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Xn--hestjournal-roj.chestpubs.orgPharmacoeconomic Evaluation of a
Combination of Ipratropium Plus
Albuterol Compared With Ipratropium
Alone and Albuterol Alone in COPD*
Mitchell Friedman, MD, FCCP; Charles W. Serby, MD;Shailendra S. Menjoge, PhD; J. Douglas Wilson, MB, PhD;Daniel E. Hilleman, Pharm D, FCCP; and Theodore J. Witek, Jr., Dr. PH Study objective: To conduct a post hoc pharmacoeconomic evaluation of two double-blind,
randomized, prospective, parallel group studies comparing the long-term efficacy and safety of
ipratropium combined with albuterol in a single inhalational canister against either bronchodi-
lator agent alone in patients with COPD.
Patients: One thousand sixty-seven patients with COPD.
Methods: The dose of each bronchodilator was two puffs four times a day (42 mg of ipratropium
bromide, 240 mg of albuterol sulfate). Pulmonary function testing was performed on days 1, 29,
57, and 85 of treatment. Outcomes, health-care resource consumption, and costs were compared
for the three treatment groups over the 85-day study period. A total of 1,067 patients were
randomized in the two studies (albuterol alone, n 5 347; ipratropium alone, n 5 362; albuterol
plus ipratropium, n 5 358).
Results: Improvement in FEV1 and area under the FEV1 response-time curve from time 0 to 4 h
(FEV1AUC0–4) was significantly greater for the combination of albuterol plus ipratropium than
either agent alone on all test days. Compared with albuterol, patients receiving ipratropium and
ipratropium plus albuterol experienced significantly fewer COPD exacerbations and patient-days
of exacerbation. In addition, the increased frequency of exacerbations observed in the albuterol
group was associated with a significant increase in the number of patient hospital days and
antibiotic and corticosteroid use. As a result, the total cost of treatment over the study period was
significantly less for ipratropium ($156 per patient) and ipratropium plus albuterol ($197 per
patient) than for albuterol ($269 per patient). Increased cost-effectiveness, defined as total
estimated treatment cost per mean change in FEV1AUC0–4, was observed in both treatment arms
Conclusions: The inclusion of ipratropium in a pharmacologic treatment regimen is associated
with a lower rate of exacerbations in COPD. The result is lower total treatment costs and
(CHEST 1999; 115:635– 641)
Key words: albuterol; cost-effectiveness; ipratropium; pharmacoeconomics
area under the FEV1 response-time curve from time 0 to 4 h *From the Section of Pulmonary Disease, Critical Care Medi- COPD is a progressive disorder characterized by
cine, and Environmental Medicine (Dr. Friedman), Tulane airflow obstruction secondary to chronic bronchitis University Medical Center, School of Medicine, New Orleans, or emphysema.1 Airflow obstruction is often associated LA; Boehringer Ingelheim Pharmaceuticals, Inc (Drs. Serby, with airway hyperreactivity that is partially reversible Menjoge, Wilson, and Witek), Ridgefield, CT; and Departmentof Pharmacy Practice (Dr. Hilleman), Creighton University with bronchodilator therapy in most COPD patients.2,3 School of Pharmacy and Allied Health Professions, Omaha, NE.
Exacerbations of disease are common in patients with The post hoc pharmacoeconomic analysis was supported by COPD.4–6 Exacerbations are associated with symp- Manuscript received July 2, 1998; revision accepted September toms that include increased dyspnea, cough, and spu- tum volume, as well as changes in sputum color.4 Correspondence to: Daniel E. Hilleman, Pharm D, FCCP, De- COPD exacerbations have also been associated with partment of Pharmacy Practice, Creighton University School ofPharmacy and Allied Health Professions, 2500 California Plaza, decrements in pulmonary function.4 Furthermore, suc- Omaha, NE 68178; e-mail: [email protected] cessful treatment of COPD exacerbation with antibiot- CHEST / 115 / 3 / MARCH, 1999 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
ics has been shown to result in improvements in peak allergic rhinitis, atopy, an eosinophil count .500 mm3, or who flow compared with placebo.4 Patients suffering an were taking cromolyn or .10 mg of prednisone per day were increased number of COPD exacerbations will incur excluded from the studies.
