Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction
Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction
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DOI：
10.1001/jamacardio.2020.7585
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发表时间：
2021-02-17
期刊：
影响因子：
24
通讯作者：
Sabatine, Marc S.
中科院分区：
文献类型：
--
作者：
Berg, David D.;Jhund, Pardeep S.;Sabatine, Marc S.
重要性达格列净已被证明可以降低慢性心力衰竭（HF）和射血分数降低（HFrEF）患者的心血管死亡或心力衰竭（HF）恶化的风险。然而，临床惯性往往是推迟启动有效therapeutis.Objective检查的临床效益与达格列净和大小的功能，接近以前的HF hospitalization.DESIGN，设置，和参与者这是一个完整的多国试验的二次分析。达格列净和预防心力衰竭不良结局试验是一项在慢性HFrEF患者中进行的达格列净双盲、安慰剂对照随机临床试验（n = 4744）。从2017年2月至2018年8月，该研究入组了纽约心脏协会II至IV级、左心室射血分数≤ 40%的患者;中位（范围）随访时间为18.2（0-27.8）个月。按照随机化后的时间，计算达格列净与安慰剂的主要疗效结局的风险比（HR）。根据试验入组前最近一次HF住院的时间评估达格列净的疗效和安全性。暴露无。主要结局和指标心血管死亡或HF恶化的复合终点。结果共纳入4744例患者（1109例女性[23.4%];平均[SD]年龄66.3 [10.9]岁）。达格列净的主要结局的降低迅速显现，在随机化后28天具有持续的统计学显著性获益（第28天的HR，0.51 [95% CI，0.28-0.94]; P = 0.03）。共有2251例患者（47.4%）既往因HF住院，1301例（27.4%）在入组前12个月内住院。在接受安慰剂治疗的患者中，根据最近一次HF住院的时间，主要结局的风险存在逐步梯度，既往从未、超过12个月前和12个月或更短时间前HF住院的患者的2年Kaplan-Meier率分别为21.1%、25.3%和33.8%（校正P = 0.003）。在这些亚组中，达格列净使主要结局的相对风险分别降低16%（HR，0.84 [95% CI，0.69-1.01]）、27%（HR，0.73 [95% CI，0.54-0.99]）和36%（HR，0.64 [95% CI，0.51-0.80]）（趋势P = 0.07）。因此，最近HF住院的患者在2年时倾向于经历更大的达格列净绝对风险降低：二点一厘（95% CI，-1.9%至6.1%），4.1%（95% CI，-3.6%至11.7%）和9.9%（95% CI，3.3%-16.5%）结论和相关性在这项研究中，用达格列净治疗与心血管死亡或HF恶化风险的快速降低相关，在随机化后很早就出现持续的统计学显著益处。最近HF住院的患者风险特别高，使用达格列净后相对和绝对风险降低幅度更大。
IMPORTANCE Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies.OBJECTIVE To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization.DESIGN, SETTING, AND PARTICIPANTS This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment.EXPOSURES None.MAIN OUTCOMES AND MEASURES Composite of cardiovascular death or worsening HF.RESULTS A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94]; P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjusted P = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, -1.9% to 6.1%), 4.1% (95% CI, -3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend).CONCLUSIONS AND RELEVANCE In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin.