SlideShare a Scribd company logo
JOURNAL CLUB
PRESENTOR: DR ASHISH KOHLI
MODERATOR: DR JASKARAN SINGH GUJRAL
Aficamten in HCM (SEQUOIA HCM TRIAL 2024)
INTRODUCTION
• Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart
diseases
•HCM is characterized by a thickened, nondilated left ventricle and often causes
exertional dyspnea and reduced exercise capacity, which can impair quality of
life
•Left ventricular outflow tract obstruction, is one of the principal determinants of
HCM-related complications and therefore is an important target for therapy
•Cardiac hypercontractility, which results from an excessive number of actin–
myosin cross-bridges within the cardiac sarcomere, is an important mechanism
that promotes outflow obstruction
•Mavacamten, a recently approved cardiac myosin inhibitor, has been shown to
improve exercise capacity and reduce symptoms in patients with obstructive
HCM
MECHANISMS OF EXERCISE LIMITATIONS IN O-HCM
AFICAMTEN
Aficamten is a reversible inhibitor of cardiac myosin that reduces left ventricular
contractility by decreasing the number of active actin–myosin cross-bridges
within the sarcomere
Aficamten was designed to have a shallow dose–response relationship and a
plasma half-life that allows for personalized dose adjustments as often as every
2 weeks (features that differentiate it from mavacamten)
In a phase 2 trial, treatment with aficamten resulted in significant reductions in
left ventricular outflow tract gradients in patients with obstructive HCM
Maron MS, Masri A, Choudhury L, et al. Phase 2 study of aficamten in
patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol
2023; 81: 34-45
MECHANISM OF ACTION
COR LOE RECOMMENDATIONS
1 B-R For patients with obstructive HCM who have persistent
symptoms attributable to LVOTO despite beta
blockers or non dihydropyridine calcium channel
blockers, adding a myosin inhibitor (adult patients
only),
or disopyramide (in combination with an
atrioventricular nodal blocking agent), or SRT
performed at
experienced centres, is recommended
Members WC et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline
for the Management of Hypertrophic Cardiomyopathy. Journal of the
American College of Cardiology. 2024 May 8.
BACKGROUND
Maron MS, et al. J Am Coll Cardiol. 2023;81(1):34–
45.
REDWOOD
HCM TRIAL
(PHASE II)
STUDY DESIGN
Phase 3, International, Double-blind, Randomized, Placebo-controlled trial
Patients with symptomatic obstructive HCM received aficamten or placebo in
addition to standard drug therapy
Total patients: 282
CONSORT
DIAGRAM
OVERVIEW OF TRIAL
INCLUSION CRITERIA
Males and females between 18 and 85 years of age, BMI <35 kg/m2
Diagnosed with HCM per the following criteria:
a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac
disease and
b. Has an end-diastolic LV wall thickness as measured by the echocardiography core
laboratory of:
• ≥15 mm in one or more myocardial segments OR
• ≥13 mm in one or more wall segments and a known-disease-causing gene
mutation or positive family history of HCM
Has resting LVOT-G ≥30 mm Hg and post-Valsalva LVOT-G ≥50 mmHg during screening
as determined by the echocardiography core laboratory
LVEF ≥60% at screening as determined by the echocardiography core laboratory
 New York Heart Association (NYHA) Functional Class II or III at screening
Hemoglobin ≥10 g/dL at screening
Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the
screening CPET per the core laboratory
Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have
been on a stable regimen for >6 weeks prior to randomization and anticipate
remaining on the same medication regimen during the trial
Patients treated with disopyramide must also be concomitantly treated with a
beta blocker and/or calcium channel blocker
EXCLUSION CRITERIA
Significant valvular heart disease- Moderate-severe valvular AS/AR, Moderate-severe
MR not due to systolic anterior motion of the mitral valve
Documented history of current obstructive coronary artery disease or H/O MI
Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy
that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis)
Prior treatment with cardiotoxic agents such as doxorubicin or similar
History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time
during their clinical course
Has any ECG abnormality considered by the investigator to pose a risk to patient safety
(eg, second degree atrioventricular block type II)
Documented paroxysmal atrial fibrillation during the screening period
Paroxysmal or permanent atrial fibrillation is only excluded IF:
- rhythm restoring treatment has been required ≤6 months prior to screening
- rate control and anticoagulation have not been achieved for at least 6 months
prior to screening
History of syncope or sustained ventricular tachyarrhythmia with exercise within
6 months prior to screening
ICD placement within 3 months or planned ICD placement during the trial
History of appropriate ICD discharge for life-threatening ventricular arrhythmia
within 6 months prior to screening
Has been treated with septal reduction therapy
Estimated glomerular filtration rate (eGFR) <30 mL/min or hepatic impairment
Has received prior treatment with aficamten or mavacamten
PROCEDURE
Eligible patients were randomly assigned in a 1:1 ratio to receive aficamten or
placebo
Randomization was performed with the use of an interactive Web-response
system and stratified according to the use of beta-blockers (yes or no) and the
method of CPET (treadmill or cycle ergometer)
Enrollment of patients taking beta-blockers and disopyramide was capped at
approximately 70% and 10% of the trial population, respectively
Enrollment of those with persistent atrial fibrillation at screening was capped at
15%
Enrollment of patients being tested with the use of a cycle ergometer was
capped at 50%
Oral aficamten or placebo (manufactured by Patheon) was administered once
daily for 24 weeks; the tablets were identical in appearance
The starting dose of aficamten was 5 mg, with three subsequent opportunities
(at weeks 2, 4, and 6) to increase the dose by 5-mg increments, to a maximum
dose of 20 mg
At each visit, an echocardiographic cardiologist who was unaware of the trial-
group assignments assessed the left ventricular outflow tract gradient at rest
and after the Valsalva maneuver and the left ventricular ejection fraction
The site investigators and trial team members were unaware of the N-terminal
pro–B-type natriuretic peptide (NT-proBNP) levels and the echocardiography
results
DOSE CHANGE REGIMEN
Aficamten in HCM (SEQUOIA HCM TRIAL 2024)
END POINTS
PRIMARY END POINT: The change from baseline to week 24 in the peak oxygen