A history and physical examination, laboratory tests (hemo- excess health-care resource utilization and costs. In- gram, electrolytes, renal and hepatic function), and a 12-lead creased costs result from treatment of COPD exacer- ECG were performed prior to and at the end of the study.
bations that typically include the addition of or in- Following a 2-week baseline period, patients were randomized to creases in doses of pharmacologic agents (eg, receive the ipratropium-albuterol combination (n 5 358), ipra- bronchodilators, antibiotics, and corticosteroids).7 Fur- tropium alone (n 5 362), or albuterol alone (n 5 347). The doseof each treatment was two puffs four times daily. Delivered doses thermore, there will be additional costs related to an for the three treatment groups were as follows: albuterol alone, increased number of clinic visits and laboratory tests, 240 mg of albuterol sulfate four times a day; ipratropium alone, 42 and in some patients, hospitalizations for COPD exac- mg of ipratropium bromide four times a day; albuterol plus ipratropium, 240 mg of albuterol sulfate plus 42 mg of ipratro- There are two primary pharmacologic classes of pium bromide four times a day. Prior theophylline and steroiduse (either inhaled or ,10 mg/d of prednisone) was continued inhaled bronchodilators used in the treatment of during the baseline period and during the active treatment phase.
COPD: b-adrenergic receptor agonists (eg, albu- Dosage increases or additions of corticosteroids or antibiotics terol) and quarternary ammonium anticholinergic were permitted during exacerbations. Clinic visits to record agents (eg, ipratropium).9 The combined use of concomitant medications and evaluate treatment side effects ipratropium plus albuterol has been shown to pro- were scheduled every 2 weeks during the 85-day treatmentperiod.
duce superior bronchodilation compared to its indi- Pulmonary function testing was performed on days 1, 29, 57, vidual components without additional side effects.10 and 85 of active treatment. Prior to testing, treatment with However, it is unknown if this improvement in theophylline preparations was withheld for 24 h and treatment bronchodilation has benefit in terms of health-care with all corticosteroids and b-agonists was withheld for 12 h.
resource utilization and the cost of management of Pulmonary function was assessed just prior to drug administra-tion and at 0.25, 0.5, and 1 h after drug administration and hourly COPD. The present study is a post hoc pharmaco- thereafter for a total of 8 h.
economic evaluation of two double-blind, random-ized, prospective, parallel group studies that were Outcome Assessment and Health-Care Resource Utilization conducted to evaluate the long-term efficacy andsafety of ipratropium combined with albuterol in a Data concerning health-care resource utilization were col- lected and available through the clinical research reports for single inhalation aerosol canister against either bron- protocols 627A and 627B, but they have not been published chodilator agent alone in patients with COPD.
previously. These health-care resource data included the numberand length of acute pulmonary exacerbations of COPD, thenumber and length of hospitalizations due to exacerbations, andthe number of patient days of increased doses or additions of Materials and Methods corticosteroids and antibiotics. A pulmonary exacerbation wasdefined as a worsening of COPD-related symptoms (ie, cough, Data Reviewed wheezing, dyspnea, sputum production, etc) for 3 consecutivedays or longer.
The efficacy and outcome data presented in this report include the results of two multicenter efficacy and safety trials (trial 627A Data Analysis and 627B) comparing ipratropium combined with albuterol(Combivent; Boehringer Ingelheim Pharmaceuticals; Ridgefield, Data are presented as the mean 6 SD where appropriate, and CT) against albuterol alone and ipratropium alone. These studies a priori level of significance of p , 0.05 was used. The primary used a common protocol and were designed to compare the efficacy end points included the peak change in FEV bronchodilating efficacy and safety of the inhalation aerosol form area under the FEV of these drugs over an 85-day treatment period. The study design 1 response-time curve (AUC) from time 0 to and the efficacy and safety results of one of these studies (627A) 1AUC0 – 4) as calculated by the trapezoidal rule. All randomized patients with evaluable data (96.8% of patients) were were published previously.10 An overview of this common study included in the efficacy analysis. End point analysis in which last design is summarized below. Both studies conformed to the observed data carried forward for missing data was used to institutional review board and informed consent provision of the conduct the efficacy analysis. In all other analyses, all randomized Code of Federal Regulations.
