Evaluation of high dose of perindopril/indapamide fixed combination in reducing blood pressure and improving end-organ protection in hypertensive patients

ABSTRACT

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.

Aim and scope: 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/m² decrease from baseline in patients whose maximum dose was Per8/Ind2.5 (from 148.5 g/m² ± 39.5 (mean ± SD) to 131 g/m²; 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.

Keywords: :

• Blood pressure reduction
• Cardiovascular protection
• Perindopril/indapamide fixed combination
• Renal protection

Transparency

Declaration of funding

The publication of the article and the data analysis was supported by Servier, who also provided access to data on file (study reports).

Declaration of financial/other relationships

J.J.M. has disclosed that he is a recipient of honorary fees from Servier and has acted as a consultant or served on the advisory board for Ipsen, Takeda, Daichi Sankyo, Pfizer, AstraZeneca, Servier and Abbot. S.L.J. has disclosed that he has no relevant financial relationships.

All peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he/she has served on speakers’ bureau for Servier, Bayer, sanofi-aventis and Boehringer-Ingelheim; Peer Reviewer 2 has disclosed that he/she has no relevant financial relationships.

Acknowledgement

The authors acknowledge Servier for providing access to data on file (study reports).

Part of the data reported in this article was presented in abstract form at the European Society of Hypertension meeting, Milan, June 200921.