Cardiovascular disease (CVD) is the leading cause of premature death and a major cause of disability worldwide (1, 2). There are two types of strategies for the prevention and control of CVD: high-risk strategies and population-based strategies. High-risk strategies focus on identifying and managing individuals at high risk of developing cardiovascular events such as myocardial infarction and stroke, for example, managing patients with hypertension. High-risk strategies are more attractive because the nature of “diagnosis and treatment” is more familiar to both the medical community and the public. The use of these strategies is more rational, and it is easier to obtain evidence from high-risk individuals. In fact, much more evidence from randomized controlled studies has been obtained for high-risk strategies (3, 4). As early as 2002, training primary care providers with tailored guidelines on the management of hypertension was proposed, and these providers were shown to be capable of significantly increasing the blood pressure control rate among targeted patients with hypertension (5). Recently, a large-scale cluster-randomized trial in China demonstrated the efficacy of antihypertensive treatment in patients with hypertension for reducing the incidence of conditions such as stroke and myocardial infarction (6). Based on this evidence from typical randomized trials of targeted high-risk individuals, most clinical guidelines recommend risk-based screening and management strategies, which have become the focus of public health policy in several countries, including China (7, 8). However, the impact of such high-risk strategies on population disease burden has long been a matter of debate because the majority of CVD cases are not developed from high-risk individuals (4, 9, 10). This important question is strongly associated with policy-making regarding the number one killer in the world but has not been evaluated in appropriately controlled studies. Previous trials assessing the effect of high-risk strategies for CVD prevention commonly recruited only the target population and followed them throughout the trials.

The China Rural Health Initiative (CRHI) study was designed to address this question with a rigorous randomized design, specifically to assess the potential population-wide impact of a pragmatic low-cost primary care program designed to improve the management of individuals with high cardiovascular risk by training primary care providers in rural China with a package of care focusing on blood pressure reduction (11). The present paper is to report the main results from the study.

The CRHI study used an innovative cluster-randomized trial in which 120 villages were recruited from 10 counties in 5 provinces in northern China. The villages were randomized at a 1:1 ratio into intervention and control groups stratified by county, with independent cross-sectional random samples drawn from each village (cluster) before and after the intervention (Figure 1). Primary care providers in the intervention villages received training to identify and manage individuals at high risk of CVD (for details, see below), and primary care providers in the control villages received no training. The CRHI study was registered at ClinicalTrials.gov (NCT01259700). Details of the CRHI study design have been published previously (11). The CRHI study was reviewed and approved by the Peking University Institutional Review Board in China and the Duke University Health System in the U.S. Cluster-level consent was obtained through a consultation process involving relevant provincial, county, regional and village authorities. Written informed consent was sought from all individuals selected for participation in the population surveys.

The study flow chart is shown in Figure 1. Of the 150 villages invited to participate in the study, 120 agreed and were randomized. One village in control was withdrawn after randomization as a consequence of the village's incorporation within an adjacent urban area. The data were obtained from a total of 5,050 adults in the baseline survey (pre-intervention survey) and 4,887 in the post-intervention survey.

The CHRI was the first randomized trial to evaluate the population-wide effectiveness of a high-risk strategy for the prevention and control of CVD—proactivity in screening and managing individuals with high cardiovascular risk—for primary care providers in rural villages of northern China. The study, conducted in 120 rural villages, demonstrated that a pragmatic primary care program targeting individuals at high risk of CVD did not lower the population mean SBP, although it produced a 10% greater increase in receiving regular primary care, a 9% greater increase in receiving advice on salt reduction, an 8% greater increase in the use of antihypertensive treatment, and a 7% greater increase in the use of aspirin among older adults. These findings raise questions about the impact of strategies that focus only on high-risk patients on the population-wide disease burden.

Why did the CRHI PCP program yield an improvement in primary care but fail to result in a substantial reduction in the mean population blood pressure level? The population-wide impact of a high-risk strategy depends upon three main factors: first, the proportion of the targeted high-risk group in the whole population; second, the efficacy of the intervention strategy in identifying those at high risk and reducing the clinical outcomes among those identified at high risk; and third, the use of the primary care system to cover all those at high risk. In the present study, only one-third of the study participants could be defined as “high-risk individuals” according to the study definition. In addition, despite the intervention substantially increasing the number of high-risk individuals receiving regular primary care from village doctors, more than half of the high-risk individuals in the community still did not receive this service. Only a third of the population was at high risk, and approximately 50% of them were receiving regular primary care, while the observed 19.8 mmHg reduction in SBP among individuals managed by village doctors in the intervention villages may indeed be valid. The effect observed among the whole population should be less than 33% of the 50% reduction in 19.8 mmHg, equating to less than 3.3 mmHg.

Furthermore, there might be significant contamination of the CRHI primary care providers’ intervention program. For instance, data from control villages showed that all secondary outcomes improved, ranging from 1.6% for aspirin use to 11.8% for receiving advice on salt intake. Why the cluster randomization design failed to prevent contamination bias is not entirely known; however, the village doctors in both the intervention and control villages belong to the same public health systems that are centrally managed by the same county health authorities, who are responsible for the capacity building, duty responsibilities and performance appraisals of the village doctors. Considering the presence of contaminating factors such as regular primary care and advice on salt intake reduction, we posit that contamination bias may have mitigated approximately 50% of the intervention effect. Consequently, the effect of the CRHI-related PCP intervention at the population level should be further reduced to approximately 1.65 mmHg on SBP. Furthermore, the standard deviations and ICCs for SBP were significantly greater than those anticipated in the original CRHI sample size calculation. Therefore, the confidence interval did cover the expected treatment effect of −1.6 mmHg reduction. Nonetheless, taking up the intervention program only by half was the fundamental factor that led to the failure of our study to detect a possible effect.

Our results demonstrated the importance of basing public health policies on evidence of effectiveness, not only efficacy. There is no doubt about the efficacy of antihypertensive treatment among high-risk patients, and there is clear evidence that the extent of the effects increases in direct proportion to the extent to which a blood pressure reduction is achieved and the initial predicted risk of a major CVD event (19–21). However, as shown from the results of the CRHI, efficacy does not guarantee effectiveness. Other studies evaluating the treatment effects of high-risk target strategies in the prevention of cardiovascular diseases have also shown that these interventions are not effective in the general population (22–24). The development of affordable effective strategies to control the growing burden of hypertension in rural China and most other resource-poor regions of the world remains a major public health challenge (25–27). Almost certainly, this will require a two-pronged approach: first, a primary care strategy that identifies all high-risk individuals in the community and substantially reduces their risk through the combination of highly effective drug treatments and lifestyle changes (25, 28–30). Second, a population-wide strategy is needed to reduce the risk of exposure to causal factors such as high salt intake (31–33). The recent success of potassium-enriched, low-sodium salt substitutes among older adults living in elderly care facilities in China showed the promise of salt substitutes as a population-wide strategy for the prevention and control of hypertension and related diseases. Recent studies demonstrated that polypill may be useful in the prevention of cardiovascular disease by improving multiple cardiovascular risk factors at the same time, particularly for underserved populations (34, 35). With lower cost and enhanced adherence, the polypill should also fit into the needs in prevention and control of cardiovascular disease in rural China. Unfortunately, the polypill is not available on China's market yet.

There were some limitations. First, due to funding restriction and lacking existing health information system, the CRHI was forced to employee blood pressure as the study outcome to reduce the sample size and cost. Future studies should consider using clinical events as the study outcome that should better reflect the intervention effect, particularly for the intervention consisted of multiple components on different risk factors. Second, no laboratory measurements were included in our protocol for high-risk individual screening, which might reduce the precision in the estimation of the 10-year cardiovascular risk. However, the intervention was tentatively tailored for scaling up in the resource-limited healthcare settings and there is evidence that the simple, inexpensive and non-invasive non-laboratory-based risk prediction model classifies individuals almost identically to the laboratory-based model (36). Although we did not employee a calculator for the risk screening but a validated risk prediction model was used when our simple criteria of high-risk was developed (14). Third, the aspirin use in the CRHI risk management protocol looks like overused according to the recent updated guidelines (37). In fact, all high-risk individuals identified according to the CRHI criteria should have a 10-year cardiovascular risk of at least 10%. In addition, the risk management protocol excluded individuals with history of cerebral and non-cerebral hemorrhage and required to initiate aspirin use only when systolic blood pressure was below 140 mmHg. Thus, the practice should be considered in line with the current guidelines.