1. Anti-Platelet Therapy Testing for Neurointerventional Procedures Where are we now?
Josser E. Delgado, M.D.
Yasha Kayan, M.D.
Neuroscience Institute
Abbott Northwestern Hospital
Consulting Radiologists, Ltd
Minneapolis, MN

2. Disclosures
Consultant for Medtronic Neurovascular, Microvention/Terumo & Penumbra Inc.

3. Background
Increasing number of endovascular devices for treatment of cerebral aneurysms are designed to be deployed within the parent artery’s lumen
Marked increase in use of potent antiplatelet agents by neurointerventionalists to prevent device thrombosis

4. Background
On-going controversy among neurointerventionalists regarding whether or not to perform antiplatelet testing
Field is split between:
“Non-testers”
“Testers”

5. Background Growing body of neurointerventional literature indicates:
High degree of variability in response to the standard 75mg daily clopidogrel dose may play important role in the thromboembolic and hemorrhagic complications encountered after endovascular treatment of cerebral aneurysms with flow diverters and stents
Increasing use of highly potent P2Y12 receptor antagonists such as prasugrel & ticagrelor may be associated with an increased risk of bleeding in the post-operative period

6. Background
VerifyNow is an assay that measures the degree of platelet reactivity after stimulation of the P2Y12 receptor with ADP
Results reported in P2Y12 reaction units (PRU)
High PRU: high degree of residual platelet reactivity & increased risk of thrombosis
Low PRU: low degree of residual platelet reactivity & increased risk of bleeding

7. Background
Prabhakaran S, Wells KR, Lee VH, et al. Prevalence and risk factors for aspirin and clopidogrel resistance in cerebrovascular stenting. AJNR Am J Neuroradiol. 2008;29:281-5.
Müller-Schunk S, Linn J, Peters N, et al. Monitoring of clopidogrel-related platelet inhibition: correlation of nonresponse with clinical outcome in supra-aortic stenting. AJNR Am J Neuroradiol. 2008;29:
Lee DH, Arat A, Morsi H, et al. Dual antiplatelet therapy monitoring for neurointerventional procedures using a point-of-care platelet function test: a single-center experience. AJNR Am J Neuroradiol. 2008;29:
Drazin D, Choulakian A, Nuno M, et al. Body weight: a risk factor for subtherapeutic antithrombotic therapy in neurovascular stenting. J Neurointerv Surg. 2011;3:
Maruyama H, Takeda H, Dembo T, et al. Clopidogrel resistance and the effect of combination cilostazol in patients with ischemic stroke or carotid artery stenting using the VerifyNow P2Y12 Assay. Intern Med. 2011;50(7): Epub April 1st, 2011.
Song TJ, Suh SH, Min PK, et al. The influence of anti-platelet resistance on the development of cerebral ischemic lesion after carotid artery stenting. Yonsei Med J. 2013;54(2):
Fifi JT, Brockington C, Narang J, et al. Clopidogrel resistance is associated with thromboembolic complications in patients undergoing neurovascular stenting. AJNR Am J Neuroradiol. 2013;34:
Goh C, Churilov L, Mitchell P, et al. Clopidogrel Hyper-Response and Bleeding Risk in Neurointerventional Procedures. AJNR Am J Neuroradiol. 2013;34:721-6.
Akbari SH, Reynolds MR, Kadkhodayan Y, et al. Hemorrhagic complications after prasugrel (Effient) therapy for vascular neurointerventional procedures. J Neurointerv Surg Jul;5(4):

