Are there meaningful differences in blood pressure control with current antihypertensive agents?

AJH

2002; 15:14S–21S

Are There Meaningful Differences in Blood Pressure Control With Current Antihypertensive Agents? Suzanne Oparil Hypertension is a major risk factor for cardiovascular disease, and small reductions in blood pressure can have a substantial impact on outcome. Effective control of hypertension per se is important in reducing morbidity and mortality, but there is growing evidence that the class of drug used in treatment may affect patient outcomes. The Heart Outcomes Prevention Evaluation (HOPE) trial provided evidence that angiotensin converting enzyme inhibitors (ACEI), agents that inhibit the renin-angiotensin system (RAS), are particularly effective in reducing the risk of cardiovascular events in a wide range of patients. These beneficial effects of ACEI may be independent of antihypertensive effect. Angiotensin receptor blockers (ARB) are the newest class of antihypertensive drug to enter clinical

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ypertension is one of the most prevalent modifiable risk factors for cardiovascular disease.1,2 The risks of stroke, myocardial infarction, cardiac failure, coronary heart disease, peripheral artery disease, cardiovascular mortality, and all-cause mortality are all substantially elevated in individuals with hypertension.1–5 Compared with normotensive individuals, men with hypertension have risk ratios for cardiac failure and stroke of 4.0 and 3.8, respectively (Fig. 1). The increase in risk is of similar magnitude in women.3 Hypertension also doubles the risk of coronary disease (risk ratios are 2.0 and 2.2 in men and women, respectively), and this remains the most common and lethal consequence of hypertension.3 The relationship between blood pressure (BP) and cardiovascular disease is positive and continuous2 and has been established independently for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure.1,4,6 –11 For example, in the Multiple Risk Factor Intervention Trial (MRFIT), baseline BP measurements were obtained from approximately 348,000 middle-aged men.11 Data collected during 11.6 years of follow-up showed that both SBP and DBP were related to the incidence of death from coronary heart disease.11 For both Received October 17, 2001. Accepted October 18, 2001. From the Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama. Address correspondence and reprint requests to Suzanne Oparil, MD, 0895-7061/02/$22.00 PII S0895-7061(01)02272-5

use. By blocking the angiotensin II type 1 receptor, ARB achieve more complete blockade of the RAS than ACEI. The ARB also have a substantially better side effect profile than ACEI, and early evidence suggests that ARB are beneficial in combating hypertension-related target organ damage. These favorable characteristics suggest that ARB should be considered as first-line treatment for hypertension. Based on comparative antihypertensive efficacy, olmesartan, a new ARB, may represent a significant addition to this drug class. Am J Hypertens 2002;15: 14S–21S © 2002 American Journal of Hypertension, Ltd. Key Words: Hypertension, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers.

indices, the relationship was statistically significant and was continuous, graded, strong, and independent of other major risk factors.11

Control of Hypertension Reduces Morbidity and Mortality Reduction of elevated BP is highly effective for reducing the risk of cardiovascular morbidity and mortality.12–15 In the Hypertension Optimal Treatment (HOT) trial, patients with an initial DBP between 100 and 115 mm Hg were randomized to one of three DBP target groups (90, 85, and 80 mm Hg).16 Achieved differences in mean DBP and SBP between the highest and lowest target groups were 4.1 and 4.0 mm Hg, respectively. These relatively small differences were associated with a 28% reduction in the risk of myocardial infarction.16 Similarly strong data have come from observational studies. In a combined analysis of nine such studies involving 420,000 individuals, MacMahon et al concluded that a prolonged difference in DBP of 5 mm Hg was associated with a 34% difference in the risk of stroke and a 21% difference in the risk of coronary heart disease.10 These studies thus show that relatively minor Professor of Medicine, Physiology, and Biophysics, Director, Vascular Biology and Hypertensive Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, 1034 Zeigler Research Building, 933 South 19th Street, Birmingham, Alabama 35294; e-mail: soparil@ uab.edu © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.

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FIG. 1. Risk of cardiovascular events by hypertensive status. Data from the Framingham Study involving 36 years of follow-up in subjects aged 35 to 64 years show the magnitude of the risk posed by hypertension. The “coronary disease” classification includes myocardial infarction, angina pectoris, sudden death, other coronary deaths, and coronary insufficiency syndrome. (Reprinted with permission from Kannel WB: Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA 1996;275:1571–1576. Copyrighted 1996, American Medical Association.3)

decreases in DBP are associated with substantial reductions in morbidity. Among elderly hypertensive patients, many of whom have isolated systolic hypertension, randomized controlled trials have shown that antihypertensive treatment is associated with reductions of 17% to 40% in the overall risk of cardiovascular disease.12–15 Table 1 shows the reductions in risk of specific cardiovascular end points achieved in the Systolic Hypertension in the Elderly Program (SHEP), the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension), the Medical Research Council (MRC) trial of treatment of hypertension in older adults, and the Systolic Hypertension in Europe (Syst-Eur) trial.12–15 MacMahon and Rodgers combined the results of three of these trials (SHEP, STOP-Hypertension, and MRC) with those from the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial and those published by Coope and Warrender.17–19 In this population of 12,483 elderly patients, a difference in SBP of 12 to 14 mm Hg was associated with a 34% reduction

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in the risk of stroke, a 19% reduction in the risk of coronary heart disease, and a 23% reduction in the risk of vascular death.19 Thus, as with diastolic pressure, relatively modest reductions in systolic pressure are associated with substantial reductions in risk. Control of hypertension is particularly beneficial among populations at very high risk for cardiovascular events, such as individuals with diabetes or nephropathy. In the HOT study, diabetic patients assigned to the 90 mm Hg DBP target group were twice as likely to experience a major cardiovascular event and three times as likely to die of cardiovascular disease than were those assigned to the 80 mm Hg group.16 In the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes were assigned to one of two BP target groups; the “tight control” group achieved a mean pressure of 144/82 mm Hg, and the “less tight control” group a mean of 154/87 mm Hg.20 Tight control was associated with a 56% reduction in the risk of cardiac failure, a 44% reduction in the risk of stroke, and a 32% reduction in the risk of diabetes-related death.20 Interestingly, in this diabetic population, tight control of BP appeared to be more effective in reducing the risk of cardiovascular disease than tight control of blood glucose.20 –22 Patients with renal disease also benefit from effective control of BP. In a summary of data from nine trials involving patients with nephropathy, Bakris et al found a significant negative relationship between mean arterial pressure and glomerular filtration rate.21 Studying patients with chronic renal disease, Lazarus et al found that each 1 mm Hg increase in SBP was associated with a 1.35 times greater risk of hospitalization for cardiovascular or cerebrovascular disease.9 These data show that effective control of BP is extremely beneficial in a wide range of patient populations.

Current Status of Hypertension Management There have been substantial improvements in the levels of awareness, treatment, and control of hypertension in the

Table 1. Reduction of cardiovascular risk associated with antihypertensive therapy in elderly hypertensive patients Risk Reduction (%)

Trial

Between-Group Difference in Mean SBP (mm Hg)*

Stroke

CHD/CAD

HF

LVF

All CVD

SHEP (1991) STOP (1991) MRC (1992) Syst-Eur (1997)

11.1 19.5 Data not published 10.1

36 47 25 42

25 NS NS NS

⫺ † ⫺ NS

54 ⫺ ⫺ ⫺

32 40 17 31

SBP ⫽ systolic blood pressure; CHD ⫽ coronary heart disease; CAD ⫽ coronary artery disease; HF ⫽ heart failure; LVF ⫽ left ventricular failure; CVD ⫽ cardiovascular disease; SHEP ⫽ Systolic Hypertension in the Elderly Program; STOP ⫽ Swedish Trial in Old Patients; NS ⫽ not statistically significant; MRC ⫽ Medical Research Council; Syst-Eur ⫽ Systolic Hypertension in Europe. * In all studies, active treatment was compared with placebo. † Not examined statistically. ⫺ Not defined as an end point.

