- Center on Health Equity and Access
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Clinical and Economic Outcomes in the Treatment of Lower Respiratory Tract Infections
Format forFormulary Submissions.
The cost of healthcare in the UnitedStates continues to steadily increase,approaching a 10% annual increase in2002.1 Despite representing only 10.5% ofhealthcare expenditures, many health planshave developed and implemented methodsthat seek to curtail spending on prescriptiondrugs. Such methods include partneringwith drug manufacturers for rebates and diseasemanagement programs,2 encouragingthe use of generic medications,3 and costshifting to patients by way of multitieredcopayments and coinsurance.4 More thanever before, health plans are asking manufacturersto demonstrate the value of pharmaceuticals,as evidenced by the requestfor pharmacoeconomic analyses and economicmodeling in the Academy ofManaged Care Pharmacy's 5
The true economic cost of pharmaceuticalsincludes more than the medicationacquisition cost. In addition to the acquisitionand preparation costs, health plansmust factor in costs of medical care, adverseevents, clinical monitoring, and treatmentfailures, all of which can be reduced byinformed medical care and appropriate first-linedrug selection. Selecting a medicationwith documented ability to improve the clinicalcourse of a disease may significantlyreduce overall healthcare costs. Health economicanalyses and models can help healthplans gauge the true cost of a product andestimate the impact of a formulary change.
The purpose of this article is to discussthe economic impact of community-acquiredpneumonia (CAP) and acute exacerbationsof chronic bronchitis (AECB); toreview outcomes studies examining currentempiric treatment of these infections; toreview current economic research ontelithromycin, the first agent in the newketolide class of antibiotics; and to determinethe potential economic impact of theaddition of this product to formulary.
Disease Burden and Economic Landscape
Community-acquired Pneumonia. CAPplaces an enormous clinical and financialburden on the healthcare system. In theUnited States, there are an estimated 5 millioncases of CAP annually, accounting formore than 10 million physician visits, 10% ofwhich require hospitalization.6,7 CAP is associatedwith significant mortality rates, andranks high among the leading causes ofdeath in the developed world. In the UnitedStates, CAP is the sixth leading cause ofdeath (3.5% of all deaths) and the most frequentinfectious cause of death amongpatients of all ages (46% of all infectiousdeaths).7,8
The sheer magnitude of CAP, with itsassociated morbidity and mortality rates,places a heavy economic burden on thehealthcare system. A study examining thetotal overall costs of CAP (including indirectcosts) determined that CAP generated $23billion worth of costs in 1994. This figureincludes direct costs of $14 billion and $9billion in lost productivity.9,10
In a separate study by Colice and colleagues,11 patient-specific CAP costs weredetermined from the administrative claimsdatabase of a national employer from theyears 1996 to 1998. Limited to the employedpopulation and their dependents(<65 years of age), claims data for 100 000patients were examined to determine treatmentcosts for managing both inpatient andoutpatient cases of CAP. A total of 7249episodes of CAP were identified; the hospitalizationrate was 19.6%. Among hospitalizedpatients, the mortality rate was 9.1%.The mean (± standard deviation) treatmentcost for an inpatient episode of CAP (includingall inpatient and outpatient medicalcare) was $10 227 ± $15 342. The per-episodecosts for inpatients that died duringhospitalization were higher than forpatients who were discharged from the hospitalalive ($15 822 ± $26 541 vs $9595 ±$13 641). For outpatient treatment of CAP,the mean per-episode cost was $466 ±$1038.11
The results of the analysis by Colice andcolleagues11 clearly demonstrate the highcosts associated with inpatient treatment ofCAP. Targeted, cost-effective treatments forCAP at the onset of disease can have a significantimpact on the subsequent clinicaland economic consequences. Therefore,continued efforts are being made to manageCAP patients more efficiently and effectivelyin the outpatient setting.7
