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Improved Blood Pressure Control with Nifedipine GITS/Valsartan Combination Versus High-Dose Valsartan Monotherapy in Mild-to-Moderate Hypertensive Patients from Asia: Results from the ADVISE Study, a Randomized Trial Yuan-Nan Ke,1 Yu-Gang Dong,2 Shu-Ping Ma,3 Hong Yuan,4 Sang-Hyun Ihm,5 & Sang Hong Baek6 on behalf of the ADVISE study group 1 Cardiovascular Department, China-Japan Friendship Hospital, Beijing, China 2 Cardiovascular Department, The First Affiliated Hospital of Zhongshan University, Guangzhou, China 3 Cardiovascular Department II, Hebei Provincial Hospital, Shijiazhuang, China 4 Cardiology Department, The Third Xiangya Hospital of Central South University, Changsha, China 5 Division of Cardiology Department of Internal Medicine, Bucheon St. Mary’s Hospital, The Catholic University of Korea, Bucheon, Korea 6 Cardiovascular Division, The Catholic University of Korea, School of Medicine, Seoul St Mary’s Hospital, Seoul, Korea

Keywords Asia; Blood pressure (BP) control; Hypertension; Nifedipine; Valsartan. Correspondence Yuan-Nan Ke, Cardiovascular Department, China-Japan Friendship Hospital, Yinghuayuan East Street, Chaoyang District, Beijing, 100029, China. Tel.: 8610 84205020(0); Fax: 8610 84205020(0); E-mail: [email protected] Sang Hong Baek, Cardiovascular Division, The Catholic University of Korea, School of Medicine, Seoul St. Mary’s Hospital, 505 Banpo-Dong Seocho-Ku, Seoul 137-040, Korea. Tel.: 82 2 2258 6030; Fax: 82 2 591 1506; E-mail: [email protected]

SUMMARY Aims: ADVISE was a 12-week, multicenter, randomized, prospective, open-label, parallelgroup study comparing combination therapy of nifedipine GITS 30 mg plus valsartan 80 mg (N + V) with high-dose valsartan (160 mg) monotherapy (V160) in Asian patients with hypertension. Methods: Patients with hypertension inadequately controlled with valsartan 80 mg for at least 4 weeks were randomized. The coprimary endpoints were the mean changes in clinic systolic and diastolic blood pressures (SBP and DBP, respectively) at Week 12. Other endpoints included blood pressure (BP) control rate, response rate, and adverse events. Results: The full analysis set (FAS) comprised 359 patients. Least squares (LS) mean changes in SBP were 18.3 mmHg (N + V; n = 177) and 16.5 mmHg (V160; n = 182) (difference: 1.9 mmHg; P = 0.0998). DBP LS mean changes were 9.8 mmHg (N + V) and 7.4 mmHg (V160) (difference: 2.4 mmHg; P = 0.0011). BP control rates were significantly higher in the N + V group (Week 4: 51.2% vs. 38.4%, P = 0.0138; Week 8: 68.3% vs. 50.3%, P = 0.0004; and Week 12: 71.2% vs. 55.5%, P = 0.0024). Similar findings were observed when patients were stratified according to smoking status, SBP baseline quartiles, and ESC/ESH guideline-defined added-risk category. The BP response rate was also higher in the N + V group compared with the V160 group. Rates of adverse drug reactions (all mild-to-moderate) were similar: 4.5% (N + V) and 4.4% (V160). Conclusions: Although one of the coprimary endpoints did not reach statistical significance, combination treatment with N + V provided a greater early and more consistent BP-lowering effect than monotherapy with V160, including superior reduction in DBP and BP control rates.

