第一部分 舒张压对强化降压治疗效果的影响

研究背景

中国老年高血压患者降压靶目标干预策略研究（STEP研究）比较了强化降压和标准降压的心血管结局并且证明收缩压小于130 mmHg的强化降压治疗具有显著的心血管获益。舒张压是重要的血压指标，和心血管不良事件之间存在潜在的J型曲线关系。强化降压在降低收缩压的同时也可能降低舒张压。然而，强化降压是否会增加低舒张压患者的心血管不良事件风险还有待研究。因此，本研究评估了强化降压在不同基线舒张压人群中的治疗效应。

研究方法

本研究是一项多中心、前瞻性、随机对照临床试验——STEP研究的事后分析。STEP研究纳入了8511名高血压患者并且随机分组接受强化降压治疗（收缩压：110至<130 mmHg）或标准降压治疗（收缩压：130至<150 mmHg）。本研究将基线舒张压当作分类变量（四分位数分组或者按照<70，70至<80，和≥80 mmHg分组）或连续变量，分析其对强化降压治疗的主要复合终点事件（包括脑卒中、急性冠脉综合征、急性失代偿性心力衰竭、冠状动脉血运重建、心房颤动和心血管死亡）、主要不良心血管事件（包括急性冠脉综合征、急性失代偿性心力衰竭、冠状动脉血运重建、心房颤动和心血管死亡）和全因死亡的影响。

研究结果

本研究共纳入8259例患者进行统计分析。平均年龄为66.2±4.8岁，46.5%为男性。舒张压较低的患者年龄较大，且基线时心血管疾病、糖尿病和高脂血症的患病率较高。本研究按照基线舒张压四分位数分组，第一、第二、第三和第四四分位数组分别包含2095、2106、2002和2056名患者。在每个舒张压四分位数分组中，强化降压治疗组的患者相比标准降压治疗组的患者，具有更低的平均达到舒张压(mean achieved DBP)。强化降压的治疗效果不受基线舒张压的影响（作为连续变量或分类变量：全部交互作用P值>0.05）。

研究结论

本研究发现基线舒张压对强化降压的治疗效果无显著影响。强化降压治疗的心血管获益并不因基线舒张压而异。我们的研究结果提示，低舒张压不应该作为应用强化降压治疗的阻碍。

研究注册信息：URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311

关键词：高血压，心血管疾病，临床试验，舒张压

第二部分 血糖水平对强化降压治疗效果的影响

研究背景

高血压是心血管疾病的主要危险因素。据报道，在收缩压干预试验（SPRINT）和中国老年高血压患者降压靶目标的干预策略研究（STEP）中，强化降压治疗可以降低高血压患者的心血管事件发生率。然而，在具有不同血糖水平的高血压患者中，强化降压治疗是否能实现类似的心血管获益仍然存在争议。因此，我们在本研究中探讨了基线血糖状态是否会对强化降压的心血管预后产生影响。

研究方法

我们对STEP研究进行了一项事后分析。所有参与STEP研究的高血压患者被随机分配接受强化降压（收缩压：110至<130 mmHg）或标准降压治疗（收缩压：130至<150 mmHg）。在本研究中，我们根据美国糖尿病学会制定的标准，以空腹血糖水平划分不同的基线血糖状态。于是，患者被分为三个亚组：（1）正常血糖组（基线空腹血糖<5.6 mmol/L，未服用降糖药物，无糖尿病史）；（2）糖尿病前期组（基线空腹血糖5.6-6.9 mmol/L，未服用降糖药物，无糖尿病史）；（3）糖尿病组（基线空腹血糖≥7.0 mmol/L、服用降糖药物、或具有糖尿病史）。本研究的主要结局为包括脑卒中、急性冠脉综合征、急性失代偿性心力衰竭、冠状动脉血运重建、心房颤动和心血管死亡的复合终点事件。我们在统计分析中使用竞争风险回归模型。另外，我们进行了敏感性分析。

研究结果

本研究共纳入8318名患者的数据进行分析。正常血糖亚组、糖尿病前期亚组和糖尿病亚组共有3275、2769和2274人。中位随访时间3.33年后，相比标准降压治疗，强化降压治疗显著降低了主要复合结局的风险（调整后的风险比[hazard ratio，HR]为0.73；95%置信区间[confidence interval，CI]为0.59-0.91）。血糖正常、糖尿病前期和糖尿病亚组的主要结局调整后HR分别为0.72（95% CI，0.49-1.04），0.69（95% CI，0.46-1.02），和0.80（95% CI，0.56-1.15）。强化降压的治疗效应不受基线血糖状态的影响（全部交互作用P值>0.05）。此外，敏感性分析的结果与主要分析结果相一致。

研究结论

本研究的结果表明，基线血糖状态不会改变强化降压对心血管预后的有利影响。也就是说，正常血糖、糖尿病前期和糖尿病的高血压患者均可从强化降压中获益。

研究注册信息：URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311

关键词：高血压，血压，临床试验，糖尿病前期，糖尿病

第三部分 残余胆固醇对强化降压治疗效果的影响

研究背景

尽管按照现行指南进行严格的血脂管理，心血管疾病依旧具有较高的残余风险。残余胆固醇是近年来定义的一类具有致病作用的脂质分子，它在心血管疾病残余风险中发挥重要作用。越来越多的证据表明，增高的残余胆固醇与血压升高相关；且高血压患者具有较高的残余胆固醇水平。这说明，高血压和残余胆固醇之间存在密切关系。然而，残余胆固醇是否影响高血压患者强化降压的治疗效果还是未知的。因此，本研究评估了强化降压的心血管效应是否会受到基线残余胆固醇的影响。

研究方法

本研究是一项基于中国老年高血压患者降压靶目标干预策略研究（STEP研究）的事后分析。参与者被随机分配进入强化降压组（收缩压：110至<130 mmHg）或标准降压组（收缩压：130至<150 mmHg）。我们利用空腹血脂相关指标，按照总胆固醇减去高密度脂蛋白胆固醇再减去低密度脂蛋白胆固醇的公式计算得到残余胆固醇的含量。本研究排除了因基线数据缺失而无法计算残余胆固醇含量以及关键协变量缺失的患者数据。我们将患者根据基线残余胆固醇三分位数进行分组（最低、中间、最高三分位数组），并分析基线残余胆固醇对强化降压的主要复合结局（脑卒中、急性冠脉综合征、急性失代偿性心力衰竭、冠状动脉血运重建、心房颤动和心血管死亡）及其组成部分和全因死亡的影响。

研究结果

我们对8206名患者进行了随访。经过3.33年的中位随访时间后，在最低、中间和最高残余胆固醇三分位数组中，主要复合结局的调整后风险比（hazard ratio，HR）及95%置信区间（confidence interval，CI）分别为1.06（0.73-1.56）、0.58（0.38-0.87）和0.67（0.46-0.96），交互作用P值为0.11。然而，在比较较高两个三分位数组（中间与最高三分位数组）与最低三分位数组时，我们观察到强化降压对主要结局的治疗效应存在明显的异质性（交互作用P值=0.033）。在全因死亡方面，最低、中间和最高残余胆固醇三分位数组的调整后HR及95% CI分别为2.48（1.30-4.73）、1.37（0.71-2.65）和0.42（0.22-0.80），交互作用P值<0.0001。

研究结论

在这项事后分析中，我们发现强化降压治疗在主要复合心血管结局和全因死亡结局方面的效应会受到基线残余胆固醇的影响。这个研究是探索性的。如果结论被证实，未来将有望通过残余胆固醇水平高低来识别强化降压治疗的更大获益者。

研究注册信息：URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311

关键词：高血压，临床试验，心血管风险，残余胆固醇，血脂

Part I. Influence of baseline diastolic blood pressure on the effects of intensive blood pressure lowering

Background

The Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial has reported that intensive blood pressure (BP) control has cardiovascular benefits on hypertensive patients. Diastolic BP (DBP), an integral component of BP, may have a potential J-shaped relationship with adverse cardiovascular events. Intensive BP control can lower DBP. However, whether intensive BP control increases the risk of adverse cardiovascular events in patients with low DBP remains to be investigated. Therefore, the current study evaluated the effects of intensive BP control in patients with different baseline DBP.

Methods

This is a post hoc analysis of the multicenter, prospective, randomized STEP trial that included 8511 hypertensive patients who were randomly assigned to receive intensive BP (systolic BP: 110 to <130 mmHg) or standard BP treatment (systolic BP: 130 to <150 mmHg). The effects of intensive BP lowering on the primary composite outcome (stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularization, atrial fibrillation, and cardiovascular death), major adverse cardiac events (a composite of the individual components of the primary outcome except for stroke), and all-cause mortality were analyzed according to baseline DBP as a categorical (quartiles, or <70, 70 to <80, and ≥80 mmHg) or as a continuous variable.

Results

A total of 8259 participants were included in this analysis. The mean age was 66.2±4.8 years, and 46.5% were men. Participants with lower DBP were slightly older and had a higher prevalence of cardiovascular disease, diabetes, and hyperlipidemia at baseline. There were 2095, 2106, 2002, and 2056 participants, respectively, in the first, second, third, and fourth baseline DBP quartiles. Within each baseline DBP quartile, participants in the intensive group had a lower mean achieved DBP than those in the standard group. The effects of intensive BP control were not modified by baseline DBP (as a continuous variable or as a categorical variable: all P values for interaction >0.05).

Conclusions

This study found no association between baseline DBP and the effects of intensive BP control in hypertensive patients. The beneficial effects of intensive BP control on cardiovascular outcomes did not differ by baseline DBP. Our results suggest that lower DBP should not be an obstacle to intensive BP control.