uptake as assessed during cardiopulmonary exercise testing
SECONDARY END POINTS:
•The change from baseline to week 24 in the KCCQ-CSS
•An improvement from baseline of at least one NYHA functional class at week 24
•The change from baseline to week 24 in the LVOT gradient after the Valsalva
maneuver
•The occurrence of a LVOT gradient of less than 30 mm Hg after the Valsalva
maneuver at week 24
•The duration of eligibility for septal reduction therapy during the 24-week
treatment period among patients who were eligible for such therapy at baseline
•The change from baseline to week 12 in the KCCQ-CSS
•An improvement from baseline of at least one NYHA functional class at week 12
•The change from baseline to week 12 in the LVOT gradient after the Valsalva
maneuver
•The occurrence of a LVOT gradient of less than 30 mm Hg after the Valsalva
maneuver at week 12
•The change in the total workload as assessed by cardiopulmonary exercise
testing at week 24
An exploratory end point was the geometric mean proportional change in the
NT-proBNP level
STATISTICAL ANALYSIS
The statistical power was calculated under the assumption that the difference
between the groups in the change from baseline in the peak oxygen uptake at
week 24 would be 1.5 ml/kg/min, with a standard deviation of 3.5 ml/kg/min
and that no more than 70% of the patients would be receiving beta blockers and
no more than 50% of the patients would undergo CPET with the use of a cycle
ergometer
 With the assumption that 10% of the primary end-point data would be missing,
it was estimated that a sample of 270 patients with a randomization ratio of 1:1
would provide the trial with at least 90% power with a two-sided type I error
level of 0.05
Primary end point was analyzed with the use of an analysis of covariance
(ANCOVA) model, with trial group, randomization stratification factors, baseline
peak oxygen uptake, and baseline weight as covariates
The primary end point was tested first at a two-sided level of 0.05. If the
primary end point showed a significant treatment effect at a two-sided P value
of less than 0.05, then the secondary end points were tested sequentially at a
two-sided level of 0.05
Secondary end points who had a response to aficamten were analyzed with the
use of the Cochran–Mantel–Haenszel test
The statistical analyses were performed with the use of SAS software, version
9.4 (SAS Institute)
RESULTS
From February 1, 2022, to May 15, 2023, a total of 543 patients were screened
for eligibility at 101 sites in 14 countries, of whom 282 underwent
randomization and received aficamten or placebo
At the end of the dose-escalation phase (week 8), 3.6%, 12.9%, 35.0%, and
48.6% of the patients assigned to the aficamten group were receiving aficamten
at a dose of 5 mg, 10 mg, 15 mg, and 20 mg, respectively
BASELINE CHARACTERISTICS
Aficamten in HCM (SEQUOIA HCM TRIAL 2024)
PRIMARY END POINT
Changes in Exercise Capacity from Baseline to Week 24
PRIMARY AND SECONDARY END POINTS
PRIMARY END POINT SUBGROUP ANALYSIS
Aficamten in HCM (SEQUOIA HCM TRIAL 2024)
SECONDARY END POINTS
Aficamten in HCM (SEQUOIA HCM TRIAL 2024)
ADVERSE EVENTS
Serious adverse events were reported in 8 patients (5.6%) in the aficamten
group and in 13 patients (9.3%) in the placebo group
One adverse event (paranoia) resulted in early discontinuation of aficamten,
and two adverse events (syncope and acute lymphocytic leukemia) resulted in
early discontinuation of placebo
Three adverse events resulted in temporary interruptions of aficemten or
placebo, including acute cholecystitis in 1 patient in the aficamten group and
bronchopneumonia and verrucous carcinoma removal in 1 patient each in the
placebo group
ADVERSE EVENTS
Aficamten in HCM (SEQUOIA HCM TRIAL 2024)
Aficamten in HCM (SEQUOIA HCM TRIAL 2024)
DISCUSSION
In this trial aficamten improved exercise capacity (as assessed by
cardiopulmonary exercise testing) over a 24-week treatment period
 Aficamten treatment was also associated with significantly greater
improvements than placebo in all the secondary end points
The efficacy of aficamten was evident by week 12, with significantly greater
improvements in left ventricular outflow tract gradients, health status, and
symptoms
In addition, the reduction in symptoms was associated with a clinically
meaningful enhancement of overall health status as evidenced by increases in
the KCCQ-CSS
In contrast to the results that were observed with mavacamten in the
EXPLORER-HCM trial, which suggested an attenuation of benefit among patients
who were receiving beta-blockers, the treatment effects of aficamten appeared
to be similar with or without background beta-blocker use
Aficamten was associated with other favorable outcomes, including a
significantly greater improvement in limiting symptoms and a substantially
greater reduction in the serum NT-proBNP level than placebo
The unique pharmacologic properties of aficamten provide some notable
distinctions between aficamten and mavacamten
The shorter half-life of aficamten enables more rapid dose escalation, which
results in the ability to identify an effective dose within weeks, providing timely
clinical benefit
No patient in the aficamten group who had a left ventricular ejection fraction of
less than 50% had an interruption of treatment or an exacerbation of heart
failure
Furthermore, the return to baseline measures of the left ventricular outflow
tract gradient, symptoms, and the left ventricular ejection fraction after the
washout period reflects a rapid reversal of the pharmacodynamic effects
MERITS OF THE TRIAL
The outcomes observed in this trial with aficamten appear to be generalizable
to the broad, global population of patients with obstructive HCM encountered in
clinical practice
Women were well represented (40.8%) in this trial
The clinical profile of the trial population included patients with typical
characteristics of obstructive HCM, including those with a range of left
ventricular outflow tract gradients and left ventricular wall thicknesses
The trial was inclusive of all conventional HCM background therapy use
LIMITATIONS
Majority population in the trial were white
The relatively short treatment period, precluding assessment of longer-term
cardiovascular outcomes
They observed that some patients who received aficamten did not have an
improvement in NYHA class. Further trials are needed to clarify the reasons for
this finding and to determine whether those patients would have symptom
relief with longer exposure to aficamten
CONCLUSION
Among patients with symptomatic obstructive HCM, treatment with aficamten
resulted in a significantly greater improvement in peak oxygen uptake than
placebo
THANKS

