Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark.
Department of Clinical Biochemistry 3011, Rigshospitalet, Copenhagen, Denmark.
JAMA Cardiol. 2022 Apr 1;7(4):435-444. doi: 10.1001/jamacardio.2021.5916.
Recent studies have questioned the presumed low-risk status of patients with asymptomatic nonsevere aortic stenosis (AS). Whether annual N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements are useful for risk assessment is unknown.
To assess the association of annual NT-proBNP measurements with clinical outcomes in patients with nonsevere AS.
DESIGN, SETTING, AND PARTICIPANTS: Analysis of annual NT-proBNP concentrations in the multicenter, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) randomized clinical trial was performed. SEAS was conducted from January 6, 2003, to April 1, 2008. Blood samples were analyzed in 2016, and data analysis was performed from February 10 to October 10, 2021. SEAS included 1873 patients with asymptomatic AS not requiring statin therapy with transaortic maximal flow velocity from 2.5 to 4.0 m/s and preserved ejection fraction. This substudy included 1644 patients (87.8%) with available blood samples at baseline and year 1.
Increased age- and sex-adjusted NT-proBNP concentrations at year 1 and a 1.5-fold or greater relative NT-proBNP concentration change from baseline to year 1. Moderate AS was defined as baseline maximal flow velocity greater than or equal to 3.0 m/s.
Aortic valve events (AVEs), which are a composite of aortic valve replacement, cardiovascular death, or incident heart failure due to AS progression, were noted. Landmark analyses from year 1 examined the association of NT-proBNP concentrations with outcomes.
Among 1644 patients, 996 were men (60.6%); mean (SD) age was 67.5 (9.7) years. Adjusted NT-proBNP concentrations were within the reference range (normal) in 1228 of 1594 patients (77.0%) with NT-proBNP values available at baseline and in 1164 of 1644 patients (70.8%) at year 1. During the next 2 years of follow-up, the AVE rates per 100 patient-years for normal vs increased adjusted NT-proBNP levels at year 1 were 1.39 (95% CI, 0.86-2.23) vs 7.05 (95% CI, 4.60-10.81) for patients with mild AS (P < .01), and 10.38 (95% CI, 8.56-12.59) vs 26.20 (95% CI, 22.03-31.15) for those with moderate AS (P < .01). Corresponding all-cause mortality rates were 1.05 (95% CI, 0.61-1.81) vs 4.17 (95% CI, 2.42-7.19) for patients with mild AS (P < .01), and 1.60 (95% CI, 0.99-2.57) vs 4.78 (95% CI, 3.32-6.87) for those with moderate AS (P < .01). In multivariable Cox proportional hazards regression models, the combination of a 1-year increased adjusted NT-proBNP level and 1.5-fold or greater NT-proBNP level change from baseline was associated with the highest AVE rates in both patients with mild AS (hazard ratio, 8.12; 95% CI, 3.53-18.66; P < .001) and those with moderate AS (hazard ratio, 4.05; 95% CI, 2.84-5.77; P < .001).
The findings of this study suggest that normal NT-proBNP concentrations at 1-year follow-up are associated with low AVE and all-cause mortality rates in patients with asymptomatic nonsevere AS. Conversely, an increased 1-year NT-proBNP level combined with a 50% or greater increase from baseline may be associated with high AVE rates.
ClinicalTrials.gov Identifier: NCT00092677.
重要性：最近的研究对无症状非重度主动脉瓣狭窄（AS）患者假定的低风险状态提出了质疑。每年测量 N 末端脑利钠肽前体（NT-proBNP）是否有助于风险评估尚不清楚。
目的：评估非重度 AS 患者每年 NT-proBNP 测量值与临床结局的相关性。
设计、地点和参与者：对多中心、双盲辛伐他汀和依折麦布在主动脉瓣狭窄（SEAS）随机临床试验中每年 NT-proBNP 浓度进行分析。SEAS 于 2003 年 1 月 6 日至 2008 年 4 月 1 日进行。在 2016 年进行了血液样本分析，数据分析于 2021 年 2 月 10 日至 10 月 10 日进行。SEAS 纳入了 1873 名无症状 AS 患者，这些患者不要求他汀类药物治疗，跨主动脉最大血流速度为 2.5 至 4.0 m/s，射血分数正常。本亚研究纳入了 1644 名患者（87.8%），这些患者在基线和第 1 年时均有可用的血液样本。
暴露情况：第 1 年时年龄和性别调整后的 NT-proBNP 浓度增加，并且从基线到第 1 年的相对 NT-proBNP 浓度变化增加 1.5 倍或更多。中度 AS 定义为基线时最大血流速度大于或等于 3.0 m/s。
主要结果和测量：注意到主动脉瓣事件（AVEs），即主动脉瓣置换术、心血管死亡或因 AS 进展导致的心力衰竭事件的复合。第 1 年的里程碑分析检查了 NT-proBNP 浓度与结局的相关性。
结果：在 1644 名患者中，996 名是男性（60.6%）；平均（SD）年龄为 67.5（9.7）岁。在有基线和第 1 年 NT-proBNP 值可用的 1594 名患者中，1228 名（77.0%）的 NT-proBNP 浓度处于参考范围内（正常），在 1644 名患者中有 1164 名（70.8%）在第 1 年处于正常范围。在接下来的 2 年随访中，正常与第 1 年增加的调整 NT-proBNP 水平相比，轻度 AS 患者的每 100 名患者年 AVE 发生率分别为 1.39（95%CI，0.86-2.23）和 7.05（95%CI，4.60-10.81）（P<.01），中度 AS 患者分别为 10.38（95%CI，8.56-12.59）和 26.20（95%CI，22.03-31.15）（P<.01）。相应的全因死亡率分别为 1.05（95%CI，0.61-1.81）和 4.17（95%CI，2.42-7.19）（P<.01），轻度 AS 患者分别为 1.60（95%CI，0.99-2.57）和 4.78（95%CI，3.32-6.87）（P<.01），中度 AS 患者分别为 4.05（95%CI，2.84-5.77）（P<.01）。在多变量 Cox 比例风险回归模型中，第 1 年增加的调整 NT-proBNP 水平与从基线增加 1.5 倍或更高的 NT-proBNP 水平变化相结合，与轻度 AS（危险比，8.12；95%CI，3.53-18.66；P<.001）和中度 AS（危险比，4.05；95%CI，2.84-5.77；P<.001）患者的最高 AVE 率相关。
结论和相关性：本研究结果表明，无症状非重度 AS 患者在第 1 年随访时 NT-proBNP 浓度正常与 AVE 和全因死亡率较低相关。相反，第 1 年 NT-proBNP 水平增加且与基线相比增加 50%或更高可能与高 AVE 率相关。
试验注册：ClinicalTrials.gov 标识符：NCT00092677。
