Niacin Plus Statin to Prevent Vascular Events

Condition(s) targeted: Cardiovascular Diseases; Heart Diseases; Cerebrovascular Accident; Coronary Disease; Atherosclerosis; Myocardial Infarction

Intervention: Extended release niacin (Drug); Simvastatin (Drug)

Phase: Phase 3

Status: Terminated

Sponsored by: Axio Research. LLC

Official(s) and/or principal investigator(s):
Ruth McBride, Study Director, Affiliation: Axio Research Corporation
William E. Boden, MD, Principal Investigator, Affiliation: Samuel S. Stratton VA Medical Center
Jeffrey Probstfield, MD, Principal Investigator, Affiliation: University of Washington

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.

Official title: AIM HIGH: Niacin Plus Statin to Prevent Vascular Events

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Primary outcome: Composite End Point of CHD Death, Nonfatal MI, Ischemic Stroke, Hospitalization for Non-ST Segment Elevation Acute Coronary Syndrome (ACS), or Symptom-driven Coronary or Cerebral Revascularization

Secondary outcome:

Composite Endpoint of CHD Death, Non-fatal MI, High-risk ACS or Ischemic Stroke

Composite Endpoint of CHD Death, Non-fatal MI, or Ischemic Stroke

Cardiovascular Mortality

Detailed description: 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.

Minimum age: 45 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Recherches Clinicar, Quebec G1J 1Z6, Canada

Cardiovascular Associates, P.C., Birmingham, Alabama 35213, United States

University of Alabama, Birmingham, Birmingham, Alabama 35294, United States

Clinical Research Consultants, Inc., Hoover, Alabama 35216, United States

Foothills Medical Centre, Calgary, Alberta T2N 2T9, Canada

Heart Health Institute, Calgary, Alberta T2E 7C5, Canada

Royal Alexandra Hospital, Edmonton, Alberta T5H 3V9, Canada

Carl T. Hayden VAMC Phoenix Medical Service, Pheonix, Arizona 85012, United States

Cardiovascular Consultants Ltd, Phoenix, Arizona 85015, United States

Diabetes Center of Excellence, Phoenix, Arizona 85016, United States

Tucson Clinical Research (Eastside Site), Tucson, Arizona 85712, United States

Tucson Clinical Research (Northwest Site), Tucson, Arizona 85741, United States

University of Arkansas, Little Rock, Arkansas 72205, United States

Vancouver Hospital, Vancouver, British Columbia V5Z 1M9, Canada

Victoria Heart Institute, Victoria, British Columbia V8R 4R2, Canada

Providence Saint Joseph Medical Center, Burbank, California 91505, United States

VA Long Beach Healthcare System, Long Beach, California 90822, United States

Providence Holy Cross Medical Center, Mission Hills, California 91345, United States

Christiana Care Health Services, Newark, Delaware 19718, United States

University of Miami, Miami, Florida 33136, United States

Heart & Vascular Research Center, Sarasota, Florida 34239, United States

James A. Haley Veteran's Hospital, Tampa, Florida 33612, United States

Idaho State University, Pocatello, Idaho 83201, United States

Parkview Research Center, Fort Wayne, Indiana 46805, United States

Iowa Heart Center, P.C., Des Moines, Iowa 50314, United States

Lipid Research Clinic, University of Iowa, Iowa City, Iowa 52240, United States

Maine Center for Lipids & Cardiovascular Health, Scarborough, Maine 04074, United States

Health Sciences Center, Diabetes Research Group, Winnipeg, Manitoba R3E 3R4, Canada

Johns Hopkins University, Baltimore, Maryland 21205, United States

University of Maryland, Baltimore, Maryland 21201, United States

Pentucket Medical Associates, Haverhill, Massachusetts 01830, United States

Veterans Affairs Health System of Ann Arbor, Michigan, Ann Arbor, Michigan 48105, United States

Grunberger Diabetes Institute, Bloomfield Hills, Michigan 48302, United States

Berman Center for Outcomes and Clinical Research, Minneapolis, Minnesota 55404, United States

HealthPartners Riverside Clinic, Minneapolis, Minnesota 55454, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

Phalen Village Clinic, St. Paul, Minnesota 55106, United States

University of Minnesota, Twin Cities, Minnesota 55414, United States

G.V. (Sonny) Montgomery VAMC, Jackson, Mississippi 39216, United States

St. Louis University, St. Louis, Missouri 63104, United States

Alegent Health Heart & Vascular Specialists, Papillion, Nebraska 68046, United States

