As-treated Research Articles

Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis.

In IVF/ICSI treatment, the process of embryo implantation is the success rate-limiting step. Endometrial scratching has been suggested to improve this process, but it is unclear if this procedure increases the chance of implantation and live birth (LB) and, if so, for whom, and how the scratch should be performed. This individual participant data meta-analysis (IPD-MA) aims to answer the question of whether endometrial scratching in women undergoing IVF/ICSI influences the chance of a LB, and whether this effect is different in specific subgroups of women. After its incidental discovery in 2000, endometrial scratching has been suggested to improve embryo implantation. Numerous randomized controlled trials (RCTs) have been conducted, showing contradicting results. Conventional meta-analyses were limited by high within- and between-study heterogeneity, small study samples, and a high risk of bias for many of the trials. Also, the data integrity of several trials have been questioned. Thus, despite numerous RCTs and a multitude of conventional meta-analyses, no conclusion on the clinical effectiveness of endometrial scratching could be drawn. An IPD-MA approach is able to overcome many of these problems because it allows for increased uniformity of outcome definitions, can filter out studies with data integrity concerns, enables a more precise estimation of the true treatment effect thanks to adjustment for participant characteristics and not having to make the assumptions necessary in conventional meta-analyses, and because it allows for subgroup analysis. A systematic literature search identified RCTs on endometrial scratching in women undergoing IVF/ICSI. Authors of eligible studies were invited to share original data for this IPD-MA. Studies were assessed for risk of bias (RoB) and integrity checks were performed. The primary outcome was LB, with a one-stage intention to treat (ITT) as the primary analysis. Secondary analyses included as treated (AT), and the subset of women that underwent an embryo transfer (AT+ET). Treatment-covariate interaction for specific participant characteristics was analyzed in AT+ET. Out of 37 published and 15 unpublished RCTs (7690 participants), 15 RCTs (14 published, one unpublished) shared data. After data integrity checks, we included 13 RCTs (12 published, one unpublished) representing 4112 participants. RoB was evaluated as 'low' for 10/13 RCTs. The one-stage ITT analysis for scratch versus no scratch/sham showed an improvement of LB rates (odds ratio (OR) 1.29 [95% CI 1.02-1.64]). AT, AT+ET, and low-RoB-sensitivity analyses yielded similar results (OR 1.22 [95% CI 0.96-1.54]; OR 1.25 [95% CI 0.99-1.57]; OR 1.26 [95% CI 1.03-1.55], respectively). Treatment-covariate interaction analysis showed no evidence of interaction with age, number of previous failed embryo transfers, treatment type, or infertility cause. This is the first meta-analysis based on IPD of more than 4000 participants, and it demonstrates that endometrial scratching may improve LB rates in women undergoing IVF/ICSI. Subgroup analysis for age, number of previous failed embryo transfers, treatment type, and infertility cause could not identify subgroups in which endometrial scratching performed better or worse. The timing of endometrial scratching may play a role in its effectiveness. The use of endometrial scratching in clinical practice should be considered with caution, meaning that patients should be properly counseled on the level of evidence and the uncertainties.

Kidney function loss and albuminuria progression with GLP-1 receptor agonists versus basal insulin in patients with type 2 diabetes: real-world evidence

BackgroundIn clinical trials enrolling patients with type 2 diabetes (T2D) at high cardiovascular risk, many glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved albuminuria status and possibly mitigated kidney function loss. However, limited data are available regarding the effects of GLP-1 RAs on albuminuria status and kidney function in real-world settings, including populations with a lower baseline cardiovascular and kidney risk. We assessed the association of GLP-1 RAs initiation with long-term kidney outcomes in the Maccabi Healthcare Services database, Israel.MethodsAdults with T2D treated with ≥ 2 glucose-lowering agents who initiated GLP-1 RAs or basal insulin from 2010 to 2019 were propensity-score matched (1:1) and followed until October 2021 (intention-to-treat [ITT]). In an as-treated (AT) analysis, follow-up was also censored at study-drug discontinuation or comparator-initiation. We assessed the risk of a composite kidney outcome, including confirmed ≥ 40% eGFR loss or end-stage kidney disease, and the risk of new macroalbuminuria. Treatment-effect on eGFR slopes was assessed by fitting a linear regression model per patient, followed by a t-test to compare the slopes between the groups.ResultsEach propensity-score matched group constituted 3424 patients, 45% women, 21% had a history of cardiovascular disease, and 13.9% were treated with sodium-glucose cotransporter-2 inhibitors at baseline. Mean eGFR was 90.6 mL/min/1.73 m2 (SD 19.3) and median UACR was 14.6 mg/g [IQR 0.0–54.7]. Medians follow-up were 81.1 months (ITT) and 22.3 months (AT). The hazard-ratios [95% CI] of the composite kidney outcome with GLP-1 RAs versus basal insulin were 0.96 [0.82–1.11] (p = 0.566) and 0.71 [0.54–0.95] (p = 0.020) in the ITT and AT analyses, respectively. The respective HRs for first new macroalbuminuria were 0.87 [0.75–0.997] and 0.80 [0.64–0.995]. The use of GLP-1 RA was associated with a less steep eGFR slope compared with basal insulin in the AT analysis (mean annual between-group difference of 0.42 mL/min/1.73 m2/year [95%CI 0.11–0.73]; p = 0.008).ConclusionInitiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function.

