The Impact of Stool Consistency on Bowel Movement Satisfaction in Patients With IBS-C or CIC Treated With Linaclotide or Other Medications: Real-World Evidence From the CONTOR Study.

GOALS: This study aimed to characterize the impact of stool consistency on patient-reported bowel movement (BM) satisfaction in patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation, with a focus on linaclotide. BACKGROUND: As new medications for constipation become available, understanding patients' perceptions of treatment effects may help clinicians manage patient expectations and inform clinical decision-making. MATERIALS AND METHODS: Data were derived from the Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform (CONTOR) study from 2 patient-reported 7-day daily BM diaries to create a dataset of 2922 diaries representing 26,524 BMs for 1806 participants. Binary variables were created for: medication(s) used in the past 24 hours and categorization of BMs as loose or watery stools (LoWS), hard or lumpy stools (HoLS), or intermediate (neither LoWS nor HoLS). The relationship between stool consistency, medication use, and BM satisfaction was analyzed using logistic regression with SEs corrected for repeated observations. RESULTS: BMs characterized as intermediate stools and LoWS were satisfactory more often (61.2% and 51.2%, respectively) than HoLS (19.4%). Participants who reported taking linaclotide rated a similar proportion of BMs as satisfactory when described as LoWS (65.6%) or intermediate (64.1%). Linaclotide use was associated with higher odds of BMs being reported as satisfactory compared with nonlinaclotide use (odds ratio: 1.23, P<0.05). CONCLUSIONS: Overall, CONTOR participants were more likely to report BMs classified as LoWS or intermediate as satisfactory, versus HoLS. Participants taking linaclotide were more likely to be satisfied, particularly those reporting LoWS, versus those not taking linaclotide.

Treatment for chronic idiopathic constipation: Use and satisfaction from a nationwide survey of US participants.

BACKGROUND: Chronic idiopathic constipation (CIC) is a disorder of gut-brain interaction characterized by a variety of bowel movement-related and abdominal symptoms. A greater understanding of medication use and satisfaction with symptom control may provide insights to optimize patient care. Therefore, we explored these aspects of the disorder in adults with CIC. METHODS: This study assessed data collected from a large nationwide survey of adult participants in the United States, querying demographics, clinical characteristics, and comorbid conditions, as well as medication use, care-seeking behaviors, and satisfaction with symptom control. Participants were grouped into the CIC cohort if they met Rome IV criteria, with controls matched 1:1 according to age, sex, race, region, and Charlson Comorbidity Index score. All data were self-reported. KEY RESULTS: Two thousand five hundred and thirty-three participants with CIC were matched 1:1 to controls. In the CIC cohort, abdominal pain was the most reported symptom leading to medication use: 15.9% of respondents were receiving a prescription medication in addition to an over-the-counter medication, while 26.3% were taking neither. In addition, only one-third were satisfied with the control of their symptoms; however, satisfaction was significantly higher in respondents taking a prescription medication (p < 0.001). The proportion of reported comorbidities was significantly higher in the CIC cohort versus the control cohort, with chronic pain, anxiety, and depression among the highest (p < 0.001 for all). CONCLUSIONS AND INFERENCES: This study emphasizes the need for better communication regarding prescription medications and their benefits, with the goal of further improving CIC patients' overall symptoms.

The Burden and Treatment of Chronic Constipation Among US Nursing Home Residents.

OBJECTIVE: To evaluate the burden of chronic constipation (CC) and the use of drugs to treat constipation (DTC) in 2 complementary data sources. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: US nursing home residents aged ≥65 years with CC. METHODS: We conducted 2 retrospective cohort studies in parallel using (1) 2016 electronic health record (EHR) data from 126 nursing homes and (2) 2014-2016 Medicare claims, each linked with the Minimum Data Set (MDS). CC was defined as (1) the MDS constipation indicator and/or (2) chronic DTC use. We described the prevalence and incidence rate of CC and the use of DTC. RESULTS: In the EHR cohort, we identified 25,739 residents (71.8%) with CC during 2016. Among residents with prevalent CC, 37% received a DTC, with an average duration of use of 19 days per resident-month during follow-up. The most frequently prescribed DTC classes included osmotic (22.6%), stimulant (20.9%), and emollient (17.9%) laxatives. In the Medicare cohort, a total of 245,578 residents (37.5%) had CC. Among residents with prevalent CC, 59% received a DTC and slightly more than half (55%) were prescribed an osmotic laxative. Duration of use was shorter (10 days per resident-month) in the Medicare (vs EHR) cohort. CONCLUSIONS AND IMPLICATIONS: The burden of CC is high among nursing home residents. The differences in the estimates between the EHR and Medicare data confirm the importance of using secondary data sources that include over-the-counter drugs and other treatments unobservable in Medicare Part D claims to assess the burden of CC and DTC use in this population.

