Desai Akshay S, Solomon Scott D, Shah Amil M, Claggett Brian L, Fang James C, Izzo Joseph, McCague Kevin, Abbas Cheryl A, Rocha Ricardo, Mitchell Gary F
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Cardiovascular Medicine, University of Utah, Salt Lake City.
JAMA. 2019 Sep 17;322(11):1077-1084. doi: 10.1001/jama.2019.12843.
Compared with enalapril, sacubitril-valsartan reduces cardiovascular mortality and heart failure hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). These benefits may be related to effects on hemodynamics and cardiac remodeling.
To determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of 40% or less enrolled across 85 US sites between August 17, 2016, and June 28, 2018. Follow-up was completed on January 26, 2019.
Randomization (1:1) to sacubitril-valsartan (n = 231; target dosage, 97/103 mg twice daily) vs enalapril (n = 233; target dosage, 10 mg twice daily) for 12 weeks.
The primary outcome was change from baseline to week 12 in aortic characteristic impedance (Zc), a measure of central aortic stiffness. Prespecified secondary outcomes included change from baseline to week 12 in N-terminal pro-B-type natriuretic peptide, ejection fraction, global longitudinal strain, mitral annular relaxation velocity, mitral E/e' ratio, left ventricular end-systolic and end-diastolic volume indexes (LVESVI and LVEDVI), left atrial volume index, and ventricular-vascular coupling ratio.
Of 464 validly randomized participants (mean age, 67.3 [SD, 9.1] years; 23.5% women), 427 completed the study. At 12 weeks, Zc decreased from 223.8 to 218.9 dyne × s/cm5 in the sacubitril-valsartan group and increased from 213.2 to 214.4 dyne × s/cm5 in the enalapril group (treatment difference, -2.2 [95% CI, -17.6 to 13.2] dyne × s/cm5; P = .78). Of 9 prespecified secondary end points, no significant between-group difference in change from baseline was seen in 4, including left ventricular ejection fraction (34%-36% with sacubitril-valsartan vs 33 to 35% with enalapril; treatment difference, 0.6% [95% CI, -0.4% to 1.7%]; P = .24). However, greater reductions from baseline were seen with sacubitril-valsartan than with enalapril in all others, including left atrial volume (from 30.4 mL/m2 to 28.2 mL/m2 vs from 29.8 mL/m2 to 30.5 mL/m2; treatment difference, -2.8 mL/m2 [95% CI, -4.0 to -1.6 mL/m2]; P < .001), LVEDVI (from 75.1 mL/m2 to 70.3 mL/m2 vs from 79.1 mL/m2 to 75.6 mL/m2; treatment difference, -2.0 mL/m2 [95% CI, -3.7 to 0.3 mL/m2]; P = .02), LVESVI (from 50.8 mL/m2 to 46.3 mL/m2 vs from 54.1 to 50.6 mL/m2; treatment difference, -1.6 mL/m2 [95% CI, -3.1 to -0.03 mL/m2]; P = .045), and mitral E/e' ratio (from 13.8 to 12.3 vs from 13.4 to 13.8; treatment difference, -1.8 [95% CI, -2.8 to -0.8]; P = .001). Rates of adverse events including hypotension (1.7% vs 3.9%) were similar in both groups.
Treatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness. The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in HFrEF.
ClinicalTrials.gov Identifier: NCT02874794.
与依那普利相比，沙库巴曲缬沙坦可降低射血分数降低的心力衰竭（HFrEF）患者的心血管死亡率和心力衰竭住院率。这些益处可能与对血流动力学和心脏重塑的影响有关。
确定与依那普利相比，沙库巴曲缬沙坦治疗HFrEF是否能改善中心主动脉僵硬度和心脏重塑。
设计、设置和参与者：2016年8月17日至2018年6月28日期间，在美国85个地点对464名射血分数为40%或更低的心力衰竭参与者进行的随机、双盲临床试验。随访于2019年1月26日完成。
随机（1:1）分为沙库巴曲缬沙坦组（n = 231；目标剂量，97/103 mg，每日两次）和依那普利组（n = 233；目标剂量，10 mg，每日两次），为期12周。
主要结局是从基线到第12周主动脉特征阻抗（Zc）的变化，这是中心主动脉僵硬度的一种测量指标。预先设定的次要结局包括从基线到第12周N末端B型利钠肽、射血分数、整体纵向应变、二尖瓣环松弛速度、二尖瓣E/e'比值、左心室收缩末期和舒张末期容积指数（LVESVI和LVEDVI）、左心房容积指数以及心室-血管耦合比的变化。
在464名有效随机分组的参与者中（平均年龄，67.3 [标准差，9.1]岁；23.5%为女性），427名完成了研究。在第12周时，沙库巴曲缬沙坦组的Zc从223.8降至218.9达因×秒/厘米⁵，依那普利组从213.2升至214.4达因×秒/厘米⁵（治疗差异，-2.2 [95%置信区间，-17.6至13.2]达因×秒/厘米⁵；P = 0.78）。在9个预先设定的次要终点中，4个终点从基线的变化在组间无显著差异，包括左心室射血分数（沙库巴曲缬沙坦组为34% - 36%，依那普利组为33%至35%；治疗差异，0.6% [95%置信区间，-0.4%至1.7%]；P = 0.24）。然而，在所有其他指标中，沙库巴曲缬沙坦组相对于依那普利组从基线的降低幅度更大，包括左心房容积（从30.4 mL/m²降至28.2 mL/m²，而依那普利组从29.8 mL/m²升至30.5 mL/m²；治疗差异，-2.8 mL/m² [95%置信区间，-4.0至-1.6 mL/m²]；P < 0.001）、LVEDVI（从75.1 mL/m²降至70.3 mL/m²，而依那普利组从79.1 mL/m²降至75.6 mL/m²；治疗差异，-2.0 mL/m² [95%置信区间，-3.7至0.3 mL/m²]；P = 0.02）、LVESVI（从50.8 mL/m²降至46.3 mL/m²，而依那普利组从54.1降至50.6 mL/m²；治疗差异，-1.6 mL/m² [95%置信区间，-3.1至-0.03 mL/m²]；P = 0.045）以及二尖瓣E/e'比值（从13.8降至12.3，而依那普利组从13.4升至13.8；治疗差异，-1.8 [95%置信区间，-2.8至-0.8]；P = 0.001）。两组包括低血压（1.7%对3.9%）在内的不良事件发生率相似。
与依那普利相比，沙库巴曲缬沙坦治疗HFrEF并未显著降低中心主动脉僵硬度。该研究结果可能有助于深入了解沙库巴曲缬沙坦在HFrEF中作用的潜在机制。
ClinicalTrials.gov标识符：NCT02874794。