Prognostic effects of microcirculation-assisted adjustment of venoarterial blood flow in extracorporeal membrane oxygenation: A prospective, pilot, randomized controlled trial

The study explored the clinical efficacy of microcirculation-assisted blood flow adjustment in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO). This prospective, pilot, randomized controlled trial was conducted from 2018 to 2021; enrolled patients were randomly assigned to the microcirculation or control group at a 1:1 ratio. Microcirculatory and clinical data were collected within 24h (T1) and at 24-48h (T2), 48-72h (T3), and 72-96h (T4) after ECMO initiation and were compared between the groups following the intention-to-treat (ITT) principle. The primary outcome was the Sequential Organ Failure Assessment (SOFA) score at T2. In addition to ITT analysis, analysis based on the as-treated (AT) principle was performed. A total of 35 patients were enrolled in this study. At T2, the SOFA score did not significantly differ between the microcirculation and control groups (16 [14.8-17] vs. 16 [12.5-18], P=0.782). Generalized estimating equation analysis demonstrated a significantly greater reduction in the SOFA score over time in the microcirculation-AT group than in the control-AT group (estimated difference:-0.767, standard error: 0.327, P=0.019). The lactate level at T2 was significantly lower in the microcirculation-AT group (2.7 [2.0-3.6] vs. 4.1 [3.0-6.6] mmol/L, P=0.029). No significant difference in the 30-day survival rate was noted between the groups. This prospective pilot study demonstrated the feasibility of microcirculation-assisted VA-ECMO blood flow adjustment despite no significant clinical benefit for critically ill patients. More efforts in personnel training and newer technologies may help achieve microcirculation optimization.

Transitions in an integrated model of renal replacement therapy in a regional health system

Introduction and objectivesThe choice of renal replacement therapy (RRT) is an important decision that determines the quality of life and survival. Most patients change from one RRT modality to another to adapt RRT to clinical and psychosocial needs. This has been called «integrated model of RRT» that implies new questions about the best sequence of techniques. Material and methodsThe study describes the impact of transitions between RRT modalities on survival using the Madrid Registry of Renal Patients (2008–2018). This study used the proportional hazards models and competitive risk models to perform an intention-to-treat (ITT), according to their 1st RRT modality and as-treated (AT) analysis, that consider also their 1st transition. ResultsA total of 8971 patients started RRT during this period in Madrid (6.6 Million population): 7207 (80.3%) on hemodialysis (HD), 1401 (15.6%) on peritoneal dialysis (PD) and 363 (4.2%) received a pre-emptive kidney transplantation (KT). Incident HD-patients were older (HD group 65.3 years (SD 15.3) vs PD group 58.1 years (SD 14.8) vs KTX group 52 years (SD 17.2); p < 0.001) and had more comorbidities. They presented higher mortality (HD group 40.9% vs PD group 22.8% vs KTX group 8.3%, p < 0.001) and less access to a transplant (HD group 30.4% vs PD group 51.6%; p < 0.001). Transitions between dialysis techniques define different groups of patients with different clinical outcomes. Those who change from HD to PD do it earlier (HD → PD: 0.7 years (SD 1.1) vs PD → HD: 1.5 years (SD 1.4) p < 0.001), are younger (HD → PD: 53.5 years (SD 16.7) vs PD → HD: 61.6 years (SD 14.6); p < 0.001), presented less mortality (HD → PD: 24.5% vs PD → HD: 32.0%; p < 0.001) and higher access to a transplant (HD → PD: 49.4% vs PD → HD: 31.7%; p < 0.001). Survival analysis by competitive risks is essential for integrated RRT models, especially in groups such as PD patients, where 51.6% of the patients were considered as lost follow-up (received a KTX after during the first 2.5 years on PD). In this analysis, survival of patients who change from one technique to another, is more similar to the destination modality than the origin one. ConclusionOur data suggest that transitions between RRT-techniques describes different patients, who associate different risks, and could be analyzed in an integrated manner to define improvement actions. This approach should be incorporated into the analysis and reports of renal registries.

