Volume 7, Issue 4

December 19, 2011    

The Biofortis-Provident team wishes the recipients of this newsletter Happy Holidays and a healthy, happy and prosperous 2012!

Biofortis-Provident News

Clinical Trials Workshop

Biofortis-Provident Clinical Research and Silliker, Inc. co-sponsored "Clinical Trials for Supporting Health-Related Product Claims: A Workshop for Industry Professionals," this past October in Chicago. Over 25 participants enjoyed the 2-day workshop presented by Dr. Kevin Maki and Dr. Tia Rains of Biofortis-Provident.

Staff Announcements

Congratulations to Andrea Lawless, MD who recently was awarded the status of Diplomate, American Board of Clinical Lipidology/Clinical Lipid Specialist.

The Addison Site has welcomed the following new Clinical Research Coordinators:

      Ashlyn Jaeger, BS, CCRC 

      Ryan Childers, CCRC

Also, Addison has welcomed the following Research Assistants to the staff:

      Ruben Diaz

      Renee LaGrippe

      Faviola Cortez, CMA

      Leticia Martinez, CMA

Our Data Management Department welcomes Katie Janowski as Clinical Data Analyst and Lisa Welper as Data Entry Technician. 

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Background:  

Although statins are effective for lowering low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular event risk by 25-35% in primary and secondary prevention trials, residual risk persists among patients with established cardiovascular disease.¹  In addition to elevated LDL-C, a low level of high-density lipoprotein (HDL)-C is an independent predictor (inverse) of coronary heart disease (CHD) risk.²  Raising HDL-C with immediate-release niacin vs. placebo and with niacin plus simvastatin vs. simvastatin alone, had been found to reduce the rate of clinical cardiovascular events and atherosclerosis progression in small clinical trials, but benefit had not been demonstrated in a large-scale outcomes trial.^3-6

Objective and Methods:  

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial was designed to evaluate whether extended-release niacin added to intensive statin therapy, compared with statin alone, would reduce the risk of cardiovascular events among patients who are particularly susceptible to residual risk, i.e., those with established atherosclerotic cardiovascular disease and atherogenic dyslipidemia.  Participants included 3414 men and women at least 45 years of age with documented stable CHD, cerebrovascular or carotid disease, or peripheral arterial disease; HDL-C <40 mg/dL for men and <50 mg/dL for women; triglycerides 150-400 mg/dL; and LDL-C <180 mg/dL (if not already taking a statin when screened for the study).  Patients were required to discontinue lipid-modifying drugs, except statins or ezetimibe, at least 4 weeks before enrollment.  After a 4- to 8-week open-label phase during which subjects received 40 mg/d simvastatin plus niacin at a dose that was increased weekly from 500 mg/d to 2000 mg/d, individuals who had an acceptable side-effect profile with at least 1500 mg niacin were randomly assigned to treatment.  Treatment groups included niacin: 40-80 mg/d simvastatin plus 1500-2000 mg/d extended-release niacin (Niaspan), and placebo: 40-80 mg/d simvastatin plus 50 mg/d immediate-release niacin in a “placebo” tablet (low-dose niacin was included to induce flushing in order to maintain the study blind).  In both groups, the dose of simvastatin was adjusted using an algorithm to achieve and maintain an LDL-C level of 40-80 mg/dL.  Subjects in both treatment groups could also receive 10 mg/d ezetimibe if needed in order to achieve this LDL-C level.  Clinic visits were conducted at 6-month intervals, and patients were also contacted via telephone periodically.

The composite primary end point was the first event of death from CHD, nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.  Secondary end points included death from CHD, nonfatal MI, high-risk acute coronary syndrome, or ischemic stroke; death from CHD, nonfatal MI, or ischemic stroke; and all deaths from cardiovascular causes.  Tertiary end points included death from CHD, death from any cause, nonfatal MI, hospitalizations for acute coronary syndrome, symptom-driven coronary or cerebral revascularizations, ischemic stroke, and ischemic stroke or stroke of uncertain origin.

A total of 3414 patients were randomly assigned to niacin (n = 1718) or placebo (n = 1696) groups.  Patients had a mean age of 64 years, 85.2% were men, 92.2% were white, 33.9% had type 1or 2 diabetes, 71.4% had hypertension, and 81.0% had metabolic syndrome.  This was an event-driven trial, and it was expected that 800 primary events would occur during a mean follow-up of 4.6 years, which would provide 85% power to detect a 25% reduction in the primary endpoint.  However, a pre-planned interim analysis determined a lack of efficacy for niacin, and an unexpected higher rate of ischemic stroke in those treated with niacin (1.6% vs. 0.9%).  Thus the trial was stopped after a mean follow-up period of 3 years.

