Published online before print October 30, 2003, doi: 10.1161/01.STR.0000098628.60758.9C
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(Stroke. 2003;34:2590.)
© 2003 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Blood Pressure Lowering for the Secondary Prevention of Stroke: One Size Fits All?
Study Coordinating Centre, Hypertension Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium
For the secondary prevention of stroke, recent guidelines1,2 recommend the prescription of blood pressure–lowering drugs to normotensive and hypertensive patients with previous cerebrovascular complications. Two large placebo-controlled trials with double-blind design3,4 generated most of the supporting evidence. In the Post-Stroke Antihypertensive Treatment Study (PATS),3 5665 Chinese patients with a history of transient ischemic attack or minor stroke were randomized to indapamide 2.5 mg/d or matching placebo. Follow-up averaged 2 years. Indapamide decreased systolic/diastolic blood pressure by 5/2 mm Hg and stroke recurrence by 29% (P<0.001).3 The Perindopril Protection Against Recurrent Stroke Study (PROGRESS)4 included 3753 whites and 2352 Asians. Patients randomized to active treatment received perindopril 4 mg/d either alone or in combination with indapamide 2.5 mg/d. Over 4 years of follow-up, active treatment reduced blood pressure by 9/4 mm Hg and the incidence of recurrent stroke by 28% (P<0.001). In both trials, hypertensive and nonhypertensive patients benefited from treatment. The blood pressure thresholds delineating hypertension were 140/90 mm Hg in PATS and 160/90 mm Hg in PROGRESS. In the nonhypertensive subgroups, the relative risk reductions in stroke recurrence amounted to 49% (n=913) and 27% (n=3189), respectively. Neither PATS3 nor PROGRESS4 indicated the level to which blood pressure should be lowered, although goals of <130 mm Hg systolic and 85 mm Hg diastolic, corresponding to current definitions of normotension,2 seem reasonable when such targets can be safely reached without side effects.
For various reasons, the PATS3 and PROGRESS4 findings cannot be extrapolated to patients with occlusive or stenotic disease of the main arteries, which sustain blood flow to the brain. About 20% of patients with transient ischemic attack or stroke have atherosclerotic lesions of the carotid arteries.5 In the presence of carotid lesions, blood pressure falls distal to the stenosis when it narrows the lumen by 
70% or when the residual lumen diameter drops to 
2 mm.6 In the absence of sufficient collateral circulation, low cerebral perfusion pressure can cause ischemia in the watershed areas between the cerebral vessels.6 Furthermore, the collateral circulation to the brain may be impaired because of an incomplete or hypofunctional circle of Willis7 or stenosis or occlusion of either the contralateral carotid artery or the basilar artery.6 In cases of severe carotid atherosclerosis, cerebral ischemia is more likely to arise when blood pressure proximal to the stenosis is within the nonhypertensive range and when it would be indiscriminately lowered. Finally, regardless of treatment status, patients with high blood pressure have a diminished capacity to autoregulate cerebral blood flow,8 so that they are more vulnerable to the potentially harmful effects of an excessive or too rapid drop in the perfusion pressure.
With regard to the generalizability of the PATS3 and PROGRESS4 findings, the report of Rothwell et al9 raises an important clinical issue. In a quantitative overview of individual patient data,9 these researchers studied the relation between stroke risk and blood pressure in patients with a history of transient ischemic attack or minor stroke who were randomized in the European Carotid Surgery Trial (ECST),10 the North American Symptomatic Carotid Endarterectomy Trial (NASCET),11 or the United Kingdom Transient Ischemic Attack Aspirin Trial (UK-TIA).12 Of the ECST and NASCET patients, 64.6% and 38.5% had ipsilateral carotid stenosis of 50%, whereas among the UK-TIA patients, this proportion was estimated to be only 6.1%. In the UK-TIA trial, the risk of stroke doubled for each 20–mm Hg increment in systolic blood pressure, whereas in the medically treated ECST and NASCET patients, the corresponding relative risks only approximated 50% and were not significant or were just borderline significant. Furthermore, among the ECST and NASCET patients with unilateral carotid lesions, the relation between stroke and blood pressure was positive, whereas among those with bilateral lesions of 70%, lower blood pressure was even associated with a greater risk of stroke. This interaction between the degree of carotid artery stenosis and blood pressure was specific because it was not present after carotid endarterectomy and because it was not observed in relation to myocardial infarction.9
The meta-analysis of Rothwell et al9 should be interpreted within the context of its limitations. Only 508 UK-TIA patients (20.8%) underwent carotid imaging. At baseline, the UK-TIA population was younger than the ECST or NASCET participants, had fewer and more recent qualifying strokes, and included fewer patients with diabetes mellitus. To what extent these differences between trials may have affected the pooled results9 is difficult to ascertain. Furthermore, to correct for the imprecision in blood pressure measurements at baseline, Rothwell et al corrected their analysis for regression dilution bias. This procedure increases the slope of the relation between the risk of stroke and blood pressure.13 From an epidemiological point of view, it provides more accurate estimates of the true impact of blood pressure on cardiovascular outcomes. However, doctors rarely have the opportunity to repeat blood pressure measurements over several years to determine a patient’s usual blood pressure. Within the much shorter time span required for therapeutic decisions, clinicians can rely on 24-hour blood pressure monitoring to approximate a patients’ usual blood pressure.13
In the PROGRESS trial,4 treatment with perindopril alone lowered blood pressure by 5/3 mm Hg but did not affect stroke recurrence (95% confidence interval, -19 to 23), whereas in the PATS trial,3 for a similar decrease in blood pressure (5/2 mm Hg), monotherapy with indapamide reduced the incidence of stroke by 29% (95% confidence interval, 22 to 43). Despite these findings, experts4,14 recommended that for patients with a history of cerebrovascular disease, long-term treatment with perindopril should be routinely considered, wherever possible in combination with indapamide, regardless of blood pressure level, type of qualifying cerebrovascular event, or geographic region. Beyond the inconsistency between these recommendations for medical treatment and the evidence, the report by Rothwell et al9 highlights that, in terms of priority, immediate blood pressure lowering might not be advisable for the group of stroke patients who have bilateral carotid lesions with a lumen narrowing of 70%. This group may first require revascularization to render safe the treatment of hypertension.15 Moreover, in the presence of significant carotid atherosclerosis, risk factor modification, including lipid-lowering treatment, should help to halt or stabilize plaque formation.15 Antiplatelet therapy with low-dose aspirin or thienopyridines in most patients and antithrombotic therapy in selected patients with atrial fibrillation are also indicated.15 In conclusion, although progressive blood pressure lowering is key to the secondary prevention of stroke,3,4 this strategy should be part of a more holistic therapeutic approach, which also accounts for anomalies in the cerebral circulation and risk factors other than just blood pressure.
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References |
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