背景：

高血压是全球心血管疾病发病和死亡的主要原因，随着中国经济的快速发展和老龄化进程的加速，以及缺乏锻炼、不健康饮食等不良的生活方式，心血管疾病的发病率不断攀升，已成为我国最主要的死亡原因，高血压是心血管疾病最重要的可改变的危险因素之一。随着人口的迅速老龄化，老年高血压患者的降压治疗也受到广泛关注。SPRINT研究证明在老年高血压患者中强化降压能显著降低心血管事件和全因死亡,最近发表的STEP研究证实在中国老年高血压患者中强化降压可以显著降低心血管事件的风险。与标准降压相比，强化降压可避免心血管事件的发生，并降低事件相关的治疗费用。然而，这种降压方案并非没有风险或成本，这是我们在成本效益分析中需要考虑的因素。同时，为了降低用药负担、提高降压药的可获得性，2019年1月中华人民共和国国务院办公厅启动实施国家药品集中采购政策，该政策在全国范围内的实施，成功地减轻了患者的用药负担。

目的：

本项研究的目的是在考虑到近年来中国实施的国家药品集中采购(National Centralized Drug Procurement，NCDP)政策导致降压药物价格下降后，利用STEP试验的心血管事件风险的数据和药物使用情况的数据，估计强化降压治疗的终身健康获益和医疗费用。

方法：

我们构建了一个微观模拟模型，该模型包括10,000名基线收缩压高于140mmHg的年龄在60至80岁的中国老年高血压人群，该模拟人群的纳入标准和基线特征与STEP研究一致。其中5000名患者接受强化降压治疗，收缩压目标为110-130mmHg，5000名患者接受标准降压治疗，收缩压目标为130-150mmHg。人群进入模型以后，我们利用模型模拟患者经历的所有的健康状态以及可能出现的结局，为了比较强化降压和标准降压的终生获益，所有人随访直至死亡或年龄到达100岁。我们假设坚持服药的患者其首次致命性或非致命性心血管事件和治疗相关的不良事件的风险与STEP试验中观察到的一致，因心血管疾病以外的原因而死亡的概率来自于国家卫生统计年鉴。未坚持用药的患者逐渐恢复至基线收缩压，采用China-PAR公式估算首次致死性或非致死性心血管事件的发生风险。本研究的主要结局是从支付方的角度考虑的增量成本效益比，次要结局是心血管事件复合终点，包括急性冠状动脉综合征、卒中、急性失代偿性心力衰竭、心房颤动和心血管原因导致的死亡。模型进行了短期验证和长期验证，短期验证比较了STEP研究中观察到的心血管事件风险与模型预测的心血管事件风险，长期验证是将基本情况中的心血管事件和全因死亡发生率的预测结果与开滦研究的长期随访结果进行比较。为了评估模型中输入参数的不确定性对结果的影响，我们进行了单因素敏感性分析，即在保持其他参数值不变的情况下，观察单个参数在其合理的范围内变化对研究结果的影响，情景分析评估了服药依从性和降压药成本的不同假设对研究结果的影响，概率敏感性分析是模型在所有参数的合理范围内随机数值。

结果：

在模型的短期验证中，强化降压治疗和标准降压治疗的心血管事件复合终点的发生率分别为10.3/1,000人年和13.7/1,000人年，STEP研究中的心血管事件复合终点的发生率分别为10.3/1,000人年和13.5/1,000人年，心血管事件复合终点的风险比在模型中模拟的结果为0.75(95% CI为 0.61-0.93)，在STEP研究中为0.76(95% CI 0.61-0.95)。在长期验证中，该模型的心血管事件复合终点的累积发生率和全因死亡累积发生率与开滦研究的长期随访结果相当。模拟结果显示，在基本情况中，在患者剩余的生命周期内，强化降压组的5,000名患者中有36.88%发生了心血管事件，标准降压组的5,000例患者中有41.28%发生了心血管事件(两组的绝对差异为4.4个百分点)，患者的平均剩余寿命在两组分别为17.71年和17.56年。接受强化降压治疗的患者的平均质量调整生命年比接受标准降压治疗的患者高0.16，每增加1个质量调整生命年，强化降压治疗的成本比标准降压治疗高12,614元人民币(3018美元)。在5000次概率模拟中，当支付意愿阈值为每获得一个质量调整生命年需要花费72,000元时[2020年1倍中国人均国内生产总值]，强化降压具有成本效益的概率为91%。单因素敏感性分析中，对增量成本效益比影响最大的参数为强化降压组的心血管疾病导致死亡的风险，当强化降压组的心血管疾病死亡的风险取最小值时，增量成本效益比达到最大，为20,998元，其他参数在其取值范围内均未使增量成本效益比超过20,000元/QALY。情景分析中，我们对干预之后用药依从性和药物成本有不同的假设，结果显示，强化降压治疗依然具有成本效益。

结论：

在中国老年高血压患者中，与标准降压治疗相比，强化降压治疗可以降低心血管事件，并且在大多数情况下具有成本效益，我们的分析从经济角度支持在老年高血压人群中实施强化降压治疗，因为这种血压干预方式在可接受的成本下提供更多的健康获益。

Background: Hypertension is the major risk factor of cardiovascular disease (CVD) and mortality all over the world, contributing to at least 7.6 million deaths annually (13.5% of all deaths). Due to the rapid economic development and the acceleration of the aging process, combined with sedentary behavior, unhealthy dietary habits, and other unfavorable lifestyle choices, the prevalence of cardiovascular disease continues to rise and has become the leading cause of death in China. Hypertension is one of the most important modifiable risk factors for cardiovascular disease. With the population rapidly aging, there has been a rise of interest in antihypertensive treatment for older hypertension patients. The SPRINT trial found that intensive blood pressure lowering in older hypertension individuals decreased cardiovascular events and all-cause mortality considerably. The recently published STEP trial revealed that intensive blood pressure treatment significantly reduced the incidence of cardiovascular events in Chinese older hypertensive patients. Compared with standard blood pressure treatment, intensive treatment may avert cardiovascular events and decrease events related treatment costs. However, this strategy is not without risks or costs, which must be taken into account in cost-effectiveness analysis. Moreover, the National Centralized Drug Procurement (NCDP) policy was launched in January 2019 by the General Office of the State Council of the People's Republic of China with the aim of reducing medication burden and improving the affordability and accessibility of medications. The implementation of this policy throughout the nation has successfully reduced the medication cost for 245 million hypertensive individuals.

Objective: The aim of this cost-effectiveness analysis was to evaluate the long-term health benefits and medical expenditures associated with intensive blood pressure treatment, while taking into consideration the reduced expense of anti-hypertensive drugs resulting from the recent implementation of the NCDP policy, utilizing the treatment and efficacy data from the STEP trial.

