The clinical, economic, and humanistic burden of treatments for exocrine pancreatic insufficiency and cost-effectiveness of treatments: A systematic literature review.

BACKGROUND: To examine the burden of exocrine pancreatic insufficiency (EPI), specifically the clinical impact of EPI on patients, their quality of life (QoL) and the cost-effectiveness of existing treatments. METHODS: A systematic literature review was conducted using key search terms for the clinical, economic, and humanistic burden. Databases were searched from 2010 to 2022, with articles screened independently by 2 reviewers at abstract and full-text stage against pre-defined eligibility criteria. RESULTS: Seventy-one publications were identified that reported relevant clinical, humanistic, and economic data. Prevalence and incidence of EPI varied across identified studies; EPI appears to be especially prevalent as a comorbid condition in patients with cystic fibrosis. EPI has a large impact on QoL, with lower QoL scores in patients with EPI compared with those without EPI. The instruments used to assess QoL, however, were inconsistent across studies. Where reported, economic burden studies highlighted that patients with EPI have higher healthcare resource utilization compared with those without, with costs increasing with disease severity. CONCLUSION: This systematic literature review highlights that patients with EPI have higher treatment costs and lower QoL scores than patients without EPI. The prevalence of EPI as a comorbid condition is high, particularly in patients with cystic fibrosis.

Matching-adjusted indirect comparison: entrectinib versus crizotinib in ROS1 fusion-positive non-small cell lung cancer.

Aim: To perform indirect treatment comparisons of entrectinib versus alternative ROS1 fusion-positive non-small cell lung cancer treatments. Methods: Relevant studies with crizotinib and chemotherapy as comparators of interest identified by systematic literature review were selected for matching-adjusted indirect comparison by feasibility assessment. Matching was based on known prognostic/predictive factors and scenario analyses were used for unreported confounders in comparator trials. Results: Entrectinib yielded significantly better responses versus crizotinib in all scenarios (odds ratio [OR]: 2.43-2.74). Overall survival (hazard ratio: 0.47-0.61) and adverse event-related discontinuation (OR: 0.79-0.90) favored entrectinib. Progression-free survival was similar across treatments, except in one scenario. Conclusion: These results suggested improved outcomes with entrectinib versus crizotinib/chemotherapy and may help to make better informed treatment decisions.

Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy.

Aim: To conduct a systematic review and meta-analysis feasibility of clinical, quality of life and economic evidence for neurotrophic tropomyosin-related receptor tyrosine kinases (NTRK) inhibitors in patients with NTRK gene fusion-positive tumors. Materials & methods: Databases were searched for studies on NTRK inhibitors in adult and pediatric patients. Results: 27 publications reported clinical data for seven interventions. Efficacy/safety data were available for two interventions only. Four trials each reported data for larotrectinib and entrectinib with pooled analyses reporting objective response rates of 75% (95% CI: 61-85) and 57.4% (43.2-70.8), respectively. No publications reported economic or quality of life evidence. Conclusion: Preliminary data demonstrate that NTRK inhibitors are well tolerated and show impressive clinical benefit; corroboration of existing studies and real-world data are required.

Comparative Efficacy of Second- and Subsequent-line Treatments for Metastatic NSCLC: A Fractional Polynomials Network Meta-analysis of Cancer Immunotherapies.

BACKGROUND: Extended onset of treatment effect and longer-term survival with anti-programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunotherapies, atezolizumab, nivolumab, and pembrolizumab, have changed the landscape of second- or subsequent-line (2L+) treatments for adults with non-small-cell lung cancer (NSCLC). This systematic literature review included phase I to IV randomized, controlled trials of 2L+ NSCLC therapies from MEDLINE, Embase, and secondary sources. MATERIALS AND METHODS: Studies of treatments approved in the European Union or United States had to be in English with ≥ 10 patients per arm. A fractional polynomials network meta-analysis (NMA) was conducted because traditional NMA of hazard ratios does not account for delayed onset of clinical effect or long-term survival observed in PD-L1/PD-1 inhibitor trials. Adjusted analyses accounted for treatment switching in the atezolizumab OAK trial. Expected survival time reflected area under the curve over the time horizon. Expected overall survival (OS) was ranked by median ranking with 95% credible intervals and by surface under the cumulative ranking curve. Of 25,115 screened records, 28 studies were included in the quantitative analyses of OS and progression-free survival. RESULTS: PD-L1/PD-1 inhibitors had comparable expected 5-year OS; all performed better than other treatment options. In unadjusted analyses, surface under the cumulative ranking curve ranked nivolumab first (87.9%), followed by atezolizumab (85.8%) and pembrolizumab (82.8%). Analyses adjusted for patients switching from docetaxel to immunotherapy ranked atezolizumab first (89.6%), followed by nivolumab (86.5%) and pembrolizumab (81.9%). CONCLUSION: This NMA applied an appropriate approach for indirect comparisons, including cancer immunotherapies, and supported robustness of PD-L1/PD-1 immunotherapies for 2L+ treatment of NSCLC.

