Stroke

1. IV thrombolysis in high-risk AIS
patients

2. On Behalf of Team
BOEHRINGER INGELHEIM INDIA

3.  Facts first: Alteplase & stroke thrombolysis in today’s world
 25th Anniversary of NINDS trial
 Thrombolysis in high-risk AIS patients
Overview
2
IV thrombolysis
in Cardio-
embolic stroke
3
IV thrombolysis in
AIS patient with
history of recent
MI
4
Management of
hypertension in
AIS
1
IV thrombolysis in
patients with
baseline
hyperglycemia

4.  IV alteplase is the “Standard of Care” <4.5h with 0.9mg/kgBW
 NINDS, ECASS 3, Pooled Analyses, SITS-MOST, SITS-ISTR, VISTA
 ∼11,000 have been studied in RCTs
 > 2,00,000 AIS patients thrombolysed World wide with Alteplase including
6185 patients from India so far (SITS registry data and on going)
 Recommended in
 National (ISA) & International (AHA/ASA, ESO) guidelines
 With Level IA or IB evidence grade
 Data do not support use of other thrombolytics
 Streptokinase, Urokinase
 Desmoteplase (DIAS 1-4)
Facts first: Take Home Messages
1. Home | SITS International. Available at: http://www.sitsinternational.org/. (Accessed: 7th January 2019). 2. J Emberson et al. Lancet 2014; 384: 1929–35. 3. CS Anderson et al. N Engl J Med 2016; 374:2313-2323 . 4. N Logallo et al. Lancet
Neurol. 2017 Oct;16(10):781-788. 5. G Thomalla et al. N Engl J Med 2018;379:611-22. 6.Campbell BC et al. N Engl J Med 2018;378:1573-82. 7. European Stroke Organisation (ESO). Cerebrovasc Dis 2008;25(5):457-507. 8. http://www.stroke-
india.org/downloads/stroke.pdf/accessed:7th January 2019. 9. . Powers , et al. Stroke. 2018;49:e46–e99.
*for patients coming within 4.5 hours of onset of symptoms
Alteplase is the only thrombolytic drug approved GLOBALLY for
treatment of AIS within window period of 4.5 hours
Innovator TNK(METALYSE) is currently not approved for treatment
for AIS by any regulatory authority ( US FDA,EMA,DCGI)

5. 25th year of NINDs trial
1. NINDS Study Group. N Engl J Med 195;333(24):1581-1587.

6. What is the evidence for IV thrombolysis in AIS?
– NINDS trial
NINDS-The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
Published 1995, NEJM
Trial objective To evaluate the efficacy and safety of thrombolytic therapy in AIS within 3 hours of
symptom onset
Methods • Sample size: 624
• Design: Placebo controlled RCT
• Time to treatment: 0-3 hrs of symptom onset
• Intervention: Alteplase vs Placebo
• NIHSS: Median 14, Min-1, Max- 37
Results: Efficacy Excellent outcome ( mRS 0-1): 39%
mRS 0-2: 21 %
NIHSS improvements: There was also an 11 percent absolute (55 percent relative)
increase in the number of patients with an NIHSS score of 0 or 1
in this group.
1. NINDS Study Group. N Engl J Med 195;333(24):1581-1587.

7. NINDS Trial: Efficacy
For the acute ischaemic
stroke patient, Alteplase
treatment means 33%
increased likelihood to
have minimal or no
disability at 90 days vs.
placebo
20.0
37.6
26.1
31.5
31.0
50.0
38.7
44.0
0
10
20
30
40
50
60
NIHSS (≤1) Barthel Index
(≥95)
Modified Rankin
Scale (≤1)
Glasgow
Outcome Scale
(=1)
Placebo (n=165)
Favourable outcomes at 90 days*
Patients
(%)
P=0.02
55%
relative increase
33%
relative increase
48%
relative increase
40%
relative increase
*For treatment with rt-PA administered within 3 hours after symptom onset
1. NINDS Study Group. N Engl J Med 195;333(24):1581-1587.
Alteplase (n=168)
Thrombolysis with tPA*
increases the chance of a
favourable outcome

8. NINDS trial safety
Mortality: at 3 months- 17 % in
Alteplase & 21 % Placebo
*any neurologic decline, any cerebral hemorrhage and <36 h following intravenous thrombolysis
.1. NINDS Study Group. N Engl J Med 195;333(24):1581-1587.
1

