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. 2021 Mar 4;18(3):e1003515. doi: 10.1371/journal.pmed.1003515

Applicability and cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese population: A cost-effectiveness modeling study

Chao Li 1,2, Kangyu Chen 3, Victoria Cornelius 4, Ewan Tomeny 5, Yang Wang 6, Xiaowei Yang 7, Xiaodan Yuan 8, Rui Qin 8, Dahai Yu 9, Zhenqiang Wu 10, Duolao Wang 2, Tao Chen 1,2,*
PMCID: PMC7971845  PMID: 33661907

Abstract

Background

The Systolic Blood Pressure Intervention Trial (SPRINT) showed significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of <120 mm Hg compared with a SBP goal of <140 mm Hg. Our study aimed to assess the applicability of SPRINT to Chinese adults. Additionally, we sought to predict the medical and economic implications of this intensive SBP treatment among those meeting SPRINT eligibility.

Methods and findings

We used nationally representative baseline data from the China Health and Retirement Longitudinal Study (CHARLS) (2011–2012) to estimate the prevalence and number of Chinese adults aged 45 years and older who meet SPRINT criteria. A validated microsimulation model was employed to project costs, clinical outcomes, and quality-adjusted life-years (QALYs) among SPRINT-eligible adults, under 2 alternative treatment strategies (SBP goal of <120 mm Hg [intensive treatment] and SBP goal of <140 mm Hg [standard treatment]). Overall, 22.2% met the SPRINT criteria, representing 116.2 (95% CI 107.5 to 124.8) million people in China. Of these, 66.4%, representing 77.2 (95% CI 69.3 to 85.0) million, were not being treated for hypertension, and 22.9%, representing 26.6 (95% CI 22.4 to 30.7) million, had a SBP between 130 and 139 mm Hg, yet were not taking antihypertensive medication. We estimated that over 5 years, compared to standard treatment, intensive treatment would reduce heart failure incidence by 0.84 (95% CI 0.42 to 1.25) million cases, reduce CVD deaths by 2.03 (95% CI 1.44 to 2.63) million cases, and save 3.84 (95% CI 1.53 to 6.34) million life-years. Estimated reductions of 0.069 (95% CI −0.28, 0.42) million myocardial infarction cases and 0.36 (95% CI −0.10, 0.82) million stroke cases were not statistically significant. Furthermore, over a lifetime, moving from standard to intensive treatment increased the mean QALYs from 9.51 to 9.87 (an increment of 0.38 [95% CI 0.13 to 0.71]), at a cost of Int$10,997 per QALY gained. Of all 1-way sensitivity analyses, high antihypertensive drug cost and lower treatment efficacy for CVD death resulted in the 2 most unfavorable results (Int$25,291 and Int$18,995 per QALY were gained, respectively). Simulation results indicated that intensive treatment could be cost-effective (82.8% probability of being below the willingness-to-pay threshold of Int$16,782 [1× GDP per capita in China in 2017]), with a lower probability in people with SBP 130–139 mm Hg (72.9%) but a higher probability among females (91.2%). Main limitations include lack of specific SPRINT eligibility information in the CHARLS survey, uncertainty about the implications of different blood pressure measurement techniques, the use of several sources of data with large reliance on findings from SPPRINT, limited information about the serious adverse event rate, and lack of information and evidence for medication effectiveness on renal disease.

Conclusions

Although adoption of the SPRINT treatment strategy would increase the number of Chinese adults requiring SBP treatment intensification, this approach has the potential to prevent CVD events, to produce gains in life-years, and to be cost-effective under common thresholds.

Tao Chen and colleagues estimate the cost-effectiveness of intensive blood pressure intervention in Chinese populations at high risk for cardiovascular disease.

Author summary

Why was this study done?

  • The Systolic Blood Pressure Intervention Trial (SPRINT) has previously demonstrated significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of < 120 mm Hg (intensive treatment) compared with a SBP goal of <140 mm Hg (standard treatment).

  • A large proportion of Chinese adults are classified as hypertensive but few of them achieve recommended blood pressure targets.

What did the researchers do and find?

  • We used nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS) (2011–2012) to assess the applicability of SPRINT to the Chinese adult population, and a validated microsimulation model to predict the cost-effectiveness of this intensive treatment among those meeting the SPRINT eligibility criteria for intensive treatment.

  • It is estimated that 116.2 million adults in China are eligible for the SPRINT intensive treatment strategy.

  • If adopted, intensive treatment has the potential to prevent 2.03 million CVD deaths, with a potential gain of 3.84 million more life-years over 5 years, and would likely be cost-effective over a lifetime.

What do these findings mean?

  • A substantial number of Chinese adults meet SPRINT eligibility criteria for intensive blood pressure treatment.

  • This evidence suggests that intensive treatment among high-risk populations could be cost-effective.

Introduction

Elevated blood pressure (BP) is the leading risk factor for cardiovascular diseases (CVDs) in China [1]. In 2015 a systolic BP (SBP) of 140 mm Hg or higher was found to be associated with over 1.7 million deaths and more than 32 million disability-adjusted life-years in China, accounting for more than 22% of global health losses from hypertension over that year [2]. Despite safe and effective antihypertensive medications having been available for decades and recommended for use under the current guideline [3,4], China still faces huge challenges with its low hypertension control rate and increasing hypertension in both prevalence and absolute numbers [5–7]. It is clear that better management is required to address this growing burden of hypertension.

