03_ijcp903 391.398

d o i : 1 0 . 1 1 1 1 / j . 1 3 6 8 - 5 0 3 1 . 2 0 0 6 . 0 0 9 0 3 . x A placebo-controlled comparison of the efficacy and tolerability ofcandesartan cilexetil, 8 mg, and losartan, 50 mg, as monotherapyin patients with essential hypertension, using 36-h ambulatoryblood pressure monitoring J - P B A G U E T 1 , S . N I S S E - D U R G E A T 2 , S . M O U R E T 1 , R . A S M A R 3 , J - M M A L L I O N 1Cardiology and Hypertension Unit,1 Grenoble University Hospital, Grenoble, Laboratoires Takeda,2 Puteaux, InstitutCardioVasculaire,3 Paris, France (1.2 mmHg Æ 9.9 mmHg) (p < 0.001). Candesartan cilexe- til 8 mg was associated with a greater reduction in DBP This double-blind, randomised, controlled study compared and SBP, relative to placebo, when compared with losartan the efficacy of candesartan cilexetil 8 mg (n ¼ 87) and 50 mg, during both daytime and night-time, and between losartan 50 mg (n ¼ 89), once daily for 6 weeks, relative to 12 and 24 h after dosing (p < 0.001). Both active treatments placebo (n ¼ 80) in patients with mild-to-moderate essential hypertension (diastolic blood pressure (DBP): 95–115 In patients with mild-to-moderate essential hyper- mmHg). Ambulatory BP measurements were done every tension, candesartan cilexetil 8 mg therefore had greater, more consistent antihypertensive efficacy throughout the At the end of the 6-week treatment, the mean change in day and the night, and long-lasting efficacy after the last DBP between the baseline and the 0–24-h period after the dose, compared with losartan 50 mg. This greater efficacy last dose of study medication was greater in patients receiving is maintained with an excellent tolerability associated with candesartan cilexetil 8 mg (À7.3 mmHg Æ 6.9 mmHg) members of the angiotensin Il type 1-receptor blocker compared with losartan 50 mg (À5.1 mmHg Æ 4.9 mmHg) Keywords: Hypertension; ambulatory blood pressure (p < 0.001). The mean change in systolic BP (SBP) during measurement; antihypertensive drug treatment; candesar- this time was greater in patients receiving candesartan losartan 50 mg (À8.8 mmHg Æ 8.9 mmHg) than placebo (AT1)-receptor blocker class (2). AT1-receptor blockers repre-sent a class of effective and well-tolerated orally active anti- Hypertension is the major treatable cause of cardiovascular hypertensive drugs. All these drugs have the common mortality in the industrialised world (1), and recent national and international guidelines emphasise the benefits of redu- vascular smooth muscle, increasing salt excretion, decreasing cing blood pressure (BP) (2–4). Indeed, even small BP reduc- cellular hypertrophy and inducing antihypertensive effects tions, when achieved at a population level, can result in major without modifying heart rate and cardiac output (6). These reduction in cardiovascular risk (5). Thus, even small differ- agents effectively control hypertension when given once daily ences in efficacy between different antihypertensive drugs and cause no significant adverse effects or laboratory abnorm- could lead to substantial differences in population outcome.
alities (7,8). Thus, fewer adverse events were reported for Five classes of antihypertensive agents are now recom- mended for the first-line treatment of hypertension; the 1-receptor blocker therapy compared with other anti- hypertensive medication such as beta-blockers and angio- newest addition to this list is the angiotensin Il type 1 tensin-converting enzyme (ACE) inhibitors. In addition, theeffectiveness of AT1-receptor blocker therapy in reducing clinical events such as stroke or end-stage renal disease in Jean-Philippe Baguet, Cardiologie et Hypertension arte´rielle, CHU hypertension and associated conditions has been shown in a de Grenoble, BP 217, 38043, Grenoble Cedex 09, France number of large trials (9–11). AT1-receptor blockers are therefore differentiated from each other on the basis of the magnitude and duration of their antihypertensive effects.
ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, April 2006, 60, 4, 391–398 Losartan was the first available AT1-receptor blocker, and stroke, severe renal impairment (creatinine clearance <30 ml/ many others have since become available. Of these, candesar- min, Cockcroft method), severe hepatic impairment (aspar- tan cilexetil shows particularly tight and long-lasting binding tate aminotransferase or alanine aminotransferase greater than to the AT1-receptor. Indeed, in a review published in 1999, twice the upper normal limit, gammaglutamyl transpeptidase candesartan cilexetil had the highest AT1-receptor-binding greater than three times the upper normal limit) and serum affinity of those compounds tested, which were ranked in potassium >5.0 mmol/l. Patients were also excluded, if con- the following order (highest affinity ¼ 1): candesartan cilex- traindicated for renin-angiotensin system interventions or if etil (1), saprisartan (1), zolasartan (3), irbesartan (5), valsartan hypersensitive to any component of the study medications.
(10), telmisartan (10), EXP-3174 (the active metabolite of This study complies with the Declaration of Helsinki and was losartan) (10), tasosartan (20), losartan (50), eprosartan (100) approved by an independent ethics committee (Grenoble, France). Written informed consent was obtained from all The most reliable way of determining whether members of patients prior to their inclusion in the study.
the AT1-receptor blocker class are similarly distinguishedfrom each other at a clinical level is by performing a direct, head-to-head comparison. The present paper comparesdirectly the antihypertensive efficacy and tolerability of two All patients recruited to the study entered an initial placebo AT1-receptor blockers, candesartan cilexetil 8 mg (13–16), run-in period. The run-in lasted 14 days for patients who had and losartan 50 mg (17–20), in adult patients with mild-to- not previously received antihypertensive treatment and 28 moderate essential hypertension, using clinic measurements days for patients who had received previous therapy.
and 36-h ambulatory BP monitoring (ABPM). At the time of Previous antihypertensive medications were discontinued dur- the start of this trial, these were the maximum approved doses ing this 28-day placebo phase. Other treatments prohibited of candesartan cilexetil and losartan in France, although during the study included antiarrhythmic and antiangina guidelines in other countries at that time recommended a agents, drugs with vasodilator or systemic vasoconstrictor maximum candesartan cilexetil dose of 16 mg and a maxi- activity, immunosuppressant and cytotoxic drugs, lithium, mum losartan dose of 100 mg per day. ABPM was used, antithyroid medication, long-term corticosteroid and no ster- because such measurements correlate more closely with target-organ damage and are more reliable in predicting clin- Patients completing the placebo run-in were randomised in ical outcomes, compared with clinic BP measurements (21).
equal numbers to receive double-blind treatment with cande- ABPM also avoid the problem of so-called ‘white-coat’ or sartan cilexetil 8 mg, losartan 50 mg or placebo, once daily ‘office’ hypertension – the tendency for BP to increase above its everyday level as a result of the often subconscious physio-logical stress induced in patients by their visits to a clinic (22).
ABPM also enables BP to be assessed throughout the dosinginterval, so that diurnal fluctuations can be observed and Clinic BP was assessed in triplicate using a mercury sphyg- permit reliable information to be obtained on clinical efficacy momanometer after the patients had rested in a lying position at night and during the latter part of the dosing interval (23).
for 10 min, and the mean of each set of three values deter- Finally, ABPM allows to provide multiple BP measurements mined. Heart rate was also measured in triplicate while and to increase the power of the study.
patients were lying, and the mean value determined.
Ambulatory DBP and SBP were measured for 36 h in eachpatient before the first dose, and 0–36 h after the last dose of study medication. Ambulatory BP values were determinedand recorded automatically at 15-minute intervals by a bra- chial pressure monitor (SpacelabsTM Model 90207, Spacelabs We enrolled a total of 433 patients from 126 general practi- Medical, Redmond, WA, USA), worn on the nondominant tioner centres and 28 cardiology centres. They were then arm that was kept intentionally still during monitoring cycles screened for inclusion in the study. Subjects were men or while the patient was awake. ABPM data were analysed women, aged 18–75 years, with mild-to-moderate essential centrally on the return of the monitor to the clinic.
hypertension [diastolic BP (DBP) of 95–115 mmHg after a2- or 4-week placebo run-in period].
The main exclusion criteria were severe hypertension, sec- ondary hypertension, heart failure (NYHA class III or IV), The primary efficacy variable was the change in mean ambu- myocardial infarction within the previous 6 months, heart latory DBP from the baseline to the 0–24-h period after the valve abnormalities, angina pectoris, arrhythmia, history of Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, April 2006, 60, 4, 391–398 group was 69 (two-sided t-test) to allow statistically mean-ingful conclusions to be reached, a p-value <0.05 was con- sidered statistically significant. Allowing for withdrawals or 1 Changes in ambulatory SBP from the baseline to the failure to provide data, we therefore set an overall enrolment 0–24-h period after the last dose of study medication, 2 Changes in ambulatory DBP and SBP from the baseline to the 0–36-h period after the last dose of study medication, 3 Changes in DBP and SBP during the daytime (7 am to 10 4 Changes in DBP and SBP between 12 and 24 h after Of the 433 screened individuals, 123 patients did not pro- 5 Changes in heart rate between the baseline and the end of gress beyond the placebo run-in, for reasons including failure to comply with inclusion criteria, loss to follow-up and with- drawal of consent. A total of 310 patients, completed theplacebo run-in, were randomised and received at least onedose of study medication (safety population). Fifty-four of these 310 patients were excluded from the efficacy (ITT) Data were divided into two populations. The safety popula- population, because they did not provide at least one com- tion comprised all patients randomised to double-blind treat- plete set of 24-h ambulatory DBP measurements. The efficacy ment. The intention-to-treat (ITT) efficacy population (ITT) population therefore comprised 256 patients.
comprised all patients who had received at least one dose ofstudy medication and who had provided at least one complete recording of ambulatory DBP made over a 24-h period afterdosing.
The efficacy (ITT) population consisted of 153 men (59.8%) Baseline characteristics for both the ITT and the safety and 103 women (40.2%). Middle-aged patients (aged 45–65 population were summarised, with comparisons of baseline years) formed the greatest proportion (64.8%) of this popula- variables between treatment groups made using two-sided tion, in which the mean age was 54.2 years. Patients aged t-tests (for quantitative variables) or w2 tests (for qualitative >65 years represented 16% of the ITT population. Baseline variables). Normal data distribution and homogeneity of patient characteristics are summarised in Table 1. There were variance were confirmed by comparing actual normal prob- no significant differences between treatment groups for any of ability plots and scatter plots of residuals with their predicted Efficacy comparisons between treatment groups were made ANOVA followed by t-tests. In addition, any effects of treatment-by-baseline and treatment-by-centre interactions Changes in DBP (baseline to 0–24-h period after dosing). The were assessed by analysis of covariance, with interaction mean change in DBP between the baseline and the 0–24-h terms disregarded if not significant.
period after the last dose of study medication was significantly Statistical significance for all efficacy comparisons was set at greater in patients receiving candesartan cilexetil 8 mg (À7.3 mmHg Æ 6.9 mmHg) than in patients receiving Between-group comparisons of adverse event incidences losartan 50 mg (À5.1 mmHg Æ 4.9 mmHg, p < 0.05), or were made on a nonstatistical basis.
placebo (0.3 mmHg Æ 6.5 mmHg, p < 0.001) (Figure 1).
The calculation of sample size for the ABPM analysis was Changes in SBP (baseline to 0–24-h period after dosing). The based on the results of a previous study (24), and these results mean change in SBP between the baseline and the 0–24-h suggest that the standard deviation of the mean for change in period after the last dose of study medication was significantly ambulatory DBP between the 12th and the 24th hour (the greater (p < 0.001) in patients receiving candesartan cilexetil main criterion adopted in this study) is close to 10 mmHg.
8 mg (À10.8 mmHg Æ 11.3 mmHg), or losartan 50 mg Furthermore, the minimum improvement of clinical value was taken as 5 mmHg. Assuming a dropout rate of approxi- receiving placebo (þ1.2 mmHg Æ 9.9 mmHg) (Figure 1).
mately 10% and a number of ‘white coat’ patients of 20%, There was no difference of the mean change in SBP the required number of evaluable patients per treatment between candesartan cilexetil and losartan groups.
ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, April 2006, 60, 4, 391–398 Table 1 Baseline characteristics of patients (intention-to-treat population, mean Æ SD) DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure.
Changes in DBP and SBP (baseline to 0–36-h period after a lower BP (p < 0.001) than those receiving placebo. There was dosing). The mean changes in DBP and SBP between the baseline no difference of the mean change in SBP between candesartan and the 0–36-h period after the last dose of study medication were cilexetil and losartan groups. Patients treated by candesartan cilexetil had a higher decrease of DBP over the 0–36-h period respectively, with candesartan cilexetil 8 mg (Figure 1). This than those treated by losartan (p < 0.01).
was compared with mean changes in DBP and SBP in patients SBP. Candesartan cilexetil 8 mg was associated with mean À8.2 mmHg Æ 8.8 mmHg, respectively, and of þ0.2 mmHg changes in DBP (Figure 2) and SBP of À7.0 mmHg Æ 7.3 Æ 6.2 and þ1.1 mmHg Æ 9.2 mmHg, respectively, in patients receiving placebo. Patients receiving either active treatment had 0–24-h and 0–36-h diastolic blood pressure (DBP) and systolic blood pressure (SBP) inpatients with mild-to-moderate hyperten- sion, after 6 weeks of once-daily treatment with candesartan cilexetil 8 mg, losartan Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, April 2006, 60, 4, 391–398 Changes in DBP and SBP (mmHg) at 12–24 h † p = 0.018 vs. losartan 50 mg ‡ p = 0.011 vs. losartan 50 mg Figure 2 Mean changes from baseline in daytime (7 am to 10 pm) and night-time (10 pm to 7 am) diastolic blood pressure (DBP), in patients with mild-to-moderate hypertension receiving once-dailycandesartan cilexetil 8 mg, losartan 50 mg or placebo. Data are means Figure 3 Mean changes in diastolic blood pressure (DBP) andsystolic blood pressure (SBP) between 12 and 24 h after receivingcandesartan cilexetil 8 mg, losartan 50 mg or placebo, in patients À10.5 mmHg Æ 12.6 mmHg, respectively, during night- with mild-to-moderate hypertension. Data are means time. These changes were higher for the DBP withcandesartan cilexetil 8 mg than those observed in patients similar in all three treatment groups (candesartan cilexetil: receiving losartan 50 mg. Indeed, with losartan, mean changes in DBP and SBP were of À4.7 mmHg Æ 4.8 mmHg (p < 0.05) and À7.9 mmHg Æ 9.5 mmHg (ns), respectively, Tolerability. The tolerability of both active drugs in this comparative study was excellent, with no clinically significant difference in the type or incidence of adverse events compared respectively, during night-time. Mean changes in DBP and with those reported by patients receiving placebo.
SBP in the placebo group were lower (p < 0.001) thanthose in the both treated groups: þ0.1 mmHg Æ 6.5 mmHg ‘Treatment-by-Baseline BP’ and ‘Treatment-by-Centre’ þ2.3 mmHg Æ 10.1 mmHg, respectively, during night-time.
Covariance analysis revealed no significant ‘treatment- Changes in DBP and SBP (12–24 h after dose). The mean by-baseline BP’ or ‘treatment-by-centre’ interactions.
changes in DBP and SBP between 12 and 24 h after dosingwere 13.0 mmHg, respectively, in patients receiving candesartancilexetil 8 mg (Figure 3). Losartan 50 mg was associated with Compliance with therapy, assessed at the end of the 6-week a smaller decrease in DBP than candesartan cilexetil treatment period, was similar in all three treatment groups.
Ninety-seven percent of patients in the candesartan cilexetil group, 100% of those in the Iosartan group and 96% of those 10.4 mmHg, p ¼ 0.057), between the same two time in the placebo group were considered highly compliant with points. These reductions were higher than changes in receiving placebo (p < 0.001 for all comparisons betweenactive treatments and placebo).
The AT1-receptor blockers are now accepted as an important Changes in heart rate. The mean changes in heart rate from advance in hypertension therapy. All members of this drug baseline to the end of the 6-week treatment period were class combine an excellent tolerability with efficacy that is at ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, April 2006, 60, 4, 391–398 least as great as that of ACE inhibitors and other first-line from the receptor more slowly than other antagonists in the antihypertensive drugs (25–29). However, it is important to class. The prolonged binding of candesartan to the receptor is establish if any one AT1-receptor blocker offers efficacy ben- reflected in a longer duration of antihypertensive action, efits over any other. This is a particularly useful distinction to compared with losartan (42). This suggests that in patients make, as even small differences in efficacy could have a major who might miss one 24-h dose, effective BP control is more impact on population outcome. Moreover, recent guidelines likely to be maintained in those receiving candesartan cilexetil have established that efficacy means more than just a short- than in those given losartan. This observation has important term effect measured in the clinic a few hours after dosing.
practical implications, because a clinically useful antihyper- The ideal antihypertensive agent shows maintained efficacy tensive therapy should be capable of maintaining BP reduc- throughout, and potentially beyond, the dosing interval, as tions, even if a dose is delayed for several hours or missed many patients often forget to take their medication at the altogether through patient oversight or other circumstances.
