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Clinical Trial
. 2023 Oct;10(5):2998-3010.
doi: 10.1002/ehf2.14418. Epub 2023 Aug 2.

Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross-over trial

Arno A van de Bovenkamp  1   2 , Kiki T J Geurkink  1 , Frank T P Oosterveer  3 , Frances S de Man  2   3 , Wouter E M Kok  2   4 , Patrick N A Bronzwaer  5 , Cor P Allaart  1   2 , Aart J Nederveen  6 , Albert C van Rossum  1   2 , Adrianus J Bakermans  6 , M Louis Handoko  1   2
Affiliations
Clinical Trial

Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross-over trial

Arno A van de Bovenkamp et al. ESC Heart Fail. 2023 Oct.

Abstract

Aims: Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF.

Methods and results: The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2 ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters.

Conclusions: Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

Keywords: Diastolic heart failure; Exercise tolerance; Heart mitochondria; Metabolism; Pulmonary wedge pressure; Swan-Ganz catheterization.

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Conflict of interest statement

M.L.H. received an educational grant and/or speaker/consultancy fees from Novartis, Boehringer Ingelheim, Daiichi Sankyo, Vifor Pharma, AstraZeneca, Bayer, MSD, and Quin; all not related to this work. All other authors report no (potential) conflict of interest.

Figures

Figure 1
Figure 1
DoPING‐HFpEF study design. 6‐MWD, six‐minute walking distance; Echo, echocardiogram; Lab, laboratory assays; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; QoL, quality of life; RHC, right heart catheterization.
Figure 2
Figure 2
Flow diagram of the DoPING‐HFpEF Trial. *Reasons for exclusion are listed in Table S2 . †Reasons for exclusion from analyses are discussed in the supporting information.
Figure 3
Figure 3
Effect on pulmonary capillary wedge pressure at multiple levels of exercise. (A) PCWP at multiple levels of exercise (primary endpoint). Point and error bar depict the mean and standard error of the mean. (B) Forest plot with subgroup analyses of change in PCWP at multiple levels of exercise. *eGFR <60 mL/min/1.73 m2 during the trimetazidine treatment period. †LV hypertrophy was defined as LVMI ≥55 g/m2 for women and ≥72 g/m2 for men. LV, left ventricular, LVMI, left ventricular mass index; NYHA, New York Heart Association class; PCWP, pulmonary capillary wedge pressure; PLR, passive leg raise.
Figure 4
Figure 4
Mean phosphorus‐31 MR spectra of the heart during placebo and trimetazidine treatment. Localized 31P‐MR spectroscopy at 3 Tesla. Placebo group mean spectrum (blue) and trimetazidine group mean spectrum (red) are overlaid on individual spectra in grey (n = 25). Myocardial PCr/ATP was quantified as the ratio of the PCr signal amplitude at 0.00 ppm over the γ‐ATP signal amplitude at −2.48 ppm, corrected for partial saturation. α‐, β‐ and γ‐ATP, α‐, β‐ and γ‐phosphate groups in adenosine triphosphate; MR, magnetic resonance; PCr, phosphocreatine; Pi, inorganic phosphate; 2,3‐DPG, 2,3‐diphosphoglycerate.
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References

    1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo‐Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021; 42: 3599–3726. - PubMed
    1. Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JG, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ, Gheorghiade M. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017; 14: 238–250. - PMC - PubMed
    1. Kumar AA, Kelly DP, Chirinos JA. Mitochondrial dysfunction in heart failure with preserved ejection fraction. Circulation. 2019; 139: 1435–1450. - PMC - PubMed
    1. De Jong KA, Lopaschuk GD. Complex energy metabolic changes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Can J Cardiol. 2017; 33: 860–871. - PubMed
    1. Phan TT, Abozguia K, Nallur Shivu G, Mahadevan G, Ahmed I, Williams L, Dwivedi G, Patel K, Steendijk P, Ashrafian H, Henning A, Frenneaux M. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009; 54: 402–409. - PubMed

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