REVIEW ARTICLE
Cerebroprotective effect of angiotensin 1 (AT I)
receptor antagonists?
W. Drenthen, A.A. Voors, J.L.J. Kappelie, D.J. van Veldhuisen
The results of the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study show that treatment with an angiotensin receptor blocker (ARB) in the acute phase of a stroke improves mortality and cardiovascula morbidity. In addition, direct comparative antihypertensive trials have demonstrated beneficial effects ofARBs in preventing stroke. These possible cerebroprotective effects ofARBs are supported by animal studies, demonstrating that stimulation ofthe AT2 receptor was related to a reduction in both cerebral infarct size and mortality. In the present report, we review both pathophysiological and clinical evidence for possible cerebroprotective effects of ARBs, independent of their effect on blood pressure. (NethHeartJ2005;13:142-6.) Key words: stroke, angiotensin, cerebral ischaemia, cerebrovascular circulation
ecently, the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study, designed to assess the safety of modest blood pressure (BP) reduction by candesartan cilexetil in the early stages of acute cerebral ischaemia, was stopped prematurely.' Vascular events were significantly (>50%) reduced in the group that received early treatment with candesartan cilexetil. Interestingly, these results could not be explained by candesartan-induced blood pressure lowering. The ACCESS study group concluded that early neurohumoral inhibition through angiotensin II W. Drenthen A.A. Voor DJ. van Veldhulsen Department of Cardiology, University Medical Centre Groningen
J.LJ. Kappelle
Department of Neurology, University Medical Centre, Utrecht
Correspondence to: W. Drenthen University Medical Centre Groningen, Department of Cardiology, PO Box 299, 9700 VB Groningen E-mail: [email protected]
142
(ATI) receptor blockade may explain the observed reduction in vascular events. Moreover, antihypertensive therapy in the early stage of an ischaemic stroke appeared to be safe. These results enhance the discussion about protective properties beyond blood pressure lowering effects of antihypertensive drugs, which are supposed to be mediated by the reninangiotensin-aldosterone system (RAAS). Drugs that increase plasma levels of angiotensin II, such as diuretics and angiotensin II (AT1) antagonists, all seem to prevent cerebrovascular accidents more efficiently than therapeutic modalities that lower angiotensin II levels, such as ACE inhibitors (ACEI) and 5-blockers (see below). In this report, the pathophysiology behind this assumed cerebroprotective phenomenon associated with angiotensin II (ATI) antagonists (ARBs) and diuretics will be explored, using animal studies and clinical trials. Background Despite a decrease in the fatality rates of in-hospital stroke, the age-adjusted stroke rate is still increasing.2 According to Tu et al. suboptimal prevention ofstroke might explain this observation.3 Optimisation of preventive therapy is of utmost importance in the battle against stroke. Antihypertensive medication is known to play an important role in this field. Blood pressure levels, both systolic (SBP) and diastolic (DBP), are directly and continuously related to the risk of stroke and coronary heart disease. A landmark Cox regression analysis of nine major prospective observational studies performed by MacMahon et al. (almost 420,000 individuals) indicated that prolonged differences in DBP of 5, 7.5 and 10 mmHg were associated with differences in stroke risk of at least 34, 46 and 56% respectively.4 Identical reductions in DBP reduced the risk of coronary heart disease by approximately 21, 29 and 37%. Subsequent meta-analyses demonstrated that antihypertensive therapy (predominantly diuretic and [B-blocker based) could reduce the risk ofstroke by 38 to 42% for each 5 to 6 mmHg decrease in DBP.56 These results correspond to the level ofrisk reduction found in the observation-based analyses. Netherlands Heart Journal, Volume 13, Number 4, April 2005
iC
Cerebroprotective effects of angiotensin 11 (AT 1) receptor antagonists?
The most compelling observational data investigating the influence of elevated blood pressure in stroke recurrence comes from a retrospective analysis of the United Kingdom Transient Ischaemic Attack (UKTIA) aspirin trial.7 In total 2435 patients with a history of minor stroke, TIA or amaurosis fugax were induded. A 5 mmHg reduction in usual DBP and a 10 mmHg in usual SBP were associated with 34% (SD 7%) and 28% (SD 8%) fewer strokes, respectively. In 1997 a meta-analysis was performed by the INdividual Data ANalysis of Antihypertensive intervention trials (INDANA) Project Collaboration group which revealed that treatment with antihypertensive drugs significantly reduced the risk of stroke recurrence by approximately 29%.8 However, the average decrease in blood pressure obtained is not mentioned. Friday et al. implied, based on their research results, that lowering diastolic blood pressure levels (even below 60 mmHg) is associated with a decrease in recurrent stroke risk.9 In the International Stroke Trial (IST) both high blood pressure and low blood pressure (SBP
Cerebroprotective effect of angiotensin 1 (AT I)
receptor antagonists?
