Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial

被引：101

作者：

Ho, Carolyn Y. ^{[1
]}

Day, Sharlene M. ^{[2
,23
]}

Axelsson, Anna ^{[3
]}

Russell, Mark W. ^{[2
]}

Zahka, Kenneth ^{[4
]}

Lever, Harry M. ^{[4
]}

Pereira, Alexandre C. ^{[5
]}

Colan, Steven D. ^{[6
]}

Margossian, Renee ^{[6
]}

Murphy, Anne M. ^{[7
]}

Canter, Charles ^{[8
]}

Bach, Richard G. ^{[8
]}

Wheeler, Matthew T. ^{[9
]}

Rossano, Joseph W. ^{[10
]}

Owens, Anjali T. ^{[23
]}

Bundgaard, Henning ^{[3
,11
]}

Benson, Lee ^{[12
]}

Mestroni, Luisa ^{[13
]}

Taylor, Matthew R. G. ^{[13
]}

Patel, Amit R. ^{[14
,15
]}

Wilmot, Ivan ^{[16
]}

Thrush, Philip ^{[17
]}

Vargas, Jose D. ^{[18
]}

Soslow, Jonathan H. ^{[19
]}

Becker, Jason R. ^{[19
,24
,25
]}

Seidman, Christine E. ^{[1
,20
]}

Lakdawala, Neal K. ^{[1
]}

Cirino, Allison L. ^{[1
]}

Burns, Kristin M. ^{[21
]}

McMurray, John J. V. ^{[22
]}

MacRae, Calum A. ^{[1
]}

Solomon, Scott D. ^{[1
]}

Orav, E. John ^{[1
]}

Braunwald, Eugene ^{[1
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[2] Univ Michigan, Ann Arbor, MI 48109 USA

[3] Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Copenhagen, Denmark

[4] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA

[5] Univ Sao Paulo, Med Sch, Lab Genet & Mol Cardiol, Heart Inst, Sao Paulo, Brazil

[6] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA

[7] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA

[8] Washington Univ, Sch Med, St Louis, MO USA

[9] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA USA

[10] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[11] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark

[12] Toronto Hosp Sick Children, Toronto, ON, Canada

[13] Univ Colorado, Anschutz Med Campus, Aurora, CO USA

[14] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

[15] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA

[16] Cincinnati Childrens Hosp Med Ctr, Heart Inst, Cincinnati, OH 45229 USA

[17] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA

[18] MedStar Heart & Vasc Inst, Washington, DC USA

[19] Vanderbilt Univ, Med Ctr, Nashville, TN USA

[20] Howard Hughes Med Inst, Chevy Chase, MD USA

[21] NIH, NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA

[22] Univ Glasgow, British Heart Fdn, Cardiovasc Res Ctr, Glasgow, Lanark, Scotland

[23] Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA

[24] Univ Pittsburgh, Sch Med, Div Cardiol, Pittsburgh, PA USA

[25] UPMC, Pittsburgh, PA USA

来源：

NATURE MEDICINE | 2021年 / 27卷 / 10期

关键词：

MUTATION CARRIERS; LOSARTAN; DISEASE; EVOLUTION; FIBROSIS; EFFICACY; BURDEN;

D O I：

10.1038/s41591-021-01505-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In a randomized phase 2 clinical trial, the angiotensin receptor blocker valsartan improved cardiac structure and function in patients with early-stage hypertrophic cardiomyopathy, a condition for which there are no effective therapies for modifying disease progression. Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years (). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

引用

页码：1818 / +

页数：14

共 23 条

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