Acute Exacerbations of ChronicBronchitis. Over 11 million noninstitutionalizedadult Americans were diagnosed withchronic bronchitis in 2001, approximately5% of the population.12 Patients with chronicbronchitis typically experience 2 acuteexacerbations per year, at which timeantibiotic therapy is usually instituted.13 It isestimated the total treatment costs forpatients with AECB is more than $1.6 billion,with $1.2 billion of these costs generatedby patients ≥65 years old.14 Further, themajority of the treatment costs (93.7%) forAECB were because of hospital costs.14
An observational study conducted inSpain in 1996-1997 attempted to determinethe total direct costs derived from themanagement of exacerbations of chronicbronchitis and chronic obstructive pulmonarydisease (COPD) by primary careproviders in an ambulatory setting. For 1month, 2414 patients with exacerbatedchronic bronchitis and COPD were followed.A total of 507 patients (21%) experienceda relapse; of these, 161 patients(31.7%) required attention in the emergencyroom and 84 patients (16.5%)required hospital admission. The totaldirect mean cost of all exacerbations was$159; hospitalized patients generated 58%of the total cost. The cost per treatingpatients who did not relapse was $58.70compared with $477.50 in patients withinitial treatment failure.15 This studydemonstrates that the effective managementof patients with AECB in the outpatientsetting is likely to result in significantcost savings.
Hospitalization and Elderly Patients.Hospitalization as a complication of CAPand AECB continues to rise, and the elderlyare the most vulnerable. Although the incidenceof CAP requiring hospitalization is258 per 100 000 people of all ages, it increasesto 962 per 100 000 people aged ≥65years.16 In 1997, Medicare patients hospitalizedwith CAP accounted for 6.2% of admissions(623 718), 6.3% of costs ($4.4 billion),7% of hospital days (4.8 million), 7.4% ofintensive care unit (ICU) days (633 232), and12.3% of hospital deaths (66 044).17 In thisgroup, 1 of 5 cases had a complex course ofillness (admitted to the ICU or requiredmechanical ventilation), and nearly half ofthe hospital costs attributable to hospitalizedCAP ($2.1 billion) were incurred by patientswith these complex courses. For hospitalizedCAP patients aged ≥65 years, the meanhospital length of stay (LOS) and costs perhospital admission were 7.6 days and $6949,respectively. The mean LOS and hospitalcosts increased for patients admitted to theICU (22% of patients; LOS, 11.3 days; costs,$14 294) and those placed on mechanicalventilation (7.4% of patients; LOS, 15.7days; costs, $23 961).17 These findings reinforcethe notion that CAP is a major clinicaland economic problem in the UnitedStates, particularly for the elderly, and theproblem will continue to grow as the agingpopulation rises.
Clinical and Economic Value ofCurrent Treatments for LowerRespiratory Tract Infections
Streptococcus pneumoniae
S pneumoniae
There are many advantages to determininga specific etiologic pathogen in patientswith lower respiratory tract infections(LRTIs). However, this is not typically donein the outpatient setting, with the specificpathogen not identified in one third to onehalf of cases.18 Choosing an antimicrobialagent that is the most cost effective, safe,and specific to probable agents is encouraged.Current recommendations from theInfectious Diseases Society of America(IDSA) for empiric antibiotic selection inCAP are based on severity of illness,pathogen probabilities, resistance patternsof (the mostcommonly implicated pathogen in CAP),and comorbid conditions.19 Current outpatientCAP recommendations from the IDSAcall for the administration of a macrolide,doxycycline, or fluoroquinolone with enhancedactivity against .20 Forpatients who are hospitalized, current IDSAand Canadian Infectious Diseases Societyrecommendations call for the administrationof a fluoroquinolone alone or anextended-spectrum cephalosporin (cefotaximeor ceftriaxone) plus a macrolide.19,20Economic analyses of randomized, clinicaltrials conducted utilizing the current treatmentsfor LRTIs have demonstrated variousresults, sometimes supporting21 and at othertimes contradicting22 these recommendations.