Methods: A microsimulation model included 10,000 hypothetical samples of Chinese individuals aged 60 to 80 years old with baseline systolic blood pressure higher than 140 mmHg. This hypothetical cohort was established utilizing the identical inclusion criteria and baseline characteristics as witnessed in the STEP trial. In this context, a total of 5000 patients received intensive blood pressure intervention aiming to reduce systolic blood pressure to a range of 110-130 mmHg, whereas another 5000 patients were subjected to standard blood pressure intervention with a systolic blood pressure target of 130-150 mmHg. After entering the model, patients could have any of the following health status: (1) treated hypertension without events; (2) stroke; (3) post-stroke; (4) acute coronary syndrome; (5) post-acute coronary syndrome; (6) heart failure; (7) post-heart failure; (8) atrial fibrillation; (9) post-atrial fibrillation; (10) death from cardiovascular causes; (11) death from causes other than cardiovascular disease. To calculate the lifetime benefits of the two treatment strategies, all patients were tracked until death or the age of 100. The risks of the initial fatal or non-fatal cardiovascular events and treatment-related adverse events in patients who complied with the medication strategy were consistent with the STEP study. Additionally, the risk of death due to causes other than cardiovascular disease was acquired from the National Statistical Yearbook. Those patients who were non-adherent to the medication gradually reverted to their baseline systolic blood pressure. Furthermore, the China-PAR equation was used to evaluate the risks of the first fatal or non-fatal cardiovascular events for those non-adherent individuals. Primary outcome was the incremental cost-effectiveness ratio (ICER) from a payer’s perspective. Secondary outcome was composite endpoint of cardiovascular events, including acute coronary syndrome, stroke, acute decompensated heart failure, atrial fibrillation, and death from cardiovascular causes. We performed both short-term validations, in which we compared the observed risks of cardiovascular events in the STEP trial to the risks of cardiovascular events predicted by our model, and long-term validations, in which we compared the predicted outcomes of cardiovascular events and all-cause mortality rates in the base case to the long-term follow-up results of the Kailuan study. To investigate the influence of uncertainty in the model's input parameters, we conducted one-way sensitivity analysis, which examined the effect of changes in individual parameters within a reasonable range on the study's results while maintaining the values of others constant. The scenario analysis examined the effect of different assumptions regarding medication adherence and the cost of antihypertensive drugs. In the probabilistic sensitivity analysis, the model randomly selected values within a reasonable range of all parameters.

Results: Short-term validation revealed that the incidence of the composite endpoint of cardiovascular events was 10.3 per 1,000 person-years in the base case for the intensive blood pressure treatment, and 13.7 per 1,000 person-years for the standard blood pressure treatment, respectively, and 10.3/1,000 and 13.5/1,000 person-years for the composite endpoint of cardiovascular events in the STEP trial. The hazard ratio (HR) for the composite endpoint of events was 0.75 (95% CI 0.61 - 0.93) in the model, and 0.76 (95% CI 0.61 - 0.95) in the STEP trial. In the long-term validation, the cumulative incidences of the composite endpoint of cardiovascular events and all-cause mortality were similar to the long-term follow-up results in the Kailuan study. According to the simulation, in the base case, 36.88% of the 5,000 patients in the intensive blood pressure treatment group and 41.28% of the 5,000 patients in the standard blood pressure treatment group experienced cardiovascular events during the remaining lifespan, resulting in an absolute difference of 4.4 percentage points between the two groups. The patients' mean remaining life expectancy was 17.71 years and 17.56 years in the two groups, respectively. Furthermore, the average number of quality-adjusted life years (QALYs) for patients receiving intensive blood pressure treatment was 0.16 higher compared to those receiving standard treatment. The intensive blood pressure treatment cost CNY12, 614 (Int$ 3018) more per QALY gained than standard blood pressure treatment. In 5000 probabilistic simulations, when the willingness-to-pay threshold was CNY 72,000 per QALY gained [one times the gross domestic product per capita in 2020], the probability of intensive blood pressure treatment being cost-effective was 91%. In one-way sensitivity analysis, the risk of death from cardiovascular causes in the intensive treatment group was the parameter that had the greatest impact on incremental cost-effectiveness ratio (ICER), reaching a maximum value of CNY 20,998 when the risk of death from cardiovascular disease in the intensive treatment group was taken as the minimum value. None of the other parameters in their range resulted in ICER value exceeding CNY 20,000 per QALY gained. The results of scenario analysis in which we made various assumptions regarding medication adherence and pharmaceutical expenses after the intervention period revealed that intensive blood pressure treatment remained cost-effectiveness.

Conclusions: Compared with standard blood pressure treatment, the implementation of intensive blood pressure treatment averted cardiovascular events among the older hypertensive patients in China. Notably, it has been demonstrated to be cost-effective in a majority of the scenarios. Our research supports the implementation of intensive blood pressure intervention in the older population from an economic perspective, since this intervention can bring extra health benefits at a reasonable cost.