Absence of Electrocardiographic Findings and Improved Function with Once-Daily Tiotropium in Patients with Chronic Obstructive Pulmonary Disease

Absence of Electrocardiographic Findings and Improved Function with Once-Daily Tiotropium in Patients with Chronic Obstructive Pulmonary Disease
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  Absence of Electrocardiographic Findings and Improved Function with Once-Daily Tiotropium in Patients with Chronic Obstructive Pulmonary Disease Henry Covelli, M.D., Sudipta Bhattacharya, M.S., Cara Cassino, M.D., Craig Conoscenti, M.D., andSteven Kesten, M.D. Study Objectives. To examine electrocardiographic findings after short- andlong-term tiotropium therapy in patients with chronic obstructivepulmonary disease (COPD), and to establish previously reportedsymptomatic efficacy. Design. Randomized, double-blind, placebo-controlled, parallel-group study. Setting. Twelve outpatient investigational centers in the United States. Patients. One hundred ninety-six patients with COPD. Intervention. Patients received either tiotropium 18 µg once/day or placebo,delivered by the HandiHaler device. Measurements and Main Results. Electrocardiography (predose and 5 minpostdose) and 24-hour Holter monitoring were performed at baseline andafter 8 and 12 weeks of treatment with tiotropium 18 µgonce/day orplacebo. Efficacy measures (spirometry, global COPD ratings, scores on theEuroQol Health Questionnaire [EQ-5D], albuterol inhaler as needed) wereincluded to demonstrate that the study population exhibited thecharacteristic improvements observed in previous tiotropium studies.Mean baseline forced expiratory volume in 1 second (FEV 1 )was 1.03 L.Mean changes in heartrate from baseline were similar in both groups. Nodifferences were noted in the percentage of patients developing rhythm orconduction abnormalities detected with electrocardiography or Holtermonitoring.Frequency of premature beats and mean maximal changes inPR, QRS, QT, QTcB, and QTcF intervals were similar in both groups. Nopatients developed new-onset QT or QTc intervals greater than 500 msec,and no differences were noted in the percentage of patients developing newQT prolongation less than 30 msec, 30–60 msec, or greater than 60 msec.At 12 weeks, predose and postdose improvements in FEV 1 were 184 and265 ml, respectively,with tiotropium versus placebo (p<0.001). Physicianand patient global COPD ratings and the EQ-5D visual analog scale scoreswere improved with tiotropium (p<0.05); as-needed albuterol was reducedby 25% relative to placebo (p<0.05). Conclusion. Tiotropium provided spirometric and symptomatic benefits inpatients with COPD and was not associated with evidence of electro-cardiographic changes in heart rate, rhythm, QT intervals, or conduction. Key Words: chronic obstructive pulmonary disease, COPD, tiotropium,electrocardiogram, Holter monitoring, spirometry, quality of life. (Pharmacotherapy 2005;25(12):1708–1718)  ABSENCE OF ELECTROCARDIOGRAPHIC FINDINGS WITH TIOTROPIUM Covelli et al Patients with chronic obstructive pulmonarydisease (COPD) often have numerous comorbidconditions; cardiovascular disease is particularlycommon. 1–5 Data from the Lung Health Studyshowed that cardiovascular disease and cancerwere the most common causes of death inpatients with mild-to-moderate COPD, and thatcoronary artery disease was the most frequentlyobserved cardiovascular disorder. 2 In addition,smoking cessation during the trial was associatedwith decreased likelihood of cardiovasculardisease, including fatal events. Other studieshave noted an increased relative risk of cardio-vascular disease in patients with COPD that was2–3times that of a matched population. 3–5 The most relevant risk factor for cardiovasculardisease in patients with COPD is smoking; malesex and older age contribute to this association.In addition, for treatment of airway disease andcommon comorbidities, patients with COPDoften receive numerous drugs that may havecardiovascular effects. Drugs that may influenceheart rate and rhythm include theophyllines,  -agonists, and anticholinergics. 