The landmark Systolic Blood Pressure Intervention Trial (SPRINT) found that participants assigned to intensive treatment (SBP goal of <120 mm Hg) had an 25% reduction in major cardiovascular events and deaths compared with standard treatment (SBP goal of <140 mm Hg), and all-cause mortality was reduced by 27% [8]. This significant finding was supported by 2 meta-analyses of randomized clinical trials [9,10] and had far-reaching implications for hypertension guidelines across the world [11,12].

The generalizability of the SPRINT intensive SBP treatment strategy to the Chinese population is unclear, and the costs incurred from intensive drug treatment and adverse events need to be weighed against the gains from preventing cardiovascular morbidity and mortality. We explored the potential benefits that could be achieved through implementing the intensive SBP treatment goal strategy proposed in SPRINT among Chinese adults. Our study used a nationally representative dataset from China and a microsimulation model, aiming to (1) estimate the numbers of Chinese adults who meet the SPRINT eligibility criteria and describe their characteristics, (2) predict medium- and long-term associated cardiovascular risk and mortality, and (3) evaluate the lifetime cost-effectiveness of intensive SBP treatment versus standard treatment among adults meeting SPRINT eligibility criteria.

Methods

This study is composed of 2 parts: population analysis and health economic modeling. It was planned at the time of study conception on the basis of our previous work [13], although no formal prospective analysis plan was recorded. A further analysis of splitting the total cost into its components was added in response to a peer reviewer’s comments (see Table G in S1 Text). This study is reported as per the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guideline (S1 CHEERS Checklist).

Design of population study

Data source and study population

We used the national baseline database of the China Health and Retirement Longitudinal Study (CHARLS), which was conducted in 2011–2012 and included 17,708 people. The study design for CHARLS has been reported previously [14,15]. CHARLS is a nationally representative survey of people aged 45 years and older in China, and participants are followed up biennially. CHARLS data are available via the website http://charls.pku.edu.cn/pages/data/2011-charls-wave1/en.html. Other relevant data are presented here and in S1 Text. Study participants are selected through multistage probability sampling and can be weighted to obtain national estimates. Detailed data including demographic characteristics, medical history, prescription drug use, clinical measurement, and laboratory testing are collected by standard questionnaires. Definitions for variables used in our study can be found in “Study variables and definition” in S1 Text. The ethics committee of Peking University Health Science Center approved CHARLS, and all participants gave written informed consent before participation.

Analytical approach

Potential eligibility for SPRINT was determined using a multistep algorithm. The sample needed to meet the following criteria: age ≥ 50 years; SBP 130–180 mm Hg on 0 or 1 antihypertensive medication class, 130–170 mm Hg on up to 2 classes, 130–160 mm Hg on up to 3 classes, or 130–150 mm Hg on up to 4 classes; and the presence of 1 or more high CVD risk conditions. Despite being part of the eligibility criteria, antihypertensive medication classes are not reported in the CHARLS database, and so in the present study we used the slightly less restrictive criterion SBP 130–180 mm Hg on any number of antihypertensive medication classes. High CVD risk conditions were defined as 1 or more of the following: history of coronary heart disease, estimated glomerular filtration rate (eGFR) of 20 to 59 ml/min/1.73 m2, 10-year risk for CVD ≥ 15% calculated using the Framingham risk score for general clinical practice, and age ≥ 75 years. Participants were not eligible if they had any of the following exclusion criteria: diabetes, a history of stroke, heart failure (HF), or end-stage renal disease. The demographic and clinical characteristics of Chinese adults meeting SPRINT eligibility criteria are presented in Table A in S1 Text. The absolute numbers overall and for subgroups of Chinese adults meeting each sequential SPRINT eligibility criterion were estimated using survey analyses with patient-level sampling weights for China.

Design of the health economic model

We developed a microsimulation model to project healthcare costs, clinical outcomes, and quality-adjusted life-years (QALYs) among the SPRINT-eligible Chinese adults for antihypertensive treatment (regardless of their BP treatment history) under 2 alternative SBP treatment strategies: SBP goal of <120 mm Hg (intensive treatment) versus SBP goal of <140 mm Hg (standard treatment). In order to maintain the correlations between the attributes of individuals (e.g., age, sex, SBP), we bootstrapped 10,000 real individuals meeting SPRINT eligibility criteria from CHARLS using TreeAge Pro 2018 R1.1. This approach contrasts with simulating hypothetical individuals via the distribution of each independent variable (e.g., mean and standard deviation for age), as the authors have done previously [13].

Model structure

In line with our previous work [13], our model is structured around 9 distinct health states. At the end of every model cycle (i.e., 1 year), an individual will either transit to another health state or remain in the same state, with the probabilities sampled from defined distributions. Subsequent to a primary event (i.e., myocardial infarction [MI], HF, or stroke), patients move to a chronic heath state in which they have a higher risk of experiencing a further CVD event or death. Also, our model includes the disease pathway of experiencing more than 1 event (e.g., the occurrence of stroke after MI) during the first year of primary event. In SPRINT, it was reported that intensive SBP treatment could increase the risk of specific adverse events, such as hypotension, syncope, electrolyte abnormalities, and acute kidney injury. However, due to the lack of local data from China, we did not specify the individual serious adverse events (SAEs) as in SPRINT. Therefore, we included a category of combined SAEs to capture the costs and harms incurred from intensive SBP treatment. Additionally, we assumed the risk of a CVD event would be the same for those with and without SAEs in our model. The overall disease path is described in S1 Fig, and the detailed disease states within each path can be found in our previous publication [13].

Transition probabilities

We estimated the primary incidence of MI/stroke [16] and HF [17] by their corresponding and validated risk equations using the individual characteristics of the SPRINT-eligible people in CHARLS. Other probabilities—including those of chronic conditions followed by a primary event, secondary events, and SAEs from antihypertensive medications—were derived from national sources and published literature. The values for the transition probabilities and their distributions are summarized in Table C in S1 Text.

Cost and utility weights

Costs were considered from a payer’s perspective. All costs are reported in 2017 international dollars according to the exchange rate published by the World Bank, based on purchasing power parity (PPP) methods (Int$1.00 = 3.54 yuan) [18]. All future costs and QALYs were discounted at 3% annually. Total costs included antihypertension treatment costs, cost of complications, and SAE costs. Specifically, for costs of BP medications, we used a nationwide cross-sectional survey on the costs and frequencies of each standard antihypertensive drug class within the combinations of medications [4] recommended by 2018 Chinese guidelines for the management of hypertension [19]. For the costs of a CVD event, we incorporated a hospitalization cost associated with such an acute event, as well as annual costs afterwards. The cost of SAEs was from a publication [20] but was only applied in the year when an SAE occurred. A detailed description of costs can be found in the “Cost” section of S1 Text and in Table D in S1 Text.

We calculated utilities by age and sex for patients with hypertension based on a Chinese population; however, as in our previous work [13], for a CVD event we adopted utility values used in other cost-effectiveness studies. Since utilities associated with SAEs were not available, we assumed a utility of 0.5 for 1 week before returning to the previous health state. This approach has been adopted and justified in previous studies [21,22].

Model validation

We validated the model through 2 strategies: First, we compared the projected life expectancy in our model with that from China life tables in 2017 [6]. Second, we also computed the predicted 5-year coronary heart disease, stroke, HF, and mortality rates among people with standard treatment from our base-case model and compared these with published data.

Base-case and sensitivity analyses

Since there is no commonly accepted cost-effectiveness threshold for China, we adopted the one calculated using the method previously recommended by the World Health Organization [23]. Here, an incremental cost-effectiveness ratio (ICER) below Int$16,782 (China’s gross domestic product per capita in 2017) implies that the intensive SBP treatment is cost-effective compared to standard treatment.

In order to examine the effect of the uncertainty of each model parameter on the result from our base-case analysis, we varied each input value in our model over a plausible range in a series of 1-way sensitivity analyses. In addition to the above deterministic sensitivity analyses, we conducted probabilistic sensitivity analyses by running our model 1,000 times, with each run sampling from prespecified distributions of each parameter. The plausible ranges and distributions for each of the model parameters are detailed in Table C and Table D in S1 Text.

Results

Number and characteristics of Chinese adults meeting SPRINT eligibility criteria

Overall, 22.2% (95% CI 20.5% to 23.9%) of Chinese adults, representing 116.2 (95% CI 107.5 to 124.8) million people, met the SPRINT criteria (Figs 1 and 2). Among Chinese adults with hypertension, 41.4% (95% CI 37.8% to 45.1%), or 93.3 million, were eligible for SPRINT. This is compared to 37.9% (95% CI 34.4%, 41.5%), or 22.8 million, among Chinese adults without hypertension (i.e., with SBP 130–139 mm Hg). Additionally, among those with treated hypertension, 37.2% (95% CI 33.6% to 40.8%), or 39.0 million, may benefit from further SBP reduction (Fig 2). The number of adults meeting each sequential SPRINT eligibility criterion are detailed in Table B in S1 Text.

Fig 1. Flow chart showing the eligibility criteria for SPRINT applied to the present study.

Fig 1

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Total number of baseline participants of the China Health and Retirement Longitudinal Study was 17,708. After excluding missing blood pressure values, there were 13,483 eligible participants included in the present analysis. CVD, cardiovascular disease; SPRINT, Systolic Blood Pressure Intervention Trial.

Fig 2. Number of Chinese adults (age ≥ 45 years) meeting each sequential SPRINT eligibility criterion.

Fig 2

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The circles are proportional to the population sizes. Hypertension defined as SBP ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg or taking antihypertensive medication. CI, confidence interval; CVD, cardiovascular disease; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial.

Compared with the overall study population, those eligible for SPRINT were more likely to be older, to be male, to smoke, and to have a SBP ≥ 140 mm Hg (Table A in S1 Text). It is noted that, of those SPRINT-eligible adults, 77.2 million (66.4%) were not being treated for hypertension, and 26.6 million (22.9%) had a SBP of 130 to 139 mm Hg, yet were not taking antihypertensive medications.

Model validation

The predictions of our microsimulation model for life expectancy and rates of MI, stroke, CVD mortality, and all-cause mortality over the 5-year period were similar to those published in other real-world Chinese studies (Table E in S1 Text).

Base-case analysis

Compared to standard treatment, intensive SBP treatment was predicted to reduce the incidence rate of HF within 5 years by 0.72% (95% CI 0.36%, 1.08%) and CVD mortality by 1.75% (95% CI 1.24%, 2.26%), though it was not predicted to significantly reduce the incidence rate for MI (0.06%; 95% CI −0.24, 0.36%) or stroke (0.31%; 95% CI 0.09%, 0.71%). Correspondingly, we estimate the 5-year event reduction would be 0.84 (95% CI 0.42, 1.25) million for HF, 2.03 (95% CI 1.44, 2.63) million for CVD mortality, 0.069 (95% CI −0.28, 0.42) million for MI, and 0.36 (95% CI −0.10, 0.82) million for stroke. Taken together, 3.84 (95% CI 1.53, 6.34) million life-years could be saved within 5 years via intensive SBP treatment compared to standard treatment, and 11.06 (95% CI 9.7, 14.73) million life-years over a lifetime (Fig 3; Table F in S1 Text).

Fig 3. Base-case 5-year and lifetime events reduced for different outcomes.

Fig 3

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“Events reduced” refers to events that would be reduced if the intensive treatment were in place instead of standard treatment. It is calculated by multiplying the event difference from our simulation by the number of SPRINT-eligible adults. CVD, cardiovascular disease; HF, heart failure; MI, myocardial infarction.

The potential changes in QALYs and total cost (consisting of antihypertension treatment costs, cost of SAEs, and cost of complications) over a lifetime are summarized in Table 1 and Table G in S1 Text. Intensive SBP treatment led to a gain of 0.38 QALYs (95% CI 0.13, 0.71), while increasing costs from $7,861 to $11,395 (an increment of $3,777 [95% CI −$208, $8,286]). This means that compared to standard treatment, intensive SBP treatment costs $10,997 (−$752, $29,027) per additional QALY gained. The estimate of the cost-effectiveness of intensive SBP treatment in most subgroups of interest was similar to the overall estimate, although less favorable ICERs were estimated for men ($12,259 per QALY gained) and those with SBP 130–139 mm Hg ($13,277 per QALY gained).

Table 1. Lifetime costs, QALYs, and ICER values for intensive versus standard blood pressure control strategies.

Outcome Total cost, international dollarsa Incremental cost, international dollars (95% UI)b QALYs Incremental QALYs (95% UI)b ICER (international dollars per QALY) (95% UI)b Probability of being cost-effective, below 1× GDP per capita Probability of being cost-effective, below 2× GDP per capita
Overall
 Intensive treatment 11,395 3,777 (−208, 8,286) 9.87 0.38 (0.13, 0.71) 10,997 (−752, 29,027) 0.828 0.981
 Standard treatment 7,861 9.51
Male
 Intensive treatment 11,203 3,806 (−188, 8,347) 10.09 0.34 (0.12, 0.63) 12,259 (−773, 33,292) 0.769 0.974
 Standard treatment 7,679 9.74
Female
 Intensive treatment 11,723 3,659 (−86, 7,984) 9.51 0.46 (0.16, 0.84) 9,004 (−354, 23,427) 0.912 0.988
 Standard treatment 8,172 9.12
Age < 75 years
 Intensive treatment 12,285 4,103 (−196, 9,025) 10.75 0.41 (0.14, 0.77) 11,119 (−722, 29,299) 0.820 0.981
 Standard treatment 8,461 10.35
Age ≥ 75 years
 Intensive treatment 7,695 2,357 (−97, 5,056) 6.21 0.25 (0.10, 0.43) 10,176 (−373, 26,429) 0.859 0.984
 Standard treatment 5,365 6.02
SBP 130–139 mm Hg
 Intensive treatment 11,375 3,914 (−178, 8,566) 10.21 0.33 (0.11, 0.60) 13,277 (−920, 33,474) 0.729 0.973
 Standard treatment 7,657 9.87
SBP ≥ 140 mm Hg
 Intensive treatment 11,403 3,682 (−175, 8,076) 9.71 0.42 (0.15, 0.77) 9,916 (−598, 26,158) 0.883 0.984
 Standard treatment 7,957 9.34
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aTo convert cost input to Chinese currency, one would multiply the cost by the purchasing power parity (PPP) rate (in this case, 3.54). Total cost includes antihypertension treatment costs, cost of complications, and serious adverse event costs.

bProbabilistic analyses based on running the model 1,000 times with the use of randomly selected values for input measurements from predefined distributions. The UIs show the 2.5 to 97.5 percentiles for the incremental differences in costs and QALYs. The uncertainty of the ICER, which was calculated as the cost per QALY gained, is shown by the probability that intensive control is cost-effective at the specified willingness-to-pay thresholds.

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; SBP, systolic blood pressure; UI, uncertainty interval.

Uncertainty analysis

We assessed the uncertainty in the estimates by means of 1,000 probabilistic simulations. Overall, there was an 82.8% probability that intensive treatment was cost-effective at a willingness-to-pay threshold of $16,782 per QALY (1× GDP per capita in 2017) and a 98.1% probability at a threshold of $33,564 per QALY (2× GDP per capita in 2017) (Table 1; S3 and S4 Figs). The probability of being cost-effective varied across different subgroups at a threshold of 1× GDP per capita; however, it became stable (around 98% probability of being cost-effective) if the threshold increased to 2× GDP per capita.

Results in S2 Fig show that our cost-effectiveness outcome is relatively insensitive to a variety of alternate assumptions, with estimated ICERs all below 1× GDP per capita (with the exception of cost for antihypertensive medication). There were 8 parameters that were especially influential to our ICER estimates: cost for antihypertensive medication, relative risk of CVD death from treatment, relative risk of stroke from treatment, cost for SAE, cost for post-stroke care, utility for SAE, relative risk of SAE from treatment, and relative risk of HF from treatment.

Discussion

Using nationally representative data we found that the SPRINT intensive SBP treatment strategy could increase the number receiving SBP treatment initiation or intensification to more than 116 million adults in China, which is 22.2% of the population. Furthermore, through a validated microsimulation model we projected that over 5 years more than 2.03 million CVD deaths could be prevented, and 3.84 million life-years could be saved, if an intensive SBP treatment target of <120 mm Hg for selected high-risk patients were adopted. In addition, our study found that intensive SBP treatment would cost Int$10,997 per QALY gained and was likely to be cost-effective (82.8% probability of being below 1× GDP per capita for China in 2017).

In 2 previous studies from the US and Canada, the investigators found that 7.6% of US adults and 5.2% of Canadian adults meet the SPRINT eligibility criteria, yet our estimate for China was much higher (22.2%). These results suggest that the uncontrolled hypertension rate in China is higher than in the US and Canada. Furthermore, with such a large population, the absolute number of people who would benefit is considerably larger in China (116 million versus 16.8 million for the US and 1.3 million for Canada) [24,25]. Remarkably, we estimated that two-thirds (66.4%) of those meeting SPRINT eligibility criteria were not treated for hypertension, which was higher than the estimates for the US (50.6%) and Canada (40.4%). Additionally, we found that 22.9% of them had SBP of 130 to 139 mm Hg, and would not previously have been considered to have hypertension and therefore would not have been recommended to take antihypertensive medication under hypertension guidelines in China [19]. Correspondingly, this proportion was 19.6% in the US and 14.3% in Canada. Taken together, these findings imply that a larger population would be affected in China if intensive SBP treatment were fully implemented.

Although significant benefits from intensive SBP goals have been demonstrated in a recent meta-analysis of 34 BP-lowering trials including SPRINT [9], there is still considerable debate over the number of SAEs and the additional investments likely required, e.g., increased drug and monitoring costs [24,26]. In addressing these issues, our modeling suggests that intensive SBP treatment could reduce CVD mortality and produce gains in life-years, but with increased risk of SAEs. These findings are consistent with a report in the US population, which projected over 100,000 deaths prevented annually, but at the cost of a considerable increase in SAEs [26]. However, from a lifetime perspective, our study provides evidence to suggest that the increased costs from BP intensification and management of SAEs are offset by health gains from prevented CVD events and deaths. The ICER for intensive SBP treatment was less than 1× GDP per capita for China in 2017, with a high probability of cost-effectiveness overall (i.e., 82.8%) and in subgroups of interest (e.g., 72.9% for those with SBP between 130 and 139 mm Hg, and 91.2% for the female population). Our findings, together with those of 3 other studies with similar conclusions from the US [22,27,28], suggest that intensive SBP treatment among high-risk populations is worthy of significant capital investment, generating QALYs through reducing CVD mortality and long-term morbidity. This is also supported by our previous research, in which we found that the adoption of SBP treatment among people with SBP between 130 and 139 mm Hg could be cost-effective.

The present study has some limitations. First, not all the information required to assess eligibility for SPRINT was collected by the CHARLS survey. However, the effect of not having taken into account these certain conditions, which are expected to have a very low rate, is thought to be minimal. Second, like all other computer simulation analyses, our approach relied on data derived from multiple sources and study types, in particular, the findings from SPRINT among the US population. Third, there is limited information on the incidence of each of the SAEs reported in SPRINT (e.g., hypotension, syncope); therefore, we could not detail the components of SAEs in our model. Also, the scarcity of data and the uncertainty of the effect of intensive management on renal complications prevented us from including long-term renal outcomes in the model. Fourth, BP measurements in SPRINT were likely done by unattended automated BP devices, which are different from the one used in CHARLS, with staff attendance during BP measurement. Studies have shown that unattended BP measurement can result in BP values that are 10–15 mm Hg lower. This may have affected the proportion of people meeting SPRINT criteria and our further modeling results. That said, evidence has shown a similar BP level and CVD risk reduction in the intensive SBP treatment group in SPRINT participants regardless of the measurement technique [29]. Fifth, our estimations of the number and proportion of Chinese adults meeting SPRINT eligibility criteria are based on survey data at 1 time point (i.e., 2011–2012), and these values may have changed with time, particularly for those with versus without hypertension treatment. Finally, although BP treatment intensification, like many other interventions, cannot not ultimately prevent the death of people, it may alter their disease progress or pathway. Therefore, our estimates of the events or deaths reduced may be confounded by the competing risk between CVD event and CVD death or non-CVD death, particularly for the lifetime estimates.

The approach described in SPRINT has had a dramatic influence on clinical practice [11,12]. The present study suggests that adoption of the SPRINT intensive SBP treatment strategy would reclassify 116 million Chinese adults as requiring SBP-lowering therapy, and if these individuals were treated, we could prevent over 2 million CVD deaths, and gain 3.84 million life-years over 5 years. Furthermore, this strategy is likely to be cost-effective over a lifetime despite greater drug costs and more SAEs.

Supporting information

S1 CHEERS Checklist

(DOCX)

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S1 Fig. Schematic depiction of the model structure.

HF, heart failure; MI, myocardial infarction.

(TIF)

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S2 Fig. One-way sensitivity analysis of model variables.

Red dashed line: 1 GDP per capita.

(TIF)

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S3 Fig. Results of the probabilistic analyses as shown in a cost-effectiveness scatter plot.

(TIFF)

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S4 Fig. Cost-effectiveness acceptability curves.

(TIFF)

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S1 Text. Supplementary methods and results for population and cost-effectiveness analysis.

(DOCX)

Click here for additional data file. (154.1KB, docx)

Abbreviations

BP

blood pressure

CHARLS

China Health and Retirement Longitudinal Study

CVD

cardiovascular disease

HF

heart failure

ICER

incremental cost-effectiveness ratio

MI

myocardial infarction

QALY

quality-adjusted life-year

SAE

serious adverse event

SBP

systolic blood pressure

SPRINT

Systolic Blood Pressure Intervention Tria

Data Availability

CHARLS data are available via the website: http://charls.pku.edu.cn/pages/data/2011-charls-wave1/en.html Other relevant data are within the manuscript and its Supporting information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Thomas J McBride

16 Apr 2020

Dear Dr Chen,

Thank you for submitting your manuscript entitled "Applicability and cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese Population" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Thomas J McBride, PhD,

PLOS Medicine

Decision Letter 1

Emma Veitch

4 Jun 2020

Dear Dr. Chen,

Thank you very much for submitting your manuscript "Applicability and cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese Population" (PMEDICINE-D-20-01125R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jun 25 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Clare Stone, PhD, Acting Chief Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*Please revise your title according to PLOS Medicine's style - this should be structured with the main study question and then the study design (eg, : cost-effectiveness modelling) after a colon in the subtitle.

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*In the last sentence of the Abstract Methods and Findings section, please note any key limitation(s) of the study's methodology. The authors might also want to include a summary in the abstract of the outcomes from any of the sensitivity analyses, not just the primary analyses, in the study as this will help readers grasp how robust the findings are to underlying assumptions used in the models.

*If possible, please modify the intext reference callouts to use numbers in square brackets (eg [1, 2]) - if referencing software is used this should be fairly quick and easy.

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Comments from the reviewers:

Reviewer #1: The propsed paper is well written and with a well done statistical analysis modeling. Furthermore conclusions are driven by founded results. However some revision is needed before it could be accepted for pubblication. The mail problem is how blood pressure was measured in the study from which data were taken for the model. In fact, SPRINT trial was hardly criticized by european reserchers and guidelines since measurements were done by unattended automated BP device. If BP in the CHARLS study has been taken differently (whit classic methods) these data could not be compared with the SPRINT one. In fact, unattended BP results in 10-15 mmHg less BP and so the main criticism is that probably SPRINT is comparing actual normal control (130 mmHg) with uncontrolled BP (150 mmHg) so only confirming the actual guidelines and not confirming the intensive treatment benefit. Please better describe methods for BP measurements and discuss this issue.

Furthermore, I din't understand why in the "base-case analysis" section authors reports only on the reduction of HF incidence and CV fatal events while not considering non fatal events. Please better describe.

-----------------------------------------------------------

Reviewer #2: The manuscript concerns a very important topic of intensifying blood pressure treatment, which is a cheap and effective option that may affect a large proportion of population. However, I have a number of questions regarding the modelling assumptions:

- Which treatment effects on cardiovascular endpoints were used in the model? eTable 3 suggests these were the hazard effects coming directly from the SPRINT trial (which is exactly what I would expect). But then what is depicted in eFigure2? Also text, lines 199-201.

- Adverse events: why is the HR of 1.43 used if SPRINT reported 1.04? Further, why is a SAE assumed to incur annual costs for the lifetime duration but the QoL decrement is assumed to be back to normal after one week? Where would the costs come from then?

- Why is it assumed that further CV events may only happen within the next year of the first one?

- In terms of the proportion of people not treated for hypertension, is it possible to use re-interview data, as presumably the situation has changed wince 2011.

- eTable 5: could the authors add description of the population / any other assumptions used in the comparator table, to make it clearer that like-with-like is being compared.

- One ICER may mask important differences in population subgroups. Could the results be presented by age groups and categories of blood pressure.

I am also struggling to understand information presented in Figure 3. What scale is it presented on? The x-axis suggests it may be on a person-level, but how can 7 deaths be averted for one person? In general, information on lifetime number of deaths avoided is not necessarily meaningful - people will have to die eventually; besides those that live longer, may well experience CV events just as much as those who live less; it's just they experience them later. Perhaps something like "numbers needed to treat to avoid 1 stroke in 5 years" would be more meaningful.

Related to this, in eTable 6, the numbers of strokes saved over lifetime is smaller than that saved over 5-years, with the trend reversed with every other endpoint. There may well be a reason for this, but it should be noted and discussed.

A few minor comments:

- Table 1: costs and ICERs should be rounded to the nearest integer, if not more; also it should be clarified what "incremental costs" refers to - total costs or just hospital costs? Ir the former, it would be very helpful to see specifically hospital costs. Treatment costs could be deduced from life expectancy & treatment cost.

- There were quite a few spelling errors, particularly in the appendix, could this be reviewed carefully.

-----------------------------------------------------------

Reviewer #3: This is a statistical review of manuscript PMEDICINE-D-20-01125R1. It is well structured, well written and the topic is of great importance. From a statistical viewpoint, I would like to see 2 main clarifications:

1/ Line 236 : Our model showed a reasonable concordance between model predicted risk estimates and published hazard ratios (HRs) (0.86 vs.0.83 for MI, 0.95 vs. 0.89 for stroke, 0.65 vs. 0.62 for HF, 0.59 vs. 0.57 for CVD mortality, 0.85 vs. 0.73 for all-cause mortality). What are these HRs ? Are they the ratios of the hazards of MI, Stroke etc between patients on intensive treatment vs standard?

Figure S2 should explain in the legend what HRs are plotted

2/ Figure 3: what is the scale of the Y-axis? Is it at the level on an individual, or is it at the scale of the whole Chinese population (based on the text line 251 this is probably the case)? Some CIs reach the negative territory - does it mean that the intensive treatment may increase MI and stroke?

I think that the legend should make clear that these are the events that would be avoided if the intensive treatment was in place instead of the standard one.

Minor points: in some instances, there are sentences where words are missing or the English could be improved. For example:

"Although adoption of the SPRINT treatment strategy would increase the number of Chinese adults requiring SBP [treatment?] intensification"

"this approach have [has?] the"

"the detailed disease states within each path could be [can be found?] in our previous publication"

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Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Thomas J McBride

27 Aug 2020

Dear Dr. Chen,

Thank you very much for submitting your revised manuscript "Applicability and Cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese Population: Cost-effectiveness Modelling" (PMEDICINE-D-20-01125R2) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to one of the original reviewers. The review is appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we still will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Sep 17 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Thomas McBride, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

1- Thank you for editing your title. Please edit again slightly: “Applicability and Cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese Population: a Cost-effectiveness modelling study”

2- Thank you for adding an Author Summary. Please edit the last point of the Author Summary to: “This evidence suggests that intensive treatment to reducing blood pressure among high-risk populations could be cost effective.” (or something similar).

3- Throughout the manuscript, please include the p-values alongside 95% CIs when relevant.

4- Thank you for adding the non-fatal events in response to reviewer 1’s second point. It does look like for MI and stroke, the reductions are not significant. Please make this clear by separating these outcomes out in the text.

5- Please include the url and any accession numbers necessary to apply for access to the CHARLS dataset.

6- Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

Comments from the reviewers:

Reviewer #2: Thank you for providing answers to my comments. I would still like to have a few points (from my original comments) clarified, and it would be helpful if these were clarified in the manuscript text as well.

* Treatment effect. Thank you for clarifying these were the SPRINT treatment effects that were used in the modelling. I would then suggest removing S2 Figure from the manuscript as it does not add anything. The simulated HRs are not simulated, but are taken from literature, so of course they will be the same when plotted against the HRs they are equal to. The small difference presumably comes from projecting subsequent events, population sampling and randomness in the simulation process.

* Cost of SAEs. So if an SAE has occurred, will the costs be applied every single year after it occurred (despite QoL being back no normal within a week) or only in a year that it occurred?

* Modelling subsequent CV events. I understand that secondary events may happen, but why can they only happen in the year after the primary event? Whilst the risk of a subsequent event is higher in the next year, it does not go away in years after that

* Proportion of people on hypertension. This comment referred to the authors' estimation that 2/3 of those meeting SPRINT eligibility criteria were not treated for hypertension (line 336, page 15; also abstract). However, this was the case in 2011, since then most likely this number has decreased. I assume that in the "standard treatment" scenario everyone was prescribed antihypertensive medications rather than just those that were recorded to do so. Could the authors confirm this please.

* eTable5: The added text just re-phrases the results that are presented. it still not clear that the populations for which results are presented (ie population in this study vs populations in references 30-37) are comparable. Could this be commented on please.

* Figure 3. What exactly does it mean to say that 7 million CVDs were averted over lifetime? Does it mean that these 7 million people died of non-CVD causes instead? It seems misleading to present this number unless there is some discussion in the text.

* Comment on Table 1: It is still unclear what costs are presented in column named "Costs, Int $". Are these hospital costs, or do they include treatment costs? Regardless, it would be very helpful to look separately at hospital costs and treatment costs.

* Spelling: there are still some spelling mistakes (eg Figure 2: "adverted" should be "averted")

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Thomas J McBride

9 Dec 2020

Dear Dr. Chen,

Thank you very much for re-submitting your manuscript "Applicability and Cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese Population: a cost-effectiveness modelling study" (PMEDICINE-D-20-01125R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and it was also seen again by one reviewer.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Dec 16 2020 11:59PM.   

Sincerely,

Thomas McBride, PhD

Senior Editor 

PLOS Medicine

plosmedicine.org

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Requests from Editors:

1- Please address the remaining comments from reviewer 2 and incorporate your responses into the main text (not just the rebuttal letter), in case readers are also unclear.

2- Please report your economic analysis according to the appropriate study design provided at http://www.equator-network.org/?post_type=eq_guidelines&eq_guidelines_study_design=economic-evaluations&eq_guidelines_clinical_specialty=0&eq_guidelines_report_section=0&s= and provide the relevant completed checklist. In the checklist please include sufficient text excerpted from the manuscript to explain how you accomplished all applicable items.

Please add the following statement, or similar, to the Methods: "This study is reported as per the XXX guideline (S1 Checklist)."

When completing the checklist, please use section and paragraph numbers, rather than page numbers.

3- Thank you for updating your data statement. However, I note that the webpage you direct to reads: “All data will be made public one year after the end of data collection.” PLOS requires that the data underlying all analyses in the paper be available at the time of publication. Can you confirm that the data are available now? If so, update the data statement to read: “CHARLS data are available via the study website: ” and provide a more specific url to direct readers to the dataset. If the dataset is not currently available, please let us know the date when it will be available.

It seems that this paper uses data from wave 1 and 2 (2011-2012), which seem to be available

here:

http://charls.pku.edu.cn/pages/data/2011-charls-wave1/en.html

and here:

http://charls.pku.edu.cn/pages/data/2012-charls-pilot-wave2/en.html

If that is correct, please use these urls in the data statement.

4- Line 65: remove “horizon”: “We estimated that over five years…”

5- Thank you for editing the language around MI and stroke. However, please further edit the line in the abstract to reflect that the 95% CIs do not predict a reduction in MI or stroke incidence. I suggest moving these outcomes to a separate sentence, e.g., “Estimated reductions of 0.069 million (95% CI: -0.28, 0.42) myocardial infarction and 0.36 million (95% CI: -0.10, 0.82) stroke incidences were not statistically significant.”

6- Thank you for your response regarding the planned analyses and your previous published model. Please note this in the methods section and cite the study.

7- At lines 56 and 157, “... aged over 45 *years*...”

8- Line 77 and throughout, please replace “subjects” with “people”.

9- Throughout the manuscript, please replace the abbreviation “y” with “years”.

10- Please remove “As a landmark study in hypertension management,” from line 388.

11- Please include information on ethics approval and consent obtained for the CHARLS study when mentioning it in the Methods section.

12- The supporting information, please replace “gender” with “sex”.

Comments from Reviewers:

Reviewer #2:

please see attached file

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachment

Submitted filename: revision.docx

Click here for additional data file. (17.7KB, docx)

Decision Letter 4

Thomas J McBride

22 Dec 2020

Dear Dr. Chen,

Thank you very much for re-submitting your manuscript "Applicability and Cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese Population: a cost-effectiveness modelling study" (PMEDICINE-D-20-01125R4) for review by PLOS Medicine.

After reviewing your most recent revision, there are 2 remaining editorial points to be addressed before we can accept.

The remaining issues that need to be addressed are listed at the end of this email. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week, but I understand that I am sending this during the holiday season. Please know that the due dates listed here are flexible. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Dec 29 2020 11:59PM.   

Sincerely,

Thomas McBride, PhD

Senior Editor 

PLOS Medicine

plosmedicine.org

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Requests from Editors:

1- Thank you for clarifying the data availability. Please also update the data availability statement in the submission metadata to read:

“CHARLS data are available via the website: http://charls.pku.edu.cn/pages/data/2011-charls-wave1/en.html

Other relevant data are within the manuscript and its Supporting Information files”

2- In your response to Reviewer 3, comment 5, you change “events averted” to “events reduced”, but I’m not sure that clarifies what the figure is reporting. Please add a bit more detail to the description in the figure legend, so it’s clear what outcomes are represented in the figure.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 5

Raffaella Bosurgi

2 Feb 2021

Dear Dr Chen, 

On behalf of my colleagues and the Academic Editor, [Kazem Rahimi], I am pleased to inform you that we have agreed to publish your manuscript "Applicability and Cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese Population: a cost-effectiveness modelling study" (PMEDICINE-D-20-01125R5) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Raffaella

Dr Raffaella Bosurgi MSc, PhD

Executive Editor, PLOS Medicine

rbosurgi@plos.org

https://twitter.com/raffi74

Remote based in London, UK

PLOS

Empowering researchers to transform science

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 CHEERS Checklist

    (DOCX)

    Click here for additional data file. (35.8KB, docx)
    S1 Fig. Schematic depiction of the model structure.

    HF, heart failure; MI, myocardial infarction.

    (TIF)

    Click here for additional data file. (3.8MB, tif)
    S2 Fig. One-way sensitivity analysis of model variables.

    Red dashed line: 1 GDP per capita.

    (TIF)

    Click here for additional data file. (8MB, tif)
    S3 Fig. Results of the probabilistic analyses as shown in a cost-effectiveness scatter plot.

    (TIFF)

    Click here for additional data file. (8.6MB, tiff)
    S4 Fig. Cost-effectiveness acceptability curves.

    (TIFF)

    Click here for additional data file. (8.6MB, tiff)
    S1 Text. Supplementary methods and results for population and cost-effectiveness analysis.

    (DOCX)

    Click here for additional data file. (154.1KB, docx)
    Attachment

    Submitted filename: Point-by-point responses PMEDICINE-D-20-01125R1_24 Jun 2020.docx

    Click here for additional data file. (170.9KB, docx)
    Attachment

    Submitted filename: Point-by-point responses PMEDICINE-D-20-01125R2_11 Sep 2020.docx

    Click here for additional data file. (286.2KB, docx)
    Attachment

    Submitted filename: revision.docx

    Click here for additional data file. (17.7KB, docx)
    Attachment

    Submitted filename: Point-by-point responses PMEDICINE-D-20-01125R3_14Dec 2020.docx

    Click here for additional data file. (399.7KB, docx)
    Attachment

    Submitted filename: Point-by-point responses PMEDICINE-D-20-01125R4_22Dec 2020.docx

    Click here for additional data file. (16.6KB, docx)

    Data Availability Statement

    CHARLS data are available via the website: http://charls.pku.edu.cn/pages/data/2011-charls-wave1/en.html Other relevant data are within the manuscript and its Supporting information files.

    Articles from PLoS Medicine are provided here courtesy of PLOS

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