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Canadian Cardiovascular Congress 2006

Vancouver, British Columbia / October 21-25, 2006

Hypertension is the primary modifiable risk factor for stroke, accounting for more than 60% of events. An increase in the risk of stroke is observed even at relatively normal blood pressure (BP) levels, such as 130/80 mm Hg, observed Dr. Ross Feldman, Chair, Clinical Pharmacology, Department of Medicine, University of Western Ontario, London. BP reduction has had a more significant impact on cerebrovascular end points than on coronary events in the majority of trials, he added. The decrease in stroke incidence is proportional to the decrease in BP achieved. A drop in systolic BP of 10 mm Hg reduces the relative risk of stroke by 35% to 40%.

Risk Reduction with RAS Inhibition

It is not definitively known whether any antihypertensive agent or class has a more distinct cerebroprotective effect than others, or whether their benefits might include effects other than BP lowering. Current Canadian Hypertension Society treatment guidelines indicate “the first criterion is BP lowering,” Dr. Feldman stressed.

Still, there is evidence that renin-angiotensin system (RAS) blockade—which has been associated with anti-atherosclerotic, antiproliferative and anti-arrhythmic effects, nephroprotection, and prevention of new-onset diabetes—leads to important reductions in the risk of stroke as well as the risk of coronary events. In his keynote address, Dr. Salim Yusuf, Professor of Medicine and Director, Population Health Research Institute, McMaster University, Hamilton, Ontario, noted, “This is one of the most important treatments that we have in cardiovascular [CV] disease… surely BP [reduction] plays a role but there are effects beyond it.” He remarked that the protective impact of RAS inhibition is exemplified by the results of the LIFE (Losartan Intervention for Endpoint Reduction) study (Dahlöf et al. Lancet 2002; 359(9311):995-1003). “In a head-on comparison of atenolol plus other agents to losartan plus other agents, the BP difference was 1 mm Hg. [There was] a 30% reduction in events in favour of losartan and most of this was a difference in stroke,” Dr. Yusuf reported.

Efficacy in Stroke Prevention

During a debate, Drs. Feldman and Jacques de Champlain, Professor of Physiology and Medicine, Université de Montréal, Quebec, presented the documented and putative advantages of ACE inhibitors and angiotensin receptor blockers (ARBs), respectively, for the reduction of primary stroke.

While all antihypertensive agents are effective, if a choice is appropriate, “allow me that fine differences between classes support the use of ACE inhibitors,” Dr. Feldman submitted. The weight of evidence for ACE inhibition is stronger in secondary than in primary prevention of stroke, he acknowledged, stressing that current guidelines for post-stroke risk reduction recommend the combination of ACE inhibitor and diuretic.

In PROGRESS (Perindopril Protection Against Recurrent Stroke Study), this regimen reduced stroke risk by 43% as compared with placebo (Lancet 2001;358(9287):1033-41). A lack of effect on stroke incidence by ACE inhibitor monotherapy was likely a fault of study design, he stated. He noted the baseline risk in the single-agent treatment arm was higher than that in the combination treatment arm and as such, the two treatment groups did not experience a similar degree of protection. In the HOPE (Heart Outcomes Prevention Study), treatment with an ACE inhibitor reduced stroke by 32% compared with placebo despite BP reduction of just under 4/3 mm Hg (Bosch et al. BMJ 2002;324(7339):699-702). “Even within a relatively normotensive population, the ACE inhibitor was clearly effective,” Dr. Feldman remarked.

In primary prevention, any form of angiotensin blockade is clinically advantageous but ARBs have achieved better results than ACE inhibitors, Dr. de Champlain countered. “My point of view [in the debate] is that probably ARBs have an additional effect beyond lowering BP, because in certain studies, it has been shown that for an equal control of BP with a comparator, there was a greater reduction in the incidence of stroke.”

