Questions and Answers: AIM-HIGH Study
May 26, 2011
- What was the purpose of the AIM-HIGH study and what questions did it plan to answer?
- How was the study designed, and what were the criteria for participation?
- Why did NHLBI feel it was important to conduct this study?
- Why was the study stopped early?
- Who decided to stop the study?
- What did the preliminary results of the study show?
- Why did more people who took niacin have strokes?
- What is niacin? What is it typically used to treat and at what dose?
- What is the recommended daily amount of niacin? What dose was used in AIM-HIGH?
- If I am taking niacin now to help control cholesterol, should I stop because of the results of AIM-HIGH?
- Am I at risk for a stroke if I take niacin?
- I take niacin as part of a vitamin or other supplement. Should I stop because of the results of AIM-HIGH?
- Given this study’s results, should I be worried about or stop taking my statin?
- What do the study results mean for people with low HDL and high triglyceride levels?
- What are the potential side effects of niacin?
- What are the potential side effects and of statins?
- Has the NHLBI notified study participants and sites of its decision to stop the study? Will study investigators be conducting any participant follow-up? If so, how long will participants be followed?
- How was AIM-HIGH funded? What was Abbott Laboratories’ relationship to this study?
- How did you address participant safety in this trial?
- How many people died during the study?
- Are there other studies similar to AIM-HIGH currently underway? Will they have to be shut down early?
- When will the data from AIM-HIGH be available?
- Where can I get more information on AIM-HIGH?
- Where can I learn more about ways to treat or prevent high cholesterol?
AIM-HIGH was meant to test whether adding high dose, extended-release niacin to a statin (simvastatin) is better than a statin alone in reducing long-term cardiovascular events in participants whose LDL or “bad” cholesterol was controlled and who had a history of cardiovascular disease, low levels of HDL or “good” cholesterol, and high levels of triglycerides, another type of fat in the blood.
The study examined whether the combination statin/niacin therapy was safe and whether it lowered the risk of total heart or vascular events including: coronary heart disease death, non-fatal heart attack, ischemic stroke (when arteries leading to the brain are blocked), hospital stays for acute coronary syndrome (a series of conditions affecting coronary arteries), and coronary or cerebral revascularizations (procedures to improve blood flow in the vessels of the heart or brain).
AIM-HIGH was a multicenter clinical trial with about 90 sites in the United States and Canada. The study began enrolling patients in 2006 and was scheduled to finish in 2012. Researchers enrolled 3,414 volunteers. Men and women had to be at least 45 years of age with established vascular disease and dyslipidemia (too much fat in the blood) to be enrolled in AIM-HIGH. "Established vascular disease" was defined as documented by the existence of any one of the following: multi-vascular coronary artery disease, history of myocardial infarction (heart attack), hospitalization for unstable angina (chest pain) with evidence of ischemia, ischemic stroke or peripheral artery disease. Many participants also had diabetes or metabolic syndrome, a combination of risk factors for heart disease.
Participants were randomly assigned to one of two groups -- that is, they had an equal chance of being assigned to each group. One group received high dose, extended-release niacin (Niaspan) while the other received a placebo, or an inactive substance. The study was double-blinded, meaning that neither the participant nor the provider knew who was getting the active study drug or a placebo. The niacin dose was up to 2,000 mg per day, depending on the highest dosage a participant could tolerate during the trial’s starting phase.
All participants received the statin simvastatin (Zocor). The simvastatin dose was adjusted to keep LDL levels within a target range of 40-80 mg/dL (1.0-2.1 mmol/L).
Some participants also received ezetimibe (Zetia), another cholesterol-lowering drug, to help reach this target LDL range.
Participants in AIM-HIGH were to be followed for 4-6 years. The study was stopped 18 months early. The actual average follow-up is 32 months.
Coronary heart disease remains the leading cause of death and disability in the United States and the Western world. There are 18.7 million people in the U.S. with a history of heart attack and/or angina (chest pain). Another 6.4 million have had a stroke, and 8 million have peripheral artery disease (PAD). The cost to treat heart disease in the U.S. will triple by 2030. This financial burden makes it even more urgent to implement strategies to prevent strokes and heart disease.
There has been great progress in advancing medical therapies for cardiovascular disease. However, people who are successfully managing their LDL cholesterol but have low HDL and high levels of triglycerides are still at risk of future cardiovascular events such as heart attack and stroke. The AIM-HIGH study was conducted to find out if a treatment to raise low HDL would reduce the risk of people with this profile.
The trial was stopped early because the study hypothesis was answered, namely there was a lack of efficacy. The addition of high dose, extended release niacin to a statin increased HDL cholesterol, as expected, but did not reduce cardiovascular events in AIM-HIGH participants. The analysis also showed that there was little to no chance that adding high-dose, extended release niacin to statin treatment would show a benefit even if the study continued to its originally planned completion.
There was also an unexplained higher rate of ischemic stroke in the high dose niacin group compared to the group on statins alone that contributed to the decision to stop the trial early. The overall frequency of stroke was less than 1 percent and previous studies of niacin therapy have not shown this increase in stroke.
The trial's Data and Safety Monitoring Board (DSMB), an independent advisory group appointed by the NHLBI that monitors trial’s progress and participant safety, reviewed the data and recommended to the NHLBI that the study be stopped. After reviewing the DSMB recommendation, the NHLBI decided to stop the AIM-HIGH trial.
