Antihypertensive efficacy of olmesartan compared with other antihypertensive drugs

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1 (2002) 16 (Suppl 2), S24 S Nature Publishing Group All rights reserved /02 $ compared with other antihypertensive drugs University Clinic Bonn, Department of Internal Medicine, Bonn, Germany The therapeutic profile of olmesartan medoxomil, which is a recently developed angiotensin II (A II) receptor blocker, has been compared with four commonly used antihypertensive therapeutic drugs (atenolol, captopril, felodipine and losartan) in five separate multicentre, randomised, double-blind, parallel-group, phase III trials. The trials were designed to compare the efficacy of individually optimised dosages of olmesartan medoxomil and the comparator agent. The primary efficacy variable in all trials was the mean change from baseline to week 12 in trough mean sitting diastolic blood pressure (DBP). Olmesartan medoxomil (10 20 mg once daily (o.d.)) showed similar efficacy to atenolol ( mg o.d.), both in patients and, when given together with hydrochlorothiazide (HCTZ) 25 mg o.d., in patients with moderate-tosevere hypertension. Olmesartan medoxomil (20 40 mg o.d.) was also similar in efficacy to felodipine (5 10 mg o.d.) in reducing BP in patients with mild-to-moderate hypertension. Compared with captopril ( mg twice daily (b.i.d.)) and losartan ( mg o.d.), in patients, olmesartan medoxomil (5 20 mg o.d. and mg o.d., respectively) was significantly superior in terms of lowering DBP from baseline to week 12. In terms of the secondary efficacy variable, which was mean change from baseline to week 12 in trough mean sitting systolic BP, olmesartan showed significant superiority to atenolol, captopril and losartan in patients with mild-to-moderate hypertension. In the longer term, compared with losartan, a lower percentage of olmesartan-treated patients required concomitant HCTZ after 12 weeks of therapy. Olmesartan was well tolerated in all studies. (2002) 16 (Suppl 2), S24 S28. DOI: /sj/jhh/ Keywords: antihypertensive agents; angiotensin II; olmesartan Introduction An angiotensin II (A II) receptor blocker is often reserved as an alternative for patients who develop cough as a side-effect when given angiotensinconverting enzyme (ACE) inhibitor therapy. Views, however, are changing and A II receptor blockers are becoming increasingly accepted as first-line treatment options for essential hypertension. The change in prescribing habits for A II receptor blockers has been prompted not only by their proven efficacy and good tolerability, 1 but also by data indicating organprotective effects. There is clinical evidence suggesting that A II receptor blockers may confer cardioprotective effects superior to those conferred by other classes of antihypertensives, while achieving similar decreases in blood pressure (BP). 2 A more persistent improvement in renal haemodynamics has also been demonstrated for A II receptor blockers in comparison with ACE inhibitors, despite equivalent BP reduction. 3 This could be important in cases of dia- Correspondence: KO Stumpe, Department of Internal Medicine, University Clinic Bonn, Wilhelmstrasse 3537, Bonn, Germany. stumpe uni-bonn.de betic nephropathy and chronic renal failure. Furthermore, expert opinion suggests that, before they prescribe longer-established antihypertensives, clinicians should consider all data concerning organ-protective effects conferred by A II receptor blockers. 4 6 Olmesartan medoxomil is a recently developed A II receptor blocker. Olmesartan medoxomil is neither a substrate for, nor an inhibitor or inducer of, cytochrome P-450 isoforms. 7,8 This property, along with other general pharmacokinetic properties, limits the risk of pharmacokinetic interactions between olmesartan once daily (o.d.) and other co-administered drugs. 7,8 The therapeutic profile of olmesartan has been compared with those of four commonly used antihypertensives during the pre-launch clinical development phase of this novel A II receptor blocker. One study compared the efficacy of olmesartan with that of the -adrenoceptor blocker atenolol (plus hydrochlorothiazide (HCTZ) background therapy) in patients with moderate-to-severe hypertension. A further four studies of patients with mild-to-moderate hypertension were carried out to compare the efficacy of olmesartan with that of atenolol, the ACE

2 inhibitor captopril, the calcium antagonist felodipine, and the A II receptor blocker losartan, respectively. These five multicentre, randomized, doubleblind, parallel-group, phase III trials were designed to compare individually optimized dosages of olmesartan and the comparator agent. The primary efficacy variable in all trials was the mean change from baseline to week 12 in trough (pre-dose) mean sitting diastolic BP (DBP). Patients were recruited from primary-care centres in Germany, Poland, Czech Republic, France, Belgium, The Netherlands, the UK and the Republic of Ireland. Existing antihypertensive therapy was discontinued before entry into the study, and hypertension severity was confirmed by the mean of three sitting DBP measurements taken on two or three separate occasions during the runin period. Details of the trials comparing olmesartan with atenolol (moderate-to-severe hypertension), captopril and losartan have been reported previously. 9 The major results for all five trials are presented in order to provide prescribers with a comprehensive assessment of the efficacy of olmesartan compared with commonly used antihypertensives. Comparison with atenolol in patients with moderate-to-severe hypertension The efficacy of olmesartan was compared with that of atenolol in patients with moderate-to-severe hypertension. Moderate-to-severe hypertension was defined as a mean sitting DBP of mm Hg. After a 4-week HCTZ run-in phase, 164 patients (baseline mean DBP of mm Hg) were randomized to receive olmesartan medoxomil 10 mg o.d. plus HCTZ 25 mg o.d., while a different group of 164 patients (baseline mean DBP of mm Hg) received atenolol 50 mg o.d. plus HCTZ 25 mg o.d. At week 4, the dose was doubled for non-responders in each group. After 12 weeks, both olmesartan and atenolol had induced comparable mean decreases from baseline in sitting DBP (17.3 mm Hg and 17.2 mm Hg, respectively; 95% confidence interval on adjusted means: 1.38; 1.23). Adjusted mean changes from baseline in sitting systolic BP (SBP), a secondary efficacy variable, were also comparable (20.4 mm Hg and 19.6 mm Hg, respectively). The changes in BP occurred in both groups of patients soon after antihypertensive therapy began, with a decrease in, and near-control of, BP demonstrated after just 2 weeks of treatment. The adjusted mean changes in BP already achieved by week 2 were 11.6 mm Hg (DBP) and 14.1 mm Hg (SBP) for patients receiving olmesartan plus HCTZ, and 12.0 mm Hg (DBP) and 15.3 mm Hg (SBP) for patients receiving atenolol plus HCTZ. The median pulse rates (range) for patients in each group were comparable: 73.3 ( ) beats per minute (bpm) at baseline and 73.3 ( ) bpm at week 12 for those receiving olmesartan medoxomil plus HCTZ, compared with 75.0 Figure 1 Change in blood pressure (BP) (adjusted mean ± s.e.m.) after 12 weeks of treatment with olmesartan compared with atenolol. *Significant difference, 95% confidence interval 6.0; 0.8. ( ) bpm at baseline and 72.0 ( ) bpm at week 12 for those receiving atenolol plus HCTZ. Comparison with atenolol in patients In another study, olmesartan was compared with atenolol in patients, defined as a mean sitting DBP of mm Hg after a 3-week placebo run-in phase. A total of 165 patients (baseline mean DBP of mm Hg) were randomized to receive olmesartan medoxomil 10 mg o.d., and a further 161 patients (baseline mean DBP of mm Hg) received atenolol 50 mg o.d. At week 4, the dose was doubled for non-responders in each group. In terms of the primary efficacy variable, the mean changes from baseline to week 12 in DBP were comparable for both treatment regimens (Figure 1). A significant difference between the groups was seen in the mean changes from baseline in SBP, however, with a greater decrease at 12 weeks in olmesartantreated patients compared with atenolol-treated patients. Table 1 shows that some superiority of olmesartan compared with atenolol, in terms of a Table 1 Change in blood pressure (BP) from baseline in patients after 4 and 8 weeks of treatment with olmesartan compared with atenolol Parameter Week Mean (± s.e.m.) change from baseline in trough sitting BP (mm Hg) Olmesartan Atenolol Two-sided 95% confidence interval Diastolic ± ± ; 1.9 BP ± ± ; 1.0 Systolic ± ± ; 0.4* BP ± ± ; 1.6* *Significant difference. S25

3 S26 decrease in SBP, was already evident after 4 and 8 weeks of treatment. The responder rate at week 12 was 78% for patients receiving olmesartan medoxomil and 79% for patients receiving atenolol (two-sided 95% confidence interval: 10.3; 7.7). The proportions of patients titrated to a higher dose were 34.5% and 32.9% for olmesartan and atenolol, respectively. Mean pulse rates (± s.d.) at baseline and at 12 weeks were 74.6 (± 8.0) bpm and 73.1 (± 8.4) bpm in the olmesartan group, and 74.0 (± 8.3) and 67.0 (± 8.7) in the atenolol group, respectively. Comparison with captopril in patients Olmesartan was compared with captopril in mildto-moderate hypertension, defined as a mean sitting DBP of mm Hg during a 3-week placebo runin phase. A total of 148 patients (baseline mean DBP of mm Hg) were randomised to receive olmesartan medoxomil 5 mg o.d., and a further 143 patients (baseline mean DBP of mm Hg) received captopril 12.5 mg b.i.d. For non-responders in each group, the dose was increased at weeks 4 and 8, to olmesartan 10 mg or 20 mg o.d. and captopril 25 mg or 50 mg b.i.d., respectively. At 12 weeks, the results showed a clear superiority for olmesartan in reducing both DBP and SBP from baseline levels (Figure 2). The adjusted mean changes from baseline in sitting DBP (± s.e.m.) were 9.9 (± 0.6) mm Hg and 6.8 (± 0.6) mm Hg, and adjusted mean changes in sitting SBP were 14.7 (± 1.1) mm Hg and 7.1 (± 1.1) mm Hg in the olmesartan and captopril groups, respectively. The 95% confidence intervals (DBP: 4.8; 1.5; SBP: 10.4; 4.7) did not encompass zero, indicating that these differences were significant. There was a significantly higher responder rate in the olmesartan than in the captopril group (53% vs 38%; respectively, P 0.01), and a smaller number of olmesartan-treated Table 2 Change in blood pressure (BP) from baseline in patients after 4 and 8 weeks of treatment with olmesartan compared with captopril Parameter Week Mean (± s.e.m.) change from baseline in trough sitting BP (mm Hg) Olmesartan Captopril Two-sided 95% confidence interval Diastolic ± ± ; 2.2* BP ± ± ; 3.1* Systolic ± ± ; 3.6* BP ± ± ; 5.6* *Significant difference. patients needed the highest dose compared with captopril-treated patients (25.0% vs 54.9%, respectively). In a higher proportion of patients, the target BP was achieved with a lower dose of olmesartan than captopril, indicating superiority of olmesartan. Table 2 shows that these changes were already evident after 4 and 8 weeks. Comparison with felodipine in patients Patients were studied to compare the efficacy of olmesartan with that of felodipine. Mild-to-moderate hypertension was defined as a mean sitting DBP of mm Hg ( mm Hg for Czech centres) during a 3-week placebo run-in phase. In total, 187 patients (baseline mean DBP of mm Hg) were randomized to receive olmesartan medoxomil 20 mg o.d., and a further 194 patients (baseline mean DBP of mm Hg) received felodipine 5 mg o.d. The dose was doubled after 4 weeks for non-responders in each group. After 12 weeks of treatment the effects of olmesartan on DBP and SBP were not significantly different from those of felodipine. The results at 2, 4 and 8 weeks also showed no significant differences between olmesartan- and felodipine-treated patients in terms of change from baseline in DBP and SBP (Table 3). The responder rates at week 12 were Table 3 Change in blood pressure (BP) from baseline in patients after 2, 4, 8 and 12 weeks of treatment with olmesartan compared with felodipine Week Mean change from baseline trough sitting BP (mm Hg) Diastolic BP Systolic BP Olmesartan Felodipine Olmesartan Felodipine Figure 2 Change in blood pressure (BP) (adjusted mean ± s.e.m.) after 12 weeks of treatment with olmesartan compared with captopril. Significant difference, 95% confidence interval 4.8; 1.5; *significant difference, 95% confidence interval 10.4;

4 82.8% vs 83.3% in the olmesartan and felodipine groups, respectively. The percentage of patients on a higher dose by week 12 was 31.7 vs 39.6 for the two groups, respectively. Comparison with losartan in patients with mildto-moderate hypertension In the study comparing olmesartan with losartan, mild-to-moderate hypertension was defined as a mean sitting DBP of mm Hg during a 3-week placebo run-in period. A total of 160 patients (baseline mean DBP of mm Hg) were randomised to receive olmesartan medoxomil 10 mg o.d., and another 156 patients (baseline mean DBP of mm Hg) received losartan 50 mg o.d. The dose was increased at week 4 for non-responders in each group. The primary time point for efficacy was 12 weeks, after which the study was extended for a further 12 weeks. From weeks 12 to 24, concomitant HCTZ at dosages of 12.5 mg or 25 mg o.d. was prescribed where necessary. Figure 3 shows that after 12 weeks of treatment olmesartan had induced a significantly greater reduction in both DBP and SBP. The adjusted mean changes in sitting DBP (± s.e.m.) in the olmesartan and losartan groups were 10.6 (± 0.5) mm Hg and 8.5 (± 0.6) mm Hg, respectively (two-sided 95% confidence interval: 3.6; 0.5). The adjusted mean changes in sitting SBP (± s.e.m.) in the olmesartan and losartan groups were 14.9 (± 1.0) mm Hg and 11.6 (± 1.0) mm Hg (two-sided 95% confidence interval: 6.0; 0.6). The responder rates at week 12 were 63% vs 52% for the olmesartan and losartan groups, respectively. The percentage of patients on a higher dose by week 12 was lower in the olmesartan group than in the losartan group (41.8% vs 63.2%). Of special interest are the results at weeks 2 and 4, when all patients received the low dose of their respective drug, as shown in Table 4. The results at weeks 16, 20 and 24 still showed some superiority for olmesartan, but the differences were no longer significant. It is noted that a lower percentage of olmesartan-treated patients needed HCTZ compared Figure 3 Change in blood pressure (BP) (adjusted mean ± s.e.m.) after 12 weeks of treatment with olmesartan compared with losartan. Significant difference, 95% confidence interval 3.6; 0.6; * significant difference, 95% confidence interval 6.0; 0.6. Table 4 Change in efficacy variables from baseline in patients after 2 and 4 weeks of treatment with olmesartan compared with losartan Parameter Week Olmesartan Losartan medoxomil Change from baseline * diastolic BP (mm Hg) * Change from baseline * systolic BP (mm Hg) * Responder rate (%) *Significant difference (95% confidence interval below zero). P BP, blood pressure. with losartan-treated patients (34.8% vs 48.0% by week 24). Tolerability Adverse events occurred at similar frequencies on the active treatments in the comparative studies and some expected differences in profile were observed. For example, among felodipine-treated patients there was a higher rate of peripheral oedema (2.6%) than among olmesartan-treated patients (0%). Overall, the great majority of adverse events in each study were mild or moderate in severity. In general, all treatments were considered to be well tolerated over the study period. Discussion The comparative studies demonstrated that, in patients with moderate-to-severe hypertension, olmesartan medoxomil (10 20 mg o.d. plus HCTZ 25 mg o.d.) had a BP-lowering effect similar to that of atenolol ( mg o.d. plus HCTZ 25 mg o.d.). The BP-lowering effects of olmesartan medoxomil and atenolol at these doses were also comparable in patients in terms of DBP. In terms of SBP reduction, however, olmesartan showed significant superiority in this group of patients. Olmesartan medoxomil (20 40 mg o.d.) was similar in efficacy to felodipine (5 10 mg o.d.) in reducing BP in patients with mild-tomoderate hypertension. Compared with both captopril ( mg b.i.d.) and losartan ( mg o.d.), however, olmesartan medoxomil (5 20 mg o.d. and mg o.d., respectively) was significantly superior in the treatment of patients with mild-tomoderate hypertension over 12 weeks. In the longer term, compared with losartan, a lower percentage of olmesartan-treated patients required concomitant HCTZ therapy. In all studies, olmesartan was well tolerated. The starting doses of olmesartan medoxomil used in all studies except for the comparison with felodipine were lower (i.e. 5 mg or 10 mg o.d.) than the S27

5 S28 recommended starting dose and maintenance dose of 20 mg o.d. 1,7 Even at these lower doses, however, olmesartan maintained efficacy similar or superior to that of the comparators. In the studies comparing olmesartan with captopril and losartan, fewer patients were titrated to higher doses of olmesartan than in the case of either captopril or losartan. (The starting doses used for the comparators in these trials matched the current recommended starting doses, ie captopril 12.5 mg b.i.d. and losartan 50 mg o.d.) It could therefore be expected that adequate BP control may be achieved in a greater proportion of patients on the recommended starting dose of olmesartan than those on the recommended starting dose of either captopril or losartan. A recent trial has compared the dose of olmesartan 20 mg with the maintenance doses of three commonly prescribed A II receptor blockers. 10,11 After 8 weeks of treatment, the reduction in mean cuff DBP (11.5 mm Hg) was significantly greater in patients treated with olmesartan than those treated with losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) (8.2, 7.9 and 9.9 mm Hg, respectively). The risk of cardiovascular events is reported to be decreased in patients with adequately controlled BP, 12 yet the majority of treated patients do not experience good BP control. 13 Novel drugs able to control BP rapidly without the need for lengthy dose titration regimens would therefore be a valuable addition to the currently available range of antihypertensive drugs. References 1 Püchler K, Laeis P, Stumpe KO. Blood pressure response, but not adverse event incidence, correlates with dose of angiotensin II antagonist. J Hypertens 2001; 19 (Suppl 1): S41 S48. 2 Thurman PA. Angiotensin II antagonism and the heart: valsartan in left ventricular hypertrophy. Cardiology 1999; 91 (Suppl 1): Birkenhager WH, de Leeuw PW. Non-peptide angiotensin type I receptor antagonists in the treatment of hypertension. J Hypertens 1999; 17: Gallagher M. Angiotensin II antagonists lead the way in hypertension management. Inpharm 1998; 1143: De Leeuw PW. How do angiotensin II receptor antagonists affect blood pressure? Am J Cardiol 1999; 84: 5K 6K. 6 Mazzolai L, Burnier M. Comparative safety and tolerability of angiotensin II receptor antagonists. Drug Safety 1999; 21: Brunner H. The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview. J Hum Hypertens 2002; 16 (Suppl 2): S13 S16. 8 Laeis P, Püchler K, Kirch W. The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interactions. J Hypertens 2001; 19 (Suppl 1): S21 S32. 9 Ball KJ, Williams PA, Stumpe KO. Relative efficacy of an angiotensin II antagonist compared with other antihypertensive agents. Olmesartan medoxomil versus antihypertensives. J Hypertens 2001; 19 (Suppl 1): S49 S Oparil S. Comparative antihypertensive efficacy of olmesartan: comparison with other angiotensin II receptor antagonists. J Hum Hypertens 2002; 16 (Suppl 2): S17 S Oparil S et al. Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens 2001; 3: Flack JM et al. Blood pressure and mortality among men with prior myocardial infarction: Multiple Risk Factor Intervention Trial Research Group. Circulation 1995; 92: Neutel JM. Safety and efficacy of angiotensin II receptor antagonists. Am J Cardiol 1999; 84: 13K 17K.