doi: 10.1111/1755-5922.12003

Introduction Hypertension has a high prevalence in Asia (around 20–35% across all regions) [1,2]. Despite an increase in the use of antihypertensive treatment, blood pressure (BP) control rates still remain low in this region [3,4]. Inadequate BP control can increase the risk of stroke, particularly in Asian populations. A recent meta-analysis showed that for each 10 mmHg increase in systolic blood pressure (SBP), there was a 44% increase in the risk of ischemic stroke and a 50% increase in the risk of hemorrhagic stroke in Asian populations, compared with a 19% increase in the risk of total stroke in

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Caucasian populations [5]. This association has also been observed in other large-scale surveys [6–8]. Achieving BP control is, therefore, important for reducing this elevated risk. Guidelines suggest that combination therapy will be required in the majority of patients, with calcium channel blockers (CCBs) being recommended in most preferred combinations [9]. Randomized and observational studies of the dihydropyridine (DHP) CCB nifedipine GITS have shown that this agent is effective both as monotherapy and when used in combination [10,11]. The TALENT study showed that when patients were randomized to nifedipine GITS 20 mg, telmisartan 80 mg, or a combination of both for 8 weeks, the BP-lowering effect was earlier and greater

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Nifedipine GITS/Valsartan in Asian Patients

with the combination than monotherapy (mean change in 24 h SBP: 10.8 mmHg vs. 6.6 mmHg [nifedipine monotherapy] and vs. 8.0 mmHg [telmisartan monotherapy], respectively) [10]. The aim of the ADVISE study was to compare the efficacy of combination therapy with nifedipine GITS plus valsartan with high-dose valsartan monotherapy in Asian patients whose BP was not controlled with valsartan 80 mg alone.

criteria were randomized 1:1 to nifedipine GITS 30 mg plus valsartan 80 mg (N + V) or valsartan 160 mg (V160; two 80-mg tablets), medication taken orally in the morning for 12 weeks. Patients attended for a visit during screening (visit 1, 7 to 0 days prior to randomization), randomization (visit 2, day 0), and then at Week 4 (visit 3), Week 8 (visit 4), and Week 12 (visit 5) (±3 days for all postrandomization visits).

Methods

Outcome Measures

ADVISE was a prospective, multicenter, randomized, openlabel, parallel-group study, which compared 12 weeks of nifedipine GITS 30 mg plus valsartan 80 mg with valsartan monotherapy 160 mg in patients whose BP was not controlled with valsartan 80 mg (all drugs were supplied by Bayer Pharma AG, Berlin, Germany and orally administered once daily). Patients were recruited from 16 centers in China and Korea between February 2010 and February 2011. The study protocol was reviewed and approved by each center’s independent ethics committee (IEC) or institutional review board (IRB), and the study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. All study subjects provided written informed consent.

The coprimary efficacy endpoints were the mean change from baseline (randomization, or the latest available nonmissing value before starting randomized treatment) in clinic SBP and DBP at Week 12, on a last observation carried forward (LOCF) basis (e.g., for missing values, data from the last patient visit were used). BP could be recorded using automated devices (two centers) or manual mercury sphygmomanometers (14 centers), but no brand was specified for mercury sphygmomanometer. BP was measured in the morning between 08.00–09.00 hours, and prior to drug administration. The patient was seated for at least 5 min before BP measurements were taken. The average of two values (taken 1–2 min apart in the seated position) were used as the reference value for inclusion in the study and determination of the efficacy of treatment. Secondary efficacy endpoints included BP response rate (defined as 10 mmHg decrease in office SBP and 5 mmHg decrease in office DBP) and BP control rate (defined as achieving a BP goal: 140/90 mmHg [12]) at Weeks 8 and 12, and change in pulse pressure (difference between SBP and DBP) at Week 12. Safety variables included adverse events (AEs), vital signs, and routine laboratory blood tests at all study visits. AEs were categorized as mild, moderate, or severe. A serious AE was defined as fatal, life-threatening, a congenital abnormality or birth defect, an important medical event, required inpatient hospitalization or prolongation of hospitalization, or resulted in persistent or significant disability or incapacity. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system version 13.1.

Patients Adult men and women aged 18–75 years with a body mass index (BMI) 140 mmHg (sitting for 5 min, no cigarettes and/or coffee/tea for 30 min before BP measurement). Subjects who had previously received monotherapy with a diuretic, angiotensin converting enzyme inhibitor, beta-blocker, or an angiotensinreceptor blocker other than valsartan and who were switched to valsartan 80 mg/day monotherapy for 4 weeks were also eligible, provided the hypertension was still not controlled. Major exclusion criteria included subjects who had severe hypertension (diastolic blood pressure [DBP] 110 mmHg and/ or SBP 180 mmHg), were receiving treatment with any antihypertensive agent other than valsartan 80 mg, or concomitant treatment with any cytochrome P450-3A4 inhibitors or inducers or potassium-sparing diuretics, had evidence of secondary hypertension, a history of cardiovascular shock, myocardial infarction or unstable angina within the previous 6 months; severe cardiac valve disease, a past or present severe rhythm or conduction disorder, type 1 or 2 diabetes mellitus, proteinuria, liver disease or liver enzyme levels more than 39 upper limit of normal, renal failure, any known malignant disease, a cerebrovascular event, subarachnoid hemorrhage or intracerebral hemorrhage within the previous 12 months, or a history of noncompliance, alcoholism or drug abuse.

Study Design All screened subjects continued on valsartan monotherapy 80 mg/day until randomization. Subjects meeting the inclusion


Statistical Analysis All subjects who were randomized and took at least one dose of study drug were included in the full analysis set (FAS). The safety analysis set was identical with the FAS. The per-protocol (PP) set included all subjects who had BP monitored at 12 weeks of treatment and had no major protocol violations. The primary efficacy analyses were conducted using the FAS, with additional analyses on the PP data set. No imputation of missing values was performed in the PP analysis. All variables were summarized using descriptive statistics, mean and standard deviation (SD) for continuous variables, and number and percentage for categorical variables. The primary efficacy endpoints, change in SBP and DBP from baseline to Week 12 (LOCF), were analyzed using analysis of covariance (ANCOVA) with treatment and center as factors and baseline mean SBP/DBP as a covariate. BP control and response rates were compared using the Cochran–Mantel–Haenszel test with center as a stratification factor, and subanalysis was performed for control rates according


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to baseline SBP quartile [1 Q 144 mmHg, 144 < 2 Q 149 mmHg, 149 < 3 Q 157 mmHg, 157 mmHg < 4 Q], smoking status (current smoker vs. nonsmoker), and ESH/ESC (2007) added-risk categories (i.e., low-moderate vs. high–very high added risk) [9]. All statistical tests were two-sided and conducted at the 5% significance level. With 151 subjects per treatment group and 1:1 randomization, the study had 90% power with a one-sided significance level of 2.5% to detect a least squares (LS) mean (e.g., baseline-adjusted mean change in BP) difference between the treatment groups of 3 mmHg (SD 8 mmHg) for the DBP change from baseline and 99% power to detect a mean difference of 6 mmHg (SD 12 mmHg) in the SBP change from baseline. Allowing for 15% invalidity, the target was 356 subjects randomized to the two treatment groups. Statistical analyses were performed using SAS release 9.1.3 (SAS Institute Inc., Cary, NC, USA).

Results A total of 391 patients were screened, and 360 patients were randomized to treatment (Figure 1). The FAS (and safety) group comprised 359 patients and the PP set included 313 patients.

A total of 321 subjects (157 [88.2%] in the N + V group and 164 [90.1%] in the V160 group) completed the study and 39 subjects (21 [11.8%] in the N + V group and 18 [9.9%] in the V160 group) withdrew prematurely from the study. The most common reasons for study discontinuation were withdrawal of consent, followed by AEs and protocol violations. The two treatment groups were comparable with respect to demographic and baseline characteristics (Table 1). The overall mean (SD) age was 55.9 (9.6) years, 52.4% were men and all were Asian. The mean (SD) treatment duration was 79.8 (17.5) and 80.4 (17.1) days in the N + V group and V160 group, respectively, of which 90.4% of subjects in the combination group and 91.2% in the monotherapy group had received study treatment for more than 10 weeks.

