The Spirometric Efficacy of Once-Daily Dosing With Tiotropium in ...

The Spirometric Efficacy of Once-Daily Dosing With Tiotropium in ...

The Spirometric Efficacy of Once-DailyDosing With Tiotropium in StableCOPD*A 13-Week Multicenter TrialRichard Casaburi, PhD, MD, FCCP; Dick D. Briggs, Jr., MD, FCCP;James F. Donohue, MD, FCCP; Charles W. Serby, MD;Shailendra S. Menjoge, PhD; and Theodore J. Witek, Jr., DrPH; for the USTiotropium Study Group†Study objective: To compare the bronchodilator efficacy and safety of tiotropium and placebo.Design: A 3-month, randomized, double-blind, placebo-controlled, multicenter trial.Setting: Outpatient.Patients: Four hundred seventy patients with stable COPD (mean FEV 1 38.6% predicted).Interventions: Tiotropium 18 g (N 279) or placebo (N 191) given once daily via a lactosebaseddry-powder inhaler device.Measurements and results: Spirometry was evaluated on days 1, 8, 50, and 92. Data wereexpressed as the mean trough (ie, before morning dose; 23 to 24 h after previous dose) andaverage response observed in the 3 h after the dose was received. Tiotropium producedsignificant improvement in trough FEV 1 and FVC, averaging 12% greater than baseline on day8; these improvements were maintained on days 50 and 92. The average postdose FEV 1 was 16%greater than baseline on day 1 and 20% greater than baseline on day 92; FVC was 17% greaterthan baseline on day 1 and 19% greater than baseline on day 92. Tiotropium was significantlymore effective than placebo in both trough and average FEV 1 and FVC response (p < 0.001).These spirometric effects were corroborated by significant improvements in daily morning andevening peak expiratory flow rate, as well as a reduction in “as-needed” albuterol use. Symptomsof wheezing and shortness of breath were significantly less in patients receiving tiotropium, andthe physician global assessment noted overall improvements with those treated with tiotropiumrelative to placebo. The most common reported adverse event after tiotropium was dry mouth(9.3% vs 1.6% relative to placebo; p < 0.05).Conclusions: These data demonstrate that tiotropium is a safe and effective once-daily anticholinergicbronchodilator and should prove useful as first-line maintenance therapy in COPD.(CHEST 2000; 118:1294–1302)Key words: anticholinergic; bronchodilator; COPD; pulmonary function; tiotropiumAbbreviations: ATS American Thoracic Society; PEFR peak expiratory flow rateThe parasympathetic nervous system plays animportant role in autonomic control of airwaysand is believed to be largely responsible for restingbronchomotor tone in COPD. 1–5 Although anticholinergicdrugs have been known to have bronchodilatingproperties for centuries, side effects limitedtheir therapeutic utility. This was overcome bythedevelopment of ipratropium bromide, whosestructural features limited absorption, thus minimizingside effects common to atropine-like drugs.During the past two decades, ipratropium bromide*From the Harbor-UCLA Research and Education Institute(Dr. Casaburi), Torrance, CA; University of Alabama at Birmingham(Dr. Briggs), Birmingham, AL; University of North CarolinaSchool of Medicine (Dr. Donohue), Chapel Hill, NC; andBoehringer Ingelheim Pharmaceuticals, Inc. (Drs. Serby, Menjoge,and Witek), Ridgefield, CT.†A complete list of participants in the US Tiotropium StudyGroup is located in the Appendix.Supported by a grant from Boehringer Ingelheim Pharmaceuticals,Inc. (BIPI), Ridgefield, CT. Dr. Casaburi is a consultant forBIPI. Drs. Briggs and Donohue are members of the BIPISpeakers Bureau.Manuscript received September 7, 1999; revision accepted May31, 2000.Correspondence to: Richard Casaburi, PhD, MD, Harbor-UCLAMedical Center, 1000 W Carson St, Torrance, CA 90509; e-mail:casaburi@ucla.edu1294 Clinical Investigations

