Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
Kidney360. 2023 May 1;4(5):631-640. doi: 10.34067/KID.0000000000000103. Epub 2023 Mar 29.
Sildenafil induced an acute effect on eGFR without change in the overall eGFR slope after 24 weeks in a heart failure with preserved ejection fraction (HFpEF) cohort. -terminal pro–brain natriuretic peptide levels and baseline diuretic use were most strongly associated with eGFR decline in this HFpEF cohort. Long-term studies are required to determine sildenafil's influence on kidney function and outcomes in HFpEF.
CKD worsens the prognosis for people with heart failure with preserved ejection fraction (HFpEF). In the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic HFpEF (RELAX) trial, sildenafil decreased eGFR compared with placebo despite favorable kidney effects in preclinical models. Since acute eGFR decline precedes long-term kidney benefits for select medications, we assessed the influence of sildenafil on acute and chronic eGFR slopes.
The RELAX trial randomized 216 participants to placebo or sildenafil and assessed 24-week changes in cardiopulmonary exercise testing, cardiovascular imaging, and laboratory data. We applied linear mixed modeling to calculate the total, acute (0–12 weeks), and chronic (3–24 weeks) eGFR slopes by treatment. Using regression modeling, we assessed respective associations between eGFR slope and baseline data and clinical end points. We repeated the analyses using a binary outcome on the basis of a substantial (≥20%) decline in eGFR.
The mean baseline eGFR was 60.8 ml/min per 1.73 m, and the mean eGFR slope during follow-up was −3.21 ml/min per 1.73 m per year. Sildenafil did not alter total eGFR slope compared with placebo (difference +0.47 ml/min per 1.73 m per year, 95% confidence interval [CI], −6.63 to 7.57 ml/min per 1.73 m per year). Sildenafil users tended to experience a more negative acute eGFR slope (difference −3.15 ml/min per 1.73 m per year) and more positive chronic slope (+2.06 ml/min per 1.73 m per year) compared with placebo, but neither difference reached statistical significance. Baseline -terminal pro–B-type natriuretic peptide and loop diuretic use were associated with worse eGFR trajectory regardless of treatment. Substantial eGFR decline was associated with increase in endothelin-1 and a greater risk of hospitalization or death (HR, 2.34, 95% CI, 1.21 to 4.53, =0.01).
Sildenafil induced an acute effect on eGFR without change in the overall eGFR slope after 24 weeks in an HFpEF cohort, suggesting lack of long-term risk related to early reduction in eGFR after initiating treatment. Long-term studies are needed to determine the effect of sildenafil on kidney function in HFpEF.
在射血分数保留的心力衰竭（HFpEF）队列中，西地那非在 24 周后没有改变整体 eGFR 斜率，对 eGFR 产生急性影响。终末期 pro–脑利钠肽水平和基线利尿剂的使用与该 HFpEF 队列中 eGFR 的下降最密切相关。需要进行长期研究来确定西地那非对 HFpEF 患者肾功能和结局的影响。
慢性肾脏病（CKD）会使射血分数保留的心力衰竭（HFpEF）患者的预后恶化。在磷酸二酯酶-5 抑制以改善舒张性心力衰竭的临床状况和运动能力（RELAX）试验中，西地那非与安慰剂相比降低了 eGFR，尽管在临床前模型中对肾脏有有利影响。由于某些药物的急性 eGFR 下降先于长期肾脏获益，我们评估了西地那非对急性和慢性 eGFR 斜率的影响。
RELAX 试验将 216 名参与者随机分配至安慰剂或西地那非组，并评估了心肺运动测试、心血管成像和实验室数据在 24 周内的变化。我们通过治疗应用线性混合模型来计算总 eGFR、急性（0-12 周）和慢性（3-24 周）eGFR 斜率。我们使用回归模型评估了 eGFR 斜率与基线数据和临床终点之间的各自相关性。我们根据 eGFR 下降≥20%的情况，使用二项结果重复了分析。
平均基线 eGFR 为 60.8 ml/min per 1.73 m，随访期间 eGFR 斜率的平均值为-3.21 ml/min per 1.73 m per year。与安慰剂相比，西地那非并未改变总 eGFR 斜率（差异为+0.47 ml/min per 1.73 m per year，95%置信区间[CI]，-6.63 至 7.57 ml/min per 1.73 m per year）。与安慰剂相比，西地那非使用者倾向于经历更负的急性 eGFR 斜率（差异为-3.15 ml/min per 1.73 m per year）和更正的慢性斜率（+2.06 ml/min per 1.73 m per year），但差异均无统计学意义。基线末端 pro–B 型利钠肽和袢利尿剂的使用与无论治疗如何的更差的 eGFR 轨迹相关。大量 eGFR 下降与内皮素-1 增加和住院或死亡风险增加相关（HR，2.34，95%CI，1.21 至 4.53，=0.01）。
在 HFpEF 队列中，西地那非在 24 周后对 eGFR 产生急性影响，而整体 eGFR 斜率没有改变，这表明在开始治疗后早期 eGFR 下降与长期风险无关。需要进行长期研究来确定西地那非对 HFpEF 患者肾功能的影响。