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United States over the past four decades, but the situation is still far from optimal. Data from phase 2 of the National Health and Nutrition Examination Survey (NHANES) III show that 32% of hypertensive adults remain unaware of their condition. A further 41% are aware that they are hypertensive but are either untreated or receive treatment that is not optimal. As a result, effective control of BP is achieved in only 27% of hypertensive individuals.23 Poor management is one factor that contributes to this statistic. Berlowitz et al studied the care of 800 hypertensive men at five Department of Veteran Affairs outpatient clinics over a 2-year period. On average, patients made more than six hypertension-related visits per year; in spite of this, 40% of patients had a BP ⱖ160/90 mm Hg at the end of the study.24 On 75% of occasions on which a BP ⱖ155/90 mm Hg was recorded, no increase in medication was prescribed, nor was there an association between elevated BP at a previous visit and a subsequent decision to change the treatment regimen.24 These data show that lack of aggressive treatment may be partly responsible for low control rates. Unpleasant side effects of drugs are known to reduce patient compliance and may also contribute to poor control of BP.25 Agents that act on the renin-angiotensin system have fewer adverse effects than diuretics, ␤-blockers, or calcium antagonists26 and may be preferred for this reason. Angiotensin converting enzyme inhibitor (ACEI) induced cough remains a problem, however. This adverse effect may occur in up to 22% of patients27 and commonly causes 3% to 4% of patients in clinical trials to discontinue treatment.28 –30 In contrast to ACEI, angiotensin receptor blockers (ARB) have a side effect profile similar to that of placebo, and are not associated with an increased incidence of cough.31 Inconvenient or complex dosing regimens may also contribute to low control rates. Medications that are taken once daily are associated with better compliance than those taken twice daily, and are preferred for this reason.23 Leenen et al showed that the percentage of prescribed doses taken on schedule was significantly higher with once-daily dosing (amlodipine; 86%) than with twicedaily dosing (diltiazem; 76%). In addition, once-daily amlodipine remained effective in the face of poor compliance (defined as patients who took ⬍80% of their pills), whereas twice-daily diltiazem showed reduced efficacy.32 Optimal control of BP is thus most likely to be achieved if patients are prescribed a highly effective drug or drug combination that requires once-daily administration and is free of adverse effects.

How Do Medications Compare in Lowering Blood Pressure and Improving Outcome? The BP-lowering efficacy of the older antihypertensive drug classes appears to be comparable. The Treatment of