9. The World before NINDS
No approval

10. Approval < 3h
The world after NINDS (+ a few years)
No approval

11. Cases treated in India over the years
2015 2016 2017 2018 2019
Saving Lives ….
2009
1648
5100
6700
11000
Year
14600
3500
Source: BI India data on file

12. Evidence for IV thrombolysis in high risk AIS
patient profiles
2
IV thrombolysis
in Cardio-
embolic stroke
3
IV thrombolysis in
AIS patient with
history of recent
MI
4
Management of
hypertension in
AIS
1
IV thrombolysis in
patients with
baseline
hyperglycemia

13. • An acute hypertensive response occurs within 24 hrs of acute stroke.
• Up to 82% of patients presenting to the ED with acute stroke have a SBP
greater than 140mmHg
• Acute stroke impairs the autoregulation of the cerebral circulation so that
the blood flow in the ischaemic area becomes passively dependent on mean
arterial pressure.
• Pre-existing HTN, Diabetes, high serum creatinine and the Cushing’s reflex
(reactive rise in BP in response to raised intracranial pressure) – can all
exacerbate HTN.
Blood Pressure and AIS
1. Grise EM and Adeoye O. (2012) Blood Pressure Control for acute ischaemic and haemorrhagic stroke. Current Opinion in Critical Care 18 (2) 132-138
2. Leonardi-Bee J., Bath, M W., Phillips, S J., Sandercock P A. for the IST Collaborative Group (2002) Blood Pressure and Clinical Outcomes in the International Stroke Trial. Stroke (33) 1315 – 1320
3. Tikhonoff V., Zhang H., Richart T. and Staessen J. (2009) Blood Pressure as a prognostic factor after acute stroke. The Lancet Neurology (8) 938 – 948

14. • There is a U-shaped relationship between presenting BP and outcome after
ischaemic stroke1,2.
• Both low and high extremes of BP are associated with a poor outcome.
• For every 10mmHg of SBP below 150mmHg the risk of early death increased
by 3.6%, the risk of late death and dependency increased by 17.9%1
• For every 10mmHg increase in SBP above 150mmHg the risk of early death
increased by 3.8%1.
• The best outcomes were observed in patients with systolic BP 140–180
mmHg1,2
Blood Pressure and AIS
1. Leonardi-Bee J., Bath, M W., Phillips, S J., Sandercock P A. for the IST Collaborative Group (2002) Blood Pressure and Clinical Outcomes in the International Stroke Trial. Stroke (33) 1315 – 1320
2. Tikhonoff V., Zhang H., Richart T. and Staessen J. (2009) Blood Pressure as a prognostic factor after acute stroke. The Lancet Neurology (8) 938 – 948

15. International Stroke Trial (n=17398)
death death or dependency
Baseline systolic blood pressure (mmHg)
<120 120-139 140-159 160-179 180-199 200+
Dead within 14 days (%) Dead or dependent at 6 months (%)
30
25
20
15
10
5
68
66
64
62
60
58
56
54
Leonardi-Bee et al, Stroke 2002; 33: 1315
The rate of recurrent ischemic
stroke within 14 days increased by
4.2% for every
10-mm Hg increase in SBP (P=0.023)

16. • Ideal blood pressure targets in AIS remain unknown
– Observational studies variable
• No clear data on fluid choice, volume, or duration
• BP with IV alteplase:
– BP <185/110 mm Hg prior to administration
– BP <180/105 mm Hg for 24 hours after administration
– Target based on BPs in RCT of IV alteplase
Some data to suggest hemorrhage risk higher with higher BPs and BP variability, but exact
BP that increases risk unknown
• BP with Intra-arterial Therapy
– Optimal BP unknown
– RCTs largely excluded BP >185/110 mm Hg
– Reasonable to use <185/110 mm Hg as guideline
Blood Pressure and AIS
Powers WJ, et al. Stroke. 2019 Dec;50(12):e344-e418

17. Recommendations COR LOE
1. Hypotension and hypovolemia should be corrected to maintain
systemic perfusion levels necessary to support organ function. I C-EO
2. Patients who have elevated BP and are otherwise eligible for
treatment with IV alteplase should have their BP carefully lowered
so that their SBP is <185 mmHgand their diastolic BP is <110
mmHgbefore IV fibrinolytic therapy is initiated.
I B-NR
3. In patients for whom mechanical thrombectomy is planned and
who have not received IV fibrinolytic therapy, it is reasonable to
maintain BP ≤185/110 mmHgbefore the procedure. IIa B-NR
4. The usefulness of drug-induced hypertension in patients with AIS
is not well established. IIb B-R
AHA/ASA-2019 guidelines recommendations
Powers WJ, et al. Stroke. 2019 Dec;50(12):e344-e418

