Benefit of treatment based on indapamide mostly combined with perindopril on mortality and cardiovascular outcomes: a pooled analysis of four trials.

OBJECTIVE: The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic indapamide monotherapy or in combination with perindopril as a blood pressure lowering drug in randomized controlled trials (RCTs). METHOD: Aggregate data from four published RCTs conducted versus matching placebo were pooled: PATS, a 2-year study (indapamide), and PROGRESS, a 4-year study (indapamide and perindopril), both in patients with a history of stroke or transient ischemic attack; ADVANCE, a 4-year study in patients with type 2 diabetes and cardiovascular risk factor (single-pill combination perindopril/indapamide) and HYVET, a 2-year study in very elderly hypertensive individuals (indapamide and an option of perindopril). The pooled effect (fixed and random) estimate (hazard ratio) was reported with corresponding 95% confidence intervals and P values. Treatment discontinuations were also analysed to assess the net benefit of the treatment. RESULTS: The population involved 24 194 patients (active: 12 113, placebo: 12 081). The fixed-effects meta-analysis of the three mortality endpoints found low statistical heterogeneity ( I2  = 0). Statistically significant risk reductions in the indapamide with or without perindopril-treated patients as compared to placebo were observed for all-cause death (-15%), cardiovascular death (-21%), fatal stroke (-36%) and all strokes (-27%). Other cardiovascular outcomes were improved (risk reduction, 22 to 36%). As expected, discontinuation rates for safety (two studies) were higher in the active group (6.4 vs. 3.9%), while they were similar when discontinuation for any reason is concerned (18.4 vs. 18.0%). CONCLUSION: Across medium to high cardiovascular risk population, long-term indapamide, mostly combined with perindopril-based treatment, provided evidence of benefit on mortality and morbidity.

Beneficial Effects of a Perindopril/Indapamide Single-Pill Combination in Hypertensive Patients with Diabetes and/or Obesity or Metabolic Syndrome: A Post Hoc Pooled Analysis of Four Observational Studies.

INTRODUCTION: To assess real-life effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in patients with hypertension (HT) and type 2 diabetes mellitus (T2DM), obesity and/or metabolic syndrome (MetS). METHODS: This post hoc analysis pooled raw data from four large observational studies (FORTISSIMO, FORSAGE, ACES, PICASSO). Patients, most with uncontrolled blood pressure (BP) on previous treatments were switched to Per/Ind (10 mg/2.5 mg) SPC at study entry. Office systolic and diastolic blood pressures (SBP and DBP) were measured at baseline, 1 month and 3 months. RESULTS: In the overall pooled population (N = 16,763), mean age was 61 ± 12 years, HT duration 11 ± 8 years, and baseline SBP/DBP 162/94 mmHg. T2DM, obesity and MetS were present in 21%, 49% and 27% of patients, respectively. Subgroups had similar mean age and HT duration to the overall population; patients with T2DM were slightly older (64 ± 10 years) with a longer HT duration (13 ± 8 years). Mean BP was approximately 160/95 mmHg in each subgroup. At 1 month, mean SBP decreased by approximately 20 mmHg in the overall population, and by a further 10 mmHg at 3 months. Similar results were observed in the three subgroups, with mean changes from baseline at 3 months of - 28 ± 15/- 13 ± 10 in T2DM; - 30 ± 15/- 14 ± 10 in obesity; and - 31 ± 15/- 15 ± 9 mmHg in MetS. BP decreases were greatest in patients with grade II or grade III HT. BP control rates (< 140/90 mmHg or 140/85 mmHg for T2DM) at 3 months were 59% in T2DM, 67% in obese, and 66% in MetS. No specific safety concerns were raised, particularly concerning ionic (Na, K) or metabolic profiles. CONCLUSIONS: Switching to Per/Ind SPC led to rapid and effective BP decreases in patients with T2DM, obesity, or MetS. BP control was achieved in 6-7 out of 10 previously treated but uncontrolled patients. Treatment was well tolerated. The results confirm the beneficial effects of a Per/Ind SPC for difficult-to-control patient populations.

Effectiveness of two-drug therapy versus monotherapy as initial regimen in hypertension: A propensity score-matched cohort study in the UK Clinical Practice Research Datalink.

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.

Feasibility of 24-h central blood pressure monitoring: experience from multinational clinical trial assessing the efficacy of perindopril/indapamide/amlodipine.

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.

Efficacy of a new single-pill combination of a thiazide-like diuretic and a calcium channel blocker (indapamide sustained release/amlodipine) in essential hypertension.

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.

Blood pressure-lowering efficacy and safety of perindopril/indapamide/amlodipine single-pill combination in patients with uncontrolled essential hypertension: a multicenter, randomized, double-blind, controlled trial.

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.