Bayesian inference for a principal stratum estimand on recurrent events truncated by death.

Recurrent events are often important endpoints in randomized clinical trials. For example, the number of recurrent disease-related hospitalizations may be considered as a clinically meaningful endpoint in cardiovascular studies. In some settings, the recurrent event process may be terminated by an event such as death, which makes it more challenging to define and estimate a causal treatment effect on recurrent event endpoints. In this paper, we focus on the principal stratum estimand, where the treatment effect of interest on recurrent events is defined among subjects who would be alive regardless of the assigned treatment. For the estimation of the principal stratum effect in randomized clinical trials, we propose a Bayesian approach based on a joint model of the recurrent event and death processes with a frailty term accounting for within-subject correlation. We also present Bayesian posterior predictive check procedures for assessing the model fit. The proposed approaches are demonstrated in the randomized Phase III chronic heart failure trial PARAGON-HF (NCT01920711).

Innovations in Pediatric Therapeutics Development: Principles for the Use of Bridging Biomarkers in Pediatric Extrapolation.

Even with recent substantive improvements in health care in pediatric populations, considerable need remains for additional safe and effective interventions for the prevention and treatment of diseases in children. The approval of prescription drugs and biological products for use in pediatric settings, as in adults, requires demonstration of substantial evidence of effectiveness and favorable benefit-to-risk. For diseases primarily affecting children, such evidence predominantly would be obtained in the pediatric setting. However, for conditions affecting both adults and children, pediatric extrapolation uses scientific evidence in adults to enable more efficiently obtaining a reliable evaluation of an intervention's effects in pediatric populations. Bridging biomarkers potentially have an integral role in pediatric extrapolation. In a setting where an intervention reliably has been established to be safe and effective in adults, and where there is substantive evidence that disease processes in pediatric and adult settings are biologically similar, a 'bridging biomarker' should satisfy three additional criteria: effects on the bridging biomarker should capture effects on the principal causal pathway through which the disease process meaningfully influences 'feels, functions, survives' measures; secondly, the experimental intervention should not have important unintended effects on 'feels, functions, survives' measures not captured by the bridging biomarker; and thirdly, in statistical analyses in adults, the intervention's net effect on 'feels, functions, survives' measures should be consistent with what would be predicted by its level of effect on the bridging biomarker. A validated bridging biomarker has considerable potential utility, since an intervention's efficacy could be extrapolated from adult to pediatric populations if evidence in children establishes the intervention not only to be safe but also to have substantive effects on that bridging biomarker. Proper use of bridging biomarkers could increase availability of reliably evaluated therapies approved for use in pediatric settings, enabling children and their caregivers to make informed choices about health care.

Prognostic Models Derived in PARADIGM-HF and Validated in ATMOSPHERE and the Swedish Heart Failure Registry to Predict Mortality and Morbidity in Chronic Heart Failure.

Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8399), and 70.6% were New York Heart Association class II (n = 5919 of 8399). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, ß-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by χ2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual's risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

Assessing Treatment Effects That Capture Disease Burden in Serious Chronic Diseases.

Serious and chronic health conditions such as cardiovascular diseases (CVDs) are posing challenges to the health system. Recently clinical trials in these fields have focused on composite endpoints that take into account both disease-related mortality and major disease-related morbidity events. It is the time to the first component of the composite endpoint experienced by a patient that is the traditional study endpoint and treatment aims are to delay the time to the first event and to reduce its frequency. As the name implies, the time-to-first composite event analysis approach focuses only on the first composite event and ignores subsequent events. For a chronic disease, this can lead to a substantial loss of potentially important information. For instance, in chronic heart failure (HF) studies, the traditional composite endpoint of HF-related hospitalizations and CVD death will ignore CVD deaths that are preceded by HF-related hospitalizations. This paper explores the limitations of the traditional time-to-first event approach and discusses the potential value of incorporating all events. The authors argue that endpoints capturing recurrent event information can lead to interpretable measures of treatment effect that better reflect disease burden than traditional time-to-first event endpoints by using the available information beyond the first event. This paper aims to raise awareness of the value and potential pitfalls of alternative treatment effect measures to facilitate meaningful cross-functional conversations among trialists and other stakeholders such as regulators, payers, and treating physicians who all are striving to the same goal-to deliver the most effective treatments to patients.

Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF).

AIMS: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis. METHODS AND RESULTS: In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar. CONCLUSIONS: In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.

Independent academic Data Monitoring Committees for clinical trials in cardiovascular and cardiometabolic diseases.

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals.

Design of the RELAXin in acute heart failure study.