has emerged as an effective maintenance bronchodilatortherapy for COPD. 1–5More recently, another important milestone inanticholinergic airway pharmacology has beenachieved with the discovery of tiotropium bromide.6–8 Like ipratropium, tiotropium is distinguishedfrom atropine by its positively charged quaternaryammonium structure that is responsible forits limited systemic absorption. On a receptor level,tiotropium has been shown to have a binding affinitysimilar for all three human muscarinic receptorsubtypes (apparent Kd: M 1 , 0.27 nM; M 2 , 0.12 nM;M 3 , 0.33 nM). However, it dissociates very slowlyfrom M 1 and M 3 receptors, which mediate bronchoconstriction(14.6- and 34.7-h half-life, respectively)and more rapidly from M 2 receptors, which inhibitacetylcholine release from cholinergic nerve endings(3.6-h half-life). For all receptor subtypes, tiotropiumdissociates much more slowly than ipratropium(0.035- to 0.26-h half-life). Taken together, thesedata indicate that tiotropium has kinetic selectivity.This slow dissociation from M 1 and M 3 receptorsresults in a prolonged duration of action in physiologicexperiments. 6–9The clinical development of tiotropium has focusedon its use as a long-acting bronchodilator inpatients with COPD. Single-dose, dose-escalating,and multiple-dose studies with tiotropium were initiallyconducted in normal volunteers. These studiesdemonstrated that there were no serious drug-relatedeffects on vital signs, ECGs, pupillometry,saliva secretion, or routine laboratory variables. 8Likewise, both single-dose and multiple-dose studieshave been conducted in COPD patients to evaluatethe bronchodilating activity of tiotropium and todetermine the optimal dose to study in long-termclinical trials. 10–12 Single doses in the range of 9 to 72g of tiotropium (base anhydrous) were administeredto 35 COPD patients as a powder in a lactosecarrier via a breath-activated inhaler. 10 This doubleblind,placebo-controlled crossover study showedsignificant bronchodilator effects of tiotropium at alldoses with an onset of action within 15 min and peakeffects (mean increases in FEV 1 of 19 to 26% greaterthan baseline values) in the range of 1 to 4 h. 10 Alldoses were well tolerated, and there were no abnormalitiesin routine laboratory assessments or clinicalevaluations.To evaluate long-term safety and efficacy and toevaluate dose-response, a randomized, double-blind,placebo-controlled trial was also conducted in 169COPD patients with once-daily doses of 4.5, 9, 18, or36 g for a period of 4 weeks. 12 All doses producedincreases in FEV 1 that were significantly greaterthan placebo. In addition, all doses were well tolerated,and there were no serious drug-related adverseevents or significant changes in routine laboratoryvariables or ECGs.From these clinical observations in COPD patients,the 18-g dose was selected as optimal for fulldevelopment in long-term clinical trials. Hence, thepurpose of the present study was to evaluate theefficacy and safety of 18-g tiotropium inhalationcapsules administered once daily for 92 days inpatients with COPD.Materials and MethodsDesign and Conduct of the StudyTwenty-five clinical centers participated in this double-blind,placebo-controlled trial with a 92-day treatment period. Thestudy was approved by each center’s institutional review board.All patients provided written informed consent.The study group consisted of outpatients of either sex whowere 40 years of age and who had a clinical diagnosis of COPDas defined by the American Thoracic Society (ATS). 13 Studyparticipants were required to have a smoking history of 10pack-years, to have clinically stable airway obstruction, and tohave an FEV 1 65% of predicted normal values and an FEV 1 70% of FVC. Patients were excluded from participation if theyhad a history of asthma, allergic rhinitis, atopy, or a total bloodeosinophil count 600/mm 3 . Patients were also excluded if theyrequired regular, daytime oxygen use or more than the equivalentof 10 mg prednisone per day to manage their COPD symptomsduring the month before entering the study. In addition, patientswere excluded if they had a recent history of myocardial infarction( 1 year), heart failure ( 3 years), or a cardiac arrhythmiarequiring drug therapy. A total of 470 patients were selected andrandomized into the trial (Table 1).TreatmentsAfter a 2-week baseline period to establish and documentclinical stability, patients were randomly assigned within eachTable 1—Baseline Values and Demographics of AllRandomized Patients*CharacteristicTiotropium(n 279)Placebo(n 191)Overall(n 470)Age, yr 65.0 8.6 65.5 9.0 65.2 8.8SexMale 186 121 307Female 93 70 163RaceWhite 264 168 432Black 15 21 36Other 0 2 2Smoking history, 64.5 33.1 60.5 30.2 62.9 32.0pack-yrDuration of9.3 8.0 8.6 6.9 9.0 7.6disease, yrFEV 1L 1.04 0.42 1.00 0.43 1.02 0.43% predicted 39 13.8 38 14.1 39 13.9FEV 1 /FVC, % 46 11.8 46 11.5 46 11.6*Values are reported as No. or mean SD.CHEST / 118 /5/NOVEMBER, 2000 1295