Calibrating longitudinal models to cross-sectional data: the effect of temporal changes in health practices.

OBJECTIVES: To assess the impact of simulating temporal changes in health-care practice patterns when calibrating longitudinal models to cross-sectional data. METHODS: A Markov model of cervical cancer was calibrated to recent age-specific US data on the prevalence of cervical abnormalities, cervical cancer incidence, and related mortality. The impact of failing to account for temporal changes in screening practices was assessed by comparing results from 1) a conventional calibration that incorrectly assumed that all women had been exposed to current screening practices in the past and 2) an historically accurate calibration that reflected the fact that US women 65 years of age and older had not received currently available screening practices at younger ages. RESULTS: The parameter set derived from conventional calibration produced a cervical cancer incidence rate of 13.4 per 100,000 among women aged 65 years and older, which is equal to the target end point. However, when this parameter set was used in the model to simulate the effects of historically correct screening, cervical incidence and related mortality in the 65 years and older age group were overestimated by 18% and 47%, respectively. Finally, when the parameter set was correctly calibrated by assuming historical changes in screening in the calibration process, excellent calibration to both incidence and mortality was obtained. CONCLUSIONS: Calibrating longitudinal models to cross-sectional data without accounting for temporal changes in clinical practice may result in a parameter set that is not as optimized as it appears and may lead to bias in evaluating the effectiveness of interventions.

Lessons learned: Chronic idiopathic constipation patient experiences with over-the-counter medications.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a prevalent functional gastrointestinal disorder diagnosed based on patient-reported symptoms and the absence of structural gastrointestinal abnormalities. Individuals with CIC typically institute dietary changes and use stool softeners or over-the-counter (OTC) laxatives, possibly at the direction of a healthcare provider, before prescription medications for CIC are initiated. Although highly prevalent, there is limited information regarding CIC patient experiences with OTC medications. METHODS: This post-hoc analysis used patient-reported data from a questionnaire administered during patient screening for a prospective linaclotide Phase 3b clinical trial in patients with CIC (N = 1482 screened). The questionnaire asked patients to report their experiences with OTC CIC medications over the preceding 6 months. RESULTS: Among patients with screening responses (N = 1423), most were female (85%) and white (66%), with a mean age of 48.9 years. A high proportion of patients had used one or more OTC medications (70% had ≥1 OTC; 19% had ≥3 OTCs), with the majority being bisacodyl (33%) and polyethylene glycol (30%). The most commonly cited reason for stopping an OTC medication was insufficient symptom relief (17-40%). The majority of patients taking OTC medications reported no or little satisfaction with the medication's effect on their constipation (62%) and CIC-specific abdominal symptoms (78%). Many patients had little to no confidence in bowel movement (BM) frequency after taking OTC medications and their confidence in their ability to predict BM timing was also low (49-81% not at all confident). CONCLUSIONS: Treatment effects on individual CIC symptoms, predictability of bowel habits, and satisfaction with treatment are all important factors for healthcare providers and patients to consider when establishing an effective treatment regimen for CIC. TRIAL REGISTRATION NUMBER: NCT01642914.

Budgetary impact of treatment with adjuvant imatinib for 1 year following surgical resection of Kit-positive localized gastrointestinal stromal tumors.

