Evaluation of high dose of perindopril/indapamide fixed combination in reducing blood pressure and improving end-organ protection in hypertensive patients.
BACKGROUND
Despite the widespread notion that controlling hypertension is essential to improve cardiovascular outcome, uncontrolled hypertension rates remain high. Fixed-dose combinations are used routinely to reduce the impact of hypertension. Treatment with fixed-combination perindopril/indapamide, for example, at the currently approved doses (perindopril 2 mg/indapamide 0.625 mg [Per2/Ind0.625] and perindopril 4 mg/indapamide 1.25 mg [Per4/Ind1.25]), reduces blood pressure, end-organ damage, and cardiovascular morbidity and mortality in a wide range of hypertensive patients.


OBJECTIVE
This article reviews three published randomised trials that evaluated the efficacy and safety of the highest dose of perindopril/indapamide (perindopril 8 mg/indapamide 2.5 mg [Per8/Ind2.5]) in blood pressure lowering and end-organ protection studies.


RESULTS
In the first (dose-finding) study, incremental reductions in SBP/DBP were observed with each dose doubling. After 8 weeks of treatment, decreases in supine SBP/DBP were statistically significant compared to placebo for all three doses, with incremental and progressive reductions with each dose doubling: ranging from SBP/DBP respectively -14/-9 mmHg for Per2/Ind0.625 to -23/-15 mmHg for Per8/Ind2.5 compared to -5/-5 mmHg for placebo. In the PICXEL and PREMIER trials, SBP/DBP decreases of 16.3/8.1 mmHg (p < 0.0001) and 2.5/2.6 mmHg, respectively, were noted when Per4/Ind1.25 was doubled to Per8/Ind2.5 (decreases from 167.7/101.7 to 151.4/93.6 in PICXEL and from 154.9/92.1 to 152.4/89.5 in PREMIER, respectively). As a consequence more patients had normalised blood pressure (22% and 17%), more patients responded to treatment (68% and 45%), and 29% and 10% of non-responders became responders, in PICXEL and PREMIER, respectively. Additional end-organ benefits were also noted with Per8/Ind2.5. In PICXEL, significant decreases from baseline in left ventricular mass were noted with all three doses, with a 17.5 g/m(2) decrease from baseline in patients whose maximum dose was Per8/Ind2.5 (from 148.5 g/m(2) +/- 39.5 (mean +/- SD) to 131 g/m(2); p < 0.0001). In PREMIER, changes in albumin excretion rate were also noted with all three doses, with a 45% reduction from baseline in patients whose maximum dose was Per8/Ind2.5 (p < 0.0001). When safety data, including potassium levels, were analysed, the increase in dose to Per8/Ind2.5 did not have a notable impact on the safety profile of perindopril/indapamide.


CONCLUSIONS
Based on data available from an evaluation of three randomised clinical trials, fixed-combination Per8/Ind2.5 provided a significant, incremental reduction in blood pressure as well as cardiac and renal end-organ protection while remaining safe and well-tolerated.
Mourad
J J
JJ
Avicenne University Hospital, AP-HP and University of Paris 13 (EA3412), Bobigny, France. jean-jacques.mourad@avc.aphp.fr
Le Jeune
S
S
D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects*; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007190:Indapamide / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000517:prevention & control*; D020913:Perindopril / Q000008:administration & dosage* / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D017186:Titrimetry; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D004338:Drug Combinations; C494243:indapamide, perindopril drug combination; D007190:Indapamide; D020913:Perindopril