Randomized Treatment Allocation Research Articles

A target trial emulation comparing the antidepressant effectiveness of selective serotonin reuptake inhibitors (SSRIs) highlighting the importance of patent-related confounding by indication.

The comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) has been subjected to relatively little research. However, a recent study based on target trial emulation suggested that sertraline may be more effective than escitalopram. To investigate whether sertraline, citalopram, and escitalopram differ in their effectiveness-assessed via the risk of psychiatric hospital admission and suicide following treatment initiation. The choice to focus on sertraline, citalopram, and escitalopram was made to limit confounding by indication, as the Danish depression treatment guideline from 2007 specifically listed these three SSRIs as first choice. We conducted a target trial emulation based on data from Danish registers. We identified all individuals that initiated treatment for depression with sertraline, citalopram, or escitalopram in the period from January 1, 2007, to March 1, 2019. These individuals were followed until psychiatric hospital admission or suicide (separate analyses), death, 1 year after treatment initiation or end of data. Cox proportional hazards regression adjusted for relevant baseline covariates was performed to emulate randomized treatment allocation, comparing the rate of psychiatric hospital admission and suicide for individuals treated with sertraline (used as reference), citalopram or escitalopram, respectively. For escitalopram, we conducted a sensitivity analysis excluding data from the period during which the drug was sold under patent, as the price of the drug during that time likely entailed a different prescription pattern, increasing the risk of ("patent-related") confounding by indication. We identified 56,865, 118,145, and 31,083 individuals initiating treatment with sertraline, citalopram, and escitalopram, respectively. Using sertraline as reference, the adjusted hazard rate ratio (aHRR) for psychiatric admission was 0.98 (95% CI = 0.91-1.05) for citalopram and 1.21 (95% CI = 1.10-1.32) for escitalopram. Notably, in the sensitivity analysis only including patients initiating treatment after the escitalopram patent had expired, the increased risk of psychiatric hospital admission associated with escitalopram treatment was no longer present (aHRR = 0.98, 95% CI = 0.82-1.18). The results of the analyses of suicide were inconclusive, due to few outcome events. Sertraline, citalopram, and escitalopram do not seem to have differential effectiveness in the treatment of depression. Taking potential patent-related, time varying, confounding by indication (via severity) into account is critical for pharmacoepidemiological studies, including those employing target trial emulation.

Data integrity of 14 randomised controlled trials

BackgroundA review of the literature on iron treatments for iron-deficient anaemia in pregnancy indicated duplication of baseline and outcome tables in two separate randomised controlled trials (RCTs) that share only a single author. AimTo assess the integrity of randomised clinical trials from Dr A.M. Darwish, Assiut University, Egypt. DesignAssessment of Research Integrity. MethodsWe tabulated the characteristics of studies, compared baseline and outcome tables between articles and looked for implausible findings. We used the distribution of baseline p-values to assess whether the summary statistics of baseline characteristics were consistent with properly conducted randomisation. ResultsWe identified 14 RCTs (1,405 participants) published between October 2004 and September 2019. Two pairs of studies showed considerable similarities in baseline characteristics, while another pair of studies was plagiarized. The analysis of baseline p-values indicated a low probability that all the studies featured randomised treatment allocation. ConclusionOur analysis of the RCTs of Dr Darwish suggests possible integrity problems. We recommend a critical investigation of the studies that have not been retracted. Until that has been completed, these studies should not be used to inform clinical practice.

Renal function and natriuresis-guided diuretic therapy-a pre-specified analysis from the PUSH-AHF trial.