More Related Content

What's hot

ο ή η, παίζω με τα άρθρα
ο ή η, παίζω με τα άρθραο ή η, παίζω με τα άρθρα
ο ή η, παίζω με τα άρθρα
Ioanna Chats
 
όλοι στον κήπο 1
όλοι στον κήπο 1όλοι στον κήπο 1
όλοι στον κήπο 1
Ioanna Chats
 
τασος το σαλιγκάρι 1
τασος το σαλιγκάρι 1τασος το σαλιγκάρι 1
τασος το σαλιγκάρι 1
Ioanna Chats
 
επαναληψη ως το κεφ. 12
επαναληψη ως το κεφ. 12επαναληψη ως το κεφ. 12
επαναληψη ως το κεφ. 12
Ioanna Chats
 
ΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣ
ΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣ
ΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣ
iliana stavrou
 
Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...
Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...
Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...
ευαγγελια παπακωστα
 
Geosinteticos en carreteras
Geosinteticos en carreterasGeosinteticos en carreteras
Geosinteticos en carreteras
rocio olga matos ambrosio
 
Recubrimiento Y Peladura De Mezclas Biyuminosas 02
Recubrimiento Y Peladura De Mezclas Biyuminosas  02Recubrimiento Y Peladura De Mezclas Biyuminosas  02
Recubrimiento Y Peladura De Mezclas Biyuminosas 02
Carmen Antonieta Esparza Villalba
 
Με το σεις και με το σας (2), σελ. 24-25
Με το σεις και με το σας (2), σελ. 24-25Με το σεις και με το σας (2), σελ. 24-25
Με το σεις και με το σας (2), σελ. 24-25
Ioanna Chats
 
Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...
Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...
Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...
Παπαδημητρακοπούλου Τζένη
 
Επανάληψη 1ης Ενότητας - Μαθηματικά - Α Δημοτικού
Επανάληψη 1ης Ενότητας - Μαθηματικά - Α ΔημοτικούΕπανάληψη 1ης Ενότητας - Μαθηματικά - Α Δημοτικού
Επανάληψη 1ης Ενότητας - Μαθηματικά - Α Δημοτικού
theodora tz
 
Punto De Inflacion Y Combustion 02
Punto De Inflacion Y Combustion 02Punto De Inflacion Y Combustion 02
Punto De Inflacion Y Combustion 02
Carmen Antonieta Esparza Villalba
 
TOPOGRAFIA GENERAL
TOPOGRAFIA GENERALTOPOGRAFIA GENERAL
TOPOGRAFIA GENERAL
BENJAQH
 
Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...
Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...
Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...
Παπαδημητρακοπούλου Τζένη
 
Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...
Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...
Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...
Παπαδημητρακοπούλου Τζένη
 
επανάληψη γλώσσας μετα τις διακοπές
επανάληψη γλώσσας μετα τις διακοπέςεπανάληψη γλώσσας μετα τις διακοπές
επανάληψη γλώσσας μετα τις διακοπές
Ioanna Chats
 
Ρινόκερος και κόκορας
Ρινόκερος και κόκοραςΡινόκερος και κόκορας
Ρινόκερος και κόκορας
theodora tz
 
Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...
Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...
Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...
Παπαδημητρακοπούλου Τζένη
 
ένα ζιζανιο στη ζύμη
ένα ζιζανιο στη ζύμηένα ζιζανιο στη ζύμη
ένα ζιζανιο στη ζύμη
Ioanna Chats
 
Παρουσίαση αποκριάςγια μεγαλους
Παρουσίαση αποκριάςγια μεγαλουςΠαρουσίαση αποκριάςγια μεγαλους
Παρουσίαση αποκριάςγια μεγαλους
Χαράλαμπος Διαμαντής
 

What's hot (20)

ο ή η, παίζω με τα άρθρα
ο ή η, παίζω με τα άρθραο ή η, παίζω με τα άρθρα
ο ή η, παίζω με τα άρθρα
 
όλοι στον κήπο 1
όλοι στον κήπο 1όλοι στον κήπο 1
όλοι στον κήπο 1
 
τασος το σαλιγκάρι 1
τασος το σαλιγκάρι 1τασος το σαλιγκάρι 1
τασος το σαλιγκάρι 1
 
επαναληψη ως το κεφ. 12
επαναληψη ως το κεφ. 12επαναληψη ως το κεφ. 12
επαναληψη ως το κεφ. 12
 
ΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣ
ΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣ
ΕΛΛΗΝΙΚΕΣ ΠΑΡΑΔΟΣΙΑΚΕΣ ΕΝΔΥΜΑΣΙΕΣ
 
Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...
Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...
Η συμβολή των γονέων και του αυτοπροσδιορισμού στην εκπαίδευση τω παιδιών με ...
 
Geosinteticos en carreteras
Geosinteticos en carreterasGeosinteticos en carreteras
Geosinteticos en carreteras
 
Recubrimiento Y Peladura De Mezclas Biyuminosas 02
Recubrimiento Y Peladura De Mezclas Biyuminosas  02Recubrimiento Y Peladura De Mezclas Biyuminosas  02
Recubrimiento Y Peladura De Mezclas Biyuminosas 02
 
Με το σεις και με το σας (2), σελ. 24-25
Με το σεις και με το σας (2), σελ. 24-25Με το σεις και με το σας (2), σελ. 24-25
Με το σεις και με το σας (2), σελ. 24-25
 
Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...
Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...
Θα γράψουμε το δικό μας βιβλίο / Φύλλα εργασίας και εκπαιδευτικό υλικό για τη...
 
Επανάληψη 1ης Ενότητας - Μαθηματικά - Α Δημοτικού
Επανάληψη 1ης Ενότητας - Μαθηματικά - Α ΔημοτικούΕπανάληψη 1ης Ενότητας - Μαθηματικά - Α Δημοτικού
Επανάληψη 1ης Ενότητας - Μαθηματικά - Α Δημοτικού
 
Punto De Inflacion Y Combustion 02
Punto De Inflacion Y Combustion 02Punto De Inflacion Y Combustion 02
Punto De Inflacion Y Combustion 02
 
TOPOGRAFIA GENERAL
TOPOGRAFIA GENERALTOPOGRAFIA GENERAL
TOPOGRAFIA GENERAL
 
Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...
Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...
Τάσος το σαλιγκάρι.Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(ht...
 
Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...
Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...
Μύτη σαν σαλάμι / Το γράμμα Μ μ / Φύλλα εργασίας και εκπαιδευτικό υλικό για τ...
 
επανάληψη γλώσσας μετα τις διακοπές
επανάληψη γλώσσας μετα τις διακοπέςεπανάληψη γλώσσας μετα τις διακοπές
επανάληψη γλώσσας μετα τις διακοπές
 
Ρινόκερος και κόκορας
Ρινόκερος και κόκοραςΡινόκερος και κόκορας
Ρινόκερος και κόκορας
 
Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...
Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...
Πεπόνι, πεπόνι! Φύλλα εργασίας και εποπτικό υλικό για την α΄ δημοτικού.(http:...
 
ένα ζιζανιο στη ζύμη
ένα ζιζανιο στη ζύμηένα ζιζανιο στη ζύμη
ένα ζιζανιο στη ζύμη
 
Παρουσίαση αποκριάςγια μεγαλους
Παρουσίαση αποκριάςγια μεγαλουςΠαρουσίαση αποκριάςγια μεγαλους
Παρουσίαση αποκριάςγια μεγαλους
 

Similar to Aficamten in HCM (SEQUOIA HCM TRIAL 2024)

HOT CLINICAL TRIALS.pptx
HOT CLINICAL TRIALS.pptxHOT CLINICAL TRIALS.pptx
HOT CLINICAL TRIALS.pptx
ihabmahmoud12
 
Mixed results for heart failure therapies, journel club
Mixed results for heart failure therapies, journel clubMixed results for heart failure therapies, journel club
Mixed results for heart failure therapies, journel club
Dr Virbhan Balai
 
BEST OF ESC 2020
BEST OF ESC 2020BEST OF ESC 2020
BEST OF ESC 2020
Praveen Nagula
 
Evolocumab and its clinical outcomes in patients of cardiovascular disease
Evolocumab and its clinical outcomes in patients of cardiovascular diseaseEvolocumab and its clinical outcomes in patients of cardiovascular disease
Evolocumab and its clinical outcomes in patients of cardiovascular disease
tarun kumar
 
PCKS9 INHIBITORS
PCKS9 INHIBITORSPCKS9 INHIBITORS
PCKS9 INHIBITORS
Shivani Rao
 
Afib NOAC residency pres
Afib NOAC residency presAfib NOAC residency pres
Afib NOAC residency pres
Matt Dickinson, PharmD, MBA
 
escpe1-191229130329.pptx
escpe1-191229130329.pptxescpe1-191229130329.pptx
escpe1-191229130329.pptx
EastmaMeili1
 
2019 ESC guidelines on pulmonary embolism
2019 ESC guidelines on pulmonary embolism2019 ESC guidelines on pulmonary embolism
2019 ESC guidelines on pulmonary embolism
Saitej Reddy
 
Recent advances in antithrombotics
Recent advances in antithromboticsRecent advances in antithrombotics
Recent advances in antithrombotics
Please hit like if you really liked my PPTs
 
Recent advances in rx of thrombotic disorders
Recent advances in rx of thrombotic disordersRecent advances in rx of thrombotic disorders
Recent advances in rx of thrombotic disorders
Please hit like if you really liked my PPTs
 
Acc ARNI 2021.pptx
Acc ARNI 2021.pptxAcc ARNI 2021.pptx
Acc ARNI 2021.pptx
Lokesh Ravi
 
REVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptx
REVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptxREVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptx
REVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptx
Nihanth73
 
Journal club af
Journal club afJournal club af
Journal club af
Priyanka Thakur
 
Case Presentations 1
Case Presentations 1Case Presentations 1
Case Presentations 1
Gamal Agmy
 
Venous Thromboembolism
Venous ThromboembolismVenous Thromboembolism
Venous Thromboembolism
ankit0019
 
Martsevich lipid-lovering therapy 2015 Vienna
Martsevich lipid-lovering therapy 2015 ViennaMartsevich lipid-lovering therapy 2015 Vienna
Martsevich lipid-lovering therapy 2015 Vienna
Fiordmaster
 
Atrial Fibrillation Guidelines 2016
Atrial Fibrillation Guidelines 2016Atrial Fibrillation Guidelines 2016
Atrial Fibrillation Guidelines 2016
SỨC KHỎE VÀ CUỘC SỐNG
 
Journal club may 2016
Journal club may 2016Journal club may 2016
Journal club may 2016
Kunal Mahajan
 
Mopett
MopettMopett
Mopett
nswhems
 
65 trial 2020
65 trial  202065 trial  2020
65 trial 2020
Bhuvana Angel
 

Similar to Aficamten in HCM (SEQUOIA HCM TRIAL 2024) (20)

HOT CLINICAL TRIALS.pptx
HOT CLINICAL TRIALS.pptxHOT CLINICAL TRIALS.pptx
HOT CLINICAL TRIALS.pptx
 
Mixed results for heart failure therapies, journel club
Mixed results for heart failure therapies, journel clubMixed results for heart failure therapies, journel club
Mixed results for heart failure therapies, journel club
 
BEST OF ESC 2020
BEST OF ESC 2020BEST OF ESC 2020
BEST OF ESC 2020
 
Evolocumab and its clinical outcomes in patients of cardiovascular disease
Evolocumab and its clinical outcomes in patients of cardiovascular diseaseEvolocumab and its clinical outcomes in patients of cardiovascular disease
Evolocumab and its clinical outcomes in patients of cardiovascular disease
 
PCKS9 INHIBITORS
PCKS9 INHIBITORSPCKS9 INHIBITORS
PCKS9 INHIBITORS
 
Afib NOAC residency pres
Afib NOAC residency presAfib NOAC residency pres
Afib NOAC residency pres
 
escpe1-191229130329.pptx
escpe1-191229130329.pptxescpe1-191229130329.pptx
escpe1-191229130329.pptx
 