BACKGROUND: Imatinib mesylate, an orally administered kinase inhibitor that targets the Kit (CD117) protein, currently has 10 approved indications including treatment of chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GIST). Treatment with adjuvant imatinib following surgical resection of localized Kit-positive GIST, the most recent FDA-approved indication (December 2008), has been shown to significantly improve recurrence-free survival (RFS) compared with surgical resection alone. Although adjuvant imatinib has proven effective in clinical trials, it is important to consider the economic impact to health plans of introducing imatinib in accordance with its new labeled indication. OBJECTIVE: To evaluate the budgetary impact over a 3-year time horizon of treating patients with localized Kit-positive GIST with 1 year of adjuvant imatinib following surgical resection. METHODS: A Markov model was developed to predict patients' transitions across health states defined by initial treatment (surgical resection followed by adjuvant imatinib 400 milligrams [mg] daily versus surgical resection alone), recurrence, and progression. Treatments for a first recurrence were (a) imatinib 400 mg daily for recurrences following resection only or after completion of 1 year of treatment with imatinib 400 mg daily and (b) imatinib 800 mg daily for recurrence during active treatment with imatinib 400 mg daily. Treatments for further progression were imatinib 800 mg daily, sunitinib, or best supportive care (BSC) following imatinib 400 mg per day, and sunitinib or BSC following imatinib 800 mg daily. Recurrence rates were derived from the American College of Surgeons Oncology Group (ACOSOG) Z9001 clinical trial, which compared 1 year of adjuvant imatinib following surgical resection with surgical resection only. The total number of patients with localized and surgically resected GIST (incidence rate of 0.36 per 100,000) was estimated from epidemiologic studies of GIST. Uptake of treatment with imatinib was estimated from unpublished data from qualitative market research funded by the study sponsor. The uptake rate assumptions reflected both (a) the percentage of patients with Kitpositive disease and (b) the percentage of clinically eligible patients who would use imatinib. Costs were estimated by combining unit costs from published sources with expected resource utilization based on the clinical trial publication and National Comprehensive Cancer Network guidelines on the treatment of patients with GIST. To obtain estimates of the budgetary impact, we compared estimated health care costs with versus without adjuvant imatinib, where health care costs with imatinib reflected the costs of treatment minus cost offsets associated with delayed or avoided recurrence or progression. All "with" scenarios assumed no additional uses other than surgically resected localized Kit-positive GIST (i.e., no change in off-label use of imatinib). The budgetary impact was estimated for the first 3 years after the introduction of adjuvant imatinib in accordance with its new labeled indication in a hypothetical plan population of 10 million persons. Results were calculated both as total budgetary impact and as per member per month (PMPM) cost in 2009 dollars. Sensitivity analyses were performed to test the robustness of model results to changes in parameter estimates. RESULTS: The model predicted 36 incident resected GIST cases per year in a health plan of 10 million members. The estimated counts of cases treated with adjuvant imatinib were 10.8, 16.2, and 21.6 in the first, second, and third years after introduction, respectively, with the annual increases attributable to changes in the proportion of patients with resected GIST assumed to use imatinib (30% in year 1, rising to 45% in year 2 and 60% in year 3). The model predicted that treatment of these cases with imatinib will increase pharmacy costs by an additional $505,144 in the first year, $757,717 in the second year, and $1,010,289 in the third year. Increased resource use associated with monitoring patients during and after treatment with adjuvant imatinib would cost an additional $21,564, $38,145, and $56,605 in the first, second, and third years, respectively. Recurrence would be avoided or delayed in 7 patients over the 3-year period. Avoided or delayed recurrences would result in cost offsets of $61,583 in the first year, $156,702 in the second year, and $233,849 in the third year. The net budgetary impact was estimated to be $465,126 in the first year (less than $0.01 PMPM), $639,159 in the second year ($0.01 PMPM), and $833,044 in the third year ($0.01 PMPM). Results of sensitivity analyses indicated that the budgetary impact in the third year is most sensitive to changes in the price of adjuvant imatinib and recurrence rates. CONCLUSIONS: The model predicted that the introduction of adjuvant imatinib for treatment of surgically resected, localized, Kit-positive GIST will lead to a net budgetary impact of $0.01 PMPM in the third year after introduction assuming change in use only in accordance with the new labeled indication. Approximately 11.7%-21.9% of the cost of adjuvant imatinib is offset by the reduction in costs associated with GIST recurrence.

Comprehensive assessment of patients with irritable bowel syndrome with constipation and chronic idiopathic constipation using deterministically linked administrative claims and patient-reported data: the Chronic Constipation and IBS-C Treatment and Outcomes Real-World Research Platform (CONTOR).

