William E. Boden, M.D., Professor of Medicine and Preventive Medicine
University at Buffalo Schools of Medicine and Public Health
May 26, 2011
Release of the Results of the AIM-HIGH Trial:
Background, Rationale, Design, and DSMB Description
While coronary heart disease survival has increased appreciably since the late 1960’s, the condition remains the leading cause of death and disability among both men and women in the western world. Over 16 million Americans have been diagnosed with coronary heart disease, a common condition that causes hardening of the arteries (or atherosclerosis) and can lead to heart attack, stroke, or death. The prevalence of heart disease and stroke, along with the death rate from these conditions, remains unacceptably high despite significant advances in both drugs and medical treatment techniques over the past four decades. Elevated low-density lipoprotein cholesterol, known as LDL or “bad” cholesterol, has long been known as a major predictor of coronary heart disease risk.
Current National Cholesterol Education Program (or NCEP) guidelines recommend aggressive LDL cholesterol reductions, typically with statins, to less than 100 mg/dL in high risk individuals, For those who are very high risk, the target is even lower (to below 70 mg/dL). Despite these guidelines, treating and achieving these recommended LDL targets has been a challenge outside of a research trial setting.
Early observational studies have demonstrated that elevated levels of LDL cholesterol are not the only predictor of increased coronary heart disease events . Low levels of high-density lipoprotein cholesterol, known as HDL or “good” cholesterol, are also recognized as a major predictor of coronary heart disease risk. The lower one’s HDL cholesterol , the higher the risk of developing coronary heart disease. Multiple small, but rigorously conducted, clinical trials have shown that raising HDL reduces coronary atherosclerotic plaque and suggests that there also may be a favorable effect on reducing cardiovascular events. In contrast to the well-defined treatment targets for LDL previously cited, NCEP has not yet established such targets for increasing HDL cholesterol.
Importantly, there is a growing number of patients for whom statins alone may not be the best therapeutic option. This group includes a large number of patients with low HDL cholesterol levels but normal LDL cholesterol , who may comprise 50% or more of all coronary heart disease patients, Statin therapy, while very effective clinically for lowering LDL cholesterol and cardiovascular risk, unfortunately raises HDL cholesterol levels only a small amount (between 5 percent and 10 percent).
This modest effect of statins on HDL cholesterol has rekindled interest in the use of niacin alone or with other drugs for patients with mixed blood lipid abnormalities. Niacin in high doses is the most effective known drug for raising HDL levels. Niacin also moderately reduces triglycerides, another fat in the blood, lipoprotein (a), an LDL-like particle, and, at higher doses, LDL cholesterol . Niacin is an essential nutrient, also known as Vitamin B3. To raise HDL cholesterol, one must take a niacin dose that is about 100 times the recommended daily allowance. Despite these multiple potential benefits, niacin’s clinical use has been limited as some patients do not tolerate the drug well at high doses. A common adverse reaction is skin flushing and itching, particularly when older, immediate-release formulations of niacin are used.
The AIM-HIGH study was designed to evaluate the effect of high-dose extended-release niacin in people who have had cardiovascular disease events related to diseased artery walls and whose LDL cholesterol is well controlled. There were strong reasons for using niacin in these patients. As I mentioned, earlier studies have shown a strong relationship between low HDL cholesterol and increased cardiovascular risk, even in participants on statin therapy. High-dose niacin is the most effective available treatment for raising HDL cholesterol. Secondly, niacin has a beneficial effect on specific blood lipids found in people with metabolic syndrome, a cluster of risk factors for heart disease. This benefit includes a further reduction in LDL cholesterol levels on top of that seen with statin treatment. Thirdly, niacin may promote a healthy effect on the inner lining of blood vessels and the inflammation associated with plaque build up in the arteries. Previous studies have shown that high-dose niacin may reduce obstructive plaque and coronary artery narrowings. Finally, niacin has been used in high doses for more than 50 years, so its side effects are well known.
AIM-HIGH is a double-blind, randomized controlled clinical trial designed to determine if high-dose extended-release niacin added to a statin would decrease the rate of cardiovascular events, compared to a statin alone. Our target population was patients with well-controlled LDL cholesterol levels (namely, a range between 40 – 80 mg/dL). The cardiovascular events we sought to reduce include death from coronary heart disease; non-fatal heart attack; and stroke due to blockage of arteries leading to the brain. We also hoped to reduce the number of hospitalizations for acute coronary syndrome, or the need for surgical revascularization of the coronary or cerebral blood vessels because of worsening symptoms. As already noted, participants had to have both a documented history of established, cardiovascular disease and an abnormal lipid profile consisting of low HDL cholesterol and high triglycerides in order to be enrolled in the study.
After signing consent forms, eligible participants were given both a statin and extended release niacin beginning at 500 mg/day. We increased the dosage to 2,000 mg/day over four to eight weeks to verify whether patients could tolerate high-dose niacin treatment. Those who could take at least 1,500 mg/day without significant side effects were then randomly assigned to extended-release niacin or a placebo containing a tiny dose (50 mg of immediate release niacin) to induce flushing. This small amount of niacin in the placebo ensured that study staff, as well as participants, could not tell who was taking the treatment or placebo.
All participants had their dose of simvastatin adjusted during the first 6 months after being assigned to a treatment group to reach a target LDL cholesterol of 40 – 80 mg/dL. Another LDL-lowering drug, ezetimibe, could be added, when required, if simvastatin treatment was ineffective in lowering the LDL cholesterol to the desired goal. Study patients were to be followed in clinic and by phone to a common end date, expected to be late 2012. All participants were treated in accordance with existing clinical practice guidelines, using standard secondary prevention therapies such as aspirin, beta-blockers, ACE inhibitors, or angiotensin-receptor blockers, as needed.
A group of independent investigators proposed AIM-HIGH, which was funded by the NHLBI based on the trial’s high scientific priority score assigned by an independent review committee. The grant is supported as a cooperative agreement with the NHLBI. Abbott Laboratories (originally Kos Pharmaceuticals) supported the trial by providing high dose extended release niacin and a significant unrestricted research grant to the investigators. Merck provided the simvastatin used in the trial.
The NHLBI appointed a Data and Safety Monitoring Board (DSMB), an independent panel of experts to oversee the scientific conduct of the trial and to ensure patient safety. Panel members were experts in the fields of lipid treatment, preventive cardiology, clinical trials, biostatistics, and medical ethics. The DSMB met up to twice a year, or more often as needed, to review all aspects of the trial. DSMB members regularly communicated with the AIM-HIGH Executive Leadership and NHLBI Project Officers on matters of study performance and safety. They carefully reviewed all reported adverse events or side effects, as well as trial endpoints, to which the trial leadership and NHLBI project staff were blinded.
Now my colleague and co-principal investigator, Dr. Jeff Probstfield, will provide the details of the trial data and the study’s results as reviewed by the DSMB.