Antihypertensive therapy for preventing recurrence in survivors of stroke and transient ischemic attack patients requires much caution. Cutting the right balance between benefit and harm calls for the classical individual evidence based considerations. Current understanding to guide practices is briefly reviewed as stroke emerges as huge challenge with increasing longevity and chronic diseases.

1. Evidence base for secondary prevention – Antihypertensive
therapy in cerebrovascular disease

2. Review Article
Evidence base for secondary prevention e
Antihypertensive therapy in cerebrovascular
disease
Abha Pandit
Asst Prof, Department of Medicine, Index Medical College Hospital & Research Centre, Indore, MP, India
a r t i c l e i n f o
Article history:
Received 11 January 2015
Accepted 3 March 2015
Available online xxx
Keywords:
Stroke
Secondary prevention of stroke
Antihypertensive therapy
Angiotensin receptor blockers
a b s t r a c t
Antihypertensive therapy for preventing recurrence in survivors of stroke and transient
ischemic attack patients requires much caution. Cutting the right balance between benefit
and harm calls for the classical individual evidence based considerations. Current under-
standing to guide practices is briefly reviewed as stroke emerges as huge challenge with
increasing longevity and chronic diseases.
Copyright © 2015, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
High blood pressure is the strongest risk factor for stroke and
half the cases are consequent to hypertension.1
Both diag-
nostic and isolated systolic hypertension are important pre-
dictors of primary or recurrent stroke and their reduction
would clearly reduce risk of stroke.2
Stroke survivors generally carry burden of continued
medications, which calls for judicious selection of drugs in a
management plan.3
Few studies have examined the value of
blood pressure control after occurrence of TIA or stroke in
prospective randomized fashion.4
This is crucial as 8 to 15
percent of surviving cases experience recurrence within a
year.5
Such second events often carry grave prognosis.6
Pa-
tients suffering stroke or TIA episodes also have increased risk
of other cardiovascular events.7
Cardiovascular event is a
composite end point inclusive of nonfatal and fatal vascular
events. Antihypertensive treatment appears to reduce recur-
rence of stroke.8
All cause of mortality in such patients does
not decline despite reduced cardiovascular events.9
2. The dilemma of antihypertensive therapy
post-stroke
Blood pressure lowering therapy in survivors of cerebro-
vascular event involves a dilemma, whether that might
worsen cerebral perfusion, if auto-regulation remains chron-
ically damaged. There may also be severe carotid artery ste-
nosis. There is no consensus over the target blood pressure
levels for secondary stroke prevention.10
Excessive night
reduction of blood pressure is understood to evoke ischemic
events.11
Auto-regulation of cerebral circulation suffers
E-mail address: drabhaindore@gmail.com.
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e3
http://dx.doi.org/10.1016/j.apme.2015.03.001
0976-0016/Copyright © 2015, Indraprastha Medical Corporation Ltd. All rights reserved.
Please cite this article in press as: Pandit A, Evidence base for secondary prevention e Antihypertensive therapy in cerebro-
vascular disease, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.03.001

