Prioritisation and design of clinical trials.

Clinical trials require participation of numerous patients, enormous research resources and substantial public funding. Time-consuming trials lead to delayed implementation of beneficial interventions and to reduced benefit to patients. This manuscript discusses two methods for the allocation of research resources and reviews a framework for prioritisation and design of clinical trials. The traditional error-driven approach of clinical trial design controls for type I and II errors. However, controlling for those statistical errors has limited relevance to policy makers. Therefore, this error-driven approach can be inefficient, waste research resources and lead to research with limited impact on daily practice. The novel value-driven approach assesses the currently available evidence and focuses on designing clinical trials that directly inform policy and treatment decisions. Estimating the net value of collecting further information, prior to undertaking a trial, informs a decision maker whether a clinical or health policy decision can be made with current information or if collection of extra evidence is justified. Additionally, estimating the net value of new information guides study design, data collection choices, and sample size estimation. The value-driven approach ensures the efficient use of research resources, reduces unnecessary burden to trial participants, and accelerates implementation of beneficial healthcare interventions.

Effectiveness of the blended-care lifestyle intervention 'PerfectFit': a cluster randomised trial in employees at risk for cardiovascular diseases.

BACKGROUND: Web-based lifestyle interventions at the workplace have the potential to promote health and work productivity. However, the sustainability of effects is often small, which could be enhanced by adding face-to-face contacts, so-called 'blended care'. Therefore, this study evaluates the effects of a blended workplace health promotion intervention on health and work outcomes among employees with increased cardiovascular risk. METHODS: In this multicentre cluster-randomised controlled trial (PerfectFit), 491 workers in 18 work units from military, police, and a hospital with increased cardiovascular risk were randomised into two intervention groups. The limited intervention (n = 213; 9 clusters) consisted of a web-based Health Risk Assessment with advice. In the extensive intervention (n = 271; 8 clusters), coaching sessions by occupational health physicians using motivational interviewing were added. One cluster dropped out after randomisation but before any inclusion of subjects. Primary outcome was self-rated health. Secondary outcomes were body weight, body mass index (BMI), work productivity, and health behaviours. Follow-up measurements were collected at 6 and 12 months. Effect sizes were determined in mixed effects models. RESULTS: At 12 months, the extensive intervention was not statistically different from the limited intervention for self-rated health (4.3%; 95%CI -5.3-12.8), BMI (- 0.81; 95%CI -1.87-0.26) and body weight (- 2.16; 95%CI -5.49-1.17). The within-group analysis showed that in the extensive intervention group body weight (- 3.1 kg; 95% CI -2.0 to - 4.3) was statistically significantly reduced, whereas body weight remained stable in the limited intervention group (+ 0.2 kg; 95% CI -1.4 to 1.8). In both randomised groups productivity loss and physical activity increased and excessive alcohol use decreased significantly at 12 months. CONCLUSIONS: There were no effects on self-rated health, body weight, and BMI. However, within the group with web-based tailored Health Risk Assessment including personalized advice body weight reduced significantly. Adding motivational coaching is promising to reduce body weight. TRIAL REGISTRATION: Retrospectively registered at the Netherlands Trial Registry with number NTR4894 , at Nov 14 2014.

A comparison between willingness to pay and willingness to give up time.

We compared the willingness-to-pay and willingness to give up time methods to assess preferences for digital subtraction angiography (DSA), computed tomography angiography (CTA) and magnetic resonance angiography (MRA). Respondents were hypertensive patients suspected of having renal artery stenosis. Data were gathered using telephone interviews. Both the willingness-to-pay and willingness to give up time methods revealed that patients preferred CTA to MRA in order to avoid DSA. The agreement between willingness-to-pay and willingness to give up time responses was high (kappa 0.65-0.85). The willingness-to-pay method yielded relatively more protest answers (12%) as compared to willingness to give up time (2%). So, our results provided evidence for the comparability of willingness to pay and willingness to give up time. The high percentage of protest answers on the willingness-to-pay questions raises questions with respect to the application of the willingness-to-pay method in a broad decision-making context. On the other hand, the strength of willingness-to-pay is that the method directly arrives at a monetary measure well founded in economic theory, whereas the willingness to give up time method requires conversion to monetary units.

Diagnostic Imaging Strategies for Occult Hip Fractures: A Decision and Cost-Effectiveness Analysis.

