ORIGINAL RESEARCH Zafirlukast in Clinical Practice Results of the Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT) in Patients with Asthma James P. Kemp, MD; Phillip E. Korenblat, MD; Joseph E. Scherger, MD, MPH; and Margaret Minkwitz, PhD San Diego, California; St. Louis, Missouri; Irvine, California; and Wilmington, Delaware BACKGROUND. Zafirlukast is an oral leukotriene receptor antagonist used in the treatment of patients with mild to moderate asthma. To investigate its effects in a clinical practice setting, we evaluated zafirlukast in a heteroge­ neous group of patients who had asthma of different degrees of severity and who were receiving concomitant asthma medications. METHODS. A total of 3759 patients were enrolled at 924 sites. Patients received zafirlukast 20 mg twice a day for 4 weeks. Pulmonary function was measured twice a day, and overall asthma symptom scores, number of nighttime awakenings, severity of morning asthma symptoms, and (32-agonist use were recorded daily. RESULTS. In the efficacy analysis (3207 evaluable patients), all parameters showed statistically significant improvement that continued throughout the 4 weeks of the trial. A total of 71 % of patients had improved pul­ monary function and 72% had improved asthma symptoms. Improvement was consistent regardless of asthma severity category and regardless of concomitant asthma medication category. More than 70% of both physicians and patients indicated there was clinical improvement in pulmonary measures as well as in asthma symptoms. Common adverse events reported were headache (3.7%), nausea (1.4%), pharyngitis (1.4%), and sinusitis (1.1%). CONCLUSIONS. Zafirlukast 20 mg twice a day is well tolerated and improves pulmonary function and asthma symptoms, regardless of asthma severity category and regardless of concomitant asthma medication category. KEY WORDS. Asthma; receptors, leukotriene; respiratory function tests; zafirlukast (non-MeSH); bronchocon- striction. (J Fam Pract 1999; 48:425-432) sthma currently affects more than 14 million for regulatory approval have shown that up to 13 weeks people in the United States.1 This chronic dis­ of zafirlukast therapy improves pulmonary function para­ ease is characterized by airway obstruction, meters, reduces the need for (Sv-agonist rescue medica­ inflammation, and heightened airway respon­ tions, and improves overall asthma symptoms when used siveness to a variety o f stimuli.2 Successful in patients with mild to moderate711 or severe12 asthma. management of long-term asthma involves the applica­One 13-week trial o f zafirlukast has also demonstrated an Ation of anti-inflammatory medications to control symp­ improved quality of life in patients with moderate toms. The development of the class of asthma medica­ reversible airflow obstruction." In addition, interim tions known as the antileukotrienes has provided a new results from an open-label extension trial13 have demon­ form o f chronic therapy for the treatment o f asthma.34 strated the long-term efficacy and safety of zafirlukast in Controlled clinical trials541 have demonstrated that patients with mild to moderate asthma The majority of antileukotriene-directed therapy produces clinical bene­ patients enrolled in those trials had mild or moderate fits in asthmatic patients. asthma and were prohibited from receiving concurrent Zafirlukast is an oral leukotriene receptor antagonist medications other than short-acting (32-agonists. indicated for the chronic treatment o f patients with mild Moreover, most of the patients were treated by specialists to moderate asthma. Controlled clinical trials designed in the fields o f asthma or allergy. The Accolate Clinical Experience and Pharma­ Submitted, revised, March 8, 1999. From the Department of Pediatrics (Allergy), University of coepidemiology Trial (ACCEPT) was designed to evalu­ California, San Diego (J.P.K.); Washington University, St. ate a different group o f patients from those enrolled in the Louis, Missouri (P.E.K.); the Department o f Family clinical trials for regulatory approval. The purpose of Medicine, University of Califomiar-Irvine (J.E.S.); the ACCEPT was to study zafirlukast in a population o f asth­ Medical Affairs Department, Zeneca Pharmaceuticals, matic patients in a clinical practice setting. With an enroll­ Wilmington, Delaware (M.M.). Requests fo r reprints should be addressed to James P. Kemp, MD, AUergy & Asthma ment o f 3759 patients, including 3207 evaluable patients, Medical Group and Research Center, 9610 Granite Ridge this clinical practice study represents the largest investi­ Drive, Suite B, San Diego, CA 92123. gation o f zafirlukast to date. 0 1999 Dowden Publishing Co/ISSN 0094-3509 The Journal o f Family Practice, Vol. 48, No. 6 (June), 1999 425 ZAFIRLUKAST IN CLINICAL PRACTICE METHODS were allowed as long as they had not been stopped or started within 4 weeks of screening; modification of Objectives and Study Design dosages, substitutions, and additions o f any asthma The primary objectives of the trial were to determine medication were discouraged. patient response to 4 weeks o