W. Drenthen, A.A. Voors, J.L.J. Kappelie, D.J. van Veldhuisen
The results of the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study show that treatment with an angiotensin receptor blocker (ARB) in the acute phase of a stroke improves mortality and cardiovascula morbidity. In addition, direct comparative antihypertensive trials have demonstrated beneficial effects ofARBs in preventing stroke. These possible cerebroprotective effects ofARBs are supported by animal studies, demonstrating that stimulation ofthe AT2 receptor was related to a reduction in both cerebral infarct size and mortality. In the present report, we review both pathophysiological and clinical evidence for possible cerebroprotective effects of ARBs, independent of their effect on blood pressure. (NethHeartJ2005;13:142-6.) Key words: stroke, angiotensin, cerebral ischaemia, cerebrovascular circulation
ecently, the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study, designed to assess the safety of modest blood pressure (BP) reduction by candesartan cilexetil in the early stages of acute cerebral ischaemia, was stopped prematurely.' Vascular events were significantly (>50%) reduced in the group that received early treatment with candesartan cilexetil. Interestingly, these results could not be explained by candesartan-induced blood pressure lowering. The ACCESS study group concluded that early neurohumoral inhibition through angiotensin II W. Drenthen A.A. Voor DJ. van Veldhulsen Department of Cardiology, University Medical Centre Groningen
J.LJ. Kappelle
Department of Neurology, University Medical Centre, Utrecht
Correspondence to: W. Drenthen University Medical Centre Groningen, Department of Cardiology, PO Box 299, 9700 VB Groningen E-mail: [email protected]
142
(ATI) receptor blockade may explain the observed reduction in vascular events. Moreover, antihypertensive therapy in the early stage of an ischaemic stroke appeared to be safe. These results enhance the discussion about protective properties beyond blood pressure lowering effects of antihypertensive drugs, which are supposed to be mediated by the reninangiotensin-aldosterone system (RAAS). Drugs that increase plasma levels of angiotensin II, such as diuretics and angiotensin II (AT1) antagonists, all seem to prevent cerebrovascular accidents more efficiently than therapeutic modalities that lower angiotensin II levels, such as ACE inhibitors (ACEI) and 5-blockers (see below). In this report, the pathophysiology behind this assumed cerebroprotective phenomenon associated with angiotensin II (ATI) antagonists (ARBs) and diuretics will be explored, using animal studies and clinical trials. Background Despite a decrease in the fatality rates of in-hospital stroke, the age-adjusted stroke rate is still increasing.2 According to Tu et al. suboptimal prevention ofstroke might explain this observation.3 Optimisation of preventive therapy is of utmost importance in the battle against stroke. Antihypertensive medication is known to play an important role in this field. Blood pressure levels, both systolic (SBP) and diastolic (DBP), are directly and continuously related to the risk of stroke and coronary heart disease. A landmark Cox regression analysis of nine major prospective observational studies performed by MacMahon et al. (almost 420,000 individuals) indicated that prolonged differences in DBP of 5, 7.5 and 10 mmHg were associated with differences in stroke risk of at least 34, 46 and 56% respectively.4 Identical reductions in DBP reduced the risk of coronary heart disease by approximately 21, 29 and 37%. Subsequent meta-analyses demonstrated that antihypertensive therapy (predominantly diuretic and [B-blocker based) could reduce the risk ofstroke by 38 to 42% for each 5 to 6 mmHg decrease in DBP.56 These results correspond to the level ofrisk reduction found in the observation-based analyses. Netherlands Heart Journal, Volume 13, Number 4, April 2005
iC
Cerebroprotective effects of angiotensin 11 (AT 1) receptor antagonists?
The most compelling observational data investigating the influence of elevated blood pressure in stroke recurrence comes from a retrospective analysis of the United Kingdom Transient Ischaemic Attack (UKTIA) aspirin trial.7 In total 2435 patients with a history of minor stroke, TIA or amaurosis fugax were induded. A 5 mmHg reduction in usual DBP and a 10 mmHg in usual SBP were associated with 34% (SD 7%) and 28% (SD 8%) fewer strokes, respectively. In 1997 a meta-analysis was performed by the INdividual Data ANalysis of Antihypertensive intervention trials (INDANA) Project Collaboration group which revealed that treatment with antihypertensive drugs significantly reduced the risk of stroke recurrence by approximately 29%.8 However, the average decrease in blood pressure obtained is not mentioned. Friday et al. implied, based on their research results, that lowering diastolic blood pressure levels (even below 60 mmHg) is associated with a decrease in recurrent stroke risk.9 In the International Stroke Trial (IST) both high blood pressure and low blood pressure (SBP
