Comparison of the AT1-Receptor Blocker, Candesartan Cilexetil, And

Home , Candesartan

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 combination 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 combination 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 automated 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. In order to maxi- ally used at the clinic was used for all blood press- mise experience with candesartan cilexetil/HCTZ, it ure measurements in that individual. was planned to randomise an extra 70 patients to Adverse reactions reported spontaneously and in this group. The actual residual standard duration response to a non-leading question were recorded at was higher than expected (8.0 mm Hg) but as the each visit. The criteria for judgment of severity and numbers of patients in the groups were 238 intensity of adverse events were defined a priori. (candesartan cilexetil/HCTZ) and 117 (lisinopril/ Resting ECG, physical and laboratory examinations HCTZ), power was maintained. were performed at fixed intervals during the study. Values judged by the investigator as clinically rel- Results evant deteriorations from baseline were defined as adverse events. All adverse events presenting when Patient characteristics the patient completed or discontinued the study In total, 418 patients from Finland, Norway, The were followed for 2–4 weeks. Netherlands and the United Kingdom were enrolled in the study. Of these, 355 were randomised. The Statistics ITT population consisted of 237 patients randomised to candesartan cilexetil/HCTZ and 116 to The primary variable was the change in sitting dia- lisinopril/HCTZ. The numbers of patients who com- stolic blood pressure from baseline to 26 weeks of pleted the double-blind period were 190 and 96, treatment. This variable and all other haemody- respectively. namic variables were tested by analysis of covari- Demographic and other baseline characteristics of ance (ANCOVA) with baseline values as covariates the ITT population are shown in Table 1. The groups The true mean difference between the candesartan were similar with respect to these variables and also cilexetil/HCTZ and the lisinopril/HCTZ group, and race, height, body mass index, medical history, dur- the corresponding two-sided 95% confidence inter- ation of hypertension and WHO stage. All but five val were estimated. A P-value of Ͻ0.05 was taken as patients were Caucasian. statistically significant. Blood pressure and heart rate in the ITT popu- Two analyses were performed for haemodynamic lation at 26 weeks are shown in Table 2 and sitting variables. An intention-to-treat (ITT) analysis blood pressures 24 h post dose for each treatment included all patients who took at least one dose of group during the randomised treatment period are double-blind medication and who had efficacy data illustrated in Figure 1. Individual data for sitting available after randomisation. The ITT population diastolic blood pressure at 26 weeks are shown in was analysed using the last value carries forward Figure 2. Differences between treatments are (LVCF) method. For patients who did not complete presented in Table 3. the study (or who had missing data at the last visit), the last available data point after randomisation was used as the week 26 (LVCF) value. The per protocol Table 1 Characteristics of patients in the intention to treat (ITT) (PP) analysis included only those patients in the ITT population. Mean ± s.d. or percentages at baseline, prior to population who met all of the inclusion criteria, and randomisation did not meet any of the exclusion criteria or any of the pre-defined study violation criteria. Candesartan Lisinopril/ The Mantel–Haenzel test, stratified for centre, was cilexetil/HCTZ HCTZ 8 mg/12.5 mg 10 mg/12.5 mg used to analyse the proportion of responders (sitting diastolic blood pressure 90 mm Hg or less and/or Number 237 116 reduction of sitting diastolic blood pressure from Age (years) 58.2 ± 9.8 56.0 ± 9.6 baseline by at least 10 mm Hg) and the proportion Male (%) 57 52 of patients with controlled diastolic blood pressure Sitting (sitting diastolic blood pressure 90 mm Hg or less) systolic blood after 26 weeks, and tolerability defined as the num- pressure (mm Hg) 169.2 ± 17.2 163.3 ± 16.9 ber of patients with at least one adverse event. Mul- diastolic blood pressure (mm Hg) 102.9 ± 5.5 101.8 ± 4.9 tiple episodes of the same adverse event were coun- heart rate (bpm) 74.9 ± 11.7 77.0 ± 13.6 ted only once. Laboratory variables were analysed by the same model used for haemodynamic vari- Standing systolic blood pressure ables or by non-parametric methods as appropriate. (mm Hg) 167.6 ± 20.1 163.7 ± 19.4 Tolerability and laboratory analyses were based on diastolic blood pressure the safety population, patients who took at least one (mm Hg) 106.6 ± 9.3 104.2 ± 7.8 dose of double-blind study medication and provided heart rate (bpm) 79.1 ± 13.2 80.2 ± 14.7 post-dose data. Treatment prior to randomisation (%) Ace inhibitors 29 37 Determination of sample size Beta-blockers 28 29 Calcium antagonists 20 20 Based on the results of previous studies, a residual Diuretics 21 18 standard deviation of 7.5 mm Hg was expected; with Others 13 8 70 patients in each group, the study was expected to

Journal of Human Hypertension Candesartan cilexetil and lisinopril plus diuretic GT McInnes et al 266 Table 2 Mean ± s.d. results for blood pressure and heart rate after Table 3 Differences between treatments (candesartan 26 weeks of treatment with candesartan cilexetil 8 mg and lisino- cilexetil/HCTZ 8/12.5 mg—lisinopril/HCTZ 10/12.5 mg) for pril 10 mg each in combination with hydrochlorothiazide (HCTZ) changes in blood pressure and heart rate from baseline to 26 12.5 mg once daily. Last value carried forward (LVCF) in the weeks (LVCF) in the ITT population. A minus sign in the adjusted intention to treat (ITT) population mean indicates that the ﬁrst treatment is more effective

Candesartan Lisinopril/ Adjusted 95% CI P-value cilexetil/HCTZ HCTZ mean 8 mg/12.5 mg 10 mg/12.5 mg Sitting Number 233 115 systolic blood pressure (mm Hg) 2.1 −2.1, 6.4 Ͼ0.200 Sitting diastolic blood pressure systolic blood − Ͼ ± ± (mm Hg) 0.5 1.6, 2.7 0.200 pressure (mm Hg) 151.1 19.1 145.9 18.4 heart rate (bpm) 2.0 −0.6, 4.6 0.133 diastolic blood pressure (mm Hg) 93.0 ± 9.3 91.2 ± 8.4 Standing heart rate (bpm) 76.7 ± 12.7 76.0 ± 12.4 systolic blood pressure (mm Hg) 4.5 −0.5, 9.4 0.076 Standing diastolic blood pressure systolic blood − Ͼ ± ± (mm Hg) 0.2 2.6, 3.1 0.200 pressure (mm Hg) 151.2 21.5 144.8 19.1 heart rate (bpm) 0.1 −3.2, 3.4 Ͼ0.200 diastolic blood pressure (mm Hg) 98.2 ± 11.2 96.1 ± 10.3 heart rate (bpm) 82.1 ± 13.7 81.2 ± 14.3

Sitting blood pressure and heart rate The adjusted mean changes from baseline to week 26 (LVCF) in sitting diastolic blood pressure, the primary variable, were 9.8 mm Hg (95% confidence interval 8.6, 11.0) and 10.3 mm Hg (8.5, 12.2) after candesartan cilexetil/HCTZ and lisinopril/HCTZ respectively. The adjusted mean difference between the treatments was 0.5 mm Hg (−1.6, 2.7, P = 0.20). Changes in individuals are shown in Figure 3. Both treatments reduced sitting diastolic blood pressure with no significant difference between the groups. Mean sitting systolic blood pressure also decreased over the treatment period in both groups. In the candesartan cilexetil/HCTZ group, the adjusted mean reduction was 16.2 mm Hg (13.9, 18.6) while in the lisinopril/HCTZ group the adjusted mean change was 18.4 mm Hg (14.8, 21.9). Figure 1 Mean (s.d.) for sitting blood pressure (mm Hg) at ran- There was no statistically significant difference domisation (0 weeks) and during treatment with candesartan between the groups (adjusted mean difference 2.1 cilexetil/HCTZ 8/12.5 mg or lisinopril/HCTZ 10/12.5 mg. mm Hg, 95% CI −2.1, 6.4; P Ͼ 0.200).

Figure 2 Individual plots for sitting diastolic blood pressure Figure 3 Individual plots for the change in sitting diastolic blood (mm Hg) at 26 weeks (LVCF) in the ITT population. pressure (mm Hg) from baseline to 26 weeks (LVCF) in the ITT population.

Journal of Human Hypertension Candesartan cilexetil and lisinopril plus diuretic GT McInnes et al 267 There was a slight, but statistically signiﬁcant, Table 5 Sitting diastolic blood pressure in the per protocol (PP) ± increase in sitting heart rate from baseline to 26 population. Mean values s.d. or (percentages) weeks in the candesartan cilexetil/HCTZ group (1.8 bpm, 95% CI 0.4, 3.3). In the lisinopril/HCTZ No. Candesartan No. Lisinopril/ − cilexetil/ HCTZ group, heart rate was little changed ( 0.2 bpm, 95% HCTZ 10 mg/12.5 mg CI −2.4, 2.0). The difference between the groups (2.0, 8 mg/12.5 mg 95% CI −0.6, 4.6) was not statistically signiﬁcant (P = 0.133). Baseline 115 101.9 ± 4.9 54 101.9 ± 5.0 26 weeks 120 89.4 ± 6.8 57 90.0 ± 8.1 Respondersa 127 80 (63.0%) 61 38 (62.3%) Standing blood pressure and heart rate Controlledb 127 71 (55.9%) 61 30 (49.2%)

