GRADE guidance 23: considering cost-effectiveness evidence in moving from evidence to health-related recommendations.

BACKGROUND: This is the 23rd in a series of articles describing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the certainty of evidence and strength of recommendations for systematic reviews, health technology assessments, and clinical guideline development. OBJECTIVES: We outline how resource utilization and cost-effectiveness analyses are integrated into health-related recommendations, using the GRADE Evidence to Decision (EtD) frameworks. STUDY DESIGN AND SETTING: Through iterative discussions and refinement, in-person, and online meetings, and through e-mail communication, we developed draft guidance to incorporate economic evidence in the formulation of health-related recommendations. We developed scenarios to operationalize the guidance. We presented a summary of the results to members of the GRADE Economic Evaluation Project Group. RESULTS: We describe how to estimate the cost of preventing (or achieving) an event to inform assessments of cost-effectiveness of alternative treatments, when there are no published economic evaluations. Evidence profiles and Summary of Findings tables based on systematic reviews of cost-effectiveness analyses can be created to provide top-level summaries of results and quality of multiple published economic evaluations. We also describe how this information could be integrated in GRADE's EtD frameworks to inform health-related recommendations. Three scenarios representing various levels of available cost-effectiveness evidence were used to illustrate the integration process. CONCLUSION: This GRADE guidance provides practical information for presenting cost-effectiveness data and its integration in the development of health-related recommendations, using the EtD frameworks.

Cost and Clinical Benefits Associated with Oncotype DX® Test in Patients with Early-Stage HR+/HER2- Node-Negative Breast Cancer in the Netherlands.

Objectives: Patients with early-stage HR+/HER2- N0 breast cancer may receive adjuvant chemotherapy in combination with surgery. However, chemotherapy does not always lead to improved survival and incurs high healthcare costs and increased adverse events. To support decision-making regarding adjuvant chemotherapy, genomic profile testing performed with tests such as the Oncotype DX® test can help healthcare practitioners decide whether chemotherapy provides any benefit to these patients. As such, a cost-consequence model was developed with the aim to estimate the economic impact of using different gene expression tests or no testing, in patients with node-negative early-stage breast cancer. Methods: A cost-consequence model was developed to estimate the economic impact of three different scenarios in the Dutch setting: (1) Oncotype DX® test, (2) MammaPrint®, and (3) and no genomic profile testing. The model included chemotherapy costs, administration costs, short- and long-term adverse event costs, productivity loss, genomic profiling testing costs, cost of cancer recurrence, and hospitalization costs. Results: A treatment paradigm with Oncotype DX resulted in average savings per patient of €6,768 vs. a paradigm with MammaPrint and €13,125 vs. a paradigm with no genomic testing. Furthermore, due to less patients receiving adjuvant chemotherapy through better targeting by the Oncotype DX test, fewer adverse events, sick days, practice visits, and hospitalizations were required compared to MammaPrint and no genomic profiling. Conclusions: Testing with Oncotype DX test in Dutch clinical practice in patients with early-stage breast cancer proved to be cost-saving versus MammaPrint and no genomic profiling tests. Introducing the Oncotype DX test to the Dutch setting will likely reduce the economic resources that are required.

Real world data in health technology assessments in kidney transplants in Germany: use of routinely collected data to address epidemiologic questions in kidney transplants in the AMNOG process in Germany.

Introduction: It is discussed whether real world data can be used in health technology assessment. Following it is of interest whether routinely collected data for quality assurance (QA) in the hospital sector is feasible to address epidemiologic questions in kidney transplantation in the AMNOG process in Germany. Objectives: To investigate the proportion of kidney transplants classified as from so-called standard criteria donors (SCD) and from expanded criteria donors (ECD) in Germany and to study the age distribution. Methods: After granted use by the Federal Joint Committee (G-BA), the data analysis was carried out by the AQUA institute, and a SPSS code was developed. Special challenge was the complex definition of SCD/ECD criteria that, in addition to donor age, takes into account combinations of donor diagnoses, creatinine, and cold ischemia time. Results: Age analyses could be performed in all patients. Median age of the adult transplant recipients in Germany was 54 years in 2012 as well as in 2013, range 18-85 and 18-82 years and a mean (SD) of 53 (14) and 52 (14) years, respectively. 63.5% (2012) and 62.5% (2013) of recipients were male. Classification in SCD/ECD transplants could be performed for 2,083 of 2,461 patients (85%; 2012) and for 1,795 of 2,079 patients (86%; 2013). Of all classifiable transplants 61.4% (2012) and 66.5% (2013) were SCD transplants. Total project time from the request to results was <6 months. Conclusions: The use of data routinely collected for QA in the hospital sector is feasible to address epidemiologic questions in kidney transplantation in the AMNOG process in Germany, which is basically following the systematic of an HTA process. All patients with kidney transplants are represented thus avoiding sampling error. Limitations include the availability of all necessary data in the QA data set. Within <6 months' time with reasonable resources it was possible to meet timelines. The analyses were accepted by the authorities.

