Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction The DEFINE-HF Trial
Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction The DEFINE-HF Trial
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DOI：
10.1161/circulationaha.119.042929
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发表时间：
2019-10-29
期刊：
影响因子：
37.8
通讯作者：
Cox, John M.
中科院分区：
文献类型：
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作者：
Nassif, Michael E.;Windsor, Sheryl L.;Cox, John M.
背景：对2型糖尿病患者的结局试验表明，使用钠-葡萄糖共转运蛋白-2抑制剂可减少因心力衰竭（HF）住院的次数。然而，这些患者中很少有心衰，而那些有心衰的患者也没有很好的特征。因此，钠-葡萄糖共转运蛋白-2抑制剂对射血分数降低的HF患者（包括伴有和不伴有2型糖尿病的患者）的影响尚不清楚。方法：DEFINE-HF（达格列净对心力衰竭伴射血分数降低患者的生物标志物、症状和功能状态的影响）是一项由研究者发起的多中心随机对照试验，研究对象为左心室射血分数= 30 mL/min/1.73m(2)、利钠肽升高的心力衰竭患者。总共有263名患者被随机分配到每天10mg的达格列净组或安慰剂组，持续12周。双重主要结局为(1)平均NT-proBNP （n端前b型利钠肽）和(2)在堪萨斯城心肌病问卷总体总结评分中，HF疾病特异性健康状况>= 5分增加或>= NT-proBNP下降20%的患者比例。结果：患者特征反映了稳定的慢性心力衰竭，射血分数降低，并高度使用最佳药物治疗。达格列净组与安慰剂组在6周和12周调整后NT-proBNP的平均差异无统计学意义(1133 pg/dL （95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304)， P=0.43）。对于堪萨斯城心肌病问卷总体总结评分或NT-proBNP有意义改善的第二个双主要终点，61.5%的达格列净治疗患者达到了这一终点，而安慰剂组为50.4%（调整or 1.8, 95% CI 1.03-3.06，名义P=0.039）。这是由于在12周时，堪萨斯城心肌病问卷总体总结评分>= 5分改善的患者比例较高（42.9 vs 32.5%，调整OR 1.73, 95% CI 0.98-3.05），以及NT-proBNP降低>= 20% （44.0 vs 29.4%，调整OR 1.9, 95% CI 1.1-3.3）。结果在有或没有2型糖尿病的患者和其他预先指定的亚组中是一致的（相互作用的所有P值=NS）。结论：在心力衰竭和射血分数降低的患者中，使用达格列净超过12周不影响平均NT-proBNP，但增加了患者在hf相关健康状况或利钠肽方面有临床意义改善的比例。达格列净对有临床意义的心衰测量的益处似乎延伸到没有2型糖尿病的患者。
Background: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction = 30 mL/min/1.73m(2), and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with >= 5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a >= 20% decrease in NT-proBNP. Results: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with >= 5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and >= 20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). Conclusions: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus.