Drug-Eluting Stents and Non-Cardiac Surgery: Learning Lessons the Hard Way

In this issue of the Journal, Bolad et al return the readers to a vital topic of optimal management for patients requiring non-cardiac surgery after treatment with percutaneous coronary intervention (PCI).¹ Even though the subject has been previously broadly discussed in the literature and despite the existing professional guidelines by the cardiology and surgery societies, there is still no consensus on the best possible care of these patients and the ways to prevent perioperative complications.^2–7

Bolad et al present a single-center analysis of outcomes on consecutive 238 patients undergoing non-cardiac surgery within 8 days to 49 months of the index PCI, using plain balloon angioplasty, bare-metal-stent (BMS) or drug-eluting stent (DES).¹ The important observations from this series are as follows: 1) definite/probable stent thrombosis (ST) was a relatively frequent cardiac event and occurred exclusively in patients who had had DES implantation (6 of 141 patients; 4.2%); the clinical presentation was ST-segment elevation myocardial infarction in all patients associated with death in one patient; 2) five of 6 cases of ST in the DES group occurred within 24 hours of surgery; 3) in four of 6 patients ST occurred later than one year after DES implantation; and 4) at the time of surgery, 4 of 6 patients were off antiplatelet therapy, 1 patient received only aspirin and one patient developed ST despite continued dual antiplatelet therapy with aspirin and clopidogrel.

Several lessons can be learned from this report. The study confirms that a significant proportion of patients (approximately every 10th patient in this series) may require non-cardiac surgery within a few years after PCI. This fact, coupled with potentially life-threatening cardiovascular complications, occurring throughout the perioperative period, should always be kept in mind when dealing with patients with coronary artery disease undergoing non-cardiac surgery. The best available antiplatelet options should be considered for these patients and decisions regarding coronary revascularization should be carefully weighted when a likely surgery may be required after PCI. 

The unpleasant evidence that is reinforced by the current report is that ST still occurs in patients undergoing non-cardiac surgery, even though perioperative management is performed in accord with the latest guidelines on perioperative cardiovascular evaluation and care.^2,3 It is currently recommended that (a) in patients with recent BMS implantation, elective non-cardiac surgery should be postponed for a minimum period of 6 weeks and optimally up to 3 months and antiplatelet therapy be continued; and (b) after DES implantation, elective surgery should be performed no sooner than 12 months of continuous dual antiplatelet therapy, and after 12 months, patients can undergo non-cardiac surgery with continuation of at least aspirin therapy.^2-4 Remarkably, however, 4 patients in the series by Bolad et al developed ST later than 1 year after DES implantation, including one patient in whom ST occurred despite continued antiplatelet therapy.¹

Maintenance of antiplatelet agents during the perioperative period is a crucial issue in patients with coronary artery disease, especially in patients after DES implantation. A multi-society advisory committee emphasizes that in patients treated with DES, who are intended for subsequent non-cardiac surgery that mandate discontinuation of thienopyridine therapy, aspirin therapy has to be continued and thienopyridine restarted as soon as possible after the surgical procedure.⁴ In line with previous reports, the majority of cases of ST in the series by Bolad et al¹ were linked to discontinuation of antiplatelet therapy.^8–11 The risk of ST is particularly increased in the highly thrombogenic environment of a perioperative period, which is associated with augmented release of endogenous catecholamines, platelet activation and hypercoagulability.^12,13 Adverse cardiac events typically develop in the early post-operative period (within the first 24 hours) requiring clinical awareness and thorough monitoring of the electrocardiographic pattern, as well as clinical and hemodynamic status. It is strongly recommended that non-cardiac surgery in patients after PCI will be carried out in institutions with immediate PCI availability, to provide timely definitive treatment of ST.

The threat of bleeding complications urges the surgeons to discontinue antiplatelet agents close to the procedure. Both aspirin and clopidogrel raise the incidence of bleeding events, and their combination carries an increase in hemorrhagic complications beyond that associated with each drug alone. For instance, in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, bleeding tended to be more frequent if coronary artery bypass grafting (CABG) was performed within 5 days of clopidogrel administration.¹⁴ Likewise, in other series of non-emergent CABG, patients with preoperative clopidogrel exposure had greater 24-hour mean chest tube output as compared to those without the clopidogrel exposure, were less frequently extubated within 8 hours, required more frequent blood transfusions, and had significantly higher rates of reoperation for bleeding.^15,16 The question is, however, whether possible occurrence of bleeding events justify perioperative discontinuation of antiplatelet agents that places a patient at risk for ST and its dreadful consequences including myocardial infarction and mortality? In fact, there are limited data focusing specifically on impact of bleeding events on the mortality of patients maintaining antiplatelet therapy through perioperative period. The data from small non-cardiac surgical series are encouraging, showing no increase in mortality in patients continuing aspirin or clopidogrel, except for patients with transurethral prostatectomy and intracranial surgery.^17-20 In a meta-analysis of 474 studies, patients receiving low-dose aspirin had significantly increased hemorrhagic risk without increase in surgical mortality.²¹ In patients with acute coronary syndromes, CABG-related major bleeding had no association with mortality, while clopidogrel when administered prior to CABG was related to less perioperative myocardial infarctions.^14,22,23 However, in the randomized, double-blind Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), treatment with prasugrel, a potent, 3rd generation thienopyridine, compared with clopidogrel was associated with an increased rate of CABG-related TIMI major bleeding, including 2 cases of fatal bleeding in the prasugrel group vs. none in the clopidogrel group.²⁴ This urged the Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee to recommend avoiding the use of prasugrel in the perioperative period.²⁵

Can we improve outcomes of patients undergoing non-cardiac surgery after coronary stenting? The use of novel antiplatelet agents including those allowing smooth bridging therapy, may open new perspectives for the perioperative care of these patients. Ticagrelor, a reversible oral non-thienopyridine antiplatelet agent, has fast (up to 3 hours) inhibition of platelet aggregation and rapid (within 12 hours) reduction of inhibition, equally useful features in patients undergoing surgery.²⁶ One of the studies highlighted that among patients having CABG between 1 to 5 days after discontinuing the drug, treatment with ticagrelor as opposed to clopidogrel was associated with lower incidence of major bleeding.²⁷ Another study showed that switching from clopidogrel to ticagrelor is feasible, without reduction in antiplatelet effect.²⁸ On-going trial is defining whether cangrelor, an intravenous, reversible, non-thienopyridine antiplatelet agent, may be safely used as bridging antiplatelet agent in patients undergoing CABG.²⁹ A short half-life of about 2.6 minutes, achieving platelet aggregation within just 30 minutes of infusion, makes cangrelor ideally suited for the bridging therapy.³⁰ Small-molecule platelet glycoprotein GP IIb/IIIa receptor inhibitor, tirofiban, has been successfully applied as a bridging agent in a small series of 30 patients with recently implanted DES: there were no cases of ST and no increase in bleeding events during the perioperative period, after discontinuation of clopidogrel and bridging therapy with tirofiban.³¹ Nonetheless, there is a quest for larger prospective studies to assess the relationship between the severity of non-cardiac surgery-related bleeding and ischemic clinical outcomes using new antiplatelet agents and strategies. Future studies should also evaluate whether bioabsorbable stents with possible elimination of the long-term use of dual antiplatelet therapy without a subsequent risk of stent thrombosis, may provide improved safety in patients requiring non-cardiac surgery.

Finally, the use of personalized medicine with genetic determination of the response to a particular antiplatelet agent and tight effective monitoring of platelet function throughout the perioperative period may provide increased safety in these patients.³² Rapid laboratory tests that show quantitative platelet inhibitory response to the specific drug may make the short perioperative period in a given individual having surgery after PCI safer.

References

1. Bolad IA, Alqaqa’a A, Khan B, Srivastav SK, von der Lohe E, Sadanandan S, Breal JA. Cardiac events after non-cardiac surgery in patients with previous coronary intervention in the drug-eluting stents era. J Invasive Cardiol 2011;23:283–286.
2. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Ornato JP, Page RL, Tarkington LG, Yancy CW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery); American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Rhythm Society; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society for Vascular Surgery. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation 2007;116:e418–499.
3. Poldermans D, Bax JJ, Boersma E, De Hert S, Eeckhout E, Fowkes G, Gorenek B, Hennerici MG, Iung B, Kelm M, Kjeldsen KP, Kristensen SD, Lopez-Sendon J, Pelosi P, Philippe F, Pierard L, Ponikowski P, Schmid JP, Sellevold OF, Sicari R, Van den Berghe G, Vermassen F, Hoeks SE, Vanhorebeek I, Vahanian A, Auricchio A, Bax JJ, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearn P, McDonag T, McGregor K, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P, De Caterina R, Agewall S, Al Attar N, Andreotti F, Anker SD, Baron-Esquivias G, Berkenboom G, Chapoutot L, Cifkova R, Faggiano P, Gibbs S, Hansen HS, Iserin L, Israel CW, Kornowski R, Eizagaechevarria NM, Pepi M, Piepoli M, Priebe HJ, Scherer M, Stepinska J, Taggart D, Tubaro M; Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of European Society of Cardiology (ESC); European Society of Anaesthesiology (ESA). Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery: the Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA). Eur J Anaesthesiol 2010;27:92–137.

4. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, O'Gara P, Whitlow P; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115:813–818.
5. Wilson SH, Fasseas P, Orford JL, Lennon RJ, Horlocker T, Charnoff NE, et al. Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol 2003;42(2):234–240.
6. van Kuijk JP, Flu WJ, Schouten O, Hoeks SE, Schenkeveld L, de Jaegere PP, et al. Timing of noncardiac surgery after coronary artery stenting with bare metal or drug-eluting stents. Am J Cardiol 2009;104:1229-1234.
7. Brancati MF, Giammarinaro M, Burzotta F, Trani C, Coroleu SF, Porto I, et al. Outcome of non-cardiac surgery after stent implantation in the DES Era: Results of the Surgery After Stent (SAS) registry. J Invasive Cardiol. 2011;23:44–49.
8. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364(9444):1519–1521. 
9. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293(19):2126–2130.
10. Ong AT, McFadden EP, Regar E, de Jaegere PP, van Domburg RT, Serruys PW. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 2005;45:2088–2092.
11. Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long term follow-up. Am J Cardiol 2006;98:352–356.
12. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: Implications for the anesthesiologist. Anesthesiology 2002;97:215–252. 
13. Priebe HJ. Triggers of perioperative myocardial ischaemia and infarction. Br J Anaesth. 2004;93:9–20
14. Fox KA, Mehta SR, Peters R et al; Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110:1202–1208. 
15. Hongo RH, Ley J, Dick SE, Yee RR. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002;40:231–237.
16. Berger JS, Frye CB, Harshaw Q, Edwards FH, Steinhubl SR, Becker RC. Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery: A multicenter analysis.J Am Coll Cardiol 2008;52:1693–1701.
17. Manning BJ, O’Brien N, Aravindan S, et al. The effect of aspirin on blood loss and transfusion requirements in patients with femoral neck fractures. Injury 2004;35:121–124.

18. Neilipovitz DT, Bryson GL, Nichol G. The effect of perioperative aspirin therapy in peripheral vascular surgery: A decision analysis. Anesth Analg 2001;93:573–580.
19. Palmer JD, Sparrow OC, Iannotti F. Postoperative hematoma: A 5-year survey identification of avoidable risk factors. Neurosurgery 1994;35:1061–1064.
20. Thurston AV, Briant SL. Aspirin and post-prostatectomy haemorrhage. Br J Urol 1993;71:574–576.
21. Burger W, Chemnitius JM, Kneissl GD, Ru¨cker G. Low-dose aspirin for secondary cardiovascular prevention—cardiovascular risks after its preoperative withdrawal versus bleeding risks with its continuation—review and meta-analysis. J Int Med 2005;257:399–414.
22. Mehran R, Pocock SJ, Nikolsky E, Clayton T, Dangas GD, Kirtane AJ, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010;55:2556–2566. 
23. Ebrahimi R, Dyke C, Mehran R, et al.Outcomes following preoperative clopidogrel administration in patients with acute coronary syndromes undergoing coronary artery bypass surgery: The ACUITY trial. J Am Coll Cardiol 2009;53:1965–1972.
24. Wiviott SD, Braunwald E, McCabe CH, et al, for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–2015.
25. https://fdaapprovalsreview.com/Prasugrel__Effient_.html
26. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27:1038–1047.
27. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007;50:1844–1851.
28. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: The RESPOND study. Circulation 2010;121:1188–1199.
29. https://clinicaltrials.gov/ct2/show/NCT00767507
30. Greenbaum AB, Grines CL, Bittl JA, Becker RC, Kereiakes DJ, Gilchrist IC, Clegg J, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: Results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J  2006;151:689.e1–689.e10.
31. Savonitto S, D'Urbano M, Caracciolo M, Barlocco F, Mariani G, Nichelatti M, Klugmann S, De Servi S. Urgent surgery in patients with a recently implanted coronary drug-eluting stent: A phase II study of 'bridging' antiplatelet therapy with tirofiban during temporary withdrawal of clopidogrel. Br J Anaesth 2010;104:285–291.

32. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849–857.

_____________________________________

From the Rambam Health Care Campus and the Technion - Israel Institute of Technology, Haifa, Israel.
The authors report no conflicts of interest regarding the content herein.
Address for correspondence: Eugenia Nikolsky, MD, PhD, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel. Email : e_nikolsky@rambam.health.gov.il