1. Dominick J. Angiolillo, MD, PhD
Bridging Antithrombotic Therapy in Patients Undergoing Cardiac and Noncardiac Surgery
Dominick J. Angiolillo, MD, PhD
University of Florida College of Medicine-Jacksonville
Director of Cardiovascular Research
Associate Professor of Medicine

2. Bridging Antithrombotic Therapy
Capodanno D and Angiolillo DJ. Circulation. 2013;128:

3. Early Surgery After Stent Placement
126,773 Stent Procedures Followed By 25,977 (20.5%)
Noncardiac Operations Within 24 Months From 2000 To 2010
Early Surgery defined as surgical procedures occurring within 6 weeks in patients treated with BMSs or within 12 months in those treated with DESs
Major surgical procedures more likely to occur within 12 months of stent placement in comparison with 12 to 24 months
Hawn MT et al. J Am Coll Surg. 2012;214:658-66

4. Facts On Surgery in ACS/PCI Patients
At the time of surgery, ACS/PCI patients are typically under treatment with aspirin with a P2Y12 receptor antagonist (i.e. mostly clopidogrel, or prasugrel/ticagrelor in case of ACS).
Surgery is one of the leading cause of early and late antiplatelet discontinuation after PCI.
Antiplatelet therapy increases the risk of bleeding for certain types of surgery.
Antiplatelet therapy discontinuation is a known predictor of stent thrombosis and exposes to a early higher risk of recurrent ischemic events.

5. Increased Thrombotic Risk In Stented Patients Undergoing Surgery
Do You Believe In The Rebound Phenomenon?
No: This hypothesis was not supported by at least two specifically designed randomized pharmacodynamic studies. “Withdrawal of protection” is a better explanation for the observed clustering of thrombotic events after discontinuation.
1. PACT Study (Randomized, double-blind, cross-over PD study – 15 healthy subjects)
Conclusions: “[…] discontinuation of clopidogrel does not result in “rebound” platelet hyperreactivity, as determined by multiple time points, assays, agonists, and agonist concentrations.”
2. Sibbing et al. (Randomized, double-blind, cross-over PD study – 69 subjects with CAD and prior stent implantation)
Conclusions: “The course of platelet aggregation values after clopidogrel cessation provides no evidence for the existence of a rebound phenomenon of platelets.”
Frelinger AL 3rd et al. Circ Cardiovasc Interv. 2010;3:442-9
Sibbing D, et al. J Am Coll Cardiol. 2010;55:558-65

6. Prothrombotic state with incompletely endothelialized stent(s)
Pathogenesis Of Stent Thrombosis, Myocardial Infarction And Death In Stented Patients Undergoing Surgery
Withdrawal of protection
Significantly increased inflammatory prothrombotic state
Significantly increased platelet adhesion and aggregation
Excessive thromboxane A2 activity
Surgical intervention with increased prothrombotic and inflammatory state
increased cytokines, neuroendocrine inflammatory mediator release
increased platelet adhesiveness and persistently high platelet counts
increased release of procoagulant factors
decreased or impaired fibrinolysis
Prothrombotic state with incompletely endothelialized stent(s)

7. 2 3 1 Surgery and Ischemia Surgery and Bleeding Bridging Therapy
Antithrombotic Therapy In ACS/PCI Patients Undergoing Cardiac And Noncardiac Surgery
Surgery and Ischemia
Is it surgery specific? Time-dependent? Lowered by DAPT?
Surgery and Bleeding
Is it surgery specific? Time-dependent? Increased by DAPT?
Bridging Therapy
What is the optimal management of DAPT in the perioperative period? 1 2 3

8. 2 3 1 Surgery and Ischemia Surgery and Bleeding Bridging Therapy
Antithrombotic Therapy In ACS/PCI Patients Undergoing Cardiac And Noncardiac Surgery
Surgery and Ischemia
Is it surgery specific? Time-dependent? Lowered by DAPT?
Surgery and Bleeding
Is it surgery specific? Time-dependent? Increased by DAPT?
Bridging Therapy
What is the optimal management of DAPT in the perioperative period? 1 2 3

9. Poldermans D, et al. Eur Heart J. 2009;30:2769-812
2009 Guidelines For Pre-operative Cardiac Risk Assessment And Perioperative Cardiac Management In Non-cardiac Surgery
Timing of non-cardiac surgery in cardiac-stable/asymptomatic patients with prior revascularization
It is recommended that non-cardiac surgery be performed in patients with recent BMS implantation after a minimum 6 weeks and optimally 3 months following the intervention I B
It is recommended that non-cardiac surgery be performed in patients with recent DES implantation no sooner than 12 months following the intervention.
Consideration should be given to postponing non-cardiac surgery in patients with recent balloon angioplasty until at least 2 weeks following the intervention
IIa
Poldermans D, et al. Eur Heart J. 2009;30:

10. Cardiac Risk Varies With Surgery
Low risk <1%*
Intermediate risk 1-5%*
High risk >5%*
Breast
Dental
Endocrine
Eye
Gynaecology
Reconstructive
Orthopaedic – minor (knee surgery)
Urologic - minor
Abdominal
Carotid
Peripheral arterial angioplasty
Endovascular aneurysm repair
Head and neck surgery
Neurological / orthopaedic – major (hip and spine surgery)
Pulmonary, renal / liver transplant
Urologic - major
Aortic and major vascular surgery
Peripheral vascular surgery
*Risk of MI and cardiac death within 30 days after surgery
Poldermans D, et al. Eur Heart J. 2009;30:

11. Mehran R et al. Lancet. 2013;382:1714-22
Different Modalities Of DAPT Cessation And Cardiovascular Risk After PCI – The PARIS Study
Prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, (N=5,031).
Categorized by modality of DAPT cessation:
Discontinuation: patients had discontinued DAPT as per recommendation of their physician who felt the patient no longer needed therapy
Interruption: patients had interrupted DAPT use on a voluntary basis and as guided by a physician due to (e.g.) surgery. DAPT was then reinstituted within 14 days
Disruption: patients had disrupted DAPT use due to bleeding or non- compliance.
Mehran R et al. Lancet. 2013;382:

12. PARIS: DAPT Cessation and 2-Year Outcomes
CV Death, Def/Prob ST, Spontaneous MI
HR (95% CI) P
Events (n)
On-DAPT
1.00 (Ref)
218
Discontinuation
0.76 (0.50, 1.14)
0.181 31
Interruption
1.05 (0.58, 1.92)
0.864 12
Disruption
2.06 (1.49, 2.83)
<0.001 54
9.82 (4.57, 21.12)
2.96 (1.21, 7.24)
1.71 (1.20, 2.44)
0-7 Days
8-30 days
31+ days
<0.001
0.017
0.003 7 5 42
0.25
0.5 1 2 4 8 16 32
Mehran R et al. Lancet. 2013;382:

13. Risk of MACE Following Noncardiac Surgery in Patients With Coronary Stents
National, Retrospective Cohort Study Of 41,989 Operations Occurring In The 24 Months After A Coronary Stent Implantation Between 2000 And 2010
Key Findings:
Underlying surgical and cardiac risk, rather than stent type, are the primary factors associated with perioperative MACE
Event rates stabilize by 6 months
DAPT continuation does not substantially mitigate risk
Hawn MT et al. JAMA. 2013;310:

14. Trials Of DAPT Duration
3 months
RESET
OPTIMIZE
48 months
6 months
OPTIDUAL
EXCELLENT
ITALIC
ISAR SAFE
PRODIGY
30 months
12 months
DAPT
ARCTIC
DES-LATE
SCORE
Completed
24 months
Ongoing
Capodanno D and Angiolillo DJ. Circulation. 2013;128:

15. Surgery And Ischemia - Summary
The risk of thrombotic and ischemic events in the perioperative period depends on three factors
Individual risk of thrombosis (clinical, angiographic)
Specific risk of surgery (higher with vascular interventions)
Time from ACS/PCI to surgery (higher within 6 months)
Briefly interrupting DAPT in proximity to surgery is not necessarily a harmful practice, especially if aspirin is continued throughout and the thienopyridine restarted as soon as possible after the procedure.
However, whether this concept can automatically be translated to all ACS/PCI patients undergoing surgery remains undefined due to the complex interplay between the variables entered in the risk equation.

