European Heart Journal Supplements (2008) 10 (Supplement A), A35–A41 doi:10.1093/eurheartj/sum082

When and how to discontinue antiplatelet therapy Michel E. Bertrand* ˆpital Cardiologique, Boulevard du Pr Leclercq, Lille 59037, France Ho

KEYWORDS Aspirin; Clopidogrel; Bleeding; Stroke; Thrombosis; Acute coronary syndromes

Antiplatelet agents reduce the risk of ischaemic events but increase the risk of bleeding. When cardiac patients on antiplatelet therapy require surgery or invasive diagnostic procedures, a decision must be made whether or not to discontinue antiplatelet therapy. Because there is little evidence from clinical trials that would aid in the formulation of comprehensive recommendations, the decision must be made on an individual basis. The patient’s inherent risk for bleeding, concomitant treatments that may increase this risk, the potential of the procedure to cause bleeding, and the patient’s risk for ischaemic events if antiplatelet therapy is stopped all must be considered. Some procedures carry a low risk of bleeding and can be carried out in most patients without discontinuing antiplatelet therapy, whereas others require close evaluation and risk stratification of the patient. Patients on antiplatelet therapy undergoing cardiac surgery, those with drug-eluting stents, and those on anticoagulation require particularly careful management. There is an urgent need for research into this complex clinical problem.

Introduction Antiplatelet agents—principally aspirin and clopidogrel, used alone or in combination—have been shown to reduce the risk of myocardial infarction (MI), ischaemic stroke, and cardiovascular death in patients with unstable angina, non–ST-elevation (NSTE)-acute coronary syndromes (ACS), and ST-elevation MI (STEMI).1–10 In patients at risk, aspirin is recommended as life-long therapy and clopidogrel is recommended for periods ranging from 1 to 12 months, or as a life-long substitute for aspirin in patients in whom aspirin is contraindicated.11–14 As a result, antiplatelet agents have become essential components of the treatment of these conditions. The most serious adverse effect associated with use of antiplatelet agents is bleeding.15 This raises the question of whether and, if so, when to discontinue antiplatelet therapy in patients who need surgery or diagnostic procedures that carry a risk of tissue injury. The question is important because discontinuation of antiplatelet agents results in recovery of platelet function, which contributes to the occurrence of ischaemic

* Corresponding author. Tel: þ33 320 92 13 34; fax: þ33 320 00 65 09. E-mail address: [email protected]

events.16–18 Unfortunately, neither good evidence from clinical trials nor authoritative guidelines are available to guide physicians faced with this dilemma. This article will review what is known about discontinuation of antiplatelet agents and suggest approaches to help physicians care for patients in this setting.

Risk factors for bleeding and ischaemic events Deciding whether to discontinue antiplatelet agents is a matter of weighing the risk of bleeding against the risk of ischaemic events. Several factors must be considered: the patient’s inherent risk for bleeding; ongoing treatments that may increase that risk; the potential of the procedure being contemplated to cause bleeding; and the risk of an ischaemic event if the antiplatelet therapy is stopped.

Inherent bleeding risk Identification of patients at high risk for bleeding is the first step in managing those on antiplatelet agents who require invasive procedures. Demographic factors that

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2007. For permissions please email: [email protected].

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increase the likelihood of bleeding are advanced age and female sex; a history of bleeding events, haemorrhagic peptic ulcer, or haemorrhagic stroke also should alert physicians to the possibility of bleeding.19 Medical conditions that increase the risk of bleeding include obesity, diabetes, hypertension, renal impairment or failure, heart failure, other major organ dysfunction, and haemostatic disorders.19,20 A multivariate regression model based on data from the Global Registry of Acute Coronary Events can be used to identify patients with STEMI, non–ST-elevation MI (NSTEMI), or unstable angina who are at high risk for bleeding.21 Significant predictors of bleeding risk in this model include female sex, renal insufficiency, history of bleeding, and, most importantly, advanced age.