In a randomized controlled trial, we recently showed that a natriuresis-guided diuretic approach improved natriuresis and diuresis in patients with acute heart failure (HF). In this pre-specified analysis, we investigated the association between (worsening) renal function, outcomes and the effect of intensive natriuresis-guided loop diuretic therapy as compared with standard of care. The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) trial randomized patients to natriuresis-guided diuretic therapy or standard of care. Serum creatinine and estimated glomerular filtration rate (eGFR) were assessed at fixed timepoints, and worsening renal function (WRF) was assessed at 72 h. The primary outcome was the interaction between randomized treatment allocation, baseline eGFR and the dual primary outcome of PUSH-AHF: total natriuresis at 24 h and time to all-cause mortality or HF rehospitalization at 180 days. In 309 patients, median baseline eGFR was 53 (35-73) ml/min/1.73 m2, and 58% had eGFR <60 ml/min/1.73 m2. Baseline eGFR did not significantly modify the treatment effect of natriuresis-guided diuretic therapy on natriuresis at 24 h (p for interaction = 0.730). However, baseline eGFR significantly modified the effect on all-cause mortality and HF rehospitalization (p for interaction = 0.017): the risk of this second primary outcome was lower in patients with lower eGFR who were randomized to the natriuresis-guided group. In the natriuresis-guided arm, eGFR decreased more (-11.0 vs. -6.91 ml/min/1.73 m2; p = 0.002) during the first 3 days, but this effect was attenuated at discharge (-10.3 vs. -8.69 ml/min/1.73 m2; p = 0.38). WRF was more frequently observed in patients randomized to natriuresis-guided treatment, but was not associated with worse clinical outcomes. Natriuresis-guided diuretic treatment improved diuresis and natriuresis irrespective of baseline eGFR and occurrence of WRF, was effective even in patients with low eGFR, and the observed effect on eGFR was transient and not associated with worse clinical outcomes.

Abstract PO2-19-11: NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer

Abstract Background The standard of care for patients with early triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efficacy. Among TNBC, BRCA mutations and other homologous recombination deficiency (HRD) signals are relatively frequent. As opposed to other types of breast cancer, TNBC show a high neoantigen load, a large number of tumour infiltrating lymphocytes (TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors (PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting. Trial design NOBLE is an EORTC phase 2, randomized, international, multicentre, open label, clinical trial. Eligible patients will undergo central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized 1:1 between olaparib vs olaparib and durvalumab for 4 cycles (16 weeks) of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 – Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) – Futility; and Step 3 (202/152) – Expansion of recruitment. The primary endpoint is the rate of pathologic complete response (pCR) at the time of surgery, defined as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the first patient. Main inclusion criteria Histologically confirmed primary TNBC, defined as: - ER and PgR ≤ 10% - HER2-negative per ASCO CAP guidelines Stage T1c-T2 N0-N1 M0 BRCA mutation and/or HRD based on methylation as determined by central testing ECOG status 0-1 Written informed consent Age ≥18 years No prior systemic therapy nor surgery for the current Main exclusion criteria Previous treatment with a PARPi or an immune-checkpoint inhibitor History of previous invasive breast cancer Bilateral and/or multifocal and/or multicentric BC Autoimmune or inflammatory disease Specific aims The aim of this study is to provide a safe and effective neoadjuvant treatment free of chemotherapy to a distinct subpopulation among patients with TNBC. We will evaluate the pCR after neoadjuvant treatment with olaparib alone and with olaparib in combination with durvalumab in patients with TNBC showing a BRCA1/2 mutation or HRD based on methylation. Statistical methods The sample size was calculated based on the minimax Simon two-stage design including an interim analysis for futility of the primary endpoint. Decision rules are pre-specified in the study protocol. Each treatment arm will be analyzed independently. There will be no formal comparison between the two experimental treatment arms. A minimization technique will be used for random treatment allocation stratifying for the type of HRD alteration, PD-L1 expression level and for TILs. Accrual We expect to start recruiting in September 2023. We aim to screen 455 patients to randomize 152 patients. Contact information for people with a specific interest in the trial Etienne Brain (study coordinator): etienne.brain@curie.fr Anne-Sophie Hamy-Petit (study co-coordinator): anne-sophie.hamy-petit@curie.fr Citation Format: Emanuel Buhrer, Eleni Xenophontos, Anne-Sophie Hamy-Petit, Jose Casas-Martin, Céline Callens, Thomas Meyskens, Coralie Poncet, Anastasia Lanzi, Etienne Brain. NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-11.

Body composition changes during breast cancer preventive treatment with anastrozole: Findings from the IBIS-II trial

BackgroundUptake to anastrozole for breast cancer prevention is low, partly due to women’s concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass. Here we assess association of anastrozole with body composition changes in a prospective sub-study from the second international breast intervention trial (IBIS-II). MethodsParticipants had DXA scans at baseline and for five years of anastrozole/placebo and beyond (between March 2004 and September 2017. Primary outcomes were changes in body weight, body fat and fat free mass at 9–18 months. A linear model was used to estimate the size of a differential effect in these outcomes by randomised treatment allocation adjusted for baseline value and time since last scan, age, 10-year breast cancer risk, smoking and HRT status. Results203 postmenopausal women were recruited (n = 95 anastrozole, n = 108 placebo), mean age 58 years (SD = 5.4), BMI 28.0 kg/m2 (SD = 5.5). There was no evidence of a strong association between anastrozole or placebo and endpoints at 9–18 months; effect size (95 %CI) for anastrozole minus placebo for body weight (per/kg) −0.11 (−1.29–1.08); body fat 0.11 (−0.75–0.96) and fat free mass −0.30 (−0.79–0.19). ConclusionsThere is unlikely to be a clinically significant change to body composition with anastrozole for breast cancer prevention.

