1. Safety of Perioperative Aspirin Use in Pancreatic Surgery Andrea M Wolf, Jordan M Winter, Salil D Gabale, Eugene P Kennedy, Ernest L Rosato, Harish Lavu, Charles J Yeo 4 October 2012

2. Disclosures The authors have no financial interests to disclose

3. Background Cardiovascular disease is the number one cause of death in the U.S. – 900,000 deaths annually Aspirin reduces the risk of thrombotic events – Most widely used anticoagulant – Recommended by USPSTF for primary prevention of cardiovascular disease and secondary prevention in those patients with risk factors

4. Platelet Activation and Aggregation

5. Requires conversion of arachidonic acid to prostaglandin by prostaglandin synthase (cyclooxygenase) Prostaglandin is further metabolized by thromboxane synthase to thromboxane A 2 (TXA 2 ) TXA 2 activates new platelets, stimulates aggregation, and enhances vasoconstriction Thromboxane synthase PG Cyclooxygenase TXA2 AA Platelet activation Platelet aggregation Vasoconstriction

6. Platelet Activation and Aggregation Requires conversion of dietary arachidonic acid to prostaglandin by prostaglandin synthase (cyclooxygenase) Prostaglandin is further metabolized by thromboxane synthase to thromboxane A 2 (TXA 2 ) TXA 2 activates new platelets, stimulates aggregation, and enhances vasoconstriction Thromboxane synthase PG Aspirin Cyclooxygenase TXA2 AA Platelet activation Platelet aggregation Vasoconstriction

7. Aspirin Effect Irreversible inhibition of cyclooxygenase – Occurs within 30 minutes of ingestion – Lasts for lifespan of platelet, 8 – 10 days Studies involving cardiovascular procedures – Significant decrease in risk of major cardio and cerebrovascular complications and 30-day mortality

8. Aspirin Withdrawl Syndrome Normal hemostasis may return within 72 – 96 hours after discontinuation. Rebound period after acute aspirin withdrawl is associated with increased thromboxane production and decreased fibrinolysis – Clinically prothrombotic state Peak in thromboxane levels and cardiovascular events at 8.5 – 10 days post cessation Standard practice of discontinuing aspirin 7-10 days preoperatively results in surgery and catecholamine surges timed with the thromboxane peak

9. Hypothesis Continuation of aspirin therapy during pancreatic surgery does not contribute to increases in adverse events

10. Methods Retrospective analysis of an institutional IRB-approved pancreatectomy database – October 2005 to February 2012 – 1044 patients 1017 evaluable subjects after exclusion criteria met Records queried for perioperative aspirin use – Aspirin continued through morning of surgery – Aspirin resumed orally on post-operative day 1 – 5000 Units of heparin subcutaneously 1 hr prior to incision

11. Results: Patient Demographics All patients (n=1017) Aspirin users (n=289, 28%) Aspirin non-users (n=728, 72%) P-value Age (yr), median (range) 65 (18-92) 69 (40-87) 62 (18-92) <0.001 Male gender, n (%) 480 (47) 173 (60)307 (42) <0.001 Pancreatico- duodenectomy, n (%) 686 (68)204 (30) 482 (70) 0.262

12. Results: Intraoperative Parameters All patients (n=1017) Aspirin users (n=289) Aspirin non- users (n=728) P-value Estimated blood loss, median (range) 400 (0-25000) 400 (25-25000) 400 (0-8400) 0.661 Intraoperative crystalloid (L), median (range) 6.8 (1-28) 6.8 (1.8-18.2)0.680 Transfused units, median (range) 0 (0-36) 0 (0-5) 0.221

13. Results: Complications All patients (n=1017) Aspirin users (n=289) Aspirin non- users (n=728) P-value Any complication (%)4347420.141 Pancreatic fistula (%)1415140.490 Delayed gastric emptying (%) 91090.502 Cardiac complication (%)91180.072

14. Results: Outcome All patients (n=1017) Aspirin users (n=289) Aspirin non- users (n=728) P-value 30-day mortality (%)1210.071 Hospital stay (d), median (range) 6 7 (4-55) 6 (3-62) 0.111 Readmission (%)1617 150.451

15. Results Comparable blood loss, intraoperative fluids, and transfusion rates No difference in overall perioperative complications Trend toward more cardiac complications in aspirin use group, but not reaching statistical significance

16. Limitations Retrospective, non-randomized Lack of data on preoperative comorbidity Patient self-reporting of aspirin use

17. Discussion The small increase in CV events in patients on aspirin therapy was not unanticipated. Investigations of patients undergoing cardiovascular procedures show that patients should not discontinue aspirin therapy. No negative effects from continued aspirin use were seen in our retrospective analysis of >1000 patients undergoing major pancreatic resection. The general practice of discontinuing aspirin therapy should be abandoned unless risk of bleeding outweighs risk of cardiovascular complication.