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Health and Economic Outcomes Trialsfor CAP. In a study by Brown and colleagues,21 investigators analyzed aggregatehospital claims data to assess the impact ofinitial antibiotic choice on 30-day mortality,total hospital costs, and hospital LOS forpatients with CAP. In this study, 44 814patients with CAP met the enrollment criteriaand were divided into 5 monotherapygroups (ie, ceftriaxone, other cephalosporins,fluoroquinolones, macrolides, or penicillins)and 4 groups that received dual therapy (ie,one of the agents listed, except macrolides,plus a macrolide). It was determined thatmortality was significantly decreased amongall dual-therapy groups (range, 2.2%-2.9%)when compared with monotherapy groups(range, 4.9%-8.2%; all <.05), and that patientsreceiving dual therapies generallyexperienced a shorter LOS compared withmonotherapy. Among patients with dual therapy,ceftriaxone plus macrolide yielded theshortest LOS and least total hospital chargescompared with monotherapy ( <.001). Inaddition, the use of fluoroquinolones orpenicillins as monotherapy or as part of dualtherapy with macrolides was associated withthe highest total hospital charges and thelongest LOSs. The study concluded that dualtherapy, including macrolides as the secondagent, provided statistically significantdecreases in mortality from CAP, along withadditional data supporting shorter LOSs andlower hospital charges.21 This study supportsCAP guidelines for dual-therapy regimens.
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In a study by Burgess and Lewis,22 a comparisonwas made between 213 hospitalizedpatients with CAP receiving a nonpseudomonal,third-generation cephalosporinwith (n = 116) or without (n = 97) amacrolide. Macrolide use was primarilyerythromycin (66%), whereas others receivedclarithromycin (19%), or oral azithromycin(15%). There were no statistical differencesbetween patients who did and did notreceive a macrolide in terms of comorbid illnesses,LOS (5.2 ± 2.8 vs 5.2 ± 3.4 days),length of intravenous (I.V.) antibiotic therapy(4.4 ± 2.5 vs 4.1 ± 2.3 days), or mortality(0.9% vs 3.1%; = .333). The study authorsconcluded that the addition of a macrolideto a nonpseudomonal, third-generationcephalosporin as initial therapy for the treatmentof hospitalized CAP patients may notbe necessary and that the results of this trialdid not support the use of dual therapy witha macrolide.
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In another study by Drummond and colleagues,23 costs, clinical consequences, andcost effectiveness were evaluated amonghospitalized CAP patients that receivedeither sequential I.V. and oral moxifloxacin(400 mg daily) monotherapy or I.V. and oralco-amoxiclav (AMC) (1.2 g I.V./625 mgoral 3 times daily) with or without clarithromycin(CLA) (500 mg twice daily) for 7 to14 days. Compared with AMC ± CLA, treatmentwith moxifloxacin resulted in morepatients reaching clinical cure 5 to 7 daysposttherapy (93.5% vs 85.2%; 95% confidenceinterval [CI], 3.1-13.6), increasedspeed of response (return to apyrexia, 2 vs 3days; = .008), and a reduction in hospitalstay (7.64 vs 8.45 days). An average cost savingsof 10% was observed in the moxifloxacingroup, mostly because of a shorter length ofhospital stay. In this study, monotherapywith moxifloxacin demonstrated clinicalbenefits and cost effectiveness comparedwith AMC ± CLA for the treatment of CAP.In addition, fluoroquinolone monotherapywas found to be clinically superior and costeffective to dual therapy with a macrolide.
Health and Economic OutcomesTrials in AECB. There are relatively fewstudies that examine economic outcomesof different AECB treatments. Rather, mosttrials include clinical end points (ie, curerates and therapy failure) and resourceutilization end points (ie, hospitalizationsand additional antibiotic use) which couldbe used to conduct a cost-efficacy analysisof the products. Two studies examiningresource utilization end points among differentAECB therapies are describedbelow.