We also found that reductions in DBP in patients receiving The results of our study clearly show that treatment with candesartan cilexetil 8 mg were larger than the reductions candesartan cilexetil 8 mg, once daily for 6 weeks, is asso- associated with losartan 50 mg, regardless of whether mea- ciated with significantly greater reductions in DBP, measured surements were made during the daytime (7 am to 10 pm) or 0–24 and 0–36 h after dosing, when compared with losartan during the night-time (10 pm to 7 am). The greater efficacy 50 mg once daily, given over the same period. This greater of candesartan cilexetil 8 mg, relative to that of losartan efficacy of candesartan cilexetil, relative to that of losartan, is 50 mg, was not therefore affected by diurnal fluctuations in consistent with the results of other direct comparisons of these BP and was maintained throughout a full 24-h period. These two agents. The results of a number of head-to-head clinical findings are consistent with those of other reports (35). All comparisons have confirmed the superior efficacy of cande- reductions in BP, whether in patients receiving candesartan sartan celexetil compared with losartan in terms of reduction cilexetil or losartan, were also achieved without a significant in BP and maintenance of antihypertensive efficacy between doses, when compared at once daily maximum doses (30–34).
The reductions in SBP in patients receiving candesartan A study performed in mild-to-moderate hypertensive patients cilexetil 8 mg or losartan 50 mg are also clinically important has found, using ABPM, that candesartan reduced both SBP in the context of the increased recognition of the significance and DBP to a significantly greater extent than losartan when of elevated SBP in cardiovascular disease (43,44).
measured at 24 or 36 h postdose (35). As previously men- As in other clinical trials, the tolerability of candesartan tioned, there are some pharmacodynamic and pharmacoki- cilexetil 8 mg and losartan 50 mg in this comparative study netic differences between these AT1-receptor blockers, which was excellent, with no clinically significant difference in the may reflect in their clinical efficacy, especially at the end of type or incidence of adverse events compared with those the dosing interval. It is possible that these differences may be reported by patients receiving placebo. This was reflected in due to molecular differences and to variations in the degree high compliance with AT1-receptor blocker therapy over the and duration of receptor blockade (36,37). In a randomised, double-blind, parallel-group study, candesartan cilexetil was In conclusion, in patients with mild-to-moderate hyperten- shown to display the highest pharmacological potency (i.e.
sion, candesartan cilexetil 8 mg had greater, more consistent antagonistic activity per mg substance) of the AT1-receptor antihypertensive efficacy, throughout both the day and the blockers studied (losartan, irbesartan, valsartan and telmisar- night, compared with that of losartan 50 mg. The persistence tan) (38). Candesartan cilexetil showed a clear dose–response of this greater antihypertensive effect beyond the 24-h dosing relationship for efficacy in the range 4–16 mg (39,40), interval might provide greater BP control in patients receiving whereas there appears to be little increase in efficacy when candesartan cilexetil 8 mg, compared with those given losar- the dose of losartan is increased from 50 to 100 mg.
tan 50 mg, if a dose is delayed or missed. Furthermore, the In addition, ambulatory monitoring allowed us to show superior antihypertensive effect of candesartan cilexetil 8 mg, that, although the antihypertensive effects of both candesartan compared with losartan 50 mg, is maintained without any cilexetil 8 mg and losartan 50 mg persisted for more than compromise of the excellent tolerability that is a general 24 h, the efficacy of candesartan cilexetil remained much characteristic of the AT1-receptor blocker class.
greater than that of losartan for at least 36 h after dosing.
This is consistent with the findings of other investigators(13,33,35,41). Indeed, significant antihypertensive effects of candesartan cilexetil have been detected 48 h after dosing, 1 Swales JD. Current clinical practice in hypertension: the when the effects of losartan have virtually disappeared (35).
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Paper received November 2005, accepted January 2006 Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, April 2006, 60, 4, 391–398

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