study center (by order of entry) to receive either tiotropium (18g) or placebo. The tiotropium (Spiriva; Boehringer Ingelheim;Ridgefield, CT) dose was labeled as base to conform to internationalnomenclature. Patients were randomized in a 3:2 ratio oftiotropium to placebo to expose a greater number of patients totiotropium for safety evaluation. Subjects took the study medicationby inhalation once daily between the hours of 8 am and 10am. This was a double-blind study in which the active medicationand placebo were delivered by identically appearing lactosebasedinhalers (HandiHaler BIPI; Ridgefield, CT). 14 To use thisdevice, patients placed a single capsule in the device, pressed abutton to puncture the capsule, and then inhaled slowly anddeeply to evacuate the powder for inhalation. Patients werepermitted to use albuterol metered-dose inhaler as needed,stable doses of theophylline, inhaled corticosteroids, and theequivalent of 10 mg/d of oral prednisone throughout the studyperiod. However, the use of all other inhaled or oral bronchodilatorswas not permitted during the treatment period. Finally, tocontrol acute COPD exacerbations during the trial, investigatorscould administer any additional medication that was deemednecessary. However, investigators could only increase or addcorticosteroids or theophylline for two periods of up to 7 dayseach for patients to remain in the trial.ObservationsBefore entry and on completion of the trial, patients underwenta medical history, physical examination, laboratory testing,and a 12-lead ECG to exclude other important diseases and tomonitor the safety of the study medication. Each subject alsoperformed peak flow measurements using a monitoring system(AirWatch Monitoring Systems; Enact Health Management Systems;Mountain View, CA) twice daily (on arising and at bedtime).Visits to the study clinic were scheduled on the first day ofstudy drug administration, at the end of the first week of therapy,and every 3 weeks thereafter throughout the 13-week treatmentperiod to assess and record adverse events, concomitant medicationuse, clinical status, and pulmonary function. At each visitduring the treatment period, the investigator recorded theCOPD symptom scores (ie, for wheezing, shortness of breath,coughing, and chest tightness) and gave a global evaluation of thepatient’s overall condition (grade range 1 [poor] to 8 [excellent]).Pulmonary Function TestingPulmonary function testing was conducted on treatment day 1and after 1, 7, and 13 weeks of therapy. On these test days,measurements of FEV 1 and FVC were recorded 1 h beforedosing, just before dosing, and at 30, 60, 120, and 180 min afterstudy drug administration (ie, tiotropium or placebo). The drugwas administered at the same time each day (between 7 am and9 am.) Spirometric maneuvers were conducted in triplicate, andthe results of the greatest FEV 1 and FVC were recorded andused in the subsequent analyses. Predicted normal values formen and women for FEV 1 and FVC were derived from publishedalgorithms. 15 Spirometers used in these trials were required tomeet ATS standards. 