Bram Ramaekers

High-sensitivity troponin assays for the early rule-out or diagnosis of acute myocardial infarction in people with acute chest pain: a systematic review and cost-effectiveness analysis

BACKGROUND Early diagnosis of acute myocardial infarction (AMI) can ensure quick and effective treatment but only 20% of adults with emergency admissions for chest pain have an AMI. High-sensitivity cardiac troponin (hs-cTn) assays may allow rapid rule-out of AMI and avoidance of unnecessary hospital admissions and anxiety. OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of hs-cTn assays for the early (within 4 hours of presentation) rule-out of AMI in adults with acute chest pain. METHODS Sixteen databases, including MEDLINE and EMBASE, research registers and conference proceedings, were searched to October 2013. Study quality was assessed using QUADAS-2. The bivariate model was used to estimate summary sensitivity and specificity for meta-analyses involving four or more studies, otherwise random-effects logistic regression was used. The health-economic analysis considered the long-term costs and quality-adjusted life-years (QALYs) associated with different troponin (Tn) testing methods. The de novo model consisted of a decision tree and Markov model. A lifetime time horizon (60 years) was used. RESULTS Eighteen studies were included in the clinical effectiveness review. The optimum strategy, based on the Roche assay, used a limit of blank (LoB) threshold in a presentation sample to rule out AMI [negative likelihood ratio (LR-) 0.10, 95% confidence interval (CI) 0.05 to 0.18]. Patients testing positive could then have a further test at 2 hours; a result above the 99th centile on either sample and a delta (Δ) of ≥ 20% has some potential for ruling in an AMI [positive likelihood ratio (LR+) 8.42, 95% CI 6.11 to 11.60], whereas a result below the 99th centile on both samples and a Δ of < 20% can be used to rule out an AMI (LR- 0.04, 95% CI 0.02 to 0.10). The optimum strategy, based on the Abbott assay, used a limit of detection (LoD) threshold in a presentation sample to rule out AMI (LR- 0.01, 95% CI 0.00 to 0.08). Patients testing positive could then have a further test at 3 hours; a result above the 99th centile on this sample has some potential for ruling in an AMI (LR+ 10.16, 95% CI 8.38 to 12.31), whereas a result below the 99th centile can be used to rule out an AMI (LR- 0.02, 95% CI 0.01 to 0.05). In the base-case analysis, standard Tn testing was both most effective and most costly. Strategies considered cost-effective depending upon incremental cost-effectiveness ratio thresholds were Abbott 99th centile (thresholds of < £6597), Beckman 99th centile (thresholds between £6597 and £30,042), Abbott optimal strategy (LoD threshold at presentation, followed by 99th centile threshold at 3 hours) (thresholds between £30,042 and £103,194) and the standard Tn test (thresholds over £103,194). The Roche 99th centile and the Roche optimal strategy [LoB threshold at presentation followed by 99th centile threshold and/or Δ20% (compared with presentation test) at 1-3 hours] were extendedly dominated in this analysis. CONCLUSIONS There is some evidence to suggest that hs-CTn testing may provide an effective and cost-effective approach to early rule-out of AMI. Further research is needed to clarify optimal diagnostic thresholds and testing strategies. STUDY REGISTRATION This study is registered as PROSPERO CRD42013005939. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Systematic review and meta-analysis of radiotherapy in various head and neck cancers: Comparing photons, carbon-ions and protons

PURPOSE To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer. METHODS A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy. RESULTS In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons. In-silico studies showed a lower dose to the organs at risk, independently of the tumor site. CONCLUSIONS For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy. Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons.