AIMS: To characterize a US population of patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) using CONTOR, a real-world longitudinal research platform that deterministically linked administrative claims data with patient-reported outcomes data among patients with these conditions. METHODS: Patients with IBS-C or CIC were identified using diagnosis and treatment codes from administrative claims. Potential respondents received a mailed survey followed by 12 monthly online follow-up surveys and 2 mailed diaries. Surveys collected symptom severity, treatment use, quality of life, productivity, and condition/treatment history. Comorbidities and healthcare costs/utilization were captured from claims data. Diaries collected symptoms, treatments, and clinical outcomes at baseline and 12 months. Data were linked to create a patient-centric research platform. RESULTS: Baseline surveys were returned by 2,052 respondents (16.8% response rate) and retention rates throughout the study were high (64.8%-70.8%). Most participants reported burdensome symptoms despite having complex treatment histories that included multiple treatments over many years. More than half (55.3%) were dissatisfied with their treatment regimen; however, a higher proportion of those treated with prescription medications were satisfied. LIMITATIONS: The study sample may have been biased by patients with difficult-to-treat symptoms as a result of prior authorization processes for IBS-C/CIC prescriptions. Results may not be generalizable to uninsured or older populations because all participants had commercial insurance coverage. CONCLUSIONS: By combining administrative claims and patient-reported data over time, CONTOR afforded a deeper understanding of the IBS-C/CIC patient experience than could be achieved with 1 data source alone; for example, participants self-reported burdensome symptoms and treatment dissatisfaction despite making few treatment changes, highlighting an opportunity to improve patient management. This patient-centric approach to understanding real-world experience and management of a chronic condition could be leveraged for other conditions in which the patient experience is not adequately captured by standardized data sources.

Budgetary impact of varenicline in smoking cessation in the United Kingdom.

OBJECTIVES: To estimate the budgetary impact of varenicline in the United Kingdom (UK) in the first 5 years after its introduction to the smoking-cessation aid market, from the National Health Service (NHS) pharmacy perspective. METHODS: The economic impact of varenicline to the national health budget is estimated in a population of current, former, and new smokers. The analyses are based on data from a variety of secondary sources including national health data, clinical trials, and meta-analyses of smoking-cessation aids. The number of patients seeking aid and the treatment patterns are estimated using 2004 national health surveys, costs for medications from national prescription drug pricing tariffs, and efficacy of the various smoking-cessation aids from clinical trial data. Sensitivity analyses were performed to evaluate the impact of varying the patient parameters and costs. RESULTS: Model estimates suggest that the budgetary impact of varenicline would be 3.6 million pound in the second year after its introduction, with a 95% confidence interval of 0.63 to 7.2 million pound, and a resultant increase of 0.05% to the total NHS pharmacy budget. The model predicts that the addition of varenicline to the market would result in an additional 162,000 successful smoking-cessation attempts and 103,000 fewer smokers over 5 years, when compared to the world without varenicline. CONCLUSION: The introduction of varenicline is likely to result in greater numbers of individuals succeeding at smoking cessation, with an approximately 3.6 million pound (0.05%) increase in the NHS pharmacy budget.

Cost-effectiveness of intensive atorvastatin therapy in secondary cardiovascular prevention in the United Kingdom, Spain, and Germany, based on the Treating to New Targets study.

The Treating to New Targets (TNT) clinical trial found that intensive 80 mg atorvastatin (A80) treatment reduced cardiovascular events by 22% when compared to 10 mg atorvastatin (A10) treatment. We evaluated the cost-effectiveness of intensive A80 vs A10 treatment in the United Kingdom (UK), Spain, and Germany. A lifetime Markov model was developed to predict cardiovascular disease-related events, costs, survival, and quality-adjusted life-years (QALYs). Treatment-specific event probabilities were estimated from the TNT clinical trial. Post-event survival, health-related quality of life, and country-specific medical-care costs were estimated using published sources. Intensive treatment with A80 increased both the per-patient QALYs and corresponding costs of care, when compared to the A10 treatment, in all three countries. The incremental cost per QALY gained was 9,500, 21,000, and 15,000 in the UK, Spain, and Germany, respectively. Intensive A80 treatment is estimated to be cost-effective when compared to A10 treatment in secondary cardiovascular prevention.