8. Background
Delgado Almandoz JE, Crandall BM, Scholz JM, et al. Pre-procedure P2Y12 reaction units value predicts perioperative thromboembolic and hemorrhagic complications in patients with cerebral aneurysms treated with the Pipeline Embolization Device. J Neurointerv Surg. 2013;5 Suppl 3:iii3-iii10. E-pub January 12th, 2013.
Sorkin GC, Dumont TM, Wach MM, et al. Carotid artery stenting outcomes: do they correlate with antiplatelet response assays? J Neurointerv Surg. 2014;6(5): E-pub June 22nd, 2013.
Delgado Almandoz JE, Crandall BM, Scholz JM, et al. Last-Recorded P2Y12 reaction units value is strongly associated with thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in patients with cerebral aneurysms treated with the Pipeline Embolization Device. AJNR Am J Neuroradiol. 2014;35(1): E-pub July 4th, 2013.
Heller RS, Dandamudi V, Lanfranchi M, et al. Effect of antiplatelet therapy on thromboembolism after flow diversion with the pipeline embolization device. J Neurosurg. 2013;119(6): E-pub Aug 23rd 2013.
Nakagawa I, Wada T, Park HS, et al. Platelet inhibition by adjunctive cilostazol suppresses the frequency of cerebral ischemic lesions after carotid artery stenting in patients with carotid artery stenosis. J Vasc Surg. 2014;59(3): E-pub November 14th, 2013.
Delgado Almandoz JE, Kadkhodayan Y, Crandall BM, et al. Variability in initial response to standard clopidogrel therapy, delayed conversion to clopidogrel hyper-response, and associated thromboembolic and hemorrhagic complications in patients undergoing endovascular treatment of unruptured cerebral aneurysms. J Neurointerv Surg E-pub Jan 7th 2014.
Tan LA, Keigher KM, Munich SA, et al. Thromboembolic complications with Pipeline Embolization Device placement: impact of procedure time, number of stents and pre-procedure P2Y12 reaction unit (PRU) value. J Neurointerv Surg E-pub Feb 19th 2014.

9. Background
González A, Moniche F, Cayuela A, et al. Antiplatelet effects of clopidogrel dose adjustment (75 mg/d vs 150 mg/d) after carotid stenting. J Vasc Surg. 2014;60(2): E-pub March 11th, 2014.
Oran I, Cinar C, Bozkaya H, et al. Tailoring platelet inhibition according to multiple electrode aggregometry decreases the rate of thrombotic complications after intracranial flow-diverting stent implantation. J Neurointerv Surg E-pub April 10th 2014.
McTaggart RA, Choudhri OA, Marcellus ML, et al. Use of thromboelastography to tailor dual-antiplatelet therapy in patients undergoing treatment of intracranial aneurysms with the Pipeline embolization device. J Neurointerv Surg E-pub April 16th 2014.
Kim B, Kim K, Jeon P, et al. Thromboembolic Complications in Patients with Clopidogrel Resistance after Coil Embolization for Unruptured Intracranial Aneurysms. AJNR Am J Neuroradiol E-pub May 15th, 2014.
Kashiwazaki D, Kuwayama N, Akioka N, et al. The roles and issues of P2Y12 percent inhibition assessed by VerifyNow assay for patients undergoing neurointervention. A prospective study. J Stroke Cerebrovasc Dis. 2014;23(7): E-pub June 21st, 2014.
Chalouhi N, Zanaty M, Jabbour P, et al. Intracerebral hemorrhage after pipeline embolization. Management of antiplatelet agents and the case for point-of-care testing. Case reports and review of the literature. Clin Neurol Neurosurg. 2014;124:21-4. E-pub June 22nd, 2014.
Bo W, Xiao-Qing L, Ning M, et al. Association of thrombelastographic parameters with post-stenting ischemic events. J Neurointerv Surg E-pub June 3rd, 2015.

10. Background
“Our data strongly suggest a correlation of insufficient clopidogrel-related platelet inhibition with an increased risk of thromboembolic events in supra-aortic stent placement”
“Anti-platelet resistance can be used to predict new ischemic lesions after CAS. Anti-platelet resistance should be evaluated in all patients prior to CAS to prevent ischemic complications related to CAS”
“In our series, clopidogrel resistance was associated with increased periprocedural thromboembolic complications from neurovascular stent-placement procedures. Targeting the clopidogrel dose to platelet inhibition assays may improve clinical outcomes and requires further study”
“Hyper-response to clopidogrel is associated with increased risk of hemorrhagic complications. Larger studies are urgently needed to validate a clinically useful threshold to define clopidogrel hyper-response and to examine the clinical effects of antiplatelet dosage adjustment”
“In our cohort, a pre-procedure PRU value of <60 or >240 was the strongest independent predictor of all and major perioperativethromboembolic and hemorrhagic complications after PED procedures”
“PRU ≤198 may be associated with a lower incidence of ischemic neurological sequelae and death post-CAS. Prospective studies are needed to validate the relationship between antiplatelet assays and outcomes post-CAS”
“In our cohort, a last-recorded P2Y12 reaction units value of <60 or >240 was the only independent predictor of all and major thromboembolic and hemorrhagic complications up to 6 months after Pipeline Embolization Device procedures”

