Comparing multiple competing interventions in the absence of randomized trials using clinical risk-benefit analysis

<p>Abstract</p> <p>Background</p> <p>To demonstrate the use of risk-benefit analysis for comparing multiple competing interventions in the absence of randomized trials, we applied this approach to the evaluation of five anticoagulants to prevent thrombosis in patients undergoing orthopedic surgery.</p> <p>Methods</p> <p>Using a cost-effectiveness approach from a clinical perspective (i.e. risk benefit analysis) we compared thromboprophylaxis with warfarin, low molecular weight heparin, unfractionated heparin, fondaparinux or ximelagatran in patients undergoing major orthopedic surgery, with sub-analyses according to surgery type. Proportions and variances of events defining risk (major bleeding) and benefit (thrombosis averted) were obtained through a meta-analysis and used to define beta distributions. Monte Carlo simulations were conducted and used to calculate incremental risks, benefits, and risk-benefit ratios. Finally, net clinical benefit was calculated for all replications across a range of risk-benefit acceptability thresholds, with a reference range obtained by estimating the case fatality rate - ratio of thrombosis to bleeding.</p> <p>Results</p> <p>The analysis showed that compared to placebo ximelagatran was superior to other options but final results were influenced by type of surgery, since ximelagatran was superior in total knee replacement but not in total hip replacement.</p> <p>Conclusions</p> <p>Using simulation and economic techniques we demonstrate a method that allows comparing multiple competing interventions in the absence of randomized trials with multiple arms by determining the option with the best risk-benefit profile. It can be helpful in clinical decision making since it incorporates risk, benefit, and personal risk acceptance.</p

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial)

Background: Based on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed – the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies. Objective: To compare TARGIT within a risk-adapted approach with whole-breast external beam radiotherapy (EBRT) over several weeks. Design: The TARGeted Intraoperative radioTherapy Alone (TARGIT-A) trial was a pragmatic, prospective, international, multicentre, non-inferiority, non-blinded, randomised (1 : 1 ratio) clinical trial. Originally, randomisation occurred before initial lumpectomy (prepathology) and, if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added in which randomisation occurred after initial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but which needed a reoperation to reopen the wound to give TARGIT as a delayed procedure. The risk-adapted approach meant that, in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, EBRT was recommended. Pragmatically, this reflected how TARGIT would be practised in the real world. Setting: Thirty-three centres in 11 countries. Participants: Women who were aged ≥ 45 years with unifocal invasive ductal carcinoma preferably ≤ 3.5 cm in size. Interventions: TARGIT within a risk-adapted approach and whole-breast EBRT. Main outcome measures: The primary outcome measure was absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary outcome measures included toxicity and breast cancer-specific and non-breast-cancer mortality. Results: In total, 3451 patients were recruited between March 2000 and June 2012. The following values are 5-year Kaplan–Meier rates for TARGIT compared with EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall [TARGIT 3.3%, 95% confidence interval (CI) 2.1% to 5.1% vs. EBRT 1.3%, 95% CI 0.7% to 2.5%; p = 0.04; Pnon-inferiority = 0.00000012] and in the prepathology stratum (n = 2298) when TARGIT was given concurrently with lumpectomy (TARGIT 2.1%, 95% CI 1.1% to 4.2% vs. EBRT 1.1%, 95% CI 0.5% to 2.5%; p = 0.31; Pnon-inferiority = 0.0000000013). With delayed TARGIT postpathology (n = 1153), the between-group difference was larger than 2.5% and non-inferiority was not established for this stratum (TARGIT 5.4%, 95% CI 3.0% to 9.7% vs. EBRT 1.7%, 95% CI 0.6% to 4.9%; p = 0.069; Pnon-inferiority = 0.06640]. The local recurrence-free survival was 93.9% (95% CI 90.9% to 95.9%) when TARGIT was given with lumpectomy compared with 92.5% (95% CI 89.7% to 94.6%) for EBRT (p = 0.35). In a planned subgroup analysis, progesterone receptor (PgR) status was found to be the only predictor of outcome: hormone-responsive patients (PgR positive) had similar 5-year local recurrence with TARGIT during lumpectomy (1.4%, 95% CI 0.5% to 3.9%) as with EBRT (1.2%, 95% CI 0.5% to 2.9%; p = 0.77). Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (TARGIT 2.6%, 95% CI 1.5% to 4.3% vs. EBRT 1.9%, 95% CI 1.1% to 3.2%; p = 0.56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1.4%, 95% CI 0.8% to 2.5% vs. 3.5%, 95% CI 2.3% to 5.2%; p = 0.0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm (3.9%, 95% CI 2.7% to 5.8% vs. 5.3%, 95% CI 3.9% to 7.3%; p = 0.099]. Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar quality-adjusted life-years, had a positive incremental net monetary benefit that was borderline statistically significantly different from zero and had a probability of \u3e 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health-care providers in the UK by £8–9.1 million each year. This does not include environmental, patient and societal costs. Limitations: The number of local recurrences is small but the number of events for local recurrence-free survival is not as small (TARGIT 57 vs. EBRT 59); occurrence of so few events (\u3c 3.5%) also implies that both treatments are effective and any difference is unlikely to be large. Not all 3451 patients were followed up for 5 years; however, more than the number of patients required to answer the main trial question (n = 585) were followed up for \u3e 5 years. Conclusions: For patients with breast cancer (women who are aged ≥ 45 years with hormone sensitive invasive ductal carcinoma that is up to 3.5 cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective as, safer than and less expensive than postoperative EBRT. Future work: The analyses will be repeated with longer follow-up. Although this may not change the primary result, the larger number of events may confirm the effect on overall mortality and allow more detailed subgroup analyses. The TARGeted Intraoperative radioTherapy Boost (TARGIT-B) trial is testing whether or not a tumour bed boost given intraoperatively (TARGIT) boost is superior to a tumour bed boost given as part of postoperative EBRT. Trial registration: Current Controlled Trials ISRCTN34086741 and ClinicalTrials.gov NCT00983684. Funding: University College London Hospitals (UCLH)/University College London (UCL) Comprehensive Biomedical Research Centre, UCLH Charities, Ninewells Cancer Campaign, National Health and Medical Research Council and German Federal Ministry of Education and Research (BMBF). From September 2009 this project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 73. See the NIHR Journals Library website for further project information