patients were used. Analysis of covariance was used to evaluatethe differences in peak FEV1 and FEV1AUC0–4 between the Study Design treatment groups. The overall incidence of adverse events, eventsrequiring discontinuation of drug therapy, and a number of Both trials enrolled patients with a diagnosis of COPD.
patients with COPD exacerbation were compared using Fisher's Patients had to be .40 years of age with a $10 pack-year history of cigarette smoking. Patients had to have stable, moderately Total health-care expenditures for the three treatment groups severe airflow obstruction defined as an FEV1 of #65% of were calculated by adding the costs of initial and add-on drug predicted normal and an FEV , 70% of FVC. Patients had to be therapy, and hospitalization costs. Initial drug therapy included using two or more pulmonary drugs (eg, b-adrenergic agonist, the costs of albuterol alone, ipratropium alone, and the combi- ipratropium, theophylline, steroid) to control symptoms in the 3 nation of ipratropium-albuterol. The cost basis for their acquisi- months prior to study entry. Patients with a history of asthma, tion costs was the 1998 PC-Price Chek average wholesale price.11 Clinical Investigations Downloaded From: http://publications.chestnet.org/ on 10/07/2016
Add-on drug therapy included the cost of adding or increasing baseline FEV1 stratified by test day and treatment the dose of inhaled or oral corticosteroids and antibiotics. The group is summarized in Table 3. The combination of cost basis for the add-on drug therapies was also the 1998PC-Price Chek average wholesale price.11 The costs of hospital- ipratropium and albuterol produced statistically sig- ization, for purposes of this study, were estimated to be $600/d.
nificant improvements in peak FEV1 compared with Total costs among the three treatment groups were compared either agent alone on all test days. The peak bron- using the Kruskal-Wallis H statistic.
chodilator effect occurred consistently at 1 h post- Cost-effectiveness ratios for each treatment were calculated using total treatment cost divided by the change in FEV dose for all treatments. The FEV1AUC0–4 efficacy and total costs divided by the combined total of exacerbation-free data are summarized in Table 4. The mean and hospitalization-free days. Incremental cost-effectiveness ra- FEV1AUC0–4 was significantly greater for the com- tios were calculated where appropriate.
bination of albuterol and ipratropium than the indi-vidual drugs on all test days.
Outcomes related to disease exacerbations during the 85-day study are summarized in Figure 1 and A total of 1,067 patients were randomized in the Table 5. Compared with the other two treatment two trials. Demographic and clinical characteristics arms, patients receiving albuterol alone experienced of the randomized patients are summarized in Table a significantly increased frequency of COPD exacer- 1. There were no significant differences between the bations (18%) and patient-days of exacerbation (770 treatment groups with regard to baseline character- days) during the 85-day follow-up. There was a istics. Patients completing the study and reasons for similar incidence of exacerbations (12%) in the study withdrawal are summarized in Table 2. Over- ipratropium alone and ipratropium plus albuterol all, there was no significant difference in the per- treatment arms of the study. In addition, the total centage of patients discontinuing therapy for any days of exacerbation were similar in the two treat- reason in the three treatment groups.
ment arms containing ipratropium (504 days vs 554 The percent improvement in peak FEV1 over days, respectively) compared with a significantly Table 1—Demographics and Clinical Characteristics of All Randomized Patients
Duration of disease, yr Percent of predicted normal FEV1 Prestudy medications, No. (%) of patients b-Adrenergics, inhaled b-Adrenergics, oral Steroids, inhaled CHEST / 115 / 3 / MARCH, 1999 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
Table 2—Patient Completion and Reasons for Withdrawal From the Clinical Trials
Protocol violation Unavailable for follow-up Completed all test days greater incidence of exacerbation (770 days) in the and ipratropium plus albuterol ($197 6 84) was sig- albuterol alone treatment arm (p , 0.05). There was nificantly less than albuterol alone ($269 6 108).
