Niacin Plus Statin to Prevent Vascular Events

This study has been terminated.
(AIM-HIGH was stopped on the recommendation of the DSMB because of lack of efficacy of niacin in preventing primary outcome events.)
Sponsor:
Collaborators:
Abbott
Information provided by (Responsible Party):
Ruth McBride, Axio Research. LLC
ClinicalTrials.gov Identifier:
NCT00120289
First received: July 6, 2005
Last updated: January 9, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Cardiovascular Diseases
Heart Diseases
Cerebrovascular Accident
Coronary Disease
Atherosclerosis
Myocardial Infarction
Drug: Extended release niacin
Drug: Simvastatin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: AIM HIGH: Niacin Plus Statin to Prevent Vascular Events

Resource links provided by NLM:


Further study details as provided by Axio Research. LLC:

Primary Outcome Measures:
  • 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 Frame: Time to first event ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Composite endpoint of CHD death, non-fatal MI, high-risk ACS or ischemic stroke [ Time Frame: Time to first event ] [ Designated as safety issue: Yes ]
  • Composite endpoint of CHD death, non-fatal MI, or ischemic stroke [ Time Frame: Time to first event ] [ Designated as safety issue: Yes ]
  • Cardiovascular mortality [ Time Frame: Time to event ] [ Designated as safety issue: Yes ]

Enrollment: 3414
Study Start Date: September 2005
Study Completion Date: December 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Extended release niacin plus simvastatin
Drug: Extended release niacin
2,000 mg/day or 1,500 mg/day if higher dose not tolerated
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
Active Comparator: 2
Simvastatin alone
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

  Hide Detailed Description

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

Ages Eligible for Study:   45 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00120289

  Show 91 Study Locations
Sponsors and Collaborators
Axio Research. LLC
Abbott
Investigators
Study Director: Ruth McBride Axio Research Corporation
Principal Investigator: William E. Boden, MD Samuel S. Stratton VA Medical Center
Principal Investigator: Jeffrey Probstfield, MD University of Washington
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ruth McBride, Co-Director, Coordinating Center, Axio Research. LLC
ClinicalTrials.gov Identifier: NCT00120289     History of Changes
Other Study ID Numbers: 226, U01HL081649, U01HL081616, U01 HL81616, U01 HL81649
Study First Received: July 6, 2005
Last Updated: January 9, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Atherosclerosis
Cardiovascular Diseases
Coronary Disease
Coronary Artery Disease
Heart Diseases
Infarction
Myocardial Infarction
Cerebral Infarction
Stroke
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Myocardial Ischemia
Ischemia
Pathologic Processes
Necrosis
Brain Infarction
Brain Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Niacin
Simvastatin
Nicotinic Acids
Niacinamide
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 23, 2014