11. Background
“Adjunctive cilostazol (triple antiplatelet therapy) in clopidogrel-resistant patients reduces the rate of clopidogrel resistance and suppresses new ischemic lesions without hemorrhagic complications, as compared with standard DAT. Antiplatelet management based on the evaluation of antiplatelet resistance would be required for prevention of perioperative thromboembolic complications in CAS”
“We found wide and dynamic variability in response to clopidogrel therapy in patients undergoing endovascular treatment of unruptured cerebral aneurysms, which was significantly associated with thromboembolic and major hemorrhagic complications in our cohort”
“There was a trend for an increased risk of a symptomatic thromboembolic event in patients with pre-procedural PRU values >208. Reloading (clopidogrel 600 mg) patients with preoperative PRU >208 was safe and may have a protective effect on thromboembolic events”
“Multiple diffusion-positive lesions (≥6 in number) occurred more frequently in patients with clopidogrel resistance after endovascular coiling for unruptured aneurysms”
“Optimal threshold, measured using the VerifyNow P2Y12 assay, can be identified using specific thresholds (26% < percent inhibition < 74%) to define patients at lower risk for ischemic and bleeding events. The threshold for hyper-response can highly predict bleeding events in perioperative period”

12. Background
ADAPT-DES study has identified an “optimal” therapeutic range of PRU in 8,000 patients undergoing coronary interventions
Our group has proposed an “acceptable” PRU range of PRU in patients undergoing endovascular treatment of cerebral aneurysms with flow diverters & stents

13. RCT on DAT for Aneurysm Tx
Hwang G, Huh W, Lee JS, et al. Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial. JAMA Neurol E-pub May 26th, 2015.

14. RCT on DAT for Aneurysm Tx
Hwang G, Huh W, Lee JS, et al. Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial. JAMA Neurol E-pub May 26th, 2015.

15. RCT on DAT for Aneurysm Tx
Standard antiplatelet preparation:
75mg clopidogrel daily & 100mg aspirin daily
≥6 days
High on-treatment platelet reactivity:
P2Y12 reaction units (PRU) >213
Aspirin reaction units (ARU) ≥550

16. RCT on DAT for Aneurysm Tx
Modified antiplatelet preparation:
High on-treatment platelet reactivity to aspirin:
300mg aspirin and 75mg clopidogrel daily
High on-treatment platelet reactivity to clopidogrel:
200mg cilostazol, 75mg clopidogrel and 100mg aspirin daily

17. RCT on DAT for Aneurysm Tx
Primary outcome:
Thromboembolic events during the early periprocedural period (within 7 days after coil embolization):
Intra-procedural thromboembolism
Transient ischemic attack
Ischemic stroke
Secondary outcomes:
Bleeding complications within 30 days after coiling
Thromboembolic events 8-30 days after coiling

18. RCT on DAT for Aneurysm Tx
Hwang G, Huh W, Lee JS, et al. Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial. JAMA Neurol E-pub May 26th, 2015.

19. RCT on DAT for Aneurysm Tx
Hwang G, Huh W, Lee JS, et al. Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial. JAMA Neurol E-pub May 26th, 2015.

20. RCT on DAT for Aneurysm Tx
Hwang G, Huh W, Lee JS, et al. Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial. JAMA Neurol E-pub May 26th, 2015.

