CONTINUING MEDICAL EDUCATION

What’s New in HCM ? Assessing The Latest Evidence

Disusun Oleh :
Intan Rahmawati G4A019010
Nabila Diar Isnaini G4A019012

Pembimbing :
dr. Rio Probo Kaneko, Sp. JP-FIHA

SMF ILMU PENYAKIT DALAM

RSUD PROF. DR. MARGONO SOEKARJO
FAKULTAS KEDOKTERAN
UNIVERSITAS JENDERAL SOEDIRMAN
PURWOKERTO
2020
 LEMBAR PENGESAHAN
CONTINUING MEDICAL EDUCATION
What’s New in HCM ? Assessing The Latest Evidence

Disusun Oleh :
Intan Rahmawati G4A019010
Nabila Diar Isnaini G4A019012

Diajukan untuk memenuhi syarat mengikuti Kepaniteraan Klinik di bagian Ilmu

Penyakit Dalam RSUD Prof. Dr. Margono Soekarjo

Telah disetujui dan dipresentasikan

Pada tanggal : Juli 2020

Pembimbing

dr. Rio Probo Kaneko, Sp. JP-FIHA

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What’s New in HCM? Assessing the Latest Evidence CME / ABIM

MOC
Anjali Tiku Owens, MD

Posted: 6/10/2020
What’s New in HCM? Assessing the Latest Evidence

Editor’s Note:

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition characterized by dyspnea, syncope, chest pain, and
palpitations. While there are no currently available treatments that can alter the disease course, patients are typically managed
with pharmacotherapies or other interventions. Additionally, new therapies are emerging that target the pathophysiologic
mechanisms of HCM and hold promise for the future.

Joy Marko, MS, APN-C, Senior Medical Education Director, Medscape Education, interviewed Anjali Tiku Owens, MD, Medical
Director of the Center for Inherited Cardiac Disease and Assistant Professor of Medicine at the Perelman School of Medicine at
the University of Pennsylvania about current and evolving treatment approaches for management of HCM.

Dr Owens, would you share some background on the disease burden of HCM?

Hypertrophic cardiomyopathy (HCM) is estimated to occur in at least 1 in 500 individuals.[1] However, many people with HCM
are asymptomatic and remain undiagnosed, suggesting that the true prevalence of this disease may be much higher than
current estimates reflect.[1,2]

HCM is a genetic condition that is transmitted from generation to generation in an autosomal dominant pattern, often caused by
pathologic variants in sarcomeric genes.[1,2] Based on current scientific knowledge, we believe the pathophysiology present in
HCM results in hypercontractility of the heart and ultimately to hypertrophy, fibrosis, and myofilament disarray (Figure 1).

HCM is diagnosed when hypertrophy of the left ventricle that is otherwise unexplained is identified, usually by cardiac imaging.
This hypertrophy results in reduced ventricular compliance and inefficient energy utilization.[1,2] As a result, patients with HCM
are at significantly increased risk of having a cardiac event or complication, as compared with the general population. These
adverse cardiac events can include progressive cardiac symptoms, functional limitation on the basis of left ventricular outflow
tract (LVOT) obstruction, or diastolic dysfunction. Patients can develop heart failure, arrhythmias -- such as atrial fibrillation or
ventricular tachycardia -- stroke, and rarely, sudden death.[1,2]

In studies examining patients with HCM who were referred to larger centers -- data that represent a potentially sicker-than-
average patient population -- researchers found a 30% to 50% risk for one of these adverse effects.[3,4] However, despite the
relatively high risk for cardiac dysfunction or complication due to HCM, research has come a long way in the last few decades in
terms of treatment that can prolong lifespan as well as improve quality of life for patients with HCM.

Figure 1. Pathophysiology of HCM[1,2]

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Can you please tell us about the subtypes of HCM?

Obstructive HCM and nonobstructive HCM are the 2 major subtypes within the broader category of HCM; we differentiate them
based on cardiac morphology and function. Obstructive HCM is more common, occurring in about two-thirds of patients.[5] In
this population there is an obstruction of blood flow on exiting the left ventricle, generally resulting from hypertrophy of the
septum and narrowing of the LVOT -- anatomically and functionally -- by anterior movement of the mitral valve during systole.

The presence, location, and amount of obstruction are usually measured at rest or during exercise using 2D and Doppler
echocardiography. Obstruction is generally considered to be present if the peak instantaneous gradient is greater than 30
millimeters of mercury. It is considered severe obstruction when the gradient is greater than 50 millimeters of mercury.

The other one-third of patients have so-called “nonobstructive” HCM. In this subtype, the gradient as examined by echo is less
than 30 millimeters of mercury.

It is important to note that within the population of patients with HCM, intracavitary gradients are dynamic and can vary
significantly based on the loading conditions of the ventricle. So, for example -- if you're dehydrated, resulting in low preload; or
you're on a vasodilating medication that reduces afterload; or if you're on a stimulant that increases cardiac contractility -- all of
these conditions can exacerbate the degree of LVOT obstruction.

I wanted to ask you about treatment next; what are the current approaches to clinical management of HCM?

At this time we don’t have any disease-modifying therapies available for HCM; most of the therapies are centered around
alleviating disease-related symptoms.[1,6] It is important to note that there are some differences in how we treat obstructive and
nonobstructive HCM. Usually for patients with symptomatic obstructive HCM both lifestyle modifications and pharmacologic
therapy are recommended. For lifestyle changes, we suggest that patients stay very well hydrated because we know that
increasing preload in the left ventricle can reduce obstruction within the left ventricle.[6] For pharmacotherapy, we often use
negative inotropic agents such as beta-blockers or nondihydropyridine calcium channel blockers to improve symptoms by
improving diastolic filling time, which reduces obstruction.[6,7] So, although these therapies were not developed to treat HCM
and don’t treat the underlying disease, they can help alleviate chest discomfort and dyspnea, they can help with microvascular
ischemia, and they can help with reducing palpitations.

When symptoms remain and limit functional capacity with obstructive HCM, we can add on therapies like disopyramide, which is
an older antiarrhythmic agent that also has negative ionotropic properties.[6,7] There are also FDA-approved invasive treatments
for obstructive HCM, including alcohol septal ablation, a catheterization-based technique, and septal myectomy, which is open

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heart surgery to reduce the size of the septum.[6] Both of those septal reduction therapies have been shown to be effective in
reducing the amount of obstruction and improving symptoms in patients with obstructive HCM.

The greater treatment problem is what to do for our patients who have nonobstructive HCM. These are the patients who often
develop symptoms of shortness of breath, exercise intolerance, fatigue, palpitations, chest discomfort, and sometimes even fluid
retention or heart failure.[6,7] We don't have any FDA-approved or even off-label therapies that address the underlying problem.
So, again, we often turn to medications that are approved for other cardiac conditions, like beta-blockers, calcium channel
blockers, or even diuretics, but unfortunately, they've not been shown to be terribly effective for patients with nonobstructive
HCM.[6,7] Heart transplant is sometimes the only option for end-stage heart failure and advanced HCM.

Another consideration for using pharmacotherapies in patients with HCM is toxicity; many of the medications we commonly use
have significant side effects that can be limiting. The HCM population spans the age range from very young to very old and can
affect young people who are otherwise healthy and very physically active. So, some of the side effects of beta-blockers and
calcium channel blockers, for instance, are really untenable and difficult for young patients to tolerate because they make them
feel fatigued, drastically reduce their energy, and slow their heart rate, leaving them feeling sluggish. It's not inconsequential to
consider lifelong drug therapy in a young person, when you consider the potential for significant side effects.

Now that we have a better idea of what current treatment entails, can you tell us what’s on the horizon for treatment of
HCM?