18. Options to Treat Arterial Hypertension in Patients With AIS Who Are Candidates for Acute Reperfusion Therapy*
Class IIb LOE C-EO
Patient otherwise eligible for acute reperfusion therapy except that BP is >185/110mmHg:
Labetalol 10–20 mg IV over 1–2 min, may repeat 1 time; or
Nicardipine 5 mg/h IV, titrate up by 2.5 mg/h every 5–15 min, maximum 15 mg/h; when desired BP reached, adjust to
maintain proper BP limits; or
Clevidipine 1–2 mg/h IV, titrate by doubling the dose every 2–5 min until desired BP reached; maximum 21mg/h
Other agents (eg, hydralazine, enalaprilat) may also be considered
*Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from acute reductions in BP such as acute
coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia.
Data derived from Jauch et al. Stroke. 2013;44:870-947
AHA/ASA-2019 guidelines recommendations (1/2)
Powers WJ, et al. Stroke. 2019 Dec;50(12):e344-e418

19. Options to Treat Arterial Hypertension in Patients With AIS Who Are Candidates for Acute Reperfusion Therapy*
Class IIb LOE C-EO
If BP is not maintained ≤185/110 mmHg,do not administeralteplase
Management of BP during and after alteplase or other acute reperfusion therapy to maintain BP ≤180/105 mmHg:
Monitor BP every 15 min for 2 h from the start of alteplase therapy, then every 30 min for 6 h, and then every hour for 16 h
If systolic BP >180–230 mmHgor diastolic BP >105–120mmHg:
Labetalol 10 mg IV followed by continuous IV infusion 2–8 mg/min;or
Nicardipine 5 mg/h IV, titrate up to desired effect by 2.5 mg/h every 5–15 min, maximum 15 mg/h;or
Clevidipine 1–2 mg/h IV, titrate by doubling the dose every 2–5 min until desired BP reached; maximum 21mg/h
If BP not controlled or diastolic BP >140 mmHg,consider IV sodium nitroprusside
*Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from acute reductions in BP such as acute
coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia.
Data derived from Jauch et al. Stroke. 2013;44:870-947
AHA/ASA-2019 guidelines recommendations(2/2)
Powers WJ, et al. Stroke. 2019 Dec;50(12):e344-e418

20. Take Home Message

21. Evidence for IV thrombolysis in high risk AIS
patient profiles
2
IV thrombolysis
in Cardio-
embolic stroke
3
IV thrombolysis in
AIS patient with
history of recent
MI
4
Management of
hypertension in
AIS
1
IV thrombolysis in
patients with
baseline
hyperglycemia

22. • Hyperglycemia
• Common in stroke patients (elevated admission blood glucose >40%, most
frequently in diabetic patients)
• Persistent hyperglycemia associated with worse outcomes
• Main risk of correction: hypoglycemia
• Hypoglycemia (<60mg/dL)
• Symptoms: autonomic and brain dysfunction
• Correct with IV push of dextrose
Blood glucose and AIS
Powers WJ, et al. Stroke. 2019 Dec;50(12):e344-e418

23. Recommendations COR LOE
1. Hypoglycemia (blood glucose <60 mg/dL) should be
treated in patients with AIS. I C-LD
2. Evidence indicates that persistent in-hospital
hyperglycemia during the first 24 hours after AIS is
associated with worse outcomes than normoglycemia,
and thus, it is reasonable to treat hyperglycemia to
achieve blood glucose levels in a range of 140 to 180
mg/dL and to closely monitor to prevent hypoglycemia.
IIa C-LD
AHA/ASA-2019 guidelines recommendations
Powers WJ, et al. Stroke. 2019 Dec;50(12):e344-e418

24.  Data on alteplase thrombolysis and non-thrombolysed patients based on
contraindications and warnings as per trial inclusion criteria
 Hyperglycaemia with BSL>180- mg/dl needs to be managed as per the latest
guidelines for stroke management
 In the data analysed, 20-25% patients were hyperglycaemic/diabetic and
presented with stroke
Virtual International Stroke Trials Archive - VISTA
Frank B, Grotta JC, Alexandrov AV, Bluhmki E, Lyden P, Meretoja A, Mishra NK, Shuaib A, Wahlgren NG, Weimar C, Lees KR. Thrombolysis in stroke despite contraindications or warnings?.
Stroke. 2013 Mar;44(3):727-33.

25. Baseline DM and Abnormal blood glucose
Frank B, Grotta JC, Alexandrov AV, Bluhmki E, Lyden P, Meretoja A, Mishra NK, Shuaib A, Wahlgren NG, Weimar C, Lees KR. Thrombolysis in stroke despite contraindications or warnings?.
Stroke. 2013 Mar;44(3):727-33.

26. Alteplase is effective and safe in AIS patients with
baseline blood glucose >180 mg/dl
Frank B, Grotta JC, Alexandrov AV, Bluhmki E, Lyden P, Meretoja A, Mishra NK, Shuaib A, Wahlgren NG, Weimar C, Lees KR. Thrombolysis in stroke despite
contraindications or warnings?. Stroke. 2013 Mar;44(3):727-33.

27. Take Home Message
 Hyperglycaemic AIS patients (baseline glucose >180mg/dL) thrombolysed
with IV alteplase had better functional outcomes with slight increase in sICH
rate.
 sICH Alteplase group 5% and control group 3.3%

28. Evidence for IV thrombolysis in high risk AIS
patient profiles
2
IV thrombolysis
in Cardio-
embolic stroke
3
IV thrombolysis in
AIS patient with
history of recent
MI
4
Management of
hypertension in
AIS
1
IV thrombolysis in
patients with
baseline
hyperglycemia

29. Stroke types and incidence
Albers et al. Chest 2004;126 (3 Suppl):438S-512S.
Thom et al. American Heart Association. Circulation 2006;113:e85-e151
Adams et al Subtypes of Acute Ischemic Stroke, Stroke 1993.
Ischaemic stroke 88%
Haemorrhagic
12%
Other
5%
Cryptogenic
30%
Cardiac
embolism
20%
Small vessel
disease
“lacunes”
25%
Atherosclerotic
cerebrovascular
disease
20%
Cardioembolic stroke represents
25-30% of all Strokes

30. Data of 13 772 patients were analyzed patients who
received IV thrombolysis for AIS from 2000 to April
2014
Cardioembolic stroke represented 30% of all strokes
Median NIHSS in
• Cardioembolic stroke – 13
• Atherothrombotic stroke- 12
• lacunar stroke-7
SITS-EAST registry
SITS-EAST- Safe Implementation of Treatments in Stroke
D. Vaclavik et al Acta Neurol Scand. 2018

31. Parameter Cardioembolic
stroke
Atherothrombotic
Stroke
Lacunar stroke other
stroke
P-value
mRS 0-1
after 3 months
1023 (35.0%) 1531 (34.5%) 640 (57.9%) 642 (50.3%) <.001
sICH (SITS-
MOST
definition)
54 (1.3%) 115 (1.9%) 5 (0.3%) 35 (1.9%) <.001
SITS-EAST registry findings
SITS-EAST- Safe Implementation of Treatments in Stroke, mRS, Modified Rankin Scale; sICH, symptomatic intracranial hemorrhage
D. Vaclavik et al Acta Neurol Scand. 2018
On comparing Atherothrombotic Stroke Vs Cardioembolic stroke:
• Atherothrombotic strokes had higher odds of sICH [OR = 1.63 (95% CI:1.07-2.47), P = .023]
• Cardioembolic stroke had better odds of
Early improvement [OR = 0.79 (95% CI: 0.72-0.86), P < .001],
Excellent clinical outcome [OR = 0.77 (95% CI: 0.67-0.87),P < .001] after IV thrombolysis

32. Take Home Message
 Cardio embolic strokes are not associated with increased mortality
 Patients are expected to have better outcomes and less sICH
 Cardioembolic strokes showed lower odds of symptomatic intracranial
hemorrhage, greater chance of early improvement, and excellent 3 months
of clinical outcome.
 The low percentage of symptomatic hemorrhage in all subtypes should
encourage physicians not to limit IVT because of fear of complications.
Vaclavik D, Vilionskis A, Jatuzis D, Karlinski MA, Gdovinova Z, Kõrv J, Tsivgoulis G, Mikulik R. Clinical outcome of cardioembolic stroke treated by intravenous thrombolysis. Acta Neurologica
Scandinavica. 2018 Mar;137(3):347-55.

33. Evidence for IV thrombolysis in high risk AIS
patient profiles
2
IV thrombolysis
in Cardio-
embolic stroke
3
IV thrombolysis
in AIS patient
with history of
recent MI
4
Management of
hypertension in
AIS
1
IV thrombolysis in
patients with
baseline
hyperglycemia

34.  Stroke following MI is not uncommon1,2,3
 22.6 per 1,000 person-months in the first 30 days with 44 fold increase in
stroke risk1
 Simultaneously in up to 5% of stroke patients2
 Global Registry of Acute Coronary Event (GRACE) trial reported an incidence
of in-hospital stroke as 0.9% in a cohort of patients presenting with acute
coronary syndrome, and the incidence was much higher in patients with STEMI
than the non-STEMI4,6
 The risk of acute stroke is highest within 5 days after acute myocardial
infarction5
Incidence of AIS in MI patients
1. Witt BJ, Brown RD Jr, Jacobsen SJ, Weston SA, Yawn BP, Roger VL. A community- based study of stroke incidence after myocardial infarction. Ann Intern Med 2005;143: 785–792.
2. Lyden PD, ed. Thrombolytic Therapy for Stroke. New Jersey: Humana Press, Inc.; 2001.
3. Saczynski JS, Spencer FA, Gore JM, Gurwitz JH, Yarzebski J, Lessard D, et al. Twenty-year trends in the incidence of stroke complicating acute myocardial infarction: Worcester heart attack study. Arch Intern Med (2008) 168:2104–10. doi:10.1001/archinte.168.19.2104.
4. Budaj A, Flasinska K, Gore JM, Anderson FA Jr, Dabbous OH, Spencer FA, et al. Magnitude of and risk factors for in-hospital and postdischarge stroke in patients with acute coronary syndromes: findings from a global registry of acute coronary events. Circulation (2005) 111:3242–7.
doi:10.1161/CIRCULATIONAHA.104.512806.
5. Mooe T, Eriksson P, Stegmayr B. Ischemic stroke after acute myocardial infarction. A population-based study. Stroke (1997) 28:762–7. doi:10.1161/ 01.STR.28.4.762.
6. Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes. Am Heart J. 2001 Feb;141(2):190-9.

35. AHA/ASA 2019 guidelines recommend use of Alteplase
in patients with recent history of MI
Powers WJ, et al. Stroke. 2019 Dec;50(12):e344-e418

36. Current Recommended Goals for BP in Acute Ischemic Stroke, <185/110
:Before starting IV-tPA & <180/105 :After starting IV-tPA
Hyperglycaemic AIS patients (baseline glucose >180mg/dL) thrombolysed with
IV alteplase had better functional outcomes with slight increase in sICH rate.
IV thrombolysis with Alteplase in cardioembolic strokes have better outcome
and lesser risk for sICH
Among stroke patients with a recent history of MI AHA/ASA 2019 guidelines
recommend use of Alteplase
Summary

38. Reserve slides

39. BP management
• Mild-to-moderately elevated BP should not routinely be lowered in the
acute phase of stroke.
• Indications for urgent BP lowering include:
• hypertensive encephalopathy, myocardial ischemia, congestive heart
failure, aortic dissection,
• thrombolytic or anticoagulant therapy is given.

40. Treating Hypertension : Against
• BP usually returns to baseline levels in few hours or days.
• BP lowering may cause infarct extension because of the ischemic
penumbra and loss of autoregulation.
• INWEST : IV nimodipine use was associated with increase in mortality and
adverse outcome.
Vemmons N, et al. Bl Press Monitor 2004; 9: 107-114. Ahmed N, et al. Stroke 2000; 31:1250-1255.
Cerebrovasc Dis 1994;4:204–210

41. Treating Hypertension : For
• May decrease early hematoma expansion in ICH and oedema in ischemic
stroke.
• IST : U-shaped relationship, both high SBP and low SBP related to poor
outcome.
• Phase II ACCESS Study (n=342) : Modest BP reduction within 36 hours of
acute ischemic stroke by oral candesartan associated with better outcome
(reduced 12-month mortality and vascular events)
Arima H, et al. Hypertension. 2010;56(5):852-8. Schrader J, et al. Stroke 2003; 34: 1699-1703.