EXPLORER-HCM & VALOR-HCM Trials - Cardionerds Twitter Journal Club

CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the EXPLORER-HCM & VALOR-HCM Trials

Table of contents for the EXPLORER-HCM & VALOR-HCM Trials summary:

Visual abstract
Summary
References
Credits
Twitter Archive

CardsJC CardioNerds VALOR - HCM infographic

CardsJC CardioNerds EXPLORER - HCM infographic

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM)

Iacopo Olivotto, Artur Oreziak, Roberto Barriales-Villa, Theodore P Abraham, Ahmad Masri, Pablo Garcia-Pavia, Sara Saberi, Neal K Lakdawala, Matthew T Wheeler, Anjali Owens, Milos Kubanek, Wojciech Wojakowski, Morten K Jensen, Juan Gimeno-Blanes, Kia Afshar, Jonathan Myers, Sheila M Hegde, Scott D Solomon, Amy J Sehnert, David Zhang, Wanying Li, Mondira Bhattacharya, Jay M Edelberg, Cynthia Burstein Waldman, Steven J Lester, Andrew Wang, Carolyn Y Ho, Daniel Jacoby, on behalf of EXPLORER-HCM study investigators*

Article Link

Mavacamten in adults with symptomatic obstructive HCM who are eligible for septal reduction therapy (VALOR-HCM)

Milind Y. Desai, Kathy Wolski, Anjali Owens, Srihari S. Naidu, Jeffrey B. Geske, Nicholas G. Smedira, Hartzell Schaff, Kathy Lampl, Ellen McErlean, Christina Sewell, David Zhang, Jay M. Edelberg, Amy J. Sehnert, Steven E. Nissen, on behalf of VALOR-HCM study investigators*

Study design and rationale of VALOR-HCM

Relevant Literature – EXPLORER-HCM & VALOR-HCM Trials

Relevant Guidelines – EXPLORER-HCM & VALOR-HCM Trials

2020 ACC/AHA Guidelines for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy¹²

2014 ESC Guidelines on Diagnosis and Management of Hypertrophic Cardiomyopathy¹³

Study Rationale – EXPLORER-HCM & VALOR-HCM Trials

EXPLORER-HCM

Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease specific. Mavacamten is a first-in-class cardiac myosin inhibitor for possible treatment of symptomatic obstructive hypertrophic cardiomyopathy.

VALOR-HCM

Currently, there are no approved medical therapy alternatives to septal reduction therapy (SRT) for patients with symptomatic drug-resistant obstructive hypertrophic cardiomyopathy. Existing therapies do not address the underlying mechanism of HCM (reduced myocardial compliance and hypercontractility). Mavacamten, a reversible cardiac myosin inhibitor, has shown promise in reducing hypercontractility and improving myocardial compliance. Despite its promise, it has not yet been elucidated if Mavacamten reduces the need for SRT in patients with advanced symptoms.

Objective

EXPLORER-HCM

To assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

VALOR-HCM

To assess if Mavacamten is safe and efficacious in reducing the need for SRT when added to maximally tolerated medical therapy among patients with obstructive hypertrophic cardiomyopathy (oHCM).

Trial

EXPLORER-HCM

A randomized, double-blind, placebo-controlled, phase 3 trial, multicenter (68 centers in 13 countries (n=251)). Co-authors employed by the funder were involved with study design, analyses, data interpretation.

VALOR-HCM

A randomized, double-blind, placebo-controlled, multicenter (approx. 20 centers in the U.S.), n = 112 participants. Patients were randomized in a 1:1 fashion (n = 56 in Mavacamten group, vs n = 56 in control group. Follow up was 16 weeks.

Intervention

EXPLORER-HCM

Patients were randomized to receive one-daily orally administered treatment with mavacamten (starting at 5mg, titrated weeks 8 and 14) or placebo for 30 weeks (EXPLORER-HCM)

VALOR-HCM

Patients were randomized to either receive placebo or Mavacamten with a starting dose of 5mg, which was titrated using core laboratory measured left ventricular ejection fraction (LVEF) and left ventricular outflow tract (LVOT) gradient at rest and with Valsalva provocation.

