Cardio vascular disease (CVD) is one of the commonest in recent days and the major cause of morbidity and mortality for those individuals. In our day-to-day practice often we prescribe antiplatelet medicines for our diabetic patients, both as primary prevention and secondary prevention of cardiovascular disease (CVD). So it is obvious that a huge number of diabetic patients are having antiplatelet therapy. It is a common practice among physicians and treating surgeons to stop aspirin prior to surgery because of fear of bleeding complications, based on theoretical risk of bleeding and on isolated case reports of excessive bleeding with aspirin therapy. This practice often predisposes the patient to adverse risk of thromboembolic events, rather than emergencies related to risk of bleeding. So any therapeutic change affecting patients’ health sequel is a matter of great concern for us, as CVD is already the largest contributor to the direct and indirect costs of diabetes management. In this review article we would see how safe is antiplatelet therapy in surgery in diabetics!
Antiplatelet Therapy and Diabetes
Antiplatelet therapy appears to have a modest effect on ischemic vascular events with the absolute decrease in events depending on the underlying CVD risk.(1-5) In the 2015 recommendations of American Diabetes Association, the use of antiplatelet therapy is very simply explained in both primary and secondary prevention of CVD.(6) Aspirin therapy is considered as primary prevention in both type 1 and type 2 diabetes who are at increased risk of CVD. Even they categorize increased risk individuals as those men aged >50 years and women aged >60 years with at least one additional major CVD risk factor like family history of CVD or hypertension or smoking or dyslipidaemia or albuminuria. For secondary prevention aspirin is recommended for any age group diabetics with a history of CVD. Further recommendation says clopidogrel should be used in aspirin allergy cases only. They very clearly mention that dual antiplatelet therapy is reasonable for up to a year after an acute coronary syndrome.
Antiplatelet Therapy and Surgical Risk
As we see, as antiplatelet agent we use aspirin and clopidogrel group of medicines. Aspirin reduces platelet aggregation for the lifespan of the platelet, ∼8-10 days and increases the risk of bleeding! But patients on aspirin therapy may require any non-cardiac or cardiac surgery; even cataract surgery, cutaneous surgery, dental extractions, etc are very common in everyday life. The current consensus and many recommendations are controversial and may not be conclusive in favour of continuing aspirin therapy. But many authors suggested that the perioperative management of anticoagulation in these patients at the time of elective surgery is debatable yet important as it involves balancing the risks of arterial or venous thromboembolism (such as ischaemic stroke, myocardial infarction, pulmonary embolism or deep vein thrombosis) if the drug is stopped, against the risk of bleeding if the antiplatelet drug is continued. However in a special situation like diabetes, which is considered as heart attack equivalent, how safe is discontinuation of antiplatelet therapy needs proper attention. Let us have a journey through medical evidence based tools like literatures, research papers, recommendations, etc in the field of some regular surgical situations to come to a conclusion whether to continue or discontinue antiplatelet therapy prior to those surgeries in our day-to-day practice.
Non-cardiac Surgery and Antiplatelet Therapy
There is strong evidence that aspirin prevents venous thromboembolism after non-cardiac surgery.(7, 8) However, the Pulmonary Embolism Prevention (PEP) trial that included 13,356 patients undergoing surgery for a hip fracture and other perioperative trials have shown that aspirin significantly increases the risk of bleeding requiring a transfusion.(7, 8) Recently published the Perioperative Ischemic Evaluation 2 (POISE-2) trial(9) included 10,010 patients from July 2010 through December 2013 at 135 hospitals in 23 countries. Patients were preparing to undergo non-cardiac surgery and were at risk for vascular complications to receive aspirin or placebo and clonidine or placebo. The results of the aspirin trial are reported here. The patients were stratified according to whether they had not been taking aspirin before the study (initiation stratum, with 5628 patients) or they were already on an aspirin regimen (continuation stratum, with 4382 patients). Patients started taking aspirin (at a dose of 200 mg) or placebo just before surgery and continued it daily (at a dose of 100 mg) for 30 days in the initiation stratum and for 7 days in the continuation stratum, after which patients resumed their regular aspirin regimen.
The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days. The primary outcome in the POISE-2 trial(9) occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P=0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P=0.04). Although the POISE-2 trial is a large study by perioperative standards, as limitation of the said study the lower boundary (0.86) and upper boundary (1.15) of the hazard ratio for the primary outcome show that they have not excluded the possibility of appreciable benefit or harm. But a meta-analysis of 474 studies showed that the use of aspirin increased intraoperative bleeding by a factor of 1.5; however, no related increased risk in morbidity or mortality was found in this systematic review.(10)
In a systemic review and meta-analysis on the potential risks and health hazards of stopping aspirin confirmed major negative impact and worrying prognostic inference of withdrawal across a greater number of individuals (50,279) at risk of recurrent cardiovascular events.(11) We know one of the problems with aspirin withdrawal is the risk of a rebound phenomenon. Abrupt cessation of aspirin results in an increase in thromboxane A2 activity and a decrease in fibrinolysis, resulting in increased platelet adhesion and aggregation.(11, 12) One recent meta-analysis found that aspirin withdrawal was associated with a significantly increased risk of myocardial infarction and death.(11) Similarly, Ferrari et al(13) and Chassot et al(14) suspected the existence of a biological platelet rebound phenomenon on disruption of aspirin therapy, thus creating a prothrombotic state which may ultimately cause fatal thromboembolic events.
We must remember the surgical trauma by itself creates a prothrombotic and proinflammatory state, including platelet activation/aggregation and reduced fibrinolytic activity(15, 16) and the perioperative administration of aspirin with its beneficial effect may prevent major vascular complications by inhibiting thrombus formation.(17) Whereas the adverse consequences of arterial thromboembolism followed by withdrawal of aspirin are much more serious, as approximately 20% of these episodes are fatal and 40% episodes can lead to serious permanent disability.(11) In any circumstances, if stopping aspirin therapy is essential, it should be limited to three or fewer days. Considerable risk of thromboembolic events increased if aspirin therapy is discontinued between 4 and 30 days.(13)
Cardiac Surgery and Antiplatelet Therapy
Data on the risk of discontinuing antiplatelet therapy in patients with coronary stents have highlighted the use of aspirin in the perioperative period.(18-20) One meta-analysis found that aspirin withdrawal was associated with a significantly increased risk of myocardial infarction and death.(11) As a result, the routine withdrawal of aspirin 7-10 days before cardiac surgery has been questioned and some recent publications recommend that aspirin should not be stopped routinely in the perioperative period.(21-24)
The evidence based clinical practice guideline by the American College of Chest Physicians clearly mentioned the probable use of aspirin and clopidogrel.(25) For percutaneous coronary intervention, pre-treatment with clopidogrel is recommended before and throughout the perioperative period. Patients with coronary stents in situ have a high thrombotic risk if antiplatelet drug therapy is interrupted; so, elective non-cardiac surgery should therefore be avoided after stent placement when patients are most prone to thrombosis. This is during the first six weeks for bare metal stents, and during the first 12 months for drug-eluting stents. They further recommended, for patients without coronary stents who are not at high risk of cardiac events, only clopidogrel can be ceased 5-7 days before surgery. It is often routine clinical practice to consult the patient’s cardiologist before stopping any of the drugs.
Antiplatelet Therapy and Cataract, Dermatologic, Ear, Nose and Throat, and Dental Extraction Surgeries
In 2003, very rightly Fijnheer et al mentioned in a review article that there is scarcity of literature regarding cataract, dermatologic, ear, nose and throat, and dental surgeries involving patients on aspirin medication.(26) In fact, few studies in dermatology literature concluded that there is no need to discontinue nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin preoperatively in patients undergoing cutaneous surgical procedure, as there is no risk of increased bleeding in patients continuing their medications.(27, 28) Modern cataract surgery rarely causes any bleeding. Topical anaesthesia removes the risk of bleeding behind the eye from local anaesthetic injections. So, one can continue aspirin unless there are specific instruction to stop.
