Browsing by Author "Jhund, Pardeep S (6506826363)"

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.

Heart failure (HF) is a global epidemic, particularly affecting the elderly and/or frail patients often with comorbidities. Amongst the comorbidities, type 2 diabetes mellitus (T2DM) is highly prevalent and associated with higher morbidity and mortality. We review the detection and treatment of T2DM in HF and the need to balance the risk of hypoglycaemia and overall glycaemic control. Despite large attributable risks, T2DM is often underdiagnosed in HF. Therefore there is a need for systematic monitoring (screening) for undetected T2DM in HF patients. Given that patients with HF are at greater risk for developing T2DM compared with the general population, an emphasis also has to be placed on regular reassessment of glycaemic status during follow-up. Therefore, glucose-lowering therapies (e.g. sodium-glucose cotransporter-2 inhibitors, SGLT-2 inhibitors) with a known benefit for the prevention or delay of HF hospitalization could be considered early in the course of T2DM, to optimise treatment and reduce cardiovascular (CV) risk. Although intensive glycaemic control has been shown to effectively reduce the risk of microvascular complications in T2DM, these same trials have shown either no reduction in CV outcomes, or even an increase in mortality with tight glycaemic control (i.e. targeting HbA1c levels <7.0%). More lenient glycaemic targets (e.g. HbA1c levels 7.0-8.0%) may be more appropriate for HF patients with T2DM. The 2016 ESC Guidelines for the diagnosis and treatment of HF proposed metformin as the first-line therapy, given its long-standing use and low risk of hypoglycaemia. More recently, several novel glucose lowering-medications have been introduced, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and SGLT-2 inhibitors. The most consistent reduction in the risk of HF hospitalisation has been shown with the three SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) which now offer improved outcomes in patients with both HF and T2DM. © The Author(s) 2019.