21. Pt develops worsening of baseline left-sided weakness from old infarct
Pipeline Case #2
POD 2
Pt develops worsening of baseline left-sided weakness from old infarct
PRU 292

22. Pipeline Case #5 PRU 2 after 13 daily 75mg clopidogrel doses POD 8
Acute onset of headache & expressive aphasia
PRU 2
after 13 daily 75mg clopidogrel doses

23. Sudden onset of headache and left-sided hemiparesis
Pipeline Case #33
POD 14
Sudden onset of headache and left-sided hemiparesis
PRU

24. Patient found unresponsive at home
Pipeline Case #48
POD 4
Patient found unresponsive at home
PRU 10
Is it the device or
is it the drugs?

25. First 48 Pipeline Procedures
Last-Recorded PRU Value
Any complication
Major complications
(mRS≥3)
< (n=9)
55.6%
33.3% (hemorrhagic)
60 – 240 (n=37)
10.8%
2.7% (hemorrhagic)
> (n=2)
100%
50% (thromboembolic)

26. First 48 Pipeline Procedures
Last-Recorded PRU Value
Any complication
Major complications
(mRS≥3)
< (n=9)
55.6%
33.3% (hemorrhagic)
60 – 240 (n=37)
10.8%
2.7% (hemorrhagic)
> (n=2)
100%
50% (thromboembolic)

27. First 48 Pipeline Procedures
Last-Recorded PRU Value
Any complication
Major complications
(mRS≥3)
< (n=9)
55.6%
33.3% (hemorrhagic)
60 – 240 (n=37)
10.8%
2.7% (hemorrhagic)
> (n=2)
100%
50% (thromboembolic)

28. First 48 Pipeline Procedures
Last-Recorded PRU Value
Any complication
Major complications
(mRS≥3)
< (n=9)
55.6%
33.3% (hemorrhagic)
60 – 240 (n=37)
10.8%
2.7% (hemorrhagic)
> (n=2)
100%
50% (thromboembolic)

29. First 48 Pipeline Procedures
In multivariate regression analysis, the only independent predictor of a major thromboembolic or hemorrhagic complication (mRS ≥3) up to 6 months in our cohort:
Last-Recorded PRU value <60 or >240

30. Ipsilateral ICH after Pipeline
Our theory:
Majority of ipsilateral post-op ICHs are due to hemorrhagic transformation of clinically-silent perioperative infarctions occurring at time of endovascular procedure in setting of hyper-response to P2Y12 receptor antagonist

31. Ipsilateral ICH after Pipeline
To date, we have performed routine MRI examinations on POD 1 in 35 asymptomatic pts after PED procedures
Any DWI hits: 29 pts (83%)
Mean: 7.4
Median: 4
Range: 0-48
<5mm in max dimension: 90%
High DWI burden (>5 DWI hits or any hit ≥10mm): 18 (51%)
Predictors of a high DWI burden:
Fusiform aneurysm morphology: 83%
Technically-difficult deployment: 69%
Procedure time >90min: 69%

32. Ipsilateral ICH after Pipeline
Low DWI burden (n=1)
Pre-procedure PRU: 233
Not technically difficult
Procedure time: 56 min
Maximum ACT: 306 sec
Asymptomatic
High DWI burden (n=48)
Pre-procedure PRU: 193
Technically difficult
Procedure time: 125 min
Maximum ACT: 266 sec
Asymptomatic

33. Ipsilateral ICH after Pipeline
POD 1 s/p urgent PED treatment of symptomatic R cavernous aneurysm
On Ticagrelor, procedure time 100 min, maximum ACT 342 sec
High DWI burden (n=48)
Routine MRI on POD 1 - Asymptomatic

34. Ipsilateral ICH after Pipeline
POD 1 s/p urgent PED treatment of symptomatic R cavernous aneurysm
On Ticagrelor, procedure time 100 min, maximum ACT 342 sec
High DWI burden (n=48)
Routine MRI on POD 1 - Asymptomatic

35. Ipsilateral ICH after Pipeline
POD 1 s/p urgent PED treatment of symptomatic R cavernous aneurysm
On Ticagrelor, procedure time 100 min, maximum ACT 342 sec
High DWI burden (n=48)
Asymptomatic
PRU 49

