Leading opinions

Intravenous thrombolysis for acute ischaemic stroke:effective blood pressure control matters

Georgios Tsivgoulis1�, Vasilios Kotsis2, and Sotirios Giannopoulos3

In this Leading opinion we summarise the observational

evidence endorsing current guidelines that advocate effec-

tive blood pressure control before and during an rtPA infusion

and indicate that a more active blood pressure-lowering

approach immediately after intravenous thrombolysis ap-

pears to be a promising therapeutic option that should be

formerly evaluated in a randomised clinical trial setting. Acute

ischaemic stroke is a highly treatable neuroemergency and

the efficacy of the available treatment is not only related to

the speed by which it is administered but also by the effective

control of modifiable adverse outcome predictors including

elevated blood pressure levels.

Key words: blood pressure, intracranial haemorrhage,

outcome, rtPA, stroke, thrombolysis

Based on data from small pilot studies (1–3), uncontrolled pre-

treatment – and during-treatment infusion – systolic blood

pressure (SBP4185 mm Hg and 180 mm Hg, respectively) or

diastolic blood pressure levels (DBP4110 mm Hg and

105 mm Hg respectively) in acute ischaemic stroke (AIS) pa-

tients were introduced in the pivotal NINDS-rt-PA Stroke Study

(4) as contraindications for thrombolysis. Current American

Heart Association (AHA), American Stroke Association (ASA)

and European Stroke Organization guidelines endorse these

thresholds and advocate against the treatment of AIS patients

with systemic thrombolysis when blood pressure (BP) levels are

uncontrolled before or during rtPA infusion (5, 6).

However, little randomised data are available to substantiate

the choice of these specific BP cut-offs. As extreme BP eleva-

tions are common in AIS (more than 25% of the participants in

the International Stroke Trial (N 5 17 938) had SBP levels

Z180 mm Hg) (7), it may be argued that rtPA treatment can

be delayed or even denied in a substantial number of AIS

patients – especially in cases of extremely elevated BP levels

unresponsive to antihypertensive treatment – because of these

stringent BP thresholds. In addition, there are observational

data indicating that lowering BP below the recommended cut-

offs may compromise functional outcome (8, 9). These findings

raise concern that aggressive BP reduction, to achieve these

arbitrary BP targets before the initiation of thrombolysis, may

reduce viable penumbral tissue and result in expansion of the

infarction and further neurological deterioration (10, 11).

On the other hand, there is mounting evidence from large,

multicentre, nonrandomised, phase IV studies that elevated

BP levels before or during alteplase infusion may be related to

adverse outcomes including a higher risk of symptomatic

IntraCranial Hemorrhage (sICH) and a lower likelihood of

complete recanalisation and three-month favourable func-

tional outcome. Pretreatment BP protocol violations have

often been found in previous studies evaluating the safety

and efficacy of IV-rtPA in AIS outside a clinical trial setting

(Table 1) (12–20). The prevalence of these BP protocol

violations ranges from 2% in Indianapolis (13), to 10�3% in

the Registry of the Canadian Stroke Network (16), and 12�4%

in a large tertiary centre rtPA registry in Phoenix (19). The

former study documented an independent association be-

tween pretreatment BP protocol violations and increased odds

of 159% for sICH – providing nonrandomised evidence to

support the currently recommended BP eligibility criteria for

IV-rtPA in AIS. This finding was consistent with a retrospective

analysis of the European Cooperative Acute Stroke Study

(ECASS) II, which showed an independent relationship be-

tween pre-treatment SBP and haemorrhagic transformation

after rtPA therapy (21). In addition, data from the rtPA Acute

Stroke Survey (evaluating individual, prospectively collected

data from 1205 patients treated with IV-rtPA in a routine

clinical setting) showed that mean BP was an independent

predictor of all rtPA-related ICH (both symptomatic and

asymptomatic) (22). Finally, a recent retrospective analysis of

the Safe Implementation of Thrombolysis in Stroke-Interna-

tional Stroke Thrombolysis Register (SITS-ISTR) documented

a strong linear association between baseline SBP (per

10 mm Hg) and the risk of sICH, while baseline DBP was notDOI: 10.1111/j.1747-4949.2010.00570.x

Conflict of interest: None declared.

Correspondence: Georgios Tsivgoulis�, Kapodistriou 3, Nea Chili,

Alexandroupolis, Greece, 68100.

E-mail: tsivgoulisgiorg@yahoo.gr1Department of Neurology, Democritus University of Thrace, University

Hospital of Alexandroupolis, Alexandroupolis, Greece2Third Department of Medicine, Aristotle University of Thessaloniki,

Thessaloniki, Greece3Department of Neurology, University of Ioannina School of Medicine,

Ioannina, Greece

& 2011 The Authors.International Journal of Stroke & 2011 World Stroke Organization Vol 6, April 2011, 125–127 125

related to sICH (23). These results were consistent with the

findings of the Safe Implementation of Thrombolysis in Stroke

Monitoring Study (SITS-MOST) reporting that a 20 mm Hg

increment in baseline SBP was independently related to a 17%

higher likelihood of sICH (24).

Preliminary evidence underscores that elevated BP levels

before or during rtPA infusion may adversely affect recanalisa-

tion. A multicentre Transcranial Doppler study (monitoring

recanalisation for two-h following an rtPA-bolus) showed that

pretreatment SBPZ185 mm Hg was associated with strikingly

high rates of persisting occlusion and partial recanalisation

(86%), whereas a 10 mm Hg increase in baseline SBP was

independently related to a 15% lower likelihood of complete

recanalisation (25). Given experimental evidence demonstrat-

ing that increased intraluminal pressure decreases rtPA ex-

pression and release in human umbilical veins or cultured

endothelial cells (26, 27), the authors hypothesised that higher

pretreatment SBP levels may have some detrimental effect on

vessel recanalisation by hampering the endogenous capacity

for fibrinolysis. This relationship was confirmed in a recent

pooled analysis of Mechanical Embolus Removal in Cerebral

Ischemia (MERCI) and Multi MERCI trials noting that higher

SBP on presentation was associated with lower revascularisa-

tion rates (28). The investigators postulated that this observa-

tion might reflect the effects of stronger haemodynamical

forces resulting in greater impaction of the clot (and therefore

more difficult mechanical retrieval) in higher arterial levels.

Higher BP levels before, during and immediately after rtPA

infusion were related to a higher likelihood of functional

dependence at three-months following stroke onset. The Com-

bined Lysis Of Thrombus in Brain Ischemia Using Transcranial

Ultrasound and Systemic TPA (CLOTBUST) investigators

reported that elevated pre-treatment SBP levels (4150 mm

Hg) were associated with 68% lower odds of functional

independence at three-months in a cohort of patients with

middle cerebral artery occlusion treated with intravenous

thrombolysis (29). Similarly, the Mutlicenter rtPA Stroke

Survey Group detected an inverse linear relationship between

baseline mean arterial pressure and favourable three-month

functional outcome among a large series (n 5 1205) of AIS

patients treated with alteplase (30). The results of both these

registries were confirmed by the SITS-ISTR investigators ana-

lysing data, from the largest database to date, on intravenous

thrombolysis for AIS. A total of 11 080 patients were involved. In

this registry, higher SBP levels at 2–24 h following an rtPA-bolus

were strongly and linearly related to higher rates of three-month

mortality and functional dependence (23). Moreover, the

investigators documented that providing antihypertensive ther-

apy during or after thrombolysis, in patients with either a

history of hypertension or moderately elevated BP, did not seem

to affect the outcomes adversely. Conversely, withholding BP-

lowering therapy in patients with a history of hypertension was

associated with high mortality, and high functional dependence

and sICH rates (23). This important observation is in line with

the recently reported single-centre experience from Houston

showing that aggressive BP lowering before alteplase infusion

using either nicardipine or labetalol was not related to poor

functional outcomes or higher rates of sICH (31).

In conclusion, there is accruing observational evidence

endorsing current guidelines that advocate effective BP control

before and during rtPA infusion, while a more active BP-

lowering approach immediately after intravenous thromboly-

sis appears to be a promising therapeutic option that needs to

be formerly evaluated in a randomised clinical trial setting. AIS

is a highly treatable neuroemergency and the efficacy of the

available treatment is not only related to the speed by which it

is administered but also by the effective control of modifiable

adverse outcome predictors, including elevated BP levels.

References

1 Haley EC Jr, Levy DE, Brott TG et al. Urgent therapy for stroke. Part II.

Pilot study of tissue plasminogen activator administered 91–180

minutes from onset. Stroke 1992; 23:641–5.

2 Brott TG, Haley EC, Levy DE et al. Urgent therapy for stroke. Part I.

Pilot study of tissue plasminogen activator administered within 90

minutes. Stroke 1992; 23:632–40.