Cost-effectiveness of second-line atezolizumab in Canada for advanced non-small cell lung cancer (NSCLC).

Aim: To assess the cost-effectiveness in Canada of atezolizumab compared with docetaxel or nivolumab for the treatment of advanced NSCLC after first-line platinum-doublet chemotherapy. Materials and methods: A three-state partitioned-survival model was developed. Clinical inputs were obtained from the phase III OAK trial comparing atezolizumab with docetaxel in patients with advanced NSCLC who progressed after first-line platinum-doublet chemotherapy. Overall survival (OS) and progression-free survival (PFS) were extrapolated beyond the trial period using parametric models. A cure model assuming a 1% cure fraction was fitted to the OS data for atezolizumab. Outcomes for nivolumab were informed by a network meta-analysis (NMA) vs atezolizumab. Resource use and costs were informed by clinical expert opinion and published Canadian sources. Utility values were obtained from the OAK trial. The perspective of the analysis was that of the Canadian publicly-funded healthcare system. The base case time horizon was 10 years, and the discount rate was 1.5% annually for both costs and effects. Scenario analyses were performed to test the robustness of the results and all analyses were performed probabilistically. Results: Atezolizumab demonstrated a quality-adjusted life-year (QALY) gain of 0.60 compared with docetaxel at an incremental cost of $85,073, resulting in an incremental cost-effectiveness ratio (ICER) of $142,074/QALY. Atezolizumab dominated nivolumab (regardless of dosing regimen), based on modest differences in both QALYs and costs. Docetaxel was most likely to be cost effective at willingness-to-pay (WTP) thresholds below $125,000/QALY gained, while atezolizumab was most likely to be cost effective beyond this WTP threshold. In most scenario analyses, the results remained robust to changes in parameters. A reduced time horizon and alternative approaches to the NMA had the greatest impact on cost-effectiveness results. Conclusion: Atezolizumab represents a cost-effective therapeutic option in Canada for the treatment of patients with advanced NSCLC who progress after first-line platinum doublet chemotherapy.

Comparative Effectiveness of Personalized Lifestyle Management Strategies for Cardiovascular Disease Risk Reduction.

BACKGROUND: Evidence shows that healthy diet, exercise, smoking interventions, and stress reduction reduce cardiovascular disease risk. We aimed to compare the effectiveness of these lifestyle interventions for individual risk profiles and determine their rank order in reducing 10-year cardiovascular disease risk. METHODS AND RESULTS: We computed risks using the American College of Cardiology/American Heart Association Pooled Cohort Equations for a variety of individual profiles. Using published literature on risk factor reductions through diverse lifestyle interventions-group therapy for stopping smoking, Mediterranean diet, aerobic exercise (walking), and yoga-we calculated the risk reduction through each of these interventions to determine the strategy associated with the maximum benefit for each profile. Sensitivity analyses were conducted to test the robustness of the results. In the base-case analysis, yoga was associated with the largest 10-year cardiovascular disease risk reductions (maximum absolute reduction 16.7% for the highest-risk individuals). Walking generally ranked second (max 11.4%), followed by Mediterranean diet (max 9.2%), and group therapy for smoking (max 1.6%). If the individual was a current smoker and successfully quit smoking (ie, achieved complete smoking cessation), then stopping smoking yielded the largest reduction. Probabilistic and 1-way sensitivity analysis confirmed the demonstrated trend. CONCLUSIONS: This study reports the comparative effectiveness of several forms of lifestyle modifications and found smoking cessation and yoga to be the most effective forms of cardiovascular disease prevention. Future research should focus on patient adherence to personalized therapies, cost-effectiveness of these strategies, and the potential for enhanced benefit when interventions are performed simultaneously rather than as single measures.