16To ensure standardized conditions on all pulmonary functiontest days, subjects were required to discontinue treatment withtheophylline preparations 24 h before pulmonary function testing(compliance was assessed by measuring theophylline levels beforepulmonary function testing and noting patients whose levelswere 5.0 g/mL). Likewise, treatment with albuterol andinhaled corticosteroids was stopped at least 12 h before pulmonaryfunction testing.Statistical AnalysisThe primary bronchodilator efficacy end point for this studywas trough FEV 1 response on the final treatment visit (92 daysafter initiation of therapy). The trough FEV 1 at any given visitwas defined as the mean of the two FEV 1 readings measured atthe end of the dosing interval, at approximately 23 to 24 h afterstudy drug administration. Trough response was defined aschange from baseline in trough FEV 1 and was considered as theprimary end point to establish the 24-h duration of action oftiotropium. Baseline FEV 1 was defined as the mean of the twopretreatment FEV 1 values measured before the first dose ofstudy medication on the randomization visit. Additional bronchodilatorvariables that were examined included the following: theFEV 1 response for the 3 h after study drug administration, theFVC response at trough (as defined for FEV 1 ), and the FVCresponse for the first 3 h after study drug administration. Finally,the peak (maximum value) and average (mean of all values) FEV 1and FVC responses (ie, change from baseline) during the first 3 hafter study drug administration were also evaluated.Less than 2% of patients could not continue the study becauseof worsening of their COPD. Their missing efficacy data wereestimated using the least favorable data observed before discontinuingthe study. For the other patients (6%) who missed studyvisits for other reasons, missing data were estimated using thepatient’s last observed data. For patients who did not complete allthe pulmonary function measurements on a specific pulmonaryfunction test day, linear interpolation was used to estimatemissing, middle spirometry measurements. Likewise, the minimumobserved spirometry measurements on a specific test daywere used to estimate values at the end of profiles that weremissing because rescue medication was taken. Finally, the lastavailable spirometry measurements were used to estimate valuesat the end of the profiles that were missing for reasons unrelatedto the patient’s treatment response.Long-term effectiveness was also evaluated by comparing themean weekly peak expiratory flow rates (PEFRs), COPD symptomscores, physician’s global evaluation scores, and “as needed”albuterol use between tiotropium and placebo groups.All statistical comparisons between the two treatment groupswere performed using analysis of covariance.ResultsA total of 470 patients were randomized; 279 totiotropium and 191 to placebo. Demographic andbaseline characteristics were similar between the twotreatment groups (Table 1). The overall mean agewas 65.2 years, 65% of the trial population was male,and 92% were white. The mean FEV 1 at screeningwas 1.02 L, and the mean percent predicted FEV 1was 38.6%. The mean FEV 1 /FVC ratio was 46.2%.The mean duration of smoking was 62.9 pack-years(range, 10.0 to 240.0 pack-years).Of the 470 patients randomized, 262 (93.9%) inthe tiotropium group and 170 (89%) in the placebogroup completed the study. Fewer patients in thetiotropium group failed to complete because ofadverse events (2.5%) and lack of efficacy (1.8%)than in the placebo group (6.3% and 3.1%, respectively).However, the difference was statistically significantonly for withdrawals because of adverseevents.1296 Clinical Investigations

EfficacyFEV 1 and FVC: Onset of a clinically significantincrease in both the FEV 1 and FVC occurred within30 min after the first dose (the first measurementafter dosing; Figs 1 and 2). Trough FEV 1 (ie, FEV 124 h after dose) reached steady-state by the nexttesting day (1 week after treatment was started) andremained 10 to 13% greater than baseline throughoutthe 13-week treatment period (Fig 3). AverageFEV 1 response during the first 3 h after dosing was0.16 L greater than predose baseline on the first dayof dosing, and the average increase ranged from 0.20to 0.21 L greater than baseline starting from the1-week assessment and continuing for the remainderof the 13-week study (Table 2). Peak FEV 1 increaseafter dosing ranged from 0.24 to 0.28 L. All FEV 1responses were significantly greater than placebo(p 0.001). FVC improvement