Research methodology in distal radius fracture care:1 step backward, 2 steps forward

The clinical practice guideline for distal radius fractures (DRF) has 29 recommendations; however, none of these recommendations were given a “strong” rating owing to limited strength of the evidence. Therefore, determining effective evidence-based treatment of patients with DRFs is crucial. To conduct best evidence clinical trials, and to properly compare results, there must be a consensus on the use of inclusion criteria and of outcome measures. This thesis aimed to investigate a critical component of the methodology used in DRF research, which might help us to improve the quality of future research. We therefore focused on an underappreciated aspect of methodology: assessment tools used for diagnosis and trial eligibility in patients with DRFs, and the quality of patient-reported outcome measures (PROMs). It appeared that the used classification systems have serious limitations and in our systematic review we found limited to no evidence for any of the measurement properties of the PROMs. This led us to perform a study following the COSMIN standards to ensure high methodological quality. Based on our results we now have strong evidence that both the PRWE and the DASH questionnaires have good content validity and are reliable and internally consistent instruments for the assessment of patients with distal radius fractures. Furthermore, we showed that spectrum bias has significant influence on the intra-observer agreement of distal radius fracture treatment plans. Finally, we show that is prudent to look more closely at methodological limitations of published research, especially the underappreciated and under-recognized methodological limitations discussed in this thesis

Effectiveness and cost-effectiveness of surgery versus casting for elderly patients with Displaced intra-Articular type C distal Radius fractures: protocol of a randomised controlled Trial with economic evaluation (the DART study)

Introduction Current literature is inconclusive about the optimal treatment of elderly patients with displaced intra-articular distal radius fractures. Cast treatment is less invasive and less expensive than surgical treatment. Nevertheless, surgery is often the preferred treatment for this common type of distal radius fracture. Patients with a non-acceptable position after closed reduction are more likely to benefit from surgery than patients with an acceptable position after dosed reduction. Therefore, this study aims to assess non-inferiority of functional outcomes after casting versus surgery in elderly patients with a non-acceptable position following a distal radius fracture.Methods and analysis This study is a multicentre randomised controlled trial (RCT) with a non-inferiority design and an economic evaluation alongside. The population consists of patients aged 65 years and older with a displaced intra-articular distal radius fracture with non-acceptable radiological characteristics following either inadequate reduction or redisplacement after adequate reduction. Patients will be randomised between surgical treatment (open reduction and internal fixation) and non-operative treatment (closed reduction followed by cast treatment). We will use two age strata (65-75 and >75 years of age) and a web-based mixed block randomisation. A total of 154 patients will be enrolled and evaluated with the patient-rated wrist evaluation as the primary outcome at 1-year follow-up. Secondary outcomes include the Disabilities of the Arm, Shoulder and Hand questionnaire, quality of life (measured by the EQ-5D), wrist range of motion, grip strength and adverse events. In addition, we will perform a cost-effectiveness and cost-utility analysis from a societal and healthcare perspective. Incremental cost-effectiveness ratios, cost-effectiveness planes and cost-effectiveness acceptability curves will be presented.Ethics and dissemination The Research and Ethics Committee approved this RCT (NL56858.100.16). The results of this study will be reported in a peer-reviewed journal. We will present the results of this study at (inter) national conferences and disseminate the results through guideline committees.Orthopaedics, Trauma Surgery and Rehabilitatio

Effectiveness and cost-effectiveness of surgery versus casting for elderly patients with Displaced intra-Articular type C distal Radius fractures: protocol of a randomised controlled Trial with economic evaluation (the DART study)

Introduction Current literature is inconclusive about the optimal treatment of elderly patients with displaced intra-articular distal radius fractures. Cast treatment is less invasive and less expensive than surgical treatment. Nevertheless, surgery is often the preferred treatment for this common type of distal radius fracture. Patients with a non-acceptable position after closed reduction are more likely to benefit from surgery than patients with an acceptable position after dosed reduction. Therefore, this study aims to assess non-inferiority of functional outcomes after casting versus surgery in elderly patients with a non-acceptable position following a distal radius fracture.Methods and analysis This study is a multicentre randomised controlled trial (RCT) with a non-inferiority design and an economic evaluation alongside. The population consists of patients aged 65 years and older with a displaced intra-articular distal radius fracture with non-acceptable radiological characteristics following either inadequate reduction or redisplacement after adequate reduction. Patients will be randomised between surgical treatment (open reduction and internal fixation) and non-operative treatment (closed reduction followed by cast treatment). We will use two age strata (65-75 and >75 years of age) and a web-based mixed block randomisation. A total of 154 patients will be enrolled and evaluated with the patient-rated wrist evaluation as the primary outcome at 1-year follow-up. Secondary outcomes include the Disabilities of the Arm, Shoulder and Hand questionnaire, quality of life (measured by the EQ-5D), wrist range of motion, grip strength and adverse events. In addition, we will perform a cost-effectiveness and cost-utility analysis from a societal and healthcare perspective. Incremental cost-effectiveness ratios, cost-effectiveness planes and cost-effectiveness acceptability curves will be presented.Ethics and dissemination The Research and Ethics Committee approved this RCT (NL56858.100.16). The results of this study will be reported in a peer-reviewed journal. We will present the results of this study at (inter) national conferences and disseminate the results through guideline committees

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality.Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.Maura Marcucci, Thomas W. Painter, David Conen, Kate Leslie, Vladimir V. Lomivorotov, Daniel Sessler ... et al