6–9 Tiotropium, an inhaled anticholinergic that hasits effect through prolonged blockade of themuscarinic M3 receptor, provides 24-hourefficacy with once-daily dosing. 10, 11 Althoughpeak plasma levels occur within 5 minutes, steadystate occurs after several weeks of treatment. 10 Results of electrocardiographic analysesperformed during clinical trials in the developmentprogram for tiotropium have been reported. 12 Data from these trials did not show evidence of significant electrophysiologic abnormalitiesduring tiotropium treatment in patients withCOPD. However, limited electrocardiographicdata wereavailable when plasma levels of tiotropium peaked. In addition, results of Holtermonitoring were reported from a single trial inwhich half the patients received tiotropium in themorning, the remainder in the evening. 11, 12 Inthis trial, Holter monitoring performed atbaseline and once after 6 weeks of treatmentshowed no effect of tiotropium on heart rate orrhythm.In our trial, we conducted additional electro-physiologic studies in patients with COPD,including both short- and long-term treatmentwith tiotropium 18 µg/day, to further elucidatethe drug’s safety profile. We also sought toconfirm the spirometric efficacy and symptomaticimprovements in patient-centered outcomesobserved in previous tiotropium studies. Methods Study DesignThe study was a 12-week, randomized, double-blind, placebo-controlled, parallel-group clinicaltrial involving patients with COPD. Cardiacevaluation was performed in all patients withstandard 12-lead electrocardiograms and 24-hourHolter monitoring. The primary efficacy outcomewas the morning predose (trough) forcedexpiratory volume in 1 second (FEV 1 )after 12weeks (day 84) of treatment with either tiotropium18 µg or matching placebo. Secondary efficacyoutcomes included predose (trough) FEV 1 onday 56 and forced vital capacity (FVC) on days56 and 84, postdose FEV 1 and FVC on all testdays, patient and physician global COPD ratings,scores on the EuroQol Health Questionnaire(EQ-5D), and treatment with rescue drug.The study was conducted in 12 investigationalsites in the United States. The protocol wasapproved by the ethics committee and/orinstitutional review board at all participatingcenters. All patients signed a written informedconsent form before any study procedures wereperformed, in accord with the Declaration of Helsinki (1996 version).PatientsPatients included in the study had a clinicaldiagnosis of COPD, wereat least 40 years of age,and had a smoking historyof at least 10 pack-years. Patients were required to have an FEV 1 of 60% or less of predicted normal 13 and an FVC of 70% or less.Patients with significant disease other thanCOPD wereexcluded. Significant disease wasdefined as a disease or condition that, in theopinion of the investigator, may put the patient atrisk because of participation in the study,or may 1709 From Pulmonary Consultants of North Idaho, Coeurd’Alene, Idaho (Dr. Covelli); and Boehringer IngelheimPharmaceuticals Inc., Ridgefield, Connecticut (Ms.Bhattacharya, and Drs. Cassino, Conoscenti, and Kesten).Funded by Boehringer Ingelheim Pharmaceuticals Inc.,Ridgefield, Connecticut.Presented at the annual conference of the AmericanCollege of Chest Physicians, Seattle, Washington, October23–28, 2004.Manuscript received February 16, 2005. Acceptedpending revisions April 26, 2005. Accepted for publicationin final form July 30, 2005.Address reprint requests to HenryCovelli, M.D.,PulmonaryConsultants of North Idaho, 700 IronwoodDrive, Suite 360, Coeur d’Alene, ID 83814;  PHARMACOTHERAPY Volume 25, Number 12, 2005 influence either the results of the study or thepatient’s ability to participate in the study.Patients also were excluded if they had a