TY - JOUR
T1 - Trimetazidine in heart failure with preserved ejection fraction
T2 - a randomized controlled cross-over trial
AU - van de Bovenkamp, Arno A.
AU - Geurkink, Kiki T. J.
AU - Oosterveer, Frank T. P.
AU - de Man, Frances S.
AU - Kok, Wouter E. M.
AU - Bronzwaer, Patrick N. A.
AU - Allaart, Cor P.
AU - Nederveen, Aart J.
AU - van Rossum, Albert C.
AU - Bakermans, Adrianus J.
AU - Handoko, M. Louis
N1 - Funding Information: M.L.H. is supported by the Dutch Heart Foundation (NHS; 2020T058) and M.L.H. and A.J.B. by an ‘Out‐of‐the‐Box’ grant from the Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands. F.S.d.M is supported by the Netherlands Organisation for Scientific Research (NWO; 917.18.338, CVON DOLPHIN, PHAEDRA) and the Dutch Heart Foundation (NHS; 2018T059). There was no relationship with industry for this study. Funding Information: M.L.H. is supported by the Dutch Heart Foundation (NHS; 2020T058) and M.L.H. and A.J.B. by an ‘Out-of-the-Box’ grant from the Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands. F.S.d.M is supported by the Netherlands Organisation for Scientific Research (NWO; 917.18.338, CVON DOLPHIN, PHAEDRA) and the Dutch Heart Foundation (NHS; 2018T059). There was no relationship with industry for this study. We thank all study participants for their participation in this demanding trial protocol. We thank the Institute of Biochemistry, Cologne, Germany, for performing the trimetazidine plasma level analyses and the Core Facility Metabolomics of the Amsterdam University Medical Centers, Amsterdam, The Netherlands, for performing plasma acylcarnitine analyses. Publisher Copyright: © 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
KW - Diastolic heart failure
KW - Exercise tolerance
KW - Heart mitochondria
KW - Metabolism
KW - Pulmonary wedge pressure
KW - Swan–Ganz catheterization
UR - http://www.scopus.com/inward/record.url?scp=85166620529&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ehf2.14418
DO - https://doi.org/10.1002/ehf2.14418
M3 - Article
C2 - 37530098
SN - 2055-5822
VL - 10
SP - 2998
EP - 3010
JO - ESC heart failure
JF - ESC heart failure
IS - 5
ER -