AIM-HIGH and HPS2-THRIVE Trials

The multicenter randomized clinical trials, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and the recent Heart Protection Study-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial, were the 2 trials designed to test the HDL-C hypothesis and potential role of niacin in reducing cardiovascular events. The AIM-HIGH trial included 3,424 subjects with established cardiovascular disease and low HDL-C levels, randomizing to high-dose niacin (intervention) versus low-dose niacin (control). Both arms received varying doses of simvastatin and ezetimibe as needed to maintain LDL-C levels at 40 to 80 mg/dl. The median baseline LDL-C, HDL-C, triglycerides (TGs), and apolipoprotein B (apoB) levels in the niacin arm were 72, 35, 163, and 81 mg/dl respectively, compared with 73, 35, 168, and 81 mg/dl, respectively, in the control group. After 3-year treatment, LDL-C, HDL-C, TGs, and apoB levels were 62, 42, 120, and 69 mg/dl, respectively, in the niacin group, whereas LDL-C, HDL-C, TGs, and apoB levels were 67, 38, 152, and 76 mg/dl, respectively, in the control group. Surprisingly, to many, after 3-year median follow-up, the trial was halted prematurely because of a lack of benefit (death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, and hospitalization for an acute coronary syndrome in 16.4% in the intervention group and 16.2% in the control niacin group, p = 0.79) and concern for an increase in stroke which was later discredited. On further post hoc analysis, Dr. John R Guyton et al showed at the 2012 American Heart Association Scientific Session that niacin might have potential benefits in the AIM-HIGH subgroup with HDL-C levels <32 mg/dl and TG levels >200 mg/dl. In this group, niacin decreased the primary end point by 37% compared with the control group (hazard ratio 0.63; 95% confidence interval 0.40 to 0.98; p = 0.017).

The larger multicenter trial, HPS2-THRIVE trial, included 25,673 patients with pre-existing cardiovascular disease. Subjects were randomized to extended release niacin and laropiprant (an antiflushing agent) versus placebo tablets. Before randomization, both arms received simvastatin 40 mg/day with or without ezetimibe to maintain total cholesterol target <135 mg/dl. In the author’s late-breaking presentation at the 2013 American College of Cardiology Scientific Sessions, Professor Jane Armitage showed that after 4-year therapy, 13.2% suffered major vascular events in the treatment group versus 13.7% in the placebo group (p = 0.29), with significant increases in nonfatal side effects in the treatment group.

Many commentaries following the AIM-HIGH and HPS2-THRIVE trials have attempted to rationalize these results. For some, the AIM-HIGH trial solidified their disbelief in the HDL-C hypothesis, whereas others have focused on the limitations of the trial’s somewhat convoluted design and ways to reconcile the results with previous surrogate end point trials. Some are reserving their judgments on HDL hypothesis until additional results from CETP inhibitor and HDL infusion studies become available, although the data from these trials have not been encouraging.

Some have interpreted the results of the AIM-HIGH and HPS2-THRIVE trials to mean that niacin’s side effects counteract the benefits on atherosclerosis to result in a net neutral effect. However, there has been little discussion in the series of the AIM-HIGH and HPS2-THRIVE commentaries directed at apoB and apolipoprotein A1 (apoA1) levels, markers of proatherogenic and atheroprotective particle concentrations, respectively. In their commentary, “SATURN and AIM-HIGH: ‘Back down to planet Earth,’” Drs. Seth Martin and Roger Blumenthal noted: “Through the particle lens, a clinical effect of niacin may be more clearly understood because the impact on atherogenic particles is modest, so a very large trial may be needed to detect an effect, especially in patients who are already aggressively treated.” Indeed, 1 key take-home message from the AIM-HIGH and HPS2-THRIVE trials may be the following: equivalent on-treatment apolipoprotein levels result in equivalent outcomes.

Apolipoprotein Concentrations in AIM-HIGH

Differences in apoB and apoA1 levels were modest after 3 years. The median apoA1 level was 1.27 g/L in the control group and 1.31 g/L in the intervention group. The median apoB level was 0.69 g/L in the intervention group compared with 0.76 g/L in the control group. Therefore, there are only small numerical differences in apolipoprotein levels between the intervention and control groups, which are of questionable clinical importance, and may be considered approximately equivalent.

