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14th Annual Scientific Meeting of the Quebec Hypertension Society

Montreal, Quebec / January 12-14, 2006

About one in four patients dies in the year following the initial event. Among survivors, the health burden is significant: approximately 25% recuperate with minor ongoing disability, 40% remain moderately to severely disabled and 10% require long-term institutional care.

Patients who have had a stroke are at extremely high vascular risk, noted Dr. Alain Milot, Clinical Professor of Medicine, Pavillon Saint-François-d’Assise, Université Laval, Quebec City, Quebec. Overall, the probability of a second stroke after a first event has been estimated at approximately 8% in the first year and 17% in the following five years. After a transient ischemic attack (TIA), the probability is 5% in the following 48 hours and 10% in the next three months. The stroke patient’s risk of myocardial infarction is also very high. According to one recent study of nearly 2500 stroke survivors, the 10-year risk of a further vascular event is 44% and the risk of mortality 43% (van Wijk et al. Lancet 2005;365(9477):2098-104). Stroke and TIA are also associated with the development of dementia. This substantial morbidity and mortality burden has an impact on quality of life, observed Dr. Milot. “People who have had a stroke are more disabled and require more assistance than those with heart disease, and report greater incapacity and depressive symptoms.” In addition, as is the case with other age-related diseases, demographic data point to an increase in the number of strokes in the next two decades that will likely increase the burden on the health care system.

The challenge for physicians is to decrease the projected impact of stroke through appropriate acute treatment and preventive action, reported Dr. Robert Côté, neurologist, Montreal General Hospital, and Associate Professor of Neurology and Neurosurgery, McGill University, Quebec. He reminded delegates that although effective neuroprotective agents remain elusive, among patient with acute hemorrhagic or ischemic stroke, early rehabilitation and effective prevention of medical complications (e.g., prevention of thromboembolic events with ASA and/or anticoagulants) have decreased mortality by approximately 30%. The thrombolytic agent r-tPA may be employed in selected patients within three hours of an ischemic stroke and leads to a 40% lower risk of mortality or dependency. Extremely elevated blood pressure (BP) is an absolute contraindication to thrombolysis in stroke, stated Dr. Côté.

Control of BP during the acute phase of ischemic stroke is a subject of some debate and uncertainty, he indicated. Both low (<155 mm Hg) and high systolic BP (>220 mm Hg) are associated with increased mortality. Arguments for letting BP stay on the high side include the need for adequate flow subsequent to loss of autoregulation and the possibility of resuming blood flow to the ischemic penumbra surrounding the infarct. Arguments in favour of lower BP include the risk of cerebral edema and/or hemorrhage. According to current guidelines, said Dr. Côté, “It’s better to err on the side of caution. We don’t treat BP aggressively unless the patient is a candidate for r-tPA, in which case the attempt is made to reach 185/110 mm Hg or lower.”

Control of Risk Factors in Primary Prevention

Control of hypertension to <140/90 mm Hg remains by far the most important preventive strategy against a first ischemic or hemorrhagic stroke, observed Dr. Pierre Larochelle, Professor of Pharmacology, Université de Montréal and Director, Clinical Research, Institut de recherches cliniques de Montréal. “BP reduction, independent of the type of treatment, is associated with a highly significant reduction in stroke. A reduction in systolic BP of about 10 mm Hg is associated with a [stroke] reduction of about 40% [and perhaps more in older patients],” he remarked, adding that each additional 10 mm Hg reduction in systolic BP, down to 115/75 mm Hg, reduces risk by a further 30%. Once the BP is below 140/90 mm Hg, the secondary effects of antihypertensive medications may be relevant.

Reducing the incidence and impact of ischemic stroke and TIA requires attention to modifiable risk factors, speakers here stressed. At least one recent meta-analysis has determined that lipid lowering with statins reduces primary manifestations of cerebrovascular disease by 25% to 30%, remarked Dr. Larochelle. Glycemic control in patients with diabetes may also be important: the UKPDS trial determined that each 1% decrease in glycated hemoglobin reduced stroke risk by 12%.

According to Dr. Larochelle, the most substantial data for a primary stroke prevention effect apply to diuretics, ß-blockers and dihydropyridine calcium antagonists. Although some recent studies of ACE inhibitors and angiotensin receptor blockers (ARBs) have been complicated by unequal BP control in the treatment groups, current data suggest an antihypertensive strategy based on an ARB is also effective when BP is relatively well controlled, while ACE inhibitors may be less effective in such circumstances (especially in black patients).

Emerging Secondary Prevention Strategies

The high vascular risk in patients who have already had an ischemic stroke is a strong argument for aggressive prevention of atherosclerosis and thrombosis in this population, remarked Dr. Guy Tremblay, Clinical Professor of Medicine, Université Laval, and cardiologist, CHUQ-Hôpital Saint-Sacrement. Lifestyle modifications and both antiplatelet and anticoagulant therapies are typically recommended. While lipid modification is less well established in this population than for patients with coronary disease, the subgroup of approximately 3000 post-stroke patients receiving a statin in the Heart Protection Study enjoyed the same 25% CV risk reduction as the overall study cohort, regardless of baseline LDL-C or total cholesterol levels, he noted.

BP control remains paramount in the post-stroke setting and is likely even more efficacious than in the primary care setting, stated Dr. Tremblay. It is not yet clear whether there is an optimal agent or treatment strategy with secondary benefits; in fact, there are as yet few randomized controlled trials conducted exclusively in post-stroke patients. In PROGRESS (Perindopril Protection Against Recurrent Stroke Study), patients randomized to receive treatment with both a diuretic and an ACE inhibitor had a lower incidence of vascular complications and stroke than those receiving only one agent or no intervention. “However, the combination treatment group was also the one in which the systolic and diastolic BP differences were the most significant [from baseline] and that still leaves the question: is it the molecule or the antihypertensive effect?” Dr. Tremblay commented.

MOSES Results

The MOSES (Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention) trial was the first to explore outcome results between an ARB and a calcium channel blocker in secondary stroke prevention (Stroke 2005;36:1218-26). According to the study report, there is experimental evidence that the ARB eprosartan may have cerebroprotective effects. In addition, it has a dual mechanism of action, in that it inhibits angiotensin II at AT1 receptors and limits activation of the sympathetic nervous system by blocking both presynaptic and post-synaptic receptors.

In MOSES, both agents normalized BP in 1405 high-risk patients who had suffered a stroke in the prior two years (Figure 1). However, patients receiving eprosartan had a 21% greater reduction (P=0.014) in the composite primary end point of all-cause mortality and all cerebrovascular and CV events (including recurrent events). This reduction over 2.5 years translated into an incidence of 13.3 vs. 16.7 events per 100 patient-years in favour of the ARB. Considered separately, cerebrovascular (P=0.026) and CV (P=0.061) end points both decreased by 25% among ARB-treated patients. In an analysis of first occurrence of events, eprosartan significantly reduced CV outcomes (P=0.03) while for cerebrovascular events, the difference between the arms was not significant (P=0.42). The number of deaths and functional capacity of survivors in the two treatment groups were not significantly different. Combination antihypertensive therapy was needed in about two-thirds of the study participants. About 46% of these received the study agent plus a diuretic.

MOSES offers preliminary support for the notion that the ARB eprosartan may exert an effect beyond BP reduction, noted Dr. Tremblay. Although its results cannot be described as conclusive for the class, the MOSES trial offers some important food for thought, and suggests that further, perhaps longer, investigation of the stroke-reducing potential of ARBs is warranted.

Figure 1. MOSES Primary End Point (morbidity and mortality)