at trough was 0.26 L(12%) greater than predose baseline after 1 week oftherapy and 0.23 L (10.5%) greater than baselineafter 13 weeks. Average FVC response during thefirst 3 h reached steady-state after 1 week of therapy,with an increase of 0.49 L (22%) greater thanbaseline and a peak FVC response ranging from 0.56Figure 2. Time course of mean FVC response after first dose(p 0.001) and response after 3 months of therapy (p 0.001)for tiotropium and placebo. The SEM for differences rangedfrom 0.01 to 0.04 L. Note the trough effect after 3 months oftherapy is approximately 10% greater than the first-day baselinevalue.L (25%) to 0.66 L (30%) greater than baseline (Table2). In all FVC comparisons, the difference betweentiotropium and placebo was statistically significant(p 0.001).PEFR: Both the morning and evening PEFRsduring the baseline period were comparable for thetwo treatment groups. The improvement in morningPEFR, measured before dosing, was significantlygreater in the tiotropium group than in the placebogroup for the entire 13 weeks (Fig 4, left). The meandifference between the two treatment groups for anygiven week ranged from 10 to 20 L/min. Statisticalsignificance (p 0.05) of this difference was demonstratedat 10 of 13 weeks. Evening PEFRs alsoimproved significantly in the tiotropium group comparedwith the placebo group for 13 weeks (Fig 4,right). The difference between the two treatmentgroups for any given week ranged from 16 to 24L/min during the 13-week treatment period(p 0.01 at all 13 weeks).Figure 1. Time course of mean FEV 1 response after first dose(p 0.001) and response after 3 months of therapy (p 0.001)for tiotropium and placebo. The SEM for differences rangedfrom 0.01 to 0.02 L. Note the trough effect after 3 months oftherapy is approximately 11% greater than the first-day baselinevalue.Physician’s Global Assessment and SymptomsPhysician global evaluations on test days weresignificantly improved (p 0.001) for patients receivingtiotropium relative to placebo from week 1through week 13 (Fig 5). Symptom scores recordedon each visit showed a significant difference favoringCHEST / 118 /5/NOVEMBER, 2000 1297

Figure 3. Mean FEV 1 trough response compared with baseline (day 1) on days 8, 50, and 92 fortiotropium and placebo groups (*p 0.05). The SEM for differences was 0.02 L.tiotropium vs placebo for wheezing and shortness ofbreath (p 0.01), but not for tightness of the chestor cough (Fig 6).Supplemental Albuterol UseAll patients were provided with albuterol for usethroughout the trial and were allowed to use it asneeded. Albuterol use was maintained in the placebogroup whereas use decreased approximately 30% inthe first week (from 3.7 to 2.6 doses) and remainedat approximately this level for the 13-week treatmentperiod in the tiotropium group (Fig 7). The differencein albuterol use between the two treatmentgroups was significant (p 0.001) at all 13 weeks. Allother respiratory concomitant medication use wassimilar for the two groups during the treatmentperiod.SafetyThe safety profile indicates a low incidence ofadverse events in the tiotropium group, comparableto that seen in patients taking placebo. During thedouble-blind portion of the trial, 61.6% of thepatients in the tiotropium group (172 of 279 patients)reported adverse events. In the placebo group,66.5% of the patients (127 of 191 patients) reportedadverse events. Adverse events that occurred in 2% of patients in the tiotropium group are listedTable 2—FEV 1 and FVC Trough, Peak, and Average Response During 13 Weeks*FEV 1 ,LFVC, LResponseTest DayTiotropium†(n 276)Placebo(n 188)Tiotropium†(n 276)Placebo(n 188)Trough 8 0.12 0.01 0.01 0.01 0.26 0.02 0.01 0.0250 0.11 0.01 0.01 0.01 0.26 0.02 0.01 0.0392 0.11 0.01 0.04 0.01 0.23 0.02 0.05 0.03Peak 1 0.24 0.01 0.08 0.01 0.56 0.02 0.21 0.028 0.28 0.01 0.07 0.01 0.66 0.03 0.24 0.0350 0.26 0.01 0.07 0.02 0.63 0.03 0.18 0.0392 0.26 0.01 0.04 0.02 0.58 0.03 0.17 0.03Average 1 0.16 0.01 0.02 0.01 0.38 0.02 0.07 0.028 0.21 0.01 0.01 0.01 0.49 0.02 0.08 0.0350 0.20 0.01 0.00 0.01 0.46 0.02 0.03 0.0392 0.20 0.01 0.02 0.02 0.42 0.03 0.02 0.03*Values are reported as mean SEM.†p 0.001 compared to placebo.1298 Clinical Investigations