Efficacy Endpoints The LS mean changes in SBP were 18.3 mmHg in the N + V group and 16.5 mmHg in the V160 group (FAS population) from baseline to Week 12 (LOCF); the LS mean difference was: 1.9 mmHg [95% CI: 4.1, 0.4 mmHg; P = 0.0998]. The LS mean changes in DBP were 9.8 mmHg (N + V) and 7.4 mmHg (V160), a significantly greater difference in favor of N + V

Screened (n = 391)

Excluded (n = 31) • Protocol violation (n = 24) • Consent withdrawal (n = 5) • Lost to follow-up (n = 2)

Randomized (n = 360)

Allocated to intervention N + V (n = 178)

Allocated to intervention V160 (n = 182)

Full analysis set (FAS) (n = 177)*

Full analysis set (FAS) (n = 182)**

• • • •

Adverse events (n = 7) Consent withdrawal (n = 7) Protocol violation (n = 5) Non-complaint (n = 2)

Study completers (n = 157)

• • • • •

Consent withdrawal (n = 6) Protocol violation (n = 6) Adverse events (n = 4) Insufficient effect (n = 1) Lost to follow-up (n = 1)

Study completers (n = 164)

*177 patients were included in the FAS as 1 patient did not receive allocated intervention; 153 were included in the per protocol set (24 patients were excluded due to protocol violation). **182 patients were included in the FAS; 160 were included in the per protocol set (22 patients were excluded due to protocol violation). Figure 1 Patient disposition during the study. N + V, nifedipine GITS 30 mg/day plus valsartan 80 mg/day; V, valsartan monotherapy 160 mg/day.

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( 2.4 mmHg [95% CI: 3.8, 1.0]; P = 0.0011; FAS). In the PP analysis, SBP LS mean changes were 19.2 mmHg (N + V) and 16.8 mmHg (V160); the LS mean difference was 2.4 mmHg [95% CI: 4.7, 0.2; P = 0.0342]. The between groups LS mean difference in DBP was 3.1 mmHg [95% CI: 4.6, 1.7 mmHg; P < 0.0001], in favor of N + V (Figure 2). Patients treated with N + V had a greater early decrease in SBP/DBP (evident at Week 4) compared with those treated with V160. The LS mean differences at Week 4 were 4.6 mmHg [95% CI: 6.9, 2.2; P = 0.0002] for SBP and 3.2 mmHg [95% CI: 4.8, 1.7; P < 0.0001] for DBP (FAS). The overall BP control rate was significantly higher in the N + V group at all postrandomization time points compared with the V160 group and increased from Week 4 onward (Week 4: 51.2% vs. 38.4% [P = 0.0138]; Week 8: 68.3% vs. 50.3% [P = 0.0004]; Week 12: 71.2% vs. 55.5% [P = 0.0024] [FAS population]) (Figure 3A). BP control rates were also higher in the N + V group than the V160 group at all postrandomization time points when patients were stratified according to smoking status (Figure 3B), added-risk categories (Figure 3C), and upper and lower SBP quartiles (Figure 3D), except Week 4 in the second lower SBP quartile. BP control with N + V also remained consistent throughout these subgroups; by contrast, BP control with V160 was less consistent, especially in the subgroups of current smokers, high–very high added-risk category and higher baseline SBP quartiles (Figure 3B–D). The response rate was higher in the N + V group than the V160 group at all postrandomization time points, including Week 12 (73.7% vs. 59.1%, respectively) (Figure 3E). There was no statistically

Table 1 Baseline and demographic characteristics of the full analysis set (FAS) population (n = 359)

Parameters Age, mean (SD), years Age