AIM-HIGH data showed that, if the trial had continued, there was less than a 1 in 10,000 chance that it would ever show a significant benefit on the primary outcome measure: a reduction in the combined rates of cardiovascular disease deaths, non-fatal heart attacks, stroke due to blockage of arteries leading to the brain, hospitalization for acute coronary syndrome, or symptom driven coronary or cerebral revascularization surgeries. Researchers are still completing data collection and analyzing the data from AIM-HIGH. They plan to report the preliminary findings in a national scientific meeting and publications in late 2011.
AIM-HIGH researchers do not yet know why there were more strokes in the niacin group. The overall rate of stroke was less than 1 percent and an increase in stroke has not been found in other niacin studies. One third of niacin group patients who suffered a stroke had stopped niacin for months to years before the event. The significance of strokes observed is uncertain and could be due to chance. The investigators will thoroughly review all study data in hopes of answering this important question.
Niacin is also known as vitamin B3. It is necessary for proper health.
Niacin is used to treat pellagra (severe niacin deficiency), a potentially fatal disease of inadequate diet, and other medical problems, at a dose of 40 to 250 mg/day.
Immediate- and extended-release preparations of niacin improve lipid (fat) levels in the blood. High dose niacin (1,000 mg to 2,000 mg or 1 to 2 grams) decreases triglyceride levels by 15 to 20 percent and increases HDL cholesterol levels by 15 to 30 percent. Reductions in LDL cholesterol are modest (less than 10 percent).
The recommended daily allowance is about 16 mg.
Study participants received a special formulation of niacin that requires a prescription. The study dose was gradually stepped up until participants were taking up to 2,000 mg (2 grams) per day or 100 times what is recommended as a daily vitamin.
People should not take more than 3,000 mg (3 grams) of niacin per day.
No, talk to your primary care doctor or cardiologist before changing any prescribed medications.
Further analysis of the study data is needed to answer this question. Niacin taken at recommended doses (such as in multivitamins) appears to be safe. Any potential risks of taking niacin in larger doses with regard to ischemic stroke will need to be further studied.
The niacin dose (up to 2,000 mg) used in AIM-HIGH was up to 100 times greater than the amount found in a typical multivitamin, which is around 20 mg. There is no known risk of adverse cardiovascular events due to taking a multivitamin that includes small amounts of niacin. Talk with your health care provider if you have concerns.
No, there is absolutely no indication from AIM-HIGH that taking statins causes any harm at the recommended dose. Statins are very effective in lowering LDL cholesterol and reducing cardiovascular risk and are safe for most people. If you are worried about your health or any medications you are taking, please consult your primary care provider or cardiologist.
Researchers are still analyzing the trial results and will not have any recommendations until all of the data have been analyzed. In the meantime, people with low HDL and high triglycerides should continue their treatment plans as recommended by their doctors. People who are similar to the study participants should discuss the AIM-HIGH findings with their health care providers.
The most commonly reported adverse effects for high dose, extended-release niacin include flushing, itching, rash, and gastrointestinal upset. These symptoms are usually worse in the early weeks of treatment and improve over time. Taking high dose, extended-release niacin in the evening about half an hour after taking an aspirin or NSAID (non-steroidal anti-inflammatory drug) can reduce symptoms.
High dose, extended-release niacin can also raise blood sugar levels and may cause a flare-up of gout due to increased uric acid.
Statins are generally well tolerated. The most common side effects are headaches and gastrointestinal distress. Serious, but rare, side effects of statins include extreme muscle pain, rhabdomyolysis (when skeletal muscle tissue breaks down and enters the bloodstream), and liver problems.
17. Has the NHLBI notified study participants and sites of its decision to stop the study? Will study investigators be conducting any participant follow-up? If so, how long will participants be followed?
We have notified all participants about the preliminary results from the study and the reason for stopping the trial. Participants will be instructed to stop taking the study medication (which contains either niacin or placebo), but to continue taking simvastatin. Study sites will be completing a final study visit to evaluate how each patient is doing, collect final safety labs to share with each participant’s primary care physician, and answer any questions the participant may have about the study.
The NHLBI has recommended investigators continue to conduct follow-ups over the phone with each participant for 12 to 18 months after the final study visit to ascertain patient health and well-being.
The study was jointly funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, and Abbott Laboratories. In addition to financial support, Abbott supplied the study with the Niaspan tablets. Abbott had no role in either the conduct of the trial or the decision to stop the study. Merck Pharmaceuticals provided the Zocor.
Participants underwent exams at the study sites every six months. During these visits, they had laboratory tests and were asked about any adverse effects they might be experiencing. Liver function tests (AST) were done every six months, while glucose tests and electrocardiograms (ECGs) were done every 12 months. Other laboratory tests were completed as needed for participants experiencing adverse side effects. Additionally, and as customary, the NHLBI appointed an independent Data and Safety Monitoring Board (DSMB) of experts who met and reviewed reports on performance and outcomes including adverse events every six months. A major function of the DSMB is to review and protect participant safety over the course of the trial.
During the study, 145 participants died. No deaths are thought to have occurred due to the treatments being tested.
The HPS2-Thrive is a similar study being conducted in Europe and China with approximately 25,000 participants. It has a broader study population and is using a high-dose, extended-release niacin that contains an anti-flushing agent. The combination of niacin and the anti-flushing agent is not approved for use in the United States. Whether that study continues is the decision of that trial’s DSMB and the groups running the trial.
Trial data is expected to be ready in late 2011.
The website for the trial is www.aimhigh-heart.com. It has detailed information about the study and how it was designed. Information is also available at: http://clinicaltrials.gov/ct2/show/NCT00120289?term=AIM-HIGH&rank=3
You can talk to your healthcare provider or a cardiologist about options for treating high cholesterol. You can also find information on the NHLBI’s website at: http://www.nhlbi.nih.gov/health/health-topics/topics/Hbc/