Enrollment Criteria

Outcomes – EXPLORER-HCM & VALOR-HCM Trials

EXPLORER-HCM

Primary Outcome- composite: 1.5mL/kg per min or greater increase in pVO2 and at least one NYHA class reduction; or a 3.0mL/kg per min or greater improvement in pVO2 and no worsening of NYHA class

Secondary Outcomes: change from baseline to week 30 in post-exercise LVOT gradient, pVO2, proportion of patients with at least one NYHA class improvement, and measures of patient reported outcomes (KCCQ-CSS and HCMSQ-SoB questionnaires

VALOR-HCM

Primary Outcome: Composite – decision to proceed with SRT or considered guideline eligible for SRT.

Secondary Outcomes: Change in postexercise LVOT gradient, NYHA Class, KCCQ-23 CSS, NT-proBNP, and cardiac troponin.

Statistical Analysis

EXPLORER-HCM

Sample size of at least 220 needed for 96% power and 25% difference between treatment groups for p<0.05. The researchers conducted an efficacy and safety analysis. Efficacy analyses used intention to treat model and patient reported outcomes were analyzed with mixed effect model repeated measure. The primary endpoint and improvement in NYHA class was analyzed using the Cochran-Mantel-Haenszel test for stratified categorical data. Continuous variables in the secondary efficacy endpoints were compared between treatment groups by ANCOVA or mixed-effect model repeated measure. Safety data was analyzed using descriptive statistics.

VALOR-HCM

A total sample size of at least 100 patients was needed to provide 95% power to detect a 50% relative difference between groups at a 2-sided αlevel of 0.05. A formal interim analysis was conducted by the iDMC after half of the patients completed the week 16 study visit. Efficacy analyses were performed on the intention to treat population. The comparison of the proportions of patients who met the primary efficacy endpoint between the mavacamten and placebo treatment groups were performed using the Cochran–Mantel–Haenszel test for stratified categorical data. Treatment success was summarized for each treatment group and estimates of group differences with the 95% confidence interval based on normal approximation. A sensitivity analysis was performed to evaluate the number of patients with both improvement of NYHA Class and reduction of all resting and provokable LVOT gradients <50 mmHg. A sequential testing procedure was used for multiplicity control of the secondary endpoints.

Participant Characteristics: – EXPLORER-HCM & VALOR-HCM Trials

EXPLORER-HCM

251 enrolled from the US, Spain, Poland and a smaller proportion from several other European counties, mean age was 58.5, 41% women, majority of participants were white.
In terms of medical history, over 40% of participants in each arm had a history of hypertension, over 25% had a family history of HCM, more than 20% in each arm had a history of HLD
Notably, around 75% of participants were on a BB as background HCM therapy

VALOR-HCM

Mean age was 60 years, 49% women, 89% were white, and 92.9% were NYHA class III or higher.
46% were on beta blockers, 15% were taking calcium channel blockers, and 32% were on combination therapy. 20% of patients were taking disopyramide.
Baseline mean LV ejection fraction (LVEF) was 76%. Peak resting LVOT gradient was 49 mmHg and mean post-exercise LVOT gradient was 84 mmHg.

Outcomes

Primary and Secondary Outcomes:

EXPLORER-HCM

VALOR-HCM

Adverse Events:

EXPLORER-HCM

11 serious adverse events were reported by ten (8%) patients on mavacamten versus 20 events reported by 11 (9%) on placebo
Serious cardiac adverse events: 4 patients in the mavacamten group (two atrial fibrillation, two stress cardiomyopathy). There were also 4 serious cardiac adverse events in the placebo group (three atrial fibrillation, one atrial fibrillation with congestive heart failure).
One patient in the placebo group experienced sudden death.
No serious events of heart failure occurred in the mavacamten group.