historyof asthma or atopy, had abnormal liver enzymelevels or evidence of chronic renal dysfunction,or had experienced a respiratory tract infectionor COPD exacerbation within 6 weeks of ran-domization. In addition, patients were excludedif they were taking systemic corticosteroids atunstable dosages or prednisone 10 mg/day orgreater (or its equivalent), or were using oxygenfor more than 12 hours/day.Patients with preexisting cardiovascular diseasewere permitted to participate in the trial unlessthey had experienced myocardial infarctionwithin the preceding 6 months, hospitalizationfor heart failure within the preceding year, or life-threatening arrhythmias requiring intervention orchange in drug therapy within the last year.Patients who qualified based on inclusion andexclusion criteria were randomized after a 2-week run-in period.During the study, treatment with respiratorydrugs such as inhaled corticosteroids, both short-and long-acting  -agonists, and theophyllineswas permitted; however, treatment withcromones, leukotriene antagonists, and inhaledanticholinergics was not permitted.Procedures Electrocardiograms and Holter Monitoring A12-lead electrocardiogram (ECG) wasperformed at the screening visit. At theconclusion of the run-in period, ECGs (predoseand 5 min postdose) and 24-hour Holtermonitoring wereperformed as baselineevaluations. The ECGs and 24-hour Holtermonitoring were repeated after 8 weeks (day 56)and 12 weeks (day 84) of randomized treatmentwith either tiotropium 18 µg once/day orplacebo, both delivered by the HandiHaler device(Boehringer Ingelheim GmbH & Co. KG,Ingelheim, Germany). The 12-lead ECGs werecentrally read by a qualified cardiologist(eResearchTechnology, Inc., Philadelphia, PA)who was blinded to treatment allocation.Data from 24-hour ECG monitoring wascentrally analyzed by an electronic Holteranalysis system and reviewed by trainedtechnicians (eResearchTechnology, Inc.). Regionsof diagnostic interest were read by a qualifiedcardiologist who was also blinded to treatmentallocation. Quality assurance was maintained byreanalysis of 2% of recordings. Spirometry Prior to and 90 minutes after dose adminis-tration, spirometry was performed at baseline,after 8 weeks (day 56), and after 12 weeks (day84) of treatment. Spirometry was performedwith calibrated spirometers while the patient wasseated, after appropriate washout of broncho-dilators. The spirometer was calibrated eachmorning before any tests were performed.Testing was done in triplicate, and the best of three efforts was defined as the highest FEV 1 andFVC obtained on any of three exhalations (notnecessarily from the same curve), meeting theAmerican Thoracic Society criteria. 14 Global Evaluations and EQ-5D Patient and physician global COPD evaluationswere completed at baseline and after 8 (day 56)and 12 weeks (day 84) of treatment. The COPDglobal evaluation consists of an 8-point scale(poor 1–2, fair 3–4, good 5–6, excellent 7–8) toevaluate a patient’soverall health status. Bothpatients and physicians were asked to rate thepatient’s COPD status according to this scale ateach visit.The EQ-5D questionnairewas completed atbaseline and after 12 weeks of treatment. TheEQ-5D is a generic quality-of-life instrumentconsisting of two parts: a 0–100 visual analogscale (VAS) and a questionnaire on which, afterbrief instruction, the patient rates five domains(mobility, self-care, usual activity, pain ordiscomfort, and anxiety or depression) as noproblems, some problems, or serious problems. 15 Use of Rescue Drug Patients recorded daily inhalation of the rescuedrug, albuterol, on a patient diary card. Meanvalues for daily albuterol therapy from the 2-week run-in period formed the baseline.Data Analysis Electrocardiograms and Holter Monitoring Baseline values for the 12-lead ECG werecalculated as the means of the screening and run-in ECGs. End points from the 12-lead ECG andthe 24-hour Holter data were analyzeddescriptively. In addition, QT, rate-corrected QTbased on Bazett’sformula (QTcB), and rate-corrected QT based on Fridericia’sformula(QTcF) intervals were analyzed using the analysisofcovariance (ANCOVA) model, with treatment 1710  ABSENCE OF ELECTROCARDIOGRAPHIC FINDINGS WITH TIOTROPIUM Covelli et al and centers as factors and the respective baselinevalues as covariates. 