OBJECTIVE: Hip fractures cause significant morbidity and mortality. Determining the optimal diagnostic strategy for the subset of patients with potential occult hip fracture remains challenging. We determined the most cost-effective strategy for the diagnosis of occult hip fractures from the choices of performing only computed tomography (CT), performing only magnetic resonance imaging (MRI), performing CT and if negative performing MRI (MRI-selective strategy) or discharging the patient without advanced imaging. METHODS: We developed a decision-analytic model to compare outcomes and costs of different diagnostic strategies for the diagnosis of an occult hip fracture from a societal perspective. Model inputs were derived from charge data, Medicare reimbursements, and the literature. Strategies with an incremental cost-effectiveness ratio (ICER) below $100,000 per quality-adjusted life-year (QALY) gained were considered cost-effective. We tested the robustness of our results using probabilistic sensitivity analysis. RESULTS: Compared to a CT strategy, MRI provides an additional 0.05 QALY at an incremental cost of $1,227 and ICER of $25,438/QALY. For facilities without MRI capability, if the cost of transfer is below $1,228, transferring the patient to a MRI-capable facility is the most cost-effective strategy. Above this cost, employing a CT and if negative transfer to a MRI-capable facility strategy was more cost-effective. When the cost of a transfer reached more than $4,039, it became more cost-effective to only obtain a CT. CONCLUSION: MRI is a cost-effective strategy for the diagnosis of an occult hip fracture. For facilities without MRI capability, the most cost-effective strategy depends on the cost of the interfacility transfer.

Comparing the cost-effectiveness of four novel risk markers for screening asymptomatic individuals to prevent cardiovascular disease (CVD) in the US population.

BACKGROUND: High sensitivity CRP (hsCRP), coronary artery calcification on CT (CT calcium), carotid artery intima media thickness on ultrasound (cIMT) and ankle-brachial index (ABI) improve prediction of cardiovascular disease (CVD) risk, but the benefit of screening with these novel risk markers in the U.S. population is unclear. METHODS AND RESULTS: A microsimulation model evaluating lifelong cost-effectiveness for individuals aged 40-85 at intermediate risk of CVD, using 2003-2004 NHANES-III (N=3736), Framingham Heart Study, U.S. Vital Statistics, meta-analyses of independent predictive effects of the four novel risk markers and treatment effects was constructed. Using both an intention-to-treat (assumes adherence <100% and incorporates disutility from taking daily medications) and an as-treated (100% adherence and no disutility) analysis, quality adjusted life years (QALYs), lifetime costs (2014 US $), and incremental cost-effectiveness ratios (ICER in $/QALY gained) of screening with hsCRP, CT coronary calcium, cIMT and ABI were established compared with current practice, full adherence to current guidelines, and ubiquitous statin therapy. In the intention-to-treat analysis in men, screening with CT calcium was cost effective ($32,900/QALY) compared with current practice. In women, screening with hsCRP was cost effective ($32,467/QALY). In the as-treated analysis, statin therapy was both more effective and less costly than all other strategies for both men and women. CONCLUSIONS: When a substantial disutility from taking daily medication is assumed, screening men with CT coronary calcium is likely to be cost-effective whereas screening with hsCRP has value in women. The individual perceived disutility for taking daily medication should play a key role in the decision.

Lifestyle interventions in patients with coronary heart disease: a systematic review.

CONTEXT: Coronary heart disease (CHD) is responsible for about 15% of all deaths worldwide and is identified as a top priority for decision makers. Both primary and secondary prevention are considered key strategies in the prevention of CHD. The aim of this study was to assess the efficacy of nonpharmacologic interventions with multiple lifestyle components in patients with established CHD in comparison to usual care. For this reason, a systematic review and meta-analysis of RCTs were performed. EVIDENCE ACQUISITION: The Cochrane Library, MEDLINE, and EMBASE databases were examined until March 31, 2012 (without start date) in order to identify studies addressing patient-tailored multifactorial lifestyle interventions aimed at reducing more than one cardiovascular risk factor in patients with established CHD. Primary endpoints were fatal and nonfatal cardiovascular events. Secondary outcomes were overall mortality and cardiovascular disease-associated hospital readmissions. EVIDENCE SYNTHESIS: The search strategy yielded 14 unique RCTs, which were considered in the qualitative analysis. Nine of them contributed to the meta-analysis. A random effects model was used to pool the data. The meta-analysis showed a significant risk reduction of 18% (relative risk 0.82, 95% CI=0.69, 0.98) of fatal cardiovascular events in patients undergoing multifactorial lifestyle interventions. Further, a nonsignificant reduction of nonfatal events, overall mortality and hospital readmissions was found. CONCLUSIONS: Multifactorial lifestyle interventions aimed at improving modifiable risk factors in patients with established CHD reduce the risk for fatal cardiovascular events. Therefore, they may have added value in secondary prevention of CHD.

Multi-detector row computed tomography angiography of peripheral arterial disease.

