Niacin Plus Statin to Prevent Vascular Events
- Conditions
- Cerebrovascular AccidentCoronary DiseaseCardiovascular DiseasesAtherosclerosisHeart DiseasesMyocardial Infarction
- Interventions
- Registration Number
- NCT00120289
- Lead Sponsor
- Axio Research. LLC
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 3414
- 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)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Combination Therapy Extended release niacin Extended release niacin plus simvastatin Combination Therapy Simvastatin Extended release niacin plus simvastatin Monotherapy Simvastatin Simvastatin alone
- Primary Outcome Measures
Name Time Method 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 Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months.
- Secondary Outcome Measures
Name Time Method Cardiovascular Mortality Time to first event measured from date of randomization through last follow-up visit (common termination), for an average of 36 months follow-up, maximum 66 months. Composite Endpoint of CHD Death, Non-fatal MI, or Ischemic Stroke Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months Composite Endpoint of CHD Death, Non-fatal MI, High-risk ACS or Ischemic Stroke Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months
Trial Locations
- Locations (91)
Clinical Research Consultants, Inc.
🇺🇸Hoover, Alabama, United States
VA Long Beach Healthcare System
🇺🇸Long Beach, California, United States
Iowa Heart Center, P.C.
🇺🇸Des Moines, Iowa, United States
Heart & Vascular Research Center
🇺🇸Sarasota, Florida, United States
University of Maryland
🇺🇸Baltimore, Maryland, United States
Parkview Research Center
🇺🇸Fort Wayne, Indiana, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Lipid Research Clinic, University of Iowa
🇺🇸Iowa City, Iowa, United States
Veterans Affairs Health System of Ann Arbor, Michigan
🇺🇸Ann Arbor, Michigan, United States
Grunberger Diabetes Institute
🇺🇸Bloomfield Hills, Michigan, United States
University of Minnesota
🇺🇸Twin Cities, Minnesota, United States
Phalen Village Clinic
🇺🇸St. Paul, Minnesota, United States
St. Louis University
🇺🇸St. Louis, Missouri, United States
New Mexico VA Healthcare Systems
🇺🇸Albuquerque, New Mexico, United States
Kaleida Health/Diabetes Center
🇺🇸Buffalo, New York, United States
VA New York Harbor Healthcare System
🇺🇸New York, New York, United States
Mid Valley Cardiology
🇺🇸Kingston, New York, United States
Columbia University
🇺🇸New York, New York, United States
Syracuse Preventive Cardiology
🇺🇸Syracuse, New York, United States
Wake Forest University - Geriatrics/Gerontology
🇺🇸Greensboro, North Carolina, United States
Wake Forest University Health Sciences - Department of Cardiology
🇺🇸Winston-Salem, North Carolina, United States
Wake Forest University School of Medicine - Internal Medicine/Endocrinology
🇺🇸Winston-Salem, North Carolina, United States
St Vincent Charity Hospital - The Center for Vascular Health
🇺🇸Cleveland, Ohio, United States
North Ohio Research, Ltd.
🇺🇸Sandusky, Ohio, United States
Pennsylvania Cardiology Associates
🇺🇸Philadelphia, Pennsylvania, United States
Cardiology Consultants of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Women's Cardiac Center at The Miriam Hospital
🇺🇸Providence, Rhode Island, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
McGuire VA Medical Center
🇺🇸Richmond, Virginia, United States
University of Virginia - UVA Cardiology
🇺🇸Charlottesville, Virginia, United States
Washington State University
🇺🇸Spokane, Washington, United States
CARE Foundation, Inc.
