Secondary Stroke Prevention

Hans-Christoph Diener
Department of Neurology and Stroke
Center
Essen Germany
 Secondary Stroke Prevention
Outline
• Prevention of early stroke recurrence
• Combination antiplatelet therapy
• Anticoagulation in patients with atrial fibrillation
(AF)
• Surgery versus stenting in symptomatic carotid
stenosis
• Patients with cryptogenic stroke
• PFO closure in cryptogenic stroke
• Treatment of intracranial stenosis
 Secondary Stroke Prevention
Outline
• Prevention of early stroke recurrence
• Long-term combination antiplatelet therapy
• Anticoagulation in patients with atrial
fibrillation
• Surgery versus stenting in symptomatic carotid
stenosis
• PFO closure in cryptogenic stroke
• Treatment of intracranial stenosis
Coull et al, BMJ, 2004
 CHANCE Trial
• 5170 Chinese patients with TIA or minor
stroke
• Randomised to aspirin monotherapy versus
aspirin plus clopidogrel (300 mg + 75 mg) for 3
weeks, followed by clopidogrel mono-therapy
• Primary endpoint: recurrent stroke (ischemic
or hemorrhagic)
 CHANCE Trial
• 303 events in mono-therapy
• 212 events in combination therapy
• HR = 0.68 sign. P< 0.001
• Any bleeding 41 versus 60 (HR 1.41, ns.)
 POINT Trial
• High risk TIA (ABCD2 >4) or minor stroke
• Randomised within 12 hours
– Patients assigned to clopidogrel in addition to aspirin
– Clopidogrel loading dose of 600mg followed by 75 mg, one
tablet daily for 90 days
– Controls assigned to placebo in addition to aspirin
• Primary endpoint at 90 days: combined vascular
endpoint
• N = 4150
 Conclusion
• Aspirin has very limited efficacy in the early
prevention of recurrent stroke (3 months)
• Aspirin plus clopidogrel could be superior to
aspirin monotherapy
 Secondary Stroke Prevention
Outline
• Prevention of early stroke recurrence
• Long term combination antiplatelet therapy
• Surgery versus stenting in symptomatic carotid
stenosis
• PFO closure in cryptogenic stroke
• Intracranial stenosis
 Is combination therapy superior to
mono-therapy?
• Aspirin plus clopidogrel
• Aspirin plus ER dipyridamole

ER = Extended Release
 MATCH: Primary Endpoint (ITT)
IS, MI, VD, rehospitalization for acute ischemic event
0.20
Cumulative event rate

Placebo + Clopidogrel

0.16 ASA + Clopidogrel

RRR: 6.4%
0.12 (p=0.244)

0.08

0.04

0.00
0 3 6 9 12 15 18
Months of follow-up
CHARISMA Primary endpoint: Stroke, MI, Vascular death
CHARISMA
 Conclusions
Based on MATCH, CHARISMA and
SPS3 in secondary stroke prevention the
combination of clopidogrel plus
aspirin is not more effective than
clopidogrel or aspirin monotherapy
The combination of clopidogrel plus
aspirin carries a higher
bleeding risk than clopidogrel
or aspirin monotherapy

H9
 European Stroke Prevention Study
ESPS 2
n = 6.602

Placebo Aspirin ER-DP Aspirin +

2x 2x
25 mg 200 mg ER-DP
2x
25 mg ASA/
(n = 1.649) (n = 1.649) (n = 1.654) 200 mg ER-DP

(n = 1.650)

Diener et al, ESPS 2 Group. J Neurol Sci 1997;151(suppl):S1-S77.

ESPS 2
Relative Risk Reduction for Stroke
(pairwise comparisons

ASS/DP ret vs. Plazebo DP ret vs. Plazebo

ASS vs. Plazebo ASS/DP ret vs. ASS
%
37,0
40 p < 0,001
35
30
23,1
25 p = 0,006
18,1
16,3 p = 0,013
20
p = 0,039
15
10
5
0
ASS+DP DP ASS

DP ret = Dipyridamol retard

ESPS 2 Group, J Neurol Sci 1997;151(suppl):S1-S77.
 Conclusion

The combination of aspirin plus modified-

release dipyridamole is superior to aspirin
monotherapy
The combination is more effective than
aspirin in high risk patients
The combination has a higher bleeding
risk
H9
 Secondary Stroke Prevention
Outline
• Prevention of early stroke recurrence
• Combination antiplatelet therapy
• Anticoagulation in patients with atrial
fibrillation (AF)
• Surgery versus stenting in symptomatic carotid
stenosis
• PFO closure in cryptogenic stroke
• Treatment of intracranial stenosis
 OAC is more effective than ASA
for secondary stroke prevention in AF
EAFT: European, multicentre RCT
1007 patients with non-rheumatic AF and recent TIA or
minor ischaemic stroke (mean follow-up 2.3 years)

OAC (INR 2.5-4.0) ASA (300 mg/day)

80
66%
Stroke risk reduction

60
vs placebo (%)

P<0.001

40
p<0.001
20 14%
n.s.
0
P=0.31
p=0.31
ASA = acetylsalicylic acid; EAFT = European atrial fibrillation trial; INR = international normalized ratio;
OAC = oral anticoagulant; RCT = randomized controlled trial; TIA = transient ischaemic attack
EAFT Study Group. Lancet 1993;342:1255–62
21
EAFT Study Group. Lancet 1993;342:1255-62
RE-LY® prior stroke subgroup analysis: time to stroke or systemic
embolism in patients with/without previous stroke or TIA
0.08 Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin
0.06 Prior stroke/TIA
Cumulative hazard rates

0.04

No prior stroke/TIA

0.02

0
0 0.5 1.0 1.5 2.0 2.5

Number at risk (prior stroke)

Follow-up (years)
Dabigatran 110 mg 1195 1159 1131 908 573 289
Dabigatran 150 mg 1233 1200 1163 938 517 321
Warfarin 1195 1159 1125 895 565 251

Number at risk (no prior stroke)

Dabigatran 110 mg 4819 4702 4578 3684 2371 1096
Dabigatran 150 mg 4843 4739 4616 3744 2427 1108
Warfarin 4827 4703 4593 3698 2325 1061

BID = twice daily; TIA = transient ischaemic attack

Adapted from Diener HC et al. Lancet Neurol 2010;9:1157–63 and data on file. Jan 2013
 ROCKET AF Subanalysis: Secondary Prevention Results
Primary Efficacy Outcome

Kaplan–Meier survival curve showing time to the primary outcome (stroke or systemic embolism)
7 Previous stroke/ TIA,
Cumulative event rate – stroke or

HR, 0.94; 95% CI, 0.77-1.16 warfarin

6 Previous stroke/ TIA,
rivaroxaban
systemic embolism (%)

5 Interaction No previous stroke/ TIA,

P = 0.23 warfarin
4
No previous stroke/ TIA,
rivaroxaban
3

2 HR, 0.77; 95% CI, 0.58-1.01

0
00 6 12
12 18
18 24 30
0 Months
Months fromrandomization
from randomisation
Intention-to-treat population.
HR, hazard ratio; TIA, transient ischemic attack.
Hankey G, et al. Lancet Neurology. 2012;11:315-22.
ARISTOTLE: Apixaban reduced the risk of stroke vs. warfarin,
whether or not patients had a previous stroke/TIA

Apixaban vs. warfarin:

10
- Previous stroke or TIA: HR:0.76; 95% CI: 0.56 to 1.03
- No previous stroke or TIA: HR: 0.82; 95% CI: 0.65 to 1.03
8
Previous stroke or TIA, warfarin
(n=1742)
Probability (%)

6
Previous stroke or TIA, apixaban
(n=1694)

4
No previous stroke or TIA, warfarin
(n=7339)
2 No previous stroke or TIA, apixaban
(n=7426)

0
0 10 12 18 24 30

Time since randomisation (months)

Adapted from Easton et al. Lancet Neurol 2012;11:503-11.