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Mild Hypertension Research Group compared the efficacy of acebutolol, amlodipine, chlorthalidone, doxazosin, and enalapril in patients with mild hypertension (baseline DBP, 90 to 99 mm Hg).33 Representative members of five major drug classes were thus compared. With the exception of a small difference in the ability of chlorthalidone and doxazosin to reduce SBP (⫺21.8 v ⫺16.1 mm Hg, respectively), there were no significant differences in efficacy among these agents. If risk reduction depends solely on the degree of BP control achieved, the results of the Treatment of Mild Hypertension Study would suggest that the class of antihypertensive drug used in treatment is unimportant. There is mounting evidence, however, that this assumption is wrong.34 Angiotensin converting enzyme inhibitors, in particular, appear to be beneficial in improving outcomes,34 and this is especially evident among patients at very high risk for cardiovascular events. In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), the Survival and Ventricular Enlargement Trial (SAVE), and the Studies of Left Ventricular Dysfunction (SOLVD), ACEI led to substantial reductions in cardiovascular morbidity and mortality.35–37 Patients enrolled in these trials had reduced left ventricular ejection fractions or congestive heart failure at baseline, and 19% to 44% were hypertensive.35–37 In the SAVE trial, the beneficial effects of captopril were shown to be independent of baseline BP.36 More recently, the results of the Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that the beneficial effects of ACEI extend to a wider range of patients. In this trial, patients with vascular disease or diabetes plus one other cardiovascular risk factor (hypertension, elevated total cholesterol, low levels of highdensity cholesterol, cigarette smoking, or microalbuminuria) were randomized to treatment with the ACEI, ramipril, or placebo for 5 years.38 Patients with evidence of left ventricular systolic dysfunction or cardiac failure were excluded from the trial. Approximately 47% of patients were hypertensive at baseline. Compared with placebo, ramipril reduced the risks of myocardial infarction, stroke, and cardiovascular mortality by 20%, 32%, and 26%, respectively,38 and these beneficial effects of ramipril were independent of hypertensive status at baseline. Over the course of the trial, mean BP changed from 139/79 mm Hg in both groups to 136/76 mm Hg in the ramipril group and 139/77 mm Hg in the placebo group. Although monitoring of BP was not as rigorous in the HOPE study as in a trial primarily designed to evaluate antihypertensive efficacy, the HOPE study investigators concluded that only a small fraction of the beneficial effects of ramipril could be attributed to the reduction in BP. The investigators concluded that inhibition of the renin-angiotensin system is of specific benefit in preventing cardiovascular events.

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Benefits of Specific Inhibition of the Renin-Angiotensin System The clinical benefits of ACEI are well established. However, these agents do not completely block the reninangiotensin system. Angiotensin converting enzyme cleaves bradykinin in addition to angiotensin I, and nonACE pathways of angiotensin II generation exist and may be clinically important. The use of ACEI thus results in incomplete blockade of angiotensin II generation and build-up of bradykinin.31 This latter effect may be responsible for the most frequent side effects of ACEI, cough39 and may contribute to a more serious but rare side effect, angioedema.40 Early attempts to block the renin-angiotensin system concentrated on the development of peptide angiotensin II receptor antagonists such as saralasin, and this avenue has been re-explored more recently with the development of the nonpeptide ARB. In contrast to ACEI, ARB offer almost complete inhibition of angiotensin II action via antagonism of its type 1 (AT1) receptor without potentiating bradykinin.31 The antihypertensive efficacy of ARB has been compared extensively with that of ACEI. Parallel-group studies carried out using captopril, enalapril, or lisinopril and all six of the older ARB (candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan) demonstrated antihypertensive efficacy of the ARB that was similar or slightly superior to that of the ACEI. The ARB were markedly superior to the ACEI in terms of side effects.41– 46 The ARB also compare favorably with calcium channel blockers, particularly with respect to side-effect profile.47–51

Influence of ARB on Morbidity and Mortality Few published studies are powered and designed to determine the effects of ARB treatment, without simultaneous ACEI administration, on morbidity and mortality. One such study is the Evaluation of Losartan in the Elderly Study (ELITE), in which elderly patients with New York Heart Association class II to IV heart failure were randomized to treatment with losartan or captopril. The use of other classes of cardiovascular drug was permitted. After 48 weeks there was no difference between treatment groups in terms of improvement in serum creatinine (the primary end point), but treatment with losartan was associated with a 46% reduction in the risk of all-cause mortality compared to captopril. Losartan was also better tolerated than captopril, and was associated with significantly fewer discontinuations.30 In a follow-up study (ELITE II), the difference in tolerability between these two drugs was confirmed, but the survival benefit associated with losartan treatment was not.29 Overall, losartan was as effective as captopril, which had been shown in previous studies to have survival benefit in heart failure. Recent preliminary data from the Valsartan Heart Failure Trial

