PMID- 32871100
OWN - NLM
STAT- MEDLINE
DCOM- 20201006
LR  - 20230623
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 396
IP  - 10253
DP  - 2020 Sep 12
TI  - Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy 
      (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.
PG  - 759-769
LID - S0140-6736(20)31792-X [pii]
LID - 10.1016/S0140-6736(20)31792-X [doi]
AB  - BACKGROUND: 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. We aimed to assess the efficacy and safety of 
      mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive 
      hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, 
      placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 
      13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 
      50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms 
      were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 
      weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial 
      evaluations included echocardiogram, electrocardiogram, and blood collection for 
      laboratory tests and mavacamten plasma concentration. The primary endpoint was a 
      1.5 mL/kg per min or greater increase in peak oxygen consumption (pVO(2)) and at 
      least one NYHA class reduction or a 3.0 mL/kg per min or greater pVO(2) increase 
      without NYHA class worsening. Secondary endpoints assessed changes in 
      post-exercise LVOT gradient, pVO(2), NYHA class, Kansas City Cardiomyopathy 
      Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy 
      Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is 
      registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, 
      and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) 
      were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 
      [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo 
      met the primary endpoint (difference +19.4%, 95% CI 8.7 to 30.1; p=0.0005). 
      Patients on mavacamten had greater reductions than those on placebo in 
      post-exercise LVOT gradient (-36 mm Hg, 95% CI -43.2 to -28.1; p<0.0001), greater 
      increase in pVO(2) (+1.4 mL/kg per min, 0.6 to 2.1; p=0.0006), and improved 
      symptom scores (KCCQ-CSS +9.1, 5.5 to 12.7; HCMSQ-SoB -1.8, -2.4 to -1.2; 
      p<0.0001). 34% more patients in the mavacamten group improved by at least one 
      NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in 
      the placebo group; 95% CI 22.2 to 45.4; p<0.0001). Safety and tolerability were 
      similar to placebo. Treatment-emergent adverse events were generally mild. One 
      patient died by sudden death in the placebo group. INTERPRETATION: 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. FUNDING: MyoKardia.
CI  - Copyright (c) 2020 Elsevier Ltd. All rights reserved.
FAU - Olivotto, Iacopo
AU  - Olivotto I
AD  - Cardiomyopathy Unit, Azienda Ospedaliera Universitaria Careggi, Florence, Italy; 
      University of Florence, Florence, Italy. Electronic address: 
      iacopo.olivotto@unifi.it.
FAU - Oreziak, Artur
AU  - Oreziak A
AD  - 1st Department of Arrhythmia, National Institute of Cardiology, Warsaw, Poland.
FAU - Barriales-Villa, Roberto
AU  - Barriales-Villa R
AD  - Unidad de Cardiopatias Familiares, Instituto de Investigacion Biomedica de A 
      Coruna, A Coruna, Spain; Complexo Hospitalario Universitario de A Coruna, A 
      Coruna, Spain; Servizo Galego de Saude, A Coruna, Spain; Universidade da Coruna, 
      A Coruna, Spain; Centro de Investigacion Biomedica en Red, Madrid, Spain.
FAU - Abraham, Theodore P
AU  - Abraham TP
AD  - Division of Cardiology, University of California San Francisco, San Francisco, 
      CA, USA.
FAU - Masri, Ahmad
AU  - Masri A
AD  - Knight Cardiovascular Institute, Oregon Health & Science University, Portland, 
      OR, USA.
FAU - Garcia-Pavia, Pablo
AU  - Garcia-Pavia P
AD  - Centro de Investigacion Biomedica en Red, Madrid, Spain; Department of 
      Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Universidad 
      Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain.
FAU - Saberi, Sara
AU  - Saberi S
AD  - Department of Internal Medicine, Division of Cardiovascular Medicine, University 
      of Michigan, Ann Arbor, MI, USA.
FAU - Lakdawala, Neal K
AU  - Lakdawala NK
AD  - Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, 
      USA.
FAU - Wheeler, Matthew T
AU  - Wheeler MT
AD  - Department of Medicine, Division of Cardiovascular Medicine, Stanford University 
      School of Medicine, Stanford, CA, USA.
FAU - Owens, Anjali
AU  - Owens A
AD  - University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
FAU - Kubanek, Milos
AU  - Kubanek M
AD  - Department of Cardiology, Institute for Clinical and Experimental Medicine, 
      Prague, Czech Republic.
FAU - Wojakowski, Wojciech
AU  - Wojakowski W
AD  - Division of Cardiology and Structural Heart Diseases, Medical University of 
      Silesia, Katowice, Poland.
FAU - Jensen, Morten K
AU  - Jensen MK
AD  - Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
FAU - Gimeno-Blanes, Juan
AU  - Gimeno-Blanes J
AD  - Inherited Cardiac Disease Unit, University Hospital Virgen de la Arrixaca, 
      Murcia, Spain.
FAU - Afshar, Kia
AU  - Afshar K
AD  - Intermountain Medical Center Heart Institute, Intermountain Medical Center, 
      Murray, UT, USA.
FAU - Myers, Jonathan
AU  - Myers J
AD  - Division of Cardiology, Veterans Affairs Palo Alto Healthcare System, Palo Alto, 
      CA, USA; Stanford University, Palo Alto, CA, USA.
FAU - Hegde, Sheila M
AU  - Hegde SM
AD  - Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, 
      USA.
FAU - Solomon, Scott D
AU  - Solomon SD
AD  - Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, 
      USA.
FAU - Sehnert, Amy J
AU  - Sehnert AJ
AD  - MyoKardia, Brisbane, CA, USA.
FAU - Zhang, David
AU  - Zhang D
AD  - MyoKardia, Brisbane, CA, USA.
FAU - Li, Wanying
AU  - Li W
AD  - MyoKardia, Brisbane, CA, USA.
FAU - Bhattacharya, Mondira
AU  - Bhattacharya M
AD  - MyoKardia, Brisbane, CA, USA.
FAU - Edelberg, Jay M
AU  - Edelberg JM
AD  - MyoKardia, Brisbane, CA, USA.
FAU - Waldman, Cynthia Burstein
AU  - Waldman CB
AD  - HCMBeat, Los Angeles, CA, USA.
FAU - Lester, Steven J
AU  - Lester SJ
AD  - Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ, USA.
FAU - Wang, Andrew
AU  - Wang A
AD  - Duke University School of Medicine, Durham, NC, USA.
FAU - Ho, Carolyn Y
AU  - Ho CY
AD  - Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, 
      USA.
FAU - Jacoby, Daniel
AU  - Jacoby D
AD  - Department of Internal Medicine, Section of Cardiovascular Medicine, Yale 
      University, New Haven, CT, USA.
CN  - EXPLORER-HCM study investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT03470545
GR  - IK6 RX002477/RX/RRD VA/United States
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20200829
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Adrenergic beta-Antagonists)
RN  - 0 (Benzylamines)
RN  - 0 (Calcium Channel Blockers)
RN  - 0 (Cardiovascular Agents)
RN  - 0 (MYK-461)
RN  - 56HH86ZVCT (Uracil)
RN  - EC 3.6.1.- (Cardiac Myosins)
SB  - IM
CIN - Lancet. 2020 Sep 12;396(10253):736-737. PMID: 32871101
EIN - Lancet. 2020 Sep 12;396(10253):758. PMID: 32919516
CIN - Nat Rev Cardiol. 2020 Nov;17(11):677. PMID: 32934371
CIN - Eur Heart J. 2020 Nov 7;41(42):4089-4090. PMID: 33099599
CIN - Lancet. 2021 Jan 30;397(10272):369. PMID: 33516331
CIN - Innovations (Phila). 2023 Jan-Feb;18(1):11-15. PMID: 36397296
MH  - Adrenergic beta-Antagonists/therapeutic use
MH  - Aged
MH  - Benzylamines/adverse effects/*therapeutic use
MH  - Calcium Channel Blockers/therapeutic use
MH  - Cardiac Myosins/*antagonists & inhibitors
MH  - Cardiomyopathy, Hypertrophic/*drug therapy/physiopathology
MH  - Cardiovascular Agents/therapeutic use
MH  - Double-Blind Method
MH  - Exercise Tolerance/physiology
MH  - Female
MH  - Hemodynamics/physiology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Oxygen Consumption/physiology
MH  - Patient Outcome Assessment
MH  - Uracil/adverse effects/*analogs & derivatives/therapeutic use
FIR - Bartunek, Jozef
IR  - Bartunek J
FIR - Bondue, Antoine
IR  - Bondue A
FIR - Van Craenenbroeck, Emeline
IR  - Van Craenenbroeck E
FIR - Kubanek, Milos
IR  - Kubanek M
FIR - Zemanek, David
IR  - Zemanek D
FIR - Jensen, Morten
IR  - Jensen M
FIR - Mogensen, Jens
IR  - Mogensen J
FIR - Thune, Jens Jakob
IR  - Thune JJ
FIR - Charron, Philippe
IR  - Charron P
FIR - Hagege, Albert
IR  - Hagege A
FIR - Lairez, Olivier
IR  - Lairez O
FIR - Trochu, Jean-Noel
IR  - Trochu JN
FIR - Axthelm, Christoph
IR  - Axthelm C
FIR - Duengen, Hans-Dirk
IR  - Duengen HD
FIR - Frey, Norbert
IR  - Frey N
FIR - Mitrovic, Veselin
IR  - Mitrovic V
FIR - Preusch, Michael
IR  - Preusch M
FIR - Schulz-Menger, Jeanette
IR  - Schulz-Menger J
FIR - Seidler, Tim
IR  - Seidler T
FIR - Arad, Michael
IR  - Arad M
FIR - Halabi, Majdi
IR  - Halabi M
FIR - Katz, Amos
IR  - Katz A
FIR - Monakier, Daniel
IR  - Monakier D
FIR - Paz, Offir
IR  - Paz O
FIR - Viskin, Samuel
IR  - Viskin S
FIR - Zwas, Donna
IR  - Zwas D
FIR - Olivotto, Iacopo
IR  - Olivotto I
FIR - Brunner-La Rocca, Hans Peter
IR  - Brunner-La Rocca HP
FIR - Michels, Michelle
IR  - Michels M
FIR - Dudek, Dariusz
IR  - Dudek D
FIR - Oko-Sarnowska, Zofia
IR  - Oko-Sarnowska Z
FIR - Oreziak, Artur
IR  - Oreziak A
FIR - Wojakowski, Wojciech
IR  - Wojakowski W
FIR - Cardim, Nuno
IR  - Cardim N
FIR - Pereira, Helder
IR  - Pereira H
FIR - Barriales-Villa, Roberto
IR  - Barriales-Villa R
FIR - Garcia Pavia, Pablo
IR  - Garcia Pavia P
FIR - Gimeno Blanes, Juan
IR  - Gimeno Blanes J
FIR - Hidalgo Urbano, Rafael
IR  - Hidalgo Urbano R
FIR - Rincon Diaz, Luis Miguel
IR  - Rincon Diaz LM
FIR - Elliott, Perry
IR  - Elliott P
FIR - Yousef, Zaheer
IR  - Yousef Z
FIR - Abraham, Theodore
IR  - Abraham T
FIR - Afshar, Kia
IR  - Afshar K
FIR - Alvarez, Paulino
IR  - Alvarez P
FIR - Bach, Richard
IR  - Bach R
FIR - Becker, Richard
IR  - Becker R
FIR - Choudhury, Lubna
IR  - Choudhury L
FIR - Fermin, David
IR  - Fermin D
FIR - Jacoby, Daniel
IR  - Jacoby D
FIR - Jefferies, John
IR  - Jefferies J
FIR - Kramer, Christopher
IR  - Kramer C
FIR - Lakdawala, Neal
IR  - Lakdawala N
FIR - Lester, Steven
IR  - Lester S
FIR - Marian, Ali
IR  - Marian A
FIR - Masri, Ahmad
IR  - Masri A
FIR - Maurer, Mathew
IR  - Maurer M
FIR - Nagueh, Sherif
IR  - Nagueh S
FIR - Owens, Anjali
IR  - Owens A
FIR - Owens, David
IR  - Owens D
FIR - Rader, Florian
IR  - Rader F
FIR - Saberi, Sara
IR  - Saberi S
FIR - Sherrid, Mark
IR  - Sherrid M
FIR - Shirani, Jamshid
IR  - Shirani J
FIR - Symanski, John
IR  - Symanski J
FIR - Turer, Aslan
IR  - Turer A
FIR - Wang, Andrew
IR  - Wang A
FIR - Wever-Pinzon, Omar
IR  - Wever-Pinzon O
FIR - Wheeler, Matthew
IR  - Wheeler M
FIR - Wong, Timothy
IR  - Wong T
FIR - Yamani, Mohamad
IR  - Yamani M
EDAT- 2020/09/02 06:00
MHDA- 2020/10/07 06:00
CRDT- 2020/09/02 06:00
PHST- 2020/07/22 00:00 [received]
PHST- 2020/08/02 00:00 [revised]
PHST- 2020/08/04 00:00 [accepted]
PHST- 2020/09/02 06:00 [pubmed]
PHST- 2020/10/07 06:00 [medline]
PHST- 2020/09/02 06:00 [entrez]
AID - S0140-6736(20)31792-X [pii]
AID - 10.1016/S0140-6736(20)31792-X [doi]
PST - ppublish
SO  - Lancet. 2020 Sep 12;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X. Epub 
      2020 Aug 29.