Journal of Human Hypertension (2000) 14, 263–269 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients GT McInnes1, KPJ O’Kane1, H Istad2, S Keina¨nen-Kiukaanniemi3 and HFCM Van Mierlo4 1University Department of Medicine and Therapeutics Western Infirmary, Glasgow G11 6NT, UK; 2Theresegt, Legesenter, Theresegt. 35B, 0354 Oslo, Norway; 3Department of Public Health Science and General Practice, Aapistie 1, 90220 Oula, Finland; 4Rembrantsplein 7, 2377 BM Oude Wetering, The Netherlands Aim: To compare candesartan cilexetil and lisinopril in ables (sitting systolic blood pressure, standing blood fixed combination with hydrochlorothiazide with respect pressure, sitting/erect heart rate, and proportion of to antihypertensive efficacy and tolerability. responders and controlled patients). Both drugs were Methods: This was a double-blind (double-dummy), ran- well tolerated but the proportion of patients with at least domised, parallel group comparison in patients with a one adverse event was significantly greater in the lisino- The proportion of .(0.020 ؍ mean sitting diastolic blood pressure 95–115 mm Hg on pril group (80% vs 69%, P prior antihypertensive monotherapy. Treatments were patients spontaneously reporting cough (23.1% vs 4.6%) candesartan cilexetil/hydrochlorothiazide 8/12.5 mg and discontinuing therapy due to adverse events (12.0% -and lisinopril/hydrochlorothiazide vs 5.9%) was also higher in the lisinopril group com (237 ؍ once daily (n .for 26 weeks. The pri- pared with the candesartan cilexetil group (116 ؍ mg once daily (n 10/12.5 mary efficacy variable was change in trough sitting dia- Conclusions: The fixed combinations of candesartan stolic blood pressure. cilexetil and hydrochlorothiazide 8/12.5 mg and lisino- Results: Changes in mean sitting diastolic blood press- pril and hydrochlorothiazide 10/12.5 mg once daily are ure did not differ significantly between the groups equally effective as antihypertensive agents. The fixed (mean difference 0.5 mm Hg; 95% confidence interval combination containing candesartan cilexetil is better .No significant differences between tolerated than that containing lisinopril .(0.20 ؍ P ,2.7 ,−1.6 the groups was found for other haemodynamic vari- Journal of Human Hypertension (2000) 14, 263–269. Keywords: ACE inhibitor; angiotensin receptor blocker; candesartan cilexetil; combination; hydrochlorothiazide; lisinopril Introduction renin-angiotensin axis and one which blocks the same pathway results in at least additive effects on Only a small proportion of treated hypertensive blood pressure.6 1,2 patients achieve target levels of blood pressure, Thiazide diuretics activate renin through their partly because available drugs have modest effi- 3,4 natriuretic action which reduces extracellular vol- cacy. Monotherapy with any of the current antihy- ume and cardiac output although, in the long term, pertensive agents leads to acceptable control in less 3 reverse autoregulation leads to normalisation of than 50% of patients. However, appropriate combi- extracellular volume and decreased peripheral nations of antihypertensive drugs can result in resistance.7 These physiological changes are associa- achievement of target blood pressure in almost 90% 5 ted with a shift in blood pressure regulation to the of individuals. renin-angiotensin system. At low doses, antihyper- Drugs in effective antihypertensive combinations tensive efficacy is maintained while adverse meta- have complementary modes of action. Thus com- bolic effects are minimised.8 bined treatment with a drug which stimulates the The renin-angiotensin system can be blocked at the stage of angiotensin II generation by inhibition of angiotensin-converting enzyme (ACE).9 This Correspondence: Dr Gordon T McInnes, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 approach is highly successful but non-specific 6NT, UK actions can lead to unwanted effects such as cough Received 23 August 1999; Revised and accepted 18 December and angioedema.10,11 The recently introduced selec- 1999 tive type I angiotensin II receptor blockers offer a Candesartan cilexetil and lisinopril plus diuretic GT McInnes et al 264 more specific approach to blockade of the renin- ation. If mean sitting diastolic blood pressure angiotensin system by antagonising the action of the exceeded 100 mm Hg and/or mean sitting systolic primary effector molecule, angiotensin II, at the AT1 blood pressure exceeded 180 mm Hg at any visit receptor, which mediates all the adverse cardio- after randomisation, the patient was seen again vascular effects of this hormone.12–15 within 2–4 weeks and if blood pressure remained Candesartan is a new, potent, angiotensin II type above these limits, the patient was withdrawn from I selective receptor blocker with tight binding to and the study. The protocol was approved by the local slow dissociation from the receptor.13,16–18 Candesar- medical ethics committee at each participating tan cilexetil is the orally administered pro-drug centre. which is hydrolysed during gastrointestinal absorp- tion into the active molecule, candesartan.13,16,18,19 Treatments Although mainly eliminated unchanged, a small proportion is in turn broken down to an inactive The patients received one of the following treat- metabolite.20 Lisinopril is an established long-acting ments once daily in the morning for a minimum of ACE inhibitor which does not require metabolism 26 weeks or a maximum of 30 weeks: for action.21 (a) One tablet of the fixed combination of candesar- The objective of this study was to compare the tan cilexetil and HCTZ 8/12.5 mg and one antihypertensive efficacy and tolerability of candes- matching placebo capsule of the fixed combi- artan cilexetil and those of lisinopril each in combi- nation of lisinopril and HCTZ. nation with low dose hydrochlorothiazide (HCTZ) (b) One capsule of the fixed combination of lisinop- in hypertensive patients with blood pressure inad- ril and HCTZ 10/12.5 mg and one matching pla- equately controlled by existing antihypertensive cebo tablet of the fixed combination of candesar- monotherapy. Fixed combination therapy should tan cilexetil and HCTZ. improve patient compliance and the lisinopril com- bination is in routine clinical use. Both candesartan Fixed combination tablets containing lisinopril cilexetil and lisinopril have shallow dose-antihyper- 10 mg and HCTZ 12.5 mg were presented in hard tensive response relationships.21,22 In hypertensive gelatine capsules without further manipulation of subjects, blood pressure reductions after candesar- the marketed formulation. The lisinopril plus HCTZ tan cilexetil and lisinopril are incremental across capsules satisfied US Pharmacopea (USP) criteria for the dose ranges 1–16 mg daily and 5–40 mg daily, in vitro dissolution. Candesartan cilexetil 8 mg daily respectively. However, the bulk of the effects are has an antihypertensive effect not significantly dif- seen after candesartan cilexetil 8 mg and lisinopril ferent from that of enalapril 10 mg daily23 and there- 10 mg daily. In this study each drug was used at sub- fore would be expected to be equivalent to lisinopril maximal doses and added efficacy obtained by the 10 mg daily.21 combination with hydrochlorothiazide. Randomisation was performed by computer in blocks of three consecutive patient numbers irres- pective of centre or country. Each patient was allo- Subjects and methods cated at random to one of the two treatment regi- Subjects mens in the proportion 2:1 (candesartan cilexetil/HCTZ: lisinopril/HCTZ). Patients aged 20–80 years with primary hyperten- Patients were instructed to return all unused sion were eligible for inclusion if sitting diastolic study medication at each study visit. Returned tab- blood pressure was 95–115 mm Hg on two occasions lets were counted to assess compliance. The criteria 1–2 weeks apart 24 h after dosing with antihyperten- for acceptable compliance during the double-blind sive monotherapy. Subjects gave written consent for study period was predetermined as an intake of at participation after full verbal and written infor- least 75% and no more than 110% of drugs. mation about the protocol and its risks. Exclusion criteria included women of child-bearing potential, recent significant cardiovascular events or con- Study variables ditions, concomitant drugs with blood pressure Blood pressure and heart rate was measured at each modulating effects, contraindications to any of the visit in the morning, immediately before drug study drugs, severe concomitant disease or con- administration, 24 h ± 2 (trough) after the previous ditions associated with poor compliance. dose. Measurements were made using a fully auto- mated device (Omron HEM-705CP).24 At the first Design visit sitting blood pressure was measured in both arms and the arm with the higher diastolic pressure This was a double-blind (double dummy), random- was used for all subsequent measurements. Sitting ised, parallel group, multicentre study. Patients who blood pressure and heart rate were recorded three satisfied the inclusion criteria had prior antihyper- times, at least 2 min apart, after the patient had tensive monotherapy withdrawn and were random- rested in a quiet room for at least 5 min. One ised without an intervening drug-free period to com- measurement of blood pressure and heart rate was bination therapy with candesartan cilexetil and made after at least 1 min standing. The values used HCTZ 8/12.5 mg or lisinopril and HCTZ 10/12.5 mg, in the statistical analysis were the means of tripli- each given once daily for 26 weeks. Patients were cate and single readings. For each patient, every seen at 2, 6, 12, 19 and 26 weeks after randomis- attempt was made to ensure that all blood pressure Journal of Human Hypertension Candesartan cilexetil and lisinopril plus diuretic GT McInnes et al 265 measurements were performed by the same individ- have a power of 88% to detect a true mean treatment ual. If the Omron device failed, the instrument usu- difference in efficacy of 4 mm Hg.