The pattern of changes in standing blood pressure aDiastolic blood pressure р90 mm Hg and/or fall у10 mg. from baseline to week 26 was similar to that in the bDiastolic blood pressure р90 mm Hg. sitting position without indication of an orthostatic effect. Standing systolic blood pressure fell by 16.0 mm Hg (13.3, 18.7) in the candesartan cilexetil/ Per protocol analysis HCTZ group and 20.5 mm Hg (16.3, 24.6) in the Results for sitting diastolic blood pressure in the PP lisinopril/HCTZ group; the difference between analysis are presented in Table 5. These findings groups (4.5 mm Hg, 95% CI −0.5, 9.4) was not sig- = confirm the lack of differences between the groups nificant (P 0.076). The corresponding changes in in the ITT analysis. The reduction from baseline to standing diastolic blood pressure were 7.8 mm Hg 26 weeks in the candesartan cilexetil/HCTZ group (6.2, 9.3) and 8.0 (5.7, 10.4) in the candesartan was 12.0 mm Hg (95% CI 10.7, 13.3) and in the cilexetil/HCTZ and lisinopril/HCTZ groups, respect- lisinopril/HCTZ group 11.0 mm Hg (95% CI 8.9, ively, the adjusted mean difference (0.2 mm Hg, − Ͼ 13.1); the difference between the groups 1.0 mm Hg 95% CI 2.6, 3.1) was not significant (P 0.200). (−1.5, 3.4) was not statistically significant (P Ͼ Heart rate was again significantly increased in the 0.200). Response rates were similar −63.0% (95% CI candesartan cilexetil/HCTZ group in the standing 54.6, 71.4) in the candesartan cilexetil/HCTZ group position (2.7 bpm, 95% CI 0.9, 4.5) but a similar and 62.3% (95% CI 50.1, 74.5) in the increase in the lisinopril/HCTZ group (2.7 bpm, Ͼ − lisinopril/HCTZ group (P 0.200). The proportions 95% CI 0.2, 5.3) did not achieve statistical signifi- of controlled patients were 55.9% (47.3, 64.5) and cance; the difference in heart rate between the 49.2% (36.6, 61.7) respectively (P Ͼ 0.200). groups (0.1 bpm, 95% CI −3.2, 3.4) was not significant (P Ͼ 0.200). Tolerability Response rates During the run-in period, adverse events were reported in 25 patients (10.5%) of the 238 patients The proportion of patients responding to the treat- later randomised to candesartan cilexetil/HCTZ and ment regimens are shown in Table 4. As defined by р in 16 of 117 patients (13.7%) later randomised to a mean sitting diastolic blood pressure 90 mm Hg lisinopril/HCTZ. Patients with adverse events dur- or a reduction of mean sitting diastolic blood press- у ing randomised therapy are shown in Table 6. ure from baseline to week 26 (LVCF) 10 mm Hg, Adverse events occurring in at least 4% of patients the estimated proportions of responders were 54.4% in each treatment group are listed in Table 7. (95% CI 48.1, 60.8) and 62.1% (95% CI 53.2, 70.9) in The proportion of patients with at least one the candesartan cilexetil/HCTZ and lisinopril/HCTZ adverse event was significantly lower in the candes- groups respectively. The difference in proportion of artan cilexetil/HCTZ group compared with the responders between the two groups was not statisti- = = lisinopril/HCTZ group (68.9% vs 79.5%, P 0.020). cally significant (P 0.094). The proportion of Withdrawal due to adverse events was also less patients with achieved sitting diastolic blood press- common in the candesartan cilexetil group (5.9% vs ure р90 mm Hg was little different between the groups: 45.1% (95% CI 38.8, 51.5) for candesartan cilexetil/HCTZ and 44.8% (95% CI 35.8, 53.9) for Table 6 Patients with adverse events. Number (percentage) of lisinopril/HCTZ (P Ͼ 0.200). patients in the study population with adverse events (AEs) during double-blind therapy

Table 4 Numbers and proportions of patients responding to the Candesartan Lisinopril/HCTZ treatment regimens at week 26 (LVCF) cilexetil/HCTZ 10 mg/12.5 mg 8 mg/12.5 mg (n = 117) Candesartan Lisinopril/HCTZ P-value (n = 238) cilexetil/HCTZ 10 mg/12.5 mg 8 mg/12.5 mg (n = 116) = Patients with AEs 164 (68.9%) 93 (79.5%) (n 237) Patients with attributable AEsa 80 (33.6%) 54 (46.2%) Respondersa 129 54.4% 72 62.1% 0.094 Patients withdrawn Controlledb 107 45.1% 52 44.8% Ͼ0.200 because of AEs 14 (5.9%) 14 (12.0%) aDiastolic blood pressure р90 mm Hg and/or fall у10 mm Hg. aAEs for which physician causality rating was possible or prob- bDiastolic blood pressure р90 mm Hg. able relationship to study drug.

Journal of Human Hypertension Candesartan cilexetil and lisinopril plus diuretic GT McInnes et al 268 Table 7 Incidence of (percent) adverse event occurring in у4% cantly in the ITT analysis. Likewise, changes in sit- of patients treated with candesartan cilexetil/HCTZ 8/12.5 mg or ting systolic blood pressure, and in standing systolic lisinopril/HCTZ 10/12.5 mg for 26 weeks and diastolic blood pressure were similar in the two Candesartan cilexetil/HCTZ Lisinopril/HCTZ (n = 117) treatment regimens. Blood pressure reductions in (n = 238) the lisinopril group were numerically greater, although differences were not statistically signifi- Dizziness/vertigo 11.8 Cough 23.1 cant. However, the PP analysis failed to confirm the Headache 11.8 Dizziness/vertigo 15.4 advantage of lisinopril-based treatment. Here, there Viral infection 8.8 Respiratory infection 9.4 were trends for greater changes in sitting diastolic Fatigue 5.9 Headache 8.5 Back pain 5.5 Viral infection 7.7 blood pressure and response rates in the candesar- Respiratory infection 5.5 Fatigue 6.0 tan cilexetil group. Therefore the two treatments can Pain 5.0 Myalgia 6.0 be considered to have equivalent antihypertensive Cough 4.6 Back pain 5.1 efficacy. The 95% confidence intervals indicate that Myalgia 4.2 Accident and/or injury 4.3 it is unlikely that the two treatments differ in effi- Nausea 4.2 Pharyngitis 4.3 cacy by 4 mm Hg or more in diastolic blood pressure.

12.0%). The main reason for discontinuation in the Heart rate lisinopril/HCTZ group was cough which was the In the sitting and standing posture, heart rate was most common new adverse reaction with that ther- increased slightly but significantly in the patients apy and much more common than in the candesar- treated with candesartan cilexetil and HCTZ. No sig- tan cilexetil group (23.1% vs 4.6%). The most com- nificant changes in heart rate were seen in the mon adverse events reported in the candesartan lisinopril/HCTZ treated patients but there were no cilexetil/HCTZ group were dizziness/vertigo and significant differences between the treatment headache (each 11.8%). Two cases of angioedema groups. Ninety-five percent confidence intervals were reported in the lisinopril/HCTZ group. exclude differences of 5 bpm in heart rate sitting or erect. Such differences in heart rate are unlikely to Laboratory variables be of clinical significance. There were no clinically relevant changes in laboratory or ECG variables. Haemoglobin concentration Tolerability was reduced slightly but significantly after both Both treatment regimens were well tolerated. Com- treatment regimens (−1.1 g/l and −1.6 g/l after can- pared with lisinopril/HCTZ a significantly lower desartan cilexetil/HCTZ and lisinopril/HCTZ proportion of patients receiving candesartan respectively). Likewise, median haematocrit fell by cilexetil/HCTZ developed at least one adverse event. 1% on both treatments. Mean serum uric acid con- Withdrawal due to adverse events was also less centration was increased significantly by both treat- common in the candesartan cilexetil group (6% vs ments: 24.5 ␮mol/l (7.1%) by candesartan 12%). cilexetil/HCTZ and 26.9 ␮mol/l (7.6%) by A much higher proportion of lisinopril/HCTZ lisinopril/HCTZ. Hyperuricaemia was reported in treated patients developed cough and discontinued 1.3% in the candesartan cilexetil/HCTZ group and therapy due to this adverse event. The incidence of 2.6% of patients in the lisinopril/HCTZ group. spontaneously reported cough was Ͼ20% in the lisi- Neither treatment was associated with clinically rel- nopril treated group compared with Ͻ5% in the can- evant changes in serum electrolytes. There were not desartan cilexetil group. Also, angioedema was significant differences between the treatment reported only in the lisinopril/HCTZ treated groups. patients; angioedema has never been recorded in patients treated with candesartan cilexetil. Cough Compliance and angioedema are well-recognised class-specific complications of all ACE inhibitors.10,11 The sug- As assessed by tablet count, compliance was good. gested mechanism reflects the lack of specificity of Overall 90% of patients in the ITT population took ACE which is also known as kininase II, the enzyme 90–110% of the study medication during the dou- responsible for degradation of various other vaso- ble-blind treatment period. The percentage of active peptides.10 Thus, ACE inhibitors not only patients taking 90–110% of study medication was reduces concentration of angiotensin II but also similar in each treatment group. results in accumulation of bradykinin, substance P and other inflammatory substances thought to be Discussion involved in these adverse reactions. The high specificity of angiotensin II antagonists for the renin- Blood pressure angiotensin system means that these drugs would For the primary efficacy variable, change in sitting not be expected to give rise to cough or angio- diastolic blood pressure over 26 weeks of treatment, edema.12,14,15 The results of this study confirm the responses to the fixed combinations of candesartan distinction between ACE inhibitors (lisinopril) and cilexetil plus HCTZ 8/12.5 mg daily and lisinopril angiotensin II antagonists (candesartan cilexetil) in plus HCTZ 10/12.5 mg daily did not differ signifi- side effect profile.

Journal of Human Hypertension Candesartan cilexetil and lisinopril plus diuretic GT McInnes et al 269 Laboratory variables associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysi- There were no clinically relevant changes in labora- ology. Ann Intern Med 1992; 117: 234–242. tory variables with either treatment. The small 11 Slater EE et al. Clinical profile of angioedema associa- reductions in haematological indices may reflect ted with angiotensin converting-enzyme inhibition. blockade of a stimulant effect of the renin-angioten- J Am Med Assoc 1988; 260: 967–970. sin system on erythropoetin production.25 Such 12 Bauer JH, Reams GP. The angiotensin II type I receptor effects have previously been reported with ACE antagonists. A new class of antihypertensive drugs. inhibitors25,26 and angiotensin II antagonists.27–29 Arch Intern Med 1995; 155: 1361–1368. The increase in serum uric acid seen in both treat- 13 McInnes G. Pocket Reference to Angiotensin II Antag- onists. Science Press: London, 1998. ment groups probably reflects the known influence 7,8 14 Messerli FH, Weber MA, Brunner HR. Angiotensin II of thiazide diuretics. Among angiotensin II antag- receptor inhibition. A new therapeutic principle. Arch onists, only losartan has been shown to affect uric Intern Med 1996; 156: 1957–1965. acid metabolism.12–14 ACE inhibitors have no known 15 Timmermans PB et al. Angiotensin II receptors and effect on serum uric acid.21 Hyperuricaemia was rare angiotensin II receptor antagonists. Pharmacol Rev with both treatments. 1993; 45: 205–251. 16 Delzcre´taz E et al. Characterisation of the angiotensin II receptor antagonist TCV-116 in healthy volunteers. Conclusions Hypertension 1995; 251: 14–21. This study demonstrates that the combination of 17 Ojima M et al. Candesartan (CV – 11974) dissociates slowly from the angiotensin AT1 receptor. Eur J Phar- candesartan cilexetil and hydrochlorothiazide macol 1997; 319: 137–146. 8/12.5 mg daily has similar antihypertensive effects 18 Shibouta Y et al. Pharmacological profile of a highly on those with lisinopril and hydrochlorothiazide potent and long-acting angiotensin II receptor antagon- 10/12.5 mg daily. However, the candesartan ists, 2-ethoxy-1-[[21-(IH-tetrazol-5-yl) biphenyl-4-yl] cilexetil/hydrochlorothiazide combination was bet- methyl]-IH-benzimidazole-7-carboxylic acid (CV- ter tolerated than the lisinopril/hydrochlorothiazide 11974), and its prodrug, (±)-1-(cyclohexyloxy- fixed combination. carbonyloxy)-ethyl 2-ethoxy-1-[[21-(IH-tetrazol-5-yl) biphenyl-4-yl] methyl]-IH-benzimidazole-7-carboxylate (TCV-116). J Pharmacol Exp Ther 1993; 266: 114–120. Acknowledgements 19 Brunner HR et al. Angiotensin II antagonists DuP 753 and TCV 116. J Hypertens 1994; 12 (Suppl 9): S29– This study was supported by a grant from Astra S34. 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