PARADIGM-HF试验中随机分组前导入期未完成的相关因素及其对LCZ696估计获益的影响
Factors Associated With Noncompletion During the Run-In Period Before Randomization and Influence on the Estimated Benefit of LCZ696 in the PARADIGM-HF Trial.
作者信息
Desai Akshay S, Solomon Scott, Claggett Brian, McMurray John J V, Rouleau Jean, Swedberg Karl, Zile Michael, Lefkowitz Martin, Shi Victor, Packer Milton
机构信息
From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (A.S.D., S.S., B.C.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.M.); Institut de Cardiologie de Montréal, Université de Montréal, Canada (J.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Division of Cardiology, Medical University of South Carolina, Ralph H. Johnston Veterans Administration Medical Center, Charleston (M.Z.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (M.L., V.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
出版信息
Circ Heart Fail. 2016 Jun;9(6). doi: 10.1161/CIRCHEARTFAILURE.115.002735.
BACKGROUND
The 8442 patients randomized in the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, in which sacubitril/valsartan (LCZ696) reduced both death and HF hospitalization more than enalapril, were a subset of 10 521 patients entering sequential, single-blind run-in periods (enalapril 10 mg twice daily for 2 weeks followed by LCZ696 200 mg twice daily for 4 to 6 weeks) to ensure short-term tolerability of the 2 study medications. We identified the predictors of run-in noncompletion and estimated the implications of noncompletion for the overall study result.
METHODS AND RESULTS
Patient factors associated with run-in noncompletion were defined in multivariable logistic regression models. The effectiveness of LCZ696 in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion; 2079 (19.8%) subjects discontinued the study during the run-in period, including 1102 (10.5%) during the enalapril phase and 977 (9.3%) during the LCZ696 phase. In multivariable models, lower systolic blood pressure, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, and ischemic cause of heart failure were associated with higher risk for run-in noncompletion. Repeat analysis of the effect of randomized treatment giving greater weight to randomized patients resembling those who did not complete the run-in did not alter the hazard ratio favoring LCZ696 over enalapril for the primary end point of cardiovascular death or heart failure hospitalization, or the additional key end points of cardiovascular death and all-cause mortality.
CONCLUSIONS
Patients with lower blood pressure, lower glomerular filtration rate, and more severe heart failure were at higher risk for noncompletion during the run-in period of PARADIGM-HF. Weighted analysis of key study outcomes accounting for the effect of run-in noncompletion did not alter the benefit of LCZ696 over enalapril.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
背景
在“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对心力衰竭患者全因死亡率和发病率影响的前瞻性比较（PARADIGM-HF）”试验中，随机分组的8442例患者接受了沙库巴曲缬沙坦（LCZ696）治疗，与依那普利相比，沙库巴曲缬沙坦降低了死亡和心力衰竭住院率。这8442例患者是10521例进入序贯单盲导入期患者的一个子集（依那普利每日2次，每次10 mg，服用2周，随后LCZ696每日2次，每次200 mg，服用4至6周），以确保两种研究药物的短期耐受性。我们确定了导入期未完成的预测因素，并估计了未完成对总体研究结果的影响。
方法和结果
在多变量逻辑回归模型中定义了与导入期未完成相关的患者因素。根据导入期完成的逆概率对随机分组的患者进行加权，从而估计LCZ696在更广泛队列（近似整个导入期人群）中的有效性；2079例（19.8%）受试者在导入期中断了研究，其中1102例（10.5%）在依那普利阶段中断，977例（9.3%）在LCZ696阶段中断。在多变量模型中，较低的收缩压、较低的估计肾小球滤过率、较高的N末端B型利钠肽原以及缺血性心力衰竭病因与导入期未完成的较高风险相关。对随机治疗效果进行重复分析，给予未完成导入期的患者更大权重，结果并未改变在心血管死亡或心力衰竭住院主要终点方面，LCZ696优于依那普利的风险比，也未改变心血管死亡和全因死亡率等其他关键终点的结果。
结论
在PARADIGM-HF试验的导入期，血压较低、肾小球滤过率较低以及心力衰竭更严重的患者未完成试验的风险较高。考虑导入期未完成影响的关键研究结果加权分析并未改变LCZ696优于依那普利的益处。
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