Developments in Exercise Capacity Assessment in Heart Failure Clinical Trials and the Rationale for the Design of METEORIC-HF.

Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity. Current guideline-directed medical therapy has indirect effects on cardiac performance with minimal impact on measured functional capacity. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases cardiac contractility and in a phase 3 cardiovascular outcomes study significantly reduced the primary composite end point of time to first heart failure event or cardiovascular death in patients with HFrEF. The objective of the METEORIC-HF trial (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure) is to assess the effect of omecamtiv mecarbil versus placebo on multiple components of functional capacity in HFrEF. The primary end point is to test the effect of omecamtiv mecarbil compared with placebo on peak oxygen uptake as measured by cardiopulmonary exercise testing after 20 weeks of treatment. METEORIC-HF will provide state-of-the-art assessment of functional capacity by measuring ventilatory efficiency, circulatory power, ventilatory anaerobic threshold, oxygen uptake recovery kinetics, daily activity, and quality-of-life assessment. Thus, the METEORIC-HF trial will evaluate the potential impact of increased myocardial contractility with omecamtiv mecarbil on multiple important measures of functional capacity in ambulatory patients with symptomatic HFrEF. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03759392.

Serial Assessment of High-Sensitivity Cardiac Troponin and the Effect of Dapagliflozin in Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of the DAPA-HF Trial.

BACKGROUND: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. METHODS: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction ≤40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. RESULTS: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7-30.2) ng/L. Over 1 year, 67.9% of patients had a ≥10% relative increase or decrease in hsTnT concentrations, and 43.5% had a ≥20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46-4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT (P-interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%-14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, -3% [-6% to 0%]; P=0.076). CONCLUSIONS: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.

AIM: To estimate the cost-effectiveness of dapagliflozin added to standard therapy, vs. standard therapy only, in patients with heart failure (HF) with reduced ejection fraction (HFrEF), from the perspective of UK, German, and Spanish payers. METHODS AND RESULTS: A lifetime Markov model was built to estimate outcomes in patients with HFrEF. Health states were defined by Kansas City Cardiomyopathy Questionnaire total symptom score, type 2 diabetes and worsening HF events. The incidence of worsening HF and all-cause mortality was estimated using negative binomial regression models and parametric survival analysis, respectively. Direct healthcare costs (2019 British pounds/Euro) and patient-reported outcomes (EQ-5D) were sourced from the existing literature and the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF), respectively; the median duration of follow-up in DAPA-HF was 18.2 months (range: 0-27.8). Future costs and effects were discounted at 3.0% for the Spanish and German analyses and 3.5% for the UK analysis. In the UK setting, treatment with dapagliflozin was estimated to increase life-years and quality-adjusted life-years (QALYs) from 5.62 to 6.20 (+0.58) and 4.13 to 4.61 (+0.48), respectively, and reduce lifetime hospitalizations for HF (925 and 820 events per 1000 patients for placebo and dapagliflozin, respectively). Similar results were obtained for Germany and Spain. The incremental cost-effectiveness ratios were £5822, €5379 and €9406/QALY in the UK, Germany and Spain, respectively. In probabilistic sensitivity analyses, more than 90% of simulations were cost-effective at a willingness-to-pay threshold of £20 000/QALY in UK and €20 000/QALY in Germany and Spain. CONCLUSION: Dapagliflozin is likely to be a cost-effective treatment for HFrEF in the UK, German and Spanish healthcare systems.