36. Ipsilateral ICH after Pipeline
Ticagrelor held on POD 1
POD 2
Asymptomatic
PRU
139
POD 1
75mg clopidogrel administered
on POD 2 & 3
POD 2

37. Ipsilateral ICH after Pipeline
POD 4 early AM
Sudden onset of severe HA & left hemiparesis
PRU 9

38. Last 50 Flow Diversion Procedures
Thromboembolic complications: 6 (12%)
Hemorrhagic complications: 2 (4%)
Complications resulting in a new disabling neurological deficit or death (mRS≥3): 1 (2%)
Hemorrhagic complication after urgent Pipeline deployment

39. Extent of Variability in Initial Patient Response to Clopidogrel
Distribution of Initial PRU value after mg daily clopidogrel doses in 100 pts

40. Delayed Conversion to Clopidogrel Hyper-Response
Change in Response to 75mg daily Clopidogrel dose in Follow-up VerifyNow Test

41. Relative Risk of Thromboembolic & Hemorrhagic Complications
Last Recorded PRU
HYPER
Responder
PRU<60
Target Range
PRU=
PRU>240 Thromboembolic Complication Risk = 60% 60
PRU
Thromboembolic p-value = 0.003
Hemorrhagic p-value = 0.016
N=100 Patients

42. Current DAT Protocol for PEDs & Stents
Initiation of DAT
17 days pre
Aspirin / Plavix dosing
81mg / 75mg
VerifyNow Test
After 10th dose & 1 day before procedure
Target P2Y12 inhibition range
PRU 95 – 207 up to POD 30
PRU 60 – 240 after POD 30
Regimen for hypo-responders
Add 200mg cilostazol
Regimen for hyper-responders
75mg QOD, q3D clopidogrel suspension
Reschedule procedure
PRU <60 or >207
Follow-up VerifyNow test
10 & 30 days p dose change

43. Current DAT protocol PRU <60 or >207
Current DAT Protocol for PEDs & Stents
Initiation of DAT
17 days pre
Aspirin / Plavix dosing
81mg / 75mg
VerifyNow Test
After 10th dose & 1 day before procedure
Target P2Y12 inhibition range
PRU 95 – 207 up to POD 30
PRU 60 – 240 after POD 30
Regimen for hypo-responders
Add 200mg cilostazol
Regimen for hyper-responders
75mg QOD, q3D clopidogrel suspension
Reschedule procedure
PRU <60 or >207
Follow-up VerifyNow test
10 & 30 days p dose change

44. Current DAT protocol Aspirin started 17 days pre-op with 81mg QD
Response to aspirin therapy assessed after 10th or 16th 81mg dose with whole-blood platelet aggregometry
If <50% inhibition, dose is increased to 325mg QD without further testing
 81mg QD provides sufficient inhibition to 82% of pts

45. Current DAT protocol First VerifyNow test after 10th clopidogrel dose
 1 week before procedure

46. Current DAT protocol PRU: >207 40-94 10-39 0-9
Clopidogrel Dosing Schedules: 0.
Add 200mg cilostazol QD 1.
75mg QD 2.
75mg QOD 3.
75mg Q3D 4.
Clopidogrel suspension, 2.5mg to 10mg daily
PRU-Based Dose Adjustments up to POD 30:
PRU:
Adjustment:
>207
Go back 1 step in dosing schedule
40-94
Advance 1 step in dosing schedule
10-39
Advance 2 steps in dosing schedule
0-9
Advance 3 steps in dosing schedule

47. Current DAT protocol PRU: >240 40-59 10-39 0-9
Clopidogrel Dosing Schedules: 0.
Add 200mg cilostazol QD 1.
75mg QD 2.
75mg QOD 3.
75mg Q3D 4.
Clopidogrel suspension, 2.5mg to 10mg daily
PRU-Based Dose Adjustments after POD 30:
PRU:
Adjustment:
>240
Go back 1 step in dosing schedule
40-59
Advance 1 step in dosing schedule
10-39
Advance 2 steps in dosing schedule
0-9
Advance 3 steps in dosing schedule