24
Novel Oral Anticoagulants in Patients With
Atrial Fibrillation and Previous Stroke or
Transient Ischemic Attack: A Systematic
Review and Meta-analysis of Randomized
Controlled Trials

G. Ntaios, V. Papavasileiou, H.C. Diener,

K. Makaritsis, P. Michel

This study was not designed to compare NOACs against one another. Comparison
Ntaios G et al. Stroke 2012 Nov 13 [Epubbetween
ahead of print] is not valid because of population differences among the studies.
NOACs
No head to head data are available.
Effects of novel oral anticoagulants vs warfarin on stroke or systemic
embolism in patients with AF and previous stroke or TIA (1)

Stroke or Systemic NOACs Warfarin Peto Odds Ratio

Embolism
Study or subgroup Events Total Events Total Weight Peto, Fixed (95% CI)
ARISTOTLE 73 1694 98 1742 22.1% 0.76 (0.56–1.03)
RE-LY 110 55 1195 65 1195 15.5% 0.84 (0.58–1.21)
RE-LY 150 51 1233 65 1195 15.0% 0.75 (0.52–1.09)
ROCKET AF 179 3754 187 3714 47.4% 0.94 (0.77–1.17)
Total (95% CI) 7876 7846 100% 0.85 (0.74–0.99)
Total events 358 415
Heterogeneity: 2=1.93, df=3 (P=0.59); I2=0%
Test for overall effect: Z=2.15 (P=0.03)

ARISTOTLE
RE-LY 110
RE-LY 150
This study was not designed to compare NOACs
against one another. Comparison between NOACs
ROCKET AF
is not valid because of population differences
among the studies. No head-to-head data are available Total
AF = atrial fibrillation; TIA = transient ischemic attack;
NOAC = novel oral anticoagulant.
Ntaios G et al. Stroke 2012 Nov 13 [Epub ahead of print]
Effects of novel oral anticoagulants vs warfarin on haemorrhagic
stroke in patients with AF and previous stroke or TIA (2)

Haemorrhagic stroke NOACs Warfarin Peto Odds Ratio

Study or subgroup Events Total Events Total Weight Peto, Fixed (95% CI)
ARISTOTLE 12 1694 31 1742 31.1% 0.42 (0.23–0.77)
RE-LY 110 2 1195 18 1195 14.5% 0.20 (0.08–0.48)
RE-LY 150 5 1233 18 1195 16.7% 0.31 (0.14–0.70)
ROCKET AF 22 3754 30 3714 37.8% 0.73 (0.32–0.62)
Total (95% CI) 7876 7846 100% 0.44 (0.32– 0.62)
Total events 41 97
Heterogeneity: 2=7.07, df=3 (P=0.07); I2=58%
Test for overall effect: Z=4.79 (P<0.00001)

ARISTOTLE
RE-LY 110
RE-LY 150
This study was not designed to compare NOACs ROCKET AF
against one another. Comparison between NOACs
is not valid because of population differences Total
among the studies. No head-to-head data are available
AF = atrial fibrillation; TIA = transient ischemic attack;
NOAC = novel oral anticoagulant.
Ntaios G et al. Stroke 2012 Nov 13 [Epub ahead of print]
NOACs: special situations

Prior
Patients >80 CrCl 30–50
Prior GI bleed intracerebral
years mL/min
bleed

Afib and
Start after TIA Cognitive Gait apraxia
carotid
or stroke impairment and falls
stenosis

Afib and stable

Afib and DVT Myocardial
coronary heart Thrombolysis
prevention infarction
disease

28
Resumption of oral anticoagulation after ICH
Kuramatsu et al. JAMA 2015

29
Suggestions for initiation or resumption of oral anticoagulation in AF
patients after an intracranial haemorrhage

Patient has a history or suffered recently from intracranial haemorrhage

Cause of bleeding
Contraindication for Intracerebral Subdural hematoma Subarachnoidal
cannot be removed
OAC haemorrhage (SDH) haemorrhage (SAH)
or treated

Consider clinical factors favouring initiation OAC

Older age Younger age

Uncontrolled hypertension
Cortical bleed
Severe white matter lesions
Multiple microbleeds (>30)
Chronic alcoholism
Need for dual antiplatelet
therapy after PCI
Well-controlled hypertension
Basal ganglia bleed
Nor or mild white matter lesions
SDH: surgical removal
SAH: aneurysm clipped or
coiled
High risk of ischemic stroke

