The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT)

Abstract

Objectives The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 x 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). Methods Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. Results As of May 2020, 296 patients have been randomized at 20 centers in Denmark. Conclusion The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of two commonly prescribed drugs with limited randomized data in patients with HFrEF.

Association between prediabetes and adverse outcomes in heart failure

“…These results are compelling and suggest the need for further assessment of the effects of SGLT2i on the progression of HF associated with prediabetes. The ongoing DANish randomized, double‐blind, placebo‐controlled trial in patients with chronic HEART failure (DANHEART) will provide important messages on the potential benefit and safety of metformin in patients with HF and with prediabetes 48 . Finally, prediabetes is an important component of metabolic syndrome.…”

Metformin for diabetes prevention: update of the evidence base

“…56 The DAN-HEART study is including people with comorbid HF and clinical diabetes or non-diabetic hyperglycaemia. 57 The main outcome will be the incidence of cardiovascular events.…”

“…104 Lactic acidosis is an extremely rare complication of treatment of type 2 diabetes with metformin, and the contraindications of this agent are designed to avoid its use during the settings of severe renal impairment and hypoperfusion/hypoxia that might predispose to metformin-associated lactic acidosis. 57 The prevalence of these conditions in subjects with non-diabetic hyperglycaemia has not been investigated to our knowledge, but it is likely to be lower than in people with type 2 diabetes of long duration who may be receiving metformin and who may be at risk of developing potential contraindications to metformin such as severe chronic kidney disease or severe acute HF, etc.…”

Intersection Between Diabetes and Heart Failure: Is SGLT2i the “One Stone for Two Birds” Approach?

“…However, all the data were generated from observational studies. The ongoing Metformin in Patients with Chronic Heart Failure and Diabetes or Insulin Resistance Trial (Met-HeFT) will be the largest randomized study to date powered to address the effects of metformin on clinical outcomes in chronic HFrEF patients [ 66 ].…”