2019 ESC guidelines on pulmonary embolism
2019 ESC guidelines on pulmonary embolism2019 ESC guidelines on pulmonary embolism
2019 ESC guidelines on pulmonary embolism
 
Recent advances in antithrombotics
Recent advances in antithromboticsRecent advances in antithrombotics
Recent advances in antithrombotics
 
Recent advances in rx of thrombotic disorders
Recent advances in rx of thrombotic disordersRecent advances in rx of thrombotic disorders
Recent advances in rx of thrombotic disorders
 
Acc ARNI 2021.pptx
Acc ARNI 2021.pptxAcc ARNI 2021.pptx
Acc ARNI 2021.pptx
 
REVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptx
REVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptxREVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptx
REVIEW OF THERAPIES FOR PULMONARY EMBOLISM .pptx
 
Journal club af
Journal club afJournal club af
Journal club af
 
Case Presentations 1
Case Presentations 1Case Presentations 1
Case Presentations 1
 
Venous Thromboembolism
Venous ThromboembolismVenous Thromboembolism
Venous Thromboembolism
 
Martsevich lipid-lovering therapy 2015 Vienna
Martsevich lipid-lovering therapy 2015 ViennaMartsevich lipid-lovering therapy 2015 Vienna
Martsevich lipid-lovering therapy 2015 Vienna
 
Atrial Fibrillation Guidelines 2016
Atrial Fibrillation Guidelines 2016Atrial Fibrillation Guidelines 2016
Atrial Fibrillation Guidelines 2016
 
Journal club may 2016
Journal club may 2016Journal club may 2016
Journal club may 2016
 
Mopett
MopettMopett
Mopett
 
65 trial 2020
65 trial  202065 trial  2020
65 trial 2020
 

Recently uploaded

How to Store Data on the Odoo 17 Website
How to Store Data on the Odoo 17 WebsiteHow to Store Data on the Odoo 17 Website
How to Store Data on the Odoo 17 Website
Celine George
 
How to Manage Early Receipt Printing in Odoo 17 POS
How to Manage Early Receipt Printing in Odoo 17 POSHow to Manage Early Receipt Printing in Odoo 17 POS
How to Manage Early Receipt Printing in Odoo 17 POS
Celine George
 
"DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ...
"DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ..."DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ...
"DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ...
thanhluan21
 
How to Create & Publish a Blog in Odoo 17 Website
How to Create & Publish a Blog in Odoo 17 WebsiteHow to Create & Publish a Blog in Odoo 17 Website
How to Create & Publish a Blog in Odoo 17 Website
Celine George
 
CTD Punjab Police Past Papers MCQs PPSC PDF
CTD Punjab Police Past Papers MCQs PPSC PDFCTD Punjab Police Past Papers MCQs PPSC PDF
CTD Punjab Police Past Papers MCQs PPSC PDF
hammadmughal76316
 
What is Rescue Session in Odoo 17 POS - Odoo 17 Slides
What is Rescue Session in Odoo 17 POS - Odoo 17 SlidesWhat is Rescue Session in Odoo 17 POS - Odoo 17 Slides
What is Rescue Session in Odoo 17 POS - Odoo 17 Slides
Celine George
 
(T.L.E.) Agriculture: Essentials of Gardening
(T.L.E.) Agriculture: Essentials of Gardening(T.L.E.) Agriculture: Essentials of Gardening
(T.L.E.) Agriculture: Essentials of Gardening
MJDuyan
 
Individual Performance Commitment Review Form-Developmental Plan.docx
Individual Performance Commitment Review Form-Developmental Plan.docxIndividual Performance Commitment Review Form-Developmental Plan.docx
Individual Performance Commitment Review Form-Developmental Plan.docx
monicaaringo1
 
Unlocking Educational Synergy-DIKSHA & Google Classroom.pptx
Unlocking Educational Synergy-DIKSHA & Google Classroom.pptxUnlocking Educational Synergy-DIKSHA & Google Classroom.pptx
Unlocking Educational Synergy-DIKSHA & Google Classroom.pptx
bipin95
 
Year-to-Date Filter in Odoo 17 Dashboard
Year-to-Date Filter in Odoo 17 DashboardYear-to-Date Filter in Odoo 17 Dashboard
Year-to-Date Filter in Odoo 17 Dashboard
Celine George
 
How to Add a Filter in the Odoo 17 - Odoo 17 Slides
How to Add a Filter in the Odoo 17 - Odoo 17 SlidesHow to Add a Filter in the Odoo 17 - Odoo 17 Slides
How to Add a Filter in the Odoo 17 - Odoo 17 Slides
Celine George
 
Edukasyong Pantahanan at Pangkabuhayan 1: Personal Hygiene
Edukasyong Pantahanan at  Pangkabuhayan 1: Personal HygieneEdukasyong Pantahanan at  Pangkabuhayan 1: Personal Hygiene
Edukasyong Pantahanan at Pangkabuhayan 1: Personal Hygiene
MJDuyan
 
NC Public Schools Involved in NCDPI, Zipline Partnership
NC Public Schools Involved in NCDPI, Zipline PartnershipNC Public Schools Involved in NCDPI, Zipline Partnership
NC Public Schools Involved in NCDPI, Zipline Partnership
Mebane Rash
 
2024 KWL Back 2 School Summer Conference
2024 KWL Back 2 School Summer Conference2024 KWL Back 2 School Summer Conference
2024 KWL Back 2 School Summer Conference
KlettWorldLanguages
 
How to Create a New Article in Knowledge App in Odoo 17
How to Create a New Article in Knowledge App in Odoo 17How to Create a New Article in Knowledge App in Odoo 17
How to Create a New Article in Knowledge App in Odoo 17
Celine George
 
Imagination in Computer Science Research
Imagination in Computer Science ResearchImagination in Computer Science Research
Imagination in Computer Science Research
Abhik Roychoudhury
 
Bedok NEWater Photostory - COM322 Assessment (Story 2)
Bedok NEWater Photostory - COM322 Assessment (Story 2)Bedok NEWater Photostory - COM322 Assessment (Story 2)
Bedok NEWater Photostory - COM322 Assessment (Story 2)
Liyana Rozaini
 
