Niacin Plus Statin to Prevent Vascular Events

Cardiovascular Diseases Clinical Trial

Official title:

AIM HIGH: Niacin Plus Statin to Prevent Vascular Events

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00120289
• Other study ID #: 226
• Secondary ID: U01HL081649U01HL
• Status: Terminated
• Phase: Phase 3
• First received: July 6, 2005
• Last updated: July 27, 2015
• Start date: September 2005
• Est. completion date: December 2012

Study information

• Verified date: July 2015
• Source: Axio Research. LLC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 3414
• Est. completion date: December 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 45 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Atherosclerosis
• Cardiovascular Diseases
• Cerebrovascular Accident
• Coronary Artery Disease
• Coronary Disease
• Heart Diseases
• Myocardial Infarction
• Stroke

Intervention

Drug:
• Extended release niacin
2,000 mg/day or 1,500 mg/day if higher dose not tolerated
• 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

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Heart Health Institute	Calgary	Alberta
Canada	Cambridge Cardiac Care Center	Cambridge	Ontario
Canada	McConnell Medical Center	Cornwall	Ontario
Canada	Royal Alexandra Hospital	Edmonton	Alberta
Canada	Queen Elizabeth II Health Sciences Center	Halifax	Nova Scotia
Canada	Hamilton Health Sciences - General Site	Hamilton	Ontario
Canada	Cardiology Associates VRH	Kentville	Nova Scotia
Canada	Clinique de Cardiologie de Lévis	Lévis	Quebec
Canada	LHSC University Hospital	London	Ontario
Canada	Montreal Heart Institute	Montreal	Quebec
Canada	Newmarket Cardiology Research Group	Newmarket	Ontario
Canada	Recherches Clinicar	Quebec
Canada	Clinique des maladies lipidiques de Québec	Québec	Quebec
Canada	New Brunswick Heart Center	St John	New Brunswick
Canada	CSSS Beauce	St-Georges de Beauce	Quebec
Canada	Memorial University of Newfoundland	St. John's	Newfoundland and Labrador
Canada	Sudbury Cardiovascular Research	Sudbury	Ontario
Canada	CSSS du Sud de Lanaudière - Hôpital Pierre-Le Gardeur	Terrebonne	Quebec
Canada	St. Michael's Hospital Health Centre	Toronto	Ontario
Canada	Vancouver Hospital	Vancouver	British Columbia
Canada	Victoria Heart Institute	Victoria	British Columbia
Canada	Health Sciences Center, Diabetes Research Group	Winnipeg	Manitoba
United States	New Mexico VA Healthcare Systems	Albuquerque	New Mexico
United States	Veterans Affairs Health System of Ann Arbor, Michigan	Ann Arbor	Michigan
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland	Baltimore	Maryland
United States	Cardiovascular Associates, P.C.	Birmingham	Alabama
United States	University of Alabama, Birmingham	Birmingham	Alabama
United States	Grunberger Diabetes Institute	Bloomfield Hills	Michigan
United States	Kaleida Health/Diabetes Center	Buffalo	New York
United States	Providence Saint Joseph Medical Center	Burbank	California
United States	University of Virginia - UVA Cardiology	Charlottesville	Virginia
United States	Cooper Clinical Trials Center	Cherry Hill	New Jersey
United States	Sterling Research Group, Ltd.	Cincinnati	Ohio
United States	St Vincent Charity Hospital - The Center for Vascular Health	Cleveland	Ohio
United States	Iowa Heart Center, P.C.	Des Moines	Iowa
United States	Duke University Medical Center	Durham	North Carolina
United States	Cardiovascular Associates of the Delaware Valley	Elmer	New Jersey
United States	Parkview Research Center	Fort Wayne	Indiana
United States	Wake Forest University - Geriatrics/Gerontology	Greensboro	North Carolina
United States	Internal Medicine Associates of Greenville	Greenville	South Carolina
United States	Pentucket Medical Associates	Haverhill	Massachusetts
United States	Clinical Research Consultants, Inc.	Hoover	Alabama
United States	Baylor College of Medicine	Houston	Texas
United States	Kelsey Research Foundation	Houston	Texas
United States	Methodist Hospital	Houston	Texas
United States	Lipid Research Clinic, University of Iowa	Iowa City	Iowa
United States	G.V. (Sonny) Montgomery VAMC	Jackson	Mississippi
United States	Mid Valley Cardiology	Kingston	New York
United States	University of Arkansas	Little Rock	Arkansas
United States	VA Long Beach Healthcare System	Long Beach	California
United States	VAMC Memphis - Hypertension/Lipid Research Clinic	Memphis	Tennessee
United States	University of Miami	Miami	Florida
United States	Berman Center for Outcomes and Clinical Research	Minneapolis	Minnesota
United States	HealthPartners Riverside Clinic	Minneapolis	Minnesota
United States	Providence Holy Cross Medical Center	Mission Hills	California
United States	Intermountain Medical Center	Murray	Utah
United States	UMDNJ -Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Columbia University	New York	New York
United States	VA New York Harbor Healthcare System	New York	New York
United States	Christiana Care Health Services	Newark	Delaware
United States	Alegent Health Heart & Vascular Specialists	Papillion	Nebraska
United States	Carl T. Hayden VAMC Phoenix Medical Service	Pheonix	Arizona
United States	Cardiology Consultants of Philadelphia	Philadelphia	Pennsylvania
United States	Pennsylvania Cardiology Associates	Philadelphia	Pennsylvania
United States	Philadelphia VA Medical Center	Philadelphia	Pennsylvania
United States	Cardiovascular Consultants Ltd	Phoenix	Arizona
United States	Diabetes Center of Excellence	Phoenix	Arizona
United States	Idaho State University	Pocatello	Idaho
United States	Portland VA Medical Center	Portland	Oregon
United States	Women's Cardiac Center at The Miriam Hospital	Providence	Rhode Island
United States	McGuire VA Medical Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	North Ohio Research, Ltd.	Sandusky	Ohio
United States	Heart & Vascular Research Center	Sarasota	Florida
United States	Maine Center for Lipids & Cardiovascular Health	Scarborough	Maine
United States	University of Washington, Coronary Atherosclerosis Research Lab	Seattle	Washington
United States	University of Washington, Northwest Lipid Research Center	Seattle	Washington
United States	VA Cardiology Research	Seattle	Washington
United States	Washington State University	Spokane	Washington
United States	St. Louis University	St. Louis	Missouri
United States	Phalen Village Clinic	St. Paul	Minnesota
United States	Syracuse Preventive Cardiology	Syracuse	New York
United States	James A. Haley Veteran's Hospital	Tampa	Florida
United States	Tucson Clinical Research (Eastside Site)	Tucson	Arizona
United States	Tucson Clinical Research (Northwest Site)	Tucson	Arizona
United States	University of Minnesota	Twin Cities	Minnesota
United States	CARE Foundation, Inc.	Wausau	Wisconsin
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

Sponsors (3)

Lead Sponsor	Collaborator
Axio Research. LLC	Abbott, National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (6)

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;36 — View Citation

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. — View Citation

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. — View Citation

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 Syndrom — View Citation

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 Metabol — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Secondary	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	No
Secondary	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	No
Secondary	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.	No

External Links

•   AIM-HIGH Web site for patients
•   NHLBI Press Release on Stopping AIM-HIGH