Akshay Bagai, MD
Dr. William Boden (Buffalo, NY) presented the primary results of the AIM-HIGH trial at the Late Breaking Clinical Trials IV session at the AHA Scientific sessions in Orlando on November 15, 2011. The AIM-HIGH trial tested the hypothesis that among patients with established vascular disease with optimally treated low-density lipoprotein cholesterol (LDL-C) on statin therapy and low high density lipoprotein cholesterol (HDL-C) levels, compared to placebo extended release niacin will reduce the composite of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization. After a 4 to 8 week run-in-phase to demonstrate tolerance to niacin, patients with vascular disease and optimally treated LDL-C and low HDL-C (<40mg/dl in men or < 50mg/dl in women) were randomized to extended-release niacin, 1.5-2g daily (n=1,718) compared with placebo (1,696). All patients received simvastatin, titrated to a LDL-C target of 40-80mg/dl. Ezetimibe was used in 215 patients to achieve this goal. The placebo tablet contained 50mg niacin to provide a flushing sensation to maintain blinding.
Mean age of the randomized group was 64 years, 15% were women, 56% had prior MI, 21% had prior stroke or cerebrovascular disease, and 94% patients were on statin therapy. From baseline to 3 years, the median change in HDL-C levels was 25% in the extended-release niacin group versus 12% in the placebo group; the median change in LDL-C levels was -14% versus -7.6% respectively.
The trial was terminated on May 25, 2011, 18 months earlier than state end date at the recommendation of the DSMB as it was evident that extended-release niacin would not be beneficial, and there was a concern regarding higher rate of ischemic stroke in the niacin group. The primary composite outcome of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary/cerebral revascularization occurred in 16.4% of the extended-release niacin group versus 16.2% of the placebo group (HR 1.02, 95% CI 0.87 to 1.21, p = 0.80). At the final analysis, there was no difference between the groups in ischemic stroke (1.6% versus 0.9%). 25% of the patients in the extended-release niacin group discontinued the study drug, compared to 20% in the placebo group (p<0.001).
In conclusion, among patients with established vascular disease with optimally treated LDL-C on statins and low HDL-C, no incremental benefit was seen with extended-release niacin despite achieving the intended result of raising HDL-C.
Dr. Philip Barter, Sydney, Australia, the discussant of the trial expressed that a lack of benefit in clinical outcomes with extended-release niacin seen in this trial should not signal the end of the HDL-C hypothesis. He stated that although there was a 25% increase in HDL-C in the extended-release niacin group, there was also a 12% increase in HDL-C in the placebo group. At 3 years, the absolute difference in HDL-C between the two groups was only 4mg/dl (42mg/dl in the extended-release niacin versus 38mg/dl in the placebo group). In addition, the absolute LDL-C difference at 3 years between the two groups was 5mg/dl. Given these small differences in HDL-C and LDL-C between the two groups, a proposed 25% reduction in the primary composite endpoint would be unrealistic to expect. The reason for the 12% raise in HDL-C in the placebo group was unclear and questions were raised whether a small dose of 50mg niacin in the placebo tablets could explain that result. Dr. Barter expressed that results of the larger and ongoing HPS2-THRIVE trial expected to be completed in 18 months will provide further light on the effect of raising HDL-C.