European Heart Journal Supplements (2004) 6 (Supplement H), H37 H42 Preventing the cardiovascular complications of hypertension Peter Trenkwalder* Department of Internal Medicine, Starnberg Hospital, Ludwig Maximilian University Munich, Starnberg, Germany KEYWORDS AT 1 -receptor blockers; Candesartan; Cardiovascular events; End-organ protection; LIFE; SCOPE; VALUE AT 1 -receptor blockers reduce blood pressure and also show other beneficial effects on target organs. Meta-analyses and studies such as the CATCH Study with candesartan show that AT 1 -receptor blockers are as effective as, or more effective than, other antihypertensive agents in reversing left-ventricular hypertrophy, while nephroprotective effects have been demonstrated in a number of clinical endpoint studies. Similarly, neuroprotective effects have been shown in laboratory and clinical studies, including the ACCESS Study with candesartan. The LIFE Study with losartan and the SCOPE Study with candesartan have investigated the impact of AT 1 -receptor blockade on cardiovascular complications in hypertension. LIFE showed that AT 1 -receptor blockade significantly reduced the risk of cardiovascular death, stroke or myocardial infarction, compared with b-blockers, while SCOPE showed a significant reduction in non-fatal stroke in candesartan-treated patients, compared with control treatment. An analysis in patients from SCOPE who did not receive open-label, add-on antihypertensive therapy after randomization showed a significant 32% reduction in major cardiovascular events with candesartan. The recently reported VALUE study found no difference in overall cardiac disease between valsartanbased and amlodipine-based therapy, but demonstrated the importance of bloodpressure control in high-risk individuals, with some cause-specific endpoints favouring amlodipine-based therapy. New-onset diabetes was less frequent with AT 1 -receptor blockade than control therapy in all of the three major intervention trials with AT 1 -receptor blockers in hypertension. 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. Introduction An ideal antihypertensive therapy should achieve three aims. First, it should normalize raised blood pressure; second, it should prevent complications of hypertension; and, third, it should achieve these aims without compromising the patient s quality of life. It is increasingly accepted that AT 1 -receptor blockers fulfil these aims: they produce dose-dependent blood-pressure reductions that are sustained for at least 24 hours (48 hours in the case of candesartan) 1 ; they show * Correspondence: Prof.Dr. Peter Trenkwalder, MD. Klinikum Starnberg, Osswaldstr. 1 D-82319 Starnberg, Germany. Tel.: +49-8151-182240; fax: +49-8151-182243. E-mail address: Peter.Trenkwalder@klinikum-starnberg.de (P. Trenkwalder). placebo-like tolerability across their full dosing range 1, and are metabolically neutral 2 ; and evidence from an increasing number of studies shows that they have beneficial effects on target organs such as the heart, kidney and brain, and reduce mortality and morbidity in hypertensive patients 3 9. Cardioprotective effects of AT 1 -receptor blockers Hypertension and other cardiovascular risk factors are key initiating events in the cardiovascular continuum, leading to the development of atherosclerosis and coronary artery disease (CAD), and subsequently to myocardial infarction and progressive deterioration in cardiac function (Fig. 1) 10. The development of left- 0169-5002/$ see front matter 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
H38 P. Trenkwalder Before After Fig. 1. The cardiovascular continuum. Adapted from Dzau and Braunwald 1991 10. ventricular hypertrophy (LVH) is a critical event in this continuum, since LVH is associated with a significantly increased risk of cardiovascular disease and stroke. Data from the Framingham study, for example, show that LVH increases the risk of heart failure approximately seven-fold, and those of stroke or death from CAD approximately six-fold 11. Antihypertensive therapy can produce regression of LVH, but the extent of this regression varies markedly between different classes of agents. A recent meta-analysis, incorporating data from 80 trials with a total of more than 4000 patients, showed that the greatest reductions in left-ventricular mass are achieved with AT 1 -receptor blockers (mean decrease 13%; 95% confidence interval [CI]: 8 18%), followed by calcium antagonists (11%; 95% CI: 9 13%), angiotensin-converting-enzyme (ACE) inhibitors (10%; 95% CI: 8 12%), diuretics (8%; 95% CI: 5 10%) and b-blockers (6%; 95% CI: 3 8%) 12.AT 1 -receptor blockers, ACE inhibitors and calcium antagonists were found to be significantly (P<0.05) more effective in reducing LVH than b-blockers. These differences have also been demonstrated in comparative studies. In one such study, 114 hypertensive patients (mean diastolic blood pressure 95 115 mmhg) were randomized to receive candesartan 16 mg once daily, or hydrochlorothiazide 25 mg once daily, for 1 year 13. Candesartan significantly (P<0.003) reduced