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(Val-HeFT) suggest that combining an ARB with an ACEI in heart failure patients significantly reduces the combined end point of all-cause mortality and morbidity, but has no effect on all-cause mortality alone.52 In addition to these mortality data, there is widespread evidence that ARB are effective in ameliorating much of the target organ damage commonly associated with hypertension. In hypertensive type 2 diabetic patients with nephropathy, losartan was as effective as enalapril in reducing urinary albumin excretion.53 In nondiabetic patients with nephropathy and hypertension, losartan and amlodipine effected almost identical reductions in BP, but only losartan reduced proteinuria.54 The beneficial effects of ARB on renal function may thus be independent of their antihypertensive effect. There is also evidence that ARB are effective in controlling atherosclerosis. Irbesartan reduced serum levels of tumor necrosis factor-␣ receptor II, vascular cell adhesion molecule–1, and superoxide in patients with premature atherosclerosis and thus appears to retard the inflammatory component of this condition.55 Losartan also attenuated the increased expression of the endothelial receptor for oxidized low-density lipoprotein (LOX-1) that occurs in hypercholesterolemic rabbits.56 In a guinea pig model of hypercholesterolemia, losartan was superior to enalapril in reducing oxidant stress, normalizing cardiac eicosanoid release, and improving myocardial dysfunction.57 Recent evidence has shown that ARB are capable of normalizing the vascular remodeling and endothelial dysfunction characteristic of hypertension and that this effect is independent of their antihypertensive activity. Schiffrin et al randomized patients with essential hypertension to 1 year of treatment with losartan or the ␤-blocker, atenolol. The two treatments resulted in almost identical reductions in BP, but only losartan normalized endothelium-dependent relaxation of resistance arteries. Treatment with losartan also reduced the media:lumen ratio of these arteries (a measure of pathological vascular remodeling), whereas atenolol had no significant effect.58 Data from animal models suggest that olmesartan, the newest ARB, are both renoprotective and antiatherosclerotic. Olmesartan was administered at two doses to Zucker diabetic rats.59 These animals develop progressive hyperglycemia, hyperinsulinemia, hyperlipidemia, glomerulosclerosis, and proteinuria,60,61 and are widely used as a model of type 2 diabetes. Treatment with olmesartan resulted in a rapid onset, dose-dependent reduction in proteinuria that was maintained over the 19 weeks of the experiment. This beneficial effect was independent of changes in BP and blood glucose level.59 In the Watanabe heritable hyperlipidemic rabbit model of atherosclerosis, 32 weeks of treatment with olmesartan (1 mg/kg) reduced atherosclerotic lesion area by 40% compared with vehicletreated controls. There was a minimal effect of treatment on BP, and no effect on plasma cholesterol level. In contrast, pravastatin (50 mg/kg) reduced plasma cholesterol but had no effect on lesion area (Fig. 2).59 Olmesartan

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FIG. 2. Olmesartan reduces atherosclerotic plaque formation. Watanabe heritable hyperlipidemic rabbits were treated for 32 weeks with olmesartan (1 mg/kg), pravastatin (50 mg/kg), or a combination of the 2 drugs. Olmesartan had no effect on plasma cholesterol level, but was associated with a significant reduction in atherosclerotic lesion area in the aorta. Pravastatin lowered cholesterol but had no effect on lesion area. The two drugs used in combination were slightly more effective than olmesartan monotherapy. * Significant difference in lesion area, P ⬍ .05. (Reprinted from Am J Cardiol, Vol. 87, Koike H, et al: New pharmacologic aspects of CS-866, the newest angiotensin II receptor antagonist, pp 33C– 36C, Copyright 2001, with permission from Excerpta Medica Inc.59)

also reduced aortic plaque formation (64% reduction) when administered to cynomolgus monkeys fed an atherogenic diet.59 These data demonstrate that the beneficial effects of ARB extend beyond treatment of hypertension. Patients with vascular remodeling, endothelial dysfunction, atherosclerosis, diabetes, cardiac failure, cardiac hypertrophy, and nephropathy may all benefit from the unique mechanism of action of this class of drugs. The excellent side effect profile of ARB31 allows these benefits to be achieved while maximizing patients’ quality of life.