Acknowledging Patient Heterogeneity in Economic Evaluation

Background and ObjectivePatient heterogeneity is the part of variability that can be explained by certain patient characteristics (e.g. age, disease stage). Population reimbursement decisions that acknowledge patient heterogeneity could potentially save money and increase population health. To date, however, economic evaluations pay only limited attention to patient heterogeneity. The objective of the present paper is to provide a comprehensive overview of the current knowledge regarding patient heterogeneity within economic evaluation of healthcare programmes.MethodsA systematic literature review was performed to identify methodological papers on the topic of patient heterogeneity in economic evaluation. Data were obtained using a keyword search of the PubMed database and manual searches. Handbooks were also included. Relevant data were extracted regarding potential sources of patient heterogeneity, in which of the input parameters of an economic evaluation these occur, methods to acknowledge patient heterogeneity and specific concerns associated with this acknowledgement.ResultsA total of 20 articles and five handbooks were included. The relevant sources of patient heterogeneity (demographics, preferences and clinical characteristics) and the input parameters where they occurred (baseline risk, treatment effect, health state utility and resource utilization) were combined in a framework. Methods were derived for the design, analysis and presentation phases of an economic evaluation. Concerns related mainly to the danger of false-positive results and equity issues.ConclusionBy systematically reviewing current knowledge regarding patient heterogeneity within economic evaluations of healthcare programmes, we provide guidance for future economic evaluations. Guidance is provided on which sources of patient heterogeneity to consider, how to acknowledge them in economic evaluation and potential concerns. The improved acknowledgement of patient heterogeneity in future economic evaluations may well improve the efficiency of healthcare.

Protons in Head-and-Neck Cancer: Bridging the Gap of Evidence

PURPOSE To use Normal Tissue Complication Probability (NTCP) models and comparative planning studies to explore the (cost-)effectiveness of swallowing sparing intensity modulated proton radiotherapy (IMPT) compared with swallowing sparing intensity modulated radiotherapy with photons (IMRT) in head and neck cancer (HNC). METHODS AND MATERIALS A Markov model was constructed to examine and compare the costs and quality-adjusted life years (QALYs) of the following strategies: (1) IMPT for all patients; (2) IMRT for all patients; and (3) IMPT if efficient. The assumption of equal survival for IMPT and IMRT in the base case analysis was relaxed in a sensitivity analysis. RESULTS Intensity modulated proton radiation therapy and IMRT for all patients yielded 6.620 and 6.520 QALYs and cost €50,989 and €41,038, respectively. Intensity modulated proton radiation therapy if efficient yielded 6.563 QALYs and cost €43,650. The incremental cost-effectiveness ratio of IMPT if efficient versus IMRT for all patients was €60,278 per QALY gained. In the sensitivity analysis, IMRT was more effective (0.967 QALYs) and less expensive (€8218) and thus dominated IMPT for all patients. CONCLUSIONS Cost-effectiveness analysis based on normal tissue complication probability models and planning studies proved feasible and informative and enables the analysis of individualized strategies. The increased effectiveness of IMPT does not seem to outweigh the higher costs for all head-and-neck cancer patients. However, when assuming equal survival among both modalities, there seems to be value in identifying those patients for whom IMPT is cost-effective.

Decision support systems for personalized and participative radiation oncology.

Abstract A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models ‘learn’ using advanced and innovative information technologies (ideally in a distributed fashion — please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi‐faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re‐evaluated (through quality assurance procedures) in different patient datasets in order to refine and re‐optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine. Graphical abstract Figure. No caption available.

Development and evaluation of an online three-level proton vs photon decision support prototype for head and neck cancer – Comparison of dose, toxicity and cost-effectiveness

To quantitatively assess the effectiveness of proton therapy for individual patients, we developed a prototype for an online platform for proton decision support (PRODECIS) comparing photon and proton treatments on dose metric, toxicity and cost-effectiveness levels. An evaluation was performed with 23 head and neck cancer datasets.

Spacers in radiotherapy treatment of prostate cancer: is reduction of toxicity cost-effective?

