Randomized Treatment Assignment Research Articles

Target Trial Emulation: A Call for More Widespread Use.

Causal inference methods intended for use with observational data have been widely available for decades, but barriers exist to their widespread adoption. These likely include lack of familiarity with several methodologic techniques often used in combination in these investigations such as inverse probability of treatment weighting and g-estimation, and the intensity of computational effort to employ these techniques. Even with these methods, critical design flaws undermine the ability to make valid causal inference in some studies. Identification of the need to explicitly pair study design elements with these causal inference methods led to development of a methodologic approach recently termed target trial emulation. This approach requires that investigators define a hypothetical randomized trial, emulate that hypothetical protocol in assembling the cohort and defining study elements and then conduct an analysis that attempts to mirror random treatment assignment. In the article by Heindel et al. (Am J Epidemiol. 2024;XXX(XX):XXXX-XXXX), the authors successfully emulate a target trial of systemic heparin during arteriovenous fistula creation on short-term endpoints by utilizing two existing randomized trials with key confounders available. Target trial emulation provides a framework to promote valid inference and generate high-quality contributions to the literature and its use should be expanded.

A phase 2 study of ipatasertib in combination with pembrolizumab for first-line treatment of recurrent or metastatic squamous cell cancer of the head and neck.

TPS6117 Background: Single agent pembrolizumab in relapsed / metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an estimated ORR of 19% and median OS of 13.6 months. There are several factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase 2 trial is designed to compare progression-free survival (PFS) in first line R/M, HNSCC patients treated with the combination ipatasertib and pembrolizumab versus pembrolizumab monotherapy treatment. Methods: In this open-label randomized phase 2 multicenter trial, patients with R/M HNSCC are treated with pembrolizumab 200mg on day 1 +/- ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ³ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with ipatasertib plus pembrolizumab compared to pembrolizumab alone using the Cox Model where randomized treatment assignment is the only variable in the model. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Ultimately, a total of 48 patients will be enrolled, with 24 patients in each cohort. To date, a total of 22 patients have been enrolled from 15 sites. Accrual is ongoing (NCT05172258). Clinical trial information: NCT05172258 .

Target trial emulation with real-world data to determine the population-level cost-effectiveness of multi-gene panel sequencing in advanced melanoma.

e21508 Background: Compared to single-gene BRAF testing to guide targeted treatment for advanced melanoma, multi-gene panels can identify additional gene mutations with known therapeutic or prognostic relevance. No randomized control trials of multi-gene panel sequencing have been completed in advanced melanoma. This study determined the population-level cost-effectiveness of multi-gene panel sequencing compared to single-gene BRAF testing for advanced melanoma. Methods: Our population-based retrospective study emulated a hypothetical pragmatic trial using comprehensive patient-level clinical and health administrative data between September 2016 and December 2018 from British Columbia, Canada. To emulate random treatment assignment, we 1:1 matched multi-gene panel patients to contemporaneous controls using a machine learning approach that maximized balance on 15 covariates. Following matching, we estimated mean three-year survival time and costs (2021 CAD), and calculated incremental net monetary benefit (INMB) for life-years gained (LYG) at $100,000/LYG using inverse probability of censoring weighted linear regression and nonparametric bootstrapping. Besides an intention-to-treat (ITT) effect, we also estimated the per-protocol (PP) effect of initiating treatment within 90 days of receiving test results additionally using inverse probability of treatment weights. We also estimated overall survival using Weibull regression and Kaplan-Meier (KM) survival analysis. Results: We matched 147 patients receiving multi-gene panel sequencing to controls, achieving good balance for all included covariates. ITT mean incremental costs were $19,541 (95%CI: -$18,939, $77,396) and mean incremental LYG were 0.22 (95%CI: -0.06, 0.50). We did not find statistically significant different differences in overall survival using the KM (P = 0.11) and Weibull regression (HR: 0.73 [95%CI: 0.51-1.03]) survival analysis in the ITT analysis. PP incremental costs were $36,367 (95%CI: -$6,653, $120,216) and incremental LYG were 0.56 (95%CI: 0.39, 1.24), with corresponding differences in overall survival using KM (P = 0.02) and Weibull regression (HR: 0.56 [95%CI: 0.36-0.87]) survival analysis. The probability of multi-gene panel sequencing being cost-effective at $100,000/LYG was 54.9% in the ITT analysis and 64.5% in the PP analysis. Conclusions: We found the cost-effectiveness of multi-gene panel sequencing to be evenly poised, with estimates favouring multi-gene panel sequencing with respect to overall survival and cost-effectiveness when accounting for probability of treatment initiation. This real-world evidence generated using randomized trial design principles can support jurisdictions’ deliberations on the reimbursement of precision oncology interventions.

Association of Diabetes with Changes in Blood Pressure during Hemodialysis: A Secondary Analysis of the Frequent Hemodialysis Network Daily Trial.

Diabetes mellitus is a common cause of kidney failure and is often complicated by autonomic neuropathy, which may have implications for blood pressure (BP) homeostasis during hemodialysis (HD). In this post hoc analysis of the Frequent Hemodialysis Network (FHN) Daily Trial, we used random effects Poisson and linear regression models to estimate the association of diabetes (vs. not) with intra-dialytic hypotension (IDH) and peri-dialytic BP parameters, respectively. We tested for differential associations according to the randomized treatment (6/week vs. 3/week HD) and pre-HD systolic BP. Of the 244 patients with intra-dialytic BP data, 100 (41%) had diabetes at baseline. The mean age was 51 ± 14 years; overall, 39% were female. In adjusted models, diabetes (vs. not) was associated with a 93% higher risk of developing IDH (IRR: 1.93; 95% CI: 1.26, 2.95). There was no evidence that the randomized treatment assignment modified the association between diabetes and IDH (pinteraction = 0.32), but more potent associations were noted among those with higher pre-HD systolic BP (pinteraction < 0.001). Diabetes (vs. not) was associated with a lower adjusted nadir intra-HD BP (-4.2; 95% CI: -8.3, -0.2 mm Hg) but not with the pre- or post-HD systolic BP. Among participants of the FHN Daily Trial, patients with diabetes had a higher risk of IDH and lower nadir intra-HD systolic BP than patients without diabetes, even when undergoing HD up to 6 times per week.

Quality Measure Adherence and Oral Health Outcomes in Children

Process-based quality measures are generally intended to promote evidence-based practices that have been proven to improve outcomes. However, due to lack of standardized implementation of diagnostic codes in dentistry, assessing the association between process and oral health outcomes has been challenging. To estimate the association of adhering to dental quality measures with patient oral health outcomes. Using a target trial emulation, a causal inference framework, this retrospective cohort study estimated the difference in the risk of developing tooth decay between US children who adhered to process-based dental quality measures (receiving topical fluoride and sealant [treated groups]) and those who did not (control groups). Electronic health records of US children and adolescents aged 0 to 18 years from January 1, 2014, to December 31, 2020, were used. To emulate random treatment assignment based on baseline confounders, coarsened exact matching was used to produce covariate balance between the treated and control groups. A time-to-event regression model produced effect estimates, adjusting for time-varying covariates. Near-far matching was used to account for unmeasured confounders as a sensitivity analysis. Data were analyzed from May 1 to August 7, 2023. Adherence to dental quality measures. Incidence of tooth decay. Among 69 212 US children aged between 0 and 18 years (mean [SD] age, 10.2 [5.0] years; 49.5% male, 50.4% female, and 0.1% unknown or transgender), 1930 (2.8%) were Asian, 2038 (2.9%) were Black, 8667 (12.5%) were Hispanic, 33 632 (48.6%) were White, and 22 945 (33.2%) were multiracial, other, or missing racial and ethnic group identification. Relative to control individuals, treated individuals were more likely to be at elevated risk of caries (fluoride measure: 16 453 [76.5%] vs 15 236 [39.8%]; sealant measure: 2264 [54.6%] vs 997 [44.0%]) and have regular dental visits (fluoride measure: 21 498 [100%] vs 13 741 [35.9%]; sealant measure: 1623 [39.2%] vs 871 [38.4%]). Adherence to quality measures was associated with reduced risk of tooth decay with adjusted hazard ratios of 0.82 (95% CI, 0.78- 0.86) for fluoride and 0.86 (95% CI, 0.76-0.97) for sealant in the matched cohort. Benefits of adhering to quality measures were greater among children at elevated vs low risk and with public vs commercial insurance for both measures. In this cohort study, adhering to dental quality measures was associated with reduced risk of tooth decay, and benefits were greater among children at elevated risk and with public insurance. These findings provide insights in facilitating targeted application of quality measures or developing more tailored quality improvement initiatives.

Polimorfismos genéticos asociados a la respuesta del carcinoma de cabeza y cuello al cetuximab

Objective: To present the main genetic polymorphisms that have been associated with the response of head and neck carcinoma to cetuximab. Method: A non-exhaustive review of articles published in the period from January 2000 to December 2022 was carried out, for this purpose the Medline (via Pubmed) and Science Direct databases were used. The guide for genetic association studies (Q-Genie) was used to evaluate the methodological quality of the included articles. Results: A total of 206 articles were identified, of which 12 met the criteria for the final analysis. Several polymorphisms were reported, such as: EGFR-R521K (AA/GA), FcγRIIIa (158VV) and FcγRIIa (131HH), KRAS-LCS6 (TG/GG), AKT2:rs8100018, PTEN: rs12569998 in its mutated variants, HIF- 1α (CT/TT) and XRCC5 (GG/AA) that were associated with survival variables, risk of progression, times to disease progression, as well as skin toxicity. Conclusions: Several polymorphisms can be associated with the response of head and neck carcinoma to treatment with cetuximab, being EGFR-R521K and FcγR IIIa-V158F the most studied. The enormous uncertainty of the results obtained does not allow firm conclusions to be reached about the influence of genetic polymorphisms on the response to cetuximab; however, they can become pharmacogenetic biomarkers in clinical practice as a valuable tool in personalized medicine, to predict drug response. This requires carrying out controlled trials with strata by genotype, with random assignment of treatment and the analysis of other variables with known prognostic value. Keywords: genetic polymorphism; cetuximab; head and neck neoplasms

Abstract 14752: FGF-23, Cardiovascular Events, and the Benefit of Canagliflozin in the CANVAS Trial

Background: The incremental prognostic value of FGF-23 with cardiovascular (CV) risk, composite kidney outcomes (KO) and treatment response was assessed in the CANVAS trial, which studied the efficacy of the sodium glucose co-transporter 2 inhibitor canagliflozin (cana) versus placebo in patients with type 2 diabetes (T2D) and high CV risk. Methods: 3188 patients with available baseline FGF-23 samples were studied. The association between FGF-23 and the composite of time to CV death or hospitalization for heart failure (HHF) (primary endpoint), HHF, CV death, major adverse CV events (MACE) and KO were assessed using multivariable Cox proportional hazard regression models adjusted for clinical risk factors. Events rates by randomized treatment assignment were calculated for FGF-23 after assignment to a ‘low risk’ (Quartiles 1-3) or ‘high risk’ (Q4) group. Results: The median level of FGF-23 was 64.1 RU/mL (IQR 48.3-94.1). A doubling of FGF-23 was significantly associated with the primary endpoint (HR, 1.32; 95% CI, 1.19-1.46; P <0.001) as well as HHF (HR, 1.53; 95% CI, 1.31-1.79, P <0.001), CV death (HR, 1.18; 95% CI, 1.03-1.35, P =0.014), and KO (HR, 1.11; 95% CI, 1.02-1.21, P =0.014) but not MACE (HR, 1.05; 0.95-1.15, P =0.3) in the fully adjusted model (Table 1). Cana yielded consistent risk reduction for the primary endpoint, HHF and KO regardless of whether patients were categorized in the high or low risk group (all P heterogeneity>0.30) (Table 2). Conclusion: High levels of FGF-23 are associated with an increased risk of CV death and HHF, HHF, CV death, and KO in patients with T2D and high CV risk. Treatment with cana provides consistent benefit across higher and lower levels of FGF-23.

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance.

Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13 970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.

Tolerability and comparative effectiveness of TNF, IL-17 and IL-23(p19) inhibitors in psoriatic arthritis: a target trial emulation study.

To compare the tolerability and effectiveness of two different classes of biological DMARDs [IL-17 and IL-23(p19) inhibitors, IL-17i and IL-23(p19)i] relative to TNF inhibitors (TNFi) regarding the drug survival rates and treatment outcomes in patients with PsA. We emulated a target trial on comparative effectiveness using observational data from a prospective cohort study based on the Parker Institute's PsA cohort (the PIPA cohort). All patients underwent interview and a clinical examination programme at baseline and at follow-up visits at 4 and 12 months. The primary endpoint, drug survival, was assessed up to 12 months from baseline. We estimated hazard ratios from proportional hazards model and used propensity score adjustment in an attempt to deconfound and emulate a random treatment assignment. We included a total of 109 patients in the intention-to-monitor population at baseline initiating either TNFi (75 patients), IL-17i (26 patients) or IL-23(19)i (8 patients). Hazard ratios in the propensity adjusted model comparing IL-17i and IL-23(p19)i with TNFi were 1.36 (95% CI 0.59-3.14) and 0.56 (95% CI 0.10-3.24), respectively. TNFi and IL-17i had comparable effects regarding response rates and changes in clinical outcomes after 12 months, whereas IL-23(p19)i tended to perform better overall. No decisive differences between drugs were observed at group level regarding drug survival and clinical outcomes after 12 months. TNFi, IL-17i and IL-23(p19)i may all be considered equally effective in the treatment of patients with PsA, advocating for investigating more in personalized treatment strategies.

No-harm calibration for generalized Oaxaca–Blinder estimators

Summary In randomized experiments, adjusting for observed features when estimating treatment effects has been proposed as a way to improve asymptotic efficiency. However, among parametric methods, only linear regression has been proven to form an estimate of the average treatment effect that is asymptotically no less efficient than the treated-minus-control difference in means regardless of the true data generating process. Randomized treatment assignment provides this do-no-harm property, with neither truth of a linear model nor a generative model for the outcomes being required. We present a general calibration method that confers the same no-harm property onto estimators leveraging a broad class of nonlinear models. This recovers the usual regression-adjusted estimator when ordinary least squares is used, and further provides noninferior treatment effect estimators using methods such as logistic and Poisson regression. The resulting estimators are noninferior to both the difference-in-means estimator and to treatment effect estimators that have not undergone calibration. We show that our estimator is asymptotically equivalent to an inverse-probability-weighted estimator using a logit link with predicted potential outcomes as covariates. In a simulation study, we demonstrate that common nonlinear estimators without our calibration procedure may perform markedly worse than both the calibrated estimator and the unadjusted difference in means.

Abstract CT047: A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck

Abstract Background: Single agent pembrolizumab in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an ORR of 19% and mOS of 13.6 months. There are many factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment (TME). Low Tregs in the TME have been correlated with clinical efficacy with PD-1 blockade in various solid tumors. Tregs play an active role in HNSCC. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. In the Ice-CAP phase I solid tumor trial, combination PD-L1 antibody and Ipatasertib demonstrated reduction of Tregs and increased CD8+ effector T cells in paired biopsy specimens. This trial is designed to compare the efficacy of combination ipatasertib plus pembrolizumab compared to pembrolizumab monotherapy in R/M HNSCC. Methods: In this prospective, two-arm, phase II, multicenter trial, patients with R/M HNSCC will be treated with pembrolizumab 200mg on day 1 with or without ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ≥ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with Ipatasertib plus pembrolizumab compared to pembrolizumab using the Cox Model where randomized treatment assignment is the only variable in the model. A total of 48 patients will be enrolled, with 24 patients in each cohort. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Accrual is ongoing (NCT05172258). Citation Format: Jacob S. Thomas, Robert Hsu, Victoria Villaflor, Jonathan Riess, Jorge Nieva, Mark Krailo, Silvio Gutkind, Dimitri Colevas. A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT047.

Efficient and flexible estimation of natural direct and indirect effects under intermediate confounding and monotonicity constraints.

Natural direct and indirect effects are mediational estimands that decompose the average treatment effect and describe how outcomes would be affected by contrasting levels of a treatment through changes induced in mediator values (in the case of the indirect effect) or not through induced changes in the mediator values (in the case of the direct effect). Natural direct and indirect effects are not generally point-identified in the presence of a treatment-induced confounder; however, they may be identified if one is willing to assume monotonicity between the treatment and the treatment-induced confounder. We argue that this assumption may be reasonable in the relatively common encouragement-design trial setting, where the intervention is randomized treatment assignment and the treatment-induced confounder is whether or not treatment was actually taken/adhered to. We develop efficiency theory for the natural direct and indirect effects under this monotonicity assumption, and use it to propose a nonparametric, multiply robust estimator. We demonstrate the finite sample properties of this estimator using a simulation study, and apply it to data from the Moving to Opportunity Study to estimate the natural direct and indirect effects of being randomly assigned to receive a Section8 housing voucher-the most common form of federal housing assistance-on risk developing any mood or externalizing disorder among adolescent boys, possibly operating through various school and communitycharacteristics.

Implementation of Ticagrelor Reduced Mortality in Routine Clinical Care: Evidence From a Natural Experiment Including 109 995 Patients With Myocardial Infarction in Sweden.

Background Effectiveness estimates from observational studies on ticagrelor use in routine clinical care are conflicting, with some contrary to the results of the pivotal randomized controlled trial of ticagrelor in acute coronary syndrome. The aim of this study was to estimate the effect of implementing and using ticagrelor in routine clinical care in patients with myocardial infarction using a natural experimental approach. Methods and Results This is a retrospective cohort study including patients hospitalized for myocardial infarction in Sweden between 2009 and 2015. The study exploited differences in the timing and speed of ticagrelor implementation between treatment centers as a source of random treatment assignment. The effect of implementing and using ticagrelor was estimated based on the admitting center's likelihood of treating patients with ticagrelor, measured as the proportion of patients treated in the 90 days before patient admission. The main outcome was 12-month mortality. The study included 109 955 patients, of whom 30 773 were treated with ticagrelor. Being admitted to a treatment center with higher past ticagrelor use was associated with a reduction in 12-month mortality (2.5 percentage points for 100% versus 0% past use [95% CI, 0.2-4.8]). The results are in line with the findings from the ticagrelor pivotal trial. Conclusions Using a natural experiment, this study finds that the implementation and use of ticagrelor in routine clinical care has reduced 12-month mortality in patients admitted to the hospital with myocardial infarction in Sweden and supports the external validity of randomized evidence on ticagrelor effectiveness.

Estimating the average treatment effect in randomized clinical trials with all-or-none compliance

Noncompliance is a common intercurrent event in randomized clinical trials that raises important questions about analytical objectives and approaches. Motivated by the Multiple Risk Factor Intervention Trial (MRFIT), we consider how to estimate the average treatment effect (ATE) in randomized trials with all-or-none compliance. Confounding is a major challenge in estimating the ATE, and conventional methods for confounding adjustment typically require the assumption of no unmeasured confounders which may be difficult to justify. Using randomized treatment assignment as an instrumental variable, the ATE can be identified in the presence of unmeasured confounders under suitable assumptions, including an assumption that limits the effect-modifying activities of unmeasured confounders. We describe and compare several estimation methods based on different modeling assumptions. Some of these methods are able to incorporate information from auxiliary covariates for improved efficiency without introducing bias. The different methods are compared in a simulation study and applied to the MRFIT.

Antithrombotic monotherapy for stable coronary artery disease and atrial fibrillation patients with and without prior coronary artery revascularization: Insights from the AFIRE trial

