journal MAPLE-HCM TRIAL review presentation

Weekly Journal Club; MAPLE-HCM Trial 1
WEEKLY JOURNAL CLUB
MAPLE-HCM trial
Presenter- Dr. Dinu K. (IMR3)
Moderator-Dr. Dessalew Mekonnen
(Consultant Internist and Cardiologist )
19/09/2025

Weekly Journal Club; MAPLE-HCM Trial
OUTLINE
• Introduction
• Objective
• Methodology
• Result
• Discussion
• Conclusion
• Strength and limitation.
• Critical appraisal
3
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Ommen, S.R. et al, 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic
Cardiomyopathy. Circulation.
Hypertrophic Cardiomyopathy Prevalence and
Characteristics
Inheritance
Pattern
Autosomal
Dominant
Sex
Distribution
Women are diagnosed
less often and later
Disease
Prevalence
Estimated
1:500
Triggers for Evaluation
Symptoms
Cardiac Event
Heart
Murmur
Abnormal EKG
or Imaging
Family history
Underlying SDOH
likely drive
differences in
prevalence, genetic
testing, and
cardiovascular
outcomes by race
and ethnicity
Differential Diagnosis: Non-HCM Causes of LV Hypertrophy
Metabolic & Multi-organ
Syndromes
RASopathies (Noonan Syndrome)
Glycogen / Lysosomal storage
diseases
Cardiac Amyloidosis
Sarcoidosis
Danon disease
Secondary Causes
Athlete’s heart
Uncontrolled
Hypertension
Valvular & subvalvular
aortic stenosis
Abbreviations: EKG indicates electrocardiogram; SDOH, social determinants of health; and RAS, reticular activating system.
4
+/- -/-
+/-

Defining Hypertrophic Cardiomyopathy in 2024
• Characterized by left ventricular hypertrophy
Asymmetric septal hypertrophy is most characteristic
• No other cardiac, systemic or metabolic disease capable of producing the
magnitude of increased LV wall thickness present
• Disease-causing variant in a sarcomere gene identified or genetic etiology
unresolved
Diagnostic Criteria in Adults
2D echocardiography or cardiac MRI
Maximal end-diastolic LV wall thickness > 15
mm
or
Maximal end-diastolic LV wall thickness 13-
14 mm if there is a family history of HCM or
a pathogenic sarcomere gene is present
Diagnostic Criteria in Children
Abbreviations: 2D indicates two dimensional; MRI, magnetic resonance imaging; mm, millimeter
5
LV wall thickness z-score > 2.5
or
LV wall thickness z-score >2 if there is a family
history of HCM or a pathogenic sarcomere
gene is present
2D echocardiography or cardiac MRI

Types
Obstru
ctive
•3/4th
Non-
Obstruc
tive
•1/4th

Pathophysiology of Hypertrophic Cardiomyopathy
Dynamic LVOT
Obstruction
Mitral Regurgitation
Metabolic/Energetic
Dysfunction
Diastolic Dysfunction
Myocardial Ischemia
Abbreviations: LVOT indicates left ventricular outflow tract.
7
Atrial and Ventricular
Arrythmias

Pharmacologic Management of Obstructive and
Non-Obstructive HCM
Abbreviations: ACEi indicates angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CCBs, calcium
channel blockers;
GDMT, guideline-directed medical therapy; HCM, hypertrophic cardiomyopathy; LVOTO, left ventricular outflow tract
obstruction; and r/t, related to
Obstructive
If persistent
dyspnea with
volume
overload,
consider
Low Dose
Diuretics
(Class 2b)
Non-Obstructive HCM Preserved
LVEF
In highly selected patients with apical HCM with severe
dyspnea or angina (NYHA class III or class IV) despite maximal
medical therapy, and with preserved EF and small LV cavity
size, apical myectomy by experienced surgeons at
comprehensive centers may be considered to reduce
symptoms (Class 2b)
Consider
Discontinuing:
• Vasodilators
• Digoxin
• High Dose
Diuretics
(Class 2b)
Verapamil
potentially
HARMFUL in:
• Severe Dyspnea
at Rest
• Very High
Gradients (>100
mmHg)
• Children < 6
Weeks (Class 3:
Harm)
1. Intravenous
Fluids
2. Phenylephri
ne ± ß-
Blocker
(without
inotropic
activity) (Class
1)
Step-Wise Approach:
1. Non-Vasodilating ß-Blocker
2. If not effective or not tolerated, switch
to Non-Dihydropyridine CCBs
3. If persistent severe symptoms,
• Add Myosin Inhibitor (ie
Mavacamten)
-OR-
• Add Disopyramide
-OR-
• Septal Reduction Therapy
performed at experienced centers
(Class 1)
ß-Blocker or
Non-
Dihydropyridine
CCBs (Class 1)
Oral Diuretic if
evidence of
congestion
(Class 2a)
Benefits of
b-Blocker
or CCBs is
not well
establishe
d (Class
2b)
Valsartan
may be
considered
to
potentially
slow adverse
cardiac
remodeling
(Class 2b)
Usefulness of
ACEi / ARBs in
symptomatic
patients with
LVEF>50% is not
well established
(Class 2b)
• ≤45 years
• Asymptomatic
• Pathogenic
sarcomere variant
carrier
• Mild phenotype:
Symptomatic:
Asymptomat
ic:
8
Symptoms r/t
LVOTO
Acute
Hypotensi
on

