Abstract
Abstract Background In hypertensive patients uncontrolled with dual therapy, perindopril, indapamide and amlodipine triple therapy form one of the core drug treatments recommended by the latest European (ESC/ESH 2018) and International (ISH 2020) Guidelines, ideally used as single-pill combination (SPC) to improve adherence to treatment. Purpose To assess efficacy and safety of the SPC of Perindopril arginine 5 mg/Indapamide 1.25 mg/Amlodipine 5 mg (P5/I1.25/A5) compared to the free combination of Perindopril tert-butylamine 4 mg/Indapamide 1.25 mg (P4/I1.25) plus Amlodipine 5 mg (P4/I1.25 +A5) and of the titration to higher doses up to P10/I.2.5/A10 for SPC and P8/I.2.5+A10 for free combination, in patients with essential uncontrolled hypertension. Methods A randomized, double-blind, controlled, 7-month phase III study in hypertensive Asian patients uncontrolled with dual therapy (Systolic Blood Pressure (SBP) ≥140 and <180mmHg and Diastolic Blood Pressure (DBP) ≥90 and <110 mmHg). After a 1-month run-in period on P4/I1.25, patients were randomized to a 6-month parallel group period to receive the triple therapy either as SPC (P5/I1.25/A5) or as free combination (P4/I1.25+A5), potentially up-titrated to higher doses after 2 and 4 months if BP remained uncontrolled. Results 532 patients (mean SBP/DBP 150.4/97.2 mmHg, mean age 56 years) were randomized to receive SPC or free combination. After 2 months of randomized treatment, a large decrease in office SBP/DBP was observed in both the SPC (-15.0/-8.6mmHg) and the free combination group (-14.5/-8.7mmHg). The SBP-lowering effect of the SPC was shown to be non-inferior to the free combination (study primary endpoint, p<0.001). In patients uncontrolled on SPC after 2 and 4 months, titration to P10/I2.5/A5 then to P10/I2.5/A10 (in 46.1 and 17.6% patients in SPC group, respectively) led to additional SBP/DBP decrease (-9.0/-5.9 mmHg and -6.1/-3.6 mmHg, respectively). After 6 months, 64.4% of patients reached BP control. ABPM data corroborated these findings. Similar results were observed in the free combination group. Over the 6-month randomized period, treatments were well tolerated, even at the highest doses of the SPC. The most frequently reported treatment-related adverse events were those already described for indapamide, perindopril and amlodipine, i.e., hyperuricemia, hypokalemia and cough, and were observed with a similar frequency in both groups. Peripheral edema and hypotension or orthostatic hypotension remained low. Conclusion Perindopril/Indapamide/Amlodipine SPC is as effective and safe as the free combination in hypertensive patients uncontrolled with dual therapy of Perindopril/Indapamide. The uptitration to higher dosages of the triple-drug SPC provided additional benefit on BP lowering and BP control without increasing pill burden.
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