3 Levy DE, Brott TG, Haley EC Jr et al. Factors related to intracranial

hematoma formation in patients receiving tissue-type plasminogen

activator for acute ischemic stroke. Stroke 1994; 25:291–7.

Table 1 Prevalence of pre-treatment blood pressure (BP) protocol violations, across different studies of systemic thrombolysis outside the randomised

clinical setting

Study Patients, n Type of BP violation Rate of BP violation (n)

Cleveland (12) 70 SBP4185 mm Hg and/or DBP4110 mm Hg 7�1% (5)

Indianapolis (13) 50 SBP4185 mm Hg and/or DBP4110 mm Hg 2�0% (1)

STARS (14) 389 SBP4185 mm Hg and/or DBP4110 mm Hg 8�2% (32)

rtPA Stroke Survey (15) 189 SBP4185 mm Hg and/or DBP4110 mm Hg 3�2% (6)

RCSN (16) 366 SBP4185 mm Hg 10�1% (37)

Cleveland Clinic HS (17) 47 SBP4185 mm Hg and/or DBP4110 mm Hg 6�4% (3)

Connecticut (18) 63 SBP4185 mm Hg and/or DBP4110 mm Hg 4�7% (3)

Phoenix (19) 510 SBP4185 mm Hg and/or DBP4110 mm Hg 12�4% (63)

Helsinki (20) 985 SBP4185 mm Hg and/or DBP4110 mm Hg 4�8% (47)

Overall 2669 SBP4185 mm Hg and/or DBP4110 mm Hg 7�4% (197)�

�95% CI: 6�4–8�4%. STARS, Standard Treatment with Alteplase to Reverse Stroke; HS, Health System; RCSN, Registry of the Canadian Stroke Network.

& 2011 The Authors.International Journal of Stroke & 2011 World Stroke Organization Vol 6, April 2011, 125–127126

Leading opinions G. Tsivgoulis et al.

4 The National Institute of Neurological Disorders and Stroke rt-PA

Stroke Study Group. Tissue plasminogen activator for acute ischemic

stroke. N Engl J Med 1995; 333:1581–7.

5 Adams HP Jr, Adams RJ, Brott T et al. Guidelines for the early

management of patients with ischemic stroke: a scientific statement

from the Stroke Council of the American Stroke Association. Stroke

2003; 34:1056–83.

6 European Stroke Organisation (ESO) Executive Committee; ESO

Writing Committee. Guidelines for management of ischaemic stroke

and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25:457–507.

7 Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA, IST Collaborative

Group. Blood pressure and clinical outcomes in the International

Stroke Trial. Stroke 2002; 33:1315–20.

8 Hill MD, Buchan AM, Canadian Alteplase for Stroke Effectiveness

Study (CASES) Investigators. Thrombolysis for acute ischemic stroke:

results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ

2005; 172:1307–12.

9 Lindsberg PJ, Soinne L, Roine RO et al. Community-based thrombolytic

therapy of acute ischemic stroke in Helsinki. Stroke 2003; 34:1443–9.

10 Oliveira-Filho J, Silva SC, Trabuco CC, Pedreira BB, Sousa EU, Bacellar

A. Detrimental effect of blood pressure reduction in the first 24 hours

of acute stroke onset. Neurology 2003; 61:1047–51.

11 Castillo J, Leira R, Garcıa MM, Serena J, Blanco M, Davalos A. Blood

pressure decrease during the acute phase of ischemic stroke is associated

with brain injury and poor stroke outcome. Stroke 2004; 35:520–6.

12 Katzan IL, Furlan AJ, Lloyd LE et al. Use of tissue-type plasminogen

activator for acute ischemic stroke: the Cleveland area experience.

JAMA 2000; 283:1151–8.

13 Lopez-Yunez AM, Bruno A, Williams LS, Yilmaz E, Zurru C, Biller J.

Protocol violations in community-based rTPA stroke treatment are asso-

ciated with symptomatic intracerebral hemorrhage. Stroke 2001; 32:12–16.

14 Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA.

Intravenous tissue-type plasminogen activator for treatment of acute

stroke: the Standard Treatment with Alteplase to Reverse Stroke

(STARS) Study. JAMA 2000; 283:1145–50.