Economic evaluation of linaclotide for the treatment of adult patients with irritable bowel syndrome with constipation in the United States.

OBJECTIVES: To use techniques of decision-analytic modeling to evaluate the effectiveness and costs of linaclotide vs lubiprostone in the treatment of adult patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Using model inputs derived from published literature, linaclotide Phase III trial data and a physician survey, a decision-tree model was constructed. Response to therapy was defined as (1) a ≥ 14-point increase from baseline in IBS-Quality-of-Life (IBS-QoL) questionnaire overall score at week 12 or (2) one of the top two responses (moderately/significantly relieved) on a 7-point IBS symptom relief question in ≥ 2 of 3 months. Patients who do not respond to therapy are assumed to fail therapy and accrue costs associated with a treatment failure. Model time horizon is aligned with clinical trial duration of 12 weeks. Model outputs include number of responders, quality-adjusted life-years (QALYs), and total costs (including direct and indirect). Both one-way and probabilistic sensitivity analyses were conducted. RESULTS: Treatment for IBS-C with linaclotide produced more responders than lubiprostone for both response definitions (19.3% vs 13.0% and 61.8% vs 57.2% for IBS-QoL and symptom relief, respectively), lower per-patient costs ($803 vs $911 and $977 vs $1056), and higher QALYs (0.1921 vs 0.1917 and 0.1909 vs 0.1894) over the 12-week time horizon. Results were similar for most one-way sensitivity analyses. In probabilistic sensitivity analyses, the majority of simulations resulted in linaclotide having higher treatment response rates and lower per-patient costs. LIMITATIONS: There are no available head-to-head trials that compare linaclotide with lubiprostone; therefore, placebo-adjusted estimates of relative efficacy were derived for model inputs. The time horizon for this model is relatively short, as it was limited to the duration of available clinical trial data. CONCLUSIONS: Linaclotide was found to be a less costly option vs lubiprostone for the treatment of adult patients with IBS-C.

Outpatient treatment of venous thromboembolism with low-molecular-weight heparin: an economic evaluation.

BACKGROUND: The development of low-molecular-weight heparins (LMWHs) has made it possible to shift treatment of deep vein thrombosis (DVT) from inpatient to outpatient settings, thereby saving costs and improving patient quality of life. OBJECTIVE: To quantify the economic benefits of early discharge of patients treated for DVT with LMWH using data pooled from multiple healthcare plans. METHODS: Data sources were integrated medical and pharmacy claims paid by 37 US health plans (the PharMetrics Integrated Outcomes Database, PharMetrics, Inc., Watertown, MA). Hospitalized patients discharged with a diagnosis of DVT were selected and grouped according to the anticoagulation therapy they received after discharge. Outcomes and costs of DVT treatment were assessed over a 1-year period. RESULTS: Patients discharged on the LMWH enoxaparin and warfarin spent 2.6 fewer days in the hospital than those discharged on warfarin alone (P< .0001), resulting in cost savings of $1911 per patient. Mean costs of outpatient management of DVT, including pharmacy and medical services, were $901 higher in the enoxaparin/warfarin cohort, but rate of readmission was lower (6.7% versus 9.0%; P < .05) and hence subsequent inpatient costs were reduced by $140 per patient. Total cost savings in the enoxaparin/warfarin cohort, net of higher outpatient costs, were $1151 per patient. CONCLUSIONS: Outpatient anticoagulation therapy for DVT with enoxaparin and warfarin is associated with earlier hospital discharge, fewer readmissions, and lower total DVT-related costs compared with warfarin monotherapy.

Use of managed care claims data in the risk assessment of venous thromboembolism in outpatients.