Figure 4. Left: mean of weekly means for morning PEFRs during 13 weeks for tiotropium and placebo(p 0.05 at 10 of 13 weeks). The SEM for differences ranged from 4 to 7 L/min. Right: mean ofweekly means for evening PEFRs during 13 weeks for tiotropium and placebo (p 0.01 at all times).The SEM for differences ranged from 4 to 7 L/ Table 3. The only event regarded as drug relatedwas dry mouth (9.3% vs 1.6%; p 0.05) which wasgenerally mild. It had a median onset of 19 days andcontinued throughout the treatment period in 57%.No patients discontinued the trial because of drymouth. There was a trend for fewer COPD exacerbationsin the tiotropium group (16% vs 21.5%), butthe difference in proportions was not significant(p 0.05, Fisher’s Exact Test).There were few serious adverse events (6.8% ineach treatment group) or events leading to withdrawal(2.5% in tiotropium group and 5.8% in theplacebo group). There was only one fatal adverseevent in this trial. A patient in the tiotropium groupwas found dead, and the cause of death was listed asa cardiac arrhythmia. The patient had a long historyof cardiovascular disease, and the family refusedautopsy. There were no differences noted betweentreatment groups for changes in laboratory values,ECGs, or results of physical examinations. No significantchanges in heart rate or BP were detected afterstudy drug administration in either group.DiscussionFigure 5. Mean global evaluation scores during 13 weeks fortiotropium and placebo (p 0.01). The SEM for differencesranged from 0.08 to 0.10.The dyspnea and diminished capacity to performexercise and activities of daily living associated withCOPD are in large part caused by chronic airflowlimitation. Improving airflow in COPD is the basisfor bronchodilator therapy in those patients. In fact,the concept that obstruction is irreversible in COPDcan be refuted by several clinical trials that showimproved airflow after inhaled therapy. 17–19In addition to smoking cessation, bronchodilatortherapy is the foundation of COPD medical management.Current guidelines recommend regular anticholinergictherapy once symptoms become persistent.1,16,20 Ipratropium bromide has been usedsuccessfully for the past two decades, 1–5 and theearly clinical development of the next generationanticholinergic drug, tiotropium, has been reportedCHEST / 118 /5/NOVEMBER, 2000 1299

Figure 6. Mean COPD symptom severity scores (0 none, 1 mild, 2 moderate, 3 severe)during 13 weeks for tiotropium and placebo (p 0.05 for wheezing and shortness of breath). The SEMfor differences ranged from 0.05 to 0.07.recently. 10–11 The primary advantage of tiotropiumhas been once-daily dosing, with 24-h effects establishedin single-dose studies 10 and a study of 1-monthduration. 12The results of this study demonstrate that tiotropiumis an effective maintenance bronchodilator forpatients with COPD. The efficacy of once-dailyadministration is supported by trough (ie, 23to24hafter dose) FEV 1 and FVC averaging 12% greaterthan baseline after 1 week of tiotropium administration.This spirometric improvement was maintainedthroughout the 13-week period without any evidenceof tachyphylaxis. In other words, the patients benefitwith improved airflow that persists for the 24-hperiod between tiotropium doses. This sustainedeffect was achieved within the first week of dosing inthis trial. This observation is supported by a recentreport in which the onset of this pharmacodynamicresponse was seen within the first few days ofdosing. 21Improvements in FEV 1 and FVC were supportedby PEFRs, recorded by the patients each morning(on awakening) and each evening. Significantlyhigher morning PEFR data confirm that the durationof action of tiotropium is 24 h. Significantlyhigher evening PEFR responses were recorded inthe tiotropium group despite the fact that albuterol,as a rescue bronchodilator, was used more often (onedose per day) in the placebo group. This emphasizesthe advantage of an effective sustained-action bronchodilator.In addition to objective measures of airflow, patientsreceiving tiotropium reported significantly lessshortness of breath and wheezing. These patientassessments were corroborated by the physician’sglobal assessments of the patient’s improved wellbeing.Thus, both the patient self-assessment andphysician’s global assessment favored the tiotropiumtherapy.The degree of bronchodilation observed in thisstudy is roughly comparable to that observed withexisting agents. 22,23 Such comparisons, however,1300 Clinical Investigations

