Perindopril Reduces Blood Pressure but Not Cerebral Blood Flow in Patients With Recent Cerebral Ischemic Stroke
Background and Purpose The relationship between high blood pressure and the incidence of stroke is well established. Currently the effects of lowering blood pressure in patients with established cerebrovascular disease is undetermined, and there is continuing concern regarding the treatment of patients soon after a stroke event. Angiotensin-converting enzyme inhibitors maintain cerebral blood flow despite lowering blood pressure in patients with heart failure and otherwise uncomplicated hypertension. We tested the hypothesis that perindopril, an angiotensin-converting enzyme inhibitor with a gradual onset of action and a minimal first-dose hypotensive effect, lowers blood pressure without adversely affecting cerebral blood flow in patients 2 to 7 days after symptoms of cerebral infarction.
Methods Patients were randomized to receive 15 days of oral perindopril (4 mg) or placebo in a double-blind study. Blood pressure was monitored semiautomatically. Cerebral blood flow was calculated from internal carotid artery and vertebral Doppler ultrasound, supplemented by middle cerebral artery blood velocities.
Results Twenty-four patients completed the protocol; four additional patients were withdrawn for reasons unrelated to treatment. Patients on perindopril had a placebo-corrected reduction in blood pressure of 19/11 mm Hg. Blood pressure remained reduced after 2 weeks of treatment. In contrast, total cerebral blood flow was unaffected by perindopril. Neurological symptoms improved similarly in both groups.
Conclusions Perindopril was well tolerated and effectively reduced blood pressure without reducing carotid territory blood flow in patients with symptoms of recent cerebral ischemia.
Blood pressure is an established risk factor for the primary incidence of stroke. A reduction of 5 mm Hg confers a population risk reduction of stroke incidence of 30%.1 The potential benefit of antihypertensive therapy after cerebral infarction is undefined, but it is likely that treatment will be of most benefit in those patients with a higher risk of future stroke, ie, those with underlying cerebrovascular disease. A definitive trial recruiting sufficient numbers of patients to demonstrate the efficacy of antihypertensive therapy as secondary prevention has not yet been performed, but a large, randomized, multicenter, placebo-controlled study using perindopril and/or a thiazide diuretic (PROGRESS) will enroll from 6000 to 8000 patients with cerebrovascular disease and mild or moderate hypertension. It is hoped that this study will clarify the relationship between BP and the secondary incidence of stroke. Perindopril is an ACE inhibitor with a gradual onset of action and a relatively long half-life allowing once daily dosing; it is less likely to cause first-dose hypotension than other shorter-acting preparations such as captopril or enalapril.2 ACE inhibitors may be particularly suited to patients with cerebrovascular disease because they do not adversely affect cerebral blood flow.3
Lowering BP within hours of acute stroke can lead to dramatic neurological deterioration, probably by reducing cerebral perfusion to the infarct zone.4 5 The Intravenous Nimodipine West European Stroke Trial (INWEST) evaluated the effects of the calcium channel blocker nimodipine in patients within 72 hours of acute stroke. Increased mortality was associated with a reduction in BP in actively treated patients.6 A BP-lowering effect was also correlated with a poor clinical outcome in a phase II study of the ion channel blocker lifarizine.7 In the first few days after acute stroke, cerebral autoregulation and local cerebral perfusion are deranged, and therefore any change in systemic BP may cause a critical reduction in local cerebral perfusion. In most cases these changes normalize within 3 to 4 days, and cerebral autoregulation is restored.8 Immediate BPs are often elevated in patients with acute stroke and resolve within several days of hospital admission.9 It would therefore seem prudent to defer consideration of patients for antihypertensive therapy for at least 72 hours after hospital admission. After this time, it is still unclear which patients should receive antihypertensive therapy and exactly when this should be instituted.
Subjects and Methods
A double-blind, randomized trial design compared 15 days of oral perindopril (4 mg/d) with placebo in patients admitted to our stroke unit with a clinical and CT diagnosis of cerebral ischemia. Patients with normal CT scans were included in the study since CT is insensitive to early signs of infarction and to small subcortical infarcts. All patients had mild to moderate hypertension (170 to 250/95 to 120 mm Hg) as defined by two BP readings within the inclusion range at least 6 hours apart within the 24 hours before entry into the study. BPs at the time of drug administration were therefore not identical to screening BP readings because the latter were recorded in the hour immediately before drug dosing. The clinical and CT stroke classifications, incidence of previously diagnosed or treated hypertension or cerebrovascular disease, and carotid stenosis on Doppler ultrasound are documented in Table 1⇓. Demographics are summarized in Table 2⇓.
Patients with severe carotid disease were excluded from the study for technical and safety reasons. Patients admitted on prescribed antihypertensive therapy had treatment discontinued according to local treatment guidelines for at least 48 hours before entry into the study. Ethical approval was obtained from the West ethical committee, and patients gave written informed consent to participate. Clinical and neurological assessments according to the NIH Stroke Scale10 were made before study entry and repeated on day 15. BP was measured semiautomatically with the use of Marquette oscillometric equipment (Marquette Electronics) before treatment and then hourly up to 10 hours after first dosing. BP measurement was repeated at 24 hours and at 2 weeks. Total cerebral blood flow was calculated from bilateral internal carotid artery Doppler ultrasound (Acuson 128, 5-MHz probe) coupled to a wall tracker device (Wall Track System, Neurodata). Arterial flow was calculated as (π×diameter2×mean velocity)/4. Details of Doppler methods used have been published previously.11 MCA velocity and resistance index were measured by transcranial Doppler (Nicolet EME TC2000, 2-MHz probe). Doppler recordings were undertaken before treatment and at 2, 4, 8, and 24 hours and repeated at 2 weeks. An additional recording of MCA velocity was made at 6 hours. Routine safety biochemistry and hematology data were collected at entry and at the conclusion of the study period. Plasma renin activity, angiotensin II activity, ACE activity, and drug plasma levels were assessed at 0, 4, 6, 8, 12, and 24 hours and at 2 weeks.
Plasma renin activity was measured by radioimmunoassay of generated angiotensin I (detection limit, 0.54 ng/mL per hour; coefficient of variation, 6.7%). Angiotensin II was determined according to Morton and Webb12 (detection limit, 2.0 pg/mL; coefficient of variation, 6.4%). ACE was assayed by incubation of plasma/serum with the ACE substrate analogue hippuryl-histidyl-leucine. The hippuric acid produced was extracted and then quantified with the use of high-performance liquid chromatography. When this assay is used, the limit of quantification is 0.05 mmol/L, and the limit of detection is 0.01 mmol/L.
Perindopril levels were assessed by the direct determination of ACE inhibitor in plasma by radioenzymatic assay with a modification of the method of Reydel-Bax et al13 and liquid chromatography-assisted assay for ACE in serum. The active metabolite perindoprilat is measured with a calibration range of 0.16 to 20 ng/mL. The limit of quantification is 0.16 ng/mL, and the limit of detection is 0.1 ng/mL.
Results were analyzed by repeated measures ANOVA and ANCOVA with the use of Statistica for Windows software (Statsoft, version 51994). With a sample size of 24 patients, we expected to detect a difference in cerebral blood flow of 16% with 80% power.
Tolerance and Safety
A total of 28 patients were recruited to the study with 24 completing the protocol. Patients were aged between 52 and 89 years. Four patients failed to complete the protocol. One patient was withdrawn after an adverse event that was not believed to be related to drug action. This event consisted of transient left arm paresthesia while the patient was undergoing carotid Doppler imaging of the right internal carotid artery 9 hours after perindopril dosing; symptoms lasted 5 minutes and did not recur. Another patient in the perindopril group was withdrawn after only one dose when his renal function was found to be mildly impaired before drug treatment. Two patients receiving placebo did not complete the study: one was lost to follow-up after transfer to an outlying hospital, and another had inadequately documented data to allow analysis. All withdrawn patients were followed up and were well at the conclusion of the study.
Perindopril was therefore well tolerated with no serious adverse events. Biochemistry and hematology results were unremarkable. Mean NIH scores in placebo and treatment groups improved in a clinically and statistically similar manner but with no difference between the two groups (Table 2⇑).
Systolic, diastolic, and mean BPs were significantly reduced in the perindopril-treated patients from 2 to 24 hours after perindopril (P<.004) and remained reduced after 2 weeks of treatment (perindopril group: 168±17/91±9 mm Hg at baseline to 150±21/79±14 mm Hg at 4 hours; placebo group: 172±26/92±14 mm Hg at baseline to 173±23/91±13 mm Hg at 4 hours; ie, a placebo-corrected reduction of 18/11 mm Hg). There was no associated change in heart rate in either group. Despite the reduction in BP, there was no reduction in total internal carotid artery flow or MCA velocity, even at the time of peak drug effect (Figure⇓). Internal carotid artery flow was increased at 8 hours in the perindopril-treated patients (P<.004). Neither common nor external carotid artery flow was significantly different between treatment and placebo groups. Determinations of velocity and blood vessel diameter in common, internal, and external carotid vessels similarly showed no difference between perindopril and placebo groups. In addition, there was no difference in the MCA resistance index (a measure of artery tone and distensibility). Renin activity and angiotensin II levels were not significantly different between perindopril and placebo groups, but ACE was inhibited by perindopril (P<.001). The AUC 0-24 for perindoprilat was 135 h·ng/mL (data not shown).
Perindopril was well tolerated in patients when administered after an acute ischemic stroke. The study was not designed to demonstrate any long-term effect on neurological outcome, but the results are reassuring since no patient suffered a drug-associated neurological deterioration.
ACE inhibitors are thought to lower BP without adversely affecting total cerebral blood flow. The role of angiotensin in the physiological control of the cerebral circulation has not been adequately defined. The configuration of the ACE gene may be important in the generation of accelerated atherosclerosis in the coronary and cerebral circulations, although there is conflicting evidence that ACE genotype is relevant in the development of cerebrovascular disease. Angiotensin II receptors regulate cerebral blood flow in rats. Large cerebral arteries containing angiotensin II receptors ameliorate increases in blood flow in response to a rise in BP.14 Treatment of hypertensive animals with ACE inhibitors resets cerebral autoregulation at a lower level, but this effect may be shared with other antihypertensive agents. In hypertensive humans without a history of stroke, captopril increases cerebral blood flow, measured by a SPECT scanning radionuclide 133Xe technique, with an inverse correlation between reduction in BP and mean cerebral blood flow.15
Two single-dose studies in healthy volunteers16 17 assessing blood flow with carotid and transcranial Doppler after ACE inhibitor administration demonstrated results similar to those in our study, with BP effectively lowered and bilateral common carotid artery flow increased. MCA flow velocity was unchanged, but there was an increase in cerebral vascular resistance index, suggesting vasoconstriction in the cerebral arterioles.16
Hypertensive stroke patients have only been assessed in two uncontrolled studies (each recruiting 12 patients). Both studies used SPECT scanning and a 133Xe inhalation technique. In one study the drug effectively lowered BP and increased cerebral blood flow to both hemispheres,17 while in the other study a fall in BP was not associated with a significant blood flow effect.18
Doppler data support the hypothesis that perindopril does not adversely affect cerebral blood flow or alter cerebral hemodynamics in a clinically significant way. The results, however, cannot be considered relevant to all patients with severe carotid disease. It is conceivable that the presence of hemodynamically significant carotid lesions may lead to a reduction in cerebral perfusion distal to a site of stenosis after the lowering of systemic BP. This may be particularly relevant in the hours and days immediately after acute stroke, when cerebral autoregulation is deranged and consequently perfusion is directly dependent on systemic BP levels. We did not consider it ethical to treat patients before 48 hours of onset of stroke symptoms since there is good trial evidence that lowering BP at this time results in adverse outcome.6 7 Further research is required to assess whether these patients are indeed more prone to neurological deterioration after BP reduction before treatment guidelines can be advised. It is also possible that while total internal carotid artery flow is preserved, local ischemic areas may become increasingly compromised as a result of a reduction in BP. Other forms of brain imaging techniques such as SPECT or positron emission tomography scanning may provide further information on the effects of BP-lowering treatment on regional perfusion, particularly in the area surrounding the cerebral infarct.
Our data suggest that starting perindopril treatment within 2 and 7 days of the onset of cerebral ischemia can successfully and safely lower BP without adversely affecting total cerebral blood flow in patients without severe carotid stenosis.
Selected Abbreviations and Acronyms
|MCA||=||middle cerebral artery|
|NIH||=||National Institutes of Health|
|SPECT||=||single-photon emission computed tomography|
This study was supported by the Institut de Reserches Internationales, Servier. We are grateful to Iain Sim for his assistance in conducting the Doppler ultrasonography.
- Received September 20, 1996.
- Revision received December 6, 1996.
- Accepted December 9, 1996.
- Copyright © 1997 by American Heart Association
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