🇺🇸Wausau, Wisconsin, United States
Vancouver Hospital
🇨🇦Vancouver, British Columbia, Canada
Royal Alexandra Hospital
🇨🇦Edmonton, Alberta, Canada
Queen Elizabeth II Health Sciences Center
🇨🇦Halifax, Nova Scotia, Canada
Cardiology Associates VRH
🇨🇦Kentville, Nova Scotia, Canada
McConnell Medical Center
🇨🇦Cornwall, Ontario, Canada
Cambridge Cardiac Care Center
🇨🇦Cambridge, Ontario, Canada
Hamilton Health Sciences - General Site
🇨🇦Hamilton, Ontario, Canada
Newmarket Cardiology Research Group
🇨🇦Newmarket, Ontario, Canada
LHSC University Hospital
🇨🇦London, Ontario, Canada
Clinique de Cardiologie de Lévis
🇨🇦Lévis, Quebec, Canada
Sudbury Cardiovascular Research
🇨🇦Sudbury, Ontario, Canada
Montreal Heart Institute
🇨🇦Montreal, Quebec, Canada
CSSS Beauce
🇨🇦St-Georges de Beauce, Quebec, Canada
CSSS du Sud de Lanaudière - Hôpital Pierre-Le Gardeur
🇨🇦Terrebonne, Quebec, Canada
Recherches Clinicar
🇨🇦Quebec, Canada
Health Sciences Center, Diabetes Research Group
🇨🇦Winnipeg, Manitoba, Canada
HealthPartners Riverside Clinic
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Cardiovascular Consultants Ltd
🇺🇸Phoenix, Arizona, United States
Diabetes Center of Excellence
🇺🇸Phoenix, Arizona, United States
University of Miami
🇺🇸Miami, Florida, United States
Cardiovascular Associates, P.C.
🇺🇸Birmingham, Alabama, United States
University of Alabama, Birmingham
🇺🇸Birmingham, Alabama, United States
Berman Center for Outcomes and Clinical Research
🇺🇸Minneapolis, Minnesota, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Sterling Research Group, Ltd.
🇺🇸Cincinnati, Ohio, United States
Portland VA Medical Center
🇺🇸Portland, Oregon, United States
Kelsey Research Foundation
🇺🇸Houston, Texas, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
Methodist Hospital
🇺🇸Houston, Texas, United States
University of Washington, Northwest Lipid Research Center
🇺🇸Seattle, Washington, United States
VA Cardiology Research
🇺🇸Seattle, Washington, United States
University of Washington, Coronary Atherosclerosis Research Lab
🇺🇸Seattle, Washington, United States
St. Michael's Hospital Health Centre
🇨🇦Toronto, Ontario, Canada
James A. Haley Veteran's Hospital
🇺🇸Tampa, Florida, United States
Providence Saint Joseph Medical Center
🇺🇸Burbank, California, United States
Providence Holy Cross Medical Center
🇺🇸Mission Hills, California, United States
Pentucket Medical Associates
🇺🇸Haverhill, Massachusetts, United States
Philadelphia VA Medical Center
🇺🇸Philadelphia, Pennsylvania, United States
Tucson Clinical Research (Eastside Site)
🇺🇸Tucson, Arizona, United States
Tucson Clinical Research (Northwest Site)
🇺🇸Tucson, Arizona, United States
Cardiovascular Associates of the Delaware Valley
🇺🇸Elmer, New Jersey, United States
Clinique des maladies lipidiques de Québec
🇨🇦Québec, Quebec, Canada
Victoria Heart Institute
🇨🇦Victoria, British Columbia, Canada
Carl T. Hayden VAMC Phoenix Medical Service
🇺🇸Pheonix, Arizona, United States
G.V. (Sonny) Montgomery VAMC
🇺🇸Jackson, Mississippi, United States
Idaho State University
🇺🇸Pocatello, Idaho, United States
New Brunswick Heart Center
🇨🇦St John, New Brunswick, Canada
Maine Center for Lipids & Cardiovascular Health
🇺🇸Scarborough, Maine, United States
Christiana Care Health Services
🇺🇸Newark, Delaware, United States
UMDNJ -Robert Wood Johnson Medical School
🇺🇸New Brunswick, New Jersey, United States
University of Arkansas
🇺🇸Little Rock, Arkansas, United States
Internal Medicine Associates of Greenville
🇺🇸Greenville, South Carolina, United States
VAMC Memphis - Hypertension/Lipid Research Clinic
🇺🇸Memphis, Tennessee, United States
Heart Health Institute
🇨🇦Calgary, Alberta, Canada
Alegent Health Heart & Vascular Specialists
🇺🇸Papillion, Nebraska, United States
Foothills Medical Centre
🇨🇦Calgary, Alberta, Canada
Cooper Clinical Trials Center
🇺🇸Cherry Hill, New Jersey, United States
Memorial University of Newfoundland
🇨🇦St. John's, Newfoundland and Labrador, Canada