Achieving blood pressure control targets in hypertensive patients of rural China – a pilot randomized trial

The study was a randomized, controlled, open-label trial conducted in Rongcheng, Shandong, China. The trial consisted of three stages: (1) screening, (2) recruitment and randomization to specific BP targets, and (3) antihypertensive treatment titrated to achieve the assigned BP target. The study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University, China and is registered in the clinical trials website (ClinicalTrials.gov, ID: NCT02817503). All participants provided written, informed consent.

During the screening stage, each participant completed a physical examination and questionnaire interview on lifestyle and history of disease and medication use. Laboratory tests included fasting lipid profile and plasma Hcy. Eligible participants were randomized, in a 1:1:1 ratio, to a SBP target of 140–150 mmHg (the standard-treatment group (Group A)), 130–140 mmHg (the moderately-intensive treatment group (Group B)) or < 130 mmHg (the intensive-treatment group (Group C)) with a fixed block size of 9. Study personnel were aware of the study-group assignments, but participants were not.

After the participants had undergone randomization, their baseline antihypertensive regimens were adjusted on the basis of the study-group assignment. The treatment algorithms were similar to those used in the SPRINT trial [10]. These algorithms and our formulary are listed in the supplemental material (Supplemental Table 1). All major classes of antihypertensive agents were included in the formulary and were provided at no cost to the participants. For all participants, the initial therapy was a daily oral dose of one tablet of enalapril-folic acid (containing 10 mg enalapril and 0.8 mg folic acid). Other drugs, including calcium-channel blockers (CCBs) (amlodipine preferred), diuretics (hydrochlorothiazide preferred), and β-blockers, were allowed, in order to achieve the SBP target. For those who could not tolerate enalapril-folic acid well, other types of antihypertensive agents could be used as alternative choices. If the target BP level was not achieved during the titration or follow-up periods, adjustment of drug type and dosage was carried out according to the protocol.

Participants were seen weekly for the first month, every 2 weeks for the next 2 months, and once a month thereafter for a total of 6 months, totaling 11 follow-up visits. For participants in Groups A and B, medications were adjusted to a target SBP of 145–149 mmHg and 135–139 mmHg, respectively. For participants in Group C, medications were adjusted to a target SBP of < 130 mmHg. The dose was reduced if the SBP was under the target on two consecutive visits. Dose adjustment was based on the mean of three BP measurements at an office visit. Self-monitored HBPM was recorded by using an electronic sphygmomanometer (Kingyield, Shenzhen, China). Additionally, CASP measurement was also conducted at office visits by using a CASP monitoring device (A-pulse CASPro, Jianzi, Singapore). Lifestyle modifications, like sodium restriction and smoking cessation, were encouraged as part of the management strategy for all study participants. The participants’ retention and adherence to treatment were also monitored at each follow-up visit.

The primary outcome was achieved mean BP levels in each of the treatment groups. The secondary outcome was the difference between the carotid-femoral pulse-wave velocity (cf-PWV), 3D carotid artery ultrasound, and Ankle-brachial Index (ABI) of each treatment group. BP measurements at an office visit were with the patient seated and having rested quietly for 10 min; the measurements were made with the use of an electronic sphygmomanometer (Kingyield, Shenzhen, China). Self-monitored HBPM was recorded by using an electronic sphygmomanometer (Kingyield, Shenzhen, China). Participants were trained on the use of the electronic sphygmomanometer for HBPM according to the protocol. Before formally recording any BP values, the patients underwent 10 days of continuous training conducted by the investigators to ensure that each participant mastered the method. The participants were requested to continuously measure BP at three time points per day (in the morning after urination and before breakfast and medication, 2 h after taking antihypertensive medication, and in the evening) for weeks 12, 16, 20, and 24, and to record the values on a HBPM self-test registration form. All data were collected 7 days before the office visit. The main objective of the HBPM protocol was to assess the reproducibility and reliability of 7-day self-monitoring prior to an office visit day. CASP was also measured at the office visits at weeks 6, 12, and 24 by using a CASP monitor device (A-pulse CASPro, Jianzi, Singapore). Epidemiological, clinical, and laboratory data were obtained at baseline. Data on cf-PWV, 3D carotid artery ultrasound, and ABI were all obtained at baseline and at the 6-month visit. Medical records and electrocardiograms were obtained for documentation of events. Serious adverse events (SAEs) were defined as events that were fatal or life-threatening, that resulted in clinically significant or persistent disability, that required or prolonged a hospitalization, or that were judged by the investigator to represent a clinically significant hazard or to cause harm to the participant, that might require medical or surgical intervention to prevent one of the other events listed above. Any condition on a short list of monitored conditions would be reported as an AE if it was evaluated in a hospital emergency department: hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia.

According to previous large-scale randomized controlled trial (RCT) studies, the rate of achieved mean BP levels in the target window is around 60%, assuming that the rate of achieved mean BP levels in this feasibility present study is 70–80% and the significance level of bilateral test α = 0.05. With an enrollment target of 30 participants of each group, we estimated that the trial would have 80% power to detect the difference between groups. We anticipated a loss to follow-up, so 35 participants were included in each group. Continuous variables were presented as mean ± standard deviation (SD) and categorical variables as frequency (%). The baseline population characteristics of the three BP groups were compared using the Kruskal-Wallis test or χ² tests. Similarly, the incidence of AEs that were likely caused by the drug or intensive BP control was compared among the three BP target groups. SBP and DBP were compared between 0- and 6-month points by paired t tests within each treatment group. Change in SBP and DBP (6-month BP minus baseline BP) was compared among the three treatment groups. Epidata 3.1 was used to build the database; double-entry mode and error checking were adopted. Data were analyzed using Empower (R) (www.​empowerstats.​com; X&Y Solutions, Inc., Boston, MA, USA).

One hundred and five 105 participants were enrolled between December 2015 and January 2016. Participants were randomized into three groups with different BP targets (Fig. 1). Baseline characteristics are shown in Table 1. The mean age of the population was 68.4 ± 5.5 years. Male participants constituted 31.4% of the participants, and 20% were former or current smokers; 15.2% of the participants had a history of diabetes. The percentage of SBP > 150 mmHg, > 140 but ≤ 150 mmHg; and > 130 but ≤ 140 mmHg at enrollment was 41.0%, 45.7%, and 13.3%, respectively. Aspirin and statins use was 5.7% and 20.0%, respectively. There were no significant differences in baseline characteristics among the three groups (P > 0.05).

The mean SBP at the end of the 6-month visit in the standard-BP-control group (A), the moderately intensive-BP-control group (B), and the intensive-BP-control group (C) was 137.2 mmHg, 131.1 mmHg, and 124.2 mmHg, respectively, while the corresponding DBPs were 77.6 mmHg, 74.9 mmHg, and 71.5 mmHg, for each group, respectively (Fig. 2A).

The mean number of antihypertensive drugs prescribed at baseline enrollment were 1.4, 1.4, and 1.5 among the standard-BP-control group (A), the moderately intensive-BP-control group (B), and the intensive-BP-control group (C), respectively, and, at the end of 6-month visit, were 1.4, 2.2, and 2.5, respectively (Fig. 2B). The distribution of antihypertensive drugs used in the different groups was shown in Fig. 2C.

Decreased SBP and DBP was expressed as ΔSBP and ΔDBP (which equals to SBP at week “x” – SBP at week “0”), respectively. After 6 months of antihypertensive treatment, the absolute decrease in SBP in Groups A, B, and C was 9.5 mmHg, 16.1 mmHg, and 26.4 mmHg, respectively, while the absolute decrease in DBP was 9.7 mmHg, 13.6 mmHg, and 18.2 mmHg, respectively (Table 2).

After 6 months of treatment, for the standard-BP-control group (A), 83% achieved SBP < 150 mmHg (29% of participants had a mean SBP in the BP target window of 140–150 mmHg, but 14% were in the 130–140 mmHg window and 40% were in the < 130 mmHg group). For the moderately intensive-BP-control group (B), 80% achieved SBP < 140 (37% of participants had a mean SBP in the target window of 130–140 mmHg, but 43% were in the < 130 mmHg group). For the intensive-BP-control group (C), 73% of participants had a mean SBP < 130 mmHg (6% of participants had a mean SBP in the target window of 140–150 mmHg, and 18% were in the target window of 130–140 mmHg) (see Supplemental Fig. 2)

In this study, 98 participants (93%) agreed to self-monitor their BP using an electronic sphygmomanometer for HBPM; and 94 of the 98 participants completed the HBPM according to protocol, including 29 men (30.9%) with a mean age of 71.0 (± 5.2) years and 65 women (69.1%) with a mean age of 67.2 (± 5.0) years. There was a consistent trend between office visit BP and HBPM (2 h after taking medication) among the three BP-control groups at each titration period (Supplemental Figure 1A). CASP was also measured at weeks 6, 12, 24. Consistent trends were also observed between CASP and office visit BP among the three groups at each titration period (Supplemental Figure 1B). CASP was generally lower than that of the office visit BP (Supplemental Table 2). At the end of 6-month titration, the difference in SBP between CASP and office visit BP was − 7.1 ± 8.0 in the standard-BP-control group (A), − 9.6 ± 8.2 in the moderately intensive-BP-control group (B), and − 9.0 ± 9.0 in the intensive-BP-control group (C).

There were no severe AEs recorded and no direct or close relationships between the occurrence of an AE and the BP titration. As shown in Table 3, there were no significant differences in AE occurrence, especially hypotension, between the intensive-BP-control group and the other groups.

Given the lack of consensus on optimal BP targets in the Chinese population, we chose three SBP targets based on American Heart Association previous and new BP guidelines [2, 11, 16] and findings from the two relevant trials: SPRINT and ACCORD [10, 17]. Our goal was to evaluate how likely each of the BP targets can be safely achieved in rural, Chinese hypertensive patients, a population with a 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 RCTs 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) [18]; the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD 2010) [17]; the Valsartan in Elderly Isolated Systolic Hypertension study (VALISH 2010) [19]; the Secondary Prevention of Small Subcortical Strokes trial (SPS3 2013) [20]; the Systolic Blood Pressure Intervention trial (SPRINT 2015) [10]; and the Heart Outcome Prevention Evaluation-3 trial (HOPE-32016) [21].

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 (hazard ratio (HR) 0.88, 95% CI 0.73–1.06, p = 0.20). However, the cardiovascular events observed in the ACCORD trial were mainly related to 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 differences 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 in ACCORD vs. 9361 in 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 being 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 130–139 mmHg or DBP 80–89 mmHg) was associated with an increased risk of subsequent cardiovascular disease (HR 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 [22].

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, β-blockers, CCBs, ACEIs, or angiotensin-II- receptor blockers (ARBs). 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 β-adrenergic blockers (for those with coronary artery disease). Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred CCB. In the International Verapamil-Trandolapril Study (INVEST) [23], 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 BP 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 [24]. For all participants, the initial therapy was a daily oral dose of one tablet of enalapril-folic acid (containing 10 mg of enalapril and 0.8 mg of folic acid) because the Hcy level of all participants was > 10 μmol/L [25]. The next step used amlodipine or hydrochlorothiazide. We also allowed β-blockers to achieve the SBP target.

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 with 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 6 months of BP medication titration, 83%, 80%, and 73% of the patients attained a BP level below the specified SBP target for Groups A, B, C, respectively. At baseline enrollment, the mean number of antihypertensive drugs prescribed was 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 (Fig. 2B). In SPRINT the mean number of BP 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 3.4–3.5) in the intensive-therapy group and 2.1 (95% CI 2.1–2.2) in the standard-therapy group.

In the process of BP medication titration, SBP fluctuated somewhat as in week 8, and we considered that ambient temperature was a potential contributor [26]. As part of BP measurements, we also recorded the ambient temperature. As shown in Supplemental Fig. 3, ambient temperature was correlated with BP levels. On the other hand, between the week-5 visit and week-8 visit, there is a Spring Festival Holiday with sufficient rest time, which is also good for BP control.

Safety issues were related to side effects of the specific antihypertensive 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 SAEs were recorded. The BP-control protocols were overall safe without any major AE for all three target groups.

The current study tested different modalities of BP measurements: office visits, self-monitored HBPM, and CASP and examined their relationships. We found a consistent pattern of BP control between HBPM and office-visit BP measurements. In addition, there was a general 8–9 mmHg difference between CASP and office visit BP.