VALOR-HCM

There were no severe adverse events noted with Mavacamten (no patients experienced chronic heart failure, syncope, or sudden cardiac death)
2 patients needing to temporarily stop the drug due to EF falling below 50%.
There were no permanent discontinuations needed due to EF falling below 30%.
Non-sustained ventricular tachycardia: 0% vs. 9.1% (Mavacamten vs placebo)
Nausea: 7.1% vs. 1.8% (Mavacamten vs placebo)

EXPLORER-HCM Trial Conclusions

Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition.

VALOR-HCM Trial Conclusions

Mavacamten significantly improved symptoms and reduced the need for septal reduction therapy among symptomatic patients with obstructive HCM who were considering SRT and on maximally tolerated medical therapy.

Limitations & Considerations

EXPLORER-HCM

Those taking background CCB vs BB were found to have a greater effect from mavacamten. In what ways do these drugs interact with each other and what does it mean for different subgroup patient populations? Authors address this in the discussions section ultimately stating this should be further studied in the future.
Participants in this study were at least 90% white in both drug and placebo groups as well. We will need further studies to understand whether this is generalizable to the larger population.
Study limitations included the exclusion of patients on disopyramide and patients with severe (NYHA class IV) symptoms. Both populations will be examined in the VALOR-HCM study (below).

VALOR-HCM

An overwhelming majority of the study participants were white, making the generalizability of the study findings difficult when considering patients of underrepresented backgrounds. A follow-up study assessing the efficacy of Mavacamten in African Americans, Hispanics, and other minority racial groups are necessary.
The short follow up period of 16 weeks may underestimate the benefits and/or safety of Mavacamten. A longer follow up period is necessary to more accurately determine the efficacy and safety of this novel therapy.
Trials studying other cardiac myosin inhibitors like Avicamten (REDWOOD-HCM trial NCT04219826) in patients with HCM are underway. Mavacamten has and will create opportunities for other drugs of the similar or same class to be studied in HCM patients.

The published archive features curated twitter highlights from the journal club event.

Ravi Patel @RBPatelMD

One of the main differences is the degree of medical therapy – patients in VALOR were allowed to be on disopyramide – they were patients on the verge of septal reduction therapy. EXPLORER was monotherapy BB or CCB #CardsJC

Of course a main difference was the goal of each trial: EXPLORER to determine if mava improved peak VO2 and NYHA class (primary EP) and VALOR to determine if mava lowers risk for SRT indication #CardsJC

Dr. Purvi Parwani @purviparwani

EXPLORER-HCM, patients randomized to mavacamten or placebo in VALOR-HCM pts were maxed out on medical treatment. and their next stop was surgery or interventional procedure #CardsJC

VALOR HCM added the alternative options of Mavacamten to highly symptomatic patients to delay surgery or maybe to avoid surgery altogether #CardsJC

Ritu Thamman MD @iamritu

Timing: #Explorer HCM 30 weeks versus 16 weeks #VALOR HCM

Measurements:

Valor used core lab-measured LVEF, LVOT gradient at rest, & Valsalva provocation

#Explorer HCM

postexercise left ventricular outflow tract gradient #CardsJC

Bipul Baibhav MD @bbaibhav

More class III patients in VALOR. Disopyramide use in VALOR . #cardsJC

Milind Desai MD MBA @DesaiMilindY

#CardsJC Valor had 93% patients in NYHA class three, Allowed diso combination therapy, echo measured titration

Dr. Purvi Parwani @purviparwani

VALOR HCM enrolled 49% women! #CardsJC

EXPLORER HCM was at 46%

Great work done by the investigators!

Nosheen Reza, MD @noshreza

Goal was to treat obstruction with CMI — low LVEF means no obstruction. And as @SrihariNaiduMD, low LVEF in HCM (i.e., LVEF =< 50%) is another phenotype that requires specific attention #CardsJC

Srihari S. Naidu, MD @SrihariNaiduMD

#CARDSJC Low EF patients are an entirely different problem. These patients should be evaluated for the etiology of the drop in function. CMI would promote further systolic dysfunction and should not be started or withdrawn.