Economic Effect and Disparity of Airport Economic Zones Utilizing the Synthetic Control Method

This study investigates the economic impact of an airport economic zone (AEZ) on a city using the synthetic control method (SCM). It is an important issue for small-sized and medium-sized cities to make effective strategic plans for AEZs according to their own characteristics. Cities have begun to imitate the successful experiences of AEZs in cities with larger economies, but they often fail to replicate the same path. Moreover, the current methods are likely to reduce the reliability of the causality argument because of the lack of random sampling and random allocation of treatment. The SCM can solve this problem. In this research, the SCM was used to investigate panel data for 37 small- and medium-sized cities in China for the period 2000–2016. The results showed that the presence of an airport had a significant positive economic effect on cities with a higher economic strength and a weak positive effect on cities with a lower economic strength in our treatment group sample. In investigating the causal mechanism for this disparity, we found that the higher the match between the types of industries laid out in the AEZ and the city’s dominant industries, the better the economic development from a long-term development perspective. In addition, since AEZs are embedded in specific socio-economic contexts, it is sometimes difficult to apply successful experiences to AEZs in less developed cities. Our research utilized a new policy evaluation method and has significant implications for decision-makers.

Rationale and design of the THIRST Alert feasibility study: a pragmatic, single-centre, parallel-group randomised controlled trial of an interruptive alert for oral fluid restriction in patients treated with intravenous furosemide

IntroductionAcute heart failure (HF) is a major cause of unplanned hospitalisation characterised by excess body water. A restriction in oral fluid intake is commonly imposed on patients as an adjunct...

Long-Term Effect of Maintenance Electroconvulsive Therapy in Patients With Depression-Data From a Small Randomized Controlled Trial.

This study aimed to compare the long-term effects of maintenance electroconvulsive therapy (M-ECT) with medication and medication only in patients with depression. A randomized controlled trial of 1 year of M-ECT with medication or medication only investigated relapse/recurrence among 56 patients in remission after electroconvulsive therapy (ECT) for depression was conducted. The results of the first year are published already and showed a significant advantage of M-ECT with medication.The current study was a long-term follow-up. When the randomized treatment allocation ended, medication was continued in both groups but M-ECT was terminated. Patients were followed for up to 10 years via Swedish national registers until the study endpoint of a new psychiatric diagnosis as an inpatient, suicide, suspected suicide, or death of another cause. Time to relapse was compared between the M-ECT with medication group and the medication-only group using Kaplan-Meier estimates. The median follow-up time was 6.5 years for the M-ECT and medication group and 3.1 years for the medication-only group. One year after randomization 22 patients remained in the M-ECT and medication group, and 14 patients remained in the medication-only group. Relapse patterns between the treatment groups after the completion of M-ECT seemed to be similar according to visual inspection. This long-term follow-up study suggests that most of the benefit achieved during the treatment period with M-ECT is maintained over several years, but the small sample size, with accompanying large statistical imprecision, makes the results uncertain. More long-term studies of M-ECT are required.Trial registration: ClinicalTrials.gov identifier: NCT00627887.

Does knowledge of blood calcium concentration at 2 days postpartum affect decisions of calcium supplementation?