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Japan Cardiovascular Research Foundation under a contract with Bayer Yakuhin Background The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial demonstrated that rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban plus a single antiplatelet therapy regarding efficacy and superior for safety endpoints in patients with atrial fibrillation and stable coronary artery disease including patients not requiring revascularization [prior percutaneous coronary intervention (PCI) or bypass grafting (CABG)]. Purpose The aim of this post-hoc subgroup analysis was to investigate the efficacy and safety of rivaroxaban monotherapy compared to combination therapy in patients with and without prior revascularization. Methods Among 2,215 patients included in the modified intention-to-treat analysis in the AFIRE trial, 1445 patients (65.2%) had undergone previous PCI alone, and 252 (11.4%) had undergone previous CABG. The remaining 518 patients (23.4%) was categorized as a group without prior revascularization and then compared with a group with prior revascularization (PCI or CABG). The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis. Results In 1697 patients with prior revascularization, efficacy and safety endpoints of rivaroxaban monotherapy were superior to combination therapy (efficacy: HR 0.62, 95%CI 0.45-0.85, p=0.003; safety: HR 0.62, 95%CI 0.39-0.98, p=0.040), whereas there were no significant differences in efficacy and safety endpoints among 518 patients without prior revascularization (efficacy: HR 1.19, 95%CI 0.67-2.11, p=0.553; safety: HR 0.47, 95%CI 0.18-1.26, p=0.125). There was a borderline interaction of efficacy endpoint (P for interaction=0.055) by randomized treatment assignment (Figure 1 and Figure 2). Compared with combination therapy, the safety benefit of rivaroxaban monotherapy on any bleeding was significant in patients without prior revascularization (HR 0.59, 95%CI 0.38-0.93, p=0.022). Conclusions In patients with prior PCI or CABG, rivaroxaban monotherapy resulted in more favorable safety and efficacy outcomes than combination therapy. There was a borderline interaction for primary efficacy outcome between prior revascularization and anti-thrombotic therapy.

Cause-Specific Mortality in Patients With Advanced Chronic Kidney Disease in the ISCHEMIA-CKD Trial

BackgroundIn ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively). ObjectivesThis prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death. MethodsThree-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified. ResultsA total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy. ConclusionsIn ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360)

Effect of Intensive Blood Pressure Control on Troponin and Natriuretic Peptide Levels: Findings From SPRINT.

Given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure and strong associations observed between hypertension and its sequelae on hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, we hypothesized that intensive systolic blood pressure (SBP) lowering would decrease levels of hs-cTnT and NT-proBNP. hs-cTnT and NT-proBNP were measured at baseline and 1 year from stored specimens in SPRINT (Systolic Blood Pressure Intervention Trial). Changes in biomarkers were evaluated continuously on the log scale and according to categories (≥50% increase, ≥50% decrease, or <50% change). The effect of intensive SBP lowering on continuous and categorical changes in biomarker levels were assessed using linear and multinomial logistic regression models, respectively. The association between changes in biomarkers on heart failure and death was assessed using multivariable-adjusted Cox proportional hazards models. Randomization to intensive SBP lowering (versus standard SBP management) resulted in a 3% increase in hs-cTnT levels over 1-year follow-up (geometric mean ratio, 1.03 [95% CI, 1.01-1.04]) and a higher proportion of participants with ≥50% increase (odds ratio, 1.47 [95% CI, 1.13, 1.90]). In contrast, randomization to intensive SBP lowering led to a 10% decrease in NT-proBNP (geometric mean ratio, 0.90 [95% CI, 0.87-0.93]) and a lower probability of ≥50% increase in NT-proBNP (odds ratio, 0.57 [95% CI, 0.46-0.72]). The association of randomized treatment assignment on change in hs-cTnT was completely attenuated after accounting for changes in estimated glomerular filtration rate over follow-up, whereas the association of treatment with NT-proBNP was completely attenuated after adjusting for change in SBP. Increases in hs-cTnT and NT-proBNP from baseline to 1 year were associated with higher risk for heart failure and death, with no significant interactions by treatment assignment. Intensive SBP lowering increased hs-cTnT, mediated by the effect of SBP lowering on reduced kidney filtration. In contrast, intensive SBP lowering decreased NT-proBNP, a finding that was explained by the decrease in SBP. These findings highlight the importance of noncardiac factors influencing variation in cardiac biomarkers and raise questions about the potential role of hs-cTnT as a surrogate marker for heart failure or death in SBP-lowering studies.