Clinical trial registration information: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311

Key words: Hypertension, Cardiovascular disease, Clinical trial, Diastolic blood pressure

Part II. Effects of intensive blood pressure control on cardiovascular outcomes in patients with different baseline glycemic status

Background

Hypertension is a leading risk factor for cardiovascular diseases. In the Systolic Blood Pressure Intervention Trial (SPRINT) and the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial, intensive blood pressure (BP) control was reported to reduce cardiovascular events in patients with hypertension However, it is controversial whether intensive BP control has similar beneficial cardiovascular effects among hypertensive patients with different glycemic status. Therefore, in this study we investigated whether baseline glycemic status influences the effects of intensive BP lowering on cardiovascular outcomes.

Methods

We performed a post hoc analysis of the STEP trial, in which participants were randomly assigned to receive intensive BP control (systolic BP: 110 to <130 mmHg) or standard BP control (systolic BP: 130 to <150 mmHg). In the present study, we defined baseline glycemic status on the basis of fasting serum glucose (FSG) according to American Diabetes Association criteria. Accordingly, participants were categorized into three subgroups: normoglycemia (with baseline FSG <5.6 mmol/l but without self-reported hypoglycemia drug use or a history of diabetes), prediabetes (with baseline FSG 5.6-6.9 mmol/l but without self-reported hypoglycemia drug use or a history of diabetes), and diabetes (with baseline FSG ≥7.0 mmol/l, self-reported hypoglycemia drug use, or a history of diabetes). The primary outcome was a composite of stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. The competing risk proportional hazards regression models were used in analysis. Sensitivity analyses were also performed.

Results

In the present study, a total of 8318 participants were included in analysis. There were 3275, 2769, and 2274 participants in the normoglycemia, prediabetes, and diabetes subgroups, respectively. After a median follow-up of 3.33 years, intensive BP control significantly reduced the risk of the primary outcome (adjusted hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.59-0.91). The adjusted HRs for the primary outcome in the normoglycemia, prediabetes, and diabetes subgroups were 0.72 (95% CI, 0.49-1.04), 0.69 (95% CI, 0.46-1.02), and 0.80 (95% CI, 0.56-1.15), respectively. The effects of intensive BP control were not modified by baseline glycemic status (all interaction P values >0.05). Furthermore, the results of the sensitivity analyses were consistent with the results of the main analyses.

Conclusions

The present study indicated that baseline glycemic status did not modify the beneficial effects of intensive BP control on cardiovascular outcomes. That is, the effects of intensive BP control on cardiovascular outcomes were consistent among participants with normoglycemia, prediabetes, and diabetes.

Clinical trial registration information: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311

Key words: Hypertension, Blood pressure, Clinical trial, Prediabetes, Diabetes

Part III. Effects of intensive versus standard blood pressure treatment according to baseline remnant cholesterol

Background

Despite the lipid management recommended by current guidelines, there is still a high residual risk of cardiovascular disease. Remnant cholesterol plays an important role in this residual risk. Emerging evidence shows that high remnant cholesterol is associated with high blood pressure. In turn, hypertensive patients often have high remnant cholesterol. There exists a close relationship between remnant cholesterol and hypertension. However, it is unknown whether remnant cholesterol modifies the effects of intensive blood pressure (BP) control. Therefore, in the current study we evaluated the association between baseline remnant cholesterol and the effects of intensive BP control.

Methods

This is a post-hoc analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Participants were initially randomized to receive intensive (systolic BP target, 110 to <130 mmHg) or standard BP treatment (systolic BP target, 130 to <150 mmHg). Remnant cholesterol was calculated as fasting total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol. Participants with missing baseline remnant cholesterol or key covariates were excluded from the current study. We analysed the effects of intensive BP lowering on the primary composite outcome (stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularization, atrial fibrillation or cardiovascular death), the components thereof and all-cause mortality by tertile of baseline remnant cholesterol (lowest, middle, highest).

Results

We followed 8206 patients for a median follow-up of 3.33 years. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the primary outcome were 1.06 (0.73-1.56), 0.58 (0.38-0.87) and 0.67 (0.46-0.96) in the lowest, middle and highest remnant cholesterol tertiles, respectively (P for interaction=0.11). However, for the primary outcome, we observed a significant heterogeneity in the treatment effects when comparing the upper two tertiles with the lowest tertile (P for interaction=0.033). For all-cause mortality, the adjusted HRs and 95% CIs were 2.48 (1.30-4.73), 1.37 (0.71-2.65), and 0.42 (0.22-0.80) in the lowest, middle and highest remnant cholesterol tertiles, respectively (P for interaction<0.0001).

Conclusions

In this post-hoc analysis, we found that baseline remnant cholesterol concentrations were associated with the effects of intensive BP control on the primary composite cardiovascular outcome and all-cause mortality in patients with hypertension. These results are hypothesis-generating and merit further study. If confirmed, the measurement of remnant cholesterol may allow identification of a subset of hypertensive patients with high remnant cholesterol who may derive greater benefit from intensive BP control.

Clinical trial registration information: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311

Key words: Hypertension, Clinical trial, Cardiovascular risk, Remnant cholesterol, Blood lipid