西地那非治疗射血分数保留的心衰无效

《美国医学会杂志》3月11日在线发表的一项24周随机试验结果显示，西地那非在改善射血分数保留的心衰患者(HFPEF)的运动能力或临床状态方面并不优于安慰剂(JAMA 2013 Mar. 11 [doi:10.1001/jama.2013.2024])。该结果同时在美国心脏病学会(ACC)2013年会上进行了报告。

梅奥医院内科学教授Margaret Redfield博士及其同事报告称，此前进行的一项单中心研究显示，磷酸二酯酶抑制剂西地那非(伟哥)可使HFPEF患者获益。但在本次随机试验中，西地那非对最大或非最大运动能力、临床状态、生活质量、左室重构、舒张功能参数或肺动脉收缩压均未见明显作用。此外，西地那非治疗似乎还与不良结局相关，表现为肾功能进一步恶化，脑钠肽前体N末端(NT-proBNP)、内皮素-1和尿酸水平提高。虽不显著，但西地那非组更多患者退出治疗、死亡或病情过重而不能接受心肺运动测试。

在这项多中心随机试验中， 113例HFPEF患者接受西地那非治疗，前12周剂量为20 mg，后12周剂量为60 mg，均为 3次/日；另外103例患者被分配至安慰剂组。受试者中位年龄69岁，48%为女性，同时还接受糖尿病、房颤、肾病和其他共病的治疗。基线时射血分数稳定，≥50%，但运动能力、中位峰值耗氧量和6分钟步行测试距离均有所下降。左房容积和其他指标与长期左室充盈压升高相一致。

结果显示，24周时，两组患者峰值耗氧量中位变化值(P=0.90)、中位临床状态评分(反映生活质量改善和死亡或住院时间的综合评分，P=0.85)以及6分钟步行试验距离变化值(安慰剂组15.0米，西地那非组5.0米，P=0.92)均无显著差异。

西地那非组血管不良事件发生率较高，包括头痛、脸红和低血压。西地那非组患者动脉弹性和全身血管阻力下降程度更大，但两组平均动脉压未见显著差异。安慰剂组和西地那非组发生心脏、呼吸或其他严重不良事件分别为16例(16%)和25例(22%)。西地那非组死亡3例，安慰剂组无死亡病例。

研究者指出，西地那非组患者中等程度但具有统计学意义的肾功能恶化在既往肺动脉高血压和勃起功能障碍研究中未见报告。

此前的单中心研究显示，与安慰剂相比，接受西地那非治疗的HFPEF患者在左室舒张功能、右室收缩功能和左室肥大方面有所获益，没有检测对运动能力的影响(Circulation. 2011;124:164-74)。但研究者指出，这些HFPEF患者共病较少，且血压、左室质量和肺动脉收缩压明显更高，加之导管插入术后肺动脉高血压、有意义的右室收缩功能不全和右心功能不全，这并非HFPEF患者的典型特征。

研究者认为，PDE-5抑制剂对心衰患者的主要治疗作用可能是通过扩大肺动脉床、增加右室收缩力以及减少心室相互依赖性。因此，若要观察到HFPEF患者的临床受益，患者肺动脉高血压和右室衰竭必需非常严重。虽然本次研究的受试者多见左室肥厚常，但其严重程度远远低于此前研究受试者。可以想象，左心室或其他器官PDE-5或环磷酸鸟苷敏感的下游通路的活化可能仅出现在与晚期左室重构相关的心衰患者中。

该研究由美国国立卫生研究院(NIH)资助，西地那非和安慰剂由辉瑞提供，研究者报告与安进、百时美施贵宝、礼来、葛兰素史克、默克、诺华、辉瑞以及罗氏等多家公司存在利益关系。

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By: M. Alex Otto, Cardiology News Digital Network

Sildenafil was no better than placebo for improving exercise capacity or clinical status in patients with heart failure and preserved ejection fraction, based on the results of a 24-week randomized trial published online in JAMA Mar. 11 and presented simultaneously at the annual meeting of the American College of Cardiology.