Figure 7. Mean weekly mean number of doses per day ofalbuterol inhalation aerosol during 13 weeks for tiotropium andplacebo. The SEM for differences ranged from 0.16 to 0.20doses.Table 3—Adverse Events With Incidence > 2% inTiotropium GroupAdverse EventTiotropium, %(n 279)Placebo, %(n 191)Body as a wholeHousehold accident 2.5 2.6Back pain 2.5 3.1Chest pain 3.2 1.6Headache 5.4 7.3Central and peripheralnervous systemDizziness 3.2 3.7Hypoesthesia 2.2 0.0GI systemAbdominal pain 2.9 0.5Constipation 2.2 1.0Diarrhea 5.0 3.1Dry mouth 9.3 1.6*Respiratory system (lower)COPD exacerbation 16.1 21.5Respiratory system (upper)Pharyngitis 2.9 1.6Sinusitis 3.6 3.1Upper respiratory tractinfection15.8 15.2*p 0.05.would best be judged by trials comparing tiotropiumdirectly with other bronchodilators. Of relevance, apreliminary report comparing tiotropium with ipratropiumfound tiotropium to have superior trough,peak, and average (6 h after dose) response. 24 Therefore,tiotropium has the potential to provide superiorbronchodilation with once-daily dosing. Additionally,the sustained airflow improvement throughout thedosing interval points to the utility of tiotropium as amaintenance drug.In assessing the therapeutic benefit of tiotropium,it is important to understand how the sustainedbronchodilation translates into other health-outcomemeasures that relate to a given patient’s quality oflife. Further studies are necessary to determinewhether the sustained improvement in airflow withtiotropium might improve sleep quality, exercisetolerance, and other quality-of-life measures in patientswith COPD. Demonstration of such benefitswould support the value of bronchodilation in impactingthis chronic disease. 25In summary, tiotropium was demonstrated to providesuperior efficacy relative to placebo for bothin-clinic spirometry and daily measurements of peakflow. These observations were accompanied by bettersymptom control and subjective global assessmentsas well as by less reliance on rescue albuterol.Other than the reported increase in dry mouth,tiotropium was judged as safe and well toleratedduring the 3 months of study. The results of thisstudy suggest that tiotropium should prove useful asonce-daily bronchodilator therapy for COPD.US Tiotropium Study GroupAppendixDevandra Amin, MD, Palm Harbor, FL; Antonio Anzueto,MD, San Antonio, TX; Robert Baughman, MD, Cincinnati, OH;Horst Blumberg, MD, St. Petersburg, FL; Dick D. Briggs, MD,Birmingham, AL; Jeffrey M. Cary, MD, Seattle, WA; RichardCasaburi, PhD, MD, Torrance, CA; Timothy Craig, DO, Hershey,PA; Arthur C. DeGraff, Jr., MD, Hartford, CT; JamesDonohue, MD, Chapel Hill, NC; Mitchell Friedman, MD, NewOrleans, LA; Donald Auerbach, MD, Cherry Hill, NJ; MichaelD. Goldman, MD, Los Angeles, CA; F. Charles Hiller, MD,Little Rock, AR; Terrence P. Kane, MD, Sarasota, FL; JillKarpel, MD, FCCP, Bronx, NY; David Levin, MD, OklahomaCity, OK; Jing Liu, MD, Salem, VA; Donald Mahler, MD,Lebanon, NH; Michael Mandel, MD, Wilkes Barre, PA; K. ScottMiller, MD, Charleston, SC; Joseph W. Ramsdell, MD, SanDiego, CA; James Skatrud, MD, Madison, WI; Jonathan D.Truwit, MD, Charlottesville, VA; and Laurence A. Weiss, MD,PA, Hallandale, FL.References1 Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessmentand management of chronic obstructive pulmonarydisease (COPD). Eur Respir J 1995; 8:1398–14202 Ferguson GT, Cherniack RM. Management of chronic obstructivepulmonary disease. N Engl J Med 1993; 328:1017–10223 Gross NJ. Ipratropium bromide. N Engl J Med 1988; 319:486–494CHEST / 118 /5/NOVEMBER, 2000 1301

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