TrimetaziDine as a Performance-enhancING drug in heart failure with preserved ejection fraction (DoPING-HFpEF): rationale and design of a placebo-controlled cross-over intervention study

LV relaxation is a highly energy-demanding process. During diastole, calcium ions are actively transported back into the sarcoplasmic reticulum of the cardiomyocyte by sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pumps, and adenosine triphosphate (ATP) is also required for cross-bridge detachment [7]. In the case of ischaemia, defined as insufficient coronary blood flow to the myocardium to meet the metabolic demand, disturbances in myocardial relaxation are among the first events to occur, even before contractility becomes impaired [8]. In HFpEF patients, Phan et al. detected a myocardial energy deficiency that may underlie malfunctioning of the active relaxation stage of diastole, particularly during exercise (Fig. 1, arrow 2) [9]. This is supported by the findings of other studies showing a correlation between reduced myocardial phosphocreatine (PCr)/ATP ratios and the severity of diastolic dysfunction [10, 11]. Interestingly, in asymptomatic patients with type 2 diabetes diastolic function was impaired and correlated with lower myocardial PCr/ATP ratios, while systolic function was preserved [10]. The myocardial PCr/ATP ratio reports on the steady-state balance between ATP turnover and ATP synthesis, and is as such an index of the in vivo myocardial energy status. It can be quantified non-invasively with phosphorus-31 magnetic resonance spectroscopy (³¹P‑MRS) [12].

Myocardial energy deficiency in HFpEF can be explained by mitochondrial dysfunction. Mitochondrial dysfunction in HFpEF is considered mainly to be a consequence of chronically increased oxidative stress, overexpression of proinflammatory cytokines, and other factors common in HFpEF known to be associated with mitochondrial abnormalities such as aging, renal dysfunction, and insulin resistance (Fig. 1, arrow 1) [7, 13, 14]. On the other hand, mitochondrial dysfunction is linked to insulin resistance, thus closing a first vicious circle (Fig. 1, arrow 4) [15, 16]. Notably, similar associations between mitochondrial dysfunction and hypertension or obesity have been observed [11, 17]. Importantly, this mechanism appears to be reversible: weight loss resulted in a near normalisation of the PCr/ATP ratio in parallel with improved diastolic function [17].

Another important contributing factor in HFpEF is the severely attenuated peak myocardial oxygen delivery during exercise, possibly related to endothelial dysfunction and impaired vasodilator capacity of the microcirculation [18]. When the energy supply-demand mismatch in heart failure further deteriorates mitochondrial function (by continuous oxidative stress), a second vicious circle is closed (Fig. 1, arrow 3) [7].

To test the ‘energy depletion’ hypothesis [9], we propose a novel intervention with a metabolism-modulating drug: trimetazidine. This drug has been approved worldwide for the symptomatic treatment of chronic stable angina [19]. Trimetazidine partially inhibits mitochondrial fatty acid β‑oxidation, by blocking long-chain 3‑ketoacyl-CoA thiolase, and concomitantly enhances glucose oxidation, because these two processes are tightly and inversely coupled by the Randle cycle [7]. As such, mitochondrial efficiency improves, because more ATP per mole of oxygen is produced via glucose oxidation. In addition, trimetazidine improves insulin sensitivity, which increases myocardial glucose uptake and enhances glucose oxidation [16]. Fragasso et al. reported that trimetazidine treatment for 3 months resulted in a 33% increase in the myocardial PCr/ATP ratio in HFrEF patients [20].

Multiple small randomised trials with trimetazidine in ischaemic and non-ischaemic cardiomyopathy have been performed in HFrEF patients: meta-analysis of these HFrEF trials demonstrates improvement in systolic and diastolic function resulting in a reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) as well as an improvement in symptoms, quality of life, and exercise tolerance after 3–6 months of treatment [19]. Studies with a follow-up of 2–5 years report a 10–50% reduction in hospitalisation and an absolute reduction in all-cause mortality of 11–30% [19]. Until now, trimetazidine or other metabolic modulators have not been tested for the treatment of HFpEF.

Our primary endpoint is to assess the effect of a 3-month trimetazidine treatment in patients with HFpEF on the change in exercise pulmonary capillary wedge pressure (PCWP) at specified exercise workloads.

Our key secondary endpoint is to evaluate the change in the myocardial PCr/ATP ratio measured by ³¹P‑MRS, and its relation to the primary endpoint. Additionally, we assess safety (frequency of adverse events) and explore NT-proBNP levels, C‑reactive protein level, 6‑min walk distance, and quality of life (Kansas City Cardiomyopathy Questionnaire, EQ-5D).

DoPING-HFpEF is a phase II (proof-of-principle) single-centre, double-blind, placebo-controlled, cross-over intervention study (Fig. 2). The study will include 25 HFpEF patients, recruited from the Amsterdam University Medical Centers’ dyspnoea/HFpEF outpatient clinic and network centres [21]. The duration of the study is two study periods of 3 months separated by a 2-week washout period (<7 months in total). Visits are planned at the start, after 6 weeks, and at the end of each treatment period.

The DoPING-HFpEF study will enroll patients with the diagnosis and symptoms of HFpEF, without contra-indications for the study drug or procedures (see Tab. 1 for all inclusion and exclusion criteria).

Trimetazidine is administered orally by (encapsulated) tablets. Trimetazidine is contra-indicated in severe renal impairment (estimated glomerular filtration rate <30 ml/min/1.73 m²). It has a safe pharmacological profile: most important but rare side-effects are parkinsonism and restless legs syndrome. No important interactions have been reported and no safety concern has been observed in the elderly population.

The dosage of trimetazidine 20 mg three times daily (TID) (twice daily in the case of moderate renal impairment) was chosen for our current study for the following reasons: (1) clinically relevant metabolic effects on the heart have been demonstrated by ³¹P‑MRS and positron-emission tomography for this dosage in HFrEF patients [16, 20]; (2) the vast majority of the literature on trimetazidine studied this dosage, and more specifically all heart-failure-related studies have used either trimetazidine 20 mg TID or 35 mg modified release twice daily [19], allowing a direct comparison of our results with the literature; and (3) to achieve the highest efficacy we use the maximally advised dosage. Adherence is checked by pill counting and analysing plasma trimetazidine levels.

The primary endpoint is change in exercise PCWP. Exercise PCWP standardised for a level of exercise is a novel primary endpoint in HFpEF trials that was introduced in the REDUCE-LAP HF trial [24]. This endpoint correlates with more traditional heart failure outcome measures, such as New York Heart Association (NYHA) class, exercise capacity, and heart-failure-related quality of life [25, 26].

The primary endpoint will be tested by a repeated measures ANOVA. However, a power calculation based on this statistical test would require imputation of multiple unknown variables, making it less reliable. Therefore, we simplified the power calculation and derived it from a paired t-test, which is also more conservative. Based on the data from the REDUCE-LAP study, we defined a clinical relevant mean reduction of exercise PCWP (at 20 W) of ∆ = 3.2 mm Hg with a standard deviation σ = 5.0 mm Hg [24]. Based on the results of the REDUCE LAP-HF I trial, showing only a minor change in exercise haemodynamics in the control group after 1 month in relatively unstable patients (NYHA III–IV) [24], we expect only a small intra-individual variation in exercise haemodynamics in our relatively stable NYHA II–III patient group. Power calculation (one-sided level of significance α = 0.05, power 1‑β = 0.80) for a paired comparison predicts a required sample size of n = 18 (NCSS PASS 15.0.5, Keysville, UT, USA). To compensate for potential drop-out, we increased the total number of patients for this study to n = 25.

Our key secondary endpoint, change in myocardial PCr/ATP, will be tested by a paired t-test. Fragasso et al. reported a change in the myocardial PCr/ATP ratio after trimetazidine treatment of (mean ± σ) 1.35 ± 0.33 to 1.80 ± 0.50 [20]. Based on these numbers, power calculation (one-sided, α = 0.05, 1‑β = 0.80, σ (difference) = 0.60) predicts a required sample size of n = 13, which is less than the total number of inclusions planned for this study.