Effect of Eplontersen on Cardiac Structure and Function in Patients With Hereditary Transthyretin Amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is associated with polyneuropathy, cardiomyopathy, or both. The effects of eplontersen on cardiac structure and function were assessed. METHODS AND RESULTS: NEURO-TTRansform was an open-label trial involving 144 adults with ATTRv polyneuropathy (49 patients [34%] with cardiomyopathy) receiving eplontersen throughout and compared with a historical placebo group (n = 60; 30 patients [50%] with cardiomyopathy) from the NEURO-TTR trial at week 65. Treatment effect (eplontersen vs placebo), presented as mean difference (95% confidence interval) was analyzed after adjusting for age, sex, region, baseline value, ATTRv disease stage, previous ATTRv treatment, and V30M transthyretin variant. There were notable differences at baseline between the eplontersen group and historical placebo. In the cardiomyopathy subgroup, 65 weeks of eplontersen treatment was associated with improvement from baseline relative to placebo in left ventricular ejection fraction of 4.3% (95% confidence interval 1.40-21.01; P = .049) and stroke volume 10.64 mL (95% confidence interval 3.99-17.29; P = .002) while the remainder of echocardiographic parameters remained stable. CONCLUSIONS: Eplontersen was associated with stable or improved measures of cardiac structure and function vs historical placebo in patients with ATTRv polyneuropathy and cardiomyopathy. Further investigation into eplontersen's effect on transthyretin amyloid cardiomyopathy is being conducted in the CARDIO-TTRansform trial.

Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan.

AIMS: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. METHODS AND RESULTS: Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nmol/L in HFrEF and 0.88 (0.68-1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status. CONCLUSIONS: MR-proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure. CLINICAL TRIAL REGISTRATION: PROVE-HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588.

Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Polypharmacy Status.

BACKGROUND: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy. OBJECTIVES: This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction. METHODS: In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death. RESULTS: Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; Pinteraction = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (Pinteraction = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status. CONCLUSIONS: In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).