f zafirlukast therapy, iden­ Each patient performed pulmonary function testing tify pharmacoepidemiologic factors predictive of using the AirWatch monitor twice a day— once in the response to zafirlukast, determine patient and physician morning before (32-agonist use and again 12 horns later. In global evaluations of zafirlukast therapy, and identify addition, patients recorded overall asthma symptom any adverse events of zafirlukast not previously scores, nighttime awakenings, morning asthma symptoms, observed. and (32-agonist use daily on diary cards. Participating investigators were identified by geograph­ Patient compliance, response to treatment, and ic region; 4 primary care physicians and 1 specialist from adverse events were assessed at visits week 2 and week each region were invited to participate. Participating 4. At each of these visits, patients were asked if they had investigators were permitted to enroll up to 5 patients at had any unusual symptoms (ie, symptoms other than each site. A total o f 3759 patients were enrolled at 924 sites allergy or asthma symptoms) since the previous visit. A in the United States and Puerto Rico between December description of each reported event and its severity was 1996 and June 1997. recorded. Investigators also recorded their assessment After a 3-day lead-in period during which baseline pul­ of the relationship of each reported event to the use of monary function values were obtained and diary card study medication. At the final study visit, both physi­ assessments were performed, patients received zafirlukast cians and patients answered specific questions on over­ 20 mg twice a day for 4 weeks. Pulmonary function testing all safety, effectiveness, and other issues regarding zafir­ was performed twice a day, and daily diary cards were lukast therapy. used to document asthma symptoms. Investigators evalu­ ated patients at a baseline visit, and again at 2 and 4 weeks Patient Population after beginning the study. At the baseline visit, patients Patients 12 years and older were eligible to participate in provided a medical and smoking history and underwent a the trial if they had symptoms of asthma within the pre­ complete physical examination. Each patient received an ceding month and were candidates for prophylactic or AirWatch Airway Monitor System (Enact Health Manage­ chronic asthma therapy. An FEVi value that was ment Systems, Inc, Mountain View, Calif) and was instruct­ between 45% and 85% o f predicted value after at least a ed in the use of this device. The AirWatch monitor is an 4-hour abstinence from (32-agonist use was required for electronic spirometry device that measures peak expirato­ study participation. PEF was evaluated both before and ry flow (PEF) and forced expiratory volume in 1 second after |32-agonist use. Patients had to have been non- (FEVi) in accordance with American Thoracic Society smokers fo r at least 6 months and have a smoking histo­ standards.14 ry of no more than 10 pack-years (ie, packs per day times To obtain baseline data, patients performed pul­ total number of years smoked). There were no restric­ monary function testing using the AirWatch monitor tions on concurrent asthma medications, but therapeutic twice a day (in the morning before ff-agonist use and regimens must have been stable within the 4 weeks again 12 hours later) for 3 days after the initial visit. before study entry. Patients with newly diagnosed asth­ Patients recorded overall asthma symptoms, nighttime ma were eligible to participate in the study if they met awakenings, morning asthma symptoms, and 132-ago­ the above criteria. nist use on daily diary cards. Asthma symptoms were Patients were excluded if they had any chronic lung scored on a 4-point scale where 0 = no symptoms, 1 = or airway problem other than asthma, if they had an mild symptoms that did not interfere with activities, 2 acute asthma exacerbation at the time o f screening, or if = moderate symptoms that interfered with some activ­ they had received more than 10 days of treatment with ities, or 3 = severe symptoms that interfered with many oral corticosteroids in the 4 w eeks before screening. activities. Nighttime awakening was recorded as a yes Patients with known active hepatic dysfunction, those or no according to whether the patient was awakened being treated with warfarin or (3-blockers, those who had during the previous night because of asthma. 132-ago­ participated in a trial with an investigational drug within nist use was recorded as number of puffs per day. the preceding 30 days, and wom en who were pregnant After the baseline period, zafirlukast 20-mg tablets or lactating were also ineligible to participate. were supplied to each patient. The first 20-mg dose of Study approval was obtained through a centralized zafirlukast was taken on the morning of day 4 of the institutional review board (Institutional Review Board, trial, and treatment with zafirlukast continued for 4 Inc, San Clemente, Calif); local institutional review board weeks. Participants in the study were instructed to approval was obtained when required.