Clinical trial NCT00120289: Niacin Plus Statin to Prevent Vascular Events
Official title: AIM HIGH: Niacin Plus Statin to Prevent Vascular Events
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cardiovascular Diseases
Heart Diseases
Cerebrovascular Accident
Coronary Disease
Atherosclerosis
Myocardial Infarction
Lead sponsor: Axio Research. LLC
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Abbott
First posted: 2005-07-15
Enrollment: 3414
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

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