Treatments that increase bleeding risk Concomitant anticoagulant or fibrinolytic drug therapy increases bleeding risk to a greater or lesser extent depending on the drug used, its dose, the duration of treatment, and the timing of administration in relation to the procedure.20

Procedures that increase bleeding risk With the invasive procedures that coronary patients are most likely to undergo, such as angiography, intra-aortic balloon pump placement, coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI), there is a lower risk of bleeding and it is relatively easy to manage if it occurs, particularly in the case of PCI with a femoral approach rather than a radial approach.20

Risks associated with discontinuation Retrospective studies show that discontinuation of aspirin therapy puts patients at risk for MI and stroke.16–18 Patients at particularly high risk are those with recent or recurrent ACS with dual oral antiplatelet therapy, recent PCI, left ventricular ejection fraction 30%, tri-vessel disease, stent of length .25 mm or, especially, a drug-eluting stent (DES), history of thrombosis in a vessel of diameter 2.5 mm, incomplete revascularization, and 2 locations of symptomatic atherothrombosis.19

Other considerations Complicating this issue is that some of the factors that put patients at high risk of bleeding also put them at risk of ischaemic events. These include the demographic factors of advanced age and female sex and medical factors such as obesity, diabetes, heart failure, and renal failure.19 Patients with these conditions present a particularly difficult dilemma for clinicians. Further compounding the problem of knowing when to discontinue antiplatelet therapy is the fact that many of the conditions that put patients at high risk for bleeding are exclusion criteria in clinical trials of antiplatelet agents.19 Thus, data on patients with these conditions are not found in the medical literature. A unified,

M.E. Bertrand

validated method of sorting and scoring patients in terms of their bleeding risk and weighing it against their risk of ischaemic events is sorely needed but is as yet unavailable.

Recommendations for patients undergoing invasive procedures Endoscopy Some evidence is available to guide clinicians performing endoscopic procedures in patients on antiplatelet therapy. A retrospective case-control study of patients who underwent endoscopic sphincterotomy recruited 40 patients who bled following the procedure and 86 ageand sex-matched controls who did not.22 After adjusting for confounding factors, the authors found no association between use of antiplatelet agents and post-procedural bleeding, although there were too few patients taking clopidogrel to draw any conclusion regarding its use. A review of 5593 patients who underwent colonoscopy included 1657 patients in whom polypectomy was performed.23 Immediate bleeding occurred in 32 patients and delayed bleeding occurred in five patients. Although use of the anticoagulant warfarin was associated with a significantly higher risk of bleeding, use of antiplatelet agents was not. Nevertheless, because of the lack of controlled clinical trials studying this issue, some authors recommend discontinuing antiplatelet agents before colonoscopy, sphincterotomy, oesophageal dilation, and endoscopic ultrasound-guided biopsy or drainage.24 Guidelines from the French Society for Digestive Endoscopy classify endoscopic procedures into three groups.25 The first group includes those with a low risk of bleeding, in which bleeding can be controlled endoscopically; this group includes gastroscopy, rectosigmoidoscopy, and colonoscopy without polypectomy. The second group includes procedures with a high risk of bleeding (1%), also with the possibility of endoscopic control, including colonic polypectomy, gastric macro-biopsy with loop polypectomy and gastric polypectomy, and endoscopic sphincterotomy. The third group includes procedures with a low risk of bleeding, but without the possibility of endoscopic control; endoscopic ultrasound fine-needle aspiration and percutaneous gastrostomy fall into this group. Given its relatively low potential to contribute to serious bleeding, there is no need to discontinue aspirin in most patients undergoing procedures in the first group; even colonoscopy with polypectomy is probably safe absent other risk factors for bleeding.25 Aspirin should be discontinued before procedures in the second and third groups, or if possible, the procedure should be postponed until the risks related to aspirin discontinuation are lower.25 There are insufficient data to extrapolate these recommendations to patients taking thienopyridines.25 Guidelines from the American Society for Gastrointestinal Endoscopy recommend discontinuing thienopyridines

When and how to discontinue antiplatelet therapy

7–10 days before procedures associated with a high risk for bleeding, including polypectomy, biliary sphincterotomy, pneumatic or bougie dilation, and percutaneous endoscopic gastrostomy.26

Dental procedures A literature review and guideline development process conducted by the Oral Medicine and Oral Surgery Francophone Society found that, based on agreement among professionals in the field, interruption of aspirin or thienopyridine therapy before dental procedures is unnecessary.27 Most such procedures carry a low risk of bleeding, and any bleeding that occurs can usually be controlled by local haemostasis.

