Risk for Men Using Inhaled Anticholinergic Drugs

A recent Archives of Internal Medicine study suggests that older men with chronic obstructive pulmonary disease (COPD) being treated with the commonly used inhaled anticholinergic bronchodilator drugs containing ipratropium (ATROVENT, COMBIVENT and DUONEB) and tiotropium (SPIRIVA) are at increased risk of acute urinary retention (AUR), a condition characterized by a sudden inability to urinate.

AUR is considered a medical emergency and can cause bladder damage, urinary tract infections, sepsis, kidney failure and death unless promptly treated. The risk of developing this adverse effect appears to be greatest in men with benign prostatic hypertrophy (BPH), or enlarged prostate.

The study, published on May 23, 2011, highlights the fact that inhaled medications used to treat lung diseases such as COPD can have serious adverse effects on organs other than the lungs. Patients taking these drugs need to be aware of these side effects so that they can be alert for early symptoms.

What is COPD?

COPD is a chronic, progressive lung disease characterized by decreased airflow. The condition is not fully reversible with bronchodilator medications. Smoking, by far, is the leading cause of COPD. COPD classically can present either as emphysema or chronic bronchitis, although some patients can have clinical features of both.

Common symptoms of COPD include coughing (with mucus or phlegm), shortness of breath, wheezing and chest tightness. In mild COPD, shortness of breath may occur only with exertion. As COPD progresses, the shortness of breath may occur with minimal activity or at rest.

The primary treatments for COPD include smoking cessation, inhaled beta-agonists (such as albuterol [COMBIVENT — also contains ipratropium — PROVENTIL, VENTOLIN, VOLMAX and VOSPIRE], salmeterol [SEREVENT and ADVAIR] and formoterol [DULERA, FORADIL, PERFOROMIST and SYMBICORT]), inhaled anticholinergic drugs, inhaled steroids, systemic steroids, pulmonary physical rehabilitation and home oxygen.

Regarding the two inhaled anticholinergic drugs currently available in the U.S., ipratropium is a short-acting bronchodilator typically administered four times per day, and tiotropium is a long-acting bronchodilator administered twice daily.

Archives study overview

Dr. Anne Stephenson and her co-authors used medical and pharmacy records of COPD patients to assess the risk of developing AUR based on the timing of exposure to these drugs before patients developed AUR and on the type and number of inhaled anticholinergic drugs prescribed. They also evaluated whether men diagnosed with BPH were at greater risk for developing this complication.

The researchers analyzed the records for all residents of Ontario, Canada, aged 66 years or older who had been diagnosed with COPD during the six-year period from April 2003 to March 2009. Of those patients diagnosed with COPD (565,073), the researchers identified all patients who were diagnosed with their first episode of AUR during an emergency room visit, same-day surgery visit or hospital admission (these patients are referred to as “index cases”).

The research team identified 11,238 index cases of AUR. Eighty-four percent of the cases were men, and 16 percent were women. Among the men with COPD who developed AUR, 5,090 also had evidence of BPH, a known risk factor for AUR.

Effect of timing of inhaled anticholinergic drug use on AUR risk

The researchers assessed how the use of any inhaled anticholinergic drug, as well as the timing of that use, affected the risk for AUR in men and women with COPD.

For this part of the study, the researchers categorized the patients into four groups based on the timing of their exposure to inhaled anticholinergic drugs prior to the index date on which the index case of AUR was diagnosed: new users, current users, past users and nonusers (see “AUR Risk in Men, by Time of Exposure and Drug Regimen” table).

The researchers found that men with COPD who were new users of inhaled anticholinergic drugs had a 1.2- to 1.7-fold higher risk for developing AUR than men who were nonusers. Male COPD patients who were current users had a 1.3-to 1.5-fold increase in risk of developing AUR than nonusers. Those men with COPD who were past users did not have a statistically significant increase in the risk for AUR compared to nonusers.

Men who have BPH without a history of prostate resection are a high-risk group for developing AUR. Not surprisingly, the researchers found that men who had both COPD and BPH without prior prostate resection to reduce the BPH had an even greater increase in risk for AUR following exposure to inhaled anticholinergic drugs. Compared to nonusers of these drugs, men who were new users and had COPD and BPH had a 1.5- to 2.2-fold higher risk for developing AUR, and current users had a 1.4- to 1.6-fold higher risk.

In contrast to men, an increased risk for AUR was not seen in women with COPD who were new, current or past users of inhaled anticholinergic drugs in comparison to nonuser women with COPD.

Effect of different inhaled anticholinergic drug regimens on AUR risk

The researchers also assessed the relative risks for AUR in men with COPD treated with different regimens of inhaled anticholinergic drugs. For this part of the study, new-user men with COPD were divided into three groups: those receiving only a short-acting inhaled anticholinergic drug (short-acting monotherapy group), those receiving only a long-acting inhaled anticholinergic drug (long-acting monotherapy group) and those receiving a combination of short-acting and long-acting inhaled anticholinergic drugs (combination therapy group).

The researchers found that men with COPD in the combination therapy group had a 1.3- to 2.7-fold greater risk of developing AUR than those men in the short-acting monotherapy group. The risk of AUR was similar for men in the short-acting monotherapy and long-acting monotherapy groups. When compared to nonusers, patients in the combination therapy group had risks 1.9 to 3.8 times greater.

COPD treatment and the Archives study results

Both the findings concerning the risk according to time of exposure to inhaled anticholinergic drugs and the risk depending on the drug regimen help to establish the causal relationship between anticholinergic drug use and the development of acute urinary retention in older men with COPD. Men with COPD, particularly those who have BPH, have an increased risk for developing this dangerous complication when using inhaled anticholinergic drugs. Given the higher risk identified in new users of these drugs, patients should be closely monitored for signs and symptoms of impending AUR (see “What You Can Do” section) during the first month of treatment.

What You Can Do

If you take ipratropium or tiotropium for COPD, you should monitor yourself for symptoms of impending AUR, such as straining to urinate, incomplete voiding, dribbling, weak urinary stream and urinary incontinence, and contact your health care provider if such symptoms develop.

If you are unable to urinate at all after a period of several hours, you should seek emergency treatment from your primary health care provider or the nearest emergency room. The initial treatment for AUR is insertion of a catheter into the bladder to drain the accumulated urine. Discontinuation or a lowering of the dose of the inhaled anticholinergic drug may be necessary. Surgery or medical treatments to reduce the size of the prostate in men who have significant BPH may also be appropriate.

If you are using a combination of short- and long-acting dosage forms, you should discuss with your physician the possibility of using a short-acting or long-acting dosage form alone, whichever works better for you, since either one alone has less risk of AUR than the combination.

Consumers should report serious adverse events or product quality problems to the Food and Drug Administration’s (FDA) MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.

• Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088