第一部分 不同血压水平人群的十年及终生心血管疾病风险

研究背景

高血压与心血管疾病风险升高之间的密切关联已获广泛证实。然而，对于依据2017年美国心脏病学会/美国心脏协会最新高血压指南标准界定的不同血压水平人群，其10年及终生心血管疾病风险有待进一步探究。此外，血压水平随时间的动态演变对上述风险指标的影响也尚未得到充分阐明。本研究拟系统评估不同血压分级人群的10年及终生心血管疾病风险，深入探讨血压的动态演变（包括从1期高血压回归至正常范围或进展至2期高血压）对心血管风险的潜在影响，从而为高血压人群的风险分层及个体化干预提供重要循证依据。

 

研究方法

本研究是一项基于开滦研究的前瞻性队列研究，以参加2006年度健康体检的96268名个体作为研究对象，并根据血压水平将其分为正常血压组（<120/80 mmHg）、血压升高组（120-129/<80 mmHg）、1期高血压组（130-139/80-89 mmHg）和2期高血压组（≥140/90 mmHg）。研究的主要终点为复合心血管事件，包括心肌梗死、脑出血和脑梗死。次要终点事件为单独的心肌梗死、脑出血和脑梗死。采用多变量校正的Cox比例风险回归模型评估不同组别的10年心血管疾病风险，使用Fine-Gray竞争风险模型计算其终生心血管疾病风险。在对血压动态演变的评估中，选取同时参加过2006年和2010年访视且有血压记录的参与者，根据两次访视的血压水平进行九宫格矩阵分析：将基线血压分组与随访血压分组交叉组合（非高血压组、1期高血压组、2期高血压组），分别评估各组的10年及终生心血管风险。

 

研究结果

在为期10年的随访中，共记录到4869例心血管事件（含3080例脑梗死、1208例心肌梗死、787例脑出血）和6680例全因死亡事件。与正常血压组相比，血压升高组、1期高血压组和2期高血压组的10年及终生心血管风险均呈阶梯式上升。其中，1期高血压组的10年心血管疾病风险增加35%（风险比[hazard ratio，HR] 1.35，95%置信区间[confidence interval，CI] 1.19-1.52），终生风险增加36%（HR 1.36，95% CI 1.25-1.49）。2期高血压组的心血管风险最高，其10年风险增加了165%（HR 2.65，95% CI 2.38-2.96），终生心血管风险增加了128%（HR 2.28，95% CI 2.10-2.48）。自2006年至2010年，12.57%的1期高血压患者进展至2期高血压，该人群10年心血管疾病风险增加了156%（HR 2.56，95% CI 2.11-3.11），终生风险增加129%（HR 2.29，95% CI 1.89-2.77）；而血压由1期高血压恢复至正常或血压升高范围的人群，其心血管风险未见显著增加（终生风险HR 1.13，95% CI 0.88-1.45）。

 

研究结论

随着血压水平的增高，心血管风险也随之增加。1期高血压与10年及终生心血管疾病风险的显著升高相关，进展至2期高血压则会导致其心血管风险进一步增加。对于血压恢复至正常或血压升高水平的个体，其心血管疾病风险呈现逆转趋势，并未显著增加。应进一步加强对血压异常人群的管理，制定强化干预策略，从而有效降低相关人群的心血管负担。

第二部分 危险因素控制水平对高血压人群心血管结局与肾脏结局的影响

第一节 危险因素控制水平对高血压人群心血管结局的影响

研究背景

现有研究表明，一些独立的危险因素指标可对心血管预后产生显著影响。然而，在强化降压治疗的背景下，高血压患者多危险因素综合控制水平与心血管结局之间的关联性尚未获得充分证据支持。更为重要的是，强化降压治疗方案是否会对危险因素控制与心血管结局的关联产生调节效应，仍有待深入研究。本研究旨在系统评估强化降压治疗背景下多危险因素控制水平与不良心血管事件之间的关系，同时重点探讨强化降压对危险因素控制与心血管预后关联的潜在调节作用，以期填补当前临床治疗中关于综合危险因素管理策略的循证空白。

