Browsing by Author "Packer, Milton (7103011367)"

Aims: The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin-angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF). Methods and results: We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), first HF hospitalization (RR 0.67, 95% CI 0.58-0.78), cardiovascular death (RR 0.76, 95% CI 0.64-0.89), and all-cause death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02. Conclusion: This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Background: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. Methods and Results: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. Conclusions: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711. © 2018 American Heart Association, Inc.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas. © 2020 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020.

Aim: There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF. Methods and results: Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre-diabetes, 6.0%–6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre-diabetes. Compared to patients with normal HbA1c, patients with pre-diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT-proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35–1.88), total HFH (RR 1.67, 95% CI 1.39–2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07–1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre-diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00–1.60) and HFH (HR 1.35, 95% CI 1.03–1.77), but not of CV death (HR 1.02, 95% CI 0.75–1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with ‘lean diabetes’ had similar mortality rates to those with a higher body mass index, but lower rates of HFH. Conclusion: Pre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711. © 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.