AIM-HIGH Study Statement to Members
On May 26, 2011, the National Heart Lung and Blood Institute (NHLBI) formally ended the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health (AIM-HIGH) trial earlier than expected due to futility. The National Lipid Association would like to provide additional commentary to our members.
The AIM-HIGH trial was the first large-scale outcomes study to evaluate the impact of adding extended-release niacin to statin therapy (simvastatin) in patients with established coronary disease. The study was designed to test whether or not increasing HDL cholesterol and lowering triglycerides in patients with low HDL cholesterol and high triglycerides will reduce the risk of recurrent cardiovascular events in patients whose LDL cholesterol was already within a desirable range with statin therapy.
According to the NHLBI, the trial found that adding extended-release niacin to statin therapy in people with heart and vascular disease did not reduce the risk of cardiovascular events, including heart attacks and stroke. Although the AIM-HIGH trial was halted early, it is important to note that participants reached their goal levels for low-density lipoprotein cholesterol (LDL-C) of less than 80 mg/dL, that, high-density lipoprotein cholesterol (HDL-C) was increased, and triglycerides were reduced.
These findings are disappointing since clinicians have used extended-release niacin to treat patients with low HDL-C since niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL-Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery.1,2 However, it should be recognized that none of these trials compared statin therapy to niacin plus statin therapy.
The findings of AIM-HIGH will require careful study to determine if there are specific reasons for the failure of niacin to provide incremental risk reduction in this population of patients. Many questions will need to be answered with the full data set including adherence to the prescribed regimens, the magnitude of the change in all lipid parameters associated with the addition of niacin, and the difference between lipoprotein concentrations between the two groups over the course of the trial. The observed higher incidence of stroke (28 vs 12) in the niacin arm will need further investigation. This trial will probably generate additional hypotheses about the effects of niacin and guide future research around the mechanisms and approaches to modification of HDL and triglyceride concentrations. One should recognize that this is a preliminary analysis and data are still being gathered and analyzed. As always, any important clinical trial needs confirmation and, fortunately, a much larger study with a similar design and measured outcomes is underway (i.e., HPS-2 THRIVE). We have much to learn on such therapeutic strategies and the value of targets beyond LDL-C.
There is no question that low concentrations of HDL cholesterol are associated with increased risk of heart disease. However, it is clear that the role of high density lipoprotein in modulating atherosclerosis is very complex. Any therapy that is found to alter the plasma concentrations in man must be studied very thoroughly with proven response in vascular disease endpoints before we can be sure that it deserves an indication for cardiovascular disease prevention. Fortunately, there are several new approaches to the problem of low HDL and associated cardiovascular risk that are under investigation.
Recommendations for clinicians
Physicians should await full availability and review of the trial before integrating this information into clinical practice. It is important to recognize the characteristics of the 3,414 patients that entered the study and were randomized to statin or to statin plus niacin therapy. The age was 64 ± 9 years, 85% were men and all had documented arteriosclerotic vascular disease. Statin therapy had been used in 94% for some period of time before enrollment. The mean LDL-C was 71 mg/dL, HDL-C 34.9 mg/dL and triglycerides 161 mg/dL at randomization to the treatment regimens. Therefore, these were patients at very high risk for CHD already treated to aggressive LDL and non-HDL targets.
Physicians should not alter their prescribing practices at this time if that would deter patients from achieving NCEP targets. A continued focus on achieving risk stratified NCEP goals and recommending diet changes and especially exercise regimens is warranted for managing cardiovascular disease in patients with known risk and low HDL levels.
Recommendations for patients
Discontinuing therapy is the wrong action and should not be done without the advice of your physician. Getting to your cholesterol goals is extremely important and you should always discuss all therapy options with your physician. Patients should work with the clinical team to emphasize diet and especially exercise in all cases to modify cholesterol levels. Furthermore, the findings presented should be interpreted with caution until the full study details are available and additional studies are completed that should provide insight into the effect of niacin in other populations.
References:
- Brown BG, et al. N Engl J Med. 2001;345:1583-1592.
- Coronary Drug Project. JAMA. 1975;231:360-381.
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The NLA contributors to this paper have provided full disclosures and their thoughts on this matter have not been influenced by bias or commercial interest. The viewpoints expressed here represent the clinical experience and opinion of our experts and the scientific evidence, which serves as the basis of clinical lipidology. All members of the organization and others reviewing this document are urged to thoroughly review the study and place this, in addition to other learned comment, in the context of meeting the interests of patient care. The NLA further discloses that the association has received educational grants from multiple manufacturers to support accredited medical educational activities. There was no funding or any interaction with any manufacturer in regard to this statement.
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