Fred M. Cox

Salmeterol Versus Theophylline in the Treatment of Asthma

BACKGROUND Although theophylline is recommended by current guidelines for the management of asthma in patients with persistent symptoms, theophylline has a narrow therapeutic index, requiring individual dose titration and regular monitoring of serum theophylline concentrations to avoid adverse effects. OBJECTIVE To compare the inhaled long-acting bronchodilator, salmeterol, with the oral bronchodilator, theophylline, in the maintenance treatment of asthma. METHODS In two multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group studies, patients received salmeterol aerosol 42 micrograms, extended-release theophylline capsules, or placebo twice daily for 12 weeks. RESULTS Of 638 adult and adolescent patients with moderate asthma who entered the prebaseline theophylline titration period, 154 were withdrawn prior to randomization (71 due to theophylline-related adverse effects); 484 patients comprised the intent-to-treat population. The mean serum theophylline concentration measured approximately seven hours postdose during the titration period in the theophylline group was 12.7 mg/L (70 mumol/L). The same dose during the treatment period resulted in a mean serum theophylline concentration between 7.6 to 7.9 mg/L (42-44 mumol/L) when measured approximately 12 hours postdose. Salmeterol was significantly more effective than theophylline or placebo in improving mean morning PEF over the entire 12 weeks (P < or = .02). Mean predose FEV1 improved significantly with salmeterol compared with placebo (P < .001); there was no difference between theophylline and placebo. Salmeterol was also significantly more effective than theophylline or placebo (P < .02) in improving asthma symptoms, reducing nighttime awakenings, and reducing the daily use of albuterol. After 12 weeks of treatment, patients in the salmeterol group expressed significantly greater overall satisfaction with their asthma medication than did patients who received theophylline (P < .01). Patients in the theophylline group experienced more gastrointestinal adverse events than did patients in the salmeterol group (P < .05). CONCLUSION Salmeterol, 42 mg twice daily, was better tolerated and significantly more effective than extended-release theophylline twice daily in the maintenance treatment of asthma.

Ondansetron: A Cost-Effective Advance in Anti-Emetic Therapy

A cost-effectiveness analysis is one form of full economic evaluation where drug acquisition costs and the costs that are incurred as a result of using a particular treatment are assessed together with clinical efficacy. This paper reviews two such studies. One of the studies was a prospective randomised cost-effectiveness study which compared ondansetron (8 mg i.v. 0, 4 and 8 h following chemotherapy) with metoclopramide (3 mg/kg i.v. followed by an infusion of 0.5 mg/kg/h for 8 h) over the first 24 h following chemotherapy in hospitalised patients receiving highly emetogenic chemotherapy. This study showed that the cost per successfully treated patient (defined in this study as having < or = 1 emetic episode and no adverse events) for these 2 treatments were approximately equal: ondansetron pounds 95 and metoclopramide pounds 92. The second study was an economic evaluation based on data collected over a 5-day period following cyclophosphamide-based chemotherapy given on an outpatient basis for the treatment of breast cancer. Patients received an intravenous dose of 16 mg dexamethasone with either 8 mg ondansetron or 60 mg metoclopramide intravenously before chemotherapy followed by oral dosing with 8 mg ondansetron or 20 mg metoclopramide 3 times daily for 5 days. The costs per successfully treated patient (defined in this study as no vomiting or retching episodes and no anti-emetic-related adverse events during the 5-day period) were comparable: ondansetron pounds 184 and metoclopramide pounds 160. A recent study has established that ondansetron (8 mg) given orally twice daily is as effective as the same dose given 3 times a day. A sensitivity analysis using the cost of an ondansetron twice daily regimen showed that ondansetron is more cost-effective than metoclopramide (pounds 133 vs. pounds 160). These cost effectiveness studies have shown that ondansetron is at least as cost-effective as metoclopramide and simplified ondansetron dosing schedules render ondansetron more cost-effective. These full economic evaluations illustrate that drug acquisition costs can be a misleading guide to the economic impact of antiemetics.

A Cost Comparison of β2‐Agonist Bronchodilators Is Not a Cost‐Effectiveness Comparison

In his recent article, “Cost Comparison of PIAgonist Bronchodilators Used in the Treatment of Asthma,”’ Dr. Charles Nightingale raises the point that clinicians must remain aware of the most cost-effective approach to providing effective clinical treatment of asthma with inhaled P2-agonist bronchodilators. The author’s understanding of what cost-effectiveness means and which therapies are most cost-effective, however, bears closer scrutiny. Dr. Nightingale states that “agents that can be dosed as needed (i.e., albuterol) are likely to be more cost-effective choices for formularies than bronchodilators such as salmeterol, which must be given twice/day on a regular basis.” This conclusion, however, is founded on several incorrect assumptions: the first is that salmeterol, a long-acting P2-agonist, is interchangeable with short-acting Pl-agonists (e .g . , albuterol) , regardless of the severity of the patient’s asthma. The most recent National Institutes of Health guidelines on the long-term management of asthma, known as the Global Initiative for Asthma (GINA) ,’ recommend that a short-acting bronchodilator be used as needed as a “reliever” for symptoms, and a long-acting bronchodilator be used daily as a “controller” for persistent symptoms. The guidelines further state that patients who require asthma medication more than once a week over a 3-month period (i.e., patients who progress from intermittent asthma to mild persistent asthma) should be treated with antiinflammatory medication, such as inhaled corticosteroids, with or without a daily longacting bronchodilator plus inhaled short-acting P2-agonists as needed (up to 4 times/day) to