Invasive Management of Obstructive HCM
Abbreviations: AF indicates atrial fibrillation; GDMT, guideline-directed medical therapy; LVOTO, HCM, hypertrophic
cardiomyopathy;
LAE, left atrial enlargement; left ventricular outflow tract obstruction; NYHA, New York Heart Association; and MR, mitral
regurgitation;
Obstructive HCM
NYHA Class III / IV or
symptoms attributable to
LVOTO
Septal Reduction
Therapy at
experienced centers
(Class 1)
Despite
GDMT
Alcohol Septal Ablation in eligible
patients is recommended in patients
whom:
• Surgery is contraindicated or declined
• Risk is considered unacceptable due to
comorbidities or advanced age (Class
1)
Surgical Myectomy is
recommended in patients
with associated cardiac
disease requiring surgical
treatment:
• Associated anomalous papillary
muscle
• Markedly elongated anterior
mitral valve leaflet
• Intrinsic mitral valve disease
• Multivessel coronary artery
disease
• Valvular aortic stenosis (Class 1)
Mitral Valve Replacement should not
be performed for sole purpose of
relieving LVOTO (Class 3:Harm)
Septal Reduction Therapy should not
be performed in asymptomatic
patients with normal exercise capacity
(Class 3:Harm)
Septal Reduction Therapy
may be considered as
alternative to escalation of
medical therapy after shared-
decision making (Class 2b)
Surgical Myectomy is reasonable in NYHA
Class II if:
• Severe PH attributable to LVOTO or MR
• LAE with 1 episodes of symptomatic AF
≥
• Poor functional capacity attributable to LVOTO
• Children or young adults Class with very high
LVOT gradients (> 100 mmHg) (Class 2b)
9

cont'd...
Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic
cardiomyopathy (oHCM) despite limited evidence of their efficacy.
Aficamten is a cardiac myosin inhibitor(CMI)
reduces left ventricular outflow tract gradients,
improves exercise capacity, and
 decreases HCM symptoms when added to standard medications.
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Weekly Journal Club; MAPLE-HCM- trial 12
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6/12/2024

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objective
the over all objectives of this head to head comparison trial is to evaluate the safety and
efficacy of aficamten as:
 first line therapy for participants recently diagnosed with symptomatic oHCM and/or
treatment naive: or
 monotherapy for participants previously receiving standard of care(SOC) medical therapy
for symptomatic oHCM.
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Methodology
trial design
multicenter, randomized ,international, double-blind, double-dummy, a head-to-head,
phase 3 trial
 study was conducted from June 2023, to August 2024, across 71 sites
in North America, Brazil, Europe, Israel, and China;
19/09/2025

Ethical clearance and funding
the trial was conducted in accordance with the principles of the Declaration of Helsinki and the
International Council for Harmonisation Good Clinical Practice guidelines.
An academic steering committee in collaboration with Cytokinetics (the sponsor)
 designed the trial,
 selected clinical trial centers,
 oversaw the conduct and monitoring of the trial
All the patients provided written informed consent.
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Procedure
Patients underwent randomization within 6 weeks after the start of screening.
patients underwent a washout of background standard therapy of up to 2 weeks beginning
at the first screening visit.
 patients reduced the dose of standard medications every 2 days until standard
medications were discontinued for at least 7 days before screening assessments.
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cont'd...
To understand whether current or recent use of standard medications or time since HCM diagnosis
influenced the effect of treatment, patients were divided into two groups:
group 1 included patients who had recently (≤12 months) received a diagnosis of HCM or had not
received standard medications in the past 12 months, regardless of the date of diagnosis;
group 2 included patients with a long-standing (>12 months) HCM diagnosis who had received
standard medications within the past 12 months.
19/09/2025