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In a study by Wilson and colleagues,24 theeffectiveness of oral moxifloxacin (400 mgdaily for 5 days) was compared with standardantibiotic therapies (amoxicillin 500mg 3 times daily for 7 days, clarithromycin500 mg twice daily for 7 days, or cefuroxime-axetil 250 mg twice daily for 7 days) inpatients with AECB. Three hundred fifty-fourpatients received moxifloxacin, and 376patients received standard therapy. At 7 to10 days after therapy, clinical success rates(cure plus improvement) were similar formoxifloxacin and the standard therapies inintent-to-treat (ITT) (87.6% vs 83.0%; 95%CI, —0.7 to 9.5) and per-protocol populations(87.2% vs 84.2%; 95% CI, —3.0 to 8.5).Moxifloxacin showed superior clinical curerates compared with standard therapy inboth ITT patients (70.9% vs 62.8%; 95% CI,1.4-14.9) and per-protocol patients (69.7%vs 62.1%; 95% CI, 0.3-15.6), and greater bacteriologicsuccess in microbiologically validpatients (91.5% vs 81.0%; 95% CI, 0.4-22.1).The mean time to the next AECB in patientswho did not require any further antibioticswas significantly longer for patients takingmoxifloxacin (132.8 ± 67.5 days) thanpatients receiving standard therapy (118.0 ±67.9 days; = 0.03). In addition, fewer patientsreceiving moxifloxacin (9.5%) requiredadditional antibiotic therapy than thosepatients receiving standard therapy (15.1%; = .045). The study authors concluded thatmoxifloxacin was equivalent to standardtherapies for clinical success and demonstratedsuperiority to standard therapies forlong-term health outcomes.
An open-label study conducted by Weiss25of 283 patients compared 10 days of therapywith clarithromycin 500 mg twice daily, levofloxacin500 mg once daily, or cefuroximeaxetil 250 mg twice daily for acute bacterialexacerbations of chronic bronchitis (ABECB).Of the 262 clinically assessable patients, clinicalcure occurred in 87.9% (80/91) ofpatients receiving clarithromycin, 87.4%(76/87) of patients receiving levofloxacin,and 79.8% (67/84) of patients receivingcefuroxime axetil; no statistical differencewas observed between treatment groups forrate of cure or improvement. There were nosignificant differences between the groupsin terms of the number of patients whorequired a change in antimicrobial regimento achieve clinical cure, hospitalization, ordiscontinuation due to adverse events. Theauthor concluded that a comparable andhigh rate of clinical cure/improvement wasobserved in patients with ABECB treatedwith 3 different classes of antimicrobials.
Clinical and Economic Value of theKetolide Class in the Treatment ofLower Respiratory Tract Infections
The CAP and AECB trials reviewed previouslydemonstrate both the supportive, andsometimes contradictory, evidence regardingthe use of currently available agents.Further, little evidence exists documentingthe economic outcomes of different AECBtreatment regimens. These issues can makethe economic assessment of treatmentoptions for cost-effectiveness evaluationsdifficult, leading to complex formulary decisions.Any new antibiotic demonstratingsimilar or improved efficacy in the treatmentof CARTIs compared with existingtherapies would be of interest to managedcare formulary decision makers, particularlyif that antibiotic also possessed evidencesupporting its cost effectiveness.
Health Outcomes in CAP and AECBwith Telithromycin.
Of the phase 3 trialsfor telithromycin, 4 trials included a post-trialanalysis of health outcomes measurements.To summarize, the CAP trials witha health outcome component studied 5 or7 days26 or 10 days27 of telithromycin with10 days of clarithromycin; the AECB trialswith a health outcome component compared5 days of telithromycin with 10 daysof clarithromycin28 or amoxicillin/clavulanate.29 The efficacy and safety outcomes ofthese trials were reviewed in the previousarticle by Dr Sbarbaro.
