No previous stroke or TIA

Report
Preventing a Second Stroke
John Camm
St. George’s University of London, UK
The GARFIELD Registry is funded by an unrestricted research grant
from Bayer Pharma AG
www.tri-london.ac.uk
Declaration of Interest
Chairman: ESC Guidelines on Atrial Fibrillation 2012 and Update 2012, ACC/AHA/ESC
Guidelines on VAs and SCD; 2012 NICE Guidelines on ACS and NSTEMI; 2008 NICE
Guidelines on heart failure; 2006 NICE Guidelines on Atrial Fibrillation
Steering Committees: multiple trials including novel anticoagulants
DSMBs: multiple trials including novel oral anticoagulants in AF
Events Committees: one trial of novel oral anticoagulants and multiple trials of
miscellaneous agents with CV adverse effects
Consultant/Advisor/Speaker: Astra Zeneca, ChanRX, Gilead, Merck, Menarini, Otsuka,
Sanofi, Servier, Xention, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi
Sankyo, Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion,
GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi, Novartis,
Takeda
Questions to be Asked
● About the first stroke
– Was it ischaemic or haemorrhagic?
– Was the patient anticoagulated?
– Was the anticoagulation known to be adequate?
● About the patient
– Is atrial fibrillation present (or was it present)?
– What is the thromboembolic risk (CHA2DS2-VASc)?
– What is the bleeding risk?
Questions to be Asked
● About the first stroke
– It was ischaemic
– The patient was not anticoagulated
– Was the anticoagulation known to be adequate?
● About the patient
– Atrial fibrillation is, or was, present
– The thromboembolic risk was moderate to high
– The bleeding risk was moderate
Anticoagulate the patient with a NOAC
Questions to be Asked
● About the first stroke
– It was haemorrhagic
– The patient was anticoagulated
– The anticoagulation status was unknown or high
● About the patient
– Atrial fibrillation is or was present
– The thromboembolic risk was moderate or high
– The bleeding is very high
Consider device based anti-thrombotic strategy
NOAC 4-trial Meta-analysis Full Dose
Pre-specified meta-analysis of all 71,683 patients
Stroke and Systemic
Embolism
Trial
RE-LY
Major Bleeding
p
p
0.0001
0.34
ROCKET-AF
0.12
0.72
ARISTOTLE
0.012
<0.0001
ENGAGE
TIMI 48*
0.10
0.0002
Combined
0.81
0.5
<0.0001
Favours DOAC
Ruff C, et al. Lancet 2013
1
0.86
0.5
Favours DOAC
* Edoxaban is not approved for clinical use in AF
0.06
1
Efficacy vs Safety
NOAC 4-trial Meta-analysis Full Dose
Pooled
Pooled
DOAC
Warfarin
Events
/Total
Events
/Total
Ischaemic Stroke
665
/29292
Hemorrhagic
stroke
Risk
Ratio
95%
CIs
p
724
/29221
0.92
0.831.02
0.10
130
/29292
263
/29221
0.49
0.380.64
<0.0001
Myocardial
Infarction
413
/29292
432
/29221
0.97
0.781.20
0.97
All Cause mortality
2022
/29292
2245
/29221
0.90
0.8510.95
0.0003
Intra-cranial
hemorrhage
204
/29287
425
/29211
0.48
0.390.59
<0.0001
Gastrointestinal
bleeding
751
/29287
591
/29211
1.25
1.011.55
0.043
Result
Efficacy
Safety
Ruff C, et al. Lancet 2013
* Edoxaban is not approved for clinical use in AF
0.25 Favours NOAC
1
2
Ischaemic Stroke:
Novel Agents vs Warfarin
%/yr
HR
(95% CI)
0.86
1.14
0.75 (0.58-0.97)
Dabigatran 110 mg
1.28
1.14
1.13 (0.89-1.42)
Rivaroxaban
1.34
1.42
0.94 (0.75-1.17)
Apixaban*
0.97
1.05
0.92 (0.74-1.13)
Ischaemic stroke vs
warfarin
%/yr
Dabigatran 150 mg
Warfarin
*Ischaemic or uncertain type of stroke
0.5
Favours NOACs
1
Favours warfarin
1.5
1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel
MR et al. NEJM 2011;365:883–91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981-92.