1-NLC-MATH7-Consolidation-Lesson1 2024.pptx
1-NLC-MATH7-Consolidation-Lesson1 2024.pptx1-NLC-MATH7-Consolidation-Lesson1 2024.pptx
1-NLC-MATH7-Consolidation-Lesson1 2024.pptx
AnneMarieJacildo
 
Is Email Marketing Really Effective In 2024?
Is Email Marketing Really Effective In 2024?Is Email Marketing Really Effective In 2024?
Is Email Marketing Really Effective In 2024?
Rakesh Jalan
 
NAEYC Code of Ethical Conduct Resource Book
NAEYC Code of Ethical Conduct Resource BookNAEYC Code of Ethical Conduct Resource Book
NAEYC Code of Ethical Conduct Resource Book
lakitawilson
 

Recently uploaded (20)

How to Store Data on the Odoo 17 Website
How to Store Data on the Odoo 17 WebsiteHow to Store Data on the Odoo 17 Website
How to Store Data on the Odoo 17 Website
 
How to Manage Early Receipt Printing in Odoo 17 POS
How to Manage Early Receipt Printing in Odoo 17 POSHow to Manage Early Receipt Printing in Odoo 17 POS
How to Manage Early Receipt Printing in Odoo 17 POS
 
"DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ...
"DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ..."DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ...
"DANH SÁCH THÍ SINH XÉT TUYỂN SỚM ĐỦ ĐIỀU KIỆN TRÚNG TUYỂN ĐẠI HỌC CHÍNH QUY ...
 
How to Create & Publish a Blog in Odoo 17 Website
How to Create & Publish a Blog in Odoo 17 WebsiteHow to Create & Publish a Blog in Odoo 17 Website
How to Create & Publish a Blog in Odoo 17 Website
 
CTD Punjab Police Past Papers MCQs PPSC PDF
CTD Punjab Police Past Papers MCQs PPSC PDFCTD Punjab Police Past Papers MCQs PPSC PDF
CTD Punjab Police Past Papers MCQs PPSC PDF
 
What is Rescue Session in Odoo 17 POS - Odoo 17 Slides
What is Rescue Session in Odoo 17 POS - Odoo 17 SlidesWhat is Rescue Session in Odoo 17 POS - Odoo 17 Slides
What is Rescue Session in Odoo 17 POS - Odoo 17 Slides
 
(T.L.E.) Agriculture: Essentials of Gardening
(T.L.E.) Agriculture: Essentials of Gardening(T.L.E.) Agriculture: Essentials of Gardening
(T.L.E.) Agriculture: Essentials of Gardening
 
Individual Performance Commitment Review Form-Developmental Plan.docx
Individual Performance Commitment Review Form-Developmental Plan.docxIndividual Performance Commitment Review Form-Developmental Plan.docx
Individual Performance Commitment Review Form-Developmental Plan.docx
 
Unlocking Educational Synergy-DIKSHA & Google Classroom.pptx
Unlocking Educational Synergy-DIKSHA & Google Classroom.pptxUnlocking Educational Synergy-DIKSHA & Google Classroom.pptx
Unlocking Educational Synergy-DIKSHA & Google Classroom.pptx
 
Year-to-Date Filter in Odoo 17 Dashboard
Year-to-Date Filter in Odoo 17 DashboardYear-to-Date Filter in Odoo 17 Dashboard
Year-to-Date Filter in Odoo 17 Dashboard
 
How to Add a Filter in the Odoo 17 - Odoo 17 Slides
How to Add a Filter in the Odoo 17 - Odoo 17 SlidesHow to Add a Filter in the Odoo 17 - Odoo 17 Slides
How to Add a Filter in the Odoo 17 - Odoo 17 Slides
 
Edukasyong Pantahanan at Pangkabuhayan 1: Personal Hygiene
Edukasyong Pantahanan at  Pangkabuhayan 1: Personal HygieneEdukasyong Pantahanan at  Pangkabuhayan 1: Personal Hygiene
Edukasyong Pantahanan at Pangkabuhayan 1: Personal Hygiene
 
NC Public Schools Involved in NCDPI, Zipline Partnership
NC Public Schools Involved in NCDPI, Zipline PartnershipNC Public Schools Involved in NCDPI, Zipline Partnership
NC Public Schools Involved in NCDPI, Zipline Partnership
 
2024 KWL Back 2 School Summer Conference
2024 KWL Back 2 School Summer Conference2024 KWL Back 2 School Summer Conference
2024 KWL Back 2 School Summer Conference
 
How to Create a New Article in Knowledge App in Odoo 17
How to Create a New Article in Knowledge App in Odoo 17How to Create a New Article in Knowledge App in Odoo 17
How to Create a New Article in Knowledge App in Odoo 17
 
Imagination in Computer Science Research
Imagination in Computer Science ResearchImagination in Computer Science Research
Imagination in Computer Science Research
 
Bedok NEWater Photostory - COM322 Assessment (Story 2)
Bedok NEWater Photostory - COM322 Assessment (Story 2)Bedok NEWater Photostory - COM322 Assessment (Story 2)
Bedok NEWater Photostory - COM322 Assessment (Story 2)
 
1-NLC-MATH7-Consolidation-Lesson1 2024.pptx
1-NLC-MATH7-Consolidation-Lesson1 2024.pptx1-NLC-MATH7-Consolidation-Lesson1 2024.pptx
1-NLC-MATH7-Consolidation-Lesson1 2024.pptx
 
Is Email Marketing Really Effective In 2024?
Is Email Marketing Really Effective In 2024?Is Email Marketing Really Effective In 2024?
Is Email Marketing Really Effective In 2024?
 
NAEYC Code of Ethical Conduct Resource Book
NAEYC Code of Ethical Conduct Resource BookNAEYC Code of Ethical Conduct Resource Book
NAEYC Code of Ethical Conduct Resource Book
 

Aficamten in HCM (SEQUOIA HCM TRIAL 2024)

  • 1. JOURNAL CLUB PRESENTOR: DR ASHISH KOHLI MODERATOR: DR JASKARAN SINGH GUJRAL
  • 3. INTRODUCTION • Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases •HCM is characterized by a thickened, nondilated left ventricle and often causes exertional dyspnea and reduced exercise capacity, which can impair quality of life •Left ventricular outflow tract obstruction, is one of the principal determinants of HCM-related complications and therefore is an important target for therapy
  • 4. •Cardiac hypercontractility, which results from an excessive number of actin– myosin cross-bridges within the cardiac sarcomere, is an important mechanism that promotes outflow obstruction •Mavacamten, a recently approved cardiac myosin inhibitor, has been shown to improve exercise capacity and reduce symptoms in patients with obstructive HCM
  • 5. MECHANISMS OF EXERCISE LIMITATIONS IN O-HCM
  • 6. AFICAMTEN Aficamten is a reversible inhibitor of cardiac myosin that reduces left ventricular contractility by decreasing the number of active actin–myosin cross-bridges within the sarcomere Aficamten was designed to have a shallow dose–response relationship and a plasma half-life that allows for personalized dose adjustments as often as every 2 weeks (features that differentiate it from mavacamten) In a phase 2 trial, treatment with aficamten resulted in significant reductions in left ventricular outflow tract gradients in patients with obstructive HCM Maron MS, Masri A, Choudhury L, et al. Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2023; 81: 34-45
  • 8. COR LOE RECOMMENDATIONS 1 B-R For patients with obstructive HCM who have persistent symptoms attributable to LVOTO despite beta blockers or non dihydropyridine calcium channel blockers, adding a myosin inhibitor (adult patients only), or disopyramide (in combination with an atrioventricular nodal blocking agent), or SRT performed at experienced centres, is recommended Members WC et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology. 2024 May 8.
  • 9. BACKGROUND Maron MS, et al. J Am Coll Cardiol. 2023;81(1):34– 45. REDWOOD HCM TRIAL (PHASE II)
  • 10. STUDY DESIGN Phase 3, International, Double-blind, Randomized, Placebo-controlled trial Patients with symptomatic obstructive HCM received aficamten or placebo in addition to standard drug therapy Total patients: 282
  • 13. INCLUSION CRITERIA Males and females between 18 and 85 years of age, BMI <35 kg/m2 Diagnosed with HCM per the following criteria: a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and b. Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of: • ≥15 mm in one or more myocardial segments OR • ≥13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM Has resting LVOT-G ≥30 mm Hg and post-Valsalva LVOT-G ≥50 mmHg during screening as determined by the echocardiography core laboratory LVEF ≥60% at screening as determined by the echocardiography core laboratory
  • 14.  New York Heart Association (NYHA) Functional Class II or III at screening Hemoglobin ≥10 g/dL at screening Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening CPET per the core laboratory Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on a stable regimen for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker
  • 15. EXCLUSION CRITERIA Significant valvular heart disease- Moderate-severe valvular AS/AR, Moderate-severe MR not due to systolic anterior motion of the mitral valve Documented history of current obstructive coronary artery disease or H/O MI Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Noonan syndrome, Fabry disease, amyloidosis) Prior treatment with cardiotoxic agents such as doxorubicin or similar History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during their clinical course Has any ECG abnormality considered by the investigator to pose a risk to patient safety (eg, second degree atrioventricular block type II) Documented paroxysmal atrial fibrillation during the screening period
  • 16. Paroxysmal or permanent atrial fibrillation is only excluded IF: - rhythm restoring treatment has been required ≤6 months prior to screening - rate control and anticoagulation have not been achieved for at least 6 months prior to screening History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening ICD placement within 3 months or planned ICD placement during the trial History of appropriate ICD discharge for life-threatening ventricular arrhythmia within 6 months prior to screening
  • 17. Has been treated with septal reduction therapy Estimated glomerular filtration rate (eGFR) <30 mL/min or hepatic impairment Has received prior treatment with aficamten or mavacamten
  • 18. PROCEDURE Eligible patients were randomly assigned in a 1:1 ratio to receive aficamten or placebo Randomization was performed with the use of an interactive Web-response system and stratified according to the use of beta-blockers (yes or no) and the method of CPET (treadmill or cycle ergometer) Enrollment of patients taking beta-blockers and disopyramide was capped at approximately 70% and 10% of the trial population, respectively Enrollment of those with persistent atrial fibrillation at screening was capped at 15% Enrollment of patients being tested with the use of a cycle ergometer was capped at 50%
  • 19. Oral aficamten or placebo (manufactured by Patheon) was administered once daily for 24 weeks; the tablets were identical in appearance The starting dose of aficamten was 5 mg, with three subsequent opportunities (at weeks 2, 4, and 6) to increase the dose by 5-mg increments, to a maximum dose of 20 mg At each visit, an echocardiographic cardiologist who was unaware of the trial- group assignments assessed the left ventricular outflow tract gradient at rest and after the Valsalva maneuver and the left ventricular ejection fraction The site investigators and trial team members were unaware of the N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and the echocardiography results
  • 22. END POINTS PRIMARY END POINT: The change from baseline to week 24 in the peak oxygen uptake as assessed during cardiopulmonary exercise testing SECONDARY END POINTS: •The change from baseline to week 24 in the KCCQ-CSS •An improvement from baseline of at least one NYHA functional class at week 24 •The change from baseline to week 24 in the LVOT gradient after the Valsalva maneuver •The occurrence of a LVOT gradient of less than 30 mm Hg after the Valsalva maneuver at week 24 •The duration of eligibility for septal reduction therapy during the 24-week treatment period among patients who were eligible for such therapy at baseline
  • 23. •The change from baseline to week 12 in the KCCQ-CSS •An improvement from baseline of at least one NYHA functional class at week 12 •The change from baseline to week 12 in the LVOT gradient after the Valsalva maneuver •The occurrence of a LVOT gradient of less than 30 mm Hg after the Valsalva maneuver at week 12 •The change in the total workload as assessed by cardiopulmonary exercise testing at week 24
  • 24. An exploratory end point was the geometric mean proportional change in the NT-proBNP level
  • 25. STATISTICAL ANALYSIS The statistical power was calculated under the assumption that the difference between the groups in the change from baseline in the peak oxygen uptake at week 24 would be 1.5 ml/kg/min, with a standard deviation of 3.5 ml/kg/min and that no more than 70% of the patients would be receiving beta blockers and no more than 50% of the patients would undergo CPET with the use of a cycle ergometer  With the assumption that 10% of the primary end-point data would be missing, it was estimated that a sample of 270 patients with a randomization ratio of 1:1 would provide the trial with at least 90% power with a two-sided type I error level of 0.05
  • 26. Primary end point was analyzed with the use of an analysis of covariance (ANCOVA) model, with trial group, randomization stratification factors, baseline peak oxygen uptake, and baseline weight as covariates The primary end point was tested first at a two-sided level of 0.05. If the primary end point showed a significant treatment effect at a two-sided P value of less than 0.05, then the secondary end points were tested sequentially at a two-sided level of 0.05 Secondary end points who had a response to aficamten were analyzed with the use of the Cochran–Mantel–Haenszel test The statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute)
  • 27. RESULTS From February 1, 2022, to May 15, 2023, a total of 543 patients were screened for eligibility at 101 sites in 14 countries, of whom 282 underwent randomization and received aficamten or placebo At the end of the dose-escalation phase (week 8), 3.6%, 12.9%, 35.0%, and 48.6% of the patients assigned to the aficamten group were receiving aficamten at a dose of 5 mg, 10 mg, 15 mg, and 20 mg, respectively
  • 30. PRIMARY END POINT Changes in Exercise Capacity from Baseline to Week 24
  • 31. PRIMARY AND SECONDARY END POINTS
  • 32. PRIMARY END POINT SUBGROUP ANALYSIS
  • 36. ADVERSE EVENTS Serious adverse events were reported in 8 patients (5.6%) in the aficamten group and in 13 patients (9.3%) in the placebo group One adverse event (paranoia) resulted in early discontinuation of aficamten, and two adverse events (syncope and acute lymphocytic leukemia) resulted in early discontinuation of placebo Three adverse events resulted in temporary interruptions of aficemten or placebo, including acute cholecystitis in 1 patient in the aficamten group and bronchopneumonia and verrucous carcinoma removal in 1 patient each in the placebo group
  • 40. DISCUSSION In this trial aficamten improved exercise capacity (as assessed by cardiopulmonary exercise testing) over a 24-week treatment period  Aficamten treatment was also associated with significantly greater improvements than placebo in all the secondary end points The efficacy of aficamten was evident by week 12, with significantly greater improvements in left ventricular outflow tract gradients, health status, and symptoms In addition, the reduction in symptoms was associated with a clinically meaningful enhancement of overall health status as evidenced by increases in the KCCQ-CSS
  • 41. In contrast to the results that were observed with mavacamten in the EXPLORER-HCM trial, which suggested an attenuation of benefit among patients who were receiving beta-blockers, the treatment effects of aficamten appeared to be similar with or without background beta-blocker use Aficamten was associated with other favorable outcomes, including a significantly greater improvement in limiting symptoms and a substantially greater reduction in the serum NT-proBNP level than placebo The unique pharmacologic properties of aficamten provide some notable distinctions between aficamten and mavacamten
  • 42. The shorter half-life of aficamten enables more rapid dose escalation, which results in the ability to identify an effective dose within weeks, providing timely clinical benefit No patient in the aficamten group who had a left ventricular ejection fraction of less than 50% had an interruption of treatment or an exacerbation of heart failure Furthermore, the return to baseline measures of the left ventricular outflow tract gradient, symptoms, and the left ventricular ejection fraction after the washout period reflects a rapid reversal of the pharmacodynamic effects
  • 43. MERITS OF THE TRIAL The outcomes observed in this trial with aficamten appear to be generalizable to the broad, global population of patients with obstructive HCM encountered in clinical practice Women were well represented (40.8%) in this trial The clinical profile of the trial population included patients with typical characteristics of obstructive HCM, including those with a range of left ventricular outflow tract gradients and left ventricular wall thicknesses The trial was inclusive of all conventional HCM background therapy use
  • 44. LIMITATIONS Majority population in the trial were white The relatively short treatment period, precluding assessment of longer-term cardiovascular outcomes They observed that some patients who received aficamten did not have an improvement in NYHA class. Further trials are needed to clarify the reasons for this finding and to determine whether those patients would have symptom relief with longer exposure to aficamten
  • 45. CONCLUSION Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo

Editor's Notes

  1. Patients assigned to the aficamten group may receive up to four escalating doses of the drug over the initial 6 weeks of the trial with changes in dose determined using the strategy shown in the table. Patients receiving aficamten start at a dose of 5 mg once daily (Dose 1) and may escalate to receive 10, 15, or 20 mg once daily based on the criteria or will stop at their current dose when the criteria are not met. † Once a patient’s aficamten dose is titrated down, no further dose escalation is permitted. If the patient’s LVEF <50% on the 5 mg dose, the patient will receive placebo
  2. Differences are given as the least-squares mean difference between the groups in the mean change from baseline for the primary end point and all the secondary end points, except for two (improvement of ≥1 NYHA functional class and left ventricular outflow tract gradient of <30 mm Hg after the Valsalva maneuver). These two end points were measured as categorical variables and are given as the percentage-point difference between the groups in the percentage of patients who had an improvement of at least one NYHA functional class and in the percentage of those who had a left ventricular outflow tract gradient of less than 30 mm Hg after the Valsalva maneuver, respectively. The difference for the geometric mean proportional change in NT-proBNP is given as the geometric least-squares mean ratio. ‡ Septal reduction therapy eligibility is defined by NYHA functional class III or IV disease and a left ventricular outflow tract gradient (at rest or after the Valsalva maneuver) of at least 50 mm Hg. This analysis was performed only in patients who met these eligibility criteria at baseline. § The proportional change in NT-proBNP was defined as the ratio of the NT-proBNP level (in picograms per milliliter) at week 24 to the baseline NT-proBNP level (in picograms per mil
  3. TEAE denotes treatment-emergent adverse event.
  4. TESAE denotes treatment-emergent serious adverse event