Anti-anginal agent is the latest drug to flop as an effective therapy remains elusive
Another fatty acid β-oxidation inhibitor failed to boost exercise capacity or ease symptoms in non-obstructive hypertrophic cardiomyopathy (HCM) in a small placebo-controlled trial.
Study participants who were randomized to trimetazidine had a smaller increase in peak oxygen consumption (VO2) during upright bicycle ergometry compared to the group assigned to placebo, resulting in their adjusted peak VO2 at 3 months being 1.35 mL/kg per minute lower (95% CI -2.58 to -0.11 mL/kg per minute), according to Perry Elliott, MD, of University College London (UCL), and colleagues.
What's more, trimetazidine was also outperformed by placebo in 6-minute walk distance (-38.4 m, 95% CI -71.7 to -5.13 m), the investigators reported in JAMA Cardiology.
"The disappointing result from this trial follows others in recent years that have failed to show a benefit in patients with non-obstructive HCM, notably those testing ranolazine [Ranexa] and spironolactone," commented Sharlene Day, MD, of University of Michigan in Ann Arbor, in an accompanying editorial.
Although one study did associate perhexiline with improved symptoms, exercise capacity, and myocardial energetics, she cautioned that this agent (a carnitine palmitoyl transferase-1 inhibitor) is unlikely to be a safe long-term therapy owing to a narrow therapeutic window and its potential hepatic and neurotoxicity.
"To date, therapeutic options are limited to a trial-and-error approach with a combination of β-blockers, calcium channel blockers, and diuretics," Day noted. "Developing effective and targeted therapies for symptomatic non-obstructive HCM is therefore imperative and represents one of the largest unmet needs in the field."
Elliott's group conducted the double-blind trial at UCL's The Heart Hospital, in 2012-2014. Participants were 51 drug-refractory symptomatic patients (70% men, mean age 50) with a maximum left ventricular outflow tract gradient of ≤50 mm Hg and a peak oxygen consumption during exercise of ≤80% of age- and sex-based predicted values.
They were randomized to trimetazidine 20 mg thrice daily or placebo for 3 months.
Trimetazidine dihydrochloride is an anti-anginal agent that works by improving the energy efficiency of the myocardium. Specifically, it directly inhibits β-oxidation to stimulate glucose oxidation and reduce fatty acid oxidation.
"Free fatty acids are less efficient as a source of myocardial energy because they require approximately 10% more oxygen than glucose to produce an equivalent amount of adenosine triphosphate. The HCM is characterized by a reduction in the concentration of high-energy phosphates in the myocardium possibly because of myocardial ischemia or an energy wasting effect of sarcomere protein gene mutations," the authors said.
Nevertheless, they observed no difference with the β-oxidation inhibitor in self-reported quality of life on the Minnesota Living with Heart Failure questionnaire. Trimetazidine and placebo groups also shared similar diastolic functions, left ventricular ejection fractions, left atrial areas, global left ventricular longitudinal systolic strains, NT-pro-BNP levels, and troponin T levels by the end of follow-up.
"This was a rigorously conducted clinical trial with a rational mechanistic target, in a population with limited empirical treatment options. Despite the negative findings, it is important to put it in context of the paucity of placebo-controlled randomized clinical trials on the HCM population as a whole, and the need for more trials like this one to advance knowledge and explore new targeted therapeutic possibilities," according to Day.
One to look out for is MAVERICK-HCM, a phase II study of the direct myosin modulator mavacamten in symptomatic, non-obstructive HCM. The trial is due to be completed this summer.
Elliott and colleagues had failed to meet enrollment targets for their trial and assessed compliance using patients' medical diaries and pill counting, the group acknowledged.
Day noted the lack of genotyping in the study as well, commenting that "a common treatment paradigm for all patients with HCM regardless of genotype may not be a reasonable expectation, and implementation of more precise and individualized approaches may ultimately be necessary."
"It is important that we also recognize the contribution of comorbid conditions, such as hypertension, diabetes, obesity, and physical inactivity, to poor cardiorespiratory fitness and symptomatic burden in patients with HCM," she urged. "It is crucial that these modifiable factors be addressed simultaneously, in combination with existing and future pharmacologic therapies, to reduce symptom burden and improve long-term outcomes for patients with non-obstructive HCM."
The study was supported by the British Heart Foundation, University College London Hospitals, and the National Institute for Health Research.
Elliott disclosed a relevant relationship with MyoKardia.
Day disclosed no relevant relationships with industry.
Source Reference: Coats CJ, et al "Effect of trimetazidine dihydrochloride therapy on exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy: a randomized clinical trial" JAMA Cardiol 2019; DOI:10.1001/jamacardio.2018.4847.
Source Reference: Day SM "Nonobstructive hypertrophic cardiomyopathy -- the high-hanging fruit" JAMA Cardiol 2019; DOI:10.1001/jamacardio.2018.4953.
Read the original article on Medpage Today: Trimetazidine Disappoints in Non-Obstructive Cardiomyopathy