An exciting part of being in the HCM field currently is that new therapies that are being developed and tested in clinical trials.
Importantly, some of these new therapies actually address what we think is the underlying pathophysiology of HCM, the
variation in sarcomere genes that leads to hypercontractility and abnormal energy utilization.

One of the drugs currently in late-stage clinical trials for both obstructive and nonobstructive HCM is called mavacamten. It is a
first-in-class modulator of cardiac myosin, and it reversibly attenuates cardiac contractility -- addressing what we think is the
underlying problem in HCM.

Efficacy and safety of mavacamten was studied in PIONEER, an open-label, phase 2 study in patients with obstructive HCM.[8]
In this trial, one cohort of patients was on background therapy of beta-blockers and received a lower dose of mavacamten (2-5
mg/day), while a second cohort had discontinued their beta-blockers and were put on a higher dose (10-20 mg/day) of
mavacamten.

The 12-week results showed that patients who received mavacamten had a marked improvement of the LVOT gradient, and
improvement of symptoms. Significant improvements were seen in both cohorts [Figure 1]. It is also important to mention that
there were no significant safety concerns identified; the most common adverse events were decreased LVEF at higher plasma
concentrations and atrial fibrillation, which could not definitively be attributed to mavacamten.

A later extension trial called PIONEER-OLE enrolled 13 patients with obstructive HCM -- these were patients who had
participated in the original PIONEER trial. Here, the researchers demonstrated the long-term benefits in reduction of the LVOT
gradient, as well as a sustained improvement in symptoms.[9] Importantly, this trial also showed a sustained reduction in NT-
proBNP, a biomarker that rises when there is increased filling pressure or excess strain in the heart. A reduction in the left atrial
volume over time was also reported, suggesting that the hemodynamic profile in these patients was improving. So, mavacamten
does appear to be effective and safe in patients with obstructive HCM.

And lastly, data on the EXPLORER-HCM trial were recently released, confirming the previous findings in the PIONEER series,
but now in a randomized setting. The results showed that, over 30 weeks, mavacamten significantly improved functional status
and quality of life and reduced symptoms, as compared with placebo; LVOT peak gradient was also improved (Table 1]).[10]

Table 1. EXPLORER-HCM Trial: Change in Functional Measures From Baseline to 30 Weeks[10]

Mavacamten Placebo P value

(n = 123) (n = 128)

Primary endpoint
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Composite of functional measures, n (%) 45 (37) 22 (17) 0.0005

Secondary endpoints

Post-exercise LVOT peak gradient, mm Hg, mean (SD) -47.2 (40.3) -10.7 (29.6) <0.0001

Peak VO2, mL/kg.min, mean (SD) 1.4 (3.1) -0.05 (3.0) 0.0006

NYHA improved ≥1 Class, n (%) 80 (65) 40 (31) <0.0001

KCCQ-CSS, mean (SD) 13.6 (14.4) 4.2 (13.7) <0.0001

HCMSQ-SoB score, mean (SD) -2.82 (2.7) -0.85 (2.4) <0.0001

Mavacamten was also recently tested in the phase 2 MAVERICK-HCM study in patients with nonobstructive HCM, with new
data being presented at the American College of Cardiology virtual meeting in March 2020.[11] This trial focused on safety and
tolerability, and the found that mavacamten was generally well tolerated by patients. Exploratory efficacy endpoints noted a
marked decrease in NT-proBNP and troponin in patients receiving mavacamten, paving the way for further investigation of the
role of this agent in nonobstructive HCM and perhaps even in subgroups of other patients with a syndrome of heart failure with
preserved ejection fraction.

In addition to mavacamten, there is another myosin inhibitor being investigated in clinical trials, which for now is being referred
to as CK-274. The safety and efficacy of this potential treatment are being studied in the REDWOOD-HCM phase 2 trial in
patients with symptomatic, obstructive HCM. The initial data are anticipated to be released in mid-2021.[12]

Another early trial in HCM treatment is called SILICOFCM, which is investigating the impact of sacubitril/valsartan on functional
capacity and other cardiac measures, as well as quality of life.[13] Sacubitril/valsartan is already FDA approved for the treatment
of chronic heart failure with reduced ejection fraction, so it will be interesting to see if it has any benefit in treating HCM, as well.