New Brunswick Heart Center, St John, New Brunswick E2L 4L2, Canada

Cooper Clinical Trials Center, Cherry Hill, New Jersey 08034, United States

Cardiovascular Associates of the Delaware Valley, Elmer, New Jersey 08318, United States

UMDNJ -Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, United States

New Mexico VA Healthcare Systems, Albuquerque, New Mexico 87108, United States

Kaleida Health/Diabetes Center, Buffalo, New York 14209, United States

Mid Valley Cardiology, Kingston, New York 12401, United States

Columbia University, New York, New York 10032, United States

VA New York Harbor Healthcare System, New York, New York 10010, United States

Syracuse Preventive Cardiology, Syracuse, New York 13202, United States

Memorial University of Newfoundland, St. John's, Newfoundland and Labrador A1B 3V6, Canada

Duke University Medical Center, Durham, North Carolina 27710, United States

Wake Forest University - Geriatrics/Gerontology, Greensboro, North Carolina 27157, United States

Wake Forest University Health Sciences - Department of Cardiology, Winston-Salem, North Carolina 27157, United States

Wake Forest University School of Medicine - Internal Medicine/Endocrinology, Winston-Salem, North Carolina 27157, United States

Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia B3H 3A6, Canada

Cardiology Associates VRH, Kentville, Nova Scotia B4N 5E3, Canada

Sterling Research Group, Ltd., Cincinnati, Ohio 45219, United States

St Vincent Charity Hospital - The Center for Vascular Health, Cleveland, Ohio 44115, United States

North Ohio Research, Ltd., Sandusky, Ohio 44870, United States

Cambridge Cardiac Care Center, Cambridge, Ontario N1R 6V6, Canada

McConnell Medical Center, Cornwall, Ontario K6H 4M4, Canada

Hamilton Health Sciences - General Site, Hamilton, Ontario L8L 2X2, Canada

LHSC University Hospital, London, Ontario N6A 5A5, Canada

Newmarket Cardiology Research Group, Newmarket, Ontario L3Y 8C3, Canada

Sudbury Cardiovascular Research, Sudbury, Ontario P3E 2N8, Canada

St. Michael's Hospital Health Centre, Toronto, Ontario M5C 2T2, Canada

Portland VA Medical Center, Portland, Oregon 97239, United States

Cardiology Consultants of Philadelphia, Philadelphia, Pennsylvania 19148, United States

Pennsylvania Cardiology Associates, Philadelphia, Pennsylvania 19106, United States

Philadelphia VA Medical Center, Philadelphia, Pennsylvania 19104, United States

Clinique de Cardiologie de Lévis, Lévis, Quebec G6V 4Z5, Canada

Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada

Clinique des maladies lipidiques de Québec, Québec, Quebec G1V 4M6, Canada

CSSS Beauce, St-Georges de Beauce, Quebec G5Y 4T8, Canada

CSSS du Sud de Lanaudière - Hôpital Pierre-Le Gardeur, Terrebonne, Quebec J6V 2H2, Canada

Women's Cardiac Center at The Miriam Hospital, Providence, Rhode Island 02906, United States

Internal Medicine Associates of Greenville, Greenville, South Carolina 29607, United States

VAMC Memphis - Hypertension/Lipid Research Clinic, Memphis, Tennessee 38104, United States

Baylor College of Medicine, Houston, Texas 77030, United States

Kelsey Research Foundation, Houston, Texas 77005, United States

Methodist Hospital, Houston, Texas 77030, United States

Intermountain Medical Center, Murray, Utah 84157, United States

University of Virginia - UVA Cardiology, Charlottesville, Virginia 22908, United States

McGuire VA Medical Center, Richmond, Virginia 23249, United States

University of Washington, Coronary Atherosclerosis Research Lab, Seattle, Washington 98105, United States

University of Washington, Northwest Lipid Research Center, Seattle, Washington 98104, United States

VA Cardiology Research, Seattle, Washington 98108, United States

Washington State University, Spokane, Washington 99202, United States

CARE Foundation, Inc., Wausau, Wisconsin 54401, United States

AIM-HIGH Web site for patients

NHLBI Press Release on Stopping AIM-HIGH

Related publications:

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: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. 2011 Mar;161(3):538-43. doi: 10.1016/j.ahj.2010.12.007. Epub 2011 Feb 2.

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 Mar;161(3):471-477.e2. doi: 10.1016/j.ahj.2010.11.017. Epub 2011 Feb 2.

Starting date: September 2005
Last updated: July 27, 2015