ROCKET AF
Subanalysis 20 prevention – Results
Kaplan-Meier survival curve: Primary efficacy endpoint
(stroke or systemic embolism)
Cumulative event rate - stroke/SE (%)
7
7,468 (52%) patients had a previous stroke
(n=4,907; 65%) or TIA (n=2,561; 34%)
Prior stroke/TIA, warfarin
No prior stroke/TIA, warfarin
Prior stroke/TIA, rivaroxaban
6
No prior stroke/TIA, rivaroxaban
5
HR: 0.94 (0.77 – 1.16)
4
3
2
HR: 0.77 (0.58 – 1.01)
1
0
0
6
12
18
Intention-to-treat population
Hankey GJ et al. Lancet Neurol 2012;11(4): 315–22
24
30
Months from randomisation
ARISTOTLE:
20 Stroke Prevention - Results
Apixaban vs. warfarin:
- 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
10
Probability (%)
8
Previous stroke or TIA, warfarin
(n=1742)
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)
Easton et al. Lancet Neurol 2012;11:503–11
ARISTOTLE:
Major Bleeding - 10 and 20 Prevention
Apixaban vs. warfarin:
- Previous stroke or TIA: HR:0.73; 95% CI: 0.55 to 0.98
- No previous stroke or TIA: HR: 0.68; 95% CI: 0.58 to 0.80
10
Previous stroke or TIA, warfarin
(n=1735)
Probability (%)
8
No previous stroke or TIA, warfarin
(n=7371)
6
Previous stroke or TIA, apixaban
(n=1687)
No previous stroke or TIA, apixaban
(n=7401)
4
2
NNT to avoid one major bleed:
– No previous stroke or TIA: 65
– Previous stroke or TIA: 54
0
0
10
12
18
24
30
Time since first dose of study drug (months)
Easton et al. Lancet Neurol 2012;11:503–11.
Comparisons between NOACs
Direct methodology
Dabigatran 110
Dabigatran 150
1195 vs 1195 pts 1233 vs 1195 pts
HR, 95% CI
ROCKET-AF
3754 vs 3714 pts
Apixaban
1694 vs 1742pts
Primary endpoint
with previous stroke
w/o previous stroke
0.84 (0.58-1.20)
0.93 (0.73-1.18)
0.75 (0.52 – 1.08)
0.60 (0.45 – 0.78)
0.94 (0.77 – 1.16)
0.77 (0.58 – 1.01)
0.76 (0.56 – 1.03)
0.82 (0.65 – 1.03)
with previous stroke
w/o previous stroke
0.89 (0.61 – 1.29)
0.92 (0.72 – 1.18)
0.76 (0.52 – 1.11)
0.58 (0.44 – 0.77)
0.98 (0.79 – 1.21)
0.76 (0.57 – 1.01)
0.71 (0.52 – 0.98)
0.84 (0.67 – 1.06)
with previous stroke
w/o previous stroke
1.26 (0.84 – 1.90)
1.04 (0.80 – 1.37)
1.0 (0.65 – 1.54)
0.66 (0.48 – 0.89)
1.03 (0.82 – 1.30)
0.88 (0.64 – 1.21)
0.86 (0.60 – 1.22)
0.97 (0.74 – 1.26)
with previous stroke
w/o previous stroke
0.11 (0.03 – 0.47)
0.44 (0.22 – 0.86)
0.27 (0.10 – 0.72)
0.25 (0.11 – 0.59)
0.73 (0.42 – 1.26)
0.41 (0.20 – 0.83)
0.40 (0.21 – 0.78)
0.59 (0.37 – 0.94)
with previous stroke
w/o previous stroke
0.20 (0.08 – 0.47)
0.35 (0.21 – 0.57)
0.41 (0.21 – 0.79)
0.43 (0.27 – 0.68)
0.74 (0.47 – 1.41)
0.46 (0.24 – 0.89)
0.37 (0.21 – 0.67)
0.44 (0.30 – 0.66)
with previous stroke
w/o previous stroke
0.66 (0.48 – 0.90)
0.85 (0.72 – 0.99)
1.01 (0.77 – 1.24)
0.91 (0.77 – 1.06)
0.97 (0.79 – 1.19)
1.11 (0.92 – 1.34)
0.73 (0.55 – 0.98)
0.68 (0.30 – 0.66)
Stroke
Ischemic/unknown
Hemorrhagic
ICH
Major bleed
Comparisons between NOACs
Indirect methodology
Rasmussen LH, et al BMJ 2012;345:e7097
AHA/ASA 2012
