Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
British Heart Foundation, University of Glasgow, Glasgow, Scotland.
JAMA Cardiol. 2022 Dec 1;7(12):1259-1263. doi: 10.1001/jamacardio.2022.3750.
Dapagliflozin was recently shown to reduce cardiovascular death or worsening heart failure (HF) events in patients with HF with mildly reduced or preserved ejection fraction in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.
To evaluate the time course of benefits of dapagliflozin on clinically relevant outcomes in this population.
DESIGN, SETTING, AND PARTICIPANTS: The DELIVER trial was a global phase 3 clinical trial that randomized patients with HF with mildly reduced or preserved ejection fraction to dapagliflozin or matching placebo. Inclusion criteria included symptomatic HF, left ventricular ejection fraction greater than 40%, elevated natriuretic peptide levels, and evidence of structural heart disease. In this prespecified secondary analysis of the DELIVER trial, to examine the timeline to onset of clinical benefit with dapagliflozin, hazard ratios (HR) and 95% CIs were iteratively estimated for the primary composite end point and worsening HF events alone with truncated data at every day postrandomization. Time to first and sustained statistical significance of dapagliflozin for these end points were then examined. Participants were enrolled from August 2018 to December 2020, and for this secondary analysis, data were analyzed from April to September 2022.
Dapagliflozin, 10 mg, once daily or matching placebo.
The primary outcome was time to first occurrence of cardiovascular death or worsening HF (hospitalization for HF or urgent HF visit requiring intravenous HF therapies).
Overall, 6263 patients were randomized across 350 centers in 20 countries. Of 6263 included patients, 2747 (43.9%) were women, and the mean (SD) age was 71.7 (9.6) years. During a median (IQR) of 2.3 (1.7-2.8) years' follow-up, 1122 primary end point events occurred, with an incidence rate per 100 patient-years of 8.7 (95% CI, 8.2-9.2). Time to first nominal statistical significance for the primary end point was 13 days (HR, 0.45; 95% CI, 0.20-0.99; P = .046), and significance was sustained from day 15 onwards. First and sustained statistical significance was reached for worsening HF events (HR, 0.45; 95% CI, 0.21-0.96; P = .04) by day 16 after randomization. Significant benefits for the primary end point and worsening HF events were sustained at 30 days, 90 days, 6 months, 1 year, 2 years, and final follow-up (primary end point: HR, 0.82; 95% CI, 0.73-0.92; worsening HF events: HR, 0.79; 95% CI, 0.69-0.91).
In the DELIVER trial, dapagliflozin led to early and sustained reductions in clinical events in patients with HF with mildly reduced or preserved ejection fraction with statistically significant reductions observed within 2 weeks of treatment initiation.
ClinicalTrials.gov Identifier: NCT03619213.
在 Dapagliflozin 评估改善射血分数保留心力衰竭患者生活（DELIVER）试验中，达格列净最近显示可降低射血分数轻度降低或保留的心力衰竭（HF）患者的心血管死亡或 HF 恶化事件。
评估在该人群中达格列净对临床相关结局的获益的时间进程。
设计、地点和参与者：DELIVER 试验是一项全球性的 3 期临床试验，将射血分数轻度降低或保留的 HF 患者随机分为达格列净或匹配安慰剂组。纳入标准包括有症状的 HF、左心室射血分数大于 40%、升高的利钠肽水平和结构性心脏病的证据。在 DELIVER 试验的这项预设次要分析中，为了检查达格列净起始临床获益的时间，在随机后每天截短数据，对主要复合终点和 HF 恶化事件单独迭代估计风险比（HR）和 95%置信区间。然后检查这些终点首次和持续达到统计学意义的时间。参与者于 2018 年 8 月至 2020 年 12 月入组，对于这项次要分析，数据于 2022 年 4 月至 9 月进行分析。
达格列净，10 mg，每日 1 次或匹配安慰剂。
主要结局为首次发生心血管死亡或 HF 恶化（HF 住院或需要静脉内 HF 治疗的紧急 HF 就诊）的时间。
总体而言，6263 名患者在 20 个国家的 350 个中心随机分组。在纳入的 6263 名患者中，2747 名（43.9%）为女性，平均（SD）年龄为 71.7（9.6）岁。在中位（IQR）2.3（1.7-2.8）年的随访期间，发生了 1122 例主要终点事件，每 100 名患者年的发生率为 8.7（95%CI，8.2-9.2）。主要终点的首次名义统计学显著性时间为 13 天（HR，0.45；95%CI，0.20-0.99；P=0.046），并且从第 15 天开始持续具有统计学意义。HF 恶化事件的首次和持续统计学意义在随机后第 16 天达到（HR，0.45；95%CI，0.21-0.96；P=0.04）。在 30 天、90 天、6 个月、1 年、2 年和最终随访时，主要终点和 HF 恶化事件的显著获益持续存在（主要终点：HR，0.82；95%CI，0.73-0.92；HF 恶化事件：HR，0.79；95%CI，0.69-0.91）。
在 DELIVER 试验中，达格列净使射血分数轻度降低或保留的 HF 患者的临床事件早期和持续减少，在治疗开始后 2 周内观察到有统计学意义的减少。
ClinicalTrials.gov 标识符：NCT03619213。
