Antihypertensive Efficacy of Olmesartan Compared with Other

Home , Losartan, Olmesartan

Journal of Human Hypertension (2002) 16 (Suppl 2), S24–S28  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Antihypertensive efﬁcacy of olmesartan compared with other antihypertensive drugs

KO Stumpe and M Ludwig University Clinic Bonn, Department of Internal Medicine, Bonn, Germany

The therapeutic profile of olmesartan medoxomil, which o.d.) in reducing BP in patients with mild-to-moderate is a recently developed angiotensin II (A II) receptor hypertension. Compared with captopril (12.5–50 mg blocker, has been compared with four commonly used twice daily (b.i.d.)) and losartan (50–100 mg o.d.), in antihypertensive therapeutic drugs (atenolol, captopril, patients with mild-to-moderate hypertension, olmesar- felodipine and losartan) in five separate multicentre, tan medoxomil (5–20 mg o.d. and 10–20 mg o.d., randomised, double-blind, parallel-group, phase III respectively) was significantly superior in terms of low- trials. The trials were designed to compare the efficacy ering DBP from baseline to week 12. In terms of the sec- of individually optimised dosages of olmesartan medox- ondary efficacy variable, which was mean change from omil and the comparator agent. The primary efficacy baseline to week 12 in trough mean sitting systolic BP, variable in all trials was the mean change from baseline olmesartan showed significant superiority to atenolol, to week 12 in trough mean sitting diastolic blood pres- captopril and losartan in patients with mild-to-moderate sure (DBP). Olmesartan medoxomil (10–20 mg once hypertension. In the longer term, compared with losar- daily (o.d.)) showed similar efficacy to atenolol (50–100 tan, a lower percentage of olmesartan-treated patients mg o.d.), both in patients with mild-to-moderate hyper- required concomitant HCTZ after 12 weeks of therapy. tension and, when given together with hydrochlorothia- Olmesartan was well tolerated in all studies. zide (HCTZ) 25 mg o.d., in patients with moderate-to- Journal of Human Hypertension (2002) 16 (Suppl 2), S24– severe hypertension. Olmesartan medoxomil (20–40 mg S28. DOI: 10.1038/sj/jhh/1001395 o.d.) was also similar in efficacy to felodipine (5–10 mg

Keywords: antihypertensive agents; angiotensin II; olmesartan

Introduction betic nephropathy and chronic renal failure. Fur- thermore, expert opinion suggests that, before they An angiotensin II (A II) receptor blocker is often prescribe longer-established antihypertensives, reserved as an alternative for patients who develop clinicians should consider all data concerning cough as a side-effect when given angiotensin- organ-protective effects conferred by A II receptor converting enzyme (ACE) inhibitor therapy. Views, blockers.4–6 however, are changing and A II receptor blockers are Olmesartan medoxomil is a recently developed becoming increasingly accepted as first-line treat- A II receptor blocker. Olmesartan medoxomil is ment options for essential hypertension. The change neither a substrate for, nor an inhibitor or inducer of, in prescribing habits for A II receptor blockers has cytochrome P-450 isoforms.7,8 This property, along been prompted not only by their proven efficacy and 1 with other general pharmacokinetic properties, lim- good tolerability, but also by data indicating organ- its the risk of pharmacokinetic interactions between protective effects. There is clinical evidence suggest- olmesartan once daily (o.d.) and other co-adminis- ing that A II receptor blockers may confer cardiopro- tered drugs.7,8 tective effects superior to those conferred by other The therapeutic profile of olmesartan has been classes of antihypertensives, while achieving similar 2 compared with those of four commonly used antihy- decreases in blood pressure (BP). A more persistent pertensives during the pre-launch clinical develop- improvement in renal haemodynamics has also been ment phase of this novel A II receptor blocker. One demonstrated for A II receptor blockers in compari- study compared the efficacy of olmesartan with that son with ACE inhibitors, despite equivalent BP ␤ 3 of the -adrenoceptor blocker atenolol (plus hydro- reduction. This could be important in cases of dia- chlorothiazide (HCTZ) background therapy) in patients with moderate-to-severe hypertension. A Correspondence: KO Stumpe, Department of Internal Medicine, further four studies of patients with mild-to-moder- University Clinic Bonn, Wilhelmstrasse 3537, 53111 Bonn, ate hypertension were carried out to compare the Germany. E-mail: stumpeȰuni-bonn.de efficacy of olmesartan with that of atenolol, the ACE Antihypertensive efficacy of olmesartan KO Stumpe and M Ludwig S25 inhibitor captopril, the calcium antagonist felodipine, and the A II receptor blocker losartan, respectively. These five multicentre, randomized, double- blind, 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 Figure 1 Change in blood pressure (BP) (adjusted mean ± s.e.m.) study, and hypertension severity was confirmed by from baseline in patients with mild-to-moderate hypertension the mean of three sitting DBP measurements taken after 12 weeks of treatment with olmesartan compared with aten- − − on two or three separate occasions during the run- olol. *Significant difference, 95% confidence interval 6.0; 0.8. in period. Details of the trials comparing olmesartan with atenolol (moderate-to-severe hypertension), (60.0–102.0) bpm at baseline and 72.0 (54.7–94.7) captopril and losartan have been reported pre- bpm at week 12 for those receiving atenolol plus viously.9 The major results for all five trials are HCTZ. presented in order to provide prescribers with a comprehensive assessment of the efficacy of olmesartan compared with commonly used antihyperten- Comparison with atenolol in patients sives. with mild-to-moderate hypertension In another study, olmesartan was compared with Comparison with atenolol in patients atenolol in patients with mild-to-moderate hyper- with moderate-to-severe hypertension tension, defined as a mean sitting DBP of 95–114 The efficacy of olmesartan was compared with that mm Hg after a 3-week placebo run-in phase. A total of atenolol in patients with moderate-to-severe of 165 patients (baseline mean DBP of 100.8 mm Hg) hypertension. Moderate-to-severe hypertension was were randomized to receive olmesartan medoxomil defined as a mean sitting DBP of 100–120 mm Hg. 10 mg o.d., and a further 161 patients (baseline mean After a 4-week HCTZ run-in phase, 164 patients DBP of 101.0 mm Hg) received atenolol 50 mg o.d. (baseline mean DBP of 105.0 mm Hg) were ran- At week 4, the dose was doubled for non-responders domized to receive olmesartan medoxomil 10 mg in each group. o.d. plus HCTZ 25 mg o.d., while a different group In terms of the primary efficacy variable, the mean of 164 patients (baseline mean DBP of 105.3 mm Hg) changes from baseline to week 12 in DBP were com- received atenolol 50 mg o.d. plus HCTZ 25 mg o.d. parable for both treatment regimens (Figure 1). A At week 4, the dose was doubled for non-responders significant difference between the groups was seen in each group. in the mean changes from baseline in SBP, however, After 12 weeks, both olmesartan and atenolol had with a greater decrease at 12 weeks in olmesartan- induced comparable mean decreases from baseline treated patients compared with atenolol-treated in sitting DBP (17.3 mm Hg and 17.2 mm Hg, patients. Table 1 shows that some superiority of respectively; 95% confidence interval on adjusted olmesartan compared with atenolol, in terms of a means: −1.38; 1.23). Adjusted mean changes from baseline in sitting systolic BP (SBP), a secondary Table 1 Change in blood pressure (BP) from baseline in patients efficacy variable, were also comparable (20.4 mm Hg with mild-to-moderate hypertension after 4 and 8 weeks of treat- and 19.6 mm Hg, respectively). The changes in BP ment with olmesartan compared with atenolol occurred in both groups of patients soon after antihypertensive therapy began, with a decrease in, and Parameter Week Mean (± s.e.m.) change from baseline in near-control of, BP demonstrated after just 2 weeks trough sitting BP (mm Hg) of treatment. The adjusted mean changes in BP already achieved by week 2 were −11.6 mm Hg Olmesartan Atenolol Two-sided − 95% confidence (DBP) and 14.1 mm Hg (SBP) for patients receiving interval olmesartan plus HCTZ, and −12.0 mm Hg (DBP) and −15.3 mm Hg (SBP) for patients receiving atenolol Diastolic 4 −11.7 ± 0.5 −12.1 ± 0.6 −1.0; 1.9 plus HCTZ. The median pulse rates (range) for BP 8 −14.2 ± 0.5 −13.9 ± 0.5 −1.7; 1.0 patients in each group were comparable: 73.3 (58.7– Systolic 4 −18.6 ± 0.9 −15.8 ± 0.9 −5.3; −0.4* 95.3) beats per minute (bpm) at baseline and 73.3 BP 8 −21.2 ± 0.9 −17.1 ± 0.9 −6.6; −1.6* (58.0–96.7) bpm at week 12 for those receiving olmesartan medoxomil plus HCTZ, compared with 75.0 *Significant difference.

Journal of Human Hypertension Antihypertensive efficacy of olmesartan KO Stumpe and M Ludwig S26 decrease in SBP, was already evident after 4 and 8 Table 2 Change in blood pressure (BP) from baseline in patients weeks of treatment. with mild-to-moderate hypertension after 4 and 8 weeks of treatment with olmesartan compared with captopril The responder rate at week 12 was 78% for patients receiving olmesartan medoxomil and 79% Parameter Week Mean (± s.e.m.) change from baseline in for patients receiving atenolol (two-sided 95% con- trough sitting BP (mm Hg) fidence interval: −10.3; 7.7). The proportions of patients titrated to a higher dose were 34.5% and Olmesartan Captopril Two-sided 32.9% for olmesartan and atenolol, respectively. 95% confidence Mean pulse rates (± s.d.) at baseline and at 12 weeks interval 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) Diastolic 4 8.3 0.5 4.6 0.5 5.1; 2.2* BP 8 −10.1 ± 0.6 −5.3 ± 0.6 −6.5; 3.1* in the atenolol group, respectively. Systolic 4 −12.4 ± 1.0 −6.1 ± 1.0 −9.0; −3.6* BP 8 −15.1 ± 1.1 −6.5 ± 1.1 −11.5; −5.6* Comparison with captopril in patients with mild-to-moderate hypertension *Significant difference. Olmesartan was compared with captopril in mild- to-moderate hypertension, defined as a mean sitting patients needed the highest dose compared with DBP of 95–114 mm Hg during a 3-week placebo run- captopril-treated patients (25.0% vs 54.9%, in phase. A total of 148 patients (baseline mean DBP respectively). In a higher proportion of patients, the of 101.0 mm Hg) were randomised to receive olme- target BP was achieved with a lower dose of olmesartan medoxomil 5 mg o.d., and a further 143 sartan than captopril, indicating superiority of olme- patients (baseline mean DBP of 102.1 mm Hg) sartan. Table 2 shows that these changes were received captopril 12.5 mg b.i.d. For non-responders already evident after 4 and 8 weeks. in each group, the dose was increased at weeks 4 and 8, to olmesartan 10 mg or 20 mg o.d. and capto- Comparison with felodipine in patients pril 25 mg or 50 mg b.i.d., respectively. with mild-to-moderate hypertension At 12 weeks, the results showed a clear superiority for olmesartan in reducing both DBP and SBP Patients were studied to compare the efficacy of from baseline levels (Figure 2). The adjusted mean olmesartan with that of felodipine. Mild-to-moder- changes from baseline in sitting DBP (± s.e.m.) were ate hypertension was defined as a mean sitting DBP −9.9 (± 0.6) mm Hg and −6.8 (± 0.6) mm Hg, and of 100–120 mm Hg (100–114 mm Hg for Czech adjusted mean changes in sitting SBP were −14.7 centres) during a 3-week placebo run-in phase. In (± 1.1) mm Hg and −7.1 (± 1.1) mm Hg in the olmes- total, 187 patients (baseline mean DBP of 104.6 artan and captopril groups, respectively. The 95% mm Hg) were randomized to receive olmesartan confidence intervals (DBP: −4.8; −1.5; SBP: −10.4; medoxomil 20 mg o.d., and a further 194 patients −4.7) did not encompass zero, indicating that these (baseline mean DBP of 105.0 mm Hg) received felo- differences were significant. There was a signifi- dipine 5 mg o.d. The dose was doubled after 4 weeks cantly higher responder rate in the olmesartan than for non-responders in each group. in the captopril group (53% vs 38%; respectively, P After 12 weeks of treatment the effects of olmesar- Ͻ 0.01), and a smaller number of olmesartan-treated tan 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 with mild-to-moderate hypertension 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.) 2 10.9 10.0 12.9 13.1 − − − − from baseline in patients with mild-to-moderate hypertension 4 13.6 12.5 15.7 14.1 − − − − after 12 weeks of treatment with olmesartan compared with cap- 8 17.3 16.3 18.9 17.7 − − − − topril. †Significant difference, 95% confidence interval −4.8; 12 17.5 17.0 19.9 19.1 −1.5; *significant difference, 95% confidence interval −10.4; −4.7.

Journal of Human Hypertension Antihypertensive efficacy of olmesartan KO Stumpe and M Ludwig S27 82.8% vs 83.3% in the olmesartan and felodipine Table 4 Change in efficacy variables from baseline in patients groups, respectively. The percentage of patients on with mild-to-moderate hypertension after 2 and 4 weeks of treatment with olmesartan compared with losartan a higher dose by week 12 was 31.7 vs 39.6 for the two groups, respectively. Parameter Week Olmesartan Losartan medoxomil Comparison with losartan in patients with mild- to-moderate hypertension Change from baseline 2 8.4 6.2* diastolic BP (mm Hg) 4 9.1 6.4* In the study comparing olmesartan with losartan, Change from baseline 2 12.1 7.6* mild-to-moderate hypertension was defined as a systolic BP (mm Hg) 4 13.0 9.5* mean sitting DBP of 95–114 mm Hg during a 3-week Responder rate (%) 2 45 30† placebo run-in period. A total of 160 patients 45432† (baseline mean DBP of 101.3 mm Hg) were randomised to receive olmesartan medoxomil 10 mg o.d., *Significant difference (95% confidence interval below zero). and another 156 patients (baseline mean DBP of †P Ͻ 0.01. BP, blood pressure. 101.9 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 with losartan-treated patients (34.8% vs 48.0% by weeks, after which the study was extended for a week 24). further 12 weeks. From weeks 12 to 24, concomitant HCTZ at dosages of 12.5 mg or 25 mg o.d. was pre- Tolerability scribed where necessary. Figure 3 shows that after 12 weeks of treatment Adverse events occurred at similar frequencies on olmesartan had induced a significantly greater the active treatments in the comparative studies and reduction in both DBP and SBP. The adjusted mean some expected differences in profile were observed. changes in sitting DBP (± s.e.m.) in the olmesartan For example, among felodipine-treated patients and losartan groups were −10.6 (± 0.5) mm Hg and there was a higher rate of peripheral oedema (2.6%) −8.5 (± 0.6) mm Hg, respectively (two-sided 95% than among olmesartan-treated patients (0%). Over- confidence interval: −3.6; −0.5). The adjusted mean all, the great majority of adverse events in each changes in sitting SBP (± s.e.m.) in the olmesartan study were mild or moderate in severity. In general, and losartan groups were −14.9 (± 1.0) mm Hg and all treatments were considered to be well tolerated −11.6 (± 1.0) mm Hg (two-sided 95% confidence over the study period. interval: −6.0; −0.6). The responder rates at week 12 were 63% vs 52% for the olmesartan and losartan Discussion groups, respectively. The percentage of patients on a higher dose by week 12 was lower in the olmesartan The comparative studies demonstrated that, in group than in the losartan group (41.8% vs 63.2%). patients with moderate-to-severe hypertension, Of special interest are the results at weeks 2 and 4, olmesartan medoxomil (10–20 mg o.d. plus HCTZ when all patients received the low dose of their 25 mg o.d.) had a BP-lowering effect similar to that respective drug, as shown in Table 4. The results at of atenolol (50–100 mg o.d. plus HCTZ 25 mg o.d.). weeks 16, 20 and 24 still showed some superiority The BP-lowering effects of olmesartan medoxomil for olmesartan, but the differences were no longer and atenolol at these doses were also comparable in significant. It is noted that a lower percentage of patients with mild-to-moderate hypertension in olmesartan-treated patients needed HCTZ compared 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-to- moderate hypertension. Compared with both captopril (12.5–50 mg b.i.d.) and losartan (50–100 mg o.d.), however, olmesartan medoxomil (5–20 mg o.d. and 10–20 mg o.d., respectively) was significantly superior in the treatment of patients with mild-to- moderate 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 Figure 3 Change in blood pressure (BP) (adjusted mean ± s.e.m.) tolerated. from baseline in patients with mild-to-moderate hypertension after 12 weeks of treatment with olmesartan compared with losar- The starting doses of olmesartan medoxomil used tan. †Significant difference, 95% confidence interval −3.6; −0.6; * in all studies except for the comparison with felodi- significant difference, 95% confidence interval −6.0; −0.6. pine were lower (i.e. 5 mg or 10 mg o.d.) than the

Journal of Human Hypertension Antihypertensive efficacy of olmesartan KO Stumpe and M Ludwig S28 recommended starting dose and maintenance dose 2 Thurman PA. Angiotensin II antagonism and the heart: of 20 mg o.d.1,7 Even at these lower doses, however, valsartan in left ventricular hypertrophy. Cardiology olmesartan maintained efficacy similar or superior 1999; 91 (Suppl 1): 3–7. to that of the comparators. In the studies comparing 3 Birkenhager WH, de Leeuw PW. Non-peptide angio- olmesartan with captopril and losartan, fewer tensin type I receptor antagonists in the treatment of hypertension. J Hypertens 1999; 17: 873–881. patients were titrated to higher doses of olmesartan 4 Gallagher M. Angiotensin II antagonists lead the way than in the case of either captopril or losartan. (The in hypertension management. Inpharm 1998; 1143: starting doses used for the comparators in these 13–15. trials matched the current recommended starting 5 De Leeuw PW. How do angiotensin II receptor antag- doses, ie captopril 12.5 mg b.i.d. and losartan 50 mg onists affect blood pressure? Am J Cardiol 1999; 84: o.d.) It could therefore be expected that adequate BP 5K–6K. control may be achieved in a greater proportion of 6 Mazzolai L, Burnier M. Comparative safety and toler- patients on the recommended starting dose of olme- ability of angiotensin II receptor antagonists. Drug sartan than those on the recommended starting dose Safety 1999; 21:23–33. of either captopril or losartan. A recent trial has 7 Brunner H. The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview. JHum compared the dose of olmesartan 20 mg with the Hypertens 2002; 16 (Suppl 2): S13–S16. maintenance doses of three commonly prescribed 8 Laeis P, Pu¨ chler K, Kirch W. The pharmacokinetic and 10,11 A II receptor blockers. After 8 weeks of treat- metabolic profile of olmesartan medoxomil limits the ment, the reduction in mean cuff DBP (11.5 mm Hg) risk of clinically relevant drug interactions. J Hyper- was significantly greater in patients treated with tens 2001; 19 (Suppl 1): S21–S32. olmesartan than those treated with losartan (50 mg), 9 Ball KJ, Williams PA, Stumpe KO. Relative efficacy of valsartan (80 mg) or irbesartan (150 mg) (8.2, 7.9 and an angiotensin II antagonist compared with other anti- 9.9 mm Hg, respectively). The risk of cardiovascular hypertensive agents. Olmesartan medoxomil versus events is reported to be decreased in patients with antihypertensives. J Hypertens 2001; 19 (Suppl 1): adequately controlled BP,12 yet the majority of S49–S56. 13 10 Oparil S. Comparative antihypertensive efficacy of treated patients do not experience good BP control. olmesartan: comparison with other angiotensin II Novel drugs able to control BP rapidly without the receptor antagonists. J Hum Hypertens 2002; 16 (Suppl need for lengthy dose titration regimens would 2): S17–S23. therefore be a valuable addition to the currently 11 Oparil S et al. Comparative efficacy of olmesartan, lo- available range of antihypertensive drugs. sartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens 2001; 3: 283–291. References 12 Flack JM et al. Blood pressure and mortality among men with prior myocardial infarction: Multiple Risk 1Pu¨ chler K, Laeis P, Stumpe KO. Blood pressure Factor Intervention Trial Research Group. Circulation response, but not adverse event incidence, correlates 1995; 92: 2437–2445. with dose of angiotensin II antagonist. J Hypertens 13 Neutel JM. Safety and efficacy of angiotensin II recep- 2001; 19 (Suppl 1): S41–S48. tor antagonists. Am J Cardiol 1999; 84: 13K–17K.

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