Niacin Plus Statin to Prevent Vascular Events
Niacin Plus Statin to Prevent Vascular Events
The purpose of this study is to determine whether raising "good cholesterol" with a drug
 based on the vitamin niacin, while lowering "bad cholesterol" with a statin drug, can prevent
 more heart disease than the statin alone.
BACKGROUND:

 Coronary heart disease (CHD) remains the leading cause of death and disability in the Western
 world, with approximately 12.6 million individuals in the United States having a history of
 myocardial infarction (MI), angina, or both. There is mounting evidence that "conventional"
 therapies aimed at traditional risk factors have not optimized clinical outcomes. For
 example, in the Heart Protection Study with 20,536 subjects, the 5-year risk of a first major
 vascular event (nonfatal MI or CHD death, stroke, or coronary or noncoronary
 revascularization) among placebo-treated patients was 25%. Treatment with simvastatin reduced
 this risk to 20% over 5 years, which would project out to a 10-year risk of 40%. (The
 National Cholesterol Education Program Adult Treatment Panel III considers "high risk" or CHD
 equivalent a 10-year risk of an event greater than 20%.) Even among patients entering the
 study with baseline low density lipoprotein cholesterol (LDL-C) already near or at goal
 (i.e., LDL-C less than 116 mg/dL) and who achieved a mean on-trial LDL-C of 70 mg/dL with
 simvastatin, the 5-year risk of an event was still 18% (projecting to a 10-year risk of 36%).
 This residual and unacceptably high risk is likely due to the increasing prevalence of
 obesity, type II diabetes mellitus, and the metabolic syndrome. These disorders are typically
 accompanied by a constellation of abnormalities that include impaired glycemic control,
 hypertension, procoagulant and inflammatory states, and atherogenic dyslipidemia. The latter
 includes a wide spectrum of lipid abnormalities (low HDL-C, high triglycerides and
 triglyceride-rich remnant lipoproteins, and a preponderance of small dense, highly-oxidizable
 LDL particles).

 Conventional LDL-C-focused therapies are not effective in targeting this type of
 dyslipidemia. Evidence that therapy directed at atherogenic dyslipidemia among patients with
 CHD can lower outcomes was shown with gemfibrozil in the VA-HIT trial, which showed a 22 to
 24% cardiovascular (CV) event reduction by raising HDL-C (by an average of 6%) and lowering
 triglycerides (by an average of 31%). Niacin is an even more effective agent for
 simultaneously raising HDL-C and lowering triglycerides and levels of small dense LDL, and
 holds the most promise among existing therapies for substantial risk reduction in this
 population when added to a statin. This was demonstrated in the HDL Atherosclerosis Treatment
 Study (HATS) trial in which atherosclerosis progression was virtually halted and CV events
 were reduced by 60 to 90% using combined niacin plus statin therapy.

 DESIGN NARRATIVE:

 AIM-HIGH is a multicenter, randomized, double-blind, parallel-group, controlled clinical
 trial designed to test whether the drug combination of extended release niacin plus
 simvastatin is superior to simvastatin alone, at comparable levels of on-treatment LDL-C, for
 delaying the time to a first major CV disease outcome over a 4-year median follow-up in
 patients with atherogenic dyslipidemia. Prior clinical trials have found only 25 to 35% CV
 risk reduction using statin monotherapy (i.e., event rate 2/3 to 3/4 of placebo rate). The
 study is needed to confirm whether statin-niacin combination therapy, designed to target a
 wider spectrum of dyslipidemic factors in addition to LDL-C, will provide a more substantial
 (greater than 50%) reduction of CV events. Epidemiologic studies confirm the high prevalence
 of atherogenic dyslipidemia and its impact on CV event rates. Preliminary clinical trials
 suggest that targeting these factors with dyslipidemic therapy will reduce CV events. The
 study will enroll an estimated 3,300 men and women more than 45 years old at high risk of
 recurrent CV events by virtue of having established CV disease together with the two
 dyslipidemic elements of metabolic syndrome: low HDL-cholesterol (HDL-C) (less than or equal
 to 40 mg/dl) and high triglycerides (TG) (greater than or equal to 150 mg/dl). The study
 specifically aims to test this hypothesis for the primary composite clinical end point of CHD
 death, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome with
 objective evidence of ischemia (troponin-positive or ST-segment deviation), or symptom-driven
 coronary or cerebral revascularization. Secondary end points include the composite of CHD
 death, nonfatal MI, ischemic stroke, or hospitalization for high-risk acute coronary
 syndrome; the composite of CHD death, nonfatal MI or ischemic stroke; and cardiovascular
 mortality.
Inclusion Criteria:

 -  Men and women aged 45 and older with established vascular disease and atherogenic
 dyslipidemia

 -  Established vascular disease defined as one or more of the following: (1) documented
 coronary artery disease (CAD); (2) documented cerebrovascular or carotid disease; (3)
 documented symptomatic peripheral arterial disease (PAD)

 -  Atherogenic dyslipidemia defined as: (1) LDL-C of less than or equal to 160 mg/dL (4.1
 mmol/L); (2) HDL-C of less than or equal to 40 mg/dL (1.0 mmol/L) for men or less than
 or equal to 50 mg/dL (1.3 mmol/L) for women; (3) TG greater than or equal to 150 mg/dL
 (1.7 mmol/L) and less than or equal to 400 mg/dL (4.5 mmol/L)

 -  For patients entering the trial on a statin: (1) the upper limit for LDL-C is adjusted
 according to the specific statin and statin dose; (2) HDL-C of less than or equal to
 42 mg/dL (1.1 mmol/L) for men or less than or equal to 53 mg/dL (1.4 mmol/L) for
 women; (3) TG greater than or equal to 125 mg/dL (1.4 mmol/L) and less than or equal
 to 400 mg/DL (4.5 mmol/L)

 Exclusion Criteria:

 -  Coronary artery bypass graft (CABG) surgery within 1 year of planned enrollment
 (run-in phase)

 -  Percutaneous coronary intervention (PCI) within 4 weeks of planned enrollment (run-in
 phase)

 -  Hospitalization for acute coronary syndrome and discharge within 4 weeks of planned
 enrollment (run-in phase)

 -  Fasting glucose greater than 180 mg/dL (10 mmol/L) or hemoglobin A1C greater than 9%

 -  For patients with diabetes, inability or refusal to use a glucometer for home
 monitoring of blood glucose

 -  Concomitant use of drugs with a high probability of increasing the risk for
 hepatotoxicity or myopathy, such as those predominantly metabolized by cytochrome P450
 system 3A4, including but not limited to cyclosporine, gemfibrozil, fenofibrate,
 itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, verapamil,
 amiodarone; lipid-lowering drugs (other than the investigational drugs) such as
 statins, bile-acid sequestrants, cholesterol absorption inhibitors (e.g., ezetimibe),
 fibrates or high-dose, antioxidant vitamins (vitamins C, E, or beta carotene) that can
 interfere with the HDL-raising effect of niacin