Efficacy and safety of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction by baseline glycaemic status (DELIVER): a subgroup analysis from an international, multicentre, double-blind, randomised, placebo-controlled trial

Type 2 diabetes and prediabetes are risk factors for heart failure and adverse heart failure outcomes. The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial showed that dapagliflozin was associated with a reduction in the primary outcome of worsening heart failure or cardiovascular mortality in patients with heart failure with mildly reduced or preserved ejection fraction. We aimed to assess the efficacy and safety of oral dapagliflozin in these patients by their baseline glycaemia categories. DELIVER was an international, multicentre, double-blind, randomised, placebo-controlled trial done in 350 health-care centres and hospitals across 20 countries. Patients aged 40 years or older with New York Heart Association class II-IV, left ventricular ejection fraction of more than 40%, elevated natriuretic peptides (N-terminal pro B-type natriuretic peptide ≥300 pg/mL or ≥600 pg/mL for patients in atrial fibrillation or flutter), and evidence of structural heart disease were randomly assigned (1:1) to 10 mg dapagliflozin or placebo, administered orally, and followed up for a median of 2·3 years (IQR 1·7-2·8). The primary outcome, a composite of time from randomisation to first worsening heart failure events (defined as an unplanned hospitalisation or urgent heart failure visit requiring intravenous therapy) or cardiovascular death, in participants with type 2 diabetes (history of or identified by HbA1c ≥6·5% [48 mmol/mol] at baseline) or prediabetes (HbA1c 5·7 to <6·5% [39 mmol/mol to <48 mmol/mol] at baseline) was compared with those with normoglycaemia (HbA1c <5·7% [39 mmol/mol]). Efficacy of dapagliflozin versus placebo was assessed according to glycaemic status and based on HbA1c as a continuous measure. The full-analysis set comprised all patients who were randomly assigned to study treatment, with patients analysed according to their randomised treatment assignment, irrespective of the treatment received (ie, intention to treat). The safety analysis set comprised patients who were randomly assigned to study treatment and who took at least one dose of investigational product, with patients analysed according to the treatment actually received. This trial is registered with ClinicalTrials.gov, NCT03619213. Between Sept 1, 2018, and Jan 18, 2021, 6263 patients were randomly assigned to oral dapagliflozin (n=3131) or placebo (n=3132). Of these patients, 1175 had normoglycaemia, 1934 had prediabetes, and 3150 had type 2 diabetes and were included in the glycaemia subgroup analysis (3515 [56·2%] of 6263 patients were men and 4435 [70·9%] were White). The incidence rate of the primary outcome was 6·9 per 100 patient-years in the normoglycaemia subgroup (reference), increasing to 7·6 per 100 patient-years in the prediabetes subgroup (hazard ratio 1·09 [95% CI 0·90-1·31]) and 10·1 per 100 patient-years in the type 2 diabetes subgroup (1·46 [1·24-1·73]; p<0·0001 for trend). Dapagliflozin reduced the risk of the primary outcome versus placebo in each subgroup (hazard ratio 0·77 [95% CI 0·57-1·04], log-rank p=0·088, for patients with normoglycaemia, 0·87 [0·69-1·08], log-rank p=0·21, for patients with prediabetes, and 0·81 [0·69-0·95], log-rank p=0·0077, for patients with type 2 diabetes; pinteraction=0·82) and across the continuous HbA1c range (pinteraction=0·85). Volume-related or renal serious adverse events or adverse events leading to discontinuation of the study drug, hypoglycaemia, and amputations were not differentially affected by treatment in any of the glycaemia categories. In patients with heart failure with mildly reduced or preserved ejection fraction, oral dapagliflozin improved heart failure outcomes to a similar extent in three glycaemia subgroups: normoglycaemia, prediabetes, and type 2 diabetes. Moreover, the heart failure benefits of dapagliflozin seem to be consistent across a continuous glycaemic range. AstraZeneca.

INVESTIGATING HETEROGENEITY OF TREATMENT EFFECT FOR CONVALESCENT PLASMA IN SEVERE COVID-19: SECONDARY ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL

INVESTIGATING HETEROGENEITY OF TREATMENT EFFECT FOR CONVALESCENT PLASMA IN SEVERE COVID-19: SECONDARY ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL

Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD.

Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.