Placing the apoB and apoA1 levels as seen in the AIM-HIGH trial in the context of other studies is illuminating. The median apoB and apoA1 levels seen in both the AIM-HIGH groups are in the first and second quartile for the Apolipoprotein-related MOrtality RISk (AMORIS) and INTERHEART studies. In the Swedish prospective AMORIS study, apoB levels at the third and fourth quartiles had risk ratios for fatal myocardial infarction of ∼2 and ∼3, respectively, whereas the risk ratios for the first and second quartiles were both ∼1. Moreover, apoA1 levels at the third and fourth quartiles had risk ratios of ∼0.5 and ∼0.4, respectively, whereas levels at the first and second quartiles were not significantly different and had risk ratios of ∼1. Similar results were found in the 52 country INTERHEART study of myocardial risk comparing 15,152 cases and 14,820 controls. Therefore, the notion that the AIM-HIGH trial failed to support the HDL hypothesis or cardiovascular benefits of adding niacin to statin therapy may be practically incorrect through the apolipoprotein lens. Rather, the trial may reinforce the importance of achieving optimal apolipoprotein levels and the lack of the ability to discriminate risk with small incremental differences in aggressively treated patients.

Apolipoprotein Concentrations in AIM-HIGH

Differences in apoB and apoA1 levels were modest after 3 years. The median apoA1 level was 1.27 g/L in the control group and 1.31 g/L in the intervention group. The median apoB level was 0.69 g/L in the intervention group compared with 0.76 g/L in the control group. Therefore, there are only small numerical differences in apolipoprotein levels between the intervention and control groups, which are of questionable clinical importance, and may be considered approximately equivalent.

Placing the apoB and apoA1 levels as seen in the AIM-HIGH trial in the context of other studies is illuminating. The median apoB and apoA1 levels seen in both the AIM-HIGH groups are in the first and second quartile for the Apolipoprotein-related MOrtality RISk (AMORIS) and INTERHEART studies. In the Swedish prospective AMORIS study, apoB levels at the third and fourth quartiles had risk ratios for fatal myocardial infarction of ∼2 and ∼3, respectively, whereas the risk ratios for the first and second quartiles were both ∼1. Moreover, apoA1 levels at the third and fourth quartiles had risk ratios of ∼0.5 and ∼0.4, respectively, whereas levels at the first and second quartiles were not significantly different and had risk ratios of ∼1. Similar results were found in the 52 country INTERHEART study of myocardial risk comparing 15,152 cases and 14,820 controls. Therefore, the notion that the AIM-HIGH trial failed to support the HDL hypothesis or cardiovascular benefits of adding niacin to statin therapy may be practically incorrect through the apolipoprotein lens. Rather, the trial may reinforce the importance of achieving optimal apolipoprotein levels and the lack of the ability to discriminate risk with small incremental differences in aggressively treated patients.

Apolipoprotein Concentrations and Lipid Profiles in HPS2-THRIVE

Subjects studied in the HPS2-THRIVE trial had very low levels of atherogenic lipid profiles at baseline. Mean baseline total cholesterol was 128 (±22) mg/dl, LDL-C 63 (±17) mg/dl, HDL-C 44 (±11) mg/dl, TGs 125 (±74) mg/dl, and apoB 0.68 (±0.14) g/L. Again, such apoB levels were present in aggressively treated subjects corresponding to the first quartile in the AMORIS and INTERHEART studies. Hence, those subjects were optimally treated before enrollment. Four years into treatment with extended release niacin resulted in 10-mg/dl (∼15.6%) decrease in LDL-C level, 33-mg/dl (26.4%) decrease in TG level, and 6-mg/dl (∼13.6%) increase in HDL-C level, without significant decrease in cardiovascular events.

Those results were shocking to many including the primary investigator who expected 10% to 15% decrease in cardiovascular events. However, comparing those results to the Emerging Risk Factor Collaboration summary of prospective studies of 302,430 subjects on major lipids and risk of vascular disease is enlightening. When comparing both studies, mean baseline HDL-C level of 44 mg/dl and post-treatment HDL-C level of 50 mg/dl in the HPS2-THRIVE trial have a comparable hazard ratio of ∼ 1. Professor Philip Barter, HDL Forum Editor, elaborated that to detect significant difference in outcomes, there must be a 17% increase in HDL-C level and baseline HDL-C level should be ≤40 mg/dl. Therefore, the outcome was rather expected based on baseline characteristics of subjects studied.

On further analysis of the data presented by Professor Jane Armitage, there was a significant interaction between baseline lipids and the impact of extended release niacin or laropiprant on outcomes with those having an LDL-C level of >77 mg/dl or a TG level of >151 mg/dl showing suggestion of benefit. Moreover, post hoc analysis showed trends of potential benefits of niacin in men and European population with significant decrease in rates of revascularizations especially in coronary revascularizations. Unfortunately, little is known about the experimental drug, laropiprant, and its potential effects on outcome of the study. Also, little attention was paid to apoB levels, which provides better risk assessment of cardiovascular events, and no further analyses were made on apoB levels in both treatment groups.