BACKGROUND: Deep vein thrombosis (DVT) is a complication of immobilizing illness in both inpatient and outpatient settings and can lead to serious complications such as pulmonary embolism (PE). DVT and PE are collectively referred to as venous thromboembolism. OBJECTIVE: To develop DVT and PE risk assessment models that can be used in office-based practice and for population-based disease management efforts. METHODS: Data were culled from integrated medical and pharmacy claims paid by 37 health plans in the United States (the PharMetrics Integrated Outcomes Database, PharMetrics Inc., Watertown, MA), and included information on adult plan members enrolled during 1998 and 1999. Patients hospitalized for DVT or PE in 1999 were identified, and potential risk factors were assessed by reviewing claims for the entire study population in 1998 to document prior DVT or immobilizing illness. The contribution of each potential risk factor to the probability of the occurrence of DVT or PE was determined by means of multiple logistic regression analysis. A risk-scoring algorithm based on regression coefficients was then developed. RESULTS: Fifty-two percent of the study population of 2.8 million plan members were women. DVT or PE occurred in 1330 of those 2.8 million individuals (47 per 100,000). Logistic regression results confirmed the role of risk factors previously reported in the literature and revealed additional risk factors that have not been reported previously, including diabetes, renal failure, rheumatoid arthritis, cellulitis, use of warfarin, use of systemic corticosteroids, and use of potassium chloride. When risk scores were applied to the study population, the 1% identified as being at highest risk had a probability for the development of venous thromboembolism that was 10 times greater than that of the population average. CONCLUSIONS: This study confirms the feasibility of using managed care claims data to develop a risk assessment tool for venous thromboembolism that can be used in office-based practice and for population-based disease management.

Primary vs secondary prophylaxis with pegfilgrastim for the reduction of febrile neutropenia risk in patients receiving chemotherapy for non-Hodgkin's lymphoma: cost-effectiveness analyses.

OBJECTIVE: Evaluate the cost-effectiveness of primary vs secondary prophylaxis (PP vs SP) with pegfilgrastim to reduce the risk of febrile neutropenia (FN) in Non-Hodgkin's Lymphoma (NHL) patients receiving myelosuppressive chemotherapy from a US payer perspective. METHODS: A Markov model was used to compare PP vs SP with pegfilgrastim in a cohort of patients receiving six cycles of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) or CHOP plus rituximab (CHOP-R) chemotherapy. Model inputs, including efficacy of pegfilgrastim in reducing risk of FN and costs, were estimated from publicly available sources and peer-reviewed publications. Incremental cost-effectiveness was evaluated in terms of net cost per life-year saved (LYS), per quality-adjusted life-year (QALY) gained, and per FN event avoided over a lifetime horizon. Deterministic and probabilistic analyses were performed to assess sensitivity and robustness of results. RESULTS: Lifetime costs for PP were $5000 greater than for SP; however, PP was associated with fewer FN events and more LYs and QALYs gained vs SP. Incremental cost-effectiveness ratios (ICERs) for PP vs SP for CHOP were $13,400 per FN event avoided, $29,500 per QALY gained, and $25,800 per LYS. CHOP-R results were similar ($15,000 per FN event avoided, $33,000 per QALY gained, and $28,900 per LYS). Results were most sensitive to baseline FN risk, cost per FN episode, and odds ratio for reduced relative dose intensity due to prior FN event. PP was cost-effective vs SP in 85% of simulations at a $50,000 per QALY threshold. LIMITATIONS: In the absence of NHL-specific data, estimates for pegfilgrastim efficacy and relative risk reduction of FN were based on available data for neoadjuvant TAC in patients with breast cancer. Baseline risks of FN for CHOP and CHOP-R were assumed to be equivalent. CONCLUSIONS: PP with pegfilgrastim is cost-effective compared to SP with pegfilgrastim in NHL patients receiving CHOP or CHOP-R.

Cost-effectiveness of 3-years of adjuvant imatinib in gastrointestinal stromal tumors (GIST) in the United States.