Recommendations for patients undergoing surgery Surgical procedures in which discontinuation of antiplatelet therapy is unnecessary In general, discontinuation of antiplatelet therapy is considered unnecessary in procedures that are not highly invasive and therefore have a low bleeding risk. Several small studies have found no excess of bleeding among patients taking aspirin who underwent dermatologic surgery.28–30 One study found a greater likelihood of bleeding among patients taking aspirin who had prolonged bleeding times, but it was easily controlled with standard measures.31 Little evidence is available regarding the effects of thienopyridines in patients undergoing dermatologic surgery.32 The French Society of Anesthesiology and Intensive Care (SFAR) considers discontinuation of aspirin unnecessary before ophthalmologic surgery.33 Because aspirin and clopidogrel have additive effects on bleeding time, a suggestion has been made to continue aspirin but discontinue clopidogrel before ophthalmologic surgery in patients on combination therapy.34 Oral, periodontal, and implant dental surgery are not associated with high rates of bleeding. Any bleeding that occurs can usually be controlled locally, so discontinuation of aspirin is not recommended.27 Aspirin therapy is recommended before carotid endarterectomy to reduce the risk of peri-operative coronary events35 and has not been found to increase bleeding risk during the procedure.33 A decision model suggested that aspirin therapy before infrainguinal revascularization surgery would increase the incidence of minor bleeding but that this would be far outweighed by a reduction in mortality and an increase in quality-adjusted life expectancy.36

Surgical procedures in which discontinuation of antiplatelet therapy is recommended SFAR has identified procedures before which aspirin therapy should be discontinued because of a significantly increased bleeding risk.33 There is a high degree of

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certainty that even low aspirin doses before hip surgery increase the risk of haemorrhage and the need for transfusion, but post-operative aspirin poses no risk in hip or knee surgery. In tonsillectomy, pre- or post-operative aspirin may contribute to peri-operative bleeding and increase the number of revision procedures for haemostasis. Ticlopidine, one of the thienopyridine antiplatelet agents, should be discontinued before transurethral resection of the prostate; whether aspirin should be discontinued is uncertain. Prostate surgery via the abdominal approach requires discontinuation of aspirin.

Cardiac surgery Although surgical haemostasis can be controlled during cardiac surgery, it is a special case in the decision whether to discontinue antiplatelet therapy. It carries a high risk of bleeding, but the patient is by definition at high risk for ischaemic events. Although aspirin can be continued in patients undergoing cardiac surgery, clopidogrel should be stopped at least 5 days before the procedure when the surgery is scheduled and the risk of ischaemia is low.11,37 In the CURE trial, which compared clopidogrel and placebo in patients with NSTE-ACS, study medication was discontinued in most patients who underwent CABG.4 There was no difference in bleeding between placebo patients and clopidogrel patients whose medication was discontinued 5 days before surgery, but a significantly higher rate of bleeding occurred in patients whose clopidogrel was discontinued 5 days before surgery (9.6% in the clopidogrel group vs. 6.3% in the placebo group, P ¼ 0.06). A recent prospective observational study of 217 patients scheduled for first-time CABG surgery examined the bleeding risks associated with continuing clopidogrel therapy until surgery.38 Patients were treated either with aspirin alone or aspirin combined with clopidogrel for 5 days before surgery. All received prophylactic low-dose aprotinin. Maintenance of clopidogrel therapy until surgery was not associated with increased post-operative bleeding or transfusion rates.

