Oral Anticoagulant + Antiplatelet Therapy = Danger

Pharmacology Watch

In this issue: Adding an anticoagulant to aspirin is of no value in patients with peripheral artery disease, older adults with coronary disease benefit from aggressive statin therapy, simvastatin may reduce the risk of dementia and Parkinson's disease by as much as 50%, MiraLax is safe for long-term use in patients with chronic constipation, the FDA green-lights Avandia, brings back Zelnorm for limited use, and recommends approving Evista for breast cancer prevention.

Patients with peripheral artery disease are at high risk for cardiovascular complications. Antiplatelet drugs are routinely prescribed for these patients, but is adding an oral anticoagulant of value? No, according to a new study. In fact, the combination may be dangerous. More than 2,100 patients with PAD were randomly assigned to antiplatelet therapy with an oral anticoagulant or to antiplatelet therapy alone. The first coprimary outcome was myocardial infarction, stroke, or death from cardiovascular causes. The second coprimary outcome was myocardial infarction, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention or death from cardiovascular causes. After an average followup of 35 months, the first coprimary outcome occurred in 132 of 1080 patients receiving combination therapy (12.2%) and 144 of 1081 patients receiving antiplatelet therapy alone (13.3%) (RR 0.92; 95% CI, 0.73 to 1.16; P = 0.48). The second coprimary outcome occurred in 172 patients receiving combination therapy (15.9%) compared to 188 patients receiving antiplatelet therapy alone (17.4%) (RR 0.91; 95% CI, 0.74 to 1.12; P = 0.37). Life-threatening bleeding occurred in 43 patients receiving combination therapy (4.0%) as compared to 13 patients receiving antiplatelet therapy alone (1.2%) (RR 3.41; is 95% CI, 1.84 to 6.35; P < 0.001). The authors conclude that adding an oral anticoagulant to antiplatelet therapy in patients with PAD was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications, but was associated with an increase in life-threatening bleeding (N Engl J Med 2007; 357: 217-227).

High-Dose Statin Therapy, Value for Older Adults

Aggressive lipid lowering with high-dose statin therapy may be of value in older adults with stable coronary disease. The multicenter study from the United States included 3,809 patients 65 years or older with coronary artery disease and cholesterol levels less than 130 mg/dl who were randomized to receive atorvastatin 10 mg or 80 mg. Patients on low-dose atorvastatin achieved average cholesterol levels of 100 mg/dl versus 70 mg/dl for high dose therapy. The primary endpoint was occurrence of first major cardiovascular event such as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. Patients treated with high-dose atorvastatin were found have a 2.3% absolute risk reduction and a 19% relative risk reduction for the primary endpoint (hazard ratio 0.81 [95% CI, 0.67 to 0.98]; P = 0.032). Mortality rates were lower for CHD, nonfatal non--procedure-related myocardial infarction, and stroke in the high-dose group. High-dose therapy was not associated with elevated creatine kinase levels. The authors conclude that treating older patients with coronary heart disease more aggressively to reduce low-density lipoprotein cholesterol levels provides additional clinical benefit (Ann Int Med 2007;147: 1-9).

Simvastatin, Best for Parkinson's Disease

Simvastatin, not atorvastatin or lovastatin, is associated with a dramatically reduced risk of dementia and Parkinson's disease (PD) according to a study from Boston University and VA database of 4.5 million individuals (95% men). In the observational study, over 700,000 subjects took simvastatin, nearly 54,000 took atorvastatin, and over 54,000 patients were prescribed lovastatin. Three models were used to evaluate the data, adjusting for covariates associated with dementia or Parkinson's disease. The first model was adjusted for age; the second model adjusted for 3 known risk factors for dementia: hypertension, cardiovascular disease, or diabetes; and the third model adjusted using the Charlson index, an index that provides broad assessment of chronic disease. Using the third model, the hazard ratio for dementia was 0.46 for simvastatin (CI 0.44-0.48, P < 0.0001) and 0.91 for atorvastatin (CI 0.80-1.02, P = 0.11). Lovastatin was not associated with a reduction in the incidence of dementia. The hazard ratio for newly acquired Parkinson's disease was 0.51 for simvastatin (CI 0.49-0.55, P < 0.001). There was no reduction in PD with atorvastatin or lovastatin. The degree of risk reduction utilizing the other models was similar with simvastatin. The authors conclude that simvastatin is associated with a strong reduction in the incidence of dementia and PD, while atorvastatin is associated with a modest reduction in incidence of dementia and Parkinson's disease that shows a trend toward significance (BMC Med published online July 19, 2007). The surprising finding suggests a difference between simvastatin and atorvastatin out of proportion to their cholesterol lowering effects, which the authors suggest may be due to the ability of simvastatin to cross the blood brain barrier more readily than other statins.

Polyethylene Glycol for Chronic Constipation

Long-term use of polyethylene glycol is safe and effective for chronic constipation according to the results of a new study from Alabama. More than 300 patients were randomized to receive polyethylene glycol 3350 (MiraLAX) in a single 17 g dose per day or placebo for 6 months. The primary endpoint of improvement of constipation on an objective scale was reached in 52% of the PEG patients and 11% placebo patients (P < 0.001). Similar efficacy was seen in a subgroup of 75 elderly patients. There were no significant adverse events other than diarrhea, flatulence and some nausea associated with PEG. The authors conclude that PEG laxative is safe and effective for use in patients with chronic constipation for up to 6 months (Am J Gastroenterol 2007;102:1436-1441). The study is particularly important because MiraLax is now available over-the-counter and long-term use by patients with chronic constipation is likely.

FDA Actions

The FDA's Oncologic Drugs Advisory Committee, on a narrow vote, recommended approval of raloxifene (Evista) for the indication of breast cancer prevention in high risk women. The approval was based on data from the Study of Tamoxifen and Raloxifene (STAR) trial, which showed a reduction of 4 cases of breast cancer per 1,000 women (50% relative risk reduction), although it was not as effective as tamoxifen in preventing noninvasive breast cancers. Similar findings were seen in the Raloxifene for Use for The Heart (RUTH) trial although this trial revealed a higher risk of fatal stroke and blood clots with raloxifene. The FDA generally follows its advisory committee recommendations. Raloxifene is already approved for the prevention of osteoporosis.

The FDA has approved restricted use of tegaserod (Zelnorm) for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in women under the age of 55 who meet certain criteria. The drug was taken off the market earlier this year when it was linked with a higher risk of cardiovascular events including heart attack, stroke, and unstable angina. Patients must have no history of heart disease and must be in critical need of the drug. Prescribing will be under an investigational new drug protocol program that has been set up by the FDA.

Rosiglitazone (Avandia-GlaxoSmithKline) is associated with an increase risk of heart failure and myocardial infarction. Despite this, the FDA's Endocrinologic and Metabolic Drugs Advisory committee along with the Drug Safety and Risk Management Advisory Committee has advised that the drug stay on the market, albeit with increased warnings. Type 2 diabetes patients who are on insulin for those with heart disease are not the candidates for the drug. The FDA will render a final decision on the drug this fall.

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) 262-5431. E-mail: jennifer.corbett@ahcmedia.com.