With the introduction of multi-detector row computed tomography (MDCT), scan speed and image quality has improved considerably. Since the longitudinal coverage is no longer a limitation, multi-detector row computed tomography angiography (MDCTA) is increasingly used to depict the peripheral arterial runoff. Hence, it is important to know the advantages and limitations of this new non-invasive alternative for the reference test, digital subtraction angiography. Optimization of the acquisition parameters and the contrast delivery is important to achieve a reliable enhancement of the entire arterial runoff in patients with peripheral arterial disease (PAD) using fast CT scanners. The purpose of this review is to discuss the different scanning and injection protocols using 4-, 16-, and 64-detector row CT scanners, to propose effective methods to evaluate and to present large data sets, to discuss its clinical value and major limitations, and to review the literature on the validity, reliability, and cost-effectiveness of multi-detector row CT in the evaluation of PAD.

Identifying key parameters in cost-effectiveness analysis using value of information: a comparison of methods.

Decisions in health care must be made, despite uncertainty about benefits, risks, and costs. Value of information analysis is a theoretically sound method to estimate the expected value of future quantitative research pertaining to an uncertain decision. If the expected value of future research does not exceed the cost of research, additional research is not justified, and decisions should be based on current evidence, despite the uncertainty. To assess the importance of individual parameters relevant to a decision, different value of information methods have been suggested. The generally recommended method assumes that the expected value of perfect knowledge concerning a parameter is estimated as the reduction in expected opportunity loss. This method, however, results in biased expected values and incorrect importance ranking of parameters. The objective of this paper is to set out the correct methods to estimate the partial expected value of perfect information and to demonstrate why the generally recommended method is incorrect conceptually and mathematically.

Cost analysis of procedures related to the management of renal artery stenosis from various perspectives.

To determine the costs associated with the diagnostic work-up and percutaneous revascularization of renal artery stenosis from various perspectives. A prospective multicenter comparative study was conducted between 1998 and 2001. A total of 402 hypertensive patients with suspected renal artery stenosis were included. Costs were assessed of computed tomography angiography (CTA), magnetic resonance angiography (MRA), digital subtraction angiography (DSA), and percutaneous revascularization. From the societal perspective, DSA was the most costly (euro 1,721) and CTA the least costly diagnostic technique (euro 424). CTA was the least costly imaging procedure irrespective of the perspective used. The societal costs associated with percutaneous renal artery revascularization ranged from euro 2,680 to euro 6,172. Overall the radiology department incurred the largest proportion of the total societal costs. For the management of renal artery stenosis, performing the analysis from different perspectives leads to the same conclusion concerning the least costly diagnostic imaging and revascularization procedure.

Cost and patency rate targets for the development of endovascular devices to treat femoropopliteal arterial disease.

PURPOSE: To determine the criteria that would make use of an endovascular device cost-effective compared with bypass surgery and percutaneous transluminal angioplasty in the treatment of femoropopliteal arterial disease. MATERIALS AND METHODS: A decision model was developed to compare treatment with the use of a hypothetical endovascular device with established therapies. Cost-effectiveness from the perspective of the health care system was considered. Outcome measures were lifetime costs and quality-adjusted life-years. With the use of net health benefit calculations and threshold analysis, combinations of costs and patency rates were determined that would make the device cost-effective compared with established therapies. In subgroup and sensitivity analyses, the effect on decision-making of sex, age, indication, lesion type, procedural risk, and society's willingness to pay for incremental gain in health were explored. RESULTS: Use of a device that costs $3,000 would be cost-effective compared with bypass surgery for critical ischemia if the 5-year patency rate is 29%-46%. Use of the same device would be cost-effective compared with angioplasty for disabling claudication and stenosis if the 5-year patency rate is 69%-86%. CONCLUSION: The target combinations of costs and patency rates found in this study are probably attainable, and further development of such endovascular devices seems warranted.

MR imaging of the menisci and cruciate ligaments: a systematic review.