left-ventricular mass, compared with baseline values, whereas no significant change was seen in hydrochlorothiazide-treated patients (Fig. 2). The reduction in ventricular mass in candesartan-treated patients was associated with significant improvements in diastolic function. Both treatments maintained mean diastolic blood pressure below 90 mmhg, suggesting that the effect of candesartan on LVH was independent of changes in blood pressure. The Candesartan Assessment in the Treatment of Cardiac Hypertrophy (CATCH) Study compared candesartan 8 16 mg and enalapril 10 20 mg in 239 hypertensive patients with LVH (echocardiographic left-ventricular mass index [LVMI] >120 g/m 2 in men or >100 g/m 2 in women) 7. Treatment was continued for 48 weeks, and LVMI was measured by two-dimensionally guided M-mode echocardiography at baseline and at 24 and 48 weeks. Both candesartan and enalapril significantly (P<0.001) reduced systolic and diastolic blood pressure, 16 mg CC n=82 25 mg HCT n=32 Fig. 2. Change in left ventricular mass in 114 hypertensive patients treated with candesartan cilexetil (CC) 16 mg or hydrochlorothiazide (HCT) 25 mg, for 1 year 13.*P<0.003 vs. baseline. compared with baseline, and there was no significant difference between the blood-pressure reductions in the two groups. The proportion of patients in whom blood-pressure control (defined as blood pressure below 140/90 mmhg) was achieved was 60.4% in the candesartan group and 60.0% in the enalapril group. Both treatments produced significant reductions in LVMI, compared with baseline: the mean decrease in LVMI was 15.0±22.6(SD) g/m 2 (10.9±15.5%) with candesartan and 13.2±23.4 g/m 2 (8.4±17.4%) with enalapril. The difference between the reductions achieved with the two treatments was not statistically significant (mean 2.0 g/m 2 candesartan minus enalapril; 95% CI: 8.3 to +4.2). The proportion of patients showing regression of LVH at 24 weeks was 30% in the candesartan group, compared with 25% in the enalapril group; the corresponding figures at 48 weeks were 36% and 30%, respectively. This study shows, therefore, that AT 1 -receptor blockade with candesartan is at least as effective as ACE inhibition with enalapril in reducing blood pressure and left-ventricular mass in hypertensive patients with LVH. Nephroprotective effects of AT 1 -receptor blockers Early studies with ACE inhibitors had shown that blockade of the renin angiotensin system has nephroprotective effects in diabetic patients 14,15, raising the possibility that similar benefits might be obtained with AT 1 -receptor blockers. Preliminary evidence to support such effects came from studies using surrogate endpoints such as microalbuminuria. In one such study, 161 hypertensive patients (sitting diastolic blood pressure 90 100 mmhg) with stable type-2 diabetes were treated with candesartan 8 16 mg once daily or placebo for 12 weeks 16. Candesartan treatment resulted in a significant reduction in urinary albumin excretion in patients with microalbuminuria, whereas urinary albumin excretion increased in placebo-treated patients (Fig. 3). The difference between the two treatments was statistically significant (P = 0.03). Subsequently, several large randomized clinical endpoint trials have confirmed the nephroprotective effects of AT 1 -receptor blockers, showing that these agents significantly reduce
Preventing the cardiovascular complications of hypertension H39 Fig. 3. Effect of treatment for 12 weeks with candesartan 8 16 mg or placebo in hypertensive patients with type-2 diabetes and microalbuminuria 16. mortality and morbidity associated with hypertensive renal disease, particularly in diabetic patients 4 6.Inthe Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study, for example, treatment with losartan was associated with significant reductions in the risk of doubling of serum creatinine and of developing end-stage renal failure 5. In the Irbesartan Diabetic Nephropathy Trial (IDNT), AT 1 -receptor blockade reduced the incidence of the primary endpoint (a composite of doubling of serum creatinine, development of end-stage renal disease, or death from any cause) by 20% compared with placebo (P = 0.02) and by 23% compared with amlodipine (P = 0.006) 4. Similarly, in the Irbesartan in patients with type-2 diabetes and Microalbuminuria (IRMA 2) Study, treatment with an AT 1 -receptor blocker resulted in a significant delay in the onset of diabetic nephropathy, compared with placebo. These nephroprotective effects were independent of changes in blood pressure. Neuroprotective effects of AT 1 -receptor blockers An increasing volume of animal and clinical data shows that AT 1 -receptor blockers may offer neuroprotective effects. In a study in stroke-prone spontaneously hypertensive rats, for example, treatment with candesartan, at doses of both 10 mg/kg (a dose producing bloodpressure reduction) and 0.1 mg/kg (which does not affect blood pressure), significantly reduced the incidence of stroke, compared with that in control animals 17. The clinical significance of such effects was investigated in the ACCESS (evaluation of Acute Candesartan Cilexetil therapy in Stroke Survivors) Study 8, which was designed to assess the safety of mild blood-pressure reduction in the early treatment of stroke, and to provide an estimate of the number of patients required for a larger efficacy and outcome study. The trial aimed to recruit 500 patients who had experienced a stroke approximately 30 hours before randomization. Patients were randomized to receive placebo or candesartan at an initial dose of 4 mg, increasing to 8 mg or 16 mg if systolic Fig. 4. Cumulative event rate (mortality and vascular events) in the ACCESS Study 8. Reproduced from Schrader et al. 2003 8 with permission of Lippincott, Williams & Wilkins. blood pressure exceeded 160 mmhg or diastolic blood pressure exceeded 100 mmhg; the aim of treatment was to achieve a 10 15% reduction in blood pressure within 24 hours. A 24-hour blood-pressure profile was obtained on day 7. If the mean daytime blood pressure at this time exceeded 135/85 mmhg, patients in the candesartan group had the dose increased or a further antihypertensive drug added, while patients originally assigned to placebo were treated with candesartan at doses titrated to achieve a clinic blood pressure below 140/90 mmhg. The primary endpoint included both death and disability, measured as the Barthel Index 18 of functional status 3 months after the 7-day placebo-treatment period. Secondary endpoints included cardiovascular and cerebrovascular complications. Blood pressures in the two treatment groups were similar at the onset of the study, during the 7-day placebo-controlled period, and throughout the subsequent 12 months of follow-up. Of the 166 patients originally randomized to placebo, 164 required candesartan treatment because of a hypertensive 24-hour blood-pressure profile on day 7, and continued on this treatment for the remainder of the study. There were no significant differences in Barthel Index between the two groups at 3 or 12 months. However, the cumulative incidence of 12-month mortality and vascular endpoints was significantly reduced in the candesartan group, compared with the placebo group (Fig. 4). Cumulative 12-month mortality was 2.9% in the candesartan group, compared with 7.2% in the placebo group, and the corresponding vascular event rates were 9.8% and 18.7%, respectively (odds ratio 0.475; 95% CI: 0.252 0.895, P = 0.0261). As a result of this difference in event rates between the two groups, the trial was stopped prematurely when 342 patients had been randomized. Prevention of diabetes mellitus in hypertension and heart failure Recent large controlled studies have shown that AT 1 -receptor blockers significantly reduce the risk of developing diabetes mellitus. In hypertensive patients, the Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study, the Study of Cognition and Prognosis in the Elderly (SCOPE) with candesartan, and
H40 P. Trenkwalder the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) Study showed reductions of 25%, 20% and 23%, respectively 3,9,19. Similarly, in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme, treatment with candesartan reduced the incidence of new-onset diabetes in patients with heart failure by 22% 20. Reduction of cardiovascular morbidity and mortality in hypertension Three large trials, the LIFE Study with losartan 3, the SCOPE study with candesartan 9, and most recently the VALUE study with valsartan 19 have investigated the impact of antihypertensive therapy with AT 1 -receptor blockers on cardiovascular mortality and morbidity. The LIFE Study involved 9193 hypertensive patients (aged 55 80 years) with LVH, who received losartan 50 100 mg or atenolol 50 100 mg, for a mean of 4.8 years. Hydrochlorothiazide, 12.5 25 mg, and other antihypertensive agents (other than ACE inhibitors, AT 1 -receptor blockers or b-blockers) could be added if required. Compared with atenolol, treatment with losartan was associated with a significant decrease in the incidence of cardiovascular death, stroke or acute myocardial infarction from 27.9 per 1000 patient-years to 23.8 per 1000 patient-years (relative risk 0.87, 95% CI: 0.77 0.98, P = 0.021) 3.AT 1 -receptor blockade also produced a significantly (P<0.0001) greater reduction in LVH, assessed by electrocardiographic criteria. In the subgroup of patients with diabetes at baseline (n = 1195), losartan reduced the incidence of cardiovascular death, stroke or myocardial infarction by 24% (P = 0.031), compared with atenolol, and there were also significant reductions in cardiovascular mortality (37% reduction, P = 0.028) and all-cause mortality (39% reduction, P = 0.002) 21. The SCOPE Study involved 4937 elderly patients (aged 70 89 years) with treated or untreated hypertension (systolic blood pressure 160 179 mmhg, diastolic blood pressure 90 99 mmhg, or both) and a Mini Mental State Examination (MMSE) score of at least 24 9. Previous antihypertensive medication was standardized to hydrochlorothiazide, 12.5 mg once daily, which was maintained throughout the study. Patients