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Journal of Human (2002) 16 (Suppl 2), S17–S23  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Comparative antihypertensive efficacy of : comparison with other II receptor antagonists

S Oparil Vascular Biology and Hypertension Program of the Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

Hypertension is a major risk factor for cardiovascular gest that they are beneficial for controlling target organ morbidity and mortality. Effective control of elevated damage that is related to hypertension. Furthermore, blood pressure (BP) has been shown to reduce this risk. unlike ACE inhibitors, these agents have a side-effect Early studies of risk reduction assumed that the mech- profile that is similar to that of placebo. Based on their anism by which BP was lowered had little impact on the efficacy in controlling hypertension and their wider benefit obtained. Recent evidence, however, suggests health benefits, together with minimal side effects, that agents that inhibit the -angiotensin system angiotensin II (A II) receptor blockers should be con- may be particularly beneficial. The results of the recent sidered as first-line agents for the treatment of hyper- Heart Outcomes Prevention Evaluation (HOPE) trial sug- tension, particularly in patients with other cardiovascu- gest that angiotensin-converting enzyme (ACE) inhibi- lar risk factors. Preliminary evidence suggests that tors have a greater impact on cardiovascular morbidity olmesartan, an A II receptor blocker currently being and mortality than would be anticipated from their anti- evaluated for approval for clinical use, may provide anti- hypertensive effects alone. Angiotensin receptor block- hypertensive efficacy that is superior to other members ers, the other major class of antihypertensive drugs that of the class. inhibit the renin-angiotensin system, have not been Journal of Human Hypertension (2002) 16 (Suppl 2), S17– widely tested in outcomes trials, but early results sug- S23. DOI: 10.1038/sj/jhh/1001394

Keywords: antihypertensive agents; angiotensin II; renin-angiotensin system; olmesartan

Introduction doubles the risk of coronary heart disease in both genders.2 Before the results of the Framingham Heart Study Hypertension is generally defined as a systolic BP became available, there was little consensus regard- (SBP) higher than 140 mm Hg and/or a diastolic BP ing the pathophysiological importance of elevated (DBP) higher than 90 mm Hg, but numerous studies blood pressure (BP), or the necessity for treatment have shown that the relationship between BP and of this condition, which was usually regarded as 1 cardiovascular disease is positive and continuous asymptomatic and benign. As a result of subsequent over a wide range of BPs.3 For example, in the Mul- extensive epidemiological research, hypertension is tiple Risk Factor Intervention Trial (MRFIT), a study now recognised as a major risk factor for cardio- that followed almost 348000 men at high risk for vascular morbidity and mortality. 11.6 years, the relative risk of death from coronary Data from the Framingham Heart Study reveal the heart disease increased gradually from 1.0 in sub- 2 magnitude of the risk imposed by hypertension. jects with a baseline SBP lower than 112 mm Hg to Figure 1 shows results of 36 years of follow-up in 2 3.7 in subjects with a baseline SBP of at least 151 subjects aged 35–64 years at enrolment. In this mm Hg.4 The relationship between DBP and cardio- study, hypertension was defined as a BP higher than vascular disease was similar. Using data from nine 140/90 mm Hg. Men who are hypertensive by this prospective observational studies that included definition are four-times more likely to experience a 420000 subjects, MacMahon and co-workers calcu- stroke or cardiac failure than normotensive control lated that the risk of stroke and coronary heart dis- subjects. Among hypertensive women, the relative ease increases gradually over a DBP range of 76–105 risk for these conditions is 3. Hypertension also mm Hg.3 The relative risk of stroke increased 10- to 12-times over this BP range.3 These findings suggest Correspondence: S Oparil, Division of Cardiovascular Disease, that the risk ratios derived from the Framingham University of Alabama at Birmingham, 1034 Zeigler Research data should be regarded as conservative estimates Building, 933 South 19th Street, Birmingham, AL 35294, USA. when assessing a patient with a substantial elevation E-mail: soparilȰuab.edu in BP.2 Antihypertensive efficacy of olmesartan S Oparil S18

Figure 1 Effect of hypertension on relative risk of cardiovascular disease in subjects aged 35–64 years from 36 years of follow-up in the Framingham Heart Study. Hypertension was defined as a BP Ͼ140/90 mm Hg. ‘Coronary disease’ includes , angina pectoris, sudden death, other coronary deaths, and coronary insufficiency syndrome. (Reproduced with permission from Refer- ence 2.)

Treatment of hypertension reduces cardiovascular complications. In the United King- cardiovascular risk dom Prospective Study (UKPDS), patients with were assigned to tight (Ͻ150/85 Lowering BP is extremely effective in reducing the mm Hg) or less tight (Ͻ180/105 mm Hg) control of incidence of cardiovascular disease in hypertensive BP.11 The mean BPs achieved in these two groups populations. Collins et al5 reviewed the results of 14 were 144/82 mm Hg and 154/87 mm Hg, respect- unconfounded randomised trials involving 37000 ively. Patients who were held to the more stringent middle-aged hypertensive subjects who had a mean BP goals experienced a significant reduction in the treatment duration of 5 years. They estimated that risk of stroke (44%) and cardiac failure (56%) com- the average difference in DBP between the subjects pared with patients with the less tight goals. Dia- allocated to antihypertensive treatment and those betes-related end points were also reduced by 24% allocated to the control groups was 5–6 mm Hg. This in the tight-control group compared with the group difference was associated with reductions of 42% with less tight control, and diabetes-related deaths and 14% in the risks of stroke and coronary heart were reduced by 32%.11 disease, respectively. Among patients with nephropathy, lower mean Antihypertensive treatment also has substantial arterial pressures are associated with slower benefits in elderly hypertensive patients, many of declines in renal function.12 Lazarus et al13 showed whom have isolated systolic hypertension. In the that tight control of BP substantially reduces the risk Systolic Hypertension in the Elderly Program of a cardiovascular event in patients with renal fail- (SHEP),6 the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension),7 the Medical ure. Analysing data from 585 chronic renal failure Research Council (MRC) trial of treatment of hyper- patients, these authors found that each 1 mm Hg tension in older adults,8 and the Systolic Hyperten- increase in SBP was associated with a 1.35-times sion in Europe (Syst-Eur)9 trials, elderly hyperten- greater risk of hospitalization for cardiovascular or sive patients were randomized to active treatments cerebrovascular disease. or placebo. Active treatments were associated with Despite the universally acknowledged benefitof a reduction of 25% in the risk of coronary artery dis- BP control, overall management of hypertension is ease, and with reductions of 25–47% in the risk of poor. Data from phase 2 of the National Health and stroke. A recent review of the SHEP data showed Nutrition Examination Survey (NHANES) III show that antihypertensive treatment reduced the risks of that effective BP control is achieved in only 27% of both haemorrhagic and ischaemic stroke.10 In all hypertensive subjects.14 In the population of hyper- trials, reductions in the overall incidence of cardio- tensive adults, 32% are unaware of their condition vascular endpoints ranged from 17 to 40%.6–9 and 41% are aware but are either untreated or Antihypertensive treatment is particularly ben- uncontrolled despite treatment.14 Although these eficial among particular subgroups of the hyperten- disappointing statistics can be attributed partly to sive population, such as patients with diabetes or lack of aggressive management by physicians,15 poor nephropathy, who are at particularly high risk of patient compliance is also a major factor.16 Incon-

Journal of Human Hypertension Antihypertensive efficacy of olmesartan S Oparil S19 venient dosing regimens and adverse events are both mately 5 mm Hg when administered over a pro- known to reduce compliance with antihyperten- longed treatment period. A prolonged reduction in sive therapy.16,17 pressure of this magnitude has been associated with a 21% reduction in the risk of coronary heart dis- 3 Comparative efficacy of antihypertensive ease, and a 34% reduction in the risk of stroke. This calculation of expected risk reduction assumes that drugs the mechanism by which BP is lowered is unimport- Only a few trials have directly compared the efficacy ant. Evidence is emerging, however, that this may of different classes of . In the not be the case. Treatment of Mild Hypertension Study (TOMHS), 902 men and women with mild hypertension were Effect of inhibition of the renin- randomized to treatment with a (chlor- ␤ ␣ angiotensin system on cardiovascular thalidone), a -blocker (acebutolol), an 1-antagonist (doxazosin), a calcium antagonist ( morbidity and mortality maleate), an angiotensin-converting enzyme (ACE) Angiotensin-converting enzyme inhibitors are inhibitor (), or placebo.18 Except for a small highly beneficial for the treatment of patients at high difference between doxazosin and chlorthalidone in risk for cardiovascular events, including those with their effects on SBP (chlorthalidone was more established atherosclerosis, left-ventricular dysfunc- effective), the five drugs were of equivalent anti- tion, postmyocardial infarction, and . In hypertensive efficacy. four major outcomes trials (Cooperative North Scan- In the Department of Veteran Affairs study, 1292 dinavian Enalapril Survival Study (CONSENSUS); men with a baseline DBP between 95 mm Hg and the Survival and Ventricular Enlargement Trial 109 mm Hg were randomized to treatment with (SAVE); the Studies of Left Ventricular Dysfunction , , clonidine, diltiazem, hydrochlo- (SOLVD); Heart Outcomes Prevention Evaluation rothiazide, prazosin or placebo.19 The drugs were (HOPE)), treatment with ACE inhibitors led to sub- titrated to a DBP goal of lower than 90 mm Hg. stantial reductions in cardiovascular morbidity and Patients who achieved this goal entered a 1-year mortality.20–23 These benefits were realized inde- maintenance phase, during which the DBP goal was pendent of the BP status of the participants at base- lower than 95 mm Hg. A positive response was line (19–24% were hypertensive in CONSENSUS defined as achievement of both goals. The study compared with 42–48% in SAVE, SOLVD and found no significant difference in response rates HOPE). among five of the six drugs – atenolol (51% The HOPE trial is particularly persuasive because response), clonidine (50%), it included a relatively broad range of high-risk (46%), captopril (42%), and prazosin (42%).19 The patients. In this 5-year trial, 9297 patients with vas- best response was achieved in diltiazem-treated cular disease or diabetes mellitus plus one other car- patients, of whom 59% reached both goals. Diltia- diovascular risk factor (hypertension, elevated total zem was significantly more effective than captopril, cholesterol levels, low high-density lipoprotein prazosin and placebo (25%).19 cholesterol levels, cigarette smoking or micro- In the TOMHS, a study in which 20% of the sub- ) were randomized to treatment with the jects were African American, mean DBP was ACE inhibitor, (10 mg once daily), or pla- approximately 5 mm Hg lower with active treatment cebo. Patients with cardiac failure, low ejection frac- than with placebo at 48 months.18 In the Department tion, overt nephropathy or uncontrolled hyperten- of Veteran Affairs study, placebo reduced DBP by an sion were excluded. Ramipril significantly reduced average of 5 mm Hg; active treatment by 10–14 the risk of stroke, myocardial infarction, or cardio- mm Hg at 1 year.19 Monotherapy at usual drug doses vascular mortality by 32%, 20% and 26%, respect- can thus be expected to reduce DBP by approxi- ively (Table 1).23 The reduction in BP associated

Table 1 Effect of ramipril on cardiovascular events in high-risk patients

Outcome Percentage of patients in treatment group Relative 95% confidence P-value risk interval Ramipril Placebo (n = 4645) (n = 4652)

MI, stroke, or CV death 14.0 17.8 0.78 0.70; 0.86 Ͻ0.001 CV death 6.1 8.1 0.74 0.64; 0.87 Ͻ0.001 MI 9.9 12.3 0.80 0.70; 0.90 Ͻ0.001 Stroke 3.4 4.9 0.68 0.56; 0.84 Ͻ0.001 Non-CV death 4.3 4.1 1.03 0.85; 1.26 0.74 Death from any cause 10.4 12.2 0.84 0.75; 0.95 0.005

MI, myocardial infarction. CV, cardiovascular. Data from the HOPE trial (Reference 23).

Journal of Human Hypertension Antihypertensive efficacy of olmesartan S Oparil S20 with ramipril in this trial was reported as minimal thelium-dependent relaxation, media-to-lumen ratio (mean reductions of 3 mm Hg in both SBP and DBP), in arteries, and stiffness of resistance arteries in although HOPE was not a BP trial and BPs were not hypertensive patients, while atenolol causes a monitored with the frequency and rigour customary reduction in BP, but fails to improve endothelial for trials of antihypertensive treatment. The mean function.37,38 , , and have BPs of the two treatment groups were very similar also been shown to reduce left ventricular mass in at the end of the trial (139/76 mm Hg in the ramipril patients with hypertension.39–41 group vs 139/77 mm Hg in the placebo group). These Angiotensin II receptor blockers may also be effec- findings suggest that inhibition of the renin-angio- tive in controlling other forms of vascular disease. tensin system provides cardiovascular benefitin has been seen to attenuate the damag- addition to that achieved from lowering BP. ing effects of oxidized low-density lipoprotein on One of the major drawbacks of ACE inhibitors is endothelial cells in vitro,42 while in vivo treatment their side-effect profile. ACE inhibitor-induced with the newest A II receptor blocker, olmesartan, cough, which affected up to 18% of patients in some results in a 40% reduction in atherosclerotic lesion studies,24 is associated with reduced compliance area in the aorta of Watanabe heritable hyperlipid- and, therefore, reduced antihypertensive efficacy.16 aemic (WHHL) rabbits compared with the vehicle- Minimizing adverse effects of treatment is parti- treated control (Figure 2). This effect was achieved cularly important in hypertensive patients, who may without any change in plasma cholesterol concen- be asymptomatic prior to treatment.16 An alternative tration.43 Both olmesartan and losartan prevent method of inhibiting the renin-angiotensin system is plaque formation in a cholesterol-fed primate model 43,44 by blocking the angiotensin II type 1 (AT1) receptor of atherosclerosis. Olmesartan has also shown using an angiotensin II (A II) receptor blocker. In promise for the treatment of . contrast to ACE inhibitors, A II receptor blockers In the Zucker diabetic fatty rat, an animal model of have a side-effect profile that is similar to that of type-2 diabetes, treatment with olmesartan resulted placebo.25 These drugs may therefore be an attract- in dose-dependent reductions in urinary protein ive alternative to ACE inhibitors for hypertensive that were independent of changes in BP patients. and plasma glucose concentration.43

Angiotensin receptor blockers Do angiotensin receptor blockers differ Six A II receptor blockers (candesartan, , in efficacy? irbesartan, losartan, , and valsartan) are The first A II receptor blocker, losartan, was currently available for the treatment of hyperten- approved for clinical use in 1995. Since then, the sion. The antihypertensive efficacy of these agents US Food and Drug Administration has approved five has been reported to be similar or slightly superior more drugs of this class. Most head-to-head com- to that of ACE inhibitors26–31 and equivalent to that parative trials of the efficacy of A II receptor blockers of the , amlodipine.32–36 have been of newer agents against losartan, the orig- Available data suggest that A II receptor blockers inal A II receptor blocker.45–48 When titrated to have a highly beneficial effect on hypertension- maximal dose, both irbesartan and candesartan have related target organ damage. It has been shown that 1 year of treatment with losartan normalizes endo-

Figure 2 Comparison of lesion area in the thoracic and abdomi- nal aorta expressed as a percentage of normalised aortic surface Figure 3 Comparison of antihypertensive efficacy of olmesartan, area in Watanabe heritable hyperlipidaemic rabbits after treat- losartan, valsartan and irbesartan. Least-squares mean change ment for 32 weeks with vehicle, olmesartan (1 mg/kg), pravastatin from baseline in sitting cuff diastolic blood pressure (DBP) after (50 mg/kg), or a combination of olmesartan and pravastatin. 8 weeks of treatment with olmesartan (20 mg once daily (o.d.)), *P Ͻ 0.05 for olmesartan alone and in combination vs vehicle. losartan (50 mg o.d.), valsartan (80 mg o.d.) or irbesartan (150 mg Values within bars are plasma cholesterol concentrations (mg/dl). o.d.). *P Ͻ 0.05 vs olmesartan; †P Ͻ 0.0005 vs olmesartan. (Data (Reproduced with permission from Reference 43.) from Reference 49.)