The effectiveness of yoga in modifying risk factors for cardiovascular disease and metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Yoga, a popular mind-body practice, may produce changes in cardiovascular disease (CVD) and metabolic syndrome risk factors. DESIGN: This was a systematic review and random-effects meta-analysis of randomized controlled trials (RCTs). METHODS: Electronic searches of MEDLINE, EMBASE, CINAHL, PsycINFO, and The Cochrane Central Register of Controlled Trials were performed for systematic reviews and RCTs through December 2013. Studies were included if they were English, peer-reviewed, focused on asana-based yoga in adults, and reported relevant outcomes. Two reviewers independently selected articles and assessed quality using Cochrane's Risk of Bias tool. RESULTS: Out of 1404 records, 37 RCTs were included in the systematic review and 32 in the meta-analysis. Compared to non-exercise controls, yoga showed significant improvement for body mass index (-0.77 kg/m(2) (95% confidence interval -1.09 to -0.44)), systolic blood pressure (-5.21 mmHg (-8.01 to -2.42)), low-density lipoprotein cholesterol (-12.14 mg/dl (-21.80 to -2.48)), and high-density lipoprotein cholesterol (3.20 mg/dl (1.86 to 4.54)). Significant changes were seen in body weight (-2.32 kg (-4.33 to -0.37)), diastolic blood pressure (-4.98 mmHg (-7.17 to -2.80)), total cholesterol (-18.48 mg/dl (-29.16 to -7.80)), triglycerides (-25.89 mg/dl (-36.19 to -15.60), and heart rate (-5.27 beats/min (-9.55 to -1.00)), but not fasting blood glucose (-5.91 mg/dl (-16.32 to 4.50)) nor glycosylated hemoglobin (-0.06% Hb (-0.24 to 0.11)). No significant difference was found between yoga and exercise. One study found an impact on smoking abstinence. CONCLUSIONS: There is promising evidence of yoga on improving cardio-metabolic health. Findings are limited by small trial sample sizes, heterogeneity, and moderate quality of RCTs.

Standardised mindfulness-based interventions in healthcare: an overview of systematic reviews and meta-analyses of RCTs.

BACKGROUND: Mindfulness-based therapies are being used in a wide range of common chronic conditions in both treatment and prevention despite lack of consensus about their effectiveness in different patient categories. OBJECTIVE: To systematically review the evidence of effectiveness MBSR and MBCT in different patient categories. METHODS: A systematic review and meta-analysis of systematic reviews of RCTs, using the standardized MBSR or MBCT programs. We used PRISMA guidelines to assess the quality of the included reviews and performed a random effects meta-analysis with main outcome measure Cohen's d. All types of participants were considered. RESULTS: The search produced 187 reviews: 23 were included, covering 115 unique RCTs and 8,683 unique individuals with various conditions. Compared to wait list control and compared to treatment as usual, MBSR and MBCT significantly improved depressive symptoms (d=0.37; 95%CI 0.28 to 0.45, based on 5 reviews, N=2814), anxiety (d=0.49; 95%CI 0.37 to 0.61, based on 4 reviews, N=2525), stress (d=0.51; 95%CI 0.36 to 0.67, based on 2 reviews, N=1570), quality of life (d=0.39; 95%CI 0.08 to 0.70, based on 2 reviews, N=511) and physical functioning (d=0.27; 95%CI 0.12 to 0.42, based on 3 reviews, N=1015). Limitations include heterogeneity within patient categories, risk of publication bias and limited long-term follow-up in several studies. CONCLUSION: The evidence supports the use of MBSR and MBCT to alleviate symptoms, both mental and physical, in the adjunct treatment of cancer, cardiovascular disease, chronic pain, depression, anxiety disorders and in prevention in healthy adults and children.

Potential bias of instrumental variable analyses for observational comparative effectiveness research.

