Newswise — In a lead article published in the June issue of the American Journal of Cardiovascular Drugs, Florida Atlantic University researcher Charles H. Hennekens, M.D., the first Sir Richard Doll Research Professor in the Charles E. Schmidt College of Biomedical Science and a renowned expert who has elucidated numerous causal, therapeutic and preventive factors in the treatment and prevention of cardiovascular disease (CVD), most notably low-dose aspirin, discusses the strengths, limitations, and clinical and regulatory considerations of fixed-dose combination therapy with statins.
Statins are used for the treatment of lipid disorders, in particular, elevated LDL (bad) cholesterol in patients with and without prior CVD. These drugs reduce risks of myocardial infarction, stroke and deaths from CVD. In the U.S. today, for secondary prevention, approximately 12.4 million people are eligible for treatment with statins and, for primary prevention, approximately 24 million are eligible. Even before the more stringent guidelines were promulgated in 2004, only about one third of eligible patients were being treated and about 37% were achieving the federally mandated goals. While newer and more potent statins such as rosuvastatin and atorvastatin can achieve the goals for the majority of patients, often statins are prescribed along with other cholesterol-lowering drugs such as nicotinic acid (niacin) or ezetimibe (Zetia).
Fixed-dose combination drugs which include statins first appeared on the market in 2004. For example, Pravigard contains pravastatin to inhibit atherosclerosis and aspirin to inhibit thrombosis. More recently, Vytorin combined simvastatin to reduce the production of LDL cholesterol and ezetimibe to reduce absorption. "The controversies surrounding fixed-dose combination statins have drawn attention to Vytorin as well as issues in drug development and approval," said Hennekens.
In his article, "Fixed-dose Combination Therapy with Statins," Hennekens cites both strengths and limitations of these therapies. The potential strengths include: (1) increased compliance; (2) convenience; and (3) cost savings. In contrast, potential limitations include: (1) reduced flexibility in dosing; (2) exposure of some patients to therapies they do not require; and (3) increased risks of adverse effects without additional benefits.
"The current FDA policy for fixed-dose combination drugs was established in 1971, and its primary goal was to implement the efficacy requirement added in 1962 to the Federal Food, Drug, and Cosmetic Act (FDCA)," said Hennekens. "The objective was to remove numerous fixed-dose combination products from the market that lacked a reasonable medical basis for combined use."
According to Hennekens, the fixed-dose combination drug approval policy remains a valid framework and includes four key components, namely efficacy, safety, independent contribution and medical need.
The article briefly describes the FDA regulatory process for the approved fixed-dose combination therapies with statins including niacin/lovastatin (trade name Advicor), ezetimibe/simvastatin (trade name Vytorin), amlodipine/atorvastatin (trade name Caduet) and aspirin/pravastatin (trade name Pravigard PAC).
Hennekens' concluding remarks note that regulatory approval of fixed-dose drug combination products includes consideration of numerous issues. For example, the efficacy of both products combined should be demonstrated to be greater than either agent alone. Finally, there must be an unmet need and the demonstration of a population at risk which would benefit from the fixed-dose drug combination.
According to the American Heart Association, approximately 73 million people in the U.S. age 20 and older have high blood pressure and one in three adults has high blood pressure. In addition, approximately 105 million Americans age 20 and older have total blood cholesterol levels of 200 mg/dL and higher, 50 million are men and 55 million are women. Of these, about 42 million have total blood cholesterol levels of 240 mg/dL or higher, 18 million are men and 24 million are women. Higher LDL cholesterol levels combined with other risk factors including hypertension increase the risks of heart attacks, strokes and deaths from cardiovascular disease.
"The availability to healthcare providers of several statins of varying efficacy on lipid levels as well as fixed-dose drug combinations, reinforces the need for astute and individual clinical judgment in the context of the results of randomized trials in order to do more good than harm," said Hennekens.
Florida Atlantic University opened its doors in 1964 as the fifth public university in Florida. Today, the University serves more than 26,000 undergraduate and graduate students on seven campuses strategically located along 150 miles of Florida's southeastern coastline. Building on its rich tradition as a teaching university, with a world-class faculty, FAU hosts ten colleges: College of Architecture, Urban & Public Affairs, Dorothy F. Schmidt College of Arts & Letters, the Charles E. Schmidt College of Biomedical Science, the Barry Kaye College of Business, the College of Education, the College of Engineering & Computer Science, the Harriet L. Wilkes Honors College, the Graduate College, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science.
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