Intradiscal oxygen-ozone chemonucleolysis versus microdiscectomy for lumbar disc herniation radiculopathy: a non–inferiority randomized control trial

BACKGROUND CONTEXTLow back pain with or without radicular leg pain is an extremely common health condition significantly impacting patient's activities and quality of life. When conservative management fails, epidural injections providing only temporary relief, are frequently utilized. Intradiscal oxygen-ozone may offer an alternative to epidural injections and further reduce the need for microdiscectomy. PURPOSETo compare the non–inferiority treatment status and clinical outcomes of intradiscal oxygen-ozone with microdiscectomy in patients with refractory radicular leg pain due to single-level contained lumbar disc herniations. STUDY DESIGN / SETTINGMulticenter pilot prospective non–inferiority blocked randomized control trial conducted in three European hospital spine centers. PATIENT SAMPLEForty-nine patients (mean 40 years of age, 17 females/32 males) with a single-level contained lumbar disc herniation, radicular leg pain for more than six weeks, and resistant to medical management were randomized, 25 to intradiscal oxygen-ozone and 24 to microdiscectomy. 88% (43 of 49) received their assigned treatment and constituted the AS-Treated (AT) population. OUTCOME MEASURESPrimary outcome was overall 6-month improvement over baseline in leg pain. Other validated clinical outcomes, including back numerical rating pain scores (NRS), Roland Morris Disability Index (RMDI) and EQ-5D, were collected at baseline, 1 week, 1-, 3-, and 6-months. Procedural technical outcomes were recorded and adverse events were evaluated at all follow-up intervals. METHODSOxygen-ozone treatment performed as outpatient day surgeries, included a one-time intradiscal injection delivered at a concentration of 35±3 μg/cc of oxygen-ozone by a calibrated delivery system. Discectomies performed as open microdiscectomy inpatient surgeries, were without spinal instrumentation, and not as subtotal microdiscectomies. Primary analyses with a non–inferiority margin of -1.94-point difference in 6-month cumulative weighted mean leg pain NRS scores were conducted using As-Treated (AT) and Intent-to-Treat (ITT) populations. In post hoc analyses, differences between treatment groups in improvement over baseline were compared at each follow-up visit, using baseline leg pain as a covariate. RESULTSIn the primary analysis, the overall 6-month difference between treatment groups in leg pain improvement using the AT population was -0.31 (SE, 0.84) points in favor of microdiscectomy and using the ITT population, the difference was 0.32 (SE, 0.88) points in favor of oxygen-ozone. The difference between oxygen-ozone and microdiscectomy did not exceed the non–inferiority 95% confidence lower limit of treatment difference in either the AT (95% lower limit, -1.72) or ITT (95% lower limit, -1.13) populations. Both treatments resulted in rapid and statistically significant improvements over baseline in leg pain, back pain, RMDI, and EQ-5D that persisted in follow-up. Between group differences were not significant for any outcomes. During 6-month follow-up, 71% (17 of 24) of patients receiving oxygen-ozone, avoided microdiscectomy. The mean procedure time for oxygen-ozone was significantly faster than microdiscectomy by 58 minutes (p<.0010) and the mean discharge time from procedure was significantly shorter for the oxygen-ozone procedure (4.3±2.9 hours vs. 44.2±29.9 hours, p<.001). No major adverse events occurred in either treatment group. CONCLUSIONSIntradiscal oxygen-ozone chemonucleolysis for single-level lumbar disc herniations unresponsive to medical management, met the non–inferiority criteria to microdiscectomy on 6-month mean leg pain improvement. Both treatment groups achieved similar rapid significant clinical improvements that persisted and overall, 71% undergoing intradiscal oxygen-ozone were able to avoid surgery.

Análisis de las transiciones en el modelo integrado de tratamiento sustitutivo renal en un sistema regional de salud

Introduction and objectivesThe choice of renal replacement therapy (RRT) is an important decision that determines the quality of life and survival. Most patients change from one RRT modality to another to adapt RRT to clinical and psychosocial needs. This has been called «integrated model of RRT» that implies new questions about the best sequence of techniques. Material and methodsThe study describes the impact of transitions between RRT modalities on survival using the Madrid Registry of Renal Patients (2008–2018). This study used the proportional hazards models and competitive risk models to perform an intention-to-treat (ITT), according to their 1st RRT modality and as-treated (AT) analysis, that consider also their 1st transition. ResultsA total of 8971 patients started RRT during this period in Madrid (6.6 Million population): 7207 (80.3%) on hemodialysis (HD), 1401 (15.6%) on peritoneal dialysis (PD) and 363 (4.2%) received a pre-emptive kidney transplantation (KTX). Incident HD-patients were older (HD group 65.3 years (SD 15.3) vs PD group 58.1 years (SD 14.8) vs KTX group 52 years (SD 17.2); p<0.001) and had more comorbidities. They presented higher mortality (HD group 40.9% vs PD group 22.8% vs 8.3% KTX group, p<0.001) and less access to a transplant (HD group 30.4% vs DP group 51.6%; p<0.001). Transitions between dialysis techniques define different groups of patients with different clinical outcomes. Those who change from HD to PD do it earlier (HD→PD: 0.7 years (SD 1.1) vs PD→HD: 1.5 years (SD 1.4) p<0.001), are younger (HD→PD: 53.5 years (SD 16.7) vs PD→HD: 61.6 years (SD 14.6); p<0.001), presented less mortality (HD→PD: 24.5% vs PD→HD: 32.0%; p<0.001) and higher access to a transplant (HD→PD: 49.4% vs PD→HD: 31.7%; p<0.001). Survival analysis by competitive risks is essential for integrated RRT models, especially in groups such as PD patients, where 51.6% of the patients were considered as lost follow-up (received a KTX after during the first 2.5 years on PD). In this analysis, survival of patients who change from one technique to another, is more similar to the destination modality than the origin one. ConclusionOur data suggest that transitions between RRT-techniques describes different patients, who associate different risks, and could be analyzed in an integrated manner to define improvement actions. This approach should be incorporated into the analysis and reports of renal registries.

