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Purpose: To compare the effectiveness on blood pressure (BP) of initial two-drug therapy versus monotherapy in hypertensive patients., Methods: Using the Clinical Practice Research Datalink, linked with Hospital Episode Statistics and Office for National Statistics, we identified a cohort of adults with uncontrolled hypertension, initiating one or two antihypertensive drug classes between 2006 and 2014. New users of two drugs and monotherapy were matched 1:2 by propensity score. Main exposure was "as-treated," ie, until first regimen change. Primary and secondary endpoints were systolic and diastolic BP control and major adverse cardiovascular event (MACE), respectively. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard models., Results: Of 54 523 eligible patients, 3256 (6.0%) were initiated to a two-drug combination. Of these, 2807 were matched to 5614 monotherapy users. Mean exposure duration was 12.7 months, with 76.5% patients changing their initial regimen. Two-drug therapy was associated with a clinically significant BP control increase in all hypertensive patients (HR = 1.17 [95%CI: 1.09-1.26]), more so in patients with grade 2-3 hypertension (HR = 1.28 [1.17-1.41]). An increase of 27% in BP control (HR = 1.27 [1.08-1.49]) was observed in patients initiating an ACEi+CCB combination compared with initiators of either single class. No significant association was found between two-drug therapy and MACE. Several sensitivity analyses confirmed the main findings., Conclusions: Few patients initiated therapy with two drugs, reflecting UK guidelines' recommendation to start with monotherapy. This study supports the greater effectiveness of two-drug therapy as the initial regimen for BP control., (© 2019 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.)

Objectives: Brachial blood pressure (BP) is a predictor of cardiovascular events. Evidence suggests that central BP (CBP) provides additional information for cardiovascular risk assessment. Methods to assess 24-h CBP are now available. Our objective was to assess the feasibility of 24-h CBP monitoring in clinical trials and its ability for drug evaluation., Methods: Data are issued from an international phase 3 randomized clinical trial comparing the efficacy of perindopril/indapamide/amlodipine vs. perindopril/indapamide (Per/Ind), in uncontrolled hypertensive patients treated with Per/Ind. 24-h ambulatory BP monitoring (ABPM) was performed at baseline and after 1-month treatment using the Mobil-O-Graph device which provide brachial BP and CBP and arterial parameters., Results: From the 345 patients included in the ABPM substudy, 276 had two valid ABPM (M0 and M1) for brachial BP assessment (80%). After applying device/software built-in and expert quality control criteria on these recordings, 210 (76%) had valid data at M0 and M1 for the assessment of CBP. After 1 month, superior ambulatory central SBP reductions were observed in the perindopril/indapamide/amlodipine (n = 101) vs. Per/Ind group (n = 109) for 24-h/daytime/night-time periods (-4.5 mmHg, P = 0.002/-5.0, P < 0001/-4.1 mmHg, P = 0.016, respectively). Similar trends were observed for pulse wave velocity and other central parameters., Conclusion: Recording 24-h central ABPM and its derived arterial parameters needs a strict expert quality control and must consider a loss of up to 39% of the population included in the ABPM substudy. This method can be used to assess drug effect.

Objectives: The current international, 12-week, double-blind, randomized, controlled trial assessed the efficacy and safety of indapamide sustained release/amlodipine single-pill combination (SPC) in mild-to-moderate hypertensive patients., Methods: Following a 4-week run-in period on amlodipine 5 mg, patients (SBP 150-180 mmHg and/or DBP < 110 mmHg) were randomized to indapamide 1.5 mg sustained release/amlodipine 5 mg SPC or amlodipine 5 mg/valsartan 80 mg SPC with conditional uptitration at week 6. Office blood pressure (BP) was assessed at baseline, weeks 6 and 12; ambulatory and home blood pressure monitoring (ABPM/HBPM) at baseline and week 12., Results: Baseline characteristics were similar in both groups (57 years, 51% men, BP 160/92 mmHg). 233 patients were randomized to IndSR/Aml and 232 to amlodipine/valsartan, of whom 48 and 57% were uptitrated, respectively. After 12 weeks, office SBP/DBP decreased similarly with both treatments (-21/-8 vs. -20/-8 mmHg) leading to BP control in 50% and BP response in 70% of patients. Uptitration was effective (P < 0.001) with both regimens, in favour of IndSR/Aml (SBP/DBP -12/-6 vs. -7/-3 mmHg, respectively). ABPM (n = 273) and HBPM (n = 194) confirmed 24-h efficacy of both regimens. In the subgroup of patients with sustained uncontrolled hypertension assessed by ABPM (n = 216), office SBP/DBP decreased by -23/-13 vs. -18/-10 mmHg, respectively (P = 0.016/P = 0.135, post-hoc analysis). Both treatments were generally well tolerated., Conclusion: Both regimens produced effective BP reductions confirmed by ABPM/HBPM. Both treatments were well tolerated, in accordance with the individual agents' safety profile., Trial Registration Number: EUDRA CT no. 2012-001690-84.

Objectives: This 4-month, double-blind, randomized, controlled trial was designed to demonstrate the superiority of perindopril/indapamide/amlodipine single pill over perindopril/indapamide after 1 month and to determine further up-titration efficacy and safety in patients with mild-to-moderate hypertension., Methods: After a 1-month run-in period on perindopril/indapamide 5/1.25 mg, patients with SBP/DBP at least 150/95 mmHg and no diabetes or renal insufficiency received perindopril/indapamide/amlodipine 5/1.25/5 mg single pill or continued on the same treatment. At 1, 2, and 3 months, patients with uncontrolled blood pressure (SBP/DBP ≥ 140/90 mmHg) were gradually up-titrated with a higher dose of the triple therapy up to perindopril/indapamide/amlodipine 10/2.5/10 mg in both groups. Efficacy was assessed on office supine SBP (main criterion) and DBP, blood pressure control, and response rates. Treatment effect on ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) parameters was also assessed in two subpopulations of 276 and 263 patients, respectively., Results: A total of 454 hypertensive patients (diabetes and renal insufficiency excluded) were randomized, 227 to each group (56% were men, mean age was 55 years, blood pressure 162.3/101.1 mmHg). After 1 month, superior SBP (-3.1 mmHg, P = 0.02) and DBP (-2.8 mmHg, P < 0.001) reductions were observed with perindopril/indapamide/amlodipine, which were even more pronounced after excluding white-coat effect in the sustained hypertension population (-5.3/-3.7 mmHg). Similar results were observed in terms of blood pressure response (72 vs. 53%, P < 0.0001) and control rates (32 vs. 25%, P = 0.005). Up-titration was effective at each visit in both treatment arms (P < 0.001). Both ABPM and HBPM results confirmed the superiority of the triple therapy at 1 month on ASBP/ADBP and HSBP/HDBP: -4.5/-2.0 mmHg for ABPM (P < 0.001/P = 0.04), and -4.9/-3.1 mmHg for HBPM (both, P < 0.001). Up-titration steps resulted in further significant decreases in both ABPM and HBPM. Both treatment regimens were well tolerated regarding adverse events or laboratory testing. In particular, peripheral edema known to be amlodipine dose dependent, appeared in only a few cases, none with the highest dose. Hypotension, orthostatic hypotension, and cough whatever the dose were infrequent. There were no treatment-related serious adverse events., Conclusion: Perindopril/indapamide/amlodipine in a single pill produces superior reductions in blood pressure compared with dual therapy. Triple therapy up-titration was well tolerated and effective leading to BP control rates of over 80%. Analysis of 24-h ABPM and HBPM results corroborated these findings.

The aim of the study was to evaluate the antihypertensive efficacy and tolerability of the low-dose combination of the angiotensin-converting enzyme inhibitor perindopril 2 mg plus the diuretic indapamide 0.625 mg (P/I) compared with the angiotensin II antagonist losartan 50 mg (L50) in the treatment of essential hypertension. Patients (n = 277) were randomised, double-blind and allocated to receive either P/I or L50 once daily for a period of 12 weeks. Responder and normalisation rates in the two groups were compared by a chi 2 test. Ambulatory blood pressure monitoring results were compared using the one-tailed Student's t-test. Normalisation rates were significantly greater in the P/I group (76.0%) than in the L50 group (60.0%) (p = 0.009). Responder rates were significantly higher in the P/I group (91.7%) than in the L50 group (81.8%) (p = 0.025). The average blood pressure reductions were: in sSBP (P/I-L50 = -2.4 mmHg; CI: 6.2; 1.3) and sDBP (P/I-L50 = -2.0 mmHg; CI: -4.2; 0.2). The average night-time SBP decrease (ABPM) was significantly greater in the P/I group (p = 0.041). The tolerability was comparable between the two groups in terms of emergent adverse events related to treatment (12.4% for P/I patients and 8.4% for L50 patients). Laboratory evaluations did not show any significant variations. It was concluded the low-dose P/I combination had significantly higher responder and normalisation rates than L50. This study also confirmed the good tolerability of both treatments.

This epidemiological study was carried out as a 3-year follow-up project to assess the incidence of transient ischemic attacks (TIAs) and strokes; 8,846 treated hypertensive patients (mean BP, 149/84 mm Hg) aged 65 years or over (mean age, 73.7 +/- 6.3 years), devoid of symptoms of dementia and with documented vascular risk factors were recruited from January 1994 to August 1995, by 1,598 general practitioners in connection with 36 referral university neurology units throughout metropolitan France. Among these patients, 506 (5.7%) had at least one cerebrovascular event during the follow-up period: 309 (3.5%) experienced one or more isolated TIAs, and 197 (2.2%) had a stroke with or without a preceding TIA. A total of 510 TIAs were reported. The stroke subtypes were ischemia, hemorrhage, and unclassified in 70, 16, and 15% of the cases, respectively. The estimated annual stroke incidence was 7.42 per thousand. Of the 197 patients who developed strokes, 51 (26%) died. This case-fatality rate should be compared with the 4.5% mortality rate observed in the whole population during the study period. The 3 subgroups (with isolated TIAs, strokes, or no events during the study) were found to differ regarding age, sedentary lifestyle, past history of cardiovascular events, duration of hypertension, and evidence of complicated hypertension (univariate analysis). The factors identified as predictive of a stroke (multivariate analysis) were: the patient's age; sedentary lifestyle; pulse pressure (SBP-DBP); identification of TIA at baseline, and presence of arrhythmias., (Copyright 2001 S. Karger AG, Basel)