BACKGROUND AND PURPOSE To compare the cost-effectiveness of treating prostate cancer patients with intensity-modulated radiation therapy and a spacer (IMRT+S) versus IMRT-only without a spacer (IMRT-O). MATERIALS AND METHODS A decision-analytic Markov model was constructed to examine the effect of late rectal toxicity and compare the costs and quality-adjusted Life Years (QALYs) of IMRT-O and IMRT+S. The main assumption of this modeling study was that disease progression, genito-urinary toxicity and survival were equal for both comparators. RESULTS For all patients, IMRT+S revealed a lower toxicity than IMRT-O. Treatment follow-up and toxicity costs for IMRT-O and IMRT+S amounted to €1604 and €1444, respectively, thus saving €160 on the complication costs at an extra charge of €1700 for the spacer in IMRT+S. The QALYs yielded for IMRT-O and IMRT+S were 3.542 and 3.570, respectively. This results in an incremental cost-effectiveness ratio (ICER) of €55,880 per QALY gained. For a ceiling ratio of €80,000, IMRT+S had a 77% probability of being cost-effective. CONCLUSION IMRT+S is cost-effective compared to IMRT-O based on its potential to reduce radiotherapy-related toxicity.

How Should We Deal with Patient Heterogeneity in Economic Evaluation: A Systematic Review of National Pharmacoeconomic Guidelines

OBJECTIVE To review and analyze recommendations from national pharmacoeconomic guidelines with regard to acknowledging patient heterogeneity in economic evaluations. METHODS National pharmacoeconomic guidelines were obtained through the ISPOR Web site. Guidance was extracted by using a developed data extraction sheet. Extracted data were divided into subcategories on the basis of consensus meetings. RESULTS Of the 26 included guidelines, 20 (77%) advised to identify patient heterogeneity. Most guidelines (77%) provided general methodological advice to acknowledge patient heterogeneity, including justifications for distinguishing subgroups (65%), prespecification of subgroups (42%), or methodology to acknowledge patient heterogeneity (77%). Stratified analysis of cost-effectiveness was most commonly advised (20 guidelines; 77%); however, guidance on the specific application of methods was scarce (9 guidelines; 34%) and generally limited if provided. Guidance to present patient heterogeneity was provided by 15 guidelines (58%), most prominently to describe the definition (31%) and justification (31%) of subgroups. CONCLUSIONS The majority of national pharmacoeconomic guidelines provide guidance on acknowledging patient heterogeneity in economic evaluations. However, because guidance is mostly not specific, its usefulness is limited. This may reflect that the importance of acknowledging patient heterogeneity is usually recognized while there is a lack of consensus on specific methods to acknowledge patient heterogeneity. We advise the further development of national pharmacoeconomic guidelines to provide specific guidance on the identification of patient heterogeneity, methods to acknowledge it, and presenting the results. We present a checklist that can assist in formulating these recommendations. This could facilitate the systematic and transparent handling of patient heterogeneity in economic evaluations worldwide.

Use of Value of Information in Healthcare Decision Making: Exploring Multiple Perspectives

BackgroundValue of information (VOI) is a tool that can be used to inform decisions concerning additional research in healthcare. VOI estimates the value of obtaining additional information and indicates the optimal design for additional research. Although it is recognized as good practice in handling uncertainty, it is still hardly used in decision making in the Netherlands.ObjectiveThis paper aims to examine the potential value of VOI, barriers and facilitators and the way forward with the use of VOI in the decision-making process for reimbursement of pharmaceuticals in the Netherlands.MethodsThree focus group interviews were conducted with researchers, policy makers, and representatives of pharmaceutical companies.ResultsThe results revealed that although all stakeholders recognize the relevance of VOI, it is hardly used and many barriers to the performance and use of VOI were identified. One of these barriers is that not all uncertainties are easily incorporated in VOI, and the results may be biased if structural uncertainties are ignored. Furthermore, not all research designs indicated by VOI may be feasible in practice.ConclusionsTo fully embed VOI into current decision-making processes, a threshold incremental cost-effectiveness ratio and guidelines that clarify when and how VOI should be performed are needed. In addition, it should be clear to all stakeholders how the results of VOI are used in decision making.

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach

Background Non-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials. Methods The frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis. Results The two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million. Conclusions This study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.