795Contribution of school meals provision/receipt to “catch up growth” in young children: A counterfactual approach

795Contribution of school meals provision/receipt to “catch up growth” in young children: A counterfactual approach

MO813ANALYSING TRANSITIONS IN THE INTEGRATED MODEL OF RENAL REPLACEMENT THERAPY IN A REGIONAL HEALTH SYSTEM

Abstract Background and Aims Every year 83,000 Europeans and 6,500 Spanish CKD patients require dialysis or transplantation. The choice of renal replacement therapy (RRT) is an important decision that determines the quality of life and survival. A single therapy option might not be adequate across a patient’s entire lifespan and a majority of patients change from one RRT modality to another to adapt RRT to clinical and psychosocial needs. Transitions should be considered as an expected progression in the patient’s treatment options. In these circumstances, there are new questions about the best sequence of techniques. Method This observational study examined a cohort of all incident patients from the Madrid Registry of Renal Patients (REMER), who initiated RRT between January 2008 and December of 2018. This study used the proportional hazards models and competitive risk models to examine the impact of transitions between RRT modalities on survival. We performed an intention-to-treat (ITT) analysis, according to the initial RRT chosen and an as treated (AT) analysis, by RRT received (Only HD, Only PD, PD then HD or HD then PD). Results A total of 8,971 patients started RRT during this period in Madrid (6.6 Million population): 7,207 on hemodialysis (HD), 1,401 on peritoneal dialysis (PD) and 363 received a pre-emptive kidney transplantation (KTX). Incident HD-patients were older and had more comorbidities. They presented higher mortality (HD group 40.9% vs PD group 22.8% vs 8.3% KTX group, p &amp;lt;0.001) and less access to a transplant (HD group 30.4% vs DP group 51.6%; p &amp;lt;0.001). Transitions between dialysis techniques define different groups of patients with different clinical outcomes. Those who change from HD to PD do it earlier (66% in less than 6 months), are younger and behave like those treated only with PD. Those who change from PD to HD do so later (1.5 years on average), are older (61.6 vs 53.5 years) and present higher mortality and less access to kidney transplantation than the group who initiates in HD and transfer to PD. Survival analysis by competitive risks is essential for integrated RRT models, especially in groups such as PD patients, where 58.6% of the patients were considered as lost follow-up (received a KTX after during the first 2.5 years on PD). This analysis reflects how patients who change dialysis modality share more characteristics with the second technique than the original one. Conclusion Our data suggest that transitions between RRT-techniques describes different patients, who associate different risks, and should be analyzed in an integrated manner to define improvement actions. This approach should be incorporated into the analysis and repports of renal registries.

Providing Health Physicals and/or Health Monitoring Services in Mental Health Clinics: Impact on Laboratory Screening and Monitoring for High Risk Populations.

Providing physical health care in specialty mental health clinics is a promising approach to improving the health status of adults with serious mental illness, but most programs examined in prior studies are not financially sustainable. This study assessed the impact on quality of care of a low-cost program implemented in New York State that allowed mental health clinics to be reimbursed by Medicaid for provision of health monitoring and health physicals (HM/HP). Medicaid claims data were analyzed with generalized linear multilevel models to examine change over time in quality of physical health care associated with HM/HP services. Recipients of HM/HP services were compared to control clinic patients [Per protocol (PP)] and with non-recipients of HM/HP services from both intervention and control clinics [As-Treated (AT)]. HM/HP clinic patients, regardless of receipt of HM/HP services, were compared with control clinic patients [Intent-to-Treat (ITT)]. Analyses were conducted with adjustment for patient demographic and clinical characteristics and prior year service use. The PP and AT analyses found significant improvement in measure of blood glucose screening for patients on antipsychotic medication and HbA1C testing for patients with diabetes (AOR range 1.26-1.33) and the AT analysis found significant improvement in cholesterol screening for patients on antipsychotic medication (AOR 1.24). However, ITT analysis found no significant changes in quality of care in HM/HP clinic caseloads relative to control clinics. The low-cost HM/HP program has the potential to benefit patients who receive supported services, but its impact is limited by remaining barriers to service implementation.