Delaying oral Ca supplementation might benefit cows with low blood Ca concentrations at 4 d in milk (DIM), a time when reduced blood total Ca (tCa) is associated with negative health and production outcomes. To implement a targeted approach to manage subclinical hypocalcemia (SCH) at the herd level, it is important to identify which cows benefit from supplemental Ca. Therefore, our objective was to determine if SCH diagnosis at 2 DIM could inform decisions of oral Ca supplementation at 2 and 3 DIM based on milk yield and 4 DIM blood Ca concentration. Data were analyzed from a previously conducted randomized controlled trial on multiparous cows (n = 518) from 4 farms in New York State. Cows were randomly assigned to 1 of 2 treatment groups at calving: (1) control (CON; no Ca supplementation, n = 259) or (2) bolus (BOL; 43 g of oral Ca administered at 2 and 3 DIM postcalving, n = 259). For each parity group (2, 3, 4+), we used generalized linear mixed models to identify serum tCa concentrations at 2 DIM that maximized the difference in milk yield to diagnose SCH. Cows were classified as normocalcemic (NC; parity 2 tCa >1.9 mmol/L, parity 3 tCa >1.87 mmol/L, n = 327; parity ≥4 had no defining threshold) or SCH (parity 2 tCa ≤1.9 mmol/L, parity 3 tCa ≤1.87 mmol/L, n = 58; parity ≥4 had no defining threshold). Parity 2 and 3 cows were further classified into 1 of 4 SCH-treatment groups (SCHTRT) based on 2 DIM SCH status and random treatment allocation: (1) NC-CON, n = 165, (2) SCH-CON, n = 28, (3) NC-BOL, n = 162, or (4) SCH-BOL, n = 30. Generalized linear mixed models were used to analyze the difference in milk yield for the first 10 wk of lactation and tCa at 4 DIM between SCHTRT groups with separate analyses performed for parities 2 and 3. Mean milk yield differed between SCHTRT groups for both parities. For parity 2, SCH-CON and SCH-BOL cows produced more milk than NC-CON and NC-BOL cows with SCH-CON producing 50.9 (95% confidence interval [CI] = 48.4, 53.4) kg/d, SCH-BOL 51.7 (49.1, 54.2) kg/d, NC-CON 47.5 (46.3, 48.7) kg/d, and NC-BOL 47.2 (45.8, 48.5) kg/d of milk. Milk yield was also different between SCHTRT groups for parity 3 with SCH-BOL cows producing more milk than NC-CON and NC-BOL cows. In parity 3, SCH-BOL cows produced 56.3 (95% CI = 53.1, 59.3) kg/d, SCH-CON 51.7 (48.6, 54.7) kg/d, NC-BOL 50.6 (49.0, 52.2) kg/d, and NC-CON 48.7 (46.9, 50.5) kg/d of milk. For both parities, SCH-CON and SCH-BOL cows had lower tCa at 2 DIM than NC-CON and NC-BOL cows. At 4 DIM, tCa concentrations were similar for all SCHTRT groups respective to parity. Our results suggest that although delayed Ca bolus administration does not improve blood Ca concentration when compared with controls, it does support increased milk production in parity 3 cows regardless of Ca status at 2 DIM. Thus, knowledge of blood Ca at 2 DIM should not affect decisions of Ca supplementation in this parity of cows.

Propofol and survival: an updated meta-analysis of randomized clinical trials

BackgroundPropofol is one of the most widely used hypnotic agents in the world. Nonetheless, propofol might have detrimental effects on clinically relevant outcomes, possibly due to inhibition of other interventions' organ protective properties. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate if propofol reduced survival compared to any other hypnotic agent in any clinical setting.MethodsWe searched eligible studies in PubMed, Google Scholar, and the Cochrane Register of Clinical Trials. The following inclusion criteria were used: random treatment allocation and comparison between propofol and any comparator in any clinical setting. The primary outcome was mortality at the longest follow-up available. We conducted a fixed-effects meta-analysis for the risk ratio (RR). Using this RR and 95% confidence interval, we estimated the probability of any harm (RR > 1) through Bayesian statistics. We registered this systematic review and meta-analysis in PROSPERO International Prospective Register of Systematic Reviews (CRD42022323143).ResultsWe identified 252 randomized trials comprising 30,757 patients. Mortality was higher in the propofol group than in the comparator group (760/14,754 [5.2%] vs. 682/16,003 [4.3%]; RR = 1.10; 95% confidence interval, 1.01–1.20; p = 0.03; I2 = 0%; number needed to harm = 235), corresponding to a 98.4% probability of any increase in mortality. A statistically significant mortality increase in the propofol group was confirmed in subgroups of cardiac surgery, adult patients, volatile agent as comparator, large studies, and studies with low mortality in the comparator arm.ConclusionsPropofol may reduce survival in perioperative and critically ill patients. This needs careful assessment of the risk versus benefit of propofol compared to other agents while planning for large, pragmatic multicentric randomized controlled trials to provide a definitive answer.Graphical

Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury: Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial.

Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients (~3200) aged 55 years and older having major thoracic surgery. Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2. The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Substudy results will be reported in 2024. This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery. NCT03310125.

Association between serum urate and flares in people with gout and evidence for surrogate status: a secondary analysis of two randomised controlled trials.