16. 2 3 1 Surgery and Ischemia Surgery and Bleeding Bridging Therapy
Antithrombotic Therapy In ACS/PCI Patients Undergoing Cardiac And Noncardiac Surgery
Surgery and Ischemia
Is it surgery specific? Time-dependent? Lowered by DAPT?
Surgery and Bleeding
Is it surgery specific? Time-dependent? Increased by DAPT?
Bridging Therapy
What is the optimal management of DAPT in the perioperative period? 1 2 3

17. Surgeries At High Risk For Bleeding
Intracranial Surgery
Cardiac device implantation
Spinal Surgery
Cardiac Surgery
Liver surgery
Spleen Surgery
Bowel resection
Kidney Surgery
Colonic polyp resection
Urologic surgery

18. Price MJ & Angiolillo DJ. J Am Coll Cardiol. 2012;59:2338-43
Offset Of The Antiplatelet Effects Of Prasugrel And Clopidogrel – The RECOVERY Study
Cumulative Proportion of Subjects
Returning to Baselinea
aReturn to baseline is defined as the return to within 60 P2Y12 reaction units (PRUs) of baseline PRU value determined prior to thienopyridine therapy
bThe day on which the proportion of subjects returning to baseline PRU in the prasugrel group is closest to that attained by the clopidogrel group on Washout Period Day 5
cThe day on which the proportion of subjects returning to baseline PRU in the prasugrel group is closest to that attained by the clopidogrel group on Washout Period Day 7
Price MJ & Angiolillo DJ. J Am Coll Cardiol. 2012;59:

19. Gurbel P, et al. Circulation 2009;120:2577-85
Offset Of The Antiplatelet Effects Of Ticagrelor And Clopidogrel – The ONSET/OFFSET Study 
Last
Maintenance Dose
Loading Dose
Time (hours)
Onset Maintenance Offset
100 90 80 70 60 50 40 30 20 10
IPA %
Ticagrelor (n=54)
Clopidogrel (n=50)
Placebo (n=12)
weeks * ‡ †
20 µM ADP- Final Extent
Gurbel P, et al. Circulation 2009;120:

20. Surgery And Bleeding - Summary
Perioperative bleeding may occur as a consequence of the surgical procedure itself, with hazards varying according to the type of intervention, or as a consequence of being on antiplatelet drugs at the time of surgery.
In many cases, discriminating between different causes of bleeding (e.g., operative vs drug-induced) is not possible.
Guidelines identify a group of surgeries and procedures that appear to be associated with a high risk for bleeding in the context of perioperative anticoagulant and antiplatelet drug use.
Cardiac surgery should be regarded as a special category and possibly distinguished from noncardiac surgeries due to incorporation of additional risk factors for bleeding.
Despite increasing bleeding, antiplatelet therapy also exerts a protective effect, hence the rationale for bridging.

21. 2 3 1 Bridging Therapy Facts on Ischemia Facts on Bleeding
Antithrombotic Therapy In Patients Undergoing Cardiac And Noncardiac Surgery
Facts on Ischemia
Is there a thrombotic risk in stented/ACS patients undergoing surgery?
Facts on Bleeding
Is there a bleeding risk with DAPT continuation before surgery?
Bridging Therapy
What is the optimal management of DAPT in the perioperative period? 1 2 3

22. Basic Concepts – Don’t forget!
Arterial (e.g. coronary) thrombosis is primarily a platelet mediated process (see efficacy of antiplatelet agents in ACS/PCI).
Therefore, bridging strategies warrant an antiplatelet and not an anticoagulant agent.
Anticoagulants not only do not have minimal platelet inhibitory effect, but can actually increase platelet reactivity (e.g. UFH).
Only reversible antiplatelet agents can be considered for bridging therapy.

23. Capodanno D and Angiolillo DJ. Circulation. 2013;128:2785-98
Proposed Bridging Protocols For Patients On DAPT Therapy With Aspirin Plus A P2Y12 Receptor Inhibitor Referred To Cardiac Or Noncardiac Surgery
Bridging Strategy With Small-molecule GPI
Low dose aspirin continued throughout
START
small molecule GPI (tirofiban, eptifibatide)
STOP
small molecule GPI (tirofiban, eptifibatide)
RESUME
small molecule GPI**
(tirofiban, eptifibatide)
Surgery
STOP
prasugrel
STOP
clopidogrel
ticagrelor
RESUME
clopidogrel***
Day -7 -6 -5 -4
-3* -2 -1
-4-6 h
+4-6 h
Follow-up
until discharge
*Tirofiban: 0.1 mcg/Kg/min; If creatinine clearance <50 mL/min, adjust to 0.05 mcg/Kg/min. Eptifibatide: 2.0 mcg/Kg/min; If creatinine clearance is <50 mL/min, adjust to 1.0 mcg/Kg/min.
**If oral administration not possible
***With mg loading dose, as soon as oral administration possible. Prasugrel or ticagrelor discouraged
Capodanno D and Angiolillo DJ. Circulation. 2013;128:

24. Cangrelor Intravenous ADP–P2Y12 receptor antagonist
Rapid acting: quick onset, quick offset
Plasma half-life of 3–5 minutes
60 minutes for return to normal platelet function N H S C F 3 O P Cl
4Na +

25. Capodanno D and Angiolillo DJ. Circulation. 2013;128:2785-98
Cangrelor
Tirofiban
Eptifibatide
Onset of action
Immediate
Potent platelet inhibition
Yes
Plasma half-life
3-5 minutes
2 hours
2.5 hours
Offset of action
1 hour
4-8 hours
4-6 hours
P2Y12-specific No
(Natural Bridge)
“Targeted” Inhibition (thienopyridine–like)
Capodanno D and Angiolillo DJ. Circulation. 2013;128:

26. Angiolillo DJ et al. JAMA 2012;307:265-74
The BRIDGE Trial
400
Cangrelor
Placebo
n=84
n=78
350
n=84
n=75
n=76
n=73
n=57
n=34
n=24
n=14
n=86
n=2
300
n=80
n=70
n=55
n=33
n=7
n=1
n=6
n=85
250
200
VerifyNow PRU
150
100 50
Baseline
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Last on-infusion sample
Pre-CABG sample
Time Point
N indicates number of patients with valid samples in the intention to treat population; PRU= P2Y12 reaction units; Data expressed as mean±SD
Angiolillo DJ et al. JAMA 2012;307:265-74

27. Capodanno D and Angiolillo DJ. Circulation. 2013;128:2785-98
Proposed Bridging Protocols For Patients On DAPT Therapy With Aspirin Plus A P2Y12 Receptor Inhibitor Referred To Cardiac Or Noncardiac Surgery
Bridging Strategy With Cangrelor
Low dose aspirin continued throughout
START
cangrelor*
STOP
cangrelor
RESUME
cangrelor**
Surgery
STOP
prasugrel
STOP
clopidogrel
ticagrelor
RESUME
clopidogrel***
Day -7 -6 -5 -4
-3* -2 -1
-1-6 h
+4-6 h
Follow-up
until discharge
*Initiate within 72 hours from P2Y12 inhibitor discontinuation at a dose of 0.75 mg/Kg/min for a minimum of 48 hours and a maximum of 7 days.
**If oral administration not possible
***With mg loading dose, as soon as oral administration possible. Prasugrel or ticagrelor discouraged
Capodanno D and Angiolillo DJ. Circulation. 2013;128:

28. Is Cangrelor Ready For The Prime Time?
[…] There were zero votes in favor of approving cangrelor as a "bridge" therapy, mainly because the panel members again felt there wasn't sufficient evidence to provide an assessment of the risks and benefits. […]
Source: theheart.org

29. Limitations Of Current Guidelines
Do not stratify bleeding risk for individual intervention.
Do not stratify the risk of thrombosis in relation to the angiographic and clinical characteristics.
Do not offer a general strategy to be applied to different types of interventions in relation to the risk of thrombosis and bleeding, but rather refer to an assessment of the risk / benefit ratio in the individual patient.
Do not provide precise operational guidelines on the management of patients at high thrombotic risk candidate for surgery not be postponed.
In case of necessity of withdrawal of antiplatelet therapy, do not specify the mode of recovery of antiplatelet therapy.

30. Rossini R et al. Eurointervention 2014 In press
A Consensus Approach
Perioperative Management Of Antiplatelet Therapy in Patients With Coronary Stents Undergoing Cardiac and non-Cardiac surgery: a Consensus Document from Italian Cardiological, Surgical, and Anesthesiological Societies
Operative protocols of perioperative DAPT management in 14 types of surgery, resulting from a consensus between cardiologists and surgeons
Cardiologists defined the ischemic risk
Surgeons defined the bleeding risk linked to different operations in their field.
Recommendations on the management of antithrombotic therapy on a “per-patient” and “per- intervention” basis
Free App available in App Store and Google Play
Stent&Surgery
Rossini R et al. Eurointervention 2014 In press

31. What Should I Do If My ACS/PCI Patient Needs Surgery
What Should I Do If My ACS/PCI Patient Needs Surgery? Case Examples and Closing Remarks
Dental procedure and Dentist wants to stop DAPT
Answer: Change Dentist.
Minor Surgery and Surgeon wants to stop DAPT
Answer: Change Surgeon.
Major Surgery requiring DAPT discontinuation
Answer: Always consider bridging with a reversible antiplatelet agent (e.g GPI, cangrelor when available), never an anticoagulant, re-start DAPT as soon as possible, and DON’T stop aspirin.