Cost-effectiveness of early treatment of ACPA-positive rheumatoid arthritis patients with abatacept.

OBJECTIVES: Studies have reported that the presence of elevated anti-citrullinated protein antibodies (ACPA)/RF levels, together with joint erosions, is associated with higher disease burden in terms of disability and mortality in rheumatoid arthritis (RA). Abatacept has been shown to be effective in this patient population with favourable comparative data against adalimumab. However, few studies have investigated the cost-effectiveness of abatacept in this population to similar treatments such as TNFs. The objective of the study was to compare the cost-effectiveness of abatacept to adalimumab as a first bDMARD in ACPA-positive RA patients who failed treatment with methotrexate (MTX) in Germany. METHODS: A decision tree model was used to estimate the cost-effectiveness, from a payer's perspective, of different treatment sequences in RA over a two year time frame. The effectiveness criteria were defined as achieving the treatment target measured by the Disease Activity Score 28 (DAS28(CRP)<2.6; "remission"). A treatment switch to a different biologic as 2nd line and 3rd line bDMARD was allowed - in case of not achieving remission with therapy - every 6 months over a two year time period. Effectiveness data was based on randomised controlled trials (RCT) identified by an updated previous systematic literature search by the Institute for Quality and Efficiency in Health Care (IQWiG). Costs of medication and other direct medical costs were considered. Cost-effectiveness of RA treatment was investigated in ACPA-positive patients and presented as overall costs per day in remission. RESULTS: For ACPA-positive patients, treatment strategies including early treatment with abatacept had lower total costs per clinical outcome compared to later use. Treatment sequences starting with abatacept resulted in lower costs per day in remission (mean 330 €/day, range 328-333 €/day) compared to sequences starting with adalimumab (mean 384 €/day, range 378-390 €/day). Choice of the second or third biologic in the treatment sequences appears to have little impact on the costs per outcome. CONCLUSIONS: The results of this analysis suggest that in ACPA-positive RA patients treatment with abatacept appears to have lower costs per response (remission) compared to treatment with adalimumab as a first bDMARD.

Cost per response for abatacept versus adalimumab in rheumatoid arthritis by ACPA subgroups in Germany, Italy, Spain, US and Canada.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to disability and reduced quality of life. Effective treatment with biologic DMARDs poses a significant economic burden. The Abatacept versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) trial was a head-to-head, randomized study comparing abatacept in serum anti-citrullinated protein antibody (ACPA)-positive patients, with increasing efficacy across ACPA quartile levels. The aim of this study was to evaluate the cost per response accrued using abatacept versus adalimumab in ACPA-positive and ACPA-negative patients with RA from the health care perspective in Germany, Italy, Spain, the US and Canada. A cost-consequence analysis (CCA) was designed to compare the monthly costs per responding patient/patient in remission. Efficacy, safety and resource use inputs were based on the AMPLE trial. A one-way deterministic sensitivity analysis (OWSA) was also performed to assess the impact of model inputs on the results for total incremental costs. Cost per response in ACPA-positive patients favoured abatacept compared with adalimumab (ACR20, ACR90 and HAQ-DI). Subgroup analysis favoured abatacept with increasing stringency of response criteria and serum ACPA levels. Cost per remission (DAS28-CRP) favoured abatacept in ACPA-negative patients, while cost per CDAI and SDAI favoured abatacept in ACPA-positive patients. Abatacept was consistently favoured in ACPA-Q4 patients across all outcomes and countries. Cost savings were greater with abatacept when more stringent response criteria were applied and also with increasing ACPA levels, which could lead to a lower overall health care budget impact with abatacept compared with adalimumab.

Clinical effectiveness of stress-reduction techniques in patients with hypertension: systematic review and meta-analysis.

OBJECTIVE: A systematic review and meta-analysis focusing on patient-relevant outcomes and blood pressure was conducted to assess the clinical effectiveness of stress-reduction techniques in adults with essential hypertension. METHODS: Systematic reviews and randomized controlled trials (RCTs) were identified as part of a systematic search in six electronic databases ending September 2012. RCTs comparing stress-reduction techniques versus no such techniques with a follow-up of at least 24 weeks and published in English or German were included. Outcomes of interest were death, cardiovascular morbidity/mortality, end-stage renal disease, health-related quality of life, adverse events, changes in blood pressure, and changes in antihypertensive medication. When appropriate, meta-analyses were used to combine data. RESULTS: Seventeen RCTs analyzing different stress-reduction techniques such as biofeedback, relaxation or combined interventions were identified. Data were not reported for most of the patient-relevant outcomes, and meta-analyses could only be used to evaluate effects on blood pressure. The data indicated a blood pressure-lowering effect, but the studies had methodological shortcomings and heterogeneity between them was high. Mean group differences for DBP ranged from -10 to 1 mmHg and for SBP from -12 to 10 mmHg. In terms of antihypertensive medication, no favorable effects of stress-reduction techniques could be identified. CONCLUSIONS: The available RCTs on stress-reduction techniques used for at least 24 weeks appeared to indicate a blood pressure-lowering effect in patients with essential hypertension, but this should be interpreted with caution because of major methodological limitations. A benefit of specific stress-reduction techniques in hypertensive patients remains unproven.