In 1992, Conti in an editorial mentioned that there is no need to stop aspirin prior to invasive surgical procedure if bleeding time is within normal limit.(29) Later on, in view of dental extractions Sonksen et al(30), Gaspar et al(31) and Little et al(32) also claimed that there is no significant intraoperative and postoperative bleeding after dental extractions as long as prolongation in bleeding time remains within acceptable limit (bleeding time up to 20 minutes). Matocha stated that risk of bleeding after dental extractions is rare in patients on low-dose aspirin therapy and the incidence of post-extraction bleeding complications, including other risk factors, does not exceed 0.2 to 2.3%.(33) Brennan et al reviewed the literature regarding the management of patients on aspirin requiring oral surgical procedures and recommended continuation of aspirin during dental extractions based on results of studies with high level of evidences.(34) Based on the review of literature, it can be concluded that current recommendations and consensus are in favour of not stopping antiplatelet dose of aspirin prior to tooth extraction and local haemostatic measures are usually successful. So, there is no justification to predispose the patient to the risk of thromboembolism at the expense of minor bleeding which can be easily controlled. However, clopidogrel should be stopped five days before surgery.(25)
Specific Risk of Clopidogrel in Surgery
The use of clopidogrel throughout the perioperative period is more controversial. Some studies have shown an increased risk of major bleeding with the use of clopidogrel within five days of coronary artery bypass grafting.(35) While recognising the increased risk of bleeding complications after coronary artery bypass grafting, some experts recommend a more tailored approach depending on individual risk with respect to ischaemic complications and bleeding.(36) For patients without coronary stents who are not at high risk of cardiac events, only clopidogrel can be ceased 5-7 days before surgery(25); to avoid further controversy, same protocol can be followed for clopidogrel since this is the only standard guideline available for this drug. If clopidogrel is the only option it should be restarted following the procedure as soon as there is adequate haemostasis, usually the morning after surgery.
So, in general since little harm was shown in continuing perioperative aspirin therapy and a trend towards improved outcome was evident, we are convinced that aspirin should be continued perioperatively in any high-risk patients. However, clopidogrel group of medicines should be stopped five days before any surgery and should be resumed following the procedure as soon as there is adequate haemostasis, usually the morning after surgery. Hypothetically, the same should be applicable to diabetic patients may be with some more beneficial outcome as diabetes itself is a known proinflammatory state. However, so far no separate study has been designed to assess outcome in diabetic population which underline definite need for further evaluation in diabetic patients in this important medical aspect.
1. Baigent C, Blackwell L, Collins R, et al.; Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–1860
2. Perk J, De Backer G, Gohlke H, et al.; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635–1701
3. Ogawa H, Nakayama M, Morimoto T, et al.; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134–2141
4. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomized placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840
5. Pignone M, Earnshaw S, Tice JA, Pletcher MJ. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis. Ann Intern Med 2006;144:326–336
6. American Diabetes Association. Cardiovascular disease and risk management. Sec. 8. In Standards of Medical Care in Diabetesd2015. Diabetes Care 2015;38(Suppl. 1): S49–S57
7. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-1302
8. Collaborative overview of randomised trials of antiplatelet therapy. III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994;308:235-246
9. Aspirin in Patients Undergoing Noncardiac Surgery. The Perioperative Ischemic Evaluation 2 (POISE-2) trial. N Engl J Med 2014; 370:1494-1503
10. Burger W, Chemnitius JM, Kneissl GD, Rucker G. Low-dose aspirin for secondary cardiovascular prevention—cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation—review and meta-analysis. J Intern Med 2005;257:399-414.
11. G. G. L. Biondi-Zoccai, M. Lotrionte, P. Agostoni et al., “A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50 279 patients at risk for coronary artery disease,” European Heart Journal 2006;27: 2667–2674
12. Beving H, Zhao C, Albage A, Ivert T. Abnormally high platelet activity after discontinuation of acetylsalicylic acid treatment. Blood Coagul Fibrinolysis 1996;7:80-4.
13. E. Ferrari, M. Benhamou, P. Cerboni, and B. Marcel, “Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis,” Journal of the American College of Cardiology, vol. 45, no. 3, pp. 456–459, 2005
14. P.-G. Chassot, A. Delabays, and D. R. Spahn, “Perioperative antiplatelet therapy: the case for continuing therapy in patients at risk of myocardial infarction,” British Journal of Anaesthesia, vol. 99, no. 3, pp. 316–328, 2007
15. Mahla E, Lang T, Vicenzi MN, et al. Thromboelastography for monitoring prolonged hypercoagulability after major abdominal surgery.Anesth Analg 2001;92:572-7.
