Tiotropium (SPIRIVA) for Chronic Obstructive Pulmonary Disease (COPD). Is it an Important Advance?

The Food and Drug Administration (FDA) approved tiotropium (SPIRIVA) in January 2004 for the long-term treatment of bronchospasm (sudden episodes of breathing problems) associated with chronic obstructive pulmonary disease (COPD), a condition that includes chronic bronchitis and emphysema. Tiotropium is not FDA- approved to treat asthma.

Tiotropium belongs to the family of drugs known as anticholinergics. Another drug in this family, ipratropium (ATROVENT), has been on the market for years and is also FDA-approved for the same use as tiotropium. The major differences between these two drugs are that tiotropium needs to be used only once a day, whereas four doses per day are required for ipratropium. Tiotropium is more than 1.5 times as expensive as ipratropium.

The studies to support the approval of tiotropium originally were submitted to the FDA in November 1994. At that time the drug’s manufacturer, Boehringer Ingelheim, also sought approval for use in patients with moderate to severe asthma. In an Annual Report dated April 29, 1999, Boehringer Ingelheim notified the FDA that clinical development in patients with asthma had been discontinued. In a submission dated October 8, 2001, the company stated that studies of the product in adults with asthma had failed to demonstrate effectiveness.

On September 6, 2002, an FDA advisory committee of outside experts recommended that tiotropium be approved for the treatment of COPD. Boehringer Ingelheim had also requested FDA approval for the drug to manage difficult or labored breathing, a symptom known as dyspnea. The advisory committee agreed unanimously that there was not substantial and convincing evidence that the drug provides a clinically meaningful effect for the symptom of dyspnea in patients with COPD.

The Medical Letter on Drugs and Therapeutics, an excellent source of drug information for pharmacists and physicians gave tiotropium a glowing review in their May 24, 2004 issue remarking that the drug is an “important advance.”

Tiotropium bromide (Spiriva HandiHaler) is a long-acting inhaled anticholinergic drug for treatment of COPD that can improve lung function, reduce symptoms, improve quality of life and decrease the number of exacerbations with once-daily dosing. The new drug has a much longer duration of action than ipratropium bromide and produces a more sustained response over time than long-acting beta2-agonists such as salmeterol. Medical Letter consultants consider it an important advance in the treatment of this disease.

Having examined the publicly available FDA reviews of the studies submitted by Boehringer Ingelheim to support the approval of tiotropium, our opinion of the therapeutic value of this drug is more subdued than that of The Medical Letter editors. In many cases, we have found the FDA reviews of new drugs to be more informative than the peer-reviewed medical literature. These reviews are independent of the manufacturer, and sometimes studies are submitted and reviewed by the agency that are never published in medical literature because their results do not shine the brightest light on the drug being reviewed.

The FDA reviews for new drugs can be found on the agency’s web page Drugs@FDA, a catalog of FDA-approved products, at: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Boehringer Ingelheim submitted six main clinical trials to support the approval of tiotropium.

Two of the trials, each lasting one year, compared the drug to a placebo. The FDA medical officer reviewing tiotropium found that it did improve breathing (bronchodilator effect). However, there was no difference between tiotropium and the placebo with regard to the number of patients with worsening COPD, time to worsening of COPD, the number of days associated with COPD worsening, and the number of hospitalizations due to COPD worsening.

These studies also included two health-related quality of life assessment surveys. The medical officer noted that for the only survey analyzed, the differences between tiotropium and placebo rarely reached the generally accepted threshold for a minimal clinically meaningful effect.

On average, patients taking tiotropium used approximately five to six fewer doses of the bronchodilator albuterol (PROVENTIL) per week than patients taking the placebo. In one of these studies, patients in the tiotropium group had statistically fewer nighttime awakenings due to COPD symptoms during the 7 of the 13 weeks this was assessed; in the second study, no effect for tiotropium on nighttime awakenings was seen.

Another two of the trials submitted by Boehringer Ingelheim to the FDA, also lasting about one year each, compared tiotropium to ipratropium. The effectiveness of the drugs was measured at a time when it would be expected that ipratropium would not be effective. The FDA medical officer commented that tiotropium’s “... demonstrated superiority over ipratropium may be construed as superiority over placebo.”

In one of these trials, the overall use of albuterol was not different between tiotropium and ipratropium users, but was statistically lower in the tiotropium group for 36 of the 52 weeks in the other study. The effect of tiotropium on worsening of COPD in these trials was not consistent.

The two trials also included two health-related quality of life assessment surveys. The medical officer noted that for one of these surveys, the difference between the tiotropium and ipratropium groups rarely reached the generally accepted threshold for a minimal clinically meaningful effect. In the other survey, there was no statistical difference between tiotropium and ipratropium.

The final two main trials submitted by Boehringer Ingelheim to the FDA compared tiotropium, placebo, and the long acting bronchodilator salmeterol (SEREVENT; see Worst Pills, Best Pills News March 2003). These trials were six months in length. In both trials tiotropium was better than the placebo in improving breathing. Interestingly, in only one of these two trials was tiotropium statistically better than a placebo in the number of doses of albuterol needed by patients.

In one of these trials, there was no statistical difference between tiotropium and placebo in the number of patients who experienced at least one episode of worsening COPD. In both of these trials, there were no notable differences between tiotropium and the placebo with regard to hospitalizations for COPD.

In the two health-related quality of life assessment surveys, there was no statistical difference between tiotropium and placebo on one of the surveys in either trial. In the other survey, tiotropium was superior to placebo in only one of the trials.

With regard to adverse drug reactions, the FDA medical officer found that the anticholinergic adverse effects such as dry mouth, urinary retention, and constipation were more frequent in women and in older patients receiving tiotropium.

The medical officer also found suggestions that tiotropium may be associated with adverse effects on the heart such as heart rate and rhythm disorders. The medical officer suggested that this potential safety issue be studied after the drug’s approval in what is known as a Phase 4 study.

The table below compares the retail cost of tiotropium and ipratropium for a one-month supply in the U.S. and in Canada. Costs are in U.S. dollars. Tiotropium is significantly more expensive than ipratropium in both countries.

Tiotropium is clearly more effective for COPD than an inactive placebo. That is why it was approved by the FDA. Even though it needs to be used only once a day, it is unclear if tiotropium is a better drug than ipratropium or salmeterol. Tiotropium’s effect on the number of extra doses of albuterol needed, on measures of worsening of COPD, and quality of life measures is inconsistent.

We have not invoked the Health Research Group’s Seven Year Rule (DO NOT use for at least seven years after approval) for tiotropium because it does offer something that ipratropium does not — once-daily dosing — but this comes at a high retail cost. We would reserve describing tiotropium as an “important advance” until studies reviewed by the FDA find that it is clearly superior to drugs already on the market in terms of therapeutic outcomes that are meaningful to patients.

What You Can Do

If you are now using ipratropium for breathing problems as a result of COPD, you may wish to switch to tiotropium. This would reduce the number of times per day you must use a drug from four to one, although there is a substantial cost associated.