BACKGROUND: Recent clinical trial data have demonstrated that 3 years vs 1 year of adjuvant imatinib therapy for patients with surgically resected Kit+ Gastrointestinal Stromal Tumors (GIST) leads to a significant improvement in recurrence-free survival and overall survival. This study assesses the cost-effectiveness of treating patients with 3 years vs 1 year of imatinib from a US payer's perspective. METHODS: A Markov model was developed to predict GIST recurrence and treatment costs. Patients enter the model after surgery and transition among three health states: free of recurrence, recurrence, and death. Recurrence, mortality, costs, and utilities were derived from clinical trial and published literature. Expected costs and quality-adjusted life years (QALYs) were estimated and discounted at 3%/year. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Patients receiving 3 years of imatinib had higher QALYs (8.53 vs 7.18) than those receiving 1 year of imatinib. Total lifetime per-patient cost was $302,100 for 3 years vs $217,800 for 1 year of imatinib. Incremental cost effectiveness ratio of 3 years vs 1 year of imatinib was $62,600/QALY. Model results were sensitive to long-term rate of GIST recurrence (beyond 5 years) and cost of imatinib. At a threshold of $100,000/QALY, 3 years vs 1 year of imatinib was cost-effective in 100% of simulations. LIMITATIONS: The model is a simplified representation of disease natural history and may not account for all possible health states and complications associated with disease. Resource utilization on treatment was estimated using the resource use data from previous trials, therefore calculated medical costs might be over-estimated compared to the real-world setting. CONCLUSIONS: Model results suggest that treatment with 3 years vs 1 year of imatinib is cost-effective at a $100,000/QALY threshold. Clinical and economic results suggest treating surgically resected Kit+ GIST patients with 3 years of imatinib would result in improved quality-adjusted survival.

Incorporating calibrated model parameters into sensitivity analyses: deterministic and probabilistic approaches.

OBJECTIVE: The aim of this study was to examine how calibration uncertainty affects the overall uncertainty of a mathematical model and to evaluate potential drivers of calibration uncertainty. METHODS: A lifetime Markov model of the natural history of human papillomavirus (HPV) infection and cervical disease was developed to assess the cost effectiveness of a hypothetical HPV vaccine. Published data on cervical cancer incidence and mortality and prevalence of pre-cursor lesions were used as endpoints to calibrate the age- and HPV-type-specific transition probabilities between health states using the Nelder-Mead simplex method of calibration. A conventional probabilistic sensitivity analysis (PSA) was performed to assess uncertainty in vaccine efficacy, cost and utility estimates. To quantify the uncertainty around calibrated transition probabilities, a second PSA (calibration PSA) was performed using 25 distinct combinations of objective functions and starting simplexes. RESULTS: The initial calibration produced an incremental cost-effectiveness ratio (ICER) of $US 4300 per QALY for vaccination compared with no vaccination, and the conventional PSA gave a 95% credible interval of dominant to $US 9800 around this estimate (2005 values). The 95% credible interval for the ICERs in the calibration PSA ranged from $US 1000 to $US 37,700. CONCLUSIONS: Compared with a conventional PSA, the calibration PSA results reveal a greater level of uncertainty in cost-effectiveness results. Sensitivity analyses around model calibration should be performed to account for uncertainty arising from the calibration process.

Comparative cost-effectiveness of stereotactic body radiation therapy versus intensity-modulated and proton radiation therapy for localized prostate cancer.

OBJECTIVE: To determine the cost-effectiveness of several external beam radiation treatment modalities for the treatment of patients with localized prostate cancer. METHODS: A lifetime Markov model incorporated the probabilities of experiencing treatment-related long-term toxicity or death. Toxicity probabilities were derived from published sources using meta-analytical techniques. Utilities and costs in the model were obtained from publicly available secondary sources. The model calculated quality-adjusted life expectancy and expected lifetime cost per patient, and derived ratios of incremental cost per quality-adjusted life year (QALY) gained between treatments. Analyses were conducted from both payer and societal perspectives. One-way and probabilistic sensitivity analyses were performed. RESULTS: Compared to intensity-modulated radiation therapy (IMRT) and proton beam therapy (PT), stereotactic body radiation therapy (SBRT) was less costly and resulted in more QALYs. Sensitivity analyses showed that the conclusions in the base-case scenario were robust with respect to variations in toxicity and cost parameters consistent with available evidence. At a threshold of $50,000/QALY, SBRT was cost-effective in 75% and 94% of probabilistic simulations compared to IMRT and PT, respectively, from a payer perspective. From a societal perspective, SBRT was cost-effective in 75% and 96% of simulations compared to IMRT and PT, respectively, at a threshold of $50,000/QALY. In threshold analyses, SBRT was less expensive with better outcomes compared to IMRT at toxicity rates 23% greater than the SBRT base-case rates. CONCLUSION: Based on the assumption that each treatment modality results in equivalent long-term efficacy, SBRT is a cost-effective strategy resulting in improved quality-adjusted survival compared to IMRT and PT for the treatment of localized prostate cancer.

Methods of model calibration: observations from a mathematical model of cervical cancer.

