Greene, Tom

Abstract Objective To evaluate the effectiveness of multiple decision aid strategies in promoting high quality shared decision making for prevention of stroke in patients with non-valvular atrial fibrillation. Design Cluster randomized controlled trial. Setting Six academic medical centers in the United States. Participants Patient participants were aged ≥18 with a diagnosis of non-valvular atrial fibrillation, at risk for stroke (CHA 2 DS 2 -VASc ≥1 for men, ≥2 for women), and scheduled for a clinical appointment to discuss stroke prevention strategies. Participating clinicians were those who manage stroke prevention strategies for participating patients. Intervention Patients were randomized to use a patient decision aid or usual care; clinicians were randomized to use an encounter decision aid or usual care with all participating patients. Main outcome measures Primary outcome measures were quality of shared decision making measured by OPTION12, knowledge of atrial fibrillation and its management, and decisional conflict. Results 1117 participants across six sites were included in the analysis. Compared with usual care, the combined use of both the patient decision aid and the encounter decision aid improved the quality of shared decision making (adjusted mean difference 12.1 (95% confidence interval (CI) 8.0 to 16.2; P<0.001), improved patients’ knowledge (odds ratio 1.68 (95% CI 1.35 to 2.09; P<0.001), and reduced patients’ decisional conflict (adjusted mean difference −6.3 (95% CI −9.6 to −3.1; P<0.001). Statistically significant improvements were also observed with the encounter decision aid alone versus usual care for all three outcomes and with the patient decision aid alone versus usual care for quality of shared decision making and knowledge. No important differences were observed in treatment choices for stroke prevention or in participants’ satisfaction. No statistically significant difference in the length of visit across study groups was detected. Conclusion Patients who received any decision aid (encounter decision aid, patient decision aid, or both) had lower decisional conflict, better shared decision making, and greater knowledge than those receiving no decision aid, except for the effect of the patient decision aid on decisional conflict, which did not reach statistical significance. The study establishes that use of either pre-visit or in-visit decision aids individually or in combination is advantageous compared with usual care. Trial registration ClinicalTrials.gov NCT04357288 .

Background: Guidelines recommend shared decision-making (SDM) for patients with atrial fibrillation (AF) making decisions regarding anticoagulation for stroke prevention. Decision support tools (e.g., Decision Aids [DAs]) facilitate SDM. However, little research has compared the effectiveness of the two most common types of DAs: (1) encounter decision aid (EDA) and (2) pre-encounter patient decision aid (PDA). Our study assessed the comparative effectiveness of PDAs and EDAs on SDM during AF clinical encounters where stroke prevention strategies were discussed. Research Question: Do decision aids (PDA or EDA), alone or in combination, improve patients’ AF decision-making experience compared to usual care? Methods: A cluster randomized multi-center trial in patients with AF comparing usual care (no DA) vs. one DA (EDA or PDA) or both DAs. Clinicians and patients were randomized independently into 4 study arms. Clinicians were randomized to use or not use the EDA for all study visits, and patients were randomized to use or not use the PDA. Co-primary outcome domains were: (1) quality of SDM (2) patient knowledge, and (3) decisional conflict. Secondary outcomes included: (1) treatment choice, (2) treatment initiation, and (3) treatment persistence. Patient characteristics were assessed. We will present comparisons of the randomized DAs on the co-primary and secondary outcomes and subgroup analyses. Results: Between December 2020-July 2023, investigators in 6 U.S. healthcare systems enrolled 1117 patients (mean (M) age 69, 63% male, 89% White) and 107 clinicians. Compared to usual care (no DA, M=31.6), SDM was better in patients receiving PDA (M=35.4) and EDA (44.5) alone or together (M=43.7; p’s<0.001). Knowledge about AF was greatest for those receiving both DAs or the PDA alone (84% accurate responses for PDA and both vs 76% with no DA, p<0.001), followed closely by the EDA alone (82%, p=0.003). Finally, both DAs (M=19.5) and EDA alone (M=20.0) had better decisional conflict scores compared to usual care (M=25.8; p’s<0.001). We will present analyses that assess the impact of DAs on secondary outcomes and interactions with DA, patient, and clinical characteristics across each outcome. Conclusions: In one of the first randomized trials examining the comparative effectiveness of EDAs and PDAs on SDM in clinical medicine, both PDAs and EDAs improved shared decision-making, decisional conflict, and knowledge compared to patients receiving usual care.

Significance Statement Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. Background Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. Methods Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. Results Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were −0.41 (95% Bayesian Credible Interval, −0.64 to −0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and −0.06 (95% Bayesian Credible Interval, −0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. Conclusions In Phase 2 trials of CKD with sample sizes of 100–200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

Background Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. Methods To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. Results The mean acute effect across all studies was −0.21 ml/min per 1.73 m 2 (95% confidence interval, −0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, −2.50 to +2.08 ml/min per 1.73 m 2 ). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. Conclusion The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Background The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. Methods We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. Results At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. Conclusions AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction.

Background: In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. Methods: SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. Results: Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level ( P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57–1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61–0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events. Conclusions: Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n =1330) or <140 mm Hg (standard group; n =1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD ( P values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (−0.47 versus −0.32 ml/min per 1.73 m 2 per year; P <0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.

Abstract Background The advancement of knowledge about control of antibiotic resistance depends on the rigorous evaluation of alternative intervention strategies. The STAR*ICU trial examined the effects of active surveillance and expanded barrier precautions on acquisition of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) in intensive care units. We report a reanalyses of the STAR*ICU trial using a Bayesian transmission modeling framework. Methods The data included admission and discharge times and surveillance test times and results. Markov chain Monte Carlo stochastic integration was used to estimate the transmission rate, importation, false negativity, and clearance separately for MRSA and VRE. The primary outcome was the intervention effect, which when less than (or greater than) zero, indicated a decreased (or increased) transmission rate attributable to the intervention. Results The transmission rate increased in both arms from pre- to postintervention (by 20% and 26% for MRSA and VRE). The estimated intervention effect was 0.00 (95% confidence interval [CI], −0.57 to 0.56) for MRSA and 0.05 (95% CI, −0.39 to 0.48) for VRE. Compared with MRSA, VRE had a higher transmission rate (preintervention, 0.0069 vs 0.0039; postintervention, 0.0087 vs 0.0046), higher importation probability (0.22 vs 0.17), and a lower clearance rate per colonized patient-day (0.016 vs 0.035). Conclusions Transmission rates in the 2 treatment arms were statistically indistinguishable from the pre- to postintervention phase, consistent with the original analysis of the STAR*ICU trial. Our statistical framework was able to disentangle transmission from importation and account for imperfect testing. Epidemiological differences between VRE and MRSA were revealed.