cont'd...
Enrollment of patients who had previously received mavacamten and those who had undergone
septal reduction therapy was capped at approximately 10% each,
 Enrollment of patients who used a cycle ergometer for exercise testing was capped at
approximately 50%.
The starting dose of aficamten was 5 mg and of metoprolol was 50 mg.
At weeks 2, 4, and 6, the dose of aficamten could be escalated in 5-mg increments and the dose of
metoprolol could be escalated in 50-mg increments, to a maximum dose of 20 mg and 200 mg,
respectively.
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Statistical Analysis
The statistical power for the primary end point was calculated under the assumption that the
difference between groups in the change in peak oxygen uptake at week 24 would be
2ml/kg/minute, with a standard deviation of 3ml/kg/minute.
With the estimated sample size of 170 patients would provide the trial with more than 90% power
to detect a difference in peak oxygen uptake at a two-sided type I error level of 0.05.
The primary end point was analyzed with the use of an analysis of covariance model, with
treatment group, randomization stratification factors, baseline peak oxygen uptake.
19/09/2025

cont'd...
Other secondary end points were analyzed with the use of a mixed model for repeated measures.
Safety analyses were performed in the safety analysis population, which included all the patients
who received at least one dose of aficamten or metoprolol.
For all subgroup analyses, the widths of the 95% confidence intervals have not been adjusted for
multiplicity and the intervals should not be used in place of hypothesis testing.
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Pablo Garcia-Pavia et al. J Am Coll Cardiol HF 2025; 13:346-357.

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Results
.
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cont'd...
At week 24, in the aficamten group a total of :
 66 (76%) were receiving 15mg or 20mg of aficamten
 the dose decreased to 0 mg for 1 patient (1%) owing to unacceptable side effects at the
lowest dose, in accordance with the dose-adjustment algorithm.
In comparison, in the metoprolol group:
 53(63%) were receiving 150mg or 200mg of metoprolol
 the dose decreased to 0 mg for 10 patients (12%) owing to unacceptable side effects at the
lowest dose.
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Secondary End Points outcomes
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Discussion
 in patients with symptomatic oHCM, aficamten monotherapy was superior to metoprolol
monotherapy on the basis of improved peak oxygen uptake after a 24wk.
Aficamten treatment was also associated with decreased symptoms and improvements in LVOT
gradient, NT-proBNP level, and left atrial volume index.
The clinical benefits of aficamten as compared with metoprolol observed in this trial are probably
secondary to a decrease in LVOT obstruction resulting from CMI.
Parallel to the change in hemodynamics, aficamten reduced the NT-proBNP level, which is
predictive of future adverse outcomes related to HCM, including heart failure.
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cont'd...
The effect of aficamten on exercise capacity appeared to be consistent across all prespecified
subgroups
In addition to providing information on the use of aficamten as monotherapy (and as first-line
therapy in a subpopulation of patients with oHCM), this trial also provides unique insights into the
dose administration,
treatment effects, and
side effects of metoprolol in patients with oHCM.
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Strength
the first Phase 3 multicenter, double-blind, head-to-head comparison of aficamten to current
standard of care (metoprolol)in adults with symptomatic oHCM
first RCT to recommend aficamten as monotherapy for treatment of oHCM.
provides unique insights into the dose administration, treatment effects, and side effects of
metoprolol in patients with obstructive HCM.
trial met its primary and secondary endpoints
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Limitation
short treatment period,
the patients enrolled in this trial had objectively less-severe measures of disease burden
We cannot exclude the possibility that other non vasodilating beta-blockers have effects different
from those of metoprolol.
bias regarding investigator assumption of treatment assignment was possible given the negative
chronotropic effect of metoprolol.
blacks were under represented
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Conclusion
this trial aimed at producing the necessary evidence to inform the use of
aficamten as potential first-line monotherapy, and its placement among the
pharmacologic option for oHCM.
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Weekly Journal Club; MAPLE-HCM trial 51
QUESTIONS AND COMMENTS
19/09/2025

Weekly Journal Club MAPLE-HCM-trial
Critical Appraisal
19/09/2025
Yes Can’t
Tell
No Comments
Did the trial address a clearly focused issue? √
Was the assignment of patients to treatment randomized? √
Were all the patients who entered the trial properly
accounted for its conclusion?
√
Were patients, health care workers and study personnel
“Blind” to treatment?
√
Were the groups similar at the start of the trial? √
Aside from the experimental intervention, were the groups
treated equally?
√
Are the results statistically and clinically significant? √
Can the results be applied to the local population? √
Are the benefits worth the harms and costs? √

Thank you!!!.
19/09/2025

journal MAPLE-HCM TRIAL review presentation

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