Update SPAF and OAC
1. Warfarin (Class I; Level of Evidence A),
dabigatran (Class I; Level of Evidence B),
apixaban (Class I; Level of Evidence B), and
rivaroxaban (Class IIa; Level of Evidence B)
are all indicated for the prevention of first and recurrent
stroke in patients with nonvalvular AF
The selection of an antithrombotic agent should be
individualized on the basis of risk factors, cost, tolerability,
patient preference, potential for drug interactions, and other
clinical characteristics, including time in INR therapeutic
range if the patient has been taking warfarin.
Furie KL, et al. Stroke 2012 Dec;43(12):3442-53
20 Stroke Prevention
Guidelines
2012 German Guidelines on secondary stroke prevention recommend:
● In patients with TIA or ischemic stroke and atrial fibrillation oral
anticoagulation is recommended (Level of evidence Ib, strength of
recommendation A)
● Patients with ischemic stroke or TIA and atrial fibrillation should
be treated with new anticoagulants (Level of evidence Ib, strength
of recommendation B)
● Apixaban is superior to aspirin (50–328 mg) in the prevention of
recurrent stroke in patients with ischemic stroke or TIA and atrial
fibrillation. Apixaban has a comparable bleeding risk as aspirin.
Aspirin should no longer be used in secondary stroke prevention in
patients with atrial fibrillation (Level of Evidence Ib, strength of
recommendation B)
Endres M, et al. 2012
PROTECT-AF:
Final Results
463 patients received Watchman and 244 warfarin
Average CHADS2 scores 2.2 and 2.3, respectively
Mean follow-up: 45 months
Rate Ratios (95% CI) for Primary Efficacy and Safety End Points and Secondary
End Points in PROTECT-AF, by Intention to Treat
End points (2621 pt/years)
Primary efficacy end point: Stroke, systemic
embolism, or cardiovascular or unexplained death
All-cause mortality
Cardiovascular mortality
Hemorrhagic stroke
Primary safety end point: serious pericardial effusion,
major bleeding, procedure-related stroke, hemorrhagic
stroke, and device embolization
Reddy VY, et al. Abstract HRS Denver 2013
RR (95% CI)
0.60 (0.41–1.05)
0.66 (0.45–0.98)
0.40 (0.21–0.72)
0.15 (0.03–0.49)
1.17 (0.78–1.95)
Left Atria Appendage Occlusion
Potential Indications
• Ischaemic stroke despite adequate anticoagulation
• High thromboembolic risk but previous intra-cerebral
bleed on anticoagulants
• High thrombo-embolic risk but previous life-threatening bleed
on anticoagulants at correct INR
• High thrombo-embolic risk but previous major bleed on
anticoagulants
• High thromboembolic risk (CHA2DS2VASc ≥ 2) with major risk of
bleeding (HASBLED ≥ 3, or need for DAPT)
•
•
High thromboembolic risk and time in therapeutic range < 65%
High thromboembolic risk and unwilling to take anticoagulants
•
Treatment of choice – best therapeutic option – patient choice
Camm A.J. 2011
Thank you for your attention

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