Journal of Human Hypertension Antihypertensive efficacy of olmesartan S Oparil S21

Figure 4 Comparison of antihypertensive efficacy of olmesartan, losartan, valsartan, and irbesartan assessed by ambulatory blood press- ure (BP) monitoring. Least-squares mean change from baseline in 24-h mean ambulatory diastolic BP (DBP) and systolic BP (SBP) after 8 weeks of treatment with olmesartan (20 mg o.d.), losartan (50 mg o.d.), valsartan (80 mg o.d.), or irbesartan (150 mg o.d.) in patients with essential hypertension. *P р 0.05 vs olmesartan. (Data from Reference 49.) been shown to be more effective than losartan in and 8.1 mm Hg, respectively) but was not signifi- reducing BP.46,48 In contrast, comparisons of losar- cantly different from the reduction seen with irbe- tan and valsartan have indicated that these agents sartan (11.3 mm Hg). As is characteristic of A II are roughly equivalent in terms of antihyperten- receptor blockers, all four drugs used in this study sive efficacy.45,47 were well tolerated.49 Olmesartan has yet to be approved for clinical use. The antihypertensive efficacy of the maintenance dose of this drug (20 mg once daily (o.d.)) was Conclusions recently compared with those of the maintenance Epidemiological research has shown that reducing doses of losartan (50 mg o.d.), valsartan (80 mg o.d.) BP by even a small amount can have a substantial and irbesartan (150 mg o.d.) in a double-blind, paral- positive impact on cardiovascular morbidity and lel-group study.49 Patients with mild-to-moderate = mortality. While all classes of antihypertensive essential hypertension (n 578) were randomized drugs are effective in lowering BP, their effective- to treatment for 8 weeks. Both cuff and ambulatory ness in clinical practice may be limited by unfavour- BP monitoring were used to assess the patients’ able adverse-effect profiles and patient non-com- response. pliance. Furthermore, there is growing evidence that After 8 weeks of treatment, the reduction in mean drugs that inhibit the renin-angiotensin system have cuff DBP (the primary efficacy variable of the study) a greater beneficial effect on cardiovascular out- was significantly greater in patients treated with comes than can be explained by their antihyperten- olmesartan (11.5 mm Hg) than in those who received sive effect alone. This has been widely demon- losartan, valsartan, or irbesartan (8.2 mm Hg, 7.9 strated for ACE inhibitors and may also be true for mm Hg and 9.9 mm Hg, respectively (Figure 3). The A II receptor blockers. Olmesartan combines the reduction in SBP with olmesartan was also greater advantages of vasoprotective effects independent of than that achieved with losartan, valsartan, and BP, a favourable (placebo-like) adverse-event profile, irbesartan (11.3 mm Hg vs 9.5 mm Hg, 8.4 mm Hg and antihypertensive efficacy superior to some of and 11.0 mm Hg), but the differences were not stat- the older A II receptor blockers. Outcome trials are istically significant. needed to assess the full cardiovascular benefits of The results of the 24-h ambulatory BP monitoring olmesartan treatment. after 8 weeks of treatment were similar to those obtained using cuff BP measurements (Figure 4). The reduction in mean 24-h DBP with olmesartan References (8.5 mm Hg) was significantly greater than the reductions obtained with losartan and valsartan (6.2 1 Kannel WB. Fifty years of Framingham Study contri- mm Hg and 5.6 mm Hg, respectively; P р 0.05) but butions to understanding hypertension. J Hum Hyper- was not significantly different from that seen with tens 2000; 14:83–90. = 2 Kannel WB. Blood pressure as a cardiovascular risk irbesartan (7.4 mm Hg; P 0.0867). A similar pattern factor: prevention and treatment. JAMA 1996; 275: was evident in the 24-h ambulatory SBP data. Olme- 1571–1576. sartan reduced mean 24-h SBP by 12.5 mm Hg after 3 MacMahon S et al. Blood pressure, stroke, and cor- 8 weeks. This decrease was significantly greater than onary heart disease. Part 1, Prolonged differences in that achieved by losartan and valsartan (9.0 mm Hg blood pressure: prospective observational studies cor-

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Journal of Human Hypertension