD study, heart attacks are generally uncommon. However, everyone's overall risk for a heart attack is different, so some people living with HIV may have a much higher overall risk depending on risk factors such as whether or not they smoke or their family history of heart attack.

When researchers want to study the risk of a heart attack associated with taking a particular drug, they try to measure the percentage change in the overall risk that results from taking that drug. This is called the relative risk. The relative risk gives us information about how much more (or less) likely a heart attack will be if the person is taking the particular drug studied compared to if they are not taking the drug. For example, a study may find a 70% increase in the relative risk of a heart attack. This means that the risk of a heart attack is 70% higher among people taking the drug than among people who are not taking the drug. The relative risk measures a change in risk, it does not measure the overall risk

In order to know what the relative risk, reported by researchers, means for you, you need to also consider your overall risk for heart attack. Your doctor can help you to determine your overall risk. If your overall risk of a heart attack is low prior to starting the drug, a 70% increased relative risk might not be significant compared to someone else whose initial overall risk for a heart attack is very high. And bear in mind that a 70% increase in relative risk does NOT mean that there is a 70% chance you will get a heart attack.

Now, onto the DAD study.


Study Details

The DAD study group analysed data from 33,308 HIV-positive people and divided them into two groups as follows:

  • 580 people who had a definite or possible heart attack
  • 32,728 people who did not have a heart attack.


Results -- Profile of People With a Heart Attack

In general, people who experienced a heart attack, compared to people who did not, were more likely to have the following features:

  • male
  • age: 50 years and older
  • have a personal or family history of cardiovascular disease (CVD)
  • diabetes
  • high blood pressure
  • abnormal lipid levels
  • be at high risk for CVD


Heart Attack Risk -- Protease Inhibitors

DAD found that the relative risk of a heart attack increased with each year that the following drugs were used:

  • indinavir (Crixivan): 12% increased relative risk for a heart attack each year
  • lopinavir-ritonavir (Kaletra): 13% increased relative risk for a heart attack each year

Both indinavir and lopinavir-ritonavir belong to the family or class of anti-HIV drugs called protease inhibitors. So far, no other protease inhibitors have been associated with an increased relative risk for heart attack in the DAD study.


Heart Attack Risk -- Nukes

Abacavir (Ziagen, and in Kivexa and Trizivir) and ddI (Videx EC) belong to a group of drugs called nukes (nucleoside analogues). For each year that a person took abacavir, DAD found that their relative risk of a heart attack increased by 7%. This risk is relatively small and has been described by expert reviewers as "marginal." However, among people who were either currently using or had used abacavir within the past six months, the relative risk of a heart attack increased 70%.

Among people who used ddI recently, there was a 41% increased relative risk for a heart attack.


Why Is Caution Needed?

The DAD study design is that of an observational or cohort study. Such studies are very good at finding associations -- in this case, between the use of a certain drug and having a heart attack. However, observational studies by their nature can only find associations; they cannot prove cause and effect. That is, they cannot prove that taking a particular medicine(s) will indeed cause a particular effect (heart attack).

Furthermore, confounding or channeling bias is a problem that bedevils observational studies and makes drawing firm conclusions difficult when interpreting the data. Observational studies are useful for finding associations that can later be explored in studies of a more robust design, such as a randomized clinical trial.

Kidney disease increases the risk for a heart attack, as a report later in this issue of TreatmentUpdate notes. However, the DAD researchers can only account for some cases of kidney disease and its impact on cardiovascular health. The issue of kidney disease and its impact on CVD health in DAD needs to be investigated further.


Substance Use

Taking stimulants such as cocaine, crystal meth and ecstasy can greatly stress the heart and blood vessels, increasing the risk for a heart attack. Also, people who inject drugs are prone to bacterial infections that attack the heart. Another large database, the French Hospital Database (FHDB), found that people who injected illicit drugs and who used abacavir were at heightened risk for a heart attack.

DAD needs to assess substance use in its records and find out if there was a link to heart attacks.


Changing Findings

DAD has previously reported that exposure to all protease inhibitors was associated with a 16% increased relative risk of heart attack for each year that these drugs were used. Now, DAD has taken into account exposure to nukes and found that only two protease inhibitors -- indinavir and lopinavir-ritonavir -- are associated with this problem.

Also, DAD previously found that the relative risk of a heart attack when using abacavir was increased by about 90%. In the present analysis the relative risk has declined but is still high, at 70%.

There may be further changes to DAD's analyses in the years ahead.


Guiding the Reader

Biomedical journals sometimes publish editorials or commentaries to help readers make sense of complex research studies. To accompany the latest report from DAD, the Journal of Infectious Diseases published an editorial that noted the limitations of observational studies. The editorial, in reflecting on how DAD did its data analysis stated:

"It could be easy to be misled by apparent induced associations."

The DAD team is aware of the study's limitations and has conducted sensitivity analyses to check for hidden biases that may occur when interpreting the data. But the editorial in the Journal of Infectious Diseases notes this about sensitivity analyses:

"Such analyses may induce or attenuate associations between treatment and outcome."

One of the issues with the association found in DAD between abacavir and heart attacks is this: Two years since the first report by DAD, there is no conclusive evidence of how abacavir might increase the risk for a heart attack. An important point to bear in mind is that the proportion of people who had a heart attack in DAD is very low -- about 2%.


What to Do?

Committees of physicians and researchers who help write treatment guidelines in the European Union and the United States are aware of DAD's strengths and weaknesses and have offered this advice about abacavir and heart attacks:

"Abacavir should be used cautiously in people at high risk for cardiovascular disease."

Since HIV infection is associated with an apparent accelerated aging of the cardiovascular system, more attention needs to be paid to reducing or ideally eliminating modifiable risk factors for a heart attack.

For more ways to have a healthy heart, see CATIE's in-depth Fact Sheet.


References

  1. Lo J, Abbara S, Shturman L, Soni A, et al. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS. 2010 Jan 16;24(2):243-53.
  2. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. Journal of Infectious Diseases. 2010 Feb 1;201(3):318-30.
  3. D:A:D Study Group, Sabin CA, Worm SW, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008 Apr 26;371(9622):1417-26.
  4. DAD Study Group, Friis-Møller N, Reiss P, et al. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medicine. 2007 Apr 26;356(17):1723-35.
  5. Aberg JA, Ribaudo H. Cardiac risk: not so simple. Journal of Infectious Diseases. 2010 Feb 1;201(3):315-7.
  6. 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, July 19-22, 2009, Cape Town, South Africa. Abstract MOAB201.
  7. Sabin CA, Worm S, Phillips AN, et al. Abacavir and increased risk of myocardial infarction. Lancet. 2008 Sep 6;372(9641):804-5.



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.
 

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