The fixed-dose combination of olmesartan/amlodipine was superior in central aortic blood pressure reduction compared with perindopril/amlodipine: a randomized, double-blind trial in patients with hypertension

Abstract

Introduction: Central blood pressure (BP), an important measure of cardiovascular risk, has been shown to be effectively reduced by calcium channel blockade with amlodipine (AML) plus renin-angiotensin system blockade by the angiotensin-converting enzyme inhibitor, perindopril (PER). The aim of the SEVITENSION study was to compare the central effects of PER/AML against renin-angiotensin system blockade with the angiotensin II receptor blocker olmesartan (OLM) plus AML.

Methods: In this multicenter, parallel group, non-inferiority study, patients received AML 10 mg during a 2- to 4-week run-in before randomization to 24 weeks of double-blind treatment with the fixed-dose combination of OLM/AML 40/10 mg or PER/AML 8/10 mg. Hydrochlorothiazide was added at Weeks 4, 8, or 12 in patients with inadequate BP control. The primary efficacy variable was the absolute change in central systolic BP (CSBP) from baseline to the final examination, measured by radial artery applanation tonometry and analyzed by parametric analysis of covariance. Secondary variables included 24-h ambulatory and seated BP measurements as well as BP normalization.

Results: Of 600 patients enrolled, 486 were randomized (244 to OLM/AML 40/10 mg, 242 to PER/AML 8/10 mg). The reduction in CSBP was larger with OLM/AML (14.5 ± 0.83 mmHg) than with PER/AML (10.4 ± 0.84 mmHg). The between-group difference was -4.2 ± 1.18 mmHg with 95% confidence intervals (-6.48 to -1.83 mmHg) within the predefined non-inferiority margin (2 mmHg). An integrated superiority test confirmed that OLM/AML was superior to PER/AML (p < 0.0001) in reducing CSBP. The superiority of OLM/AML over PER/AML was also established for the majority of secondary efficacy variables; at the final examination, 75.6% of OLM/AML recipients achieved BP normalization (mean seated systolic BP/diastolic BP <140/90 mmHg) compared with 57.5% of PER/AML recipients (p < 0.0001).

Conclusion: The combination of OLM/AML was superior to PER/AML in reducing CSBP and other efficacy measures, including a significantly higher rate of BP normalization.

Trial registration: ClinicalTrials.gov NCT01101009.

Fig. 1

Patient flow. AE adverse events, AML amlodipine, BP blood pressure, FAS full analysis set, OLM olmesartan, PER perindopril, PPS per protocol set, SAF safety analysis set

Fig. 2

Absolute change from Week 0 to the final examination in mean central systolic blood pressure by treatment group (LOCF approach for the PPS). AML amlodipine, CSBP central systolic blood pressure, LOCF last observation carried forward, OLM olmesartan; PER perindopril, PPS per protocol set

Fig. 3

Forest plot of the differences between patients treated with OLM/AML 40/10 mg and PER/AML 8/10 mg in the absolute change from Week 0 to final examination in CSBP in the primary efficacy endpoint (PPS) and the FAS. P values represent the comparison between OLM/AML and PER/AML. Filled circles indicate the position of the point estimates for between-group differences and vertical lines indicate the 95% confidence intervals. AML amlodipine, BP blood pressure, CI confidence interval, FAS full analysis set, OLM olmesartan, PER perindopril, PPS per protocol set

Fig. 4

Forest plot of the differences between patients treated with OLM/AML 40/10 mg and PER/AML 8/10 mg in the absolute change from Week 0 to the final examination in secondary a systolic BP parameters and b diastolic BP parameters. P values represent the superiority comparison between OLM/AML and PER/AML in the FAS. Filled circles indicate the position of the point estimates for between-group differences and vertical lines indicate the 95% confidence intervals. AML amlodipine, BP blood pressure, CI confidence interval, DBP diastolic blood pressure, FAS full analysis set, OLM olmesartan, PER perindopril, SBP systolic blood pressure

Fig. 5

Proportion of patients with blood pressure normalized at the final examination using criteria based upon the 2007 ESH/ESC guidelines (SBP/DBP <140/90 or <130/80 mmHg for diabetic/CKD patients) [12] and on the 2009 ESH reappraisal (SBP/DBP <140/90 mmHg) [13] in the FAS. AML amlodipine, CKD chronic kidney disease, DBP diastolic blood pressure, ESC European Society of Cardiology, ESH European Society of Hypertension, FAS full analysis set, OLM olmesartan, PER perindopril, SBP systolic blood pressure