BACKGROUND: Mathematical models are commonly used to predict future benefits of new therapies or interventions in the healthcare setting. The reliability of model results is greatly dependent on accuracy of model inputs but on occasion, data sources may not provide all the required inputs. Therefore, calibration of model inputs to epidemiological endpoints informed by existing data can be a useful tool to ensure credibility of the results. OBJECTIVE: To compare different computational methods of calibrating a Markov model to US data. METHODS: We developed a Markov model that simulates the natural history of human papillomavirus (HPV) infection and subsequent cervical disease in the US. Because the model consists of numerous transition probabilities that cannot be directly estimated from data, calibration to multiple disease endpoints was required to ensure its predictive validity. Goodness of fit was measured as the mean percentage deviation of model-predicted endpoints from target estimates. During the calibration process we used the manual, random and Nelder-Mead calibration methods. RESULTS: The Nelder-Mead and manual calibration methods achieved the best fit, with mean deviations of 7% and 10%, respectively. Nelder-Mead accomplished this result with substantially less analyst time than the manual method, but required more intensive computing capability. The random search method achieved a mean deviation of 39%, which we considered unacceptable despite the ease of implementation of that method. CONCLUSIONS: The Nelder-Mead and manual techniques may be preferable calibration methods based on both performance and efficiency, provided that sufficient resources are available.

Cost effectiveness of intensive lipid-lowering treatment for patients with congestive heart failure and coronary heart disease in the US.

BACKGROUND: A recent study found fewer hospitalizations for congestive heart failure (CHF) patients receiving high-dose versus low-dose statin therapy. OBJECTIVE: To examine the cost effectiveness of high-dose versus low-dose statin therapy in CHF patients. METHODS: Two scenarios (literature-based [base-case scenario] vs trial-based post-event mortality [alternative scenario]) assessed the cost effectiveness of atorvastatin 80 mg/day (A80) versus atorvastatin 10 mg/day (A10) in patients with both CHF and coronary heart disease (CHD) [CHF/CHD], using a lifetime Markov model. The model predicts treatment-specific probabilities of major and minor cardiovascular events and death, based on clinical trial data. The quality of life and costs were literature based. Measures included costs per life-year saved (LYS) and QALY gained. Health consequences and costs were discounted at 3.0% annually. Analyses were conducted from the payer perspective and valued in $US, year 2006-7 values. RESULTS: Literature-based mortality estimates (base case) increased life-years and QALYs for A80 compared with A10 (incremental cost-effectiveness ratios [ICERs]: $US9600 per LYS; $US13 600 per QALY). At a willingness to pay of $US100 000 per QALY, A80 was cost effective in 80% of simulations. A10 dominated A80 when using trial-based mortality estimates (alternative scenario). At a willingness to pay of $US100 000 per QALY, A80 was cost effective in 48% of simulations. CONCLUSIONS: Intensive A80 treatment may be cost effective versus A10 in cardiovascular prevention in CHF/CHD patients in the US, due to projected gains in life expectancy and health-related quality of life. However, the results are highly sensitive to assumptions about the mortality rate in the model. When using the mortality rate observed in the trial, A10 dominates A80.

Does Type of Tumor Histology Impact Survival among Patients with Stage IIIB/IV Non-Small Cell Lung Cancer Treated with First-Line Doublet Chemotherapy?

Chemotherapy regimens may have differential efficacy by histology in nonsmall cell lung cancer (NSCLC). We examined the impact of histology on survival of patients (N = 2,644) with stage IIIB/IV NSCLC who received first-line cisplatin/carboplatin plus gemcitabine (C/C+G) and cisplatin/carboplatin plus a taxane (C/C+T) identified retrospectively in the SEER cancer registry (1997-2002). Patients with squamous and nonsquamous cell carcinoma survived 8.5 months and 8.1 months, respectively (P = .018). No statistically significant difference was observed in survival between C/C+G and C/C+T in both histologies. Adjusting for clinical and demographic characteristics, the effect of treatment regimen on survival did not differ by histology (P for interaction = .257). There was no statistically significant difference in hazard of death by histology in both groups. These results contrast the predictive role of histology and improved survival outcomes observed for cisplatin-pemetrexed regimens in advanced nonsquamous NSCLC.