Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes - AIM-HIGH

Description:

The goal of this trial was to compare treatment with extended-release niacin versus placebo among statin-treated patients with established (non-acute) vascular disease and optimally treated low-density lipoprotein cholesterol (LDL-C) and with low high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides.

Hypothesis:

Extended-release niacin will reduce cardiovascular events.

Study Design

  • Blinded
  • Placebo Controlled
  • Stratified
  • Randomized
  • Parallel

Patient Populations:

  • Patients at least 45 years of age with established vascular disease, optimally treated LDL-C, and low HDL-C
  • Established vascular disease was documented by coronary angiography or by prior myocardial infarction, or carotid angiography or prior ischemic stroke, or peripheral arterial disease.

    Number of enrollees: 3,414
    Duration of follow-up: 32 months
    Mean patient age: 64 years

Exclusions:

  • Acute coronary syndrome within 4 weeks
  • Unstable angina
  • Unrevascularized left main trunk disease
  • Coronary artery bypass grafting within 12 months
  • Planned percutaneous coronary intervention
  • Stroke within 8 weeks
  • Impaired glucose tolerance
  • Ejection fraction <30%
  • Cardiogenic shock
  • Concomitant valvular disease
  • Resuscitated out-of-hospital sudden death
  • Uncontrolled hypertension
  • Active peptic ulcer disease
  • Active liver disease
  • Recent history of gout
  • Renal insufficiency
  • Pregnancy
  • Significant comorbidities
  • AIDS or HIV
  • Active substance abuse

Primary Endpoints:

  • Coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization

Secondary Endpoints:

  • Coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for high-risk acute coronary syndrome
  • Coronary heart disease death, nonfatal myocardial infarction, or ischemic stroke
  • Cardiovascular death
  • All-cause death

Drug/Procedures Used:

After a 4- to 8-week run-in phase to demonstrate tolerance to niacin, patients with cardiovascular disease, optimally treated LDL-C, and low HDL-C (<40 mg/dl in men or <50 mg/dl in women) were randomized to extended-release niacin, 1500-2000 mg daily (n = 1,718) compared with placebo (n = 1,696).

All patients received simvastatin, which was titrated to LDL-C of 40-80 mg/dl. Some patients also received ezetimibe to achieve this goal (n = 215).

Patients in the placebo group received immediate-release niacin 50 mg to provide a flushing sensation and maintain blinding.

Principal Findings:

Overall, 3,414 patients were randomized. The mean age was 64 years, 15% were women, 56% had prior myocardial infarction, 21% had prior stroke or cerebrovascular disease, 82% had metabolic syndrome, 73% had hypertension, and 34% had diabetes. The mean glycated hemoglobin level was 6.7%, mean HDL-C was 35 mg/dl, and the mean LDL-C was 76 mg/dl. The duration of prior statin therapy was >5 years in 39%.

The median change in HDL-C levels from baseline to 3 years was 25% in the extended-release niacin group versus 12% in the placebo group. The median change in LDL-C levels from baseline to 3 years was -14% versus -7.6%, respectively.

The trial was terminated 18 months early when it was evident that extended-release niacin would not be beneficial. 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 (p = 0.80).

Coronary heart disease death: 1.2% versus 1.5%, nonfatal myocardial infarction: 5.4% versus 4.7%, ischemic stroke: 1.6% versus 0.9%, hospitalization for acute coronary syndrome: 3.7% versus 4.0%, and symptom-driven coronary/cerebral revascularization: 4.7% versus 5.1%, respectively, for extended-release niacin versus placebo.

Discontinuation of study drug: 25% versus 20% (p < 0.001), which was mostly due to flushing: 6.1% versus 2.5%.

Interpretation:

Among patients with established (non-acute) vascular disease with optimally treated LDL-C, and low HDL-C, the addition of extended-release niacin was not beneficial. This therapy was effective at raising HDL-C; however, adverse cardiovascular events were not reduced. Moreover, there was a small (numerical) excess in ischemic strokes.

The optimal management of patients with low HDL-C has been challenging. Robust epidemiological data support that low HDL-C is an independent predictor of poor cardiovascular outcomes. Other studies have attempted to raise HDL-C with mixed results. Niacin was more beneficial than ezetimibe at reducing carotid intimal media thickness in the ARBITER 6-HALTS trial. That trial also highlights the limitations of surrogate outcomes at predicting clinical events. Gemfibrozil was beneficial in the VA-HIT trial; however, that study predated the use of statins. Fenofibrate failed to reduce cardiovascular outcomes in the ACCORD trial, and the CTEP inhibitor torcetrapib actually increased cardiovascular outcomes in the ILLUMINATE trial. The larger and ongoing HPS2-THRIVE trial will also provide answers on the effect of raising HDL-C.

References:

The AIM-HIGH Investigators. Niacin in Patients With Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011;Nov 15:[Epub ahead of print].

Presented by Dr. William Boden at the American Heart Association Scientific Sessions, Orlando, FL, November 15, 2011.

The AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: Rationale and study design. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH). Am Heart J 2011;161:471-7.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging, Hypertension

Keywords: Fenofibrate, Cerebral Revascularization, Myocardial Infarction, Acute Coronary Syndrome, Stroke, Gemfibrozil, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Quinolines, Coronary Disease, Peripheral Arterial Disease, Simvastatin, Hemoglobin A, Glycosylated, Metabolic Syndrome X, Cholesterol, Azetidines, Coronary Angiography, Niacin, Triglycerides, Hospitalization, Hypertension, Diabetes Mellitus


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