were originally randomized to receive candesartan, 8 16 mg, or placebo. However, for ethical reasons 84% of patients in the placebo group received other antihypertensive medication on an open-label basis. Thus, the placebo group should actually be considered an active control group. The mean duration of follow-up was 3.7 years. During the course of the study, 25% of patients in the candesartan group received candesartan alone, 26% received candesartan plus low-dose hydrochlorothiazide (given already at baseline), and 49% received candesartan plus open-label add-on therapy. The corresponding figures in the control group were 16%, 18% and 66%, respectively. Mean blood pressure decreased from 166.0/90.3 mmhg to 145.2/79.9 mmhg Fig. 5. Incidence of total and non-fatal stroke in the SCOPE Study 9. in the candesartan group, and from 166.5/90.4 mmhg to 148.5/81.6 mmhg in the control group. The mean difference in blood-pressure reductions achieved in the two groups was 3.2/1.6 mmhg (P<0.001 for both groups) in favour of the candesartan group. The incidence of the primary endpoint (a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) was reduced by 10.9% (95% CI: 6.0% to +25.1%, P = 0.19) in the candesartan group, compared with the control group. The incidence of total and non-fatal stroke was reduced by 24% (P = 0.056) and 28% (P = 0.04), respectively, in candesartan-treated patients compared with the control group (Fig. 5). Thus, in the SCOPE Study, a relatively modest difference in blood pressure between the candesartan and control groups was associated with a significant reduction in nonfatal stroke, and a trend towards a reduction in major cardiovascular events. A recent post hoc analysis from the SCOPE Study has investigated the incidence of clinical events in the subset of patients in each group who did not receive add-on antihypertensive therapy (n = 2098) 22. In these patients, candesartan significantly reduced the incidence of a first major cardiovascular event by 32.1% (P = 0.013), compared with the control group (Fig. 6). Overall mortality was also significantly reduced, by 27% (P = 0.018), in the candesartan group. The mean difference in blood pressure between the candesartan Fig. 6. Incidence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke in patients in the SCOPE Study who were not receiving add-on open-label antihypertensive therapy. Reproduced from Lithell et al. 2004 22 with permission of Lippincott, Williams & Wilkins.
Preventing the cardiovascular complications of hypertension H41 and control groups in this subset of patients was 4.6/2.6 mmhg. A further analysis has investigated the effect of candesartan in patients with isolated systolic hypertension (n = 1518) 23. In these patients, candesartan was associated with a significant decrease of 42.5% (P = 0.049) in the risk of fatal or non-fatal stroke, compared with the control group. The mean difference in blood pressure in these groups was approximately 2/1 mmhg. The SCOPE and LIFE Studies, together with the IDNT and RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) 5 studies in diabetic patients were subjected to meta-analysis by the Blood Pressure Lowering Treatment Trialists Collaboration 24. This analysis showed that, compared with control antihypertensive therapies, AT 1 -receptor blockers reduced the risk of major cardiovascular events by approximately 10%, and that of stroke or heart failure by approximately 15 20%. The VALUE study, however, did not find any difference in its primary endpoint, a composite of cardiac mortality and morbidity, between valsartan-based therapy and amlodipine-based therapy 19. A total of 15,245 hypertensive patients (mean age 67 years) with a high risk of cardiovascular disease were randomized to valsartan 80 160 mg or amlodipine 5 10 mg once daily, for a mean follow-up of 4.2 years. Hydrochlorothiazide, and subsequently other antihypertensive agents, could be added in both groups as necessary. Although the incidence of the primary endpoint was similar in the two groups, myocardial infarctions were significantly less frequent in the amlodipine group, and there was also a trend for less stroke. This appeared to be linked to a greater reduction in blood pressure in the amlodipine group, especially during the first part of the study, and thus highlights the importance of strict blood-pressure control in high-risk individuals. The incidence of heart failure tended to be lower with valsartan. Conclusions There is now good evidence that in addition to reducing blood pressure AT 1 -receptor blockers exert protective effects on target organs such as the heart, kidney and brain. The SCOPE and LIFE studies have shown that AT 1 -receptor blockade can reduce the incidence of cardiovascular complications of hypertension, compared with control therapies. The VALUE study, however, did not find a benefit of valsartan-based therapy compared with amlodipine-based therapy, and the study reinforces the need for strict blood-pressure control in high-risk individuals. 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