Ritu Thamman MD @iamritu

In #VALOR HCM those pts whose EF dropped on mavactem recovered completely once the drug was stopped… will need to see if this happens in a late get sample size(56 in trial) and for a longer duration( 16 weeks in trial) #CardsJC

Safety and need clinical lab flows that can check #echofirst EF efficiently – eventually an are where #automation AI calculated values will be implemented #CardsJC @DesaiMilindY

Ravi Patel @RBPatelMD

Mava for HOCM is the ultimate #enrichmenttrial. Must select patients most likely to benefit from drug with least likelihood of harm. Congrats to investigators for acknowledging this in planning and serial echo as part of study protocols. Teachs us a lot about mava #CardsJC

The EMBARK Trial of mava in HFpEF will similarly include only LVEF >60% with LVH – to try to #enrich for the HFpEF phenotype that would benefit most from this drug

Linked: https://clinicaltrials.gov/ct2/show/NCT04766892

Dr. Purvi Parwani @purviparwani

Correct only two patients from each group decided to have septal reduction therapy at the end of the study! Even the secondary endpoints of resting & valsalva LVOT gradient, NYHA class, BNP, Troponin, and QOL met. #CardsJC

Srihari S. Naidu, MD @SrihariNaiduMD

As long as symptoms improve alongside the reduction in eligibility for SRT, which they did, then these are congruent and are a meaningful primary outcome. Avoiding or delaying more aggressive treatment with use of meds first line has always been how we treat #HCM.

Ritu Thamman MD @iamritu

outcomes at 16 week were impressive based on up or down titration of 5mg mavacamten at 8 & 12 weeks based on core lab-measured LVEF, LVOT gradient at rest, & Valsalva. would this happen in the real world? @DesaiMilindY @CardioNerds #CardsJC

Responses:

Nosheen Reza, MD @noshreza

Real world mavacamten/Camzyos initiation and treatment will be serially #EchoFirst-guided — Rx will be restricted through REMS program

Linked: https://news.bms.com/news/corporate-financial/2022/U.S.-Food-and-Drug-Administration-Approves-Camzyos-mavacamten-for-the-Treatment-of-Adults-With-Symptomatic-New-York-Heart-Association-Class-II-III-ObstructiveHypertrophic-Cardiomyopathy-HCM-to-Improve-Functional-Capacity-and-Symptoms/default.aspx?linkId=162893103

Dr. Purvi Parwani @purviparwani

Yup under the trade name CAMZYOS – Mavacamten Prescribers must be certified and patients and pharmacies must be enrolled in the REMS Program.

Restricted use is given concern for systolic dysfunction! #CardsJC @DesaiMilindY @SrihariNaiduMD

Nosheen Reza, MD @noshreza

A testament to the clinical investigators who drove these trials and patient enrollments to targets and completion, while learning (and teaching) how to navigate using a first-in-class drug!

Ritu Thamman MD @iamritu

a validated instrument Kansas City Cardiomyopathy Questionnaire was used in #VALOR & showed improvement in QOL which correlated w objective data: 17.9% pts treated w mavacamten remained “eligible”to receive SRT (defined LVOT gradient ≥ 50 mm Hg & NYHA class III-IV #CardsJC

Ravi Patel @RBPatelMD

The effect size of KCCQ CS improvement in EXPLORER was more than impressive – it was remarkable! The effect size is larger than any HF GDMT drug – it rivals QOL improvement of transcatheter therapies! It is an important finding for patients who are suffering from sx #CardsJC

Nosheen Reza, MD @noshreza

I do often return to this work by @HeitnerStephen re: KCCQ as QoL correlate in #cvHCM — highlights HCM-specific physical/social limitations that are not well-captured by existing health status assessment tools

#CardsJC @CardioNerds

Linked: https://www.ahajournals.org/doi/10.1161/circ.136.suppl_1.16887

Christopher Kramer MD @ChrisKramerMD

Mortality is low enough in HCM (<1% per year) that it is next to impossible to show mortality benefits with such drugs. That’s why QOL is so important here. #CardsJC

Jason Feinman, MD @jjfein

BB followed by CCB and then Disopyramide if still symptomatic are all class 1 recommendations for symptom management in HCM #CardsJC

Dr. Purvi Parwani @purviparwani

The New wonder drug for HCM patients! real-world data awaits but currently this is a major win for our patients! #CardsJC

Srihari S. Naidu, MD @SrihariNaiduMD

(responding to tweet above)

Agreed. We and others are ramping up our CMI clinics to try and prepare for referrals and eager patients. How we handle existing meds and de novo med naive patients is still yet to be determined. #cardsjc @WestchesterMed

Everything is consistently positive – anatomical, biochemical, functional, and clinical benefits – thus quite believable. The questions are already discussed – cost, generalizability, interactions, long term management and sustainability, as well as anything unforeseen. #cardsjc

Ritu Thamman MD @iamritu

Mavacamten is a paradigm shift in drug development designed with a hypothesis-driven path: decreasing ATPase activity of cardiac myosin heavy chain #VALOR #EXPLORER results are impressive although want to see longer follow up results too #CardsJC

Nosheen Reza, MD @noshreza

Real world data coming with the DISCOVER-HCM registry #CardsJC

Link to an older news story:

Linked:https://www.globenewswire.com/news-release/2020/11/11/2124742/37418/en/MyoKardia-Collaborates-with-the-American-College-of-Cardiology-and-PINNACLE-Veradigm-to-Launch-Patient-Registry-of-Hypertrophic-Cardiomyopathy.html

Ravi Patel @RBPatelMD

Double-blind, placebo controlled, rigorous inclusion/exclusion criteria, excellent clinical center enrollment of patients with HOCM, strict imaging protocols, novel action of drug….in combination make results believable to me #CardsJC

Jason Feinman, MD @jjfein

The results seemed to be even better than expected. Based on the initial trial design VALOR-HCM predicted a 70% event rate in the placebo group and a 35% in the intervention, the actual results were 76.8% v. 17.8% #CardsJC

Srihari S. Naidu, MD @SrihariNaiduMD

The ability to avoid costly SRT will factor into this, as well as potentially avoid outpatient and inpatient visits. On flip side the increase in echos and visits upfront detracts somewhat, as well as any hiccups through drug interactions. #cardsjc

Cost may severely limit generalizability where it was most needed – outside of COEs in rural or poor communities who can’t travel and don’t have commercial insurance. Let’s keep pushing so this is mitigated. #cardsjc Lots of implications here for ethnic minorities.

Although the trial avoided primarily myectomy, alcohol ablation of course is cheaper on balance #cardsjc

Ravi Patel @RBPatelMD

Great timing of #CardsJC coinciding with FDA approval of mavacamten for symptomatic HOCM

Muthu Vaduganathan @mvaduganathan

U.S. Food and Drug Administration Approves Camzyos™ (mavacamten) for the Treatment of Adults With Symptomatic New York Heart Association Class II-III Obstructive Hypertrophic Cardiomyopathy (HCM) to Improve Functional Capacity and Symptoms https://news.bms.com/news/details/2022/U.S.-Food-and-Drug-Administration-Approves-Camzyos-mavacamten-for-the-Treatment-of-Adults-With-Symptomatic-New-York-Heart-Association-Class-II-III-ObstructiveHypertrophic-Cardiomyopathy-HCM-to-Improve-Functional-Capacity-and-Symptoms/default.aspx

Dr. Purvi Parwani @purviparwani

HCM is underdiagnosed. Limited centers to offer Rx in obstructive HCM. Mostly undertreated, unfortunately.I do think having a noninvasive Rx will help us with both underdiagnosis and under-Rx. #CardsJC

Srihari S. Naidu, MD @SrihariNaiduMD

Kassem Farhat @kassemfarhatMD

Camzyos (mavacamten) is the first and only cardiac myosin inhibitor approved by the #FDA indicated for the treatment of adults with symptomatic NYHA class II-III #HCM to improve functional capacity and symptoms. #CardioTwitter #MedTwitter #HeartFailure

Christopher Kramer MD @ChrisKramerMD

It would be great to see a trial comparing beta blockers to the myosin inhibitors as initial therapy. I suspect the latter would win out and become 1st line therapy down the road. #CardsJC

The other long term question is whether the reverse remodeling (lower LV mass, wall thickness, and smaller left atrium) seen over 18 weeks in the CMR substudy of Explorer-HCM will last or even be more pronounced with longer use #CardsJC @cardionerds

Nosheen Reza, MD@noshreza

As @RBPatelMD mentioned earlier, EMBARK-HFpEF is currently enrolling – Study of Mavacamten in Participants With HFpEF and Elevation of NT-proBNP With or Without Elevation of cTnT #CardsJC

Linked: https://clinicaltrials.gov/ct2/show/NCT04766892

Gregg Fonarow MD @gcfmd

#CardsJC

Safety is paramount

More trial data with longer f/u needed to understand if any clinical significance

Dr. Purvi Parwani @purviparwani

#Cardiac Myosin Inhibitors with myosin modulation, decrease in the EF was the concern, for initial studies, EF cutoff appropriate. Long-term Data is needed. #CardsJC

Dr. Purvi Parwani @purviparwani

Milind Desai MD MBA @DesaiMilindY

#CardsJC Hot off the press: FDA approves mavacamten just now.

#CardsJC cannot make this up: live Twitter Journal club. I’ve never done anything like this. And the drug is approved as We are live

W. H. Wilson Tang, MD @WilsonTangMD

It is important to celebrate the basic science discoveries in myosin biology that have refined our understanding of disease mechanisms and provided important proof of principles in oHVM pathophysiology #CardsJC

Christopher Kramer MD @ChrisKramerMD

From HCMR, the 6 subtypes of HCM as identified by CMR #CardsJC @CardioNerds

Ritu Thamman MD @iamritu

Did the phenotype matter in #VALOR HCM in terms of the core lab-measured LVEF, LVOT gradient at rest, and Valsalva provocation #Echofirst measurements? #CardsJC

Milind Desai MD MBA @DesaiMilindY

#CardsJC We should focus on patient with HCM, not just the genetic phenotype. Using current available data, only 40% patients are genotype positive.

Christopher Kramer MD @ChrisKramerMD

#CardsJC Remember that in most studies, only 40% or so of HCM patients will have identifiable HCM-associated mutation, so genetic response will only be at best, modestly helpful @CardioNerds

Robert Mentz, MD @robmentz

Great points here – understanding the patient population including background therapy is critical to interpretation and future implementation #CardsJC

Hina Chaudhry, MD @Hinaheartdoc

I wonder how many cardiotwitterati know that #mevacamten is the result of bench science research by one of the original #WIC, an extraordinary physician scientist who I’ve looked up to since I was a resident Dr. Christine Seidman?

SUMMARY:

Dr. Martin Campbell, Internal Medicine Resident, Emory University School of Medicine

Dr. Bhavya Varma, Internal Medicine Resident, Johns Hopkins Hospital

VISUAL ABSTRACT:

Dr. Rawan Amir, Internal Medicine Resident, University of Maryland

JOURNAL CLUB PROMO GRAPHIC:

Shivani Reddy, Medical Student, Western Michigan University Homer Stryker M.D. School of Medicine

TWEET PREPARATION:

Dr. Kate Wilcox, Medicine/Pediatrics Resident, Medical College of Wisconsin

HOUSE TAUSSIG CHIEF FELLOW:

Dr. Ahmed Ghoneem, Internal Medicine Resident, Beth Israel Lahey Health

DIRECTOR of JOURNAL CLUB:

Dr. Devesh Rai, @DeveshRaiMD, Cardiology fellow at Rochester General Hospital

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