The Depth of Cooperation and Institutional Strength: Assessing the Design of Regional Trade Agreements

193 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2005.This study expands our understanding of the different ways that states engage in international co-operation. What can account for variations in the extent of international cooperation? What can explain differences in the strength of the international institutions that govern cooperation? To answer these questions, this project addresses two aspects of regional trade agreements (RTAs): the depth of cooperation and the strength of treaty institutions. The explanation of the depth focuses on the negotiations that produce regional trade agreements. The distribution of preferences among the negotiating states conditions the bargaining environment, and consequently, the outcome of negotiations. This approach generates two linked hypotheses. First, the higher the average preference for depth among the members will result in deeper cooperation in RTAs. Second, the more the member's preferences diverge, the shallower the final agreement. Turning to institutions, this study focuses on compliance to explain the institutional strength of regional trade agreements. Expectations of non-compliance are exacerbated by the depth of an agreement, creating an incentive to establish strong enforcement institutions. These hypotheses are tested using an innovative data set of regional trade agreements. Each expectation receives strong support. The results of this study have implications for a wide variety of research dealing with international trade cooperation, compliance, enforcement, the European Union, and international institutions.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

The Depth of Cooperation and Institutional Strength: Assessing the Design of Regional Trade Agreements

193 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2005.This study expands our understanding of the different ways that states engage in international co-operation. What can account for variations in the extent of international cooperation? What can explain differences in the strength of the international institutions that govern cooperation? To answer these questions, this project addresses two aspects of regional trade agreements (RTAs): the depth of cooperation and the strength of treaty institutions. The explanation of the depth focuses on the negotiations that produce regional trade agreements. The distribution of preferences among the negotiating states conditions the bargaining environment, and consequently, the outcome of negotiations. This approach generates two linked hypotheses. First, the higher the average preference for depth among the members will result in deeper cooperation in RTAs. Second, the more the member's preferences diverge, the shallower the final agreement. Turning to institutions, this study focuses on compliance to explain the institutional strength of regional trade agreements. Expectations of non-compliance are exacerbated by the depth of an agreement, creating an incentive to establish strong enforcement institutions. These hypotheses are tested using an innovative data set of regional trade agreements. Each expectation receives strong support. The results of this study have implications for a wide variety of research dealing with international trade cooperation, compliance, enforcement, the European Union, and international institutions.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

The Institutional Design of Riparian Treaties: The Role of River Issues

International agreements governing rivers vary considerably in whether they contain institutional provisions for joint monitoring, conflict resolution, enforcement, and/or the delegation of authority to intergovernmental organizations. This article develops an explanation for why some river management treaties include more institutional provisions while others contain fewer, if any. The authors argue that certain types of issues related to river use—water quantity, water quality, and navigation—tend to be difficult to manage and prone to noncompliance. When forming treaties to address these specific issues, states will be more likely to include institutional provisions. The authors test the link between these river use issues and institutional design using a data set of 315 river treaties signed since 1950. The results show that highly contentious issues—and in particular water quantity and navigation—have a greater effect on the institutional design of river treaties than contextual and power politics factors.cooperation, conflict, water, international institutions, transboundary rivers

Replication data for: Complying by Denying: Explaining Why States Develop Nonproliferation Export Controls

This archive contains replication data and the supplemental appendix for the article: Stinnett, Douglas, Bryan Early, Cale Horne, and Johannes Karreth. 2011. "Complying by Denying: Explaining Why States Develop Nonproliferation Export Controls." International Studies Perspectives 12 (3), 308-326. We provide original data for the nonproliferation export control systems of 30 randomly selected countries, measured in multiple dimensions