Instrumental variable analysis is an increasingly popular method in comparative effectiveness research (CER). In theory, the instrument controls for unobserved and observed patient characteristics that affect the outcome. However, the results of instrumental variable analyses in observational settings may be biased if the instrument and outcome are related through an unadjusted third variable: an "instrument-outcome confounder." The authors identified published CER studies that used instrumental variable analysis and searched the literature for potential confounders of the most common instrument-outcome pairs. Of the 187 studies identified, 114 used 1 or more of the 4 most common instrument categories: distance to facility, regional variation, facility variation, and physician variation. Of these, 65 used mortality as an outcome. Potential unadjusted instrument-outcome confounders were observed in all studies, including patient race, socioeconomic status, clinical risk factors, health status, and urban or rural residency; facility and procedure volume; and co-occurring treatments. Only 4 (6%) instrumental variable CER studies considered potential instrument-outcome confounders outside the study data. Many effect estimates may be biased by the failure to adjust for instrument-outcome confounding. The authors caution against overreliance on instrumental variable studies for CER.

Cost-effectiveness of intensive lipid lowering therapy with 80 mg of atorvastatin, versus 10 mg of atorvastatin, for secondary prevention of cardiovascular disease in Canada.

BACKGROUND: The TNT study compared high dose atorvastatin (80 mg) versus moderate atorvastatin (10 mg) treatment in 10,001 patients with stable coronary heart disease (CHD), over 4.9 years. Intensive lipid-lowering with atorvastatin (80 mg) reduced major cardiovascular events by 22%. OBJECTIVES: To assess the cost-effectiveness of intensive lipid-lowering versus moderate lipid lowering treatment from the perspective of the Canadian Ministries of Health. METHODS: A lifetime Markov model was developed to predict cardiovascular (CV) events, costs, survival, and quality-adjusted life years (QALYs) for CHD patients receiving 80 mg versus 10 mg of atorvastatin. Predictions were also made for 10- and 5-year horizons. Treatment-specific event risks were used until five years. Beyond year five, equivalent CV risks were assumed for all patients. Medical-care costs and post-event survival were estimated using Canadian data. Health utility scores were obtained from published studies. Benefits and costs were discounted 5% annually. Probabilistic and deterministic sensitivity analyses were performed. RESULTS: Treatment with atorvastatin (80 mg) over a lifetime horizon resulted in increased costs (Can$16,542 vs. Can$15,365), survival (10.12 vs. 10.03 life years), and QALYs (7.71 vs. 7.61) per patient compared with atorvastatin (10 mg), yielding an incremental cost-effectiveness of Can$12,946 per life year gained and Can$11,969 per QALY. The incremental cost per QALY remained below Can$50,000 in 98.1% of 1000 simulations. Results were robust to variations in event hazard ratios, costs, health utility values, and discount rate. CONCLUSION: Intensive atorvastatin (80 mg) treatment is predicted to be cost-effective versus atorvastatin (10 mg) for CHD patients in Canada.

Cost-effectiveness of magnetic resonance guided focused ultrasound for the treatment of uterine fibroids.

OBJECTIVES: The aim of this study is to evaluate the cost-effectiveness of Magnetic Resonance Guided Focused Ultrasound (MRgFUS) compared with alternative treatments for uterine fibroids in the United States. METHODS: We used techniques of decision analysis and data from secondary sources to develop and estimate an economic model of the management of uterine fibroids among premenopausal women. Patients in the model receive treatment with MRgFUS, uterine artery embolization (UAE), abdominal myomectomy, hysterectomy, or pharmacotherapy. The model predicts total costs (including subsequent procedures) and quality-adjusted life-years (QALYs) for each treatment strategy over a lifetime horizon, discounted at 3 percent, from a societal perspective. Data on treatment efficacy and safety were obtained from published and unpublished studies. Costs (2005 US$) were obtained from an analysis of a large administrative database and other secondary sources. Lost productivity costs were included in the base-case analysis, but excluded in a sensitivity analysis. RESULTS: UAE was associated with the most QALYs (17.39), followed by MRgFUS (17.36), myomectomy (17.31), hysterectomy (17.18), and pharmacotherapy (16.70). Pharmacotherapy was the least costly strategy ($9,200 per patient), followed by hysterectomy ($19,800), MRgFUS ($27,300), UAE ($28,900), and myomectomy ($35,100). Incremental cost-effectiveness ratios (cost per QALY gained) were $21,800 for hysterectomy, $41,400 for MRgFUS, and $54,200 for UAE; myomectomy was more costly and less effective than both MRgFUS and UAE. Results were sensitive to MRgFUS recurrence rates, MRgFUS procedure costs, and assumptions about quality of life following hysterectomy. CONCLUSIONS: Our findings suggest that MRgFUS is in the range of currently accepted criteria for cost-effectiveness, along with hysterectomy and UAE.

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.

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.