BACKGROUND: Acute heart failure (AHF) remains a major public health burden with a high prevalence and poor prognosis. Relaxin is a naturally occurring peptide hormone that increases cardiac output, arterial compliance, and renal blood flow during pregnancy. The RELAX-AHF-1 study will evaluate the effect of RLX030 (recombinant form of human relaxin 2) on symptom relief and clinical outcomes in patients with AHF. METHODS: The protocol includes a completed phase 2 234-patient dose-finding study (Pre-RELAX-AHF) and an ongoing phase 3 1,160-patient trial (RELAX-AHF-1). Patients with AHF and systolic blood pressure >125 mm Hg are randomized within 16 hours of presentation to a 48-hour IV infusion of RLX030 or placebo. The 30 µg/kg per day dose of RLX030 was chosen for RELAX-AHF-1 based on effects on dyspnea, clinical outcomes, and safety observed in Pre-RELAX-AHF. Primary efficacy end points in RELAX-AHF-1 are (1) the area under the curve of change of the dyspnea Visual Analog Scale from baseline through day 5 and (2) whether the patient reports moderately to markedly better dyspnea at 6, 12, and 24 hours. Secondary efficacy end points include days alive and out of the hospital through day 60 and cardiovascular death or rehospitalization for heart failure or renal failure through day 60. Patients will be followed up through day 180 for mortality. As of September 19, 2011, 978 patients have been enrolled. CONCLUSIONS: Pre-RELAX-AHF results suggested that infusion of RLX030 may accelerate dyspnea relief and improve prognosis in patients hospitalized with AHF. RELAX-AHF-1 will further evaluate these effects.

Prospective randomized multicenter trial of fibrin sealant versus thrombin-soaked gelatin sponge for suture- or needle-hole bleeding from polytetrafluoroethylene femoral artery grafts.

OBJECTIVE: We evaluated the safety and efficacy of the fibrin sealant Beriplast P (FSBP; Aventis-Behring) for hemostasis in anastomosis of polytetrafluoroethylene (PTFE) grafts to the femoral artery. METHODS: In a single-blinded randomized prospective multicenter clinical trial, FSBP was compared with thrombin-soaked gelatin sponge (TSG) for efficacy in stopping bleeding from needle or suture holes in PTFE grafts after anastomosis to the femoral artery. Patients were randomized to FSBP application, which requires a 3-minute period of arterial clamping to enable the fibrin clot to adhere, or to TSG application, which requires pressure from gauze sponges, after completion of the femoral artery anastomosis. The primary end point was hemostasis, defined as absence of any detectable bleeding as judged by the operating surgeon, by 4 minutes after randomization. Secondary end points included actual time from randomization to hemostasis, time to beginning of wound closure, measured blood loss (weighed sponges), incidence of recurrent bleeding, stay in the intensive care unit, and hospital length of stay. Data were analyzed with the intention-to-treat method. RESULTS: Two hundred thirty-five subjects were enrolled at 26 medical centers; 34 were subsequently excluded from the study. Of the 201 randomized subjects, 100 received FSBP and 99 received TSG. Hemostasis was achieved by 4 minutes in 64 subjects (63%) in the FSBP group and 40 subjects (40%) in the TSG group (P =.0018). In the FSBP group, compared with the TSG group, time to hemostasis was shorter (median, 4.0 minutes; 95% confidence interval [CI], 3.8-4.18 minutes vs median, 5.6 minutes, 95% CI, 4.5-7.0; P =.008), blood loss was less (mean, 4.0 +/- 29.7 g vs mean, 15.6 +/- 28.4 g; P <.0001), and time to wound closure was shorter (median, 15 minutes; 95% CI, 10.47-18.67 minutes vs median, 22.8 minutes; 95% CI, 18.67-30.67; P =.005). There were no differences in recurrent bleeding or any other adverse events. There was no significant difference in ICU stay, but hospital length of stay was shorter in the FSBP group compared with the TSG group, and the difference approached significance (median, 6.5 days; 95% CI, 5.00-7.00 days vs median, 7.0 days; 95% CI,. 6.00-8.00 days; P =.0565). CONCLUSION: FSBP is more effective than TSG for achieving hemostasis of needle or suture hole bleeding from PTFE femoral artery grafts.

Pharmacokinetic analysis of plasma-derived and recombinant F IX concentrates in previously treated patients with moderate or severe hemophilia B.

BACKGROUND: Hemophilia B is an X-linked bleeding disorder that affects approximately 1 in 25,000 males. Therapy for acute bleeding episodes consists of transfusions of plasma-derived (pd-F IX) or recombinant (r-F IX) concentrates. STUDY DESIGN AND METHODS: A double-blind, two-period crossover study was initiated to assess the pharmacokinetics of pd-F IX and r-F IX and to address patient-specific variables that might influence in vivo recovery. Study product was administered by a single bolus infusion (50 IU/kg) to 43 previously treated patients in the nonbleeding state, and F IX:C levels were measured over a period of 48 hours after infusion. RESULTS: The mean in vivo recovery in the pd-F IX group was 1.71 +/- 0.73 IU per dL per IU per kg compared with 0.86 +/- 0.31 IU per dL per IU per kg with r-F IX (p