16 Usually, the continuousend points were summarized using mean ±SD;the nominal end points were summarized usingpercentages.Baseline heart rate and QT, QTcB, QTcF, PR,and QRS intervals were defined as the average of the ECG values obtained during the screeningvisit and the randomization visit. Abnormalrhythm on ECG was defined as the occurrence of at least two consecutive abnormal heart beats,arrhythmia as any abnormal heart beat, andabnormal conduction as any change in thenormal atrioventricular conduction. A newfinding (onset) in the 12-lead ECG was definedas not present at baseline but present at any timeduring the treatment period.Analysis of 24-hour Holter monitoring wasrestricted to Holter procedures with at least 18hours of data. For this analysis, a pause wasdefined as the absence of a beat for 3 seconds orlonger. Data regarding supraventricular prematurebeats (SVPBs) and ventricular prematurebeats(VPBs)—total, run (at least three abnormal beatsin a row), and pair events—from the 24-hourHolter monitoring were normalized by dividingthe respective end-point values by the analyzedhours for each patient before data were analyzed.Atrend analysis of the SVPB total values wasperformed using tables documenting individualpatient shifts from baseline to the end of thetreatment period. For this analysis, each patient’svalue was normalized by dividing the raw valueby the respective analyzed time and thenmultiplying the derived values by 24 hours. Thepatients were then assigned to one of eightcategories according to their normalized SVPBvalue (< 10, 10 to < 30, 30 to < 50, 50 to < 100, 100to<500,500 to < 1000, 1000 to < 2000, or ≥ 2000).Asimilar analysis was performed for VPB total.Simple descriptive summaries (total number,mean, and SD) of the changes from baseline todays 56 and 84 in heartrate variability data (SDof the normal interval [NN] (SDNN), square rootof the mean squared differences of successiveNNs [RMSSD], intervals differing by 50 msec[NN50] divided by the total number of NNs[pNN50], and triangular index) were calculated. 17 The sample was calculated based on troughFEV 1 data from previous tiotropium trials. 18–20 The study was not powered to detect significantdifferences in parameters from the 12-lead ECGand the 24-hour Holter studies as therewas no apriori hypothesis or data to supportasamplecalculation. Efficacy The primary end point of predose (trough)FEV 1 at 12 weeks was analyzed using theANCOVA model with treatment and centers asfactors and the baseline FEV 1 values as covariate.Secondary efficacy end points—including allsecondary spirometry end points, patient andphysician global evaluations, EQ-5D VAS scores,and weekly mean number of occasions of rescuedrug use/day over time—were analyzed using thesame ANCOVA model used for analysis of theprimary end point. Missing efficacy dataresulting from early patient withdrawal due toworsening of COPD were imputed using leastfavorable data observed prior to discontinuation.In all other cases, missing efficacy data followingpatient withdrawal were imputed using lastobservation carried forward. Missing values fromthe EQ-5D questionnaire were not imputed.Descriptive statistics (expressed as number andpercentage) were provided for each response (noproblems, some problems, and serious problems)for the five domains of the EQ-5D questionnaire.The analysis was conducted by categorizingresponses as “no problems” or “any problems”(which included “some problems” and “seriousproblems”). The Wilcoxon rank sum test wasused to compare