In the CAP trials, information about theuse of additional healthcare resources(beyond those required by protocol) were collectedon healthcare resource utilization casereport forms by investigators at the end oftherapy, at the posttherapy/test of cure visit,and at the late posttherapy visit. Theseresources were documented and then translatedinto expenses in relation to the treatmentsprovided. Protocol-derived healthcareresources included x-rays; ECGs; physicianvisits, tests, and procedures; microbiologicand bacteriologic tests; and measurement ofsafety parameters (ie, hematology, biochemistry,urinalysis). Nonprotocol-derivedhealthcare resources included ER visits; additionalcontact with general practitioners, pulmonaryand infectious disease specialists,community nurses, and other healthcare professionals;healthcare related home contacts;additional ambulatory and inpatient tests andprocedures; hospitalizations related to CAP;and concomitant medications (includingadditional antibiotics) related to respiratorytract infections.
In the AECB trials, both studies capturedAECB-related hospitalizations; in addition,the study with amoxicillin/clavulanatedocumented unscheduled AECB-relatedoutpatient visits, ER visits, additionalrespiratory-related antibiotic therapy, andtime lost from work. In each of these trials,analyses were performed on data collectedfor the ITT population of patients (randomizedpatients who received at least 1 dose ofstudy medication) rather than the per-protocolpopulation (randomized patients whocompleted therapy), as that populationmore closely reflects patients seen in clinicalpractice.
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In the CAP analyses, pooled data from thestudies revealed significantly fewer CAP-relatedhospitalizations for patients treatedwith 7 or 10 days of telithromycin comparedwith clarithromycin (1.2% vs 3.6%; = .017),and the number of CAP-related days spentin the hospital was lower for patients receivingtelithromycin (9 vs 34 hospital days per100 patients).30 Pooled data revealed no differencein the percentage of patients takingtelithromycin (14%) or clarithromycin (17%)who required additional antibiotics.30 In theAECB trials, differences in the percentage ofpatients who had an AECB-related hospitalizationwere seen between telithromycinand amoxicillin/clavulanate (2.5% vs 4.4%)and telithromycin and clarithromycin (0.4%vs 1.4%); however, these differences did notachieve statistical significance.28,31 AECB-relatedER visits were significantly less amongpatients receiving telithromycin thanpatients receiving clarithromycin (0% vs 2.8%; <.01),28 and the number of AECB-relateddays spent in the hospital was lower forpatients receiving telithromycin comparedwith patients receiving amoxicillin/clavulanate(17.5 vs 41.9 hospital days per 100 patients).31
Economic Outcomes with Telithromycin.The cost analyses covered 3 major drivers ofhealthcare resource utilization: hospitalizationcosts; outpatient visit, lab test, and procedurecosts; and medication costs. Studyinvestigators blinded to treatment groupsevaluated whether hospitalizations werecondition-related or not; only hospitalizationsconsidered related to the condition ofinterest were included in the cost analyses.The cost of study medications (telithromycinand comparators) were not calculated atthe time of analysis because of the unavailabilityof public price information fortelithromycin in the United States.
Redbook
For the CAP studies, estimates of costs foroutpatient visits, lab tests, and procedureswere based on the Medicare Resource-basedRelative Value Scale, whereas inpatient hospitalcosts were estimated using the averageper-diem cost rate for short-term hospitals,as published by the American HospitalAssociation during the year in which eachtrial was conducted. When additional antibioticswere warranted, the average wholesaleprice, as published in during theyear of the study, was used.32
For the AECB studies, the study with clarithromycinestimated costs for outpatientand ER visits using the 1999 MedicalExpenditure Panel Survey, and estimatedhospitalization costs using the 2000 NationwideInpatients Sample of the HealthcareCost and Utilization Project.
For both of the CAP analyses and both ofthe AECB analyses, the total average directcosts per patient (excluding study medicationcosts) were lower for the telithromycinversus the competitor product; however,these differences did not achieve statisticalsignificance due to the large variance in cost.In the CAP study examining 10 days oftelithromycin therapy, telithromycin useresulted in a total cost savings per patient of$378 compared with clarithromycinpatients.30 Of this difference, $201 (53%)was due to higher hospitalization costs,whereas the majority of the balance ofcosts were attributable to I.V. antibiotic use(61 days among patients receiving telithromycinvs 93 days among patients receivingclarithromycin).33 In the CAP study examining7 days of telithromycin therapy, telithromycinuse for 7 days resulted in a total costsavings per patient of $419 compared withclarithromycin patients.30 Again, the majorityof this difference (90% or $378) wasbecause of higher hospitalization costs.34
Pooled data of the 7- or 10-day telithromycinregimens in the CAP studies revealedthat most of the additional costs per CAPpatient came from increased hospitalizationdays for patients on comparator therapy.Patients treated with telithromycin had significantlyfewer CAP-related hospitalizationsand spent less total days in the hospital comparedwith patients treated with clarithromycin.Therefore, hospitalization costs fortelithromycin patients were considerablylower than for patients receiving clarithromycin($224 vs $622 per patient, respectively).30 The average per-patient cost ofadditional resource use for telithromycinwas considerably less than that for clarithromycin,with a per-patient savings of $398for telithromycin.30
An indication of the potential financialimpact of these savings can be realized byassuming a 100 000-member health planwith an estimated 2% incidence of CAP(2000 patients with CAP). At a savings of$398 per patient, $796 000 in savings couldbe realized per year for patients receivingtelithromycin in place of clarithromycin inan outpatient setting.
In the AECB study with amoxicillin/clavulanate,telithromycin resulted in fewer hospitalizationsthan amoxicillin/clavulanateamong patients with AECB. This contributedto a cost savings of $304 per patient treatedwith telithromycin compared with amoxicillin/clavulanate.31 In the AECB study withclarithromycin, there were less AECB-relatedand non-AECB respiratory-related hospitalizationsfor patients receiving telithromycincompared with clarithromycin; these differencescontributed to a $54 difference perpatient difference in AECB costs and a $146difference in respiratory-related care costs.28This study also assessed the time lost fromwork because of AECB. In the telithromycingroup only 23% (21/91) of the employedpatients reported lost time, compared with31% (30/98) for clarithromycin use.28 Giventhe prevalence of these LRTIs, such differencesin patient outcomes have the potentialto have a major impact on the total costsassociated with their care.
Conclusion
The true economic cost of pharmaceuticalsincludes far more than the productacquisition cost. By selecting an appropriateagent, clinical outcomes can be improved,which can reduce the overall costs of treatment.Health economic analyses can assistin estimating the overall costs associatedwith a particular pharmaceutical agent.Such models can help health plans analyzeagents considered for formulary placement.The magnitude of the LRTIs, CAP, andAECB, and the empiric nature in which theyare treated make them primary candidatesfor economic evaluation. Targeted, cost-effectivetreatments for both CAP and AECBcan provide significant benefit to a plan andits members.
Many studies have attempted to assessthe clinical impact of initial antibiotic selectionin LRTIs, whereas fewer studies andanalyses have examined the economic outcomesof that decision. In this article,reviews of different CAP and AECB studiesexamining the clinical and economic endpoints of traditional empiric therapiesdemonstrated the ambiguous results thatmany managed care decision makersencounter during antibiotic formulary considerations.Any new antibiotic able todemonstrate similar or improved clinicalend points compared with existing productswhile also possessing economic evidencedemonstrating the cost effectiveness of theproduct would position itself as a strong candidatefor formulary inclusion.
Telithromycin exhibited similar efficacycompared with comparators in CAP andAECB clinical trials. Although telithromycinwas found to be as clinically effective as itscomparators, large cost savings were documentedin groups receiving telithromycintreatment in these studies. Results from 4clinical studies in CAP and AECB with poststudyhealth outcomes utilization analyseshave consistently demonstrated a lower useof health resource utilization in thetelithromycin group versus its comparators.Cost savings have ranged from $146 to $378per patient in AECB and CAP. There isstrong economic evidence from the clinicaltrial data that patients treated initially withtelithromycin can provide economic savingsto a health plan and improved clinical outcomesto its members.
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