To our knowledge, this is the first randomized trial to test the feasibility and safety of the BP control protocol (including medication titration) to achieve three different BP control targets in rural Chinese hypertensive patients. This trial gained real world experience and laid the foundation for a future large-scale BP target study. Below we discuss what we learned from this trial and how it relates to the literature.
BP Control Targets: Given the lack of consensus on optimal BP targets in Chinese population, we chose three systolic BP targets based on American Heart Association previous and new BP guidelines [2,11,17] and findings from the two relevant trials: SPRINT and ACCORD [10,18]. Our goal was to evaluate how likely each of the BP targets can be safely achieved in rural Chinese hypertensive patients, a population with low BP control rate and at high-risk of stroke. Our ultimate goal of the management of hypertension is for the prevention of end organ damage, including stroke, cardiovascular events, and renal dysfunction.
The benefits of BP lowering were demonstrated in randomized controlled trials of hypertensive patients. The following trials contributed to the changes in the BP targets in the major hypertension management guidelines from 2000 to 2018: the Hypertension in the Very Elderly Trial (HYVET 2003) [19]; the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD 2010) [18]; the Valsartan in Elderly Isolated Systolic Hypertension study (VALISH 2010) [20]; the Secondary Prevention of Small Subcortical Strokes trial (SPS3 2013) [21]; the Systolic Blood Pressure Intervention trial (SPRINT 2015) [10]; and the Heart Outcome Prevention Evaluation-3 trial (HOPE-3 2016) [22].
Of note, in contrast to the findings of “SPRINT”, which showed a benefit of tighter BP control, the ACCORD trial showed no significant difference in cardiovascular events and all-cause mortality between the intensive treatment (mean SBP 119.3 mmHg) and the standard treatment (mean SBP 133.5 mmHg); cardiovascular events and death from cardiovascular causes (HR 0.88, 95%CI 0.73–1.06, p=0.20). However, the cardiovascular events observed in the ACCORD trial were mainly ischemic heart disease, but the prevalence of cerebrovascular disease was significantly reduced in the intensive-treatment group (HR 0.59, 95%CI 0.39–0.89, p=0.01). There were important difference between the two trials. The ACCORD trial enrolled participants with diabetes exclusively, whereas SPRINT excluded participants with diabetes; in addition, the sample size differed (4733, ACCORD vs. 9361, SPRINT). The ACCORD trial also used a factorial design that included comparisons of standard and intensive glycemic and lipid treatment targets in the same trial. SPRINT enrolled an older cohort (mean age, 68 years vs. 62 years in the ACCORD trial), with 28% of the participants 75 years of age or older, and included participants with chronic kidney disease.
Limited data were available for Asian populations. A recent study among 248,8101 Koreans aged 20 through 39 years found that stage 1 hypertension (SBP, 130-139mmHg or DBP, 80-89mmHg) was associated with an increased risk of subsequent cardiovascular disease (Hazard ratio, 1.25 for men; 1.27 for women) during a median follow-up duration of 10 years. Among Koreans, young adults with hypertension, defined by the 2017 ACC/AHA criteria, may be at increased risk of cardiovascular disease [23].
Choice of Anti-Hypertension Drugs: Drug choice is related to the clinical indications, cost, availability, insurance coverage, and patient preference. In the ACCORD trial, a strategy of treatment to specific SBP goals was tested, rather than testing any specific drug regimen. All major classes of antihypertensive drugs and many combination medications were provided by the study. All antihypertensive regimens were to include a drug class that had demonstrated efficacy in reducing cardiovascular events in participants with diabetes: diuretics, beta-blockers, calcium channel blockers (CCB), angiotensin converting-enzymes (ACE) inhibitors, or angiotensin receptor blockers (ARB). The treatment algorithms of SPRINT were similar to the ACCORD trial. The SPRINT investigators also prescribed other antihypertensive medications (not provided by the study). The protocol encouraged, but did not mandate, the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes, including thiazide-type diuretics (encouraged as the first-line agent), loop diuretics (for participants with advanced chronic kidney disease), and beta-adrenergic blockers (for those with coronary artery disease). Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker. In the International Verapamil-Trandolapril Study (INVEST) [24] patients were randomly assigned to either a calcium antagonist (verapamil sustained release) vs. a non-calcium antagonist (atenolol). Trandolapril and/or hydrochlorothiazide was administered to achieve blood pressure goals.
In this present trial, the antihypertensive drugs were provided at no cost to the participants; and all the antihypertensive regimens included drug classes that had been shown to result in a reduction in stroke or cardiovascular events [25]. For all participants, the initial therapy was a daily oral dose of 1 tablet of enalapril–folic acid (containing 10mg of enalapril and 0.8mg of folic acid) because the homocysteine level of all participants was >10μmol/L [26]. The next step used amlodipine or hydrochlorothiazide. β-blockers were also allowed, to achieve the SBP target.
Feasibility: Feasibility encompasses the likelihood of lowering BP to the prespecified target, the number of drugs required to achieve that goal, and whether patients can tolerate and comply to the regimen. In this trial, all patients completed the 6-month follow-up with the exception of only one participant in the intensive BP control group (the patient had to travel out of town for an emergency). After six months of BP medication titration, 83%, 80%, and 73% of the patients attained a BP level below the specified SBP target for Group A, B, C, respectively. At baseline enrollment, the mean number of antihypertensive drugs prescribed were 1.4, 1.4, and 1.5 among the three groups. After 6 months of follow up, the number of drugs prescribed were 1.4, 2.2, and 2.5 (Figure 2B). In SPRINT the mean number of blood-pressure medications was 2.8 in the intensive treatment group and 1.8 in the standard treatment group. In the ACCORD study the mean number of medications after the first year was 3.4 (95% CI, 3.4 to 3.5) in the intensive therapy group and 2.1 (95% CI, 2.1 to 2.2) in the standard-therapy group.
Safety: Safety issues were related to side effects of a specific anti-hypertensive drug used; safety surrounding the use of multiple drugs in combination; and safety related to the BP target and the corresponding risk of hypotension. The major side effects observed in the current study were cold symptoms, dry cough, and vertigo, all of which were similar between the three groups (Table 3). No SAE were recorded. The BP control protocols were overall safe without any major AE for all three target groups.
Modality of BP Monitoring: The current study tested different modalities of BP measurements: office visits, self-monitored HBPM, and CASP and examined their relationships. We found consistent pattern of BP control between HBPM and office visit BP measurements. In addition, there was a general 8-9mmHg difference between CASP and office visit BP.
Strengths and limitations of this study
This pilot randomized trial was the first step to address critical questions: what is the optimal BP control target and how to achieve it in Chinese population? This trial aimed to evaluate the feasibility and safety to achieve prespecified BP targets (<150, <140, and <130mmHg) using a standard BP control protocol among hypertensive patients in rural China, which constitutes over 61.2% of Chinese population. This trial fully considered rural Chinese population’s characteristics such as socio-economic status, compliance, education level and lifestyle, which are quite different from western populations. This trial has following limitations: the sample size was small. The study had a short duration and was unable to evaluate long-term health outcomes. It was conducted in rural Chinese hypertensive patients, so generalization of the trial findings to other population requires caution. There are more left-behind women than men in rural China, so we have included more women. Salt intake is high in northern China, but apart from lifestyle modification, we haven’t accurately measured salt intake in this study.