Journal of Human Hypertension (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 olmesartan: comparison with other angiotensin 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 renin-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 myocardial infarction, 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 Diabetes Study (UKPDS), patients with type 2 diabetes 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 antihypertensive drug. 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 diuretic (chlor- ␤ ␣ angiotensin system on cardiovascular thalidone), a -blocker (acebutolol),