Is There a Difference in the Antihypertensive Efficacy of Angiotensin Receptor Blockers? Few studies allow direct comparison of more than two ARB. Exceptions to this are a meta-analysis of randomized controlled trials62 and a crossover study,63 both of which compared the efficacy of losartan, valsartan, irbesartan, and candesartan at low doses (50, 80, 150, and 8 mg, respectively) and after titration to double these doses. The meta-analysis revealed no differences among these drugs in their ability to reduce BP, either at the starting dose or after forced or elective titration.62 In the crossover study, valsartan and irbesartan reduced BP more effectively than losartan when the drugs were used at their starting doses, but the difference was not maintained after elective dose titration.63 In a recent randomized, double-blind, parallel-group study, the efficacy of the newest ARB (olmesartan, 20 mg) was compared with that of losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg) in patients with mild-tomoderate essential hypertension.64 After 8 weeks of treat-

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FIG. 3. Least squares mean change from baseline in sitting cuff diastolic blood pressure (DBP) after 8 weeks of treatment with olmesartan, losartan, valsartan, or irbesartan. *P ⬍ .05 v olmesartan; †P ⬍ .005 v olmesartan; ‡P ⬍ .0005 v olmesartan.

ment, the reduction in trough sitting cuff DBP (the primary efficacy variable) was significantly greater in the olmesartan group (11.5 mm Hg) than in the groups treated with losartan (8.2 mm Hg), valsartan (7.9 mm Hg), or irbesartan (9.9 mm Hg; Fig. 3). Substantial reductions in SBP were also achieved (olmesartan, 11.3 mm Hg; losartan, 9.5 mm Hg; valsartan, 8.4 mm Hg; irbesartan, 11.0 mm Hg), although the differences among groups were not significant. Olmesartan was significantly more effective than losartan and valsartan in reducing 24-h mean DBP and SBP (Fig. 4), and was more effective than all three comparator drugs in reducing SBP in the last 4 h of the interdosing period. The results of ambulatory BP monitoring carried out in this study thus reinforced the data obtained using cuff measurements. There were no significant differences among treatment groups in the overall incidence of clinical or laboratory adverse events. The efficacy data from this study thus show that olmesartan may have some advantages over older ARB in the treatment of essential hypertension.

FIG. 4. Least squares mean change from baseline in 24-h mean ambulatory DBP and systolic blood pressure (SBP) after 8 weeks of treatment with olmesartan (20 mg once daily), losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg) in patients with essential hypertension. * P ⱕ .05 compared with olmesartan. BP ⫽ blood pressure; other abbreviation as in Fig. 3.

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Summary and Conclusions Hypertension is widely recognized as a major risk factor for cardiovascular events, and even small reductions in BP have a substantial impact on patient outcome. Apparently minor differences in the antihypertensive efficacy of drugs may therefore have a significant effect on morbidity. It is also becoming evident that the mechanism by which elevated BP is controlled may have an effect on patient outcome. In particular, ACEI appear to reduce the risk of cardiovascular events, and this effect may be independent of the antihypertensive actions of these drugs. The benefits of ACEI are tempered by their side effects, however, which may reduce patient compliance. The recent introduction of ARB allows physicians to inhibit the reninangiotensin system using a class of drugs with a placebolike side effect profile. The antihypertensive efficacy of ARB is similar to that of ACEI, and early evidence suggests that ARB are effective in controlling hypertensionassociated target organ disease. The newest ARB, olmesartan, is not only a more effective antihypertensive agent than some of the early drugs of this class but has also been shown to protect against target organ disease. In the absence of large-scale outcomes trials comparing different ARB, differentiation among these agents should be made on the basis of their antihypertensive efficacy.

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