门诊治疗的心力衰竭临床恶化的重要性：来自血管紧张素受体脑啡肽酶抑制剂与血管紧张素转换酶抑制剂前瞻性比较以确定对心力衰竭试验全球死亡率和发病率影响的证据（PARADIGM-HF）
Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting: Evidence From the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF).
作者信息
Okumura Naoki, Jhund Pardeep S, Gong Jianjian, Lefkowitz Martin P, Rizkala Adel R, Rouleau Jean L, Shi Victor C, Swedberg Karl, Zile Michael R, Solomon Scott D, Packer Milton, McMurray John J V
机构信息
From BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
出版信息
Circulation. 2016 Jun 7;133(23):2254-62. doi: 10.1161/CIRCULATIONAHA.115.020729. Epub 2016 Apr 20.
BACKGROUND
Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or temporary intravenous treatment in the community or emergency department (ED), without hospital admission. We studied the frequency and prognostic importance of these episodes of worsening in the Prospective Comparison of ARNI (angiotensin-receptor-neprilysin inhibitor) with ACEI (angiotensin-converting enzyme inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF).
METHODS AND RESULTS
Outpatient intensification of HF therapy was added to an expanded composite outcome with ED visits, HF hospitalizations, and cardiovascular deaths. In an examination of first nonfatal events, 361 of 8399 patients (4.3%) had outpatient intensification of HF therapy without a subsequent event (ie, ED visit/HF hospitalizations) within 30 days; 78 of 8399 (1.0%) had an ED visit without previous outpatient intensification of HF therapy or a subsequent event within 30 days; and 1107 of 8399 (13.2%) had HF hospitalizations without a preceding event. The risk of death (in comparison with no-event patients) was similar after each manifestation of worsening: outpatient intensification of HF therapy (hazard ratio, 4.8; 95% confidence interval, 3.9-5.9); ED visit (hazard ratio, 4.5; 95% confidence interval, 3.0-6.7); HF hospitalizations (hazard ratio, 5.9; 95% confidence interval, 5.2-6.6). The expanded composite added 14% more events and shortened time to accrual of a fixed number of events. The benefit of sacubitril/valsartan over enalapril was similar to the primary outcome for the expanded composite (hazard ratio, 0.79; 95% confidence interval, 0.73-0.86) and was consistent across the components of the latter.
CONCLUSIONS
Focusing only on HF hospitalizations underestimates the frequency of worsening and the serious implications of all manifestations of worsening. For clinical trials conducted in an era of heightened efforts to avoid HF hospitalizations, inclusion of episodes of outpatient treatment intensification (and ED visits) in a composite outcome adds an important number of events and shortens the time taken to accrue a target number of end points in an event-driven trial.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
背景
许多心力衰竭（HF）病情恶化的情况在社区或急诊科（ED）通过增加口服治疗或临时静脉治疗来处理，而无需住院。我们在血管紧张素受体脑啡肽酶抑制剂（ARNI）与血管紧张素转换酶抑制剂（ACEI）前瞻性比较以确定对心力衰竭试验全球死亡率和发病率影响（PARADIGM-HF）中研究了这些病情恶化情况的发生频率及其预后重要性。
方法与结果
将门诊强化HF治疗纳入一个扩大的综合结局，该结局包括ED就诊、HF住院和心血管死亡。在对首次非致命事件的检查中，8399例患者中有361例（4.3%）进行了门诊强化HF治疗，且在30天内未发生后续事件（即ED就诊/HF住院）；8399例中有78例（1.0%）发生了ED就诊，之前未进行门诊强化HF治疗且在30天内未发生后续事件；8399例中有1107例（13.2%）发生了HF住院，之前未发生过事件。每种病情恶化表现后死亡风险（与无事件患者相比）相似：门诊强化HF治疗（风险比，4.8；95%置信区间，3.9 - 5.9）；ED就诊（风险比，4.5；95%置信区间，3.0 - 6.7）；HF住院（风险比，5.9；95%置信区间，5.2 - 6.6）。扩大的综合结局增加了14%的事件，并缩短了达到固定数量事件的时间。沙库巴曲缬沙坦相对于依那普利的益处与扩大综合结局的主要结局相似（风险比，0.79；95%置信区间，0.73 - 0.86），且在后者各组成部分中一致。
结论
仅关注HF住院会低估病情恶化的频率以及所有病情恶化表现的严重影响。对于在大力避免HF住院的时代进行的临床试验，在综合结局中纳入门诊治疗强化（和ED就诊）事件会增加大量事件，并缩短在事件驱动试验中达到目标数量终点所需的时间。
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