Cerebrovascular accidents are one of the leading causes of morbidity and mortality worldwide. The World Health Organization (WHO) found that in 1990 stroke accounted for 4.3 million mortalities, the third most common cause of death worldwide. Projecting forward to 2020, the incidence of stroke-related death is expected to rise to 7.7 million per year.
High blood pressure is one of the most common and powerful contributing factors to stroke and hypertensive patients have a four-fold increased risk of stroke compared with the reference population. Starting at about 115mmHg systolic blood pressure, cerebrovascular risk linearly increases, doubling for every 20mmHg increment. This implies that, even within the normotensive range, the risk of stroke increases progressively with the elevation of BP. Three-quarters of all strokes occur among patients traditionally considered normotensive, mostly due to the concomitant presence of other additional cardiovascular risk factors. Clinical trials on hypertension have demonstrated that effective treatment of high blood pressure has a significant effect on the prevention of all major cardiovascular events. Several large meta-analyses have consistently shown that effective blood pressure reduction lowers the incidence of stroke by about 40%. Epidemiological surveys suggest that less effective control of blood pressure is associated with a higher incidence of stroke in different countries.
The benefits of blood pressure reduction, however, are not strictly proportional to stroke incidence. It is suggested that different classes of antihypertensive drugs may have specific properties for organ protection and cerebrovascular accident prevention. The results of a large meta-analysis, comparing newer drugs to established ones, do not find one specific class of drugs better for stroke prevention in hypertension. Prevailing opinion is that tight control of blood pressure levels can effectively reduce stroke-related morbidity and mortality and there is no proof that any pleiotropic properties of these anti-hypertensive classes provide additional stroke protection.
More recently the availability of results from large outcome studies in hypertension has generated new interest towards the possibility that other mechanisms, and particularly those related to the activity of the angiotensin II, may contribute to the pathogenesis of stroke in hypertension. Most of these studies have been conducted with anti-hypertensive agents that counteract the renin-angiotensin system (RAS), in particular ACE inhibitors and angiotensin II receptor blockers (ARBs).
Clinical Evidence of Stroke Prevention by RAS Blocking Agents
Evidence supporting the cerebrovascular protective activity of RAS blocking agents is provided by clinical studies performed with ACE inhibitors, demonstrating a significant reduction in stroke incidence. These benefits have been largely attributed to blood pressure reduction, as most clinical trials compared ACE inhibitors with placebo. Data have been derived from the results of the PROGRESS (Perindopril pROtection against REcurrent Stroke Study), which included 6,105 hypertensive patients with a history of stroke. Although the reduction in systolic blood pressure with perindopril monotherapy was around 5mmHg, compared with placebo, there was no significant reduction in the risk of recurrent stroke. In contrast, in those patients who received combination therapy with perindopril and indapamide, there was a highly significant 40% reduction in the risk of stroke and the presence of a further significant lowering of systolic blood pressure levels (around 12mmHg). In the HOPE (Heart Outcomes Prevention Evaluation) study a total of 9,297 patients at high-risk were randomly assigned 10mg/die of ramipril or matching placebo. At the end of the study, a reduction of 3-4mmHg was indeed observed in the ACE inhibitor-treated group compared with the placebo-treated group. Such a reduction is considered meaningful in high-risk individuals, leading to a significant reduction in the rates of stroke in patients treated with ramipril compared with those treated with placebo. More recently, the publication of the results of the ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm) study has highlighted that the benefits of a calcium channel blocker (CCB)-based strategy with the addition of ACE inhibitor, in the prevention of stroke over those achieved with traditional anti-hypertensive agents, based on the combination of a β-blocker and thiazide diuretic. In this study the beneficial influence of the therapeutic regimen based on newer drugs, including ACE inhibitors, had a greater blood pressure lowering effect than that observed in the group receiving atenolol plus the thiazide diuretic.
In contrast to this evidence, which may be interpreted as favourable to ACE inhibitor-based regimen, in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) the chlortalidone-based regimen lowered blood pressure more than ACE inhibitors throughout the 10-year follow-up period in highrisk hypertensive patients. It focused on the incidence of stroke, while the relative risk was non-significant comparing amlodipine with chlorthalidone.
Chlorthalidone proved superior to lisinopril, particularly in black patients, this is in agreement with multiple reports of poorer blood pressure response to ACE inhibitors in this racial group of patients. Also the results of the ANBP2 (Second Australian National Blood Pressure Study) group did not fully support the superiority of ACE inhibitors over conventional therapy with regard to stroke incidence. In fact, in this study, the incidence of stroke was roughly similar in two treatment groups alongside comparable blood pressure reductions.
The beneficial effects of ACE inhibitors on preventing stroke seen in hypertension trials seem to be largely linked to a blood pressure lowering effect (see Table 1). In particular, the studies show that with ACE inhibitors benefits in lowering stroke incidence were systematically linked to the significant blood pressure lowering effect of these drugs.
