Niacin Beats Ezetimibe Head to Head

Pharmacology Watch

In this issue: Statin and niacin increase HDL-C, omeprazole reduces effectiveness of clopidogrel, darbe-poetin increases risk of stroke, statins decrease risk of gallstone disease, FDA Actions.

Statin plus niacin or ezetimibe?

Raising HDL-cholesterol (HDL-C) with niacin plus a statin is superior to lowering LDL-cholesterol (LDL-C) with ezetimibe plus statin in reversing atherosclerosis according to the widely reported ARBITER trial published on-line in the New England Journal of Medicine in November and simultaneously reported at the American Heart Association meeting in Orlando, FL. The trial enrolled more than 200 patients with coronary heart disease or a coronary heart disease equivalent who were receiving long-term statin therapy with an LDL-C < 100 mg/dL along with an HDL-C < 50 mg/dL for men or 55 mg/dL for women. The patients were randomly assigned to receive extended-release niacin (target is 2000 mg/day) or ezetimibe (10 mg/day). The primary endpoint was the difference in change from baseline in mean and maximal carotid intima-media thickness after 14 months. The trial was terminated early in July of 2009. Both drugs were effective in their roles — the mean HDL-C in the niacin group increased by 18.4% over the 14-month study period (P < 0.001) and the mean LDL-C level in the ezetimibe group decreased by 19.2% (P < 0.001). Niacin significantly reduced LDL-C and triglycerides as well, while ezetimibe lead to a reduction in HDL-C and triglycerides. Niacin was superior to ezetimibe in reducing the primary endpoint, leading to a reduction of both mean (P = 0.001) and maximal carotid intima-media thickness (P ≤ 0.001 for all comparisons). Paradoxically, greater reductions in LDL-C seen with ezetimibe were significantly associated with increases in the carotid intima-media thickness. The incidence of major cardiovascular events was also lower in the niacin group than in the ezetimibe group (1% vs 5%; P = 0.04 by the chi square test) (published on-line at: www.nejm.org; Nov. 15, 2009).

The study has received enormous attention not only because of the primary endpoint, but also because of the significant reduction in major adverse cardiac events in the niacin group, even though the numbers were quite small. At least one editorialist laments the early termination of the study and feels that it is impossible to make recommendations regarding the "adjuvant agent of choice" based on the small numbers (The HALTS Trial — Halting Atherosclerosis or Halted Too Early; published on-line at: www.nejm.org; Nov. 15, 2009). Still, this study provides enough evidence to consider adding niacin to a statin in patients who are at risk of or have low HDL-C. It also deals another blow to ezetimibe (Zetia®) and its partner drug ezetimibe/simvastatin (Vytorin®).

Omeprazole's effect on clopidogrel

The FDA has issued a warning regarding the combination of clopidogrel (Plavix®) with omeprazole (Prilosec®) citing new data that suggest that the combination reduces clopidogrel's effectiveness by about half. Studies reported in 2009 suggested that omeprazole may block clopidogrel's conversion to its active metabolite via CYP2C19, an enzyme that is inhibited by omeprazole. New studies requested by the FDA from the manufacturers confirm a significant interaction between the two drugs, which can significantly hinder clopidogrel's ability to prevent platelet aggregation in patients at risk for heart disease. Omeprazole and clopidogrel are commonly prescribed together to prevent GI bleeding. At this time it is unclear whether this interaction extends to other proton pump inhibitors, although physicians are encouraged to avoid a combination of clopidogrel with esomeprazole (Nexium®, cimetidine (Tagamet®), and other drugs known to inhibit CYP2C19. The FDA is recommending that patients who need GI protection in conjunction with clopidogrel may safely use ranitidine (Zantac®), famotidine (Pepcid®), nizatidine (Axid®), or oral antacids.

Darbepoetin and risk of stroke

Darbepoetin alfa (Aranesp®) is commonly used in patients with chronic kidney disease and diabetes for the treatment of anemia. A new study suggests that the drug may be associated with increased risk of stroke in this patient population. More than 4000 patients with diabetes, chronic kidney disease, and anemia were randomly assigned to darbepoetin alfa to achieve a hemoglobin level of 13 g/dL or placebo with rescue darbepoetin alfa if hemoglobin levels dropped < 9 g/dL. The primary endpoints were the composite outcomes of death or cardiovascular event, and death or end-stage renal disease. After a follow up of 2.5 years, darbepoetin alfa was ineffective at preventing either primary outcome, and, more importantly, the rate of fatal or nonfatal stroke occurred almost twice as often in the treatment group (101 patients assigned to darbepoetin alfa vs 53 patients assigned to placebo; HR, 1.92; 95% confidence interval, 1.38-2.68; P < 0.001). The authors conclude that the use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who are not undergoing dialysis did not reduce the outcome of death, cardiovascular events, or renal events, but was associated with increased risk of stroke. For many "this risk will outweigh the potential benefits" of the drug (N Engl J Med 2009;361:2019-2032). Erythropoiesis-stimulating agents have come under fire in the treatment of cancer-associated anemia, and now in renal patients as well. As pointed out in an accompanying editorial, the risks and benefits of these agents must be weighed, namely an increased risk of stroke vs a perceived improvement in quality of life (N Engl J Med 2009;361:2089-2090).

Statins and gallstone disease

Statins have been shown to reduce the risk of cardiovascular disease and death from all causes. Now another potential benefit is being reported: Statins may reduce gallstone disease. Utilizing a large patient database from the United Kingdom, researchers looked at the risk of developing gallstones followed by cholecystectomy in relation to exposure to lipid-lowering agents. The longer patients took statins, the lower the risk for gallstone disease, with patients who had filled 20 or more prescriptions noticing 36% reduction in risk (AOR, 0.64; 95% confidence interval, 0.59-0.70). The authors conclude that long-term use of statins is associated with a decrease risk of gallstones followed by cholecystectomy (JAMA 2009;302:2001-2007).

FDA Actions

The FDA has approved a new topical treatment for the treatment of post-herpetic neuralgia (PHN). The capsaicin 8% patch must be applied to the skin by a health care professional since placement may be quite painful, requiring the use of a local topical anesthetic. The patch is applied for one hour during which patients must be monitored, including observation for increases in blood pressure. The patches may be cut to conform to the area of pain and up to 4 patches may be used. The one-hour application is reported to provide up to 12 weeks of reduced pain from PHN. The capsaicin 8% patch will be manufactured by Lohmann Therapie-Systems and distributed by NeurogesX as Qutenza™.

The FDA has approved romidepsin for the treatment of cutaneous T-cell lymphoma in patients who received at least one prior systemic therapy. The drug is a histone deacetylase inhibitor, the first of a new class of antineoplastics. Romidepsin will be marketed as Istodax® by Gloucester Pharmaceuticals.


This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: paula.cousins@ahcmedia.com.