At 2 years of treatment, median HDL-C levels had increased by 25% (from 35 to 42 mg/dL) and 9.8% (from 35 to 38 mg/dL) in the niacin and placebo groups, respectively.  Triglycerides decreased by 28.6% in the niacin group and by 8.1% in the placebo group; and LDL-C decreased by 12.0% in the niacin group and by 5.5% in the placebo group.  Similar lipid changes persisted through 3 years of follow-up.  The primary endpoint occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio of 1.02; 95% CI 0.87 to 1.21; p = 0.79 by the log-rank test).  Similarly, there were no significant effects of niacin therapy on the secondary or tertiary endpoints.

The AIM-HIGH trial results are disappointing, but caution is warranted in the interpretation of the results.⁷  Differences between the groups in LDL-C (~5 mg/dL) and HDL-C (~4 mg/dL) in favor of niacin were small.  Use of higher dose simvastatin therapy and ezetimibe to maintain target levels of LDL-C were significantly more common in the placebo group than in the niacin group, contributing to a narrowing of the differences in lipoprotein lipid levels between the groups.  Also, dropout was higher in the niacin group than in the placebo group.  In contrast to some of the earlier trials with niacin therapy, participants in AIM-HIGH had a background of effective therapies for lowering blood pressure, modulation of the renin-angiotensin system and platelet inhibition.  Thus, although the results provided no evidence for a benefit in the primary or secondary endpoints, it is premature to rule out benefit in all situations.

Fortunately, a much larger trial has been underway for several years in Europe, the Heart Protection Study-2 Treatment of High-Density Lipoprotein to Reduce the Incidence of Vascular Events (HPS-2 THRIVE), and results are expected in 2013.  In HPS-2 THRIVE, extended release niacin is being concomitantly administered with laropiprant, a prostaglandin receptor blocker which significantly reduces the flushing associated with niacin, to more than 25,000 men and women 50-80 years of age with a history of myocardial infarction, cerebrovascular atherosclerotic disease, peripheral arterial disease, diabetes mellitus, or any evidence of symptomatic CHD.  The results from HPS-2 THRIVE should provide additional insight regarding the benefits and risks of niacin therapy and is large enough to allow meaningful analyses for key subgroups.  Moreover, trials are underway with other therapies that target increases in HDL-C and/or improvements in HDL functionality that will help to shed light on the role of HDL modulation in CHD prevention.⁸  In the meantime, emphasis in clinical lipidology should remain on attainment of treatment goals for LDL-C and non-HDL-C recommended by the National Cholesterol Education Program’s Adult Treatment Panel.⁹

References:  

1.  Cholesterol Treatment Trialists’(CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681.

2.  Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk: the PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 1996;124 (Suppl):S11-S20.

3.  The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360-381.

4.  Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255.

5.  Brown BG, Zhao XG, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.

6.  Giugliano RP. Niacin at 56 years of age – Time for early retirement? N Engl J Med. 2011. 10.156/NEJMe1112346.

7.  National Lipid Association. Further results of AIM-HIGH presented at AHA 2011 Scientific Sessions. Statement to NLA members. http://lipid.org/pages/statement.php. Accessed on November 19, 2011.

8.  Davidson MH. Focusing on high-density lipoprotein for coronary heart disease risk reduction. Cardiology Clinics. 2011;29:105-122.

9.  Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation. 2002;106:3143-3421.

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• Toth PP, Maki KC. Practical Lipid Management: London: John Wiley & Sons. Practical Lipid Management: Concepts and Controversies, is a text on the clinical management of dyslipidemias. As its title suggests, the book provides a straightforward and practical approach to the identification and treatment of abnormalities in lipid metabolism. The target audience consists of family physicians, internists, nurse practitioners, physician assistants, cardiologists, endocrinologists and allied health professionals involved in the care of patients with lipid disorders. The book is available for purchase at Amazon.com.

About Biofortis-Provident

Biofortis-Provident Clinical Research has a team of research professionals with extensive experience in the design and conduct of clinical trials to evaluate medical and functional foods, pharmaceuticals, dietary supplements and medical devices.

For more information, visit our web site: http://www.providentcrc.com and http://www.biofortis.eu.

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