title: Comparative efficacy and safety profile of amlodipine 5 mg/losartan 50 mg fixed-dose combination and amlodipine 10 mg monotherapy in hypertensive patients who respond poorly to amlodipine 5 mg monotherapy: an 8-week, multicenter, randomized, double-blind phase III noninferiority study.
abstract: BACKGROUND
  The number of hypertensive patients achieving treatment targets is not ideal with therapies that engage a single mechanism of action, and combination therapies using different mechanisms of action can increase drug efficacy in a synergistic way.
  
  
  OBJECTIVE
  This noninferiority study compared the clinical efficacy and safety profile of fixed-dose combination of amlodipine/losartan 5/50 mg and amlodipine 10 mg monotherapy in essential hypertensive patients who respond poorly to amlodipine 5 mg monotherapy.
  
  
  METHODS
  This was a double-blind, multicenter, randomized trial of hypertensive patients (N = 185) aged ≥18 years taking amlodipine 5 mg during the run-in treatment period but failed to achieve sitting diastolic blood pressure (DBP) <90 mm Hg. After randomization into the amlodipine/losartan 5/50 mg fixed-dose combination group (n = 92) and the amlodipine 10 mg monotherapy group (n = 93), treatment was maintained without dose escalation for 8 weeks. The noninferiority margin was prespecified as 4 mm Hg after 8 weeks of treatment for the difference of the average change in DBP between treatments. The primary efficacy evaluation of noninferiority was tested using a confidence interval approach with a 97.5% 1-sided lower confidence limit using the average difference in DBP measured at baseline and 8 weeks.
  
  
  RESULTS
  After 8 weeks, the DBP of both groups decreased from baseline by 8.9 (6.1) and 9.4 (7.5) mm Hg, respectively (difference = -0.5 [6.9] mm Hg, 95% CI: -2.5 to 1.5). Secondary end points of reductions in DBP after 4 weeks (-8.1 [6.7] vs -9.9 [7.3] mm Hg, difference = -1.8 mm Hg, 95% CI: -3.9 to 0.2) and sitting systolic blood pressure after 4 (-10.2 [11.8] vs -12.8 [10.2] mm Hg, difference = -2.6 mm Hg, 95% CI: -5.9 to 0.6) and 8 weeks (-12.2 [11.0] vs -13.4 [11.3] mm Hg, difference = -1.2 mmHg, 95% CI: -4.4 to 2.1) were comparable between the 2 treatment groups. There were 38 adverse events in 20 patients (21.7%) in the amlodipine/losartan 5/50 mg fixed-dose combination group and 31 in 24 patients (26.1%) in the amlodipine 10 mg monotherapy group; most were mild. There were 7 adverse events in 6 patients (6.5%) related to treatment in the fixed-dose combination group and 13 in 10 patients (10.9%) in the monotherapy group (P = 0.30).
  
  
  CONCLUSIONS
  Fixed-dose combination amlodipine/losartan 5/50 mg was not inferior in terms of reductions in DBP after 8 weeks of treatment and had comparable safety profile to amlodipine 10 mg in patients who did not respond to amlodipine 5 mg monotherapy. ClinicalTrials.gov identifier: NCT00940667.
authors.affiliation: Cardiology Division, Yonsei University Medical College, Severance Cardiovascular Hospital, Seoul, Korea. smkang@yuhs.ac
authors.forename: Seok-Min
authors.initials: SM
authors.lastname: Kang
authors.forename: Jong-Chan
authors.initials: JC
authors.lastname: Youn
authors.forename: Shung Chull
authors.initials: SC
authors.lastname: Chae
authors.forename: Chang Gyu
authors.initials: CG
authors.lastname: Park
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Yang
authors.forename: Moo Hyun
authors.initials: MH
authors.lastname: Kim
authors.forename: Taek Jong
authors.initials: TJ
authors.lastname: Hong
authors.forename: Cheol Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Jae Joong
authors.initials: JJ
authors.lastname: Kim
authors.forename: Dong Gu
authors.initials: DG
authors.lastname: Shin
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Jeong
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Jung
authors.forename: Jung Han
authors.initials: JH
authors.lastname: Yoon
authors.forename: Si Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Jun
authors.initials: J
authors.lastname: Kwon
authors.forename: Seung Yun
authors.initials: SY
authors.lastname: Cho
mesh_terms: D000328:Adult; D017311:Amlodipine / Q000008:administration & dosage* / Q000009:adverse effects; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects; D016009:Chi-Square Distribution; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D056910:Republic of Korea; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004338:Drug Combinations; D017311:Amlodipine; D019808:Losartan