48. 75mg QOD/QMF/Q5D to 2.5-10mg QD suspension
Current DAT protocol
Dose Adjustment: N:
Mean PRU Pre:
Mean PRU Post:
Mean PRU Change:
% In-Range post:
75mg QD to 150mg QD 11
259
171
(-) 88
82%
75mg QD to 75mg QOD 34 42
100
(+) 68
68%
75mg QD/QOD to 75mg Q3D 33 22 70
(+) 48
49%
75mg QD/QOD/Q3D to 75mg QMF 26 28 92
(+) 64
65%
75mg QOD/QMF/Q5D to mg QD suspension 16 13
147
(+) 134
81%

49. 75mg QOD/QMF/Q5D to 2.5-10mg QD suspension
Current DAT protocol
Dose Adjustment: N:
Mean PRU Pre:
Mean PRU Post:
Mean PRU Change:
% In-Range post:
75mg QD to 150mg QD 11
259
171
(-) 88
82%
75mg QD to 75mg QOD 34 42
100
(+) 68
68%
75mg QD/QOD to 75mg Q3D 33 22 70
(+) 48
49%
75mg QD/QOD/Q3D to 75mg QMF 26 28 92
(+) 64
65%
75mg QOD/QMF/Q5D to mg QD suspension 16 13
147
(+) 134
81%

50. Current DAT protocol
1 clopidogrel hypo-responder experienced a major hemorrhagic complication as a result of doubling the clopidogrel dose without re-testing prior to the procedure (PRU 24610)
To date, no clopidogrel hyper-responder has experienced a major thromboembolic complication as a result of a clopidogrel dose reduction

51. Current DAT protocol 29% outside target PRU range after 10 75mg doses
Efficacy of 17-Day DAT Protocol in Reaching Target PRU Range Pre-Procedure
29% outside
target PRU range
after 10 75mg doses

52. Current DAT protocol 86% who were in-range at 10 days
Efficacy of 17-Day DAT Protocol in Reaching Target PRU Range Pre-Procedure
86% who were
in-range at 10 days
remained in-range
at 17 days
After initial dose
adjustment
93% reached
target PRU range

53. Current DAT protocol Overall 88% were in-range at 17 days
Efficacy of 17-Day DAT Protocol in Reaching Target PRU Range Pre-Procedure
Overall 88% were
in-range at 17 days

54. Current DAT protocol 64% who were in-range pre-procedure
Post-Procedure Conversion to Clopidogrel Hyper-Response
64% who were
in-range pre-procedure
had a delayed conversion to
clopidogrel hyper-response
7-14 days post-procedure

55. First 98 Flow Diversion Procedures
Last-Recorded PRU Value
Any complication
Major complications
(mRS≥3)
< (n=10)
60%
40% (hemorrhagic)
60 – 240 (n=86)
12.8%
1.2% (hemorrhagic)
> (n=2)
100%
50% (thromboembolic)

56. First 98 Flow Diversion Procedures
Last-Recorded PRU Value
Any complication
Major complications
(mRS≥3)
< (n=10)
60%
40% (hemorrhagic)
60 – 240 (n=86)
12.8%
1.2% (hemorrhagic)
> (n=2)
100%
50% (thromboembolic)
p-value <0.0001

57. VerifyNow is a reliable assay for platelet function testing
Conclusion
VerifyNow is a reliable assay for platelet function testing
High PRU value increases relative risk of thrombosis
Low PRU value increases relative risk of bleeding

58. Conclusion
Level 1 evidence now available demonstrating that modifying DAT for clopidogrel hypo-responders decreases rate of thromboembolic complications
RCTs needed to determine if modifying DAT for clopidogrel hyper-responders decreases rate of hemorrhagic complications

59. Conclusion
Wide and dynamic variability in patient response to P2Y12 receptor antagonists administered
64% of pts experience a delayed conversion to clopidogrel hyper-response in the post-procedure period
 general anesthesia effect?

60. Conclusion
Minimizing risk of perioperative complications following flow-diversion & stenting will enable us to continue to expand the frontiers of endovascular aneurysm treatment

61. Thank you!