Association Between Intravitreal Aflibercept and Serious Non-ocular Haemorrhage Compared with Intravitreal Ranibizumab: A Multicentre Observational Cohort Study.

Intravitreal anti-vascular endothelial growth factor (VEGF) drugs aflibercept and ranibizumab are used in neovascular retinal diseases but may be associated with non-ocular haemorrhage. Our objective was to compare the risk of non-ocular haemorrhage with intravitreal aflibercept versus intravitreal ranibizumab and with individual intravitreal anti-VEGFs versus intravitreal dexamethasone. A retrospective cohort study was conducted using four Italian claims databases, covering 18 million inhabitants from 2011 to 2016. Incident aflibercept users were matched 1:4 to incident ranibizumab users. The outcome was incident non-ocular haemorrhage requiring hospitalisation. Incidence per 1000 person-years (PYs) was estimated. Patients were followed for 180days using an intention-to-treat (ITT) approach. An as-treated (AT) approach was also employed, using grace periods of 60 or 90days. Analyses were repeated for aflibercept versus dexamethasone and ranibizumab versus dexamethasone. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. We identified incident users of intravitreal ranibizumab (n = 21,766), aflibercept (n = 3150) and dexamethasone (n = 3900). The incidence of haemorrhage was four events per 1000 PYs for each drug. Aflibercept was not associated with increased risk versus ranibizumab at 180days (HR 0.97 [95% CI 0.37-2.56]). Results were consistent in the AT analysis (HR 1.19 [95% CI 0.52-2.75]). No increased risk was found for aflibercept and ranibizumab at 180days versus dexamethasone (HR 0.70 [95% CI 0.30-2.60] and HR 0.67 [95% CI 0.33-1.38], respectively). No association was identified between intravitreal aflibercept and non-ocular haemorrhage versus ranibizumab. A comparable risk for these intravitreal anti-VEGFs and intravitreal dexamethasone was observed.

Abstract 149: Successful Reperfusion After Endovascular Treatment Predicted Favorable Outcome in the Basilar Artery Occlusion Endovascular Intervention versus Standard Medical Treatment (BEST) Trial

Background: Several randomized trials have demonstrated a strong benefit of endovascular reperfusion in the anterior circulation strokes. The association between successful reperfusion and outcomes is less well established in acute vertebrobasilar artery occlusions (VBAO). We aim to investigate the association between successful reperfusion and 90-day favorable outcome in BEST trial. Methods: The BEST trial was a multicenter randomized controlled trial of endovascular treatment versus medical treatment alone in VBAO. In the current analysis, we included patients who underwent endovascular treatment in the As-Treated Population of our trial. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction Score (mTICI) 2b/3 post-intervention. Favorable outcome was defined as mRS 0-3. Logistic regression was used to investigate the association between successful reperfusion and outcome. Results: The trial was terminated prematurely in September-2017 after enrolling 131 patients due to a high cross-over rate (Control to the ET=14; ET to Control=3). A total of 77 patients received endovascular treatment were included in this analysis. Baseline characteristics and outcome measures according to Intention-To-Treat (IIT), Per-Protocol (PP), and As-Treated (AT) analyses are summarized in Table 1 . Successful reperfusion was achieved in 70.1% (54/77) patients. Multivariable logistic regression adjusted for age and baseline NIHSS score showed that successful reperfusion was significantly associated with favorable outcome at 90 days (adjusted OR, 3.16; 95% CI, 1.05 to 9.48, p=0.04) as well as a strong trend towards lower 90-day mortality (adjusted OR, 0.36; 95% CI, 0.12 to 1.06, p=0.06). Conclusion: Endovascular reperfusion was associated with better 90-day functional outcome and a trend towards lower mortality in the BEST Trial. Table 1: Baseline Characteristics and Outcomes Measures:

Active Treatment or No Treatment (ACT or NOT) for Persisting Pregnancy of Unknown Location;&amp;nbsp; A Randomized Clinical Trial