 

研究方法

本研究基于中国老年高血压患者降压靶目标干预策略研究（Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients，STEP）的数据进行分析，并排除了基线危险因素数据不完整的受试者。主要研究指标为基线危险因素控制水平，纳入评估的危险因素包括体重指数、低密度脂蛋白胆固醇水平、空腹血糖水平、吸烟及饮酒情况、体育活动情况和肾功能情况。主要结局为心血管事件复合终点，即首次发生的脑卒中（含缺血性或出血性脑卒中）、急性冠脉综合征（含急性心肌梗死或因不稳定型心绞痛住院）、急性失代偿性心力衰竭、冠状动脉血运重建、心房颤动和全因死亡。纳入的人群根据基线危险因素控制水平（≥6、5、4、≤3）被分为4组，采用Cox比例风险回归模型计算风险比（Hazard Ratio，HR）及95%置信区间（Confidence Interval，CI），并评估多重危险因素控制程度与心血管结局之间的相关性。

 

研究结果

在排除了174名基线生活方式信息及生化检验结果不完整的受试者后，共有8337名受试者被纳入分析，中位随访时间为3.19年。研究结果显示，每增加一个未控制的危险因素，主要终点的发生风险增加24%（HR 1.24，95% CI 1.11-1.37）。与最佳危险因素控制组（≥6）相比，控制≤3个危险因素的受试者心血管风险增加95%（HR 1.95，95% CI 1.37-2.77）。在本研究分析的7个危险因素中，肾功能、空腹血糖和饮酒情况与主要结局的关联最为显著。进一步分析显示，多重危险因素控制的心血管保护效应独立于强化降压治疗状态（交互作用检验P=0.71），提示无论是否采用强化降压治疗方案，均应同等重视危险因素的全方位控制以优化心血管预后。

 

研究结论

在高血压患者中，心血管风险与基线危险因素控制水平显著相关。被控制在理想范围内的危险因素越多，该人群未来出现心血管事件的风险越低。无论高血压人群采用何种降压方案，基线危险因素控制策略均可对其产生心血管保护效应。本研究结果表明，临床上需要采取全面的基线危险因素控制，以更有效地降低高血压患者的心血管疾病风险。

 

第二部分 危险因素控制水平对高血压人群心血管结局与肾脏结局的影响

第二节 危险因素控制水平对高血压人群肾脏结局的影响

研究背景

高血压与慢性肾脏病在病理生理学上存在双向恶性循环，即持续升高的血压直接加速肾脏功能的恶化，而肾功能的进行性下降也会加剧血压的升高。既往研究证实高血压患者发生肾功能不全的风险显著增加，然而现有研究尚未阐明上述增高的风险是否能够通过多重危险因素的协同干预实现有效缓解。因此，阐明这一科学问题不仅对改善高血压患者的肾脏预后具有重要临床价值，更能够为构建涵盖心肾保护的多维度治疗策略提供关键理论依据。

 

研究方法

本研究为基于开滦队列开展的一项前瞻性队列研究，主要研究指标为危险因素（包括收缩压、低密度脂蛋白胆固醇、空腹血糖及体重指数）的控制数量。本研究的分析包括两个部分，分别探讨了基线危险因素控制程度与慢性肾脏病发生和发展之间的关联。纳入人群根据危险因素控制水平分组，并采用多因素校正的Cox比例风险回归模型计算风险比（Hazard Ratio，HR）和95%置信区间（Confidence Intervals，CI），以评估危险因素控制程度与肾脏结局的关联。

 

研究结果

在中位随访时间为13.40年的研究期间，本研究共纳入了77356名既往无肾脏疾病的高血压患者及按照年龄和性别1:1匹配的非高血压对照组人群，以探讨危险因素控制对高血压人群新发慢性肾脏病风险的影响。在调整了潜在混杂因素后，研究结果显示每多控制一个危险因素，新发慢性肾脏病的风险减少18%（HR 0.82，95% CI 0.81-0.84）。与仅控制≤1个危险因素组相比，全部4个危险因素均得到控制的参与者，其慢性肾脏病风险降低42%（HR 0.58，95% CI 0.52-0.63）。与血压正常的个体相比，高血压人群新发慢性肾脏病的风险显著增加，但被控制的基线危险因素越多，相应风险的增幅越小。在针对慢性肾脏病进展风险的研究中，本研究纳入了9543名高血压和6799名非高血压且既往罹患慢性肾脏病的人群，中位随访时间为11.88年。研究结果显示，每额外控制一个危险因素，慢性肾脏病进展的风险可降低18%（HR 0.82，95% CI 0.78-0.86）。当有三个危险因素得到控制时，高血压患者与正常血压个体在慢性肾脏病进展方面的风险无显著差异。进一步分析显示，与正常血压人群相比，控制全部四个基线危险因素的高血压人群，其慢性肾脏病进展风险显著下降31%（HR 0.69，95% CI 0.53-0.89）。

 

研究结论

在高血压患者中，基线危险因素控制水平与慢性肾功能不全的发生和发展密切相关。被控制的基线危险因素越多，肾功能下降的风险越低。全面控制血压、血脂、血糖、体重指数这四项危险因素，可使高血压相关慢性肾脏病的发生及进展风险趋于消除，这一研究结果强调了在临床实践中实施全面危险因素管理的重要性。

 

 

第三部分 降压药物种类对高血压人群心血管结局与肾脏结局的影响

研究背景

在目前的临床实践中，不同类别降压药物在降低心血管与肾脏疾病风险的最优选择仍存在争议。本研究旨在探讨在血压控制良好的高血压患者中，长期使用特定类别的降压药物对心血管及肾脏结局的影响。

 

研究方法

本研究基于中国老年高血压患者降压靶目标干预策略研究（Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients，STEP）的数据，纳入了既往无脑卒中病史的中国老年高血压患者。在排除了234例失访和20例缺乏随机后血压记录的个体后，最终纳入8257例受试者进行分析。本研究的主要研究指标为各类降压药物的相对用药时间，定义为该类药物的用药持续时间与对应个体从随机化至发生终点事件（或随访结束）的总观察时间的比值。主要复合终点为首次发生的以下任一事件，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、心房颤动或心血管死亡。次要终点为主要复合终点中各独立组成部分和肾脏不良结局。采用Cox比例风险回归模型评估各终点事件的风险比（Hazard Ratio，HR）及95%置信区间（Confidence Interval，CI）。

 

研究结果

在中位随访3.34年的观察期内，更长的血管紧张素II受体拮抗剂（Angiotensin II Receptor Blocker，ARB）或钙通道阻滞剂（Calcium Channel Blocker，CCB）的用药时间与主要终点事件风险显著降低相关。ARB用药时间每增加1个单位，心血管风险降低45%（HR 0.55，95% CI 0.43-0.70），而CCB对应风险的降幅为30%（HR 0.70，95% CI 0.54-0.92）。与之相反，β受体阻滞剂用药时间每增加1个单位，主要终点风险增加120%（HR 2.20，95% CI 1.81-2.68）。次要终点分析显示，ARB与CCB用药时间的延长与全因死亡和心血管死亡风险显著降低相关。值得注意的是，ARB的长期使用在降低脑卒中、急性冠脉综合征和主要心血管不良事件风险方面表现出额外获益。此外，在主要终点事件、主要心血管不良事件、脑卒中等临床结局的发生风险上，ARB较CCB展现出更显著的保护作用（P<0.05）。在肾脏结局方面，利尿剂的长期使用与肾脏不良结局风险显著增加相关（HR 1.71，95% CI 1.37-2.13），其他类别降压药物对肾脏结局未呈现出显著关联。

 

研究结论

相较于利尿剂与β受体阻滞剂，ARB及CCB均显示出更优的心血管保护作用。在这两类药物中，ARB较CCB表现出了更显著的心血管获益。然而，β受体阻滞剂的长期使用与心血管风险增加相关，这可能源于适应证导致的选择偏倚。在四类降压药物中，仅利尿剂的长期使用与肾脏不良结局风险增加相关。基于上述发现，本研究支持将ARB作为首选降压药物以优化心血管风险控制策略；同时，对于有肾功能障碍的人群，需谨慎使用利尿剂类的降压药物。

Part I. Ten-year and lifetime cardiovascular disease risk stratified by blood pressure levels

Background

The 10-year and lifetime cardiovascular disease (CVD) risks for populations with different blood pressure levels, as defined by the latest 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines, still require further investigation. Furthermore, it’s also unclear how the temporal dynamics of blood pressure levels affect the corresponding risk. This study aims to investigate the association of different blood pressure levels and their dynamic changes, including reverting from stage 1 hypertension to normal-elevated blood pressure or progressing to stage 2 hypertension, with 10-year and lifetime CVD risks. These findings will contribute critical evidence for stratified risk management and personalized intervention strategies for hypertensive individuals.

 

Methods

This prospective cohort study, based on the Kailuan Study, involved 96,268 participants who underwent the health check-up in 2006. All individuals were categorized by blood pressure levels into 4 groups: normal (<120/80 mmHg), elevated (120-129/<80 mmHg), stage 1 hypertension (130-139/80-89 mmHg), and stage 2 hypertension (≥140/90 mmHg). The primary endpoint encompassed composite cardiovascular events, including myocardial infarction, cerebral hemorrhage, and cerebral infarction. The secondary endpoints included the independent components of the primary endpoint. We estimated the 10-year CVD risk using multivariable-adjusted Cox proportional hazards models and calculated lifetime risk through Fine-Gray competing risk models. To assess the dynamic changes of blood pressure on the risk of CVD, we re-examined the blood pressure in individuals who participated in both the 2006 and 2010 visits and divided them into three groups using the above-mentioned blood pressure classifications (normal-elevated range, stage 1 hypertension, and stage 2 hypertension). Further, they were cross-combined into nine subgroups according to their 2006 and 2010 blood pressure levels. The 10-year and lifetime risks of CVD were calculated in each group to evaluate the effect of dynamic change in blood pressure levels on the results of the analysis.

 

Results

Over a ten-year follow-up period, a total of 4,869 cardiovascular events were documented (3,080 ischemic strokes, 1,208 myocardial infarctions, and 787 intracerebral hemorrhages) and 6,680 all-cause deaths. Compared to the normal blood pressure group, the elevated, stage 1, and stage 2 hypertension groups exhibited a stepwise increase in 10-year and lifetime CVD risk. Specifically, compared with the normal blood pressure group, the stage 1 hypertension group had a 35% higher 10-year risk (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.19-1.52) and a 36% higher lifetime risk (HR 1.36, 95% CI 1.25-1.49). Stage 2 hypertension posed the highest risk, with a 165% increase in 10-year risk (HR 2.65, 95% CI 2.38-2.96) and a 128% increase in lifetime CVD risk (HR 2.28, 95% CI 2.10-2.48). By 2010, 12.57% of the participants with stage 1 hypertension had progressed to stage 2, resulting in a 156% increase in 10-year CVD risk (HR 2.56, 95% CI 2.11-3.11) and a 129% increase in lifetime risk (HR 2.29, 95% CI 1.89-2.77). There was no appreciable change in risk in those with stage 1 hypertension whose blood pressure reverted to the normal-elevated range (lifetime risk: HR 1.13, 95% CI 0.88-1.45).

 

Conclusions

Elevated blood pressure levels are associated with an increased risk of cardiovascular diseases. Stage 1 hypertension is associated with a significant increase in 10-year and lifetime CVD risk. Furthermore, progression to stage 2 hypertension further amplifies the  CVD risk. Regression from stage 1 hypertension to the normal-elevated range is not associated with a significant increase in the risk, suggesting a potential reversal of the adverse trend. Further efforts should be made to strengthen the management of people with abnormal blood pressure and to develop enhanced intervention strategies, in order to effectively lower the cardiovascular burden for this population group.

Part II. Influence of Multiple Risk Factor Control Level on Cardiovascular and Renal Outcomes in Hypertensive Patients

Section I. Influence of Multiple Risk Factor Control Level on Cardiovascular Outcomes in Hypertensive Patients

Background

Currently, several independent risk factors have been shown to have a significant impact on cardiovascular prognosis. However, the relationship between joint risk factor control and cardiovascular outcomes in hypertensive patients with intensive blood pressure intervention is not well understood. Moreover, it remains to be further investigated whether intensive blood pressure-lowering strategy influences the relationship between joint risk factor control and cardiovascular outcomes. This study aims to evaluate the relationship between comprehensive risk factor management and cardiovascular risk in hypertensive patients, as well as its interactive effects with intensive antihypertensive therapy.

 

Methods

We performed an analysis of data from the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients trial. Participants without complete baseline risk factor data were excluded. The following 7 risk factors were involved in the analysis: body mass index, low-density lipoprotein cholesterol, fasting serum glucose, smoking, alcohol consumption, physical activity, and renal function. The primary outcome in the present study was defined as a composite of stroke (ischemic or hemorrhagic), acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation and all-cause mortality. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI), and estimate the association between baseline risk factor control levels (≥6, 5, 4, and ≤3) and cardiovascular outcomes.

 

Results 

After excluding 174 participants with incomplete baseline lifestyle or blood parameters records, a total of 8337 participants were involved in the analysis and the median follow-up period was 3.19 years. Each additional risk factor uncontrolled was associated with a 24% higher cardiovascular risk (HR 1.24, 95% CI 1.11-1.37). Compared with participants with optimal risk factor control (≥6), those with ≤3 factors controlled exhibited 95% higher cardiovascular risk (HR 1.95, 95% CI 1.37-2.77). Among the 7 risk factors analyzed in this study, the three risk factors that demonstrated the strongest associations with the primary outcome were renal function, fasting serum glucose and alcohol consumption. The corresponding protective effects of multiple risk factor modification were not influenced by intensive or standard antihypertensive treatment (P for interaction=0.71).

 

Conclusions

A stepwise association was observed between cardiovascular risk and the number of baseline risk factor controlled in hypertensive patients. The more risk factors were modified, the less cardiovascular risk was observed, irrespective of different blood pressure-lowering strategies. Comprehensive baseline risk factor control strategies are warranted to reduce cardiovascular disease risk in hypertensive patients.

Part II. Influence of Multiple Risk Factor Control Level on Cardiovascular and Renal Outcomes in Hypertensive Patients

Section II. Influence of Multiple Risk Factor Control Level on Renal Outcomes in Hypertensive Patients

Background

There is a vicious circle between hypertension and chronic kidney disease (CKD), where elevated blood pressure contributes to the progression of renal disease, and the decline in kidney function further exacerbates hypertension. Previous studies demonstrated that the risk of kidney dysfunction is significantly elevated among individuals with hypertension. However, it remains unclear whether this increased risk can be mitigated by joint risk factor control. Therefore, addressing this question not only contributes to renal function improvement in hypertensive patients, but also establishes crucial theoretical foundations for developing multidimensional treatment strategies for cardio-renal protection.

 

Methods

Data from the Kailuan cohort were utilized in this study. The main exposure was the count of optimized risk factors, including systolic blood pressure, low-density lipoprotein cholesterol, fasting blood glucose, and body mass index. This study had a two-part analysis to investigate the association between the degree of joint baseline risk factor control and the development and progression of CKD. Participants were categorized based on their level of baseline risk factor control. Multivariable-adjusted Cox proportional hazards regression analysis was employed to calculate the hazard ratio (HR) and 95% confidence intervals (CI).

 

Results

During a median follow-up of 13.40 years, incident CKD was investigated in 77,356 hypertensive and 1:1 age- and sex-matched non-hypertensive counterparts. Each additional risk factor controlled was associated with an 18% reduction in the risk of incident CKD (HR 0.82, 95% CI 0.81-0.84) after adjusting for potential confounders. Compared to those with ≤1 controlled risk factor, participants with all four factors controlled had a 42% lower risk of CKD (HR 0.58, 95% CI 0.52-0.63). Individuals with hypertension exhibited a significantly elevated risk of developing incident CKD compared to their normotensive counterparts. Nevertheless, the magnitude of this increased risk progressively decreased with each additional risk factor controlled. CKD progression was assessed in 9,543 hypertensive and 6,799 non-hypertensive participants, all with pre-existing CKD, with a median follow-up of 11.88 years. Having each additional risk factor controlled was linked to an 18% reduction in the risk of CKD progression (HR 0.82, 95% CI 0.78-0.86). Notably, when three risk factors were optimally controlled, no excess risk of CKD progression was observed between hypertensive and normotensive individuals. Further analysis showed that, compared to normotensive individuals, hypertensive participants who controlled all four risk factors had a 31% lower risk of CKD progression (HR 0.69, 95% CI 0.53-0.89).

 

Conclusions

Risk factor control is associated with a progressive and cumulative reduction in kidney dysfunction risk in hypertensive patients. Effectively managing more risk factors leads to a lower risk of renal function decline. Individuals who maintain all four risk factors within target ranges can mitigate, or even eliminate, the excess risk of CKD development and progression associated with hypertension. These findings highlight the importance of a comprehensive approach to risk factor management in clinical practice.

Part III. Impact of Antihypertensive Drug Classes on Cardiovascular and Renal Outcomes

Background

The optimal class of antihypertensive drugs for reducing cardiovascular and kidney disease risk remains unclear in current clinical practice. This study investigated whether prolonged exposure to specific antihypertensive drug classes is associated with lower cardiovascular and renal risk in individuals with well-controlled blood pressure.

 

Methods

This study utilized data from the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial, which enrolled elderly Chinese patients with hypertension without a history of stroke. After excluding 234 patients who were lost to follow-up and 20 patients without blood pressure records after randomization, a total of 8,257 patients were included in this study. The relative time on each antihypertensive drug class (medication time/event time) was calculated. The primary outcome was a composite of the first occurrence of stroke, acute coronary syndrome (ACS), acute decompensated heart failure, coronary revascularization, atrial fibrillation, and cardiovascular death. Secondary endpoints included individual components of the primary outcome and kidney outcome. Cox regression analysis was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for each outcome.

 

Results

Over a median 3.34 years follow-up, longer relative exposure to angiotensin II receptor blockers (ARBs) or calcium channel blockers (CCBs) significantly reduced the primary outcome risk. Each unit increase in relative time on ARBs lowered cardiovascular risk by 45% (HR 0.55, 95% CI 0.43-0.70), compared to a 30% reduction with CCBs (HR 0.70, 95% CI 0.54-0.92). In contrast, each unit increment in relative time on beta-blockers was associated with a higher risk of primary outcome (HR 2.20, 95% CI 1.81-2.68). Regarding secondary outcomes, longer exposure to ARBs and CCBs was significantly associated with a lower risk of all-cause and cardiovascular mortality. Longer exposure to ARBs produced additional benefits by reducing the risk of stroke, ACS, and major adverse cardiac events (MACE). The HR per-unit increase in relative time on ARBs remained consistently lower than that of CCBs for the primary outcome, MACE, and stroke (all P<0.05). Further, the long-term administration of ARBs, CCBs, and beta-blockers showed no significant association with kidney dysfunction. Conversely, extended use of diuretics was significantly correlated with an elevated risk of adverse renal outcome (HR 1.71, 95% CI 1.37-2.13).

 

Conclusions

ARBs and CCBs were superior to diuretics and beta-blockers in reducing composite cardiovascular outcomes. ARBs provided better cardiovascular benefits compared to CCBs. Longer exposure to beta-blockers was associated with a higher cardiovascular risk, which might reflect a selection bias based on medical indications. Furthermore,  long-term use of diuretics was associated with an increased risk of adverse kidney outcomes. Based on these findings, our study supported the clinical preference for ARBs as the first-line antihypertensive treatment to optimize cardiovascular risk management strategies. For patients with renal dysfunction, diuretics should be used with caution.