Niacin Plus Statin to Prevent Vascular Events

NCT ID: NCT00120289

Last Updated: 2016-04-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 3414 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-09-30
• Study Completion Date: 2012-12-31

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.

Conditions

Cardiovascular Diseases; Heart Diseases; Cerebrovascular Accident; Coronary Disease; Atherosclerosis; Myocardial Infarction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Combination Therapy

Extended release niacin plus simvastatin

Group Type: EXPERIMENTAL

Extended release niacin

Intervention Type: DRUG

2,000 mg/day or 1,500 mg/day if higher dose not tolerated

Simvastatin

Intervention Type: DRUG

Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target

Monotherapy

Simvastatin alone

Group Type: ACTIVE_COMPARATOR

Simvastatin

Intervention Type: DRUG

Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target

Interventions

Extended release niacin

2,000 mg/day or 1,500 mg/day if higher dose not tolerated

Intervention Type: DRUG

Simvastatin

Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target

Intervention Type: DRUG

Other Intervention Names

Niaspan; Zocor

Eligibility 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

• Minimum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Abbott

INDUSTRY

Sponsor Role: collaborator

Axio Research. LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Ruth McBride

Co-Director, Coordinating Center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ruth McBride

Role: STUDY_DIRECTOR

Axio Research Corporation

William E. Boden, MD

Role: PRINCIPAL_INVESTIGATOR

Samuel S. Stratton VA Medical Center

Jeffrey Probstfield, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

Cardiovascular Associates, P.C.

Birmingham, Alabama, United States

University of Alabama, Birmingham

Birmingham, Alabama, United States

Clinical Research Consultants, Inc.

Hoover, Alabama, United States

Carl T. Hayden VAMC Phoenix Medical Service

Pheonix, Arizona, United States

Cardiovascular Consultants Ltd

Phoenix, Arizona, United States

Diabetes Center of Excellence

Phoenix, Arizona, United States

Tucson Clinical Research (Eastside Site)

Tucson, Arizona, United States

Tucson Clinical Research (Northwest Site)

Tucson, Arizona, United States

University of Arkansas

Little Rock, Arkansas, United States

Providence Saint Joseph Medical Center

Burbank, California, United States

VA Long Beach Healthcare System

Long Beach, California, United States

Providence Holy Cross Medical Center

Mission Hills, California, United States

Christiana Care Health Services

Newark, Delaware, United States

University of Miami

Miami, Florida, United States

Heart & Vascular Research Center

Sarasota, Florida, United States

James A. Haley Veteran's Hospital

Tampa, Florida, United States

Idaho State University

Pocatello, Idaho, United States

Parkview Research Center

Fort Wayne, Indiana, United States

Iowa Heart Center, P.C.

Des Moines, Iowa, United States

Lipid Research Clinic, University of Iowa

Iowa City, Iowa, United States

Maine Center for Lipids & Cardiovascular Health

Scarborough, Maine, United States

University of Maryland

Baltimore, Maryland, United States

Johns Hopkins University

Baltimore, Maryland, United States

Pentucket Medical Associates

Haverhill, Massachusetts, United States

Veterans Affairs Health System of Ann Arbor, Michigan

Ann Arbor, Michigan, United States

Grunberger Diabetes Institute

Bloomfield Hills, Michigan, United States

Berman Center for Outcomes and Clinical Research

Minneapolis, Minnesota, United States

HealthPartners Riverside Clinic

Minneapolis, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

Phalen Village Clinic

Saint Paul, Minnesota, United States

University of Minnesota

Twin Cities, Minnesota, United States

G.V. (Sonny) Montgomery VAMC

Jackson, Mississippi, United States

St. Louis University

St Louis, Missouri, United States

Alegent Health Heart & Vascular Specialists

Papillion, Nebraska, United States

Cooper Clinical Trials Center

Cherry Hill, New Jersey, United States

Cardiovascular Associates of the Delaware Valley

Elmer, New Jersey, United States

UMDNJ -Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

New Mexico VA Healthcare Systems

Albuquerque, New Mexico, United States

Kaleida Health/Diabetes Center

Buffalo, New York, United States

Mid Valley Cardiology

Kingston, New York, United States

VA New York Harbor Healthcare System

New York, New York, United States

Columbia University

New York, New York, United States

Syracuse Preventive Cardiology

Syracuse, New York, United States

Duke University Medical Center

Durham, North Carolina, 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

Sterling Research Group, Ltd.

Cincinnati, Ohio, United States

St Vincent Charity Hospital - The Center for Vascular Health

Cleveland, Ohio, United States

North Ohio Research, Ltd.

Sandusky, Ohio, United States

Portland VA Medical Center

Portland, Oregon, United States

Philadelphia VA Medical Center

Philadelphia, Pennsylvania, 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

Internal Medicine Associates of Greenville

Greenville, South Carolina, United States

VAMC Memphis - Hypertension/Lipid Research Clinic

Memphis, Tennessee, United States

Kelsey Research Foundation

Houston, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

Methodist Hospital

Houston, Texas, United States

Intermountain Medical Center

Murray, Utah, United States

University of Virginia - UVA Cardiology

Charlottesville, Virginia, United States

McGuire VA Medical Center

Richmond, Virginia, United States

University of Washington, Northwest Lipid Research Center

Seattle, Washington, United States

University of Washington, Coronary Atherosclerosis Research Lab

Seattle, Washington, United States

VA Cardiology Research

Seattle, Washington, United States

Washington State University

Spokane, Washington, United States

CARE Foundation, Inc.

Wausau, Wisconsin, United States

Heart Health Institute

Calgary, Alberta, Canada

Foothills Medical Centre

Calgary, Alberta, Canada

Royal Alexandra Hospital

Edmonton, Alberta, Canada

Vancouver Hospital

Vancouver, British Columbia, Canada

Victoria Heart Institute

Victoria, British Columbia, Canada

Health Sciences Center, Diabetes Research Group

Winnipeg, Manitoba, Canada

New Brunswick Heart Center

Saint John, New Brunswick, Canada

Memorial University of Newfoundland

St. John's, Newfoundland and Labrador, Canada

Queen Elizabeth II Health Sciences Center

Halifax, Nova Scotia, Canada

Cardiology Associates VRH

Kentville, Nova Scotia, Canada

Cambridge Cardiac Care Center

Cambridge, Ontario, Canada

McConnell Medical Center

Cornwall, Ontario, Canada

Sudbury Cardiovascular Research

Greater Sudbury, Ontario, Canada

Hamilton Health Sciences - General Site

Hamilton, Ontario, Canada

LHSC University Hospital

London, Ontario, Canada

Newmarket Cardiology Research Group

Newmarket, Ontario, Canada

St. Michael's Hospital Health Centre

Toronto, Ontario, Canada

Clinique de Cardiologie de Lévis

Lévis, Quebec, Canada

Montreal Heart Institute

Montreal, Quebec, Canada

Recherches Clinicar

Québec, Quebec, Canada

Clinique des maladies lipidiques de Québec

Québec, Quebec, Canada

CSSS Beauce

St-Georges de Beauce, Quebec, Canada

CSSS du Sud de Lanaudière - Hôpital Pierre-Le Gardeur

Terrebonne, Quebec, Canada

Countries

United States; Canada

References

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.

Reference Type: BACKGROUND

PMID: 21392609 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21392600 (View on PubMed)

AIM-HIGH Investigators; Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255-67. doi: 10.1056/NEJMoa1107579. Epub 2011 Nov 15.

Reference Type: RESULT

PMID: 22085343 (View on PubMed)

Teo KK, Goldstein LB, Chaitman BR, Grant S, Weintraub WS, Anderson DC, Sila CA, Cruz-Flores S, Padley RJ, Kostuk WJ, Boden WE; AIM-HIGH Investigators. Extended-release niacin therapy and risk of ischemic stroke in patients with cardiovascular disease: the Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglycerides: Impact on Global Health Outcome (AIM-HIGH) trial. Stroke. 2013 Oct;44(10):2688-93. doi: 10.1161/STROKEAHA.113.001529. Epub 2013 Jul 23.

Reference Type: RESULT

PMID: 23881958 (View on PubMed)

Albers JJ, Slee A, O'Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, Xu P, Marcovina SM. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013 Oct 22;62(17):1575-9. doi: 10.1016/j.jacc.2013.06.051. Epub 2013 Aug 21.

Reference Type: RESULT

PMID: 23973688 (View on PubMed)

Guyton JR, Slee AE, Anderson T, Fleg JL, Goldberg RB, Kashyap ML, Marcovina SM, Nash SD, O'Brien KD, Weintraub WS, Xu P, Zhao XQ, Boden WE. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013 Oct 22;62(17):1580-4. doi: 10.1016/j.jacc.2013.07.023. Epub 2013 Jul 31.

Reference Type: RESULT

PMID: 23916935 (View on PubMed)

Ronsein GE, Vaisar T, Davidson WS, Bornfeldt KE, Probstfield JL, O'Brien KD, Zhao XQ, Heinecke JW. Niacin Increases Atherogenic Proteins in High-Density Lipoprotein of Statin-Treated Subjects. Arterioscler Thromb Vasc Biol. 2021 Aug;41(8):2330-2341. doi: 10.1161/ATVBAHA.121.316278. Epub 2021 Jun 17.

Reference Type: DERIVED

PMID: 34134520 (View on PubMed)

Tuteja S, Qu L, Vujkovic M, Dunbar RL, Chen J, DerOhannessian S, Rader DJ. Genetic Variants Associated With Plasma Lipids Are Associated With the Lipid Response to Niacin. J Am Heart Assoc. 2018 Oct 2;7(19):e03488. doi: 10.1161/JAHA.117.008461.

Reference Type: DERIVED

PMID: 30371334 (View on PubMed)

Toth PP, Jones SR, Slee A, Fleg J, Marcovina SM, Lacy M, McBride R, Boden WE. Relationship between lipoprotein subfraction cholesterol and residual risk for cardiovascular outcomes: A post hoc analysis of the AIM-HIGH trial. J Clin Lipidol. 2018 May-Jun;12(3):741-747.e11. doi: 10.1016/j.jacl.2018.03.077. Epub 2018 Mar 9.

Reference Type: DERIVED

PMID: 29627296 (View on PubMed)

O'Brien KD, Hippe DS, Chen H, Neradilek MB, Probstfield JL, Peck S, Isquith DA, Canton G, Yuan C, Polissar NL, Zhao XQ, Kerwin WS. Longer duration of statin therapy is associated with decreased carotid plaque vascularity by magnetic resonance imaging. Atherosclerosis. 2016 Feb;245:74-81. doi: 10.1016/j.atherosclerosis.2015.11.032. Epub 2015 Dec 1.

Reference Type: DERIVED

PMID: 26708287 (View on PubMed)

Study Documents

Document Type: Individual Participant Data Set

NHLBI provides controlled access to IPD through BioLINCC. Access requires registration, evidence of local IRB approval or certification of exemption from IRB review, and completion of a data use agreement.

View Document

Document Type: Study Protocol

View Document

Document Type: Study forms

View Document

Related Links

http://www.aimhigh-heart.com/

AIM-HIGH Web site for patients

Other Identifiers

U01HL081649

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01HL081616

Identifier Type: NIH

Identifier Source: secondary_id

View Link

226

Identifier Type: -

Identifier Source: org_study_id