Comparison of two single-pill dual combination antihypertensive therapies in Chinese patients: a randomized, controlled trial

The present study was a multi-center, randomized, actively controlled, parallel-group trial (ClinicalTrials.gov identifier number, NCT03682692) for the comparison between amlodipine besylate 5 mg/benazepril 10 mg (amlodipine/benazepril group) and benazepril 10 mg/hydrochlorothiazide 12.5 mg (benazepril/hydrochlorothiazide group) in patients with stage 1 or 2 hypertension from July 2018 to June 2021 in 20 hospitals and community health centers across China. The study protocol (Additional file 1) was approved by the ethics committee of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, and, as necessary, also by the ethics committees of the participating hospitals. All patients gave written informed consent.

The study consisted of a 4-week benazepril-treatment run-in period and a subsequent 24-week randomized treatment period. If at a screening visit, previously untreated patients or previously treated patients on antihypertensive monotherapy had a blood pressure of 140–179 mmHg systolic or 90–109 mmHg diastolic and were willing to discontinue previous antihypertensive therapy, they entered the run-in period with antihypertensive monotherapy of benazepril 10 mg per day for the determination of eligibility. If eligible according to the average of six blood pressure readings obtained at two clinic visits 2 weeks apart and the tolerability to the benazepril monotherapy during the run-in period, patients were randomly assigned to receive amlodipine/benazepril one tablet per day or benazepril/hydrochlorothiazide one tablet per day for 24 weeks after stratification for study center. The study medication could be stopped in the presence of symptomatic hypotension or any other serious adverse events related to the study medication. Patients were instructed to take the study medication from 06:00 to 08:00 every morning before breakfast. If clinic systolic/diastolic blood pressure could not be controlled to the target (< 140/90 mmHg) during follow-up, the study medication could be up-titrated to two tablets per day. If there was no compelling indication, other antihypertensive agents or drugs of potential blood pressure-lowering action should not be used during the 24-week study treatment period. The study medication was supplied free of charge for the whole study period.

Men and women of 18 to 75 years of age were eligible for the trial, if the following inclusion and exclusion criteria were fulfilled. The average of the six clinic blood pressure readings measured at two clinic visits during the run-in phase with benazepril 10 mg per day was in the range of 140–179 mmHg systolic or 90–109 mmHg diastolic. No intolerable dry cough occurred with the benazepril monotherapy. The patients were able to attend the clinic visit on his/her own.

The exclusion criteria included the presence of life-threatening diseases, secondary hypertension, coronary heart disease, myocardial infarction, heart failure, stroke or dementia, abnormal liver (serum liver enzymes alanine aminotransferase or aspartate aminotransferase ≥ twice of the upper limit) and renal function (serum creatinine ≥ 1.5 mg/dL [133 µmol/L] or proteinuria on a dipstick test), the presence of contraindications to dihydropyridine CCBs or diuretics, and current participation in another trial.

Diabetes mellitus, defined as a plasma glucose of at least 7.0 mmol/L fasting or as the use of antidiabetic agents, was not an exclusion criterion. The estimated glomerular filtration rate (eGFR) was calculated from serum creatinine by the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [21]. Chronic kidney disease was defined as an eGFR less than 60 mL/min/1.73 m².

After 4 weeks of run-in period, eligible patients were randomized to the two study groups in a 1:1 ratio. Using the SAS software, an individual study statistician generated the randomization table with a block of four after stratification for the study center. The study investigators and coordinators were kept blinded before randomization. After the investigators, who enrolled the patients, sent the copy of the randomization tables to the coordinating center, one staff in the coordinating center assigned the randomization number and the treatment group according to the randomization table by center and table sequence.

Patients were randomly assigned to amlodipine 5 mg/benazepril 10 mg one tablet per day or to benazepril 10 mg/hydrochlorothiazide 12.5 mg one tablet per day. During each follow-up visit, the study medication could be up-titrated to amlodipine/benazepril or benazepril/hydrochlorothiazide two tablets per day to control clinic systolic/diastolic blood pressure to a level below 140/90 mmHg.

After randomization, patients were followed up every 4 weeks on normal working days in the morning. The follow-up time of the day was recorded. Clinic blood pressure and pulse rate were measured at baseline and at each of the follow-up visits. Ambulatory blood pressure monitoring was performed at baseline and at the end of the 24-week follow-up. Home blood pressure monitoring was performed for 7 days before each clinic visit at randomization and during follow-up. The responsible physicians collected information on the use of medications, adverse events, and serious adverse events at each follow-up visit. Blood and urinary biochemical measurements were performed at baseline and 4 and 24 weeks of follow-up. Hypercholesterolemia was defined as serum total cholesterol ≥ 5.18 mmol/L. Hypertriglyceridemia was defined as serum triglycerides ≥ 1.70 mmol/L. Dyslipidemia was defined as serum total cholesterol ≥ 5.18 mmol/L and/or serum triglycerides ≥ 1.70 mmol/L.

Clinic blood pressure was measured three times consecutively with a 30–60 s interval after at least 5 min rest in the sitting position using a validated automated blood pressure monitor (HEM 9200T, Omron Healthcare, Kyoto, Japan). These three blood pressure readings were averaged for the clinical decisions at each follow-up visit and for the present analysis.

Ambulatory blood pressure monitoring was performed using an oscillometric ambulatory blood pressure monitor (TM2430, A&D Co., Ltd., Tokyo, Japan), which was programmed to obtain ambulatory blood pressure readings at 20-min intervals in the day (06:00–22:00) and at 30-min intervals at night (22:00–06:00). Daytime and nighttime were defined as the short clock time intervals from 08:00 to 18:00 and from 23:00 to 05:00, respectively. Valid recordings should cover more than 20 h and include at least 10 and five readings in the daytime and nighttime, respectively. The 24-h mean values of blood pressure and pulse rate were weighted for the time interval between consecutive readings.

Home blood pressure monitoring was performed using the same device as clinic blood pressure measurement (HEM 9200T, Omron Healthcare, Kyoto, Japan). Patients were provided with an Omron HEM 9200T monitor and requested to measure their blood pressure at home for seven consecutive days before each clinic visit at randomization and during follow-up. During the 7 days of home blood pressure monitoring, patients were asked to measure blood pressure three times in the morning before breakfast and three times in the evening at least 2 h after supper in the sitting position. Valid home blood pressure recordings should cover at least 5 days within a week, both in the morning and evening.

For clinic, ambulatory, and home blood pressure measurements, a standard cuff was used when the arm circumference was 32 cm or smaller. Otherwise, a large cuff was used.

The primary outcome was the change from baseline to 24 weeks of treatment in 24-h ambulatory systolic blood pressure. Secondary outcomes included the change from baseline to 24 weeks of treatment in 24-h ambulatory diastolic blood pressure, daytime and nighttime systolic and diastolic blood pressure, and clinic and home systolic and diastolic blood pressure.

All adverse events were documented for information on symptoms, severity, treatment, and outcome. The routine and biochemical tests of blood and urine were performed for clinical laboratory safety evaluations. Any clinically significant changes in physical examinations and laboratory findings were also recorded as adverse events.

Assuming that the difference of 24-h ambulatory systolic blood pressure change after 24 weeks of treatment between the two groups is 2.5 mmHg and the standard deviation is 10 mmHg, α is 0.05, and the power is 80%, the sample size of each group should be 252 patients. The actual number of patients randomized in this study is 560. Among 560 eligible patients randomly assigned to amlodipine/benazepril 5/10 mg (n = 282) or benazepril/hydrochlorothiazide 10/12.5 mg (n = 278), 213 and 212 patients, respectively, who completed the study and had a valid repeat ambulatory BP recording during follow-up and were included in the efficacy analysis.

Data management and statistical analysis were performed using the SAS software, version 9.4 (SAS Institute, Cary, NC, USA). The efficacy analysis was performed in the patients who completed the 24-week study and had a valid repeat 24-h ambulatory blood pressure recording at 24 weeks of follow-up. The safety analysis was performed on all patients who had ever started the study medication. Continuous and categorical variables were compared using the Student t-test and X² test, respectively. Blood pressure and pulse rate changes from baseline were calculated by subtracting the values at baseline from those during follow-up. Analysis of covariance was performed to calculate the least square mean changes with standard error and the between-group mean difference with 95% confidence intervals (CI) with baseline values as covariate and treatment group as a factor. We also applied generalized estimating equation (GEE) analysis to compare blood pressure-lowering efficacy between the groups by considering the center as a possible bias.

Of the 894 screened patients, 334 were excluded because of ineligible blood pressure (n = 77), intolerable cough (n = 12), hyperuricemia (n = 8), proteinuria (n = 5), serious adverse event (n = 1), fulfilling the exclusion criteria of previous stroke (n = 1), stomach upset (n = 1), withdrawal of the consent (n = 116), and withdrawal with unknown reasons (n = 113). Finally, 560 (62.6%) were randomly assigned to receive amlodipine 5 mg/benazepril 10 mg one tablet per day (n = 282) or benazepril 10 mg/hydrochlorothiazide 12.5 mg one tablet per day (n = 278). A total of 213 patients in the amlodipine/benazepril and 212 in the benazepril/hydrochlorothiazide group completed the study and had a valid repeat ambulatory blood pressure recording during follow-up and were therefore included in the efficacy analysis. Among these patients, 125 patients in the amlodipine/benazepril and 119 in the benazepril/hydrochlorothiazide group had a valid home blood pressure recording at baseline and 24 weeks of follow-up (Fig. 1). All 560 randomized patients were included in the safety analysis.

Patients were comparable between the two randomization groups in all demographic and clinical characteristics at baseline (Table 1). Clinic systolic/diastolic blood pressure was on average 150.9/92.7 mmHg and 151.2/92.5 mmHg in the amlodipine/benazepril and benazepril/hydrochlorothiazide groups, respectively.