3. dysfunction in stroke survivors and cerebral perfusion there-
fore becomes dependent on the blood pressure levels.12
Long
standing hypertensive disease elevates the lower limit of
mean blood pressure for proper cerebral perfusion.13
A left
ventricular hypertrophy with longstanding hypertension ac-
companies structural/functional alteration in small coronary
vessels. Coronary circulation in such instance is subject to be
compromised by decrease in blood pressure.
In patients with carotid stenosis, narrowing of lumen
above 70% or residual lumen diameter is 2 mm or less, the
blood pressure falls distal to stenosis. Such a state, without
adequate collateral circulation results in low cerebral perfu-
sion pressure. Ischemia would be caused in border zones be-
tween vascular territories. Bilateral carotid or basilar artery
stenosis would worsen the state further.14
It was shown that
patients with previous ischemic stroke in the middle cerebral
artery territory, have an impaired cerebral perfusion, with 30%
lowered basal blood flow, and flow velocities more dependant
on blood pressure levels.15
3. Target lowering of blood pressure in
secondary prevention
Prevailing guidelines on antihypertensive therapy stress
control to <140/90 mmHg in uncomplicated hypertension. For
hypertension associated with coronary artery disease, dia-
betes or chronic kidney disease target is 130/80 mmHg. Most
clinical trials demonstrate benefit of antihypertensive treat-
ment usually with blood pressure controlled at 140/
90 mmHg.16,17
The coronary circulation is dependant on dia-
stolic blood pressure, but cerebral circulation mostly depends
on systolic blood pressure. Coronary circulation is much less
tolerant than cerebral to major reduction in diastolic BP. The
benefit of reduction in systolic blood pressure in stroke sur-
vivors was examined with reference to precise level of control.
Significant benefits occurred in patients with a baseline sys-
tolic blood pressure of atleast 160 mm Hg or between 140 and
159 mm Hg. Those with lower baseline values of systolic BP
failed to show significant benefit compared to placebo.18
4. Which antihypertensive drugs?
By focusing on individual cases managed with specific drugs,
heterogenous findings may be avoided. Outcomes of angio-
tensin II receptor antagonist were compared with those of
nitredepine in patients with history of cerebrovascular
event.19
The ARBs conferred enhanced benefit for the com-
posite endpoint of cardiovascular events. Angiotensin is
believed to aggravate risk of stroke, proportionately more than
predictable from increase in blood pressure. Similarly Angio-
tensin converting enzyme inhibitors and angiotensin re-
ceptors antagonists have protective effects against stroke
which are independent of blood pressure lowering effects.20
Activation of rennin-angiotensin-aldosterone system leads
the pathophysiology of hypertension and atherosclerotic
vascular disease. When angiotensin receptor blockers are
given, they block AT-1 receptors, while AT-2 receptors get
scope of unopposed stimulation. AT-1 block also triggers
heavy increase in angiotensin II formation, by feedback loop.
The AT-2 receptor stimulation in such cases is protective
against stroke through several mechanisms.21
Contemporary recommendations highlight choice of spe-
cific antihypertensive drugs and blood pressure targets should
be individualized on basis of multiple considerations. These
include pharmacological properties, mechanism of action,
specific patient characteristics suited to specific drug choices
(e.g. carotid stenosis, renal failure, diabetes, heart disease
etc).22
The right drugs and their right use to achieve appro-
priate target of blood pressure reduction must be contem-
plated in individualized evidence based function. Optimal
subacute and chronic treatment following stroke should be
tailored to suit needs of individual patient, with inclusion of at
least one antihypertensive agent.
Conflicts of interest
The author has none to declare.
r e f e r e n c e s
1. Abbott RDCJ, Rodriguez BL, Masaki KH, Propper JS, Ross GW,
Petrowich H. Age related changes in risk factor effects on the
incidence of thromboembolic and haemorrhagic stroke. J Clin
Endocrinol. 2003;56:479e486.
2. Lawes CM, Bennett DA, Fegin VI, Rodgers A. Blood pressure
and stroke e an overview of published reviews. Stroke.
2004;35:776e785.
3. Ostwald S, Wasserman J, Davis S. Medications, co-morbidities
and medical complications in stroke survivors- the CAReS
study. Rehabil Naurs. 2006;31:10e14.
4. Luders S. Drug therapy for the secondary prevention of stroke
in hypertensive patients. Drugs. 2007;67:955e963.
5. Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW,
Schopflocher DP. The high risk of stroke immediately after
transient ischemic attack e a population based study.
Neurology. 2004;62:2015e2020.
6. Vernino S, Brown RD, Seivar JJ, Sicks JD, Petty GW,
O’fallon WM. Case specific mortality after first cerebral
infarction e a population based study. Stroke.
2003;34:1828e1832.
7. Sacco RL, Adams R, Alber SG, Alberts MJ, Benavente O,
Furie K. Guidelines for prevention of stroke in patients with
ischemic stroke or transient ischemic attack. Stroke.
2006;37:607e617.
8. Rashid P, Leonardi-Be J, Bath P. Blood pressure reduction and
secondary prevention of stroke and other vascular events e a
systematic review. Stroke. 2003;34:2741e2748.
9. Lakhon SE, Sapko MT. Blood pressure lowering treatment for
preventing stroke reccurrence. Int Arch Med. 2009;2:30.
10. Castilla-Gyerra L, Fernandez-Moreno M, Del C, Espino-
Montoro A, Lopez-Chozas JM. Ambulatory blood pressure
monitoring in stroke survivors- do we really control our
patients? Eur J Intern Med. 2009;20:760e763.
11. Sare GM, Gray LG, Wardlaw J, Chen C, Bath PM. Efficiency of
nitric oxide in stroke trial. Blood Press Monit. 2009;20:760e763.
12. Ruland S, Aiyagari V. Cerebral autoregulation and blood
pressure lowering. Hypertension. 2007;49:977e978.
13. Kaplan NM, Rose BD. Treatment of Hypertension in patients
who have a stroke. www.aptodate.com.
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e32
Please cite this article in press as: Pandit A, Evidence base for secondary prevention e Antihypertensive therapy in cerebro-
vascular disease, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.03.001

4. 14. Kantola I, Terent A, Kataja M, Breig-Asberg E. ACE inhibition
therapy with spirapril increases nocturnal hypotensive
episodes in elderly hypertensive patients. J Hypertens.
2001;15:873e878.
15. Novak V, Hu K, Desrochers L. Cerebral flow velocities during
daily activities depend on blood pressure in patients with
chronic ischemic infarctions. Stroke. 2010;41, 66e66.
16. Zanchetti A, Grassi G, Mancia G. When should
antihypertensive drug treatment be initiated and to what
levels should systolic blood pressure be lowered- a critical
appraisal. J Hypertens. 2009;27:923e934.
17. Chrysant SG. Effectiveness of lowering blood pressure to
prevent stroke versus to prevent coronary event. Am J Cardiol.
2010;106:825e829.
18. Arima H, Chalmers J, Wood ward M. The Progress
collaborative Group- target blood pressures are safe and
effective for the prevention of recurrent stroke: the Progress
trial. J Hypertens. 2006;24:1201e1208.
19. Schrader J, Liiders S, Kulschewski A, Hammersen F, Plate K.
Morbidity and mortality after stroke- eprosartan compared
with nitredipine for secondary prevention: principal result of
a prospective randomized controlled study. Stroke.
2005;34:1218e1224.
20. Castilla-Guerra I, Fernandez-Moreno MC, Jimewez-
Hernandex MD. Blockage of the rennin angiotensin in the
secondary prevention of stroke- beneficial effects beyond
blood pressure reduction? Stroke. 2009;40:75.
21. Strauss MH, Hall A. Angiotensin receptor blockers should be
regarded as first line drugs for stroke prevention in both
primary and secondary prevention setting. Stroke.
2009;40:3161e3162.
22. Furie KL, Kasner SE, Adams RJ. Guidelines for prevention of
stroke in patients with ischemic stroke or transient ischemic
attack. Stroke. 2011;42:227e276.
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e3 3
Please cite this article in press as: Pandit A, Evidence base for secondary prevention e Antihypertensive therapy in cerebro-
vascular disease, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.03.001

5. Apollohospitals:http://www.apollohospitals.com/
Twitter:https://twitter.com/HospitalsApollo
Youtube:http://www.youtube.com/apollohospitalsindia
Facebook:http://www.facebook.com/TheApolloHospitals
Slideshare:http://www.slideshare.net/Apollo_Hospitals
Linkedin:http://www.linkedin.com/company/apollo-hospitals
Blog:Blog:http://www.letstalkhealth.in/