Safety of Inhaled Anticholinergics for COPD Scrutinized

Pharmacology Watch

In the Issue: Ongoing safety review of tiotropium; raloxifene reduces the risk of endometrial cancer; one-day treatment with famciclovir may be as effective as 3-day treatment with valacyclovir; new Clinical Practice Guideline from the American College of Physicians regarding pharmacologic treatment for low bone density and osteoporosis; FDA Actions.

The safety of inhaled anticholinergics for the treatment of chronic obstructive pulmonary disease (COPD) has come under scrutiny in recent months. In July, the FDA issued an "Early Communication" about an ongoing safety review of tiotropium (Spiriva®) the most widely used agent for the treatment of COPD. The review is focused on a possible increased risk of stroke and is based on a pooled analysis of 29 trials which showed the risk of stroke at 8 patients per 1000 treated with tiotropium versus 6 patients per 1000 treated with placebo.

Now two new studies suggest that inhaled anticholinergics (ipratropium [Atrovent®] and tiotropium) increase the risk for all-cause mortality and cardiovascular disease in patients with COPD. In a large meta-analysis (JAMA 2008;300:1439-1450), researchers reviewed 17 trials involving nearly 15,000 patients with COPD who were randomized to an inhaled anticholinergic or control. The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. The primary outcome occurred in 1.8% of patients receiving inhaled anticholinergics and 1.2% of patients receiving control therapy (RR 1.58, 95% CI, 1.21-2.06; P < 0.001). Inhaled anticholinergics significantly increased risk of MI, cardiovascular death, and all-cause mortality (RR 1.26). When the analysis was restricted to long-term trials, the risk was even greater for cardiovascular death, MI, or stroke (RR 1.73). The number needed to harm for MI was 174 per year, while the number needed to harm for cardiovascular death was 40 per year. The authors concluded that inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

In a second nested, case-control study (Ann Intern Med 2008;149:380-390), the National Veterans Affairs databases were used to review all-cause mortality, respiratory and cardiovascular deaths, and exposure to COPD medications including inhaled corticosteroids, ipratropium, long-acting beta agonists, and theophylline in the 6 months preceding death. The adjusted odds ratios for all-cause mortality were 0.80 for inhaled chronic steroids, 1.11 for ipratropium, 0.92 for long-acting beta agonists, and 1.05 for theophylline. Ipratropium was associated with increased cardiovascular deaths (OR 1.34), whereas inhaled corticosteroids were associated with reduced risk for cardiovascular death (OR 0.80). The authors conclude that there is a possible association between ipratropium and elevated risk for all-cause and cardiovascular death and that further studies are needed. They also suggest that the risk of ipratropium may be somewhat mitigated by concomitant use of inhaled corticosteroids, but caution should be exercised if ipratropium is used alone in patients with recently diagnosed COPD.

Raloxifene reduces endometrial cancer risk

It is well known that raloxifene reduces the risk of breast cancer; now there is evidence that the drug reduces the risk of endometrial cancer as well. Raloxifene (Evista®) is a selective estrogen receptor modulator (SERM) that is indicated for treatment and prevention of osteoporosis and for breast cancer prevention. Researchers from the University of Pennsylvania compared endometrial cancer rates in women on raloxifene, tamoxifen, and non-users of SERMs in a case-control study of 547 women with endometrial cancer and 1410 controls. After adjustment for other risk factors the odds of endometrial cancer among raloxifene users was 50% that of non-users (OR = 0.50; 95% CI, 0.29-0.85), whereas tamoxifen users had 3 times the odds of developing endometrial cancer compared to raloxifene users (OR = 3.0; 95% CI, 1.3-6.9). Among raloxifene users who developed endometrial cancer, the tumors had a more favorable histologic profile and were predominantly stage I and low grade. The authors conclude that raloxifene users have significantly lower risk of developing endometrial cancer compared with tamoxifen users and SERM non-users, perhaps even suggesting a role for raloxifene and prevention of endometrial cancer (J Clin Oncol 2008; 26:4151-4159).

One-day famciclovir = three-day valacyclovir

For patients with recurrent genital herpes outbreaks, one-day treatment with famciclovir may be as effective as 3-day treatment with valacyclovir, according to a new study. In a double-blind parallel group study, 1179 adults with a history of recurrent genital herpes were randomized to receive either famciclovir 1000 mg twice daily for one day vs valacyclovir 500 mg twice daily for 3 days. Patients initiated treatment within 6 hours after a recurrence. Approximately one-third of patients in each group aborted genital herpes outbreaks altogether, but for those who went on to develop lesions, median time to healing was 4.25 days for famciclovir vs 4.08 days for valacyclovir. Time to healing was the same in both groups and the incidence of adverse affects was 23.2% for famciclovir vs 22.3% for valacyclovir. The study demonstrates that a single day of famciclovir (1000 mg twice daily) is equivalent to 3 days of valacyclovir (Clin Infect Dis 2008;47:651-658). Other regimens for treatment of recurrent HSV episodes include acyclovir 800 mg 3 times daily for two days or 400 mg three times daily for 3-5 days, famciclovir 125 mg twice a day for 3-5 days, or valacyclovir 500 mg twice daily for 3 days. Both acyclovir and famciclovir are available generically, but acyclovir is considerably less expensive; however, the convenience of a one-day treatment with famciclovir may be worth the extra cost for many patients.

New practice guideline for osteoporosis

The American College of Physicians has issued a Clinical Practice Guideline regarding the pharmacologic treatment of patients with low bone density or osteoporosis (Ann Intern Med 2008; 149:404-415). The expert committee recommends that clinicians offer pharmacologic treatment to men and women who have known osteoporosis and to those who have experienced fragility fractures. They also recommend that pharmacologic treatment should be considered for men and women who are at risk of developing osteoporosis and that the choice of pharmacologic treatment should be based on assessment of risk and benefits in individual patients. The guideline reviews different treatment modalities including bisphosphonates, calcitonin, estrogen, teriparatide, SERMs, testosterone, and calcium plus vitamin D. Left unanswered are the questions of duration of treatment with bisphosphonates and the optimal dose of calcium and vitamin D.

FDA actions

The FDA has issued warning letters to Ranbaxy Laboratories Ltd. of India in an Import Alert for the company's generic drugs produced in two Indian plants. The warning letters identify concerns about deviations from U.S. current Good Manufacturing Practice requirements at Ranbaxy's manufacturing facilities and the Import Alert allows officials to detain at the rest border any active pharmaceutical ingredients manufactured at Ranbaxy facilities. Ranbaxy manufacturers more than 30 generic drugs including commonly used antibiotics, antihypertensives, and antivirals.

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: