Which Inhaler Combination is Best for COPD Treatment?

Pharmacology Watch

Two recent large studies have looked at the effects of various inhaler combinations on outcomes in patients with COPD. In the first, published in the February 22 issue of the New England Journal of Medicine, researchers from the United Kingdom looked at over 6,000 patients with COPD in a randomized, double-blind trial comparing salmeterol plus fluticasone inhaler twice daily (in a single inhaler) vs salmeterol alone, fluticasone alone, or placebo for 3 years. The primary outcome was death from any cause, the frequency of exacerbations, health status, and spirometry values. The all-cause mortality was 12.6% in the combination therapy group, 13.5% in the salmeterol group, 16.0% in the fluticasone group and 15.2% in the placebo group. The hazard ratio for death in the combination therapy group was 0.825 vs placebo (P = 0 .052), a level that did not reach statistical significance, but was associated with a 17.5% relative reduction in mortality. The mortality rate for salmeterol alone or fluticasone alone did not differ from placebo. Combination therapy was associated with a statistically significant lower rate of exacerbations (P < 0.001). The probability of having pneumonia was higher among patients receiving fluticasone alone or medications containing fluticasone (N Engl J Med. 2007;356:775-789). An accompanying editorial suggests that the findings show that monotherapy with fluticasone should not be recommended, monotherapy with a bronchodilator may be an option, and that combination therapy "offers statistically significant advantages for health status, frequency of exacerbations, use of oral steroids... and protection against a decline in lung function" (N Engl J Med. 2007;356:851-854).

In the second study, 449 patients with moderate or severe COPD were treated with the anticholinergic inhaler tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone/salmeterol. The primary endpoint was COPD exacerbation that required treatment with systemic steroids or antibiotics. After one year there was no difference in the rate of exacerbation between tiotropium alone (62.8%), tiotropium plus salmeterol (64.8%), or tiotropium plus fluticasone/salmeterol (60.0%). Tiotropium plus fluticasone/ salmeterol improved lung function (P = 0 .049), disease-specific quality of life (P = 0 .01), and reduced the number of hospitalizations for COPD exacerbation and all-cause hospitalization compared with tiotropium plus placebo. The authors conclude that adding fluticasone/salmeterol to treatment with tiotropium did not influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates (early release Annals of Internal Medicine 2/20/2007, print date 4/17/2007). So, what is the upshot of these papers? Combination inhalation therapy in patients with COPD works best, bronchodilator plus steroid inhalation therapy should continue to be the recommended regimen perhaps along with an anticholinergic inhaler.

First Antihypertensive Drug Approved in Last 10 Years: Aliskiren

The FDA has approved the first of new class of antihypertensive drugs, and the first new antihypertensive medication to be approved in more than 10 years. Aliskiren is an oral renin inhibitor, inhibiting the renin-angiotensin system earlier in the cascade than angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The drug is a once-a-day oral agent that is approved for use as monotherapy or in combination with other antihypertensives.

Aliskiren's effect is additive with hydrochlorothiazide, and seems to be well-tolerated with other cardiovascular agents. It will be available in 150 and 300 mg doses. The FDA approval was based on 6 placebo-controlled trials in more than 2,000 patients in which the blood- pressure-lowering effect was maintained for up to one year. The drug seems be effective across all age ranges, but is slightly less effective in African-American patients as compared to Caucasians and Asians, as is the case with ACEI's and ARBs. The primary side effect is diarrhea, which was seen in 2% of patients, usually on higher doses. Angioedema was also rarely noted. As with other drugs that affect the renin-angiotensin system, aliskiren should not be used during pregnancy. Aliskiren will be marketed by Novartis Pharmaceuticals, and will be marketed under the trade name Tekturna.

Alternate Treatment for Osteoporosis

Antiresorptive agents are standard therapy for osteoporosis. These drugs, which include the bisphosphonates (alendronate, risedronate, etc.) prevent bone breakdown, but they do not stimulate production of new bone. A new study looks at recombinant human parathyroid hormone (1-84) (PTH), a bone forming agent, as an alternative treatment for osteoporosis. In an 18 month, randomized, double-blind, placebo-controlled, parallel group study, 2,532 postmenopausal women with low bone mineral density at the hip or lumbar spine were randomized to receive 100 µg of PTH or placebo daily by subcutaneous injection. All received additional calcium 700 mg/d and vitamin D 400 U/d. The main outcome was new or worsened vertebral fractures, changes in bone mineral density as well as safety of the medication. PTH significantly reduced the risk for new or worsened vertebral fractures. The relative risk varied depending on the assumptions about women who did not complete the trial, but there was improvement in all subgroups. PTH also resulted in increased bone mineral density compared to placebo of 6.9% at the spine and 2.1% at the hip compared to placebo, but decreased bmd at the forearm. PTH also resulted in increased percentage of participants with hypercalciuria, hypercalcemia, and nausea by 24%, 23%, and 14% respectively compared to placebo. The authors conclude that parathyroid hormone (1-84) reduced the overall risk for new or worsened vertebral fractures in postmenopausal women with osteoporosis, and suggest that PTH provides an alternative therapy option for fracture prevention (Ann Int Med. 2006;146:326-339). This study adds a second option for anabolic (bone-forming) agents along with teriparatide.

Roche's Oseltamivir: Scrutiny, Bird Flu, and New Drug Applications

Roche's oseltamivir (Tamiflu) has come under scrutiny in Japan after 2 students who took the drug fell to their deaths in February. The drug has been associated with abnormal behavior in anecdotal reports including a Japanese boy who ran in front of a truck after taking the drug in 2004. Roche counters that influenza can cause abnormal behavior and denies a link between the medication and psychiatric problems. The drug has previously been associated with delirium, and the FDA has required labeling urging close monitoring for abnormal behavior since November 2006. Countries worldwide are stockpiling oseltamivir in case of avian influenza outbreak. Meanwhile Roche has filed a new drug application with the FDA for pediatric doses of the drug for children one year and older. The new capsules and a 30 milligram and 45 mg capsule would join the 75 mg adult strength capsule.

FDA Actions

The FDA has approved duloxetine (Cymbalta) for the treatment of generalized anxiety disorder. The drug is currently approved for the treatment of major depressive disorder in the management of diabetic peripheral neuropathic pain. The FDA approved duloxetine 60 mg once daily for the treatment of anxiety based on three randomized, double-blind placebo-controlled trials in 800 patients.

The FDA has approved lisdexamfetamine dimesylate capsules for the treatment of attention deficit/hyperactivity disorder in children age 6-12. Lisdexamfetamine is a pro-drug of dextroamphetamine that may be associated with less drug abuse than dextroamphetamine. The once-a-day drug will be available in 30, 50, and 70 mg strengths. Lisdexamfetamine is marketed by New River Pharmaceuticals under the trade name Vyvanase.

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.