Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.
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DOI：
10.1001/jama.2013.2024
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发表时间：
2013-03-27
影响因子：
120.7
通讯作者：
Braunwald, Eugene
中科院分区：
文献类型：
--
作者：
Redfield, Margaret M.;Chen, Horng H.;Borlaug, Barry A.;Semigran, Marc J.;Lee, Kerry L.;Lewis, Gregory;LeWinter, Martin M.;Rouleau, Jean L.;Bull, David A.;Mann, Douglas L.;Deswal, Anita;Stevenson, Lynne W.;Givertz, Michael M.;Ofili, Elizabeth O.;O'Connor, Christopher M.;Felker, G. Michael;Goldsmith, Steven R.;Bart, Bradley A.;McNulty, Steven E.;Ibarra, Jenny C.;Lin, Grace;Oh, Jae K.;Patel, Manesh R.;Kim, Raymond J.;Tracy, Russell P.;Velazquez, Eric J.;Anstrom, Kevin J.;Hernandez, Adrian F.;Mascette, Alice M.;Braunwald, Eugene
对实验性和人类心力衰竭的研究表明，磷酸二酯酶-5抑制剂可以增强心血管功能，从而在射血分数保持不变的情况下增强心力衰竭的运动能力。目的：比较磷酸二酯酶-5型抑制剂西地那非与安慰剂对射血分数保持不变的心力衰竭患者运动能力和临床状态的影响。对216名心力衰竭、射血分数≥50%、N端脑利钠肽原升高或侵入性充盈压升高和运动能力降低的稳定门诊患者进行的多中心、双盲、安慰剂对照、随机临床试验。参与者从2008年10月到2012年2月在美国和加拿大的26个中心随机进行。西地那非(n=113)或安慰剂(n=103)口服，每日3次，每次20毫克，持续12周，随后每日口服60毫克，每日3次，持续12周。主要终点是治疗24周后最大耗氧量的变化。次要终点包括6分钟步行距离的变化和三级分级综合临床状态评分，其中患者根据死亡时间、心血管或心脏肾脏住院时间以及24周后未接受心血管或心脏肾脏住院的参与者的生活质量变化进行排名(范围1-N)。中位年龄69岁，48%的患者为女性。基线时，中位峰值氧耗量(11.7ml/kg/min)和6min步行距离(308m)降低，E/e‘中位数(16)、左房容量指数(44ml/m2)和肺动脉收缩压(41 Mm Hg)与慢性升高的左心室充盈压一致。在24周时，接受安慰剂[−0.20(−0.70，1.00)]或西地那非[−0.20(−1.20，1.10)；p=0.90]的患者的峰值氧耗(ml/kg/min)的中位数(四分位数范围)变化没有显著差异。在接受安慰剂(95.8)或西地那非(94.2)的患者中，24周时的平均临床状态等级评分(值越高表明状态更好；没有治疗效果的期望值=95)没有显著差异(p=0.85)。接受安慰剂[15.0(−26.0，45.0)]或西地那非[5.0(−37.0，55.0)；p=0.92]的患者在24周后6分钟步行距离(米)的变化也没有显著差异。接受安慰剂治疗的患者中有78人(76%)和接受西地那非治疗的患者中有90人(80%)发生了不良事件。接受安慰剂治疗的患者中有16人(16%)和接受西地那非治疗的患者中有25人(22%)发生了严重的不良反应。与安慰剂相比，服用西地那非24周的慢性磷酸二酯酶-5抑制剂治疗不会改变心力衰竭和射血分数保留的患者的运动能力或临床状态。ClinicalTrials.gov编号，NCT00763867
Studies in experimental and human heart failure suggest that phosphodiesterase type-5 inhibitors may enhance cardiovascular function, and thus, exercise capacity in heart failure with preserved ejection fraction. To determine the effect of the phosphodiesterase type-5 inhibitor, sildenafil, in comparison to placebo on exercise capacity and clinical status in heart failure with preserved ejection fraction. Multicenter, double-blind, placebo-controlled, parallel design, randomized clinical trial of 216 stable outpatients with heart failure, ejection fraction ≥ 50%, elevated N-terminal pro-brain natriuretic peptide or elevated invasively-measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in the United States and Canada. Sildenafil (n=113) or placebo (n=103) administered orally at 20 mg three times daily for 12 weeks followed by 60 mg three times daily for 12 weeks. Primary endpoint was change in peak oxygen consumption after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance and a three tier hierarchical composite clinical status score where patients were ranked (range 1-N) based on time to death, time to cardiovascular or cardiorenal hospitalization and change in quality of life for participants alive without cardiovascular or cardiorenal hospitalization at 24 weeks. Median age was 69 years and 48% of patients were female. At baseline, median peak oxygen consumption (11.7 ml/kg/min) and six-minute walk distance (308 meters) were reduced and median E/e′ (16), left atrial volume index (44 ml/m2) and pulmonary artery systolic pressure (41 mmHg) were consistent with chronically-elevated left ventricular filling pressures. At 24 weeks, median (interquartile range) changes in peak oxygen consumption (ml/kg/min) in patients who received placebo [−0.20 (−0.70, 1.00)] or sildenafil [−0.20 (−1.20, 1.10); p=0.90] were not significantly different. The mean clinical status rank score (higher value indicates better status; expected value with no treatment effect = 95) was not significantly different (p=0.85) at 24 weeks in patients who received placebo (95.8) or sildenafil (94.2). Changes in six-minute walk distance (meters) at 24 weeks in patients who received placebo [15.0 (−26.0, 45.0)] or sildenafil [5.0 (−37.0, 55.0); p=0.92] were also not significantly different. Adverse events occurred in 78 (76%) of patients who received placebo and 90 (80%) of patients who received sildenafil. Serious adverse events occurred in 16 (16%) of patients who received placebo and 25 (22%) of patients who received sildenafil. Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction. clinicaltrials.gov number, NCT00763867
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