anti-platelet therapy testing for neurointerventional procedures where are we now? josser e....

Anti-Platelet Therapy Testing for Neurointerventional

Procedures

Where are we now?Josser E. Delgado, M.D.

Yasha Kayan, M.D.

Neuroscience InstituteAbbott Northwestern HospitalConsulting Radiologists, Ltd

Minneapolis, MN

Disclosures

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

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

Background• On-going controversy among

neurointerventionalists regarding whether or not to perform antiplatelet testing

• Field is split between:– “Non-testers”– “Testers”

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

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

Background1. 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;29:281-5.2. 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;29:786-91.

3. 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;29:1389-1394.

4. Drazin D, Choulakian A, Nuno M, et al. Body weight: a risk factor for subtherapeutic antithrombotic therapy in neurovascular stenting. J Neurointerv Surg. 2011;3:177-81.

5. 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):695-8. Epub April 1st, 2011.

6. 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):288-94.

7. 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;34:716-20.

8. 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.

9. Akbari SH, Reynolds MR, Kadkhodayan Y, et al. Hemorrhagic complications after prasugrel (Effient) therapy for vascular neurointerventional procedures. J Neurointerv Surg. 2013 Jul;5(4):337-43.

Background10. 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.

11. 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):373-8. E-pub June 22nd, 2013.

12. 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):128-35. E-pub July 4th, 2013.

13. 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):1603-10. E-pub Aug 23rd 2013.

14. 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):761-7. E-pub November 14th, 2013.

15. 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. 2014. E-pub Jan 7th 2014.

16. 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. 2014. E-pub Feb 19th 2014.

Background17. 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):428-35. E-pub March 11th, 2014.

18. 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. 2014. E-pub April 10th 2014.

19. 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. 2014. E-pub April 16th 2014.

20. 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. 2014. E-pub May 15th, 2014.

21. 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):1830-6. E-pub June 21st, 2014.

22. 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.

23. Bo W, Xiao-Qing L, Ning M, et al. Association of thrombelastographic parameters with post-stenting ischemic events. J Neurointerv Surg. 2015. E-pub June 3rd, 2015.

Background1. “Our data strongly suggest a correlation of insufficient clopidogrel-

related platelet inhibition with an increased risk of thromboembolic events in supra-aortic stent placement”

2. “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”

3. “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”

4. “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”

5. “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”

6. “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”

7. “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”

Background8. “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”

9. “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”

10. “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”

11. “Multiple diffusion-positive lesions (≥6 in number) occurred more frequently in patients with clopidogrel resistance after endovascular coiling for unruptured aneurysms”

12. “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”

Background• ADAPT-DES study has identified an

“optimal” therapeutic range of 95-207 PRU in 8,000 patients undergoing coronary interventions

• Our group has proposed an “acceptable” PRU range of 60-240 PRU in patients undergoing endovascular treatment of cerebral aneurysms with flow diverters & stents

RCT on DAT for Aneurysm Tx

23. 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. 2015. E-pub May 26th, 2015.

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. 2015. E-pub May 26th, 2015.


• 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


• 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


• 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


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. 2015. E-pub May 26th, 2015.


POD 2Pt develops worsening of baseline left-sided weakness from old infarct

PRU 292

Pipeline Case #2

POD 8Acute onset of headache & expressive aphasia

PRU 2after 13 daily

75mg clopidogrel

doses

Pipeline Case #5

POD 14Sudden onset of headache and left-sided hemiparesis

PRU0

Pipeline Case #33

Pipeline Case #48POD 4

Patient found unresponsive at home

PRU10Is it the device

oris it the drugs?

Last-Recorded PRU Value

Any complication Major complications(mRS≥3)

<60 (n=9) 55.6% 33.3% (hemorrhagic)

60 – 240 (n=37)

10.8% 2.7% (hemorrhagic)

>240 (n=2) 100%50%

(thromboembolic)

First 48 Pipeline Procedures



<60 (n=9)

55.6%33.3%

(hemorrhagic)

60 – 240 (n=37)


>240 (n=2) 100%50%

(thromboembolic)




<60 (n=9) 55.6% 33.3% (hemorrhagic)

60 – 240 (n=37)


>240 (n=2)

100%50%

(thromboembolic)




<60 (n=9) 55.6% 33.3% (hemorrhagic)

60 – 240 (n=37)

10.8%2.7%

(hemorrhagic)

> 240 (n=2)

100%50%

(thromboembolic)


In multivariate regression analysis, theonly 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


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

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%


Low DWI burden (n=1)Pre-procedure PRU: 233Not technically difficultProcedure time: 56 minMaximum ACT: 306 sec

Asymptomatic

High DWI burden (n=48)Pre-procedure PRU: 193

Technically difficultProcedure time: 125 minMaximum ACT: 266 sec

Asymptomatic


POD 1 s/p urgent PED treatment of symptomatic R cavernous aneurysmOn Ticagrelor, procedure time 100 min, maximum ACT 342 sec

High DWI burden (n=48)Routine MRI on POD 1 - Asymptomatic


POD 1 s/p urgent PED treatment of symptomatic R cavernous aneurysmOn Ticagrelor, procedure time 100 min, maximum ACT 342 sec

High DWI burden (n=48)Asymptomatic PRU

49


Ticagrelor held on POD 1POD 2

AsymptomaticPOD 1 POD 2

PRU139


75mg clopidogrel administered on POD 2 & 3

POD 4 early AMSudden onset of severe HA & left hemiparesis

PRU9


• 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

Last 50 Flow Diversion Procedures

Extent of Variability in Initial Patient Response to

ClopidogrelDistribution of Initial PRU value after 8-9 75mg daily clopidogrel doses in 100 pts

Delayed Conversion to Clopidogrel Hyper-Response

Change in Response to 75mg daily Clopidogrel dose in Follow-up VerifyNow Test

0 50 100 150 200 250 300

HYPO ResponderPRU >240

PRU<60 Major

Hemorrhagic

Complication Risk =

11%

PRU <240 Thromboembolic Complication Risk= 3.6%

PRU>60 Major Hemorrhagic Complication Risk= 0%

240

HYPERResponder

PRU<60Target RangePRU= 60-240

PRU>240 Thromboembol

ic Complication

Risk = 60%0 60 PRU

N=100 PatientsThromboembolic p-value = 0.003

Hemorrhagic p-value = 0.016

Relative Risk of Thromboembolic &

Hemorrhagic ComplicationsLast Recorded PRU

Current DAT protocolCurrent 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 rangePRU 95 – 207 up to POD 30PRU 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

Current DAT protocolCurrent 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 30PRU 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

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

Current DAT protocolFirst VerifyNow test after10th clopidogrel dose

1 week before procedure

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


Current DAT protocol

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




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 2.5-10mg QD suspension

16 13 147 (+) 134 81%


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

2.5-10mg QD suspension

16 13 147 (+) 134 81%


• 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 24610)

• To date, no clopidogrel hyper-responder has experienced a major thromboembolic complication as a result of a clopidogrel dose reduction


Efficacy of 17-Day DAT Protocol in Reaching Target 60-240 PRU Range Pre-Procedure


29% outsidetarget PRU range

after 10 75mg doses



After initial doseadjustment

93% reachedtarget PRU range

86% who werein-range at 10 daysremained in-range

at 17 days



Overall 88% werein-range at 17 days

Post-Procedure Conversion to Clopidogrel Hyper-Response


64% who werein-range pre-procedure

had a delayed conversion toclopidogrel hyper-response7-14 days post-procedure



<60 (n=10)

60% 40% (hemorrhagic)

60 – 240 (n=86)


>240 (n=2) 100%50%

(thromboembolic)

First 98 Flow Diversion Procedures



<60 (n=10)

60% 40% (hemorrhagic)

60 – 240 (n=86)

12.8%1.2%

(hemorrhagic)

>240 (n=2) 100%50%

(thromboembolic)p-value <0.0001

First 98 Flow Diversion Procedures

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

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

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?

Conclusion• Minimizing risk of perioperative

complications following flow-diversion & stenting will enable us to continue to expand the frontiers of endovascular aneurysm treatment

Thank you!

anti-platelet therapy testing for neurointerventional procedures where are we now? josser e....

Documents

j neuroradiol

clopidogrel resistance

degree of platelet reactivity

neurovascular stenting

narang j

linn j

j neurointerv

bleeding risk