Sildenafil (Viagra), a phosphodiesterase-5 inhibitor, was shown beneficial in a previous single-center study of patients with heart failure and preserved ejection fraction (HFPEF). In the randomized trial, however, sildenafil had no significant effect "on maximal or submaximal exercise capacity, clinical status, quality of life, left ventricular remodeling, diastolic function parameters, or pulmonary artery systolic pressure," wrote lead investigator Dr. Margaret Redfield, professor of medicine at the Mayo Clinic in Rochester, Minn., and her colleagues (JAMA 2013 Mar. 11 [doi:10.1001/jama.2013.2024]).

Further, sildenafil appeared to be associated with poorer outcomes as "renal function worsened more and NT-proBNP [N-terminal fragment of the precursor to brain-type natriuretic peptide], endothelin-1, and uric acid levels increased more in patients treated with sildenafil," the researchers wrote. There was a trend, though not significant, for more patients in the sildenafil group to withdraw consent, die, or be too ill to perform the cardiopulmonary exercise test. 

The researchers randomized 113 HFPEF patients to 20 mg of sildenafil 3 times daily for 12 weeks, followed by 60 mg 3 times daily for 12 weeks; 103 others were randomized to placebo in the multicenter trial.

At week 24, there were no statistically significant differences between the placebo and sildenafil groups in median changes in peak oxygen consumption (P = 0.90); median clinical status rank score—a composite of quality of life changes and times to death or hospitalization (P = 0.85); or changes in 6-minute walk distance (placebo 15.0 m, sildenafil 5.0 m, P = 0.92).

The median age in the trial was 69 years, 48% of the patients were women, and patients were under treatment for diabetes, atrial fibrillation, kidney disease, and other comorbidities. They were stable at baseline with ejection fractions equal to or greater than 50%, but had reduced exercise capacity, median peak oxygen consumption, and 6-minute walk distances. Their left atrial volumes and other measurements were consistent with chronically elevated left ventricular filling pressures.

A higher incidence of vascular adverse events was seen in the sildenafil group and included headache, flushing, and hypotension. Arterial elasticity and systemic vascular resistance tended to decrease more in sildenafil patients, but there were no significant changes in mean arterial pressure between the two groups.

Cardiac, respiratory, or other serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Three people died in the sildenafil arm, but none in the placebo arm.

The "modest but statistically significant worsening of renal function" in sildenafil patients has not been reported before in studies of pulmonary arterial hypertension and erectile dysfunction, the investigators noted.

A previous single-center study found a benefit for sildenafil over placebo in HFPEF for left ventricular diastolic function, right ventricular systolic function, and left ventricular hypertrophy; the effect on exercise capacity was not tested (Circulation. 2011;124:164-74).

"In that study, patients with HFPEF had fewer comorbidities and significantly higher blood pressure, left ventricular mass, and pulmonary artery systolic pressure…[plus] catheterization-documented pulmonary arterial hypertension, profound right ventricular systolic dysfunction, and right ventricular failure. [The] profile [was] somewhat atypical for HFPEF cohorts," the investigators wrote.

"It may be that the primary therapeutic effects of PDE-5 inhibitors in heart failure involve the drugs’ ability to dilate the pulmonary vascular bed, enhance right ventricular contractility, and reduce ventricular  interdependence, and that pulmonary arterial hypertension and right ventricular failure must be significant in order to observe clinical benefit in HFPEF," they wrote.

"Although left ventricular hypertrophy was common in participants in this study, it was far less severe than among participants in the [previous] study. ... Conceivably, activation of PDE-5 or of cyclic guanosine monophosphate–sensitive downstream pathways in the left ventricle or other organs may occur only in heart failure associated with advanced left ventricular remodeling," they wrote.

The study was funded by the National Institutes of Health. Pfizer donated the sildenafil and matched placebo. The investigators reported commercial relationships with many companies, including Amgen, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Pfizer, and Roche.