Increasing physical activity for the treatment of hypertension: a systematic review and meta-analysis.

BACKGROUND: Low physical activity has been identified as a major risk factor for cardiovascular disease. Medical societies therefore recommend increased physical activity be part of any antihypertensive therapy. OBJECTIVE: Focusing on patient-relevant outcomes such as mortality and cardiovascular events, this review was conducted to assess the long-term effects of interventions aiming at increasing physical activity in comparison with no such interventions on adult patients with essential hypertension. DATA SOURCES: We searched for high-quality systematic reviews in MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (Cochrane Reviews), Database of Abstracts of Reviews of Effects (Other Reviews) and Health Technology Assessment Database (Technology Assessments) published between 1997 and February 2009 and for randomized controlled trials (RCTs) in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (Clinical Trials) published before September 2012. Additional studies were identified by hand searching reference lists of reviews. STUDY SELECTION: RCTs with at least 24 weeks' follow-up that evaluated the effect of increased physical activity on the blood pressure of adults with essential hypertension were included in our review. Primary outcomes were all-cause mortality, cardiovascular morbidity and mortality, end-stage renal disease, quality of life and adverse events. STUDY APPRAISAL AND SYNTHESIS METHODS: When appropriate, we used random effects meta-analyses to determine mean difference with 95 % confidence intervals for each endpoint. All data were analysed using the Review Manager software version 5.0.24 from the Cochrane Collaboration. RESULTS: None of the included nine trials, covering 891 patients with hypertension, provided sufficient data on patient-relevant outcomes such as mortality, cardiovascular events or injuries related to physical activity. Information on changes in systolic and diastolic blood pressure was provided for all included trials. The majority of the included RCTs reported that increased physical activity led to a decrease in systolic and diastolic blood pressure of 5-10 and 1-6 mmHg, respectively, but due to marked heterogeneity in the meta-analyses both for systolic and diastolic blood pressure (I² = 70.0 and 73.0 %), no effect estimates were provided. LIMITATIONS: About 50 % of the included trials were small, evaluating at most 20 participants per study group, and more than twothirds were deemed to have a high risk of bias. CONCLUSIONS: Although a decrease in blood pressure is shown to be a consequence of increased physical activity, RCTs of appropriate study size and quality that examine potential patient-relevant benefits or harms still need to be conducted to evaluate whether physical activity really improves the health of patients with essential hypertension.

All nations depend on the global knowledge pool--analysis of country of origin of studies used for health technology assessments in Germany.

BACKGROUND: Health Technology Assessments (HTAs) are used to inform decision-making and their usefulness depends on the quality and relevance of research and specific studies for health-policy decisions. Little is known about the country of origin of studies used for HTAs. OBJECTIVE: To investigate which countries have made the largest contributions to inform health policy decisions through studies included in HTAs in Germany. METHODS: The country of origin was extracted from all studies included in HTAs of the German Institute for Quality and Efficiency in Health Care, (IQWiG), published from 2/2006 to 9/2010. Studies were ranked according to the total number of studies per country, adjusted for population size, gross domestic product (GDP), and total health expenditure. RESULTS: 1087 studies were included in 54 HTA reports. Studies were assigned to 45 countries. Most of the studies (27%) originated from the United States (USA), 18% were multinational, followed by 7% from the United Kingdom (UK) and 5% from Germany. Nordic countries led the ranking when adjusting for population size/million (ranks 1-3,6,9/45 countries), GDP/billion US$ (1,2,5,9,14/45), or health expenditure/billion US$ (1,3,5,12,13/45). The relative contribution of the UK was stable in the analyses when adjusted for population size (7/45), GDP (7/45), and health expenditure (9/45), whereas the USA (13, 18, and 30/45) and Germany (17, 19, and 21/45) dropped in the ranking. CONCLUSIONS: More than half of the studies relevant for evidence-informed decision-making in Germany originated from the USA, followed by multinational research and the UK. Only 5% of the studies originated from Germany. According to our findings, there appears to be some discrepancy between the use of globally generated evidence and the contribution to the knowledge pool by individual countries.