During the study treatment period, the study medication in the amlodipine/benazepril group remained one tablet per day in 276 (97.9%) patients and was up-titrated to two tablets per day in 6 (2.1%) patients. The corresponding numbers in the benazepril/hydrochlorothiazide group were 262 (94.2%) and 16 (5.8%), respectively.

During follow-up, clinic systolic/diastolic blood pressure was not significantly (p ≥ 0.09) different between the two treatment groups at any clinic visit (Fig. 2). At 24 weeks of follow-up, clinic systolic/diastolic blood pressure was reduced from baseline by − 21.9 ± 0.72/ − 15.3 ± 0.48 mmHg and − 21.4 ± 0.72/ − 13.9 ± 0.48 mmHg in the amlodipine/benazepril (n = 213) and benazepril/hydrochlorothiazide groups (n = 212), respectively. The corresponding blood pressure control rate was 91.1% and 88.2% (p = 0.33), respectively.

Twenty-four-hour ambulatory systolic blood pressure change, the primary outcome, was − 13.8 ± 1.17 mmHg (from 143.5 ± 14.1 mmHg at baseline to 129.7 ± 13.7 mmHg at 24 weeks) in the amlodipine/benazepril group and − 12.3 ± 1.17 mmHg (from 142.8 ± 13.4 mmHg at baseline to 130.5 ± 12.7 mmHg at 24 weeks) in the benazepril/hydrochlorothiazide group (Tables 1, 2 and 3). The between-group difference (95% CI) was − 1.51 (− 4.76 to 1.74, p = 0.36) mmHg. Among the secondary ambulatory blood pressure outcomes, the between-group differences were not statistically different between the two randomization groups except for the 2.74 mmHg greater reduction in daytime diastolic blood pressure (95% CI, − 5.20 to − 0.27 mmHg, p = 0.03) in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (Table 3). GEE analysis by considering the center as a possible bias produced similar results (Additional file 2: Table S1). The ambulatory blood pressure trajectory according to the time of the day showed blood pressures of all hours of the day were comparable at baseline and 24 weeks of follow-up except for diastolic blood pressure at 24 weeks. Diastolic blood pressure in several daytime hours at 24 weeks was significantly lower in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (p < 0.05, Fig. 3).

Home blood pressure was measured in a subgroup of patients (n = 244) and reduced similarly in the amlodipine/benazepril (n = 125) and benazepril/hydrochlorothiazide groups (n = 119) at each of the follow-up visits (p ≥ 0.30, Table 3).

We performed subgroup analyses in patients with white-coat (n = 58) and sustained hypertension (n = 367), in patients who were previously untreated (n = 286) and treated with antihypertensive medication (n = 139) and in subgroups according to gender, age (≥ 60 vs < 60 years), and clinic (≥ 150 vs < 150 mmHg) and 24-h systolic blood pressure at baseline (≥ 140 vs < 140 mmHg). The interaction was statistically significant in none of these subgroups (p ≥ 0.058). Nonetheless, the 24-h systolic blood pressure reduction was significantly greater in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group in patients aged ≥ 60 years (− 5.91 mmHg; 95% CI, − 11.8 to − 0.04 mmHg; p = 0.048, Fig. 4).

One serious adverse event of cerebral hemorrhage occurred during the run-in period of the trial. This patient was hospitalized for 22 days and discharged with stable vital signs. The event was not related to the use of benazepril. The patient was not randomized into the study treatment phase.

During the randomized treatment period, among all 560 randomized patients included in the safety analysis, no serious adverse events were reported, and adverse events were reported in 109 (38.7%) and 124 (44.6%) patients in the amlodipine/benazepril and benazepril/hydrochlorothiazide groups, respectively (p = 0.15). The incidence rate of dry cough was significantly lower in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (5.3% vs 10.1%, p = 0.04, Table 4). At 24 weeks of follow-up, serum potassium concentration was significantly (p < 0.001) lower in the benazepril/hydrochlorothiazide group than in the amlodipine/benazepril group (4.04 ± 0.34 vs 4.17 ± 0.37 mmol/L, p < 0.001, Additional file 3: Table S2), with a significant difference between the two groups in the changes from baseline (0.10 mmol/L; 95% CI, 0.03 to 0.17 mmol/L; p = 0.006, Additional file 4: Table S3). The incidence rate of hypokalemia, however, was only slightly and non-significantly (p = 0.65) higher in the benazepril/hydrochlorothiazide group than in the amlodipine/benazepril group (12.6 vs 11.4%, Table 4). The prevalence of dyslipidemia changed from 64.8% at baseline to 48.9% at 24 weeks of follow-up in the amlodipine/benazepril group and from 58.0% at baseline to 57.4% at 24 weeks of follow-up in the benazepril/hydrochlorothiazide group, with no between-group difference at baseline (p = 0.10) and a significant difference at 24 weeks of follow-up (p = 0.04, Additional file 3: Table S2). During follow-up, the use of lipid-lowering drugs was reported in four patients (3 in the amlodipine/benazepril group and 1 in the benazepril/hydrochlorothiazide group), and the change in serum total cholesterol or serum triglycerides from baseline between the two groups was not statistically significant (p ≥ 0.76, Additional file 4: Table S3).