Thank you for that information, it certainly sounds like there is some promising research being done. Last question,
what are your thoughts about how clinical care for patients with HCM may change, if and when new therapies become
available?

I think if we're able to discover targeted therapies for HCM -- those that address the underlying pathophysiology of
hypercontractility, decreased compliance, and abnormal energetics -- we will have a major breakthrough in the treatment of this
disease. In the process, we will likely see a decline in use of therapies that are currently used to manage symptoms, in favor of
a treatment that actually changes the underlying disease process and can alter progression instead of simply treating the
symptoms.

However, medication that attenuates contractility needs to be used with caution, so clinicians will have to monitor patients
closely to assess their response and changes in cardiac function. There is a small subset of patients with HCM, as we talked
about earlier, who ultimately transition to advanced heart failure and can develop systolic dysfunction. So, again, I think you
have to be careful about attenuating contractility; but in the right phase of disease, these targeted therapies may prove to be
extremely beneficial for our patients with HCM, both young and old.

Thank you for your time and for sharing your insights on HCM treatment.

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Abbreviations
ATPase = adenosine triphosphatase
HCM = hypertrophic cardiomyopathy
HCMSQ-SoB = Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath Questions
KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire Clinical Summary Score
LVEF = left ventricular ejection fraction
LVOT = left ventricular outflow tract
NT-proBNP = N-terminal pro hormone B-type natriuretic peptide
NYHA = New York Heart Association
SD = standard deviation
VO2 = volume of oxygen uptake

References

1. Maron B. Clinical course and management of hypertrophic cardiomyopathy. N Engl J Med. 2018;379:655-668.
2. Makavos G, Kairis C, Tselegkidi ME, et al. Hypertrophic cardiomyopathy: an updated review on diagnosis, prognosis, and
treatment. Heart Fail Rev.2019;24:439-459.
3. Hreybe H, Zahid M, Sonel A, et al. Noncardiac surgery and the risk of death and other cardiovascular events in patients
with hypertrophic cardiomyopathy. Clin Cardiol. 2006;29:65-68.
4. Ho CY, Day SM, Ashley EA, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from
the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 2018;138(14):1387-1398.
5. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular
outflow tract obstruction. Circulation. 2006;114:2232-2239.
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with mavacamten: one-year results from PIONEER-OLE. Presented at the 2019 American Heart Association Scientific
Sessions; November 18, 2019; Philadelphia, PA. Abstract RF295.
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the treatment of obstructive hypertrophic cardiomyopathy [press release]. Brisbane, CA: MyoKardia; May 12, 2020.
http://investors.myokardia.com/news-releases/news-release-details/myokardia-announces-primary-and-all-secondary-
endpoints-met. Accessed May 15, 2020.
11. Ho CY, Mealiffe ME, Bach RG, et al. Safety and efficacy of mavacamten in symptomatic non-obstructive hypertrophic
cardiomyopathy: The MAVERICK-HCM study. Presented at American College of Cardiology/World Congress of
Cardiology ACC.20/WCC Virtual session.
12. Cytokinetics announces start of REDWOOD-HCM, a phase 2 clinical trial of ck-3773274 [press release]. San Francisco,
CA: Cytokinetics; January 6, 2020. http://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-
start-redwood-hcm-phase-2-clinical-trial. Accessed May 15, 2020.
13. Tafelmeier M, Baessler A, Wagner S, et al. Design of the SILICOFCM study: effect of sacubitril/valsartan vs lifestyle
intervention on functional capacity in patients with hypertrophic cardiomyopathy. Clin Cardiol. 2020 Mar 3. [Epub ahead
of print]

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