treatments in each of the fiveEQ-5D domains. Results Of 225 patients screened for participation inthe trial, 196 wererandomized to receive eitherthe study drug (tiotropium) or placebo. Fourrandomized patients were discontinued from thestudy after the baseline Holter monitor indicatedruns of apparently asymptomatic ventriculartachycardia. A total of 10 patients in thetiotropium group and 17 in the placebo groupdiscontinued the trial after randomization. Thedifferences between the two groups were morefrequent occurrences of worsening of COPD andcomplaints of lack of efficacy in the placebogroup.Baseline CharacteristicsMean patient age was 65 years; 58% of thepatients were men (Table 1). Mean baselineFEV 1 was 1.03 L (39% predicted). Approximately77% of patients reported dyspnea as their initialsymptom of COPD, and 85% reported thatdyspnea was the most troublesome symptomrelated to COPD. Except for a slightly higher 1711  PHARMACOTHERAPY Volume 25, Number 12, 2005 proportion of men in the tiotropium group,baseline demographics weresimilar in the twogroups.At trial entry, comorbid conditions reported forthe study cohort consisted of 29.1% with cardiacdisorders (ischemic disease, dysrhythmias,conduction disorders, and heartfailure), 43.4%with hypertension, 10.2% with diabetes mellitus,and 16.8% with hyperlipidemia. Approximately86% of the study cohort reported takingpulmonary drugs at trial entry (Table 2). Inhaledanticholinergics, long-acting  -agonists, inhaledcorticosteroids, and theophyllines were used by61%, 51%, 56%, and 6% of patients, respectively.The proportion of patients using inhaled long-acting  -agonists was slightly higher in theplacebo group.ElectrocardiogramsMean ±SD changes in heart rate from baselineto average during treatment were similar in bothgroups (tiotropium group -0.28 ±6.2 beats/min,placebo group 0.78 ±6.2 beats/min). Changesfrom baseline to 5 minutes after the first dose of study drug were -0.18 ±6.3 and 0.48 ±6.4 forthe tiotropium and placebo groups, respectively.Changes in heartrate on predose and postdoseECGs on days 56 and 84 are presented in Table 3.No differences were noted in the percentage of patients developing abnormal rhythms(tiotropium 10.8%, placebo 9.4%) or new-onsetarrhythmia (tiotropium 12.6%, placebo 14.0%).New onset of abnormal conduction was observedin 2.6% and 6.9% of tiotropium- and placebo-treated patients, respectively, with no relevantdifferences between groups in types of disorders.Frequency of premature beats was similar in bothgroups. No statistically significant differenceswere noted between tiotropium and placebogroups in mean change from baseline for theaverage and maximum values for PR, QRS, QT,QTcB, and QTcF intervals during treatment. Nopatients developed new-onset QT or QTc longerthan 500 msec, and no differences were noted inthe percentage of patients developing new QT 1712 Table 1. Baseline Characteristics of the Study Patients TiotropiumPlaceboGroupGroupTotalCharacteristic(n=100)(n=96)(N=196)No. (%) of PatientsMen66 (66.0)47 (49.0)113 (57.7)Smokers40 (40.0)35 (36.5)75 (38.3)Mean ±SDAge (yrs)65.8 ±8.963.3 ±9.264.6 ±9.1Smoking history (pack-yrs)66.0 ±35.665.0 ±31.265.5 ±33.4COPD duration (yrs)10.1 ±8.110.4 ±7.710.2 ±7.9FEV 1 (L)1.06 ±0.370.99 ±0.421.03 ±0.40FEV 1 (% predicted)40.2 ±13.038.6 ±13.839.4 ±13.4FVC (L)2.49 ±0.712.29 ±0.702.39 ±0.71 COPD = chronic obstructive pulmonary disease; FEV 1 =forced expiratory volume in 1 sec; FVC =forced vital capacity. Table 2. Drug and Oxygen Therapy at Baseline No. (%) of PatientsTiotropiumPlaceboGroupGroupTotalTherapy(n=100)(n=96)(N=196)Anticholinergics61 (61.0)59 (61.5)120 (61.2)Short-acting  agonist78 (78.0)68 (70.8)146 (74.5)Long-acting  agonist44 (44.0)56 (58.3)100 (51.0)Inhaled corticosteroids54 (54.0)56 (58.3)110 (56.1)Theophylline4 (4.0)7 (7.3)11 (5.6)Oral steroids3(3.0)1(1.0)4(2.0)Oxygen4 (4.0)3 (3.1)7 (3.6)
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