Study: Long-Term Use of Clopidogrel for DES Patients

Pharmacology Watch

Patients with coronary artery disease who have received intra-coronary, drug-eluding stents (DES) may benefit from longer courses of clopidogrel than is currently standard. Researchers at Duke looked at 4,666 patients undergoing percutaneous coronary interventions with bare metal stents (BMS) (n = 365) or DES (n = 1501). Patients were followed up at 6, 12, and 24 months with the main outcomes being death, non-fatal MI, and the composite of death or MI at 24-month follow-up. For patients who received DES and were event free at 6 months, use of clopidogrel was a significant predictor of fewer events at 24 months (death rate 2.0% with clopidogrel vs 5.3% without , P = 0.3; death/MI 3.1% vs 7.2%, P = 0.02). However the same was not seen for BMS patients, with no significant difference in death rate or death/MI in the patients who took clopidogrel. For DES patients who were event free at 12 months, use of clopidogrel continued to improve outcomes (death rate 0% with clopidogrel versus 3.5% without, P = .004; death/MI 0% versus 4.5%, P < 0.001). For patients with BMS who were event free at 12 months, use of clopidogrel was still not associated with any change in death rate (3.3% vs 2.7% P = 0.57) or death/MI (4.7% 3.6%, P = 0.44). The authors conclude that extended use of clopidogrel in patients with drug-eluding stents may reduce the rate of death and MI. However the appropriate duration of clopidogrel administration has not yet been determined. (JAMA early release article posted 12/05/06). Implications of the study are significant in that current recommendations following PCI with drug eluting stents is for 3 to 6 months of clopidogrel. Several studies have shown that these stents have increase risk of catastrophic stent thrombosis, higher than bare metal stents, months after the procedure. This has led some experts to recommend long-term use of clopidogrel, perhaps even lifetime use in patients who have received a DES. While the study does not make recommendations, it does confirm the fact that clopidogrel is beneficial for patients who received a DES for up to 2 years.

Drug Labels — A Prescription for Misunderstanding?

Prescription drug labels are commonly misunderstood according to a new study in the Annals of Internal Medicine. Nearly 400 English-speaking patients were enrolled in the study to assess their understanding of 5 different medication labels, all had relatively common instructions. Patients with low literacy, defined as 6th-grade level or less, were less likely to understand all 5 labels. Patients with low literacy read the instruction, "Take two tablets by mouth twice daily," but only 35% could demonstrate the number of pills to be taken daily. Patients who had multiple prescriptions were significantly more likely to misunderstand prescription labels. The authors admit that the patient's actual drug-taking behaviors were not observed, so authors could not demonstrate a link between misunderstanding the labels and actual medication errors. Still the authors suggest that patients of all ages would benefit from additional efforts to improve the clarity of prescription labels and suggest that the text and format of existing prescription containers should be redesigned and standardized (Ann Int Med. 2006;145: Epub ahead of print).

Osteonecrosis of the Jaw — New Side-Effect to Bisphosphate Use

With the widespread use of bisphosphonates for the prevention and treatment of osteoporosis, a new side effect, osteonecrosis of the jaw, has emerged as a concern. A new "Perspective" piece in the New England Journal of Medicine (November 30) helps answer the question, "Osteonecrosis of the Jaw—Do Bisphosphonates Pose a Risk?" Osteonecrosis of the jaw is characterized by exposed bone in the mandible, maxilla, or palate, and is often associated with dental disease, dental surgery, oral trauma, periodontitis, and poor dental hygiene. The author points out that the first case of osteonecrosis associated with bisphosphonates was reported in 2003, nearly 10 years after the drugs were first approved. Most reported cases are associated with high-dose intravenous bisphosphonates given to control metastatic bone disease where the rate is reported from 1.3% to 7%. The average patient with osteonecrosis had been receiving intravenous bisphosphonate therapy for 1.5 to 3 years. Use of oral bisphosphonates to treat osteoporosis involves doses that are often 10 times lower than intravenous doses. Fewer than 50 cases of osteonecrosis of the jaw have been associated with oral bisphosphonates, or approximately 1 in 100,000 patient years. There is concern that with long-term use of oral bisphosphonates, the rate of osteonecrosis may increase in the future. Some have even suggested that osteoporosis patients take a "drug holiday" after 5 years of therapy to reduce the risk; however, the benefit of the strategy is unclear at this time. A routine dental evaluation is reasonable prior to starting bisphosphonates; however, there is no reason to stop the drugs prior to dental treatment. Some oral surgeons advocate temporarily withholding drugs if invasive dental care is needed, but given the very long half-life of these drugs, it is unclear whether temporary cessation will have any effect on reducing the risk of osteonecrosis, and more research is needed (N Eng J Med. 2006; 355:2278-2281).

Beta-Blockers and Depression — Unlinked?

Many physicians are cautious about the use of beta-blockers after myocardial infarction because of the risk of depression. A new study suggests that this concern may be unwarranted. Researchers from the Netherlands looked at 127 patients who had a myocardial infarction and were not taking beta-blockers versus 254 MI patients who were taking beta-blockers at 3, 6, and 12 months post MI. Outcomes were scores on 2 commonly used depression scales. No significant differences were found between beta-blocker users and non-beta-blocker users regarding the presence of depressive symptoms or depressive disorder, although a trend towards more depression was seen in patients with long-term use of beta-blockers and patients on higher doses. Use of a hydrophilic versus lipophilic beta blocker made no significant difference. The authors conclude that in post MI patients, use of beta-blockers is not associated with an increase in depressive symptoms or depressive disorders in the first year (J Am Coll Cardio. 2006;48:2209-2214).

FDA Actions

The FDA has approved telbivudine for the treatment of chronic hepatitis B virus (HBV) infections in adults. The drug is approved for patients with evidence of viral complication in either persistent elevations in serum transaminases or histologically active disease. The approval was based on a one-year study, and more than 1,300 patients showed significant decreases in HBV-virus DNA levels compared with lamivudine. Telbivudine, which is given as a 600 mg oral daily dose, will be marketed by Idenix Pharmaceuticals and Novartis as "Tyzeka."

FDA has approved the first generic version of ondansetron injection (Zofran) for the prevention of nausea and vomiting associated with chemotherapy and prevention of postoperative nausea and vomiting. The generic product will be manufactured by Teva and SICOR Pharmaceuticals. GlaxoSmithKline, which previously held the patent for Zofran, had 2005 sales of nearly $850 million.

The FDA has approved expanded use of Herceptin for HER2-positive, early-stage breast cancer after mastectomy or lumpectomy. Previously, the drug was only approved for HER2- positive, metastatic breast cancer.

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: