Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction The INDIE-HFpEF Randomized Clinical Trial

被引:207
作者
Borlaug, Barry A. [1 ]
Anstrom, Kevin J. [2 ]
Lewis, Gregory D. [3 ]
Shah, Sanjiv J. [4 ]
Levine, James A. [5 ]
Koepp, Gabe A. [5 ]
Givertz, Michael M. [6 ]
Felker, G. Michael [2 ]
LeWinter, Martin M. [7 ]
Mann, Douglas L. [8 ]
Margulies, Kenneth B. [9 ]
Smith, Andrew L. [10 ]
Tang, W. H. Wilson [11 ]
Whellan, David J. [12 ]
Chen, Horng H. [1 ]
Davila-Roman, Victor G. [8 ]
McNulty, Steven [2 ]
Desvigne-Nickens, Patrice [13 ]
Hernandez, Adrian F. [2 ]
Braunwald, Eugene [6 ]
Redfield, Margaret M. [1 ]
机构
[1] Mayo Clin, Rochester, MN USA
[2] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA
[3] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA
[4] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA
[5] Mayo Clin, Scottsdale, AZ USA
[6] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA
[7] Univ Vermont, Med Ctr, Burlington, VT USA
[8] Washington Univ, St Louis, MO USA
[9] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA
[10] Emory Univ, Emory Sch Med, Atlanta, GA 30322 USA
[11] Cleveland Clin, Cleveland, OH 44106 USA
[12] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA
[13] NHLBI, Bldg 10, Bethesda, MD 20892 USA
来源
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION | 2018年 / 320卷 / 17期
关键词
HEMODYNAMICS; NITRATE; COMORBIDITIES;
D O I
10.1001/jama.2018.14852
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
IMPORTANCE There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF. OBJECTIVE To determine the effect of 4 weeks' administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018. INTERVENTIONS Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks. MAIN OUTCOMES AND MEASURES The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks. RESULTS Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, -0.20 [95% CI, -0.56 to 0.16]; P = .27). There were no significant between-treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, -15 [95% CI, -264 to 234]; P = .91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, -1.4 to 3.5]; P = .39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, -0.1 to 0.2]; P = .43), echocardiographic E/e' ratio (16.4 vs 16.6; difference, 0.1 [95% CI, -1.2 to 1.3]; P = .93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, -53 to 75]; P = .74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase. CONCLUSIONS AND RELEVANCE Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity.
引用
收藏
页码:1764 / 1773
页数:10
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