no significant difference among any of the three The difference in total cost between ipratropium treatment arms in regards to exacerbation duration alone and the ipratropium plus albuterol combina- (average of 12.1 days for all three groups).
tion product was not significant. Total cost adjusted The increased frequency of exacerbations in the by the percent of the combined number of days both albuterol arm of the study was associated with a exacerbation free and hospital free was $277 for statistically significant increase in the number of total albuterol, $159 for ipratropium, and $201 for the hospital days and greater corticosteroid and antibi- combination product. The reason for the lower total otic use compared with the other two treatment arms cost was a lower cost associated with add-on and (p , 0.05). Although the average hospital length of dose-adjusted pulmonary drugs and lower hospital- stay was similar among the three treatment groups, ization costs.
the number of patients being hospitalized in the Increased cost-effectiveness, defined as total treat- albuterol group (n 5 11) was greater compared to ment cost per FEV1AUC0–4, was observed in both the combination of ipratropium and albuterol treatment arms containing ipratropium (Table 6).
(n 5 5) and to ipratropium alone (n 5 3). There was Ipratropium alone and the albuterol/ipratropium a significant increase in the total number of hospital combination were significantly more cost-effective days for albuterol alone (103 days) compared to than albuterol alone based on total cost per either ipratropium alone (20 days) or to ipratropium FEV1AUC0–4 (p , 0.05). Differences in cost-effec- plus albuterol (46 days).
tiveness between ipratropium alone and ipratropium The total cost of treating COPD over the 85-day plus albuterol were significant only on test day 1. As follow-up period is summarized in Figure 2. Al- both treatment arms containing ipratropium were though the acquisition cost of ipratropium alone ($94 associated with a lower total cost and were more per patient) and the combination product ($106 per effective in regard to bronchodilation than albuterol patient) was greater than albuterol alone ($63 per alone, an incremental cost-effectiveness analysis was patient), the mean total treatment cost of patients not performed.
receiving ipratropium alone or the albuterol/ipratro-pium combination was significantly less than albu-terol alone. The mean total per patient cost over the 85-day follow-up for ipratropium alone ($156 6 69) Exacerbations of COPD contribute substantially to the cost and reduced quality of life of the patients Table 3—Percent Improvement* in Peak FEV1 Over
Baseline FEV1 According to Treatment Group and
Table 4 —Mean FEV
1AUC0 – 4
Test Day No.
*p , 0.01 for all comparisons of combination with its components.
†p Values for significance of differences from the combination.
*p Values for significance of differences from the combination.
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exacerbations in COPD since the treatment arm con-taining both ipratropium and albuterol demonstrated alower number of exacerbations, rather than albuterolusage alone increasing the number of exacerbations.
As pointed out by Anthonisen,13 COPD exacerba- tions occur with a frequency of approximately 0.1 perpatient per month of follow-up. As a result, a largegroup of patients must be followed up for considerableperiods of time to accumulate enough exacerbations toanalyze. We have analyzed the results of two prospec-tive randomized, double-blind, parallel-group studiesthat enrolled 1,067 patients who were followed upclosely for 3 months. Based on the frequency of COPDexacerbations projected by Anthonisen,13 the present Figure 1. COPD exacerbation frequency in the three treatment study had a sample size and a duration of follow-up groups during the 85-day study.
with sufficient power to compare exacerbation ratesbetween the treatment groups.13 In addition, the num-ber and duration of exacerbations observed in the with this disease.4,5,12 Although the etiology and albuterol treatment arm are consistent with those pre- optimal management of exacerbations are unknown, dicted for a 3-month study, based on previously pub- it is believed that infection usually plays an initiating lished reports.4,5 role, and empiric therapy typically includes antibiot- The definition of exacerbation used in the present ics and corticosteroids.4–6 To our knowledge, the study is valid based on the following. Similar to the impact of traditional bronchodilators on the fre- definition used in the present study, other published quency of exacerbations of COPD has not been studies of COPD patients have also utilized changes in clinical symptoms to define exacerbations.4,5,12 The results of the present study demonstrate that the For example, Anthonisen et al4 defined exacerbation long-term use of ipratropium alone or the combination as an increase in dyspnea or sputum production, or a of ipratropium plus albuterol is associated with fewer change in sputum color, cough, or wheeze, which are exacerbations of COPD than the use of albuterol alone.
