Comparison between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on the Risk of Stroke Recurrence and Longitudinal Progression of White Matter Lesions and Silent Brain Infarcts on MRI (CEREBRAL Study): Rationale,Design,and Methodology

Abstract

Objectives

Patients with a history of ischemic stroke are known to develop new ischemic stroke. While asymptomatic, the presence and progression of silent brain infarcts and white matter lesions on magnetic resonance imaging are associated with an increased risk of future strokes. Both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are recommended for the primary and secondary prevention of stroke, but there are no direct comparisons of angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers regarding their cerebroprotective effects, including their effect on asymptomatic cerebral lesions detected by magnetic resonance imaging.

Methods

Elderly (65 years or older) patients with essential hypertension who underwent cerebral magnetic resonance imaging and were found to have any cerebral ischemic lesions, such as cerebral infarction, silent brain infarct, or white matter lesion, were enrolled in this CEREBRAL study. Patients who agreed to participate were enrolled in the randomized controlled trial portion. Patients who did not agree to participate in the randomized controlled trial were enrolled in the cohort study portion. After two-years of angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers treatment, follow-up magnetic resonance imaging examination will be performed. The primary end-point is the composite of (1) occurrence of a fatal or nonfatal cerebrovascular event or (2) progression of cerebrovascular lesions as evaluated by magnetic resonance imaging, including white matter lesions or silent brain infarcts. After enrollment, cognitive function was evaluated, if possible, using the Mini-Mental State Examination.

Conclusions

Our study will clarify whether angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are more effective for preventing primary and recurrence of ischemic stroke, including the progression of asymptomatic cerebral lesions on magnetic resonance imaging, in elderly hypertensive patients.

Keywords

angiotensin-converting enzyme inhibitors angiotensin II receptor blockers asymptomatic cerebral lesion hypertension magnetic resonance imaging stroke recurrence

Get full access to this article

View all access options for this article.

References

Ueshima

. Explanation for the Japanese paradox: prevention of increase in coronary heart disease and reduction in stroke. J Atheroscler Thromb 2007; 14:278–86.

Staessen

Gasowski

Wang

. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000; 355:865–72.

Rashid

Leonardi-Bee

Bath

. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systemic review. Stroke 2003; 34:2741–8.

The HOPE Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145–53.

PROGRESS Collaborative Group. Randomized trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischemic attack. Lancet 2001; 358:1033–41.

Bunier

Bruner

. Angiotensin II receptor antagonists. Lancet 2000; 355:637–45.

Schrader

Lüders

Kulschewski

. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005; 36:1218–26.

Whitebread

Mele

Kamber

De Gasparo

. Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun 1989; 163:284–91.

Hollenberg

Sever

. The past, present and future of hypertension management: a potential roll for AT1-receptor antagonists. J Renin Angiotensin Aldosterone Syst 2000; 1:5–10.

10.

Häuser

Jöhren

Saavedra

. Characterization and distribution of angiotensin II receptor subtypes in the mouse brain. Eur J Pharmacol 1998; 348:101–14.

11.

Iwai

Liu

Chen

. Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor simulation. Circulation 2004; 110:843–8.

12.

Vermeer

Hollander

Van Dijk

Hofman

Koudstaal

Breteler

. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003; 34:1126–9.

13.

De Leeuw

De Groot

Achten

. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 2001; 70:9–14.

14.

Folstein

McHugh

. ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–98.

15.

Anderson

Teo

Gao

. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol 2011; 10:43–53.

16.

Van Dijk

Prins

Vrooman

Hofman

Koudstaal

Breteler

. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences. Rotterdam Scan Study. Stroke 2008; 39:2712–9.

17.

The Japanese Society of Hypertension Committee for the Guidelines for Management of Hypertension. Measurement and clinical evaluation of blood pressure. Hypertens Res 2009; 32:11–23.

18.

Fazekas

Chawiuk

Alavi

Hurtig

Zimmerman

. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR 1987; 149:351–8.

19.

Scheltens

Barkhof

Leys

. A semiquantitative rating scale for the assessment of signal hyperintensities on magnetic resonance image. J Neurol Sci 1993; 114:7–12.

20.

Kario

Pickering

Matsuo

Hoshide

Schwartz

. Shimada K. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001; 38:852–8.

21.

Prins

Van Straaten

ECW

Van Dijk

. Measuring progression of cerebral white matter lesions on MRI. Neurology 2004; 62:1533–9.

22.

Kobayashi

Okada

Koide

Bokura

Yamaguchi

. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 1997; 28:1932–9.

23.

Hata

Tanizaki

Kiyohara

. Ten year recurrence after first ever stroke in a Japanese community: the Hisayama study. J Neurol Neurosurg Psychiatry 2005; 76:368–72.