PURPOSE: To systematically review and synthesize published data on the diagnostic performance of magnetic resonance (MR) imaging of the menisci and cruciate ligaments and to assess the effect of study design characteristics and magnetic field strength on diagnostic performance. MATERIALS AND METHODS: Articles published between 1991 and 2000 were included if at least 30 patients were studied, arthroscopy was the reference standard, the magnetic field strength was reported, positivity criteria were defined, and the absolute numbers of true-positive, false-negative, true-negative, and false-positive results were available or derivable. Pooled weighted and summary receiver operating characteristic (ROC) analyses were performed for tears of both menisci and both cruciate ligaments separately and for the four lesions combined, by using random effects models. Differences were assessed according to lesion type. RESULTS: Twenty-nine of 120 retrieved articles were included. Pooled weighted sensitivity was higher for medial meniscal tears than that for lateral meniscal tears. However, pooled weighted specificity for the medial meniscus was lower than that for the lateral meniscus. In summary ROC analyses performed per lesion, various study design characteristics were found to influence diagnostic performance. Higher magnetic field strength significantly improved discriminatory power only for anterior cruciate ligament tears. When all lesions were combined in one overall summary ROC analysis, magnetic field strength was a significant but modest predictor of diagnostic performance. CONCLUSION: Diagnostic performance of MR imaging of the knee is different according to lesion type and is influenced by various study design characteristics. Higher magnetic field strength modestly improves diagnostic performance, but a significant effect was demonstrated only for anterior cruciate ligament tears.

Elective endovascular versus open surgical repair of abdominal aortic aneurysms: systematic review of short-term results.

PURPOSE: To summarize and compare published short-term results of elective endovascular and open surgical repair of abdominal aortic aneurysms. MATERIALS AND METHODS: A MEDLINE search of the English literature was performed. Studies with at least 10 patients in each treatment group were included if they reported patient characteristics, complications, and mortality. Two reviewers independently extracted the data. A random-effects model was used to pool the data and calculate pooled odds ratios (endovascular vs open surgical repair). RESULTS: Nine studies were included, reporting results of 1,318 procedures (687 endovascular repair and 631 open surgical repair). Mean blood loss was 456 mL for endovascular repair and 1,202 mL for open surgical repair (P =.003). On average, patients undergoing endovascular repair spent 0.5 days in the intensive care unit and 3.9 days in the hospital, and patients undergoing open surgical repair spent 2.2 days (P =.04) in the intensive care unit and 10.3 days (P =.02) in the hospital. The pooled 30-day-mortality was 0.03 for endovascular repair (95% CI: 0.02, 0.04) and 0.04 for open surgical repair (95% CI: 0.00, 0.07) (P =.03), and the odds ratio was 0.55 (95% CI: 0.33, 0.92). The pooled local and/or vascular complication rate was 0.16 for endovascular repair (95% CI: 0.06, 0.25) and 0.12 for open surgical repair (95% CI: 0.06, 0.18) (P =.46), and the odds ratio was 0.97 (95% CI: 0.62, 1.54). The pooled systemic and/or remote complication rate was 0.17 for endovascular repair (95% CI: 0.09, 0.25) and 0.44 for open surgical repair (95% CI: 0.21, 0.66) (P <.001), and the odds ratio was 0.22 (95% CI: 0.11, 0.45). CONCLUSION: On the basis of this systematic review, endovascular repair results in less blood loss, shorter intensive care unit and hospital stays, lower 30-day mortality, and lower systemic and/or remote complication rates than those of open surgical repair.

Peripheral arterial disease: therapeutic confidence of CT versus digital subtraction angiography and effects on additional imaging recommendations.

PURPOSE: To compare multi-detector row computed tomographic (CT) angiography and digital subtraction angiography (DSA) prior to revascularization in patients with symptomatic peripheral arterial disease for the purpose of assessing recommendations for additional imaging and physician confidence ratings for chosen therapy. MATERIALS AND METHODS: In a randomized controlled trial, 73 patients were assigned to CT angiography, and 72 were assigned to DSA. Physician confidence in the treatment decision was measured as a continuous outcome on a scale of 0-10 (uncertain to certain) and as a dichotomous outcome (further imaging recommended, yes or no). Mean confidence scores and additional imaging recommendations were compared between CT and DSA groups in an intention-to-diagnose-and-treat analysis. To detect trends in confidence, confidence scores were plotted over time, and multiple linear regression analysis was performed. To detect trends in additional imaging recommendations, logistic regression analysis was used. Data from eligible nonrandomized patients were analyzed separately. RESULTS: No statistically significant difference in baseline characteristics between randomized groups was found. CT had a lower confidence score than did DSA (7.2 vs 8.2, P < .001). Further imaging was recommended more often after CT (25 of 71 patients, 35%) than after DSA (nine of 66 patients, 14%; P = .003). Analysis of trends demonstrated increasing (but not statistically significant) confidence in CT and stable confidence in DSA. No significant difference was found in baseline characteristics between randomized and nonrandomized patients. Among nonrandomized patients, no significant difference in mean confidence score (8.2 vs 8.3, P = .26) was found between CT (n = 24) and DSA (n = 26). CONCLUSION: With CT angiography, physician confidence decreases with an associated increase in additional imaging prior to revascularization in patients with symptomatic peripheral arterial disease. Given that CT is less invasive than DSA, results suggest that CT may replace DSA in selected cases.