Tranexamic Acid in Patients Undergoing Noncardiac Surgery

BACKGROUND Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, −2.6 percentage points; 95% CI, −3.8 to −1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, −1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established.P.J. Devereaux, M. Marcucci, T.W. Painter, D. Conen, V. Lomivorotov, D.I. Sessler, M.T.V. Chan, F.K. Borges, M.J. Martínez, Zapata, C.Y. Wang, D. Xavier, S.N. Ofori, M.K. Wang, S. Efremov, G. Landoni, Y.V. Kleinlugtenbelt, W. Szczeklik, D. Schmartz, A.X. Garg, T.G. Short, M. Wittmann, C.S. Meyhoff, M. Amir, D. Torres, A. Patel, E. Duceppe, K. Ruetzler, J.L. Parlow, V. Tandon, E. Fleischmann, C.A. Polanczyk, A. Lamy, S.V. Astrakov, M. Rao, W.K.K. Wu, K. Bhatt, M. de Nadal, V.V. Likhvantsev, P. Paniagua, H.J. Aguado, R.P. Whitlock, M.H. McGillion, M. Prystajecky, J. Vincent, J. Eikelboom, I. Copland, K. Balasubramanian, A. Turan, S.I. Bangdiwala, D. Stillo, P.L. Gross, T. Cafaro, P. Alfonsi, P.S. Roshanov, E.P. Belley, Côté, J. Spence, T. Richards, T. VanHelder, W. McIntyre, G. Guyatt, S. Yusuf, and K. Leslie, for the POISE-, Investigator

Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery : An International Randomized Controlled Trial

Background: Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. Objective: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. Design: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723) Setting: 110 hospitals in 22 countries. Patients: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. Intervention: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80mm Hg or greater; before and for 2 days after surgery, renin– angiotensin–aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60mm Hg or greater; all antihypertensive medications were continued before and after surgery. Measurements: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. Results: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P =0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. Limitation: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. Conclusion: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications.Maura Marcucci, Thomas W. Painter, David Conen, Vladimir Lomivorotov, Daniel I. Sessler, Matthew T.V. Chan, Flavia K. Borges, Kate Leslie, Emmanuelle Duceppe, María Jose Martínez-Zapata, Chew Yin Wang, Denis Xavier, Sandra N. Ofori, Michael Ke Wang, Sergey Efremov, Giovanni Landoni, Ydo V. Kleinlugtenbelt, Wojciech Szczeklik, Denis Schmartz, Amit X. Garg, Timothy G. Short, Maria Wittmann, Christian S. Meyhoff, Mohammed Amir, David Torres, Ameen Patel, Kurt Ruetzler, Joel L. Parlow, Vikas Tandon, Edith Fleischmann, Carisi A. Polanczyk, Andre Lamy, Raja Jayaram, Sergey V. Astrakov, William Ka Kei Wu, Chao Chia Cheong, Sabry Ayad, Mikhail Kirov, Miriam de Nadal, Valery V. Likhvantsev, Pilar Paniagua, Hector J. Aguado, Kamal Maheshwari, Richard P. Whitlock, Michael H. McGillion, Jessica Vincent, Ingrid Copland, Kumar Balasubramanian, Bruce M. Biccard, Sadeesh Srinathan, Samandar Ismoilov, Shirley Pettit, David Stillo, Andrea Kurz, Emilie P. Belley-Côte, Jessica Spence, William F. McIntyre, Shrikant I. Bangdiwala, Gordon Guyatt, Salim Yusuf, and P.J. Devereaux, on behalf of the POISE-3 Trial Investigators and Study Group

Accelerated surgery versus standard care in hip fracture (HIP ATTACK) : an international, randomised, controlled trial

Background: Observational studies have suggested that accelerated surgery is associated with improved outcomes in patients with a hip fracture. The HIP ATTACK trial assessed whether accelerated surgery could reduce mortality and major complications. Methods: HIP ATTACK was an international, randomised, controlled trial done at 69 hospitals in 17 countries. Patients with a hip fracture that required surgery and were aged 45 years or older were eligible. Research personnel randomly assigned patients (1:1) through a central computerised randomisation system using randomly varying block sizes to either accelerated surgery (goal of surgery within 6 h of diagnosis) or standard care. The coprimary outcomes were mortality and a composite of major complications (ie, mortality and non-fatal myocardial infarction, stroke, venous thromboembolism, sepsis, pneumonia, life-threatening bleeding, and major bleeding) at 90 days after randomisation. Patients, health-care providers, and study staff were aware of treatment assignment, but outcome adjudicators were masked to treatment allocation. Patients were analysed according to the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT02027896). Findings: Between March 14, 2014, and May 24, 2019, 27 701 patients were screened, of whom 7780 were eligible. 2970 of these were enrolled and randomly assigned to receive accelerated surgery (n=1487) or standard care (n=1483). The median time from hip fracture diagnosis to surgery was 6 h (IQR 4\u20139) in the accelerated-surgery group and 24 h (10\u201342) in the standard-care group (p&lt;0\ub70001). 140 (9%) patients assigned to accelerated surgery and 154 (10%) assigned to standard care died, with a hazard ratio (HR) of 0\ub791 (95% CI 0\ub772 to 1\ub714) and absolute risk reduction (ARR) of 1% ( 121 to 3; p=0\ub740). Major complications occurred in 321 (22%) patients assigned to accelerated surgery and 331 (22%) assigned to standard care, with an HR of 0\ub797 (0\ub783 to 1\ub713) and an ARR of 1% ( 122 to 4; p=0\ub771). Interpretation: Among patients with a hip fracture, accelerated surgery did not significantly lower the risk of mortality or a composite of major complications compared with standard care. Funding: Canadian Institutes of Health Research