Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling.

BACKGROUND: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. AIM: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. METHODS: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. RESULTS: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13-3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08-7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95-1.91], p = 0.10), which did not translate into a significant survival benefit. CONCLUSION: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

Bayesian interim analysis for prospective randomized studies: reanalysis of the acute myeloid leukemia HOVON 132 clinical trial.

Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a "7 + 3" induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81-1.69), 1.05 (95% CI 0.86-1.30), 1.00 (95% CI 0.84-1.19), and 1.02 (95% CI 0.87-1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.

Multidimensional Thresholding for Individual-Level Preference Elicitation.

OBJECTIVES: Multiple methods are available for collecting health preference information. However, information on the design and analysis of novel methods is limited. This article aims to provide the first introduction into the design and analysis of multidimensional thresholding (MDT). METHODS: We introduce MDT as a 2-step approach: First, participants rank the largest possible improvements in all considered attributes by their importance. Second, participants complete a series of systematically combined trade-off questions. Hit-and-Run sampling is used for obtaining preference weights. We also use a computational experiment to compare different MDT designs. RESULTS: The outlined MDT can generate preference information suitable for specifying a multiattribute utility function at the individual level. The computational experiment demonstrates the method's ability to recover preference weights at a high level of precision. While all designs in the computation experiment perform comparably well on average, the design outlined in the paper stands out with a high level of precision even if differences in relative attribute importance are large. CONCLUSION: MDT is suitable for preference elicitation, in particular if sample sizes are small. Future research should help improve the methods (e.g., remove the need for an initial ranking) to increase the potential reach of MDT.

Attitudes of healthcare professionals and drug regulators about progression-free survival as endpoint in the advanced cancer setting.

PURPOSE: To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to explore to what extent these attitudes influence the willingness to trade between PFS and toxicity. METHODS: Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the "Stichting Hemato-Oncologie voor Volwassenen Nederland" (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents' willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR). RESULTS: Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS. CONCLUSION: Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients.

Natriuresis-guided diuretic therapy in acute heart failure: a pragmatic randomized trial.

Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute heart failure (AHF). Here, to assess whether natriuresis-guided diuretic therapy in patients with AHF improves natriuresis and clinical outcomes, we conducted the pragmatic, open-label Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure trial, in which 310 patients (45% female) with AHF requiring treatment with intravenous loop diuretics were randomly assigned to natriuresis-guided therapy or standard of care (SOC). In the natriuresis-guided arm, natriuresis was determined at set timepoints, prompting treatment intensification if spot urinary sodium levels were <70 mmol l-1. The dual primary endpoints were 24 h urinary sodium excretion and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The first primary endpoint was met, as natriuresis in the natriuresis-guided and SOC arms was 409 ± 178 mmol arm versus 345 ± 202 mmol, respectively (P = 0.0061). However, there were no significant differences between the two arms for the combined endpoint of time to all-cause mortality or first heart failure rehospitalization, which occurred in 46 (31%) and 50 (31%) of patients in the natriuresis-guided and SOC arms, respectively (hazard ratio 0.92 [95% confidence interval 0.62-1.38], P = 0.6980). These findings suggest that natriuresis-guided therapy could be a first step towards personalized treatment of AHF. ClinicalTrials.gov registration: NCT04606927 .

Trajectories of renal biomarkers and new-onset heart failure in the general population: Findings from the PREVEND study.

AIMS: Renal dysfunction is one of the most critical risk factors for developing heart failure (HF). However, the association between repeated measures of renal function and incident HF remains unclear. Therefore, this study investigated the longitudinal trajectories of urinary albumin excretion (UAE) and serum creatinine and their association with new-onset HF and all-cause mortality. METHODS AND RESULTS: Using group-based trajectory analysis, we estimated trajectories of UAE and serum creatinine in 6881 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study and their association with new-onset HF and all-cause death during the 11-years of follow-up. Most participants had stable low UAE or serum creatinine. Participants with persistently higher UAE or serum creatinine were older, more often men, and more often had comorbidities, such as diabetes, a previous myocardial infarction or dyslipidaemia. Participants with persistently high UAE had a higher risk of new-onset HF or all-cause mortality, whereas stable serum creatinine trajectories showed a linear association for new-onset HF and no association with all-cause mortality. CONCLUSION: Our population-based study identified different but often stable longitudinal patterns of UAE and serum creatinine. Patients with persistently worse renal function, such as higher UAE or serum creatinine, were at a higher risk of HF or mortality.

What Factors Make EU Regulators Want to Communicate Drug Safety Issues Related to SGLT2 Inhibitors? An Online Survey Study.

INTRODUCTION: Previous studies have found differences in the communication of safety issues among medicines regulatory agencies. OBJECTIVES: To explore (1) to what extent regulators' opinions regarding the need to communicate safety issues related to sodium-glucose cotransporter-2 (SGLT2) inhibitors might be influenced by their concern about the safety issue, and (2) whether regulators' concerns might be influenced by certain characteristics of the safety issue or by the demographic and professional characteristics and attitudes of the regulators. METHODS: An online cross-sectional survey study with a rating-based conjoint analysis among clinical and pharmacovigilance assessors from the EU regulatory network was performed between April and June 2021. Regulators were invited by email, and participants were asked about their level of concern and their opinion regarding the need to communicate about 12 scenarios defined by four characteristics: adverse drug reaction, source of information, causality, and frequency. The outcomes for the first objective were to update the summary of product characteristics (SmPC; yes/no) and to send direct healthcare professional communications (DHPC; yes/no). The determinant was regulators' level of concern (range 0-100%). The outcome of the second objective was regulators' level of concern, and the determinants were the characteristics of the safety issue, demographic and professional characteristics, and attitudes of the regulators (beliefs about medicines and risk perception). RESULTS: A total of 222 regulators completed the survey (64% women; mean age 46 ± 10 years). Depending on the scenario, 54-94% and 25-74% of the participants would update the SmPC or send a DHPC, respectively. The participants' level of concern influenced their opinions regarding the need to update the SmPC and send a DHPC (odds ratio (OR) 13.0; 95% confidence interval (CI) 7.8-21.7 and OR 13.6; 95% CI 9.5-19.2, respectively, for every 10% increase in the level of concern). All characteristics of the safety issue influenced the level of concern. Younger participants, women, and those working for Eastern European agencies had a higher level of concern than older participants, men, and those working in other regions. Beliefs about medicines and general risk perception also influenced their concern. CONCLUSIONS: The opinion regarding the need to communicate safety issues was influenced by the concern of regulators. Regulators' concern was influenced by the characteristics of the safety issue, demographic characteristics, and attitudes. Diverse groups of experts regarding such factors would ensure that various views are incorporated in risk communication decisions.

Multimarker Analysis of Serially Measured GDF-15, NT-proBNP, ST2, GAL-3, cTnI, Creatinine, and Prognosis in Acute Heart Failure.

BACKGROUND: Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk. METHODS: TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling. RESULTS: Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78-2.57) unadjusted, 1.96 (1.49-2.53) after adjustment for clinical confounders and 1.44 (1.05-1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78-3.33) and 1.52 (1.15-2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785). CONCLUSIONS: Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice. REGISTRATION: URL: https://www.trialregister.nl/trial/1783; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893.).

A simulated maximum likelihood procedure for analyzing imprecise trade-off thresholds between the benefits and harms of medicines.

Stated preference studies in which information on the willingness to trade-off between the benefits and harms of medicines is elicited from patients or other stakeholders are becoming increasingly mainstream. Such trade-offs can mathematically be represented by a weighted additive function, with the weights, whose ratios determine how much an individual is willing to trade-off between the treatment attributes, being the response vector for the statistical analysis. One way of eliciting trade-off information is through multi-dimensional thresholding (MDT), which is a bisection-based approach that results in increasingly tight bounds on the values of the weights ratios. While MDT is cognitively less demanding than other, more direct elicitation methods, its use complicates the statistical analysis as it results in weights data that are region censored. In this article, we present a simulated maximum likelihood (SML) procedure for fitting a Dirichlet population model directly to the region-censored weights data and perform a series of computational experiments to compare the proposed SML procedure to a naive approach in which a Dirichlet distribution is fitted to the centroids of the weights boundaries obtained with MDT. The results indicate that the SML procedure consistently outperformed the centroid-based approach, with the centroid-based approach requiring three bisection steps per trade-off to achieve a similar precision as the SML procedure with one bisection step per trade-off. Using the newly proposed SML procedure, MDT can be applied with smaller sample sizes or with fewer questions compared to the more naïve centroid-based approach that was applied in previous applications of MDT.

Long-term outcomes of atrioventricular septal defect and single ventricle: A multicenter study.

OBJECTIVE: The study objective was to analyze survival and incidence of Fontan completion of patients with single-ventricle and concomitant unbalanced atrioventricular septal defect. METHODS: Data from 4 Dutch and 3 Belgian institutional databases were retrospectively collected. A total of 151 patients with single-ventricle atrioventricular septal defect were selected; 36 patients underwent an atrioventricular valve procedure (valve surgery group). End points were survival, incidence of Fontan completion, and freedom from atrioventricular valve reoperation. RESULTS: Median follow-up was 13.4 years. Cumulative survival was 71.2%, 70%, and 68.5% at 10, 15, and 20 years, respectively. An atrioventricular valve procedure was not a risk factor for mortality. Patients with moderate-severe or severe atrioventricular valve regurgitation at echocardiographic follow-up had a significantly worse 15-year survival (58.3%) compared with patients with no or mild regurgitation (89.2%) and patients with moderate regurgitation (88.6%) (P = .033). Cumulative incidence of Fontan completion was 56.5%, 71%, and 77.6% at 5, 10, and 15 years, respectively. An atrioventricular valve procedure was not associated with the incidence of Fontan completion. In the valve surgery group, freedom from atrioventricular valve reoperation was 85.7% at 1 year and 52.6% at 5 years. CONCLUSIONS: The long-term survival and incidence of Fontan completion in our study were better than previously described for patients with single-ventricle atrioventricular septal defect. A concomitant atrioventricular valve procedure did not increase the mortality rate or decrease the incidence of Fontan completion, whereas patients with moderate-severe or severe valve regurgitation at follow-up had a worse survival. Therefore, in patients with single-ventricle atrioventricular septal defect when atrioventricular valve regurgitation exceeds a moderate degree, the atrioventricular valve should be repaired.

A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function.

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function.

Determinants of quality of life in acute heart failure patients with and without comorbidities: a prospective, observational study.

AIMS: The relation between non-cardiac comorbidities and health-related quality of life (HRQoL) in patients with heart failure (HF) has been studied to a limited extent. To investigate the HRQoL and their determinants among HF patients with and without comorbidities. METHODS AND RESULTS: TRIUMPH (TRanslational Initiative on Unique and novel strategies for Management of Patients with Heart failure) is a Dutch prospective, multicentre study enrolling 496 acute HF patients between 2009 and 2014. We included 334 patients who had completed the HRQoL questionnaires at baseline. The HRQoL was measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) en EuroQuality-of-life five Dimensions (EQ-5D). Comorbidity was defined as having a history of at least one of the following comorbidities: chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and/or cerebrovascular accident. Patients with comorbidity (n = 205, 61%) had lower scores on the physical limitation scale and clinical summary score of the KCCQ (P = 0.03 and P = 0.01, respectively). Female sex, COPD, previous HF, increasing body mass index (BMI), elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), high systolic blood pressure, and the presence of anxiety and/or depression negatively influenced the HRQoL among HF patients with comorbidity. Besides anxiety and depression, we hardly found any other determinant of HRQoL in patients without comorbidity. CONCLUSION: Heart failure patients without comorbidity had better HRQoL than patients with comorbidity. Sex, previous HF, BMI, COPD, systolic blood pressure, NT-proBNP levels, and also anxiety and depression were determinants of HRQoL in patients with comorbidity. In those without comorbidity, apart from anxiety and depression, no further determinants of HRQoL were found.

Parenteral Prostanoids in Pediatric Pulmonary Arterial Hypertension: Start Early, Dose High, Combine.

Rationale: There are currently no data supporting specific dosing and weaning strategies for parenteral prostanoid therapy in children with pulmonary arterial hypertension (PAH). Objectives: To describe the clinical practice of intravenous (IV) or subcutaneous (SC) prostanoid therapy in pediatric PAH and identify dosing strategies associated with favorable outcome. Methods: From an international multicenter cohort of 275 children with PAH, 98 patients who received IV/SC prostanoid therapy were retrospectively analyzed. Results: IV/SC prostanoids were given as monotherapy (20%) or combined with other PAH-targeted drugs as dual (46%) or triple therapy (34%). The median time-averaged dose was 37 ng/kg/min, ranging 2-136 ng/kg/min. During follow-up, IV/SC prostanoids were discontinued and transitioned to oral or inhaled PAH-targeted therapies in 29 patients. Time-dependent receiver operating characteristic analyses showed specific hemodynamic criteria at discontinuation of IV/SC prostanoids (mean pulmonary arterial pressure < 35 mm Hg and/or pulmonary vascular resistance index < 4.4 Wood units [WU]⋅m2) identified children with favorable long-term outcome after IV/SC prostanoid discontinuation, compared with patients who do not meet those criteria (P = 0.027). In the children who continued IV/SC prostanoids until the end of follow-up, higher dose (>25 ng/kg/min), early start after diagnosis, and combination with other PAH-targeted drugs were associated with better transplant-free survival. Conclusions: Early initiation of IV/SC prostanoids, higher doses of IV/SC prostanoids, and combination with additional PAH-targeted therapy were associated with favorable outcome. Transition from IV/SC prostanoid therapy to oral or inhaled therapies is safe in the long term in selected children, identified by reaching hemodynamic criteria for durable IV/SC prostanoid discontinuation while on IV/SC prostanoid therapy.

The value of anticancer drugs - a regulatory view.

The high prices of new anticancer drugs and the marginal added benefit perceived by some stakeholders have fuelled a debate on the value of anticancer drugs in the European Union, even though an agreed definition of what constitutes a drug's value does not exist. In this Perspective, we discuss the value of drugs from different viewpoints and objectives of decision makers: for regulators, assessment of the benefit-risk balance of a drug is a cornerstone for approval; payers rely on cost-effectiveness analyses carried out by health technology assessment agencies for reimbursement decisions; for patients, treatment choices are based on personal preferences and attitudes to risk; and clinicians can use several scales (such as the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)) that have been developed as an attempt to measure value objectively. Although a unique definition that fully captures the concept of value is unlikely to emerge, herein we discuss the importance of understanding different perspectives, and how regulators can help to inform different decision makers.

Association of Early Blood Pressure Decrease and Renal Function With Prognosis in Acute Heart Failure.

OBJECTIVES: The aim of this study was to investigate the association between systolic blood pressure (SBP) drop, worsening renal function (WRF), and prognosis in patients with acute heart failure (AHF). BACKGROUND: A large drop in SBP early after hospital admission for AHF might be associated with increased risk for WRF and prognosis. However, there is a paucity of data regarding the interaction between WRF and a drop in SBP on clinical outcomes. METHODS: A post hoc analysis among 6,544 patients with AHF enrolled in the RELAX-AHF-2 (Relaxin in Acute Heart Failure-2) trial was performed. Blood pressure was uniformly and repetitively measured. Peak SBP drop was defined as the difference between baseline SBP and lowest SBP documented during the first 48 hours. WRF was defined by an increase in serum creatinine of ≥0.3 mg/dL from baseline to day 5. RESULTS: Peak SBP drop was independently associated with a higher risk for WRF (HR: 1.11 per 10 mm Hg SBP drop; P < 0.001), 5-day worsening heart failure (HR: 1.12 per 10 mm Hg SBP drop; P = 0.006), and 180-day cardiovascular death (HR: 1.09 per 10 mm Hg SBP drop; P = 0.026) after adjustment for potential confounders including baseline SBP. There was no interaction between the prognostic value of early SBP drop according to the presence or absence of WRF. CONCLUSIONS: In patients hospitalized for AHF, a greater early drop in SBP was associated with a higher incidence of WRF, worsening heart failure, and an increased risk for 180-day cardiovascular death. However, the association between SBP drop and prognosis was not influenced by WRF. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778).

Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure.

OBJECTIVES: The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF). BACKGROUND: Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline. METHODS: A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified. RESULTS: HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF. CONCLUSIONS: Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150).

A heart failure phenotype stratified model for predicting 1-year mortality in patients admitted with acute heart failure: results from an individual participant data meta-analysis of four prospective European cohorts.

BACKGROUND: Prognostic models developed in general cohorts with a mixture of heart failure (HF) phenotypes, though more widely applicable, are also likely to yield larger prediction errors in settings where the HF phenotypes have substantially different baseline mortality rates or different predictor-outcome associations. This study sought to use individual participant data meta-analysis to develop an HF phenotype stratified model for predicting 1-year mortality in patients admitted with acute HF. METHODS: Four prospective European cohorts were used to develop an HF phenotype stratified model. Cox model with two rounds of backward elimination was used to derive the prognostic index. Weibull model was used to obtain the baseline hazard functions. The internal-external cross-validation (IECV) approach was used to evaluate the generalizability of the developed model in terms of discrimination and calibration. RESULTS: 3577 acute HF patients were included, of which 2368 were classified as having HF with reduced ejection fraction (EF) (HFrEF; EF < 40%), 588 as having HF with midrange EF (HFmrEF; EF 40-49%), and 621 as having HF with preserved EF (HFpEF; EF ≥ 50%). A total of 11 readily available variables built up the prognostic index. For four of these predictor variables, namely systolic blood pressure, serum creatinine, myocardial infarction, and diabetes, the effect differed across the three HF phenotypes. With a weighted IECV-adjusted AUC of 0.79 (0.74-0.83) for HFrEF, 0.74 (0.70-0.79) for HFmrEF, and 0.74 (0.71-0.77) for HFpEF, the model showed excellent discrimination. Moreover, there was a good agreement between the average observed and predicted 1-year mortality risks, especially after recalibration of the baseline mortality risks. CONCLUSIONS: Our HF phenotype stratified model showed excellent generalizability across four European cohorts and may provide a useful tool in HF phenotype-specific clinical decision-making.

Effect of Dapagliflozin on Clinical Outcomes in Patients With Chronic Kidney Disease, With and Without Cardiovascular Disease.

BACKGROUND: Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease. METHODS: In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease. RESULTS: Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 [95% CI, 0.48-0.78]) and secondary (0.61 [0.47-0.79]) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 [0.40-1.13] versus 0.70 [0.52-0.94], respectively; P-interaction=0.88), and all-cause mortality (0.63 [0.41-0.98] versus 0.70 [0.51-0.95], respectively; P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease. CONCLUSIONS: Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150.