Use of serum urate as a treatment target and outcome measure has become controversial in view of the 2017 American College of Physicians guidelines, which advocated a treat-to-symptom rather than a treat-to-target serum urate approach to gout management. The relevance of serum urate as a treatment target measure implies that achievement of target serum urate is causally associated with improvement in patient-important outcomes such as reduction in the number of gout flares. The aim of this study was to assess the causal relationship between achieving target serum urate and the occurrence of gout flares. We analysed individual patient-level data from two randomised trials on urate-lowering therapies in people with gout conducted in Nottingham, UK, and New Zealand. We included participants randomly assigned to immediate dose escalation in the New Zealand study and all participants in the Nottingham study (a nurse-led gout care group and a general practitioner-led usual care group). Individuals who on average achieved a serum urate concentration less than 6 mg/dL (0·36 mmol/L) based on data at 6, 9, and 12 months post-baseline were defined as serum urate responders. The primary outcome was the proportion of participants having at least one gout flare, and the secondary outcome was the mean number of flares per participant per month, from 12 to 24 months after baseline, compared between serum urate responders and non-responders. In adjusted logistic regression models, serum urate at baseline, previous flare history (in the year preceding study entry), presence of tophi at baseline, and, for the Nottingham dataset, the original randomisation group, were included as covariates. The Nottingham study was registered with ClinicalTrials.gov, NCT01477346. The New Zealand study was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000845932. From the combined individual data from both trials, we identified 343 serum urate responders and 245 serum urate non-responders. Significantly fewer serum urate responders had a gout flare than did serum urate non-responders between 12 and 24 months (91 [27%] of 343 vs 156 [64%] of 245; adjusted odds ratio [OR] 0·29 [95% CI 0·17 to 0·51], p<0·0001). The mean number of flares per participant per month between 12 and 24 months was significantly lower in serum urate responders than in serum urate non-responders (adjusted mean difference -1·41 [95% CI -1·77 to -1·04], p<0·0001). This association was independent of the original randomised treatment allocation. Achieving an average serum urate concentration less than 6 mg/dL is associated with an absence of gout flares and a reduction in the number of flares in the subsequent 12 months in people with gout. These results support a treat-to-target serum urate approach in the management of gout. None.

Treatment selection using prototyping in latent-space with application to depression treatment.

Machine-assisted treatment selection commonly follows one of two paradigms: a fully personalized paradigm which ignores any possible clustering of patients; or a sub-grouping paradigm which ignores personal differences within the identified groups. While both paradigms have shown promising results, each of them suffers from important limitations. In this article, we propose a novel deep learning-based treatment selection approach that is shown to strike a balance between the two paradigms using latent-space prototyping. Our approach is specifically tailored for domains in which effective prototypes and sub-groups of patients are assumed to exist, but groupings relevant to the training objective are not observable in the non-latent space. In an extensive evaluation, using both synthetic and Major Depressive Disorder (MDD) real-world clinical data describing 4754 MDD patients from clinical trials for depression treatment, we show that our approach favorably compares with state-of-the-art approaches. Specifically, the model produced an 8% absolute and 23% relative improvement over random treatment allocation. This is potentially clinically significant, given the large number of patients with MDD. Therefore, the model can bring about a much desired leap forward in the way depression is treated today.

A Markov decision process for response adaptive designs

The randomized treatment allocation process in a response adaptive clinical trial is formulated as a stochastic sequential decision problem and an algorithm is proposed to approximate the optimal value under the average reward criterion. When the information of previous treatment allocations and associated responses are summarized with sufficient statistics for unknown parameters, the decision process becomes a Markov process, on which a span-contractor operator is defined. It is proven that the average reward under the policy identified from the span-contractor operator converges almost surely to the optimal value. Numerical results reveal that the sequential procedure based on the controlled Markov process shows superior ethical advantage and at the same time produces good statistical power for large sample sizes such as 200 or larger.