The beneficial effect of ARBs on stroke has also been observed also in the presence of comparable blood pressure reductions. This interpretation is consistently validated by several recent meta-analyses, supporting the idea that ARBs provide protective effects in terms of stroke incidence reduction beyond blood pressure control. On average, in the Blood Pressure Lowering Treatment Trialists' Collaboration meta-analysis, the risk of stroke was significantly reduced with ARB-based regimens compared with other active treatment, including β-blockers, CCBs and diuretics.
Convincing evidence that ARBs have favourable effects on the risk of stroke that go beyond blood pressure reductions can be seen in the results of a large interventional trial, the LIFE (Losartan Intervention For Endpoint reduction) study. In the presence of comparable blood pressure reductions between two treatments groups, the losartan-based regimen significantly reduced the risk of the primary composite end-point (cardiovascular death, stroke and myocardial infarction (MI)) compared with the atenolol-based regimen. In particular, losartan significantly reduced the incidence of fatal and non-fatal stroke compared with atenolol in hypertensive patients with left ventricular hypertrophy. Similar additional benefits on stroke, in the presence of comparable affects on blood pressure, were observed in the cohorts of patients with diabetes mellitus and dramatically in patients with isolated systolic hypertension, in which for the same blood pressure reduction, the risk of stroke declined by 55% in the group treated with the ARB losartan.
Further sub-studies from LIFE have demonstrated that losartan effectively reduced more than atenolol left ventricular hypertrophy and left atrial dimensions, and prevented more effectively new development of atrial fibrillation in patients in sinus rhythm or maintain sinus rhythm after an episode of atrial fibrillation. All these effects of losartan on relevant clinical markers have contributed to explain part of the beneficial effect on stroke, provided by ARB-based anti-hypertensive strategy.
The Study on Cognition and Prognosis in the Elderly (SCOPE), which recruited elderly patients with predominantly systolic hypertension, demonstrated the ability of the ARB candesartan to produce a statistically significant 28% reduction in the incidence of non-fatal stroke and a non-significant 24% reduction in total stroke compared with placebo (which was indeed mostly active treatment), after a four-year follow-up. These results, however, could be partly explained by a difference in blood pressure between the two arms (amounting in this case to 3.2/1.6mmHg in favour of candesartan).
The Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE) was aimed at comparing the long-term effects of anti-hypertensive therapy on the incidence of cardiovascular morbidity and mortality amongst patients. In the study, 15,245 high-risk hypertensive patients, with the same level of achieved blood pressure, were randomly assigned to a valsartan or amlodipine-based regimen. The primary end-point was defined as time to first cardiac event, while the secondary end point was fatal and non-fatal stroke. Unfortunately, for objective interpretation of the study, a greater blood pressure reduction was seen with amlodipine than valsartan throughout the study. This was especially true during the first six months of follow-up, during which the highest frequency of cardiovascular events, including stroke, was recorded. Fatal and non-fatal stroke occurred slightly less in the amlodipine group (3.7% of patients) than the amlodipine group (4.2%) of patients.
The Morbidity and mortality after StrokeÔÇöEprosartan vs nitrendipine for Secondary prevention (MOSES) study enrolled a total of 1,405 hypertensive patients with a history of cerebrovascular events, randomised to an anti-hypertensive regimen based on either ARB eprosartan or CCB nitrendipine 10mg. The primary end-point was a composite of mortality from all causes and the number of cardiovascular and cerebrovascular events, including all recurrent events. Despite blood pressure control being similar, the eprosartan-based regimen lowered primary end-points significantly more than the nitrendipine.
Together with the previous studies analysing stroke incidence with ARBs and other comparators, the MOSES study reinforces the hypothesis that ARBs may exert cerebrovascular protection beyond a blood pressure lowering effect. It is unclear whether this action is linked to inhibition of RAS of the specific interaction of ARBs with the angiotensin II receptor network. This might be clarified as a result of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomised Assessment Study in ACE intolerant subjects with cardiovascular Disease (ONTARGET-TRASCEND) trials. These studies look at the effect of therapy with the AT1 receptor blocker telmisartan and the ACE inhibitor ramipril, both alone and in combination, on stroke incidence in high-risk individuals.
Conclusions
Stroke is one the most devastating cardiovascular diseases, occurring in 30.9 million individuals worldwide each year, causing approximately four million deaths and many more cases of transient or permanent disability. High blood pressure is the most important, modifiable risk factor for developing cerebrovascular accidents. In addition, angiotensin II is important in the pathophysiological mechanism of stroke. Much evidence points to how selective blockade of angiotensin II at the receptor level and the related binding of angiotensin II to AT2 receptors may effectively antagonise the key mechanisms involved pathogenesis of cerebrovascular events.
In hypertensive patients, especially those with additional cardiovascular risk factors or conditions such as diabetes or target organ damage, even small decreases in blood pressure levels are associated with a large reduction in incidence of cerebrovascular events. The benefits of blood pressure reductions; however, are not strictly proportional to stroke incidence. It has been suggested that the different classes of anti-hypertensive drugs may have specific roles in organ protection and cerebrovascular accident prevention. The results of the available clinical trials document the efficacy of ARBs on stroke prevention in addition to their anti-hypertensive effect. In particular, the hypothesis of greater cerebrovascular protection by AT1 ARBs has great promise that warrants further investigation.