Management of oral antiplatelet therapy in patients undergoing surgery Little evidence is available and comprehensive guidelines have not been developed to determine how to manage antiplatelet therapy in surgical patients. As a practical matter, the surgeon, cardiologist, haematologist, and anaesthesiologist should consult on each case regarding the risk of peri-operative bleeding if antiplatelet therapy is continued and the risk of ischaemic events if therapy is discontinued.37 If neither course is acceptable, postponement of the surgery should be considered, if possible. In its review of the literature, the Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology (ESC) found a relatively low risk of bleeding during CABG in patients whose

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antiplatelet therapy had not been discontinued .5 days before surgery.11 Nevertheless, in the interests of caution, the Task Force recommended that in patients with a low risk of progressing to MI or death, oral antiplatelet agents should be discontinued 5 days before the procedure and reinstituted as soon as possible thereafter. Surgical measures to minimize bleeding and platelet transfusions may be required in such cases. A balanced approach to managing antiplatelet therapy in surgical patients is being addressed in the ongoing STRATAGEM trial, which will recruit 1500 patients with symptomatic stable atherothrombotic disease receiving antiplatelet therapy who are scheduled for noncoronary surgery.39 Ten days before surgery, patients will discontinue their current antiplatelet regimen and be randomized to receive aspirin 75 mg/day or placebo until surgery. It is hoped that this low-dose antiplatelet regimen will protect against peri-operative ischaemic events without an increase in bleeding.

Patients with drug-eluting stents undergoing surgery The presence of a DES adds another consideration when a patient on antiplatelet therapy needs surgery. In the ESC guidelines for PCI, dual antiplatelet therapy is recommended in patients with DESs for a period of 6–12 months after stent placement,40 but more recently the U.S. Food and Drug Administration recommended dual antiplatelet treatment for 12 months.41 Discontinuation of antiplatelet therapy is associated with increased rates of stent thrombosis.42–44 If possible, at least 2–4 weeks should elapse between placement of a stent and major non-cardiac surgery.45 If surgery cannot be postponed, the recommendations of an SFAR task force may be helpful (Table 1).37 Patients who are at high risk of

stent thrombosis should be identified, including those with a history of stent thrombosis; those with .1 stent, long stents, a stent placed at a bifurcation, a stent in the left main artery or in small arteries, or incomplete revascularization; and those who have complicating conditions such as diabetes, heart failure, or low ejection fraction. If the patient is not at high risk of bleeding and if the surgery is not associated with significant blood loss, aspirin therapy should be continued. Thienopyridine discontinuation 5 days before the procedure should be considered on a case-by-case basis. If there is a high risk of bleeding, withdrawal of both agents should be considered. If surgery is urgent or cannot be postponed for 5 days, discontinuation will not be possible or effective at the time of surgery and optimal surgical and pharmacological haemostasis must be employed. If clopidogrel is discontinued before surgery, resuming therapy with a 300-mg loading dose may be considered. If aspirin is discontinued, resuming with a loading dose .160 mg may be considered. Although the task force suggested substituting non-steroidal anti-inflammatory agents or heparin for antiplatelet agents, the efficacy of the former and the safety of the latter have been questioned.19,37

Treatment of acute bleeding If bleeding occurs in a surgical patient whose antiplatelet therapy has not been discontinued, all antiplatelet drugs should be stopped immediately. The principles of managing major bleeding remain the same, and should include intravenous fluid, transfusion of packed red blood cells, and whatever surgical or other measures are necessary.20 If the bleeding is gastrointestinal and can be controlled with endoscopic injection and

Table 1 Recommendations of the French Society of Anesthesiology and Intensive Care (SFAR) regarding management of antiplatelet therapy in patients with drug-eluting stents (DESs). Interventions must be postponed 6 weeks after an acute coronary event37 Risk of stent thrombosis (to be evaluated with the cardiologist)a

Major

Moderate

Haemorrhagic risk of the invasive or surgical procedure (to be evaluated with the physician or the surgeon)b Major

Intermediate

Minor

Postpone intervention 6 months to 1 year after stent positioning