Over the five years of the LIFE study, for example, “the BP [in the two treatment arms] was identical, but... the losartan-treated group had a 25% lower incidence of stroke than the atenolol-treated group,” Dr. de Champlain cited. In study patients with isolated systolic hypertension, the reduction in stroke was 40%. The results of LIFE were primarily achieved through a decrease in atherothrombotic ischemic stroke, which accounts for the largest proportion of cerebrovascular events, he added. A recent report by the Jikei Heart Study Group offers support for the beneficial impact of ARBs in high-risk individuals, Dr. de Champlain indicated. This analysis of 3000 Japanese patients with hypertension, ischemic heart disease and/or heart failure compared the CV event reduction achieved with valsartan and other antihypertensive therapies (primarily calcium channel blockade). “The BP was absolutely identical in the two treatment groups and… there was a 40% [greater] prevention of stroke in those receiving the valsartan vs. the conventional therapy,” he observed. “After three years, the study was stopped, because of the results showing a better protection with the ARB.”

On the other hand, Dr. de Champlain noted, according to a recent meta-analysis of five large trials including patients with hypertension, those treated with ACE inhibition vs. diuretics and beta blockers experienced 9% more strokes (Verdecchia et al. Hypertension 2005;46(2):386-92). “This was not [statistically] significant but you can see there is a trend,” he commented.

According to Dr. Yusuf, an additional important question is whether ARB treatment during a stroke might alleviate the severity and consequences of the event. In a small trial evaluating this possibility, neurological status was better and recurrent stroke mortality lower in patients receiving candesartan rather than other antihypertensive agents (Schrader et al. Stroke 2003;34(7):1699-703).

Proposed Mechanisms for ARB Benefit

Several mechanisms may contribute to a reduction in stroke risk by ARBs, Dr. de Champlain suggested. Given the likelihood that the RAS is involved in the development of stroke, he noted, “Why would ARBs be better? Because they block more specifically the mechanisms whereby stroke will happen. Probably they are better blockers of the angiotensin molecule, which by acting on the AT1 receptor will cause a vasoconstriction in the vessel but in addition, will be pro-oxidant or pro-inflammatory [and lead to] cerebrovascular insufficiency.”

AF Reduction May Be Key

A second possibility is that the reduction in stroke with ARB treatment is mediated by prevention of atrial fibrillation (AF), the most important cause of stroke in elderly individuals. LIFE study investigators reported that losartan treatment reduced stroke by 45% in patients with AF (P=0.039) and left ventricular hypertrophy, and reduced new-onset AF by 33% (P<0.001) (Wachtell et al. J Am Coll Cardiol 2005;45(5):705-11, 712-9). In a substudy, they determined that one stroke could be prevented if nine patients with AF were treated with losartan for five years; the numbers needed to treat were 24 in patients with isolated systolic hypertension, 25 in those with known cerebrovascular disease and 54 for the overall LIFE study cohort (Kizer at al. Hypertension 2005;45(1):46-52).

A similar reduction in AF has been observed in other studies of ARB therapy, the most recent of which was VALUE (Valsartan Antihypertensive Long-term Use Evaluation), Dr. de Champlain reported. The effect may be related to a reduction in left ventricular and left atrial size, he stated, although the exact mechanism is unknown.

A link between angiotensin blockade and AF reduction is of great interest, Dr. Yusuf agreed. “As you know, there is a fair amount of data in people with heart failure and left ventricular dysfunction indicating that ACE inhibitors and ARBs prevent AF.

Examination of the effects and mechanisms of ARBs in stroke prevention continues. One recent animal study showed that cerebral infarction volume was approximately halved in those receiving systemic pretreatment with candesartan vs. placebo. “These are mechanisms you cannot predict from just BP lowering,” Dr. Yusuf stated.

RAS blockade for CV and cerebrovascular protection constitutes an active field of study, he concluded, and within the next few years such trials as ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global) should yield additional important insights into the capacity of ACE inhibitors and ARBs to prevent stroke and other CV end points.