Consider LAA Consider LAA Intiate or resume

occlusion occlusion OAC after 4-8 weeks
NOACs: special situations

Prior
Patients >80 CrCl 30–50
Prior GI bleed intracerebral
years mL/min
bleed

Afib and
Start after TIA Cognitive Gait apraxia
carotid
or stroke impairment and falls
stenosis

Afib and stable

Afib and DVT Myocardial
coronary heart Thrombolysis
prevention infarction
disease

31
Initiation or resumption of anticoagulation depends on
severity of stroke

Time to re-initiation depends on infarct size:

1 – 3 – 6 – 12 day rule (Diener’s Law)

TIA Mild Moderate Severe

stroke stroke stroke

As soon as imaging 3–5 days after 5–7 days after 2 weeks after
has excluded a symptom onset stroke onset stroke onset
cerebral haemorrhage

Day 1 3 6 12

*Mild = NIHSS score <8; moderate = NIHSS score 8–16; severe = NIHSS score >16
TIA, transient ischaemic attack
Huisman et al. Thromb Haemost 2012
 Suggestions for initiation or resumption of oral anticoagulation in
AF patients after an acute stroke or TIA
TIA or Ischemic Stroke
Exclusion of intracerebral bleeding (ICB) by CT or MRI

Moderate Severe
TIA Mild Stroke
Stroke Stroke
(NIHSS <8)
(NIHSS 8-15) (NIHSS >16)

Consider additional clinical factors favouring early / delayed

Low NIHSS (<8) initiation High NIHSS
Small/no brain infarction on MRI
Large/moderate brain infarction
High recurrence risk e.g. cardiac
Needs PEG/major surgical
thrombus on echo
intervention
No need for PEG
Needs carotid surgery
No need for carotid surgery
Haemorrhagic transformation
No haemorrhagic transformation
Neurologically unstable
Clinically stable
Elderly patient
Young patient
Uncontrolled hypertension
Blood pressure is controlled

Exclude
haemorrhagic Exclude haemorrhagic
transformation by transformation by CT
CT or MRI at day 6 or MRI at day 12

1 day after 3 days after 6 days after 12 days after

Start OAC acute event acute event acute event acute event
 Conclusion
• Oral anticoagulation is highly effective in
secondary stroke prevention in patients with
AF
• As a group the NOACs are superior to warfarin
in preventing recurrent stroke, intracranial
hemorrhage, major bleeding and death
• Time of initiation or resumption of OAC after
stroke depends on the etiology (ischemic
versus hemorrhagic) and other factors
 Secondary Stroke Prevention
Outline
• Prevention of early stroke
recurrence
• Combination antiplatelet therapy
• Surgery versus stenting in
symptomatic carotid stenosis
• PFO closure in cryptogenic stroke
Stenting or Angioplasty in Patients
with Carotid Stenosis?

Stent
 CREST
• Carotid surgery versus angioplasty plus
stenting
• 2502 patients
• 47% asymptomatic, 53% symptomatic
• Mean age 69 Jahre
• 35% females
• Degree of stenosis for inclusion
60% (asymptomatic), 50% (symptomatic)
 CREST
Variable Stenting Surgery p
N 1262 1240
Primary* 7,2% 6,8% n. s.
30 days 5,2% 4,5% n. s.
Stroke 4,1% 2,3% Sign.
MI 1,1% 2,3% Sign.
Cranial Nerve 0.3% 4,8% Sign.
Ipsilat. Stroke 2,0% 2,4% n. s.
*Primary: Stroke, MI, Death, Ipsilateral Stroke, 4 years
Age dependency in CREST
 Conclusions
• Endarterectomy has a lower complication
rate than stenting
• Re-stenosis is higher after stenting
• Endarterectomy is preferred in females and
patients >70 years
• Protection devices are not protecting
• Complication rate needs to be <6%
 Secondary Stroke Prevention
Outline
• Prevention of early stroke recurrence
• Combination antiplatelet therapy
• Surgery versus stenting in symptomatic carotid
stenosis
• Treatment of symptomatic intracranial
stenosis
• PFO closure in cryptogenic stroke
 Conclusion
Best medical therapy is more effective in
patients with symptomatic intracranial stenosis
compared to stenting
 Secondary Stroke Prevention
Outline
• Prevention of early stroke recurrence
• Combination antiplatelet therapy
• Anticoagulation in patients with atrial fibrillation
(AF)
• Surgery versus stenting in symptomatic carotid
stenosis
• Patients with cryptogenic stroke
• PFO closure in cryptogenic stroke
• Treatment of intracranial stenosis
Patients with Embolic Stroke of Undetermined Source
are a subset of patients with cryptogenic stroke