similar to the criteria used to define exacerbations in Since the number of exacerbations was not significantly the present study. In a more recent trial, Collet et different between the two ipratropium treatment arms, al12 defined COPD exacerbations as a change in it would appear that the inclusion of ipratropium in a sputum color, texture, or quantity, the presence of pharmacologic treatment regimen alters the rate of one additional symptom of shortness of breath or Table 5—Outcomes of COPD Patients Related to Disease Exacerbation During the 85-Day Study
No. (%) of patients with exacerbation No. of days per exacerbation Total no. of patient-days of exacerbation No. of hospitalizations due to exacerbation Hospital length of stay, d Total no. of hospital days No. of patients adding or increasing doses of corticosteroids No. of patient-days of increased or added corticosteroid use No. of patients adding or changing antibiotics No. of patient-days of changed or added antibiotic use *p , 0.05 albuterol alone vs ipratropium alone and albuterol alone vs albuterol plus ipratropium.
CHEST / 115 / 3 / MARCH, 1999 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
Figure 2. Total treatment costs over the 85-day follow-up period for the three treatment groups.
cough or fever, and either an unscheduled clinic visit which patients receiving ipratropium or ipratropium or a prescription for an antibiotic. In another study, plus a b-agonist had lower total health-care costs the symptoms of increased dyspnea, changes in compared to treatment with a b-agonist alone.8 The sputum characteristics, malaise, etc, had to be reduced costs observed in the present study resulted present for at least 48 h.5 In the present study, a from reductions in add-on drug therapy and hospital- more stringent definition of 72 h of symptom dura- ization. Third, superior bronchodilation (peak FEV1 tion was used to establish an exacerbation.
and FEV1AUC0–4) was observed in the ipratropium The reduction in total cost for the treatment arms plus albuterol arm, compared to its individual drug containing ipratropium (Fig 2) has relevance to the components (ipratropium or albuterol). The addition of management of COPD in which side effect profile, a b-agonist to ipratropium in the combined treatment total cost, and improvement in lung function are all arm did not significantly increase total treatment cost, important factors involved in selecting an appropriate but did result in improved cost-effectiveness. When pharmacologic treatment regimen. First, in the present study of 1,067 patients with moderate-to-severe COPD, there was no difference in side effect fre- 1AUC0 – 4, there was an average 42% lower cost for quency among the three treatment arms. Fewer exac- the ipratropium treatment arms compared with albu- erbations were noted in both treatment arms contain- terol alone for all pulmonary function test days. Thus, ing ipratropium (mean 33%) compared with the the observed improvement in physiologic function in albuterol arm, translating into a 24% lower cost. These the combination treatment arm magnified the differ- data are similar to preliminary results observed in a ence in total in costs relative to albuterol alone. These 3-year retrospective study in patients with COPD in data, taken along with the convenience and assumedincreased compliance with use of a single inhaler,suggest that an inhaler bronchodilator regimen com-bining ipratropium and albuterol differs from adminis- Table 6 —Cost-effectiveness Calculated as Total Cost
tration of albuterol or ipratropium alone with regard to ($) per Mean FEV1AUC0–4
physiologic improvement as well as lower health-care costs. As a result, this combination should be consid- ered early in the management of moderate-to-severe As previously stated, the exact mechanisms respon- sible for COPD exacerbations are unknown. The present study, although designed to determine the frequency and duration of exacerbations, was not de- Clinical Investigations Downloaded From: http://publications.chestnet.org/ on 10/07/2016
signed to examine the possible mechanisms involved in COPD exacerbations. It has been suggested that alter- 1 American Thoracic Society. Standards for the diagnosis and ations in mucus production or rheology by glands, care of patients with chronic obstructive pulmonary disease.