16. Samama CM, Thiry D, Elalamy I, et al. Perioperative activation of hemostasis in vascular surgery patients. Anesthesiology 2001;94:74-8.
17. Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg 2001;88:787-800
18. Serruys PW, Kutryk MJ, Ong AT. Coronary-artery stents. N Engl J Med2006;354:483-95.
19. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol2000;35:1288-94.
20. Vicenzi MN, Meislitzer T, Heitzinger B, Halaj M, Fleisher LA, Metzler H. Coronary artery stenting and non-cardiac surgery—a prospective outcome study. Br J Anaesth 2006;96:686-93.
21. Fleisher LA, Beckman JA, Brown KA, et al. 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. Circulation2007;116:e418-e499
22. Merritt JC, Bhatt DL. The efficacy and safety of perioperative antiplatelet therapy. J Thromb Thrombolysis 2004;17:21-7
23. Chassot PG, Delabays A, Spahn DR. Perioperative use of anti-platelet drugs. Best Pract Res Clin Anaesthesiol 2007;21:241-56
24. O’Riordan JM, Margey RJ, Blake G, O’Connell PR. Antiplatelet agents in the perioperative period. Arch Surg 2009;144:69-76
25. Douketis JD, Berger PB, Dunn AS, Jaffer AK, et al. the perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 suppl):2995-3395
26. R. Fijnheer, R. T. Urbanus, and H. K. Nieuwenhuis. Withdrawing the use of acetylsalicylic acid prior to an operation usually not necessary. Nederlands Tijdschrift voor Geneeskunde; 2003:vol.147,no.1,21–25
27. C. Lawrence, A. Sakuntabhai, and S. Tiling-Grosse, “Effect of aspirin and nonsteroidal antiinflammatory drug therapy on bleeding complications in dermatologic surgical patients,” Journal of the American Academy of Dermatology;1994:vol.31,no.6,988–992
28. E. M. Billingsley and M. E. Maloney, “Intraoperative and postoperative bleeding problems in patients taking warfarin, aspirin, and nonsteroidal antiinflammatory agents: a prospective study,” Dermatologic Surgery; 1997:vol.23,no.5,381–385
29. C. R. Conti, “Aspirin and elective surgical procedures (editor’s note),” Clinical Cardiology;1992:vol.15, no.10, 709–710
30. J. R. Sonksen, K. L. Kong, and R. Holder, “Magnitude and time course of impaired primary haemostasis after stopping chronic low and medium dose aspirin in healthy volunteers,” British Journal of Anaesthesia. 1999.vol.82, no.3,360–365
31. R. Gaspar, L. Ardekian, B. Brenner, M. Peled, and D. Laufer, “Ambulatory oral procedures on low-dose aspirin,” Harefuah;1999:vol.136, no.2;108–110
32. J. W. Little, C. S. Miller, R. G. Henry, and B. A. McIntosh, “Antithrombotic agents: implications in dentistry,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics.2002;vol.93, no.5;544–551
33. D. L. Matocha, “Postsurgical complications,” Emergency Medicine Clinics of North America, vol. 18, no. 3, pp. 549–564, 2000.
34. M. T. Brennan, R. L. Wynn, and C. S. Miller, “Aspirin and bleeding in dentistry: an update and recommendations,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology.2007; vol.104, no.3;316–323
35. Yedes S, Wunderink RG. Effect of clopedogrel on bleeding aftercoronary artery bypass surgery. Crit Care Med 2001;29:2271-5
36. Fitchett D, Eikelboom J, Fremes S, Mazer D, et al. Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: a position statement of the Canadian Cardiovascular Society. Can J Cardiol 2009;25:683-9
Dr Basab Ghosh [MBBS, MDRC (Chennai), Dip Diab]
Dr Basab’s Diabetes Care
Opposite Ramnagar 3,
T G Road Extn, Krishnanagar