Haemorrhagic (8%)1 All strokes

Ischaemic (92%)1,2
25% large artery 5% unusual
atherosclerotic (e.g. dissections,
stenosis2,3 arteritis)2,3

25% small artery 25% cryptogenic 20% major-risk

disease (lacunar (no known source cardiogenic
stroke)2,3 cause)2,3 embolism2,3

If clearly specified diagnostic

criteria are fulfilled

ESUS2
ESUS = embolic stroke of undetermined source
1. Andersen K et al. Stroke 2009;40:2068–72; 2. Adams HP et al. Stroke 1993;24:35–41; 49
3. Hart RG et al. Lancet Neurol 2014;13:429–38
Embolic Stroke of Undetermined Source (ESUS)
RE-SPECT ESUS® – Design

Primärer Endpunkt:
Schlaganfall
Therapieende
Indexschlaganfall Dabigatran (150 oder 110 mg 2 x tgl.)†
(ESUS)* n = 3000
Placebo (für ASS)
R
“Diagnoseweg“: ASS (100 mg 1 x tgl.)
MRT-/CT-Untersuchung n = 3000
zum Ausschluss von Placebo (für Dabigatran)
Lakunen; Carotis-US und
≥ 24-stündige Rhythmus-
aufzeichnung zum
Ausschluss von VHF
30-tägiger
Follow-Up
0 Tage - 3 Monate‡ 0,5 - 3 Jahre

* mRS ≤ 3, Alter ≥ 60 oder 50-59 Jahre mit zusätzlichen Risikofaktoren; † Alle Patienten erhalten Dabigatran 150 mg 2 x tgl., ausgenommen Patienten ≥ 75 Jahre oder mit einer CrCl
von 30-50 ml/min. Diese Patienten erhalten Dabigatran 110 mg 2 x tgl.; ‡ 0 Tage - 6 Monate bei Patienten > 60 Jahre mit zusätzlichen Risikofaktoren.
CrCl = Kreatinin-Clearance; mRS = modifizierte Rankin-Skala; R = Randomisierung; US = Ultraschall
Adaptiert aus der Boehringer Ingelheim Pressemitteilung vom 19.11.2013; Link: http://www.boehringer-ingelheim.com/news/news_
releases/press_releases/2013/19_november_2013_dabigatranetexilate1.html; aufgerufen im Januar 2014; http://www.boehringer-ingelheim.de/
presse/archiv_pressemitteilungen/press_releases_2014p/04_maerz_2014_dabigatranetexilat.html
51
Diener HC et al. Link: http://www.eurostroke.eu/pupongoings.asp; aufgerufen im Januar 2014
 Secondary Stroke Prevention
Outline
• Prevention of early stroke recurrence
• Combination antiplatelet therapy
• Surgery versus stenting in symptomatic carotid
stenosis
• Treatment of intracranial stenosis
• PFO closure in cryptogenic stroke
 PFO Closure in Cryptogenic Stroke

At present 3 negative randomised trials (with a

trend for efficacy for PFO closure)
For which patients is PFO closure
recommended?
Clinical circumstances indicating paradoxical emboli
Recurrent stroke in patient <65 years on aspirin or
warfarin
 Secondary Stroke Prevention
Summary
• Prevention of early stroke recurrence
• Combination antiplatelet therapy
• Anticoagulation in AF
• Surgery versus stenting in symptomatic carotid
stenosis
• Stroke prevnetion in ESUS
• PFO closure in cryptogenic stroke
• Treatment of intracranial stenosis