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Respir Dis 1986; 133:814 – 819 There are several possible mechanisms by which 4 Anthonisen R, Manfreda J, Warren C, et al. Antibiotic alterations in cholinergic tone might affect exacerbation therapy in exacerbations of chronic obstructive pulmonary rates. As pointed out by Barnes and Jarnes,15 the disease. Ann Intern Med 1987; 106:196 –204 mechanisms by which anticholinergic bronchodilators 5 British Thoracic Society Research Committee. Oral N-acetylcys- may have a greater effect on airway function in COPD teine and exacerbation rates in patients with chronic bronchitis are uncertain, since if cholinergic tone were the only and severe airway obstruction. Thorax 1985; 40:832–835 6 Nicotra M, Rivera M, Awe R. Antibiotic therapy in acute reversible component, it might be predicted that b2- exacerbations of chronic bronchitis: a controlled study using agonists would be equally effective in inhibiting cholin- tetracycline. Ann Intern Med 1982; 97:18 –21 ergic tone. Thus, it has been suggested that anticholin- 7 Dompeling E, van Schayek C, Van Grunsven P, et al. Slowing ergics might have a greater effect than b2-agonists in the deterioration of asthma and chronic obstructive pulmonary COPD because of some additional effects on mucus disease observed during bronchodilators therapy by adding secretion.15 Cholinergic nerve fibers travel down the inhaled corticosteroids. Ann Intern Med 1993; 118:770–778 vagus nerve and synapse in parasympathetic ganglia 8 Hilleman D, Wadibia E, Shinn B. Outcomes and costs of chronic COPD: impact of disease severity and treatment that are located within the airway wall.16 From these approaches [abstract]. Pharmacotherapy 1996; 16:494 ganglia, short postganglionic fibers travel to airway 9 Chapman K. Therapeutic algorithm for chronic obstructive smooth muscle and submucosal glands.15,16 Cholin- pulmonary disease. Am J Med 1991; 91:175–235 ergic effects on the airways are mediated by muscarinic 10 Combivent Inhalational Aerosol Study Group. In chronic receptors on target cells in the airways.17,18 Cholinergic obstructive pulmonary disease, a combination of ipratropium agents are potent stimulators of mucus secretion in and albuterol is more effective than either agent alone: an human airways in vitro and act predominantly on 85-day multicenter trial. Chest 1994; 105:1411–1419 11 Price-Chek PC: version 2.16. St. Louis, MO: Medi-Span, submucosal glands that are the major source of mucus in the proximal airways.19 Goblet cells, which are the 12 Collet J, Shapiro S, Ernst P, et al. Effects of an immunos- major source for mucus in peripheral airways, are timulating agent on acute exacerbations and hospitalizations under cholinergic control.20 Ipratropium has been in patients with chronic obstructive pulmonary disease. Am J shown to block the effects of some irritants and inhaled Respir Crit Care Med 1997; 156:1719 –1724 13 Anthonisen N. OM-85 BV for COPD. Am J Respir Crit Care toxins, such as cigarette smoke, which are mediated via Med 1997; 156:1713–1714 a cholinergic reflex.19,21 Thus, it may be that the 14 Lloberes P, Ramis L, Montserrat J, et al. Effect of three inclusion of ipratropium in the treatment regimen different bronchodilators during an exacerbation of chronic reduced goblet cell secretion and thus improved airway obstructive pulmonary disease. Eur Respir J 1988; 1:536 –539 obstruction in peripheral airways.
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Tendances Récentes Emergentes et Nouvelles Drogues Tendances récentes émergentes et nouvelles drogues Marseille 2009 – juin 2010 Présentation du dispositif TREND Marseille 2010 .7 Les espaces étudiés. 7 1.1 Espace urbain et espace festif. 7 1.2 L'expérimentation d'un élargissement du champ d'observation. 7 Les outils de recueil des données. 8