Rationale for a Clinical Trial That Compares Acute Stroke Rehabilitation at Inpatient Rehabilitation Facilities to Skilled Nursing Facilities: Challenges and Opportunities

In the United States, approximately 400,000 patients with acute stroke are discharged annually to inpatient rehabilitation facilities (IRFs) or skilled nursing facilities (SNFs). Typically, IRFs provide time-intensive therapy for an average of 2-3 weeks, whereas SNFs provide more moderately intensive therapy for 4-5 weeks. The factors that influence discharge to an IRF or SNF are multifactorial and poorly understood. The complexity of these factors in combination with subjective clinical indications contributes to large variations in the use of IRFs and SNFs. This has significant financial implications for health care expenditure, given that stroke rehabilitation at IRFs costs approximately double that at SNFs. To control health care spending without compromising outcomes, the Institute of Medicine has stated that policy reforms that promote more efficient use of IRFs and SNFs are critically needed. A major barrier to the formulation of such policies is the highly variable and low-quality evidence for the comparative effectiveness of IRF- vs SNF-based stroke rehabilitation. The current evidence is limited by the inability of observational data to control for residual confounding, which contributes to substantial uncertainty around any magnitude of benefit for IRF- vs SNF-based care. Furthermore, it is unclear which specific patients would receive the most benefit from each setting. A randomized controlled trial addresses these issues, because random treatment allocation facilitates an equitable distribution of measured and unmeasured confounders. We discuss several measurement, practical, and ethical issues of a trial and provide our rationale for design suggestions that overcome some of these issues.

FC 119SURVIVAL BENEFIT OF KIDNEY TRANSPLANTATION COMPARED TO REMAINING ON WAITLIST ACROSS DIFFERENT AGES OF TRANSPLANT CANDIDATES: A RETROSPECTIVE COHORT STUDY USING TARGET TRIAL EMULATION

Abstract Background and Aims Kidney transplantation is considered to be the optimal treatment strategy for eligible end stage renal disease patients. However, the body of evidence to underpin the anticipated survival advantage for kidney transplant recipients is weak, as random treatment allocation to either kidney transplantation or remaining on dialysis is not feasible and previously reported results obtained from observational studies did not allow for causal interpretation. The aim of this study is to investigate survival differences of kidney transplantation compared to remaining waitlisted on dialysis across different transplant candidate ages applying causal inference methodology. Method We conducted a retrospective cohort study using the Austrian Dialysis and Transplant Registry. We included all maintenance dialysis patients who were waitlisted for their first kidney transplant between January 2000 and December 2018 and utilized repeated updates on waitlisting status and relevant covariates. To estimate the causal effect of kidney transplantation compared to remaining waitlisted on all-cause survival we applied a sequential Cox approach mimicking a series of target trials, where each trial started at the time of a transplantation. In each of these emulated trials transplanted patients were classified as treated and patients with current active waitlisting status as controls, and the groups were balanced for covariates by inverse probability weighting. Controls who were transplanted at later times were censored but assigned to the treated group in a later target trial of the series. All trials were combined into a single data set and analyzed by a Cox proportional hazards model using inverse probability weighting also to adjust for artificial censoring. Additionally, we evaluated potential effect modifications by age at trial initiation (continuous) and stratified our analyses by time on waitlist before trial initiation (up to 1 year, between 1 and 2 years, and more than 2 years). Results are reported as hazard ratios (HRs), 5-year survival probabilities and restricted mean survival time together with respective bootstrap confidence intervals (CIs). Results The study cohort consisted of 4206 patients, of whom one third were women and the mean age was 52 years. In total, 3399 patients (81%) received a transplant and 1256 patients died. The median time from waitlisting to transplantation was 1.8 years. Overall, patients who received a kidney transplant had a significant survival benefit compared to patients who remained waitlisted (HR 0.36, 95% CI 0.29 to 0.43). Assessing survival across different ages showed a significant benefit for kidney transplantation for patients between 32 and 77 years of age at time of transplantation (e.g. HR at age of 70: 0.43, 95% CI 0.33 to 0.54). For older and younger patients our analysis did not provide definitive conclusions due to limited sample sizes. Transplanted patients had higher predicted survival and longer restricted mean survival time compared to patients remaining waitlisted. For example, within 5 years after engraftment, a transplanted patient 70 years of age at trial initiation had a 0.28 higher survival probability (95% CI 0.20-0.37) and was expected to gain 0.75 years of survival time. Our stratified analyses showed a survival benefit for kidney transplantation regardless of time on waitlist before trial initiation across all ages. Conclusion Our study provides robust evidence based on state-of-the-art causal inference methodology for increased survival after kidney transplantation across different transplant candidate ages and irrespective of time on waiting list.

THE DEVELOPMENT OF RESISTANT HYPERTENSION INDEPENDENT OF THE PRECEDING PERIOD OF THE BLOOD PRESSURE CONTROL IS ASSOCIATED WITH THE INCREASED RISK OF CARDIOVASCULAR EVENTS AND DEATH

Objective: Resistant hypertension (RH) is associated with the increased risk of cardiovascular events (CVEs); that excess risk is often attributed to the legacy of the previous period of uncontrolled blood pressures (BPs). We used the database of the ASCOT trial to evaluate the risk of CVEs (non-fatal myocardial infarction, fatal coronary heart disease, and fatal/non-fatal stroke) and death, after controlling for the cumulative mean of BPs for a preceding period of 2-years (using area-under-curve [AUC]). Design and method: 18,926 hypertensive patients were initially followed up for the development of RH or not for a period of 2-years. During that period, we calculated the AUC of the cumulative mean BPs (AUCcmBPs) until the RH diagnosis or the end of the 2-year period if no-RH. These patients were then followed up from this new baseline for the risk of CVEs or death. We estimated incidence rates and developed a multivariable Cox regression model after adjusting for a-priori confounders (age, sex, socio-economic status, BMI, total cholesterol, HDL-cholesterol, systolic-BP at baseline, randomized treatment allocation, diabetes, other vascular diseases) and the AUCcmBPs. Interaction tests were done for those who were taking antihypertensive medications prior to the randomization or not. Results: About one-third (n = 5,660) developed RH by the end of 2-years. During the further median follow-up of 3.9 years, there were 1113 CVEs and 745 deaths. The incidence rate of CVE and death was higher in those with RH vs those without (34.8 and 18.9 per 1,000 person-years vs 24.0 and 15.4, respectively). In the multivariable model after controlling for the AUCcmBPs, those with RH, as compared to those without, had a significantly higher risk of CVE and death (HR: 1.15 [95% CI 1.03–1.27], p-value = 0.010, and 1.16 [1.02–1.33], p-value = 0.028, respectively). This excess in the risk didn’t differ significantly between those who were on prior antihypertensive therapy or not (interaction test p-value = 0.430 and p-value = 0.310, respectively). Conclusions: After accounting for prior BPs, the presence of RH is associated with the increased risk of CVEs and death; which could be because of the additional risk due to associated genotypical or phenotypical factors.

Geography, generalisability, and susceptibility in clinical trials

Randomised clinical trials (RCTs) are generally considered the highest standard of evidence in medical research, as randomised treatment allocation promotes homogeneity in baseline characteristics between treatment groups, maximising internal validity and reducing both bias and confounding. RCTs, however, often enrol a convenience clinical sample, and can face challenges of external validity if that sample does not represent the full population at risk, or the full range of co-exposures and susceptibility factors likely to be encountered in clinical practice.

Clinical efficacy of hyaluronate-containing embryo transfer medium in IVF/ICSI treatment cycles: a cohort study.

STUDY QUESTIONDoes the duration of embryo exposure to hyaluronic acid (HA) enriched medium improve the rate of live birth events (LBEs)?SUMMARY ANSWERThe use of embryo transfer (ET) medium rich in HA improves LBE (a singleton or twin live birth) regardless of the duration of exposure evaluated in this study, but does not alter gestation or birthweight (BW).WHAT IS KNOWN ALREADYHA-enriched medium is routinely used for ET in ART to facilitate implantation, despite inconclusive evidence on safety and efficacy.STUDY DESIGN, SIZE, DURATIONA cohort study was performed evaluating clinical treatment outcomes before and after HA-enriched ET medium was introduced into routine clinical practice. In total, 3391 fresh ET procedures were performed using low HA and HA-rich medium in women undergoing publicly funded IVF/ICSI treatment cycles between May 2011 and April 2015 were included in this cohort study.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 1018 ET performed using low HA medium were compared with 1198, and 1175 ET following exposure to HA-rich medium for 2–4 h (long HA exposure) or for 10–30 min (short HA exposure), respectively. A multiple logistic regression analysis was used to compare clinical outcomes including BW, gestational age and sex ratios between groups, whilst adjusting for patient age, previous attempt, incubator type and the number of embryos transferred.MAIN RESULTS AND THE ROLE OF CHANCEThe use of HA-rich medium for ET was positively and significantly associated with improved clinical pregnancy rate and LBE, for both exposure durations: long HA (odds ratio (OR) = 1.21, 95% CI: 0.99–1.48), short HA (OR = 1.32, 95% CI: 1.02–1.72) and pooled OR = 1.26, 95% CI: 1.03–1.54, relative to the use of low HA medium. A comparative analysis of the risks of early pregnancy loss following long HA exposure (OR = 0.76, 95% CI: 0.54–1.06), short HA exposure (OR = 0.84, 95% CI: 0.54–1.30) and late miscarriage (OR = 0.88, 95% CI: 0.51–1.53) (OR = 1.41, 95% CI 0.72–2.77), were lower and not statistically significant. Similarly, ordinary regression analysis of the differences in BW at both HA exposures; pooled OR = −0.9 (−117.1 to 115.3), and adjusted BW between both HA cohorts; pooled OR = −13.8 (−106.1 to 78.6) did not show any differences. However, a difference in gestational age (pooled OR −0.3 (−3.4 to 2.9)) and sex ratio (pooled OR 1.43 (0.95–2.15)) were observed but these were not statistically significant relative to low HA medium.LIMITATIONS, REASONS FOR CAUTIONThe strength of a randomized treatment allocation was not available in this evaluation study, therefore effects of unmeasured or unknown confounding variables cannot be ruled out.WIDER IMPLICATIONS OF THE FINDINGSThe result of this large cohort study strengthens the case for using HA-rich medium routinely at transfer, while adding the important clinical information that duration of exposure may not be critical. The composition and effects of commercial IVF culture media on success rate and safety remains a major controversy despite increasing calls for transparency and evidence-based practice in ART. Nonetheless, the lack of differences in BW and gestational age observed in this study were reassuring. However, an appraisal of clinical outcomes and appropriate research investigations are required for the continuous evaluation of efficacy and safety of HA.STUDY FUNDING/COMPETING INTEREST(S)T.A. is funded by a Clinical Doctoral Research Fellowship (CDRF) grant (reference: ICA-CDRF-2015-01-068) from the National Institute for Health Research (NIHR). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The authors declare no conflict of interest.

Thromboxane metabolite excretion is associated with serious vascular events in diabetes mellitus: a sub-study of the ASCEND trial

Abstract Background Platelet activation plays a major role in the atherothrombotic complications of diabetes. Thromboxane (TX)A2 is a pro-thrombotic prostanoid, synthesized via cyclooxygenase-1 and released by activated platelets. The metabolism of TXA2 in vivo leads to a major stable end-product, 11-dehydro-TXB2 (TXM), measurable in urine and reflecting the whole-body rate of TXA2 biosynthesis. In two large trials of high-risk, aspirin-treated (mostly, without diabetes) patients, (CHARISMA and HOPE trials), the baseline rate of urinary TXM excretion was an independent predictor of future cardiovascular events. Purpose The aim of the ASCEND (A Study of Cardiovascular Events in Diabetes) TXM sub-study was to investigate the association between baseline urinary TXM and future serious vascular events or revascularization (SVE-R), major bleeds and incident cancer independent of other risk factors and treatment, in people with diabetes and no manifest cardiovascular disease at trial entry. Methods Urinary TXM was measured by a previously GC/MS-validated, immunoassay in 6,487 participants with eligible baseline samples. Analyses excluded 539 participants using NSAIDs. TXM appeared log-normally distributed, so analyses were by quintiles and per SD (=0.622) of continuous loge TXM. The association of loge TXM with outcome was adjusted by basic factors (age, sex, sample volume and randomized treatment allocation) and by the predictors of log TXM (smoking, type 2 diabetes treated with insulin or oral hypoglycaemics, HDL cholesterol, body mass index, urinary albumin/creatinine ratio, eGFR). The association of log TXM with non-vascular, non-cancer MedDRA outcomes was investigated to determine whether TXM had a general effect on outcome. During a mean of 6.6 years follow-up there were 618 SVE-Rs, 206 bleeds and 700 cancers among these patients. Results Log TXM correlated significantly with SVE-R, hazard ratio (HR) per 1 SD of log TXM: 1.13 (1.04–1.23), p=0.003 (Figure 1, panel a), non-significantly with major bleeds [HR 1.15 (1.00–1.32), p=0.055] (Figure 1, panel b), and marginally significantly with cancer [HR 1.09 (1.01–1.17), p=0.03] (Figure 1, panel c). There was no association of log TXM with non-vascular non-cancer MedDRA outcomes (HR per 1 SD, 0.99; 99% CI, 0.94–1.05). Conclusion The rate of urinary TXM excretion, a non-invasive biomarker of TXA2-mediated platelet activation in vivo, is log-linearly associated with serious vascular events independent of other risk factors in people with diabetes. Its potential association with cancer must be viewed as hypothesis-generating and needs confirmation. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): IMI1: Surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools (SUMMIT).