15 Tanne D, Bates VE, Verro P et al. Initial clinical experience with IV

tissue plasminogen activator for acute ischemic stroke: a multicenter

survey. The t-PA Stroke Survey Group. Neurology 1999; 53:424–7.

16 Nadeau JO, Shi S, Fang J et al. TPA use for stroke in the Registry of the

Canadian Stroke Network. Can J Neurol Sci 2005; 32:433–9.

17 Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM, Cleve-

land Clinic Health System Stroke Quality Improvement Team. Quality

improvement and tissue-type plasminogen activator for acute is-

chemic stroke: a Cleveland update. Stroke 2003; 34:799–800.

18 Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombo-

lysis for acute stroke in routine clinical practice. Arch Intern Med 2002;

162:1994–2001.

19 Tsivgoulis G, Frey JL, Flaster M et al. Pre-tissue plasminogen activator

blood pressure levels and risk of symptomatic intracerebral hemor-

rhage. Stroke 2009; 40:3631–4.

20 Meretoja A, Putaala J, Tatlisumak T et al. Off-label thrombolysis is not

associated with poor outcome in patients with stroke. Stroke 2010;

41:1450–8.

21 Larrue V, von Kummer RR, Muller A, Bluhmki E. Risk factors for severe

hemorrhagic transformation in ischemic stroke patients treated with

recombinant tissue plasminogen activator: a secondary analysis of the

European–Australasian Acute Stroke Study (ECASS II). Stroke 2001;

32:438–41.

22 Tanne D, Kasner SE, Demchuk AM et al. Markers of increased risk of

intracerebral hemorrhage after intravenous recombinant tissue plas-

minogen activator therapy for acute ischemic stroke in clinical

practice: the Multicenter rt-PA Stroke Survey. Circulation 2002;

105:1679–85.

23 Ahmed N, Wahlgren N, Brainin M et al. Relationship of blood pressure,

antihypertensive therapy, and outcome in ischemic stroke treated with

intravenous thrombolysis. Retrospective analysis from safe implemen-

tation of thrombolysis in Stroke – International Stroke Thrombolysis

Register (SITS-ISTR). Stroke 2009; 40:2442–9.

24 Wahlgren N, Ahmed N, Eriksson N et al. Multivariable analysis of

outcome predictors and adjustment of main outcome results to

baseline data profile in randomized controlled trials: Safe Implementa-

tion of Thrombolysis in Stroke-Monitoring Study (SITS-MOST).

Stroke 2008; 39:3316–22.

25 Tsivgoulis G, Saqqur M, Sharma VK et al. CLOTBUST Investigators.

Association of pretreatment blood pressure with tissue plasminogen

activator-induced arterial recanalization in acute ischemic stroke.

Stroke 2007; 38:961–6.

26 Sjogren LS, Doroudi R, Gan L, Jungersten L, Hrafnkelsdottir T, Jern S.

Elevated intraluminal pressure inhibits vascular tissue plasminogen

activator secretion and downregulates its gene expression. Hyperten-

sion 2000; 35:1002–8.

27 Ulfhammer E, Ridderstrale W, Andersson M, Karlsson L, Hrafnkels-

dottir T, Jern S. Prolonged cyclic strain impairs the fibrinolytic system

in cultured vascular endothelial cells. J Hypertens 2005; 23:1551–7.

28 Nogueira RG, Liebeskind DS, Sung G, Duckwiler G, Smith WS,

MERCI, Multi MERCI Writing Committee. Predictors of good clinical

outcomes, mortality, and successful revascularization in patients with

acute ischemic stroke undergoing thrombectomy: pooled analysis of

the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and

Multi MERCI Trials. Stroke 2009; 40:3777–83.

29 Molina CA, Alexandrov AV, Demchuk AM et al. CLOTBUST Investi-

gators. Improving the predictive accuracy of recanalization on stroke

outcome in patients treated with tissue plasminogen activator. Stroke

2004; 35:151–6.

30 Demchuk AM, Tanne D, Hill MD et al. Predictors of good outcome

after intravenous tPA for acute ischemic stroke. Neurology 2001; 57:

474–80.

31 Martin-Schild S, Hallevi H, Albright KC et al. Aggressive blood pressure-

lowering treatment before intravenous tissue plasminogen activator

therapy in acute ischemic stroke. Arch Neurol 2008; 65:1174–8.

& 2011 The Authors.International Journal of Stroke & 2011 World Stroke Organization Vol 6, April 2011, 125–127 127

G. Tsivgoulis et al. Leading opinions