Background: Women in early gestation without a pregnancy visualized on ultrasound and serial hCG values consistent with a nonviable gestation are at high risk for ectopic pregnancy. The goal of this trial was to determine if active management is superior to expectant management, and if two active management strategies are non-inferior. Methods: This multi-center study, 255 women with a persistent pregnancy of unknown location were randomized to expectant management or active management in a 1:2 ratio, and 1:1 within active management to a) uterine evacuation followed by methotrexate if needed or b) empiric methotrexate. The primary outcome was successful resolution of the pregnancy without change from initial strategy. Findings: Women treated with active management had a significantly higher percentage of successful resolution, Rate ratio 1·43 (1·04–1·96) intention to treat (ITT) and 1·64 (1·39–1·94) as treated (AT) and a lower rate of unscheduled surgery RR 0·43 (0·25-0·74) ITT and 0·24 (0·11-0·55) AT. Methotrexate was non-inferior to uterine evacuation (difference=6·6% (-8.4% to 21.6%) ITT. As treated, time to resolution was 8·1 days shorter after uterine evacuation compared to methotrexate. All strategies were safe and were rated with high acceptability and satisfaction. Women expressed a preference for expectant management with differential cross-over within this trial. Interpretation: A greater percentage of women achieved uneventful resolution with active management compared to expectant management with at least a 50% reduction in unscheduled interventions. Uterine evacuation resulted in a shorter time to resolution. Acceptability and safety of treatment were high for all strategies, but subjects expressed a preference for expectant management. Trial Registration: The trial was performed under IND #56407 and clinical trial registration number NCT02152696. Funding Statement: This work was supported by the National Institutes of Health (NIH)/ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Declaration of Interests: Dr. Barnhart reports consulting fees to Swiss Precision Diagnostics and Bayer. Dr. Hansen reports research grants from Roche Diagnostics and Ferring outside of the submitted work. Dr. Diamond reports institutional grants/contracts from Bayer, ObsEva, and AbbVie; serving as a member of the Board of Directors and a stockholder of Advanced Reproductive Care; and serving as a Consultant for Seikagaku, Actamax, AEGEA, Temple Therapeutics, and ARC Medical Devices. Dr. Steiner reports consulting fees from Seikagaku and Prima-Temp. Dr. Cedars reports research funding from Ferring Pharmaceuticals outside of the submitted work. Dr. Wild reports Ablacare PCOS, Amgen Repatha in Pg and Partners Mass General Menopause Reviews, outside of the submitted work. Dr Hoeger reports consultation to Bayer and Ablacare and research funding from Abbvie. Dr. Krawetz reports a research grant from Merck outside of the submitted work. Dr. Santoro reports consulting for Ansh Lab, and is a Scientific Advisor to Astellas and Menogenix, Inc. Ethics Approval Statement: The protocol was approved by a National Institutes of Health appointed advisory board and a data and safety monitoring board. The University of Pennsylvania served as single IRB (IRB # 815013).

What is Compared in a Clinical Trial?

In a randomized clinical trial (RCT), there are universally accepted rules of thumb for choice of alpha (α: 0.05) and power (1-β: 0.80). These choices require consideration and need to be anything but automatic. Next level of consideration should be given to what we actually chose to compare: the value / effect of the intervention per se or that of the intervention strategy. There is a subtle difference which hinges on which dataset we analyze. Possible data sets are intention to treat (ITT), per protocol or on treatment (PP), as treated (AT). And on the highest level, are we interested in how likely we are to observe the data (that suggests the intervention has some effect) in the event that the null hypothesis (that our intervention has no effect) is, in fact, true or as an entirely different construct, how likely is it that the intervention has some effect given our observed data? These are fundamental questions that we appear to decide on, when we chose alpha (α: 0.05) and power (1-β: 0.80) automatically, without giving them the thought process they deserve.

Identifying compliant participants through data matching improved estimation of intervention efficacy: randomized trials with opt-in/opt-out strategies

ObjectivesWe propose a data-matching approach to estimate intervention efficacy for randomized controlled trials (RCTs) when there is noncompliance to the allocated treatment with induced selection bias. Study Design and SettingWe considered a large RCT to compare health care costs and hospital length of stay 12 months after randomization. Participants allocated to the intervention group were eligible to receive health-coaching and disease-management services. An opt-out approach was adopted for recruitment. Control-group participants received usual care but were allowed to opt-in to receive the intervention. Using “nearest-neighbor”-matched data, we identified compliant participants in both arms to estimate intervention efficacy. Results were compared with intention-to-treat (ITT), instrumental-variable–adjusted ITT, per-protocol (PP), and as-treated (AT) analyses. ResultsThe ITT estimated an intervention effect of a 1.5% reduction in cost, but 56.7% of intervention-group participants did not receive health coaching. The PP and AT found an increase in cost of 9.4% and 17.1%, respectively. The matching method estimated a 12.3% reduction in cost. After adjustment for baseline covariates, the intervention group had lower same-day admission cost (13.6%; 95% CI: 7.3%–20.0%; P < 0.001) and shorter hospital stay (11.2%; 95% CI: 2.6%–19.9%; P = 0.021). ConclusionOpt-in/opt-out strategies in RCTs misled intervention comparisons and the matching approach improved estimation of intervention efficacy.

A Web-Based Clinical System for Cohort Surveillance of Specific Clinical Effectiveness and Safety Outcomes: A Cohort Study of Non-Vitamin K Antagonist Oral Anticoagulants and Warfarin.

BackgroundConventional systems of drug surveillance lack a seamless workflow, which makes it crucial to have an active drug surveillance system that proactively assesses adverse drug events.ObjectiveThe aim of this study was to develop a seamless, Web-based workflow for comparing the safety and effectiveness of drugs in a database of electronic medical records.MethodsWe proposed a comprehensive integration process for cohort surveillance using the National Taiwan University Hospital Clinical Surveillance System (NCSS). We studied a practical application of the NCSS that evaluates the drug safety and effectiveness of novel oral anticoagulants (NOACs) and warfarin by cohort tree analysis in an efficient and interoperable platform.ResultsWe demonstrated a practical example of investigating the differences in effectiveness and safety between NOACs and warfarin in patients with nonvalvular atrial fibrillation (AF) using the NCSS. We efficiently identified 2357 patients with nonvalvular AF with newly prescribed oral anticoagulants between 2010 and 2015 and further developed 1 main cohort and 2 subcohorts for separately measuring ischemic stroke as the clinical effectiveness outcome and intracranial hemorrhage (ICH) as the safety outcome. In the subcohort of ischemic stroke, NOAC users exhibited a significantly lower risk of ischemic stroke than warfarin users after adjusting for age, sex, comorbidity, and comedication in an intention-to-treat (ITT) analysis (P=.01) but did not exhibit a significantly distinct risk in an as-treated (AT) analysis (P=.12) after the 2-year follow-up. In the subcohort of ICH, NOAC users did not exhibit a different risk of ICH both in ITT (P=.68) and AT analyses (P=.15).ConclusionsWith a seamless and Web-based workflow, the NCSS can serve the critical role of forming associations between evidence and the real world at a medical center in Taiwan.

Analysis of Different Data Sets of the Same Clinical Trial May Yield Different Results

In a randomized clinical trial (RCT), analysis of different data sets of the same clinical trial may change the meaningfulness of the difference between the study groups depending on which data sets are compared. Possible data sets are intention to treat (ITT), per protocol or on treatment (PP), as treated (AT). The specific conditions that may cause the greatest likelihood of affecting the outcome, depending on the choice of data sets compared should be further investigated.

COMPARATIVE EFFECTIVENESS OF TWO-DRUG THERAPY VERSUS MONOTHERAPY AS INITIAL REGIMEN IN HYPERTENSION

Objective: Clinical trials have shown initial combination therapy to be more effective on blood pressure (BP) control than initial monotherapy but few studies examined the question in a large primary care database. The main objective of this study was to evaluate relative effectiveness on BP of an initial two-drug therapy compared to monotherapy in hypertension (HT). Design and method: In the UK Clinical Practice Research Datalink with hospitalisation and mortality data linkage, we identified a cohort of adults with uncontrolled HT and initiating one or two antihypertensive drug class(es) (among ACEIs, ARBs, CCB, BB, thiazide-like diuretics) between 2006 and 2014, with follow-up until February 2016. New users of 2-drugs and monotherapy were matched 1:2 using a propensity score. Exposure was defined as intention-to-treat (ITT) or as treated (AT), i.e. until first regimen change. Primary and secondary endpoints were respectively BP control and serious cardiovascular event (SCE). Analyses in planned subgroups, according to HT severity or most frequent classes of drugs (ACEi, CCB) used specific propensity scores. Results: Among 54,523 eligible hypertensive patients included, 3,256 patients were initiated on 2 drugs of which 2,807 (86.2%) were matched to 5,614 monotherapy new users (mean SBP/DBP 164.6/94.8 mm Hg). During a mean follow-up (ITT) of 4.6 years, mean exposure duration (AT) was 12.7 months, with 76.5% patients changing initial regimen. In the AT analysis, use of 2 drugs was associated with 17% increased BP control in all hypertensive patients (HR [95%CI]: 1.17 [1.09–1.26]), increasing to 28% in patients with grade 2–3 HT (1.28 [1.17–1.41]), and 27% in patients with ACEi+CCB (1.27 [1.08–1.49]). A positive association was also observed in the ITT analysis of all hypertensive patients (1.08 [1.03–1.13]) or those with grade 2–3 HT (1.10 [1.03–1.18]). For SCE, overall no significant association with 2-drug therapy was found. Conclusions: In line with UK guidelines, only a small fraction of hypertensive patients used two drugs in combination as initial therapy. This large population-based cohort study supports the evidence of greater effectiveness of 2-drug therapy for BP control, while additional data would be required for SCE.

A mHealth-based care model for improving hypertension control in stroke survivors: Pilot RCT

PurposeHypertension (HTN) is significantly under-treated in stroke survivors.We examined usability and efficacy of a mHealth -based care model for improving post-stroke HTN control (Funding: AHRQ R21HS021794). MethodsWe used a RCT design. Planned study duration was 90 days. Intervention arm (IA) participants measured their BP daily using a smart phone and wireless BP monitor. This was transmitted automatically to the study database. Investigators (Physician + PharmD) made bi-weekly medication adjustments to achieve the BP goal. Control arm (CA) participants received a digital BP monitor and usual care. We examined Usability (measured with Marshfield System Usability Survey) and HTN control efficacy using an ITT (intent-to-treat) and as-treated (AT) analyses. ResultsFifty participants (IA = 28; CA = 22) completed the study. The Marshfield survey question, “I thought the system was easy to use” mean score was 4.6, (5 = strongly agree). Mean SBP declined significantly between enrollment and study completion in the IA. In ITT, IA SBP declined 9.88 mm, p = 0.005. In AT, IA SBP declined 10.81 mm, p = 0.0036. CA SBP decline was 5–6 mm Hg (not significant). In the ITT, baseline HTN control (SBP < 140 mm Hg) was 50% in IA and CA. At study completion, HTN was controlled in 82% (23/28) of IA and 64% (14/22) of CA (p = 0.14). In the AT, HTN was controlled in 89% (23/26) of IA and 58% (14/24) of CA, (p = 0.015). ConclusionA mHealth-based HTN care model had excellent usability and provided better HTN control than usual care in stroke survivors.Clinical Trial.gov: NCT01875094

Abstract TP136: Dual versus Mono Antiplatelet Therapy in Acute Ischemic Stroke Patients Due to Large Artery Atherosclerosis

Background: Although dual antiplatelet treatment with aspirin and clopidogrel is widely used in stroke patients due to large artery atherosclerosis (LAA), there are limited data to justify this. Methods: We used a multicenter, prospective stroke registry database (CRCS-K) to analyze acute ischemic stroke patients due to LAA who were treated with aspirin alone or combination of aspirin and clopidogrel from May, 2008 to May 2015. Results were analyzed by intention-to-treat (ITT), as-treated (AT), and per-protocol (PP) method. Primary endpoint was the 1-year composite outcome of stroke recurrence, myocardial infarction (MI), and all-cause death. To balance the differences between groups, a frailty model with inverse probability of treatment weighting was used. Results: A total of 5,934 patients due to LAA were treated either aspirin alone (n=3,031, 51%) or combination of aspirin and clopidogrel (n=2,903, 49%). Primary outcome was 14% (n=410) in aspirin alone group and 12% (n=353) in aspirin plus clopidogrel group. In ITT analysis, compared to aspirin alone, aspirin plus clopidogrel did not decrease the hazards of primary outcome (adjusted hazards ratio, 0.86; 95% confidence intervals, 0.74-1.01; p=0.06), but decreased all-cause mortality significantly (0.80; 0.66-0.98; p=0.03). Stroke recurrence and a composite of stroke recurrence, MI, and vascular death were not reduced by aspirin plus clopidogrel. Results of AT and PP analyses are shown in the table below. Conclusion: Addition of clopidogrel to aspirin may decrease all-cause death and perhaps the composite of stroke recurrence, MI and all-cause death in patients with large artery atherosclerotic stroke.

Abstract 102: Consistency of Efficacy of PFO Closure in the Gore Reduce Trial

Background: The Gore REDUCE Clinical Study (REDUCE) demonstrated superiority of PFO closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients with cryptogenic stroke. Methods: We randomized 664 subjects with cryptogenic stroke at 63 multinational sites in a 2:1 ratio to either antiplatelet therapy plus PFO closure (with Gore HELEX Septal Occluder or Gore CARDIOFORM Septal Occluder) or antiplatelet therapy alone. Co-primary endpoints were freedom from recurrent clinical ischemic stroke through ≥2 years and incidence of new brain infarct (defined as the composite of clinical ischemic stroke and silent brain infarct) at 2 years. Primary analyses were performed on the intention-to-treat (ITT) population. Per-protocol (PP) analysis included only subjects randomized and treated according to critical protocol requirements (excluding those who violated key eligibility criteria, did not receive the therapy to which they were randomized, or did not comply with protocol-required medical regimen). As-treated (AT) analysis assessed all subjects based on treatment received, regardless of study assignment. Results: PFO closure was associated with a highly consistent reduction in risk compared to medical therapy alone in all three analytic cohorts (Table). Conclusions: Among selected patients with cryptogenic stroke and PFO, closure of the PFO plus antiplatelet therapy was superior to antiplatelet therapy alone for reducing the risk of subsequent ischemic stroke.