Treatment adherence in a randomised controlled trial of pirfenidone in HFpEF: determinants and impact on efficacy

Aims: Medication adherence in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. This study sought to evaluate treatment adherence in the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial, identify factors that predict adherence, and understand the impact of missed medication doses on treatment efficacy.Methods: Adherence was evaluated at each study visit through pill counts and diary cards. Univariable and multivariable regression models were used to assess the relationship between adherence and baseline characteristics. Instrumental variable regression was used to estimate the causal effect of pirfenidone treatment duration on myocardial fibrosis, measured using cardiovascular magnetic resonance extracellular volume.Results: Complete adherence data was available in 54 of 80 participants completing the trial. Mean adherence with study medication was 94.7% and 96.9% in the pirfenidone and placebo groups respectively. Each additional day of treatment with pirfenidone resulted in a significant decrease in myocardial extracellular volume (–0.004%; 95% confidence interval: -0.007% to -0.001%; p=0.007). Associations with adherence included older age, higher symptom burden, lower body weight and smaller right ventricular size. Limitations of adherence assessments were highlighted. Conclusion: Adherence with study medication in the PIROUETTE trial was very high among patients for whom complete adherence data was available. Importantly, each additional day of treatment reduced myocardial fibrosis. Potential predictors of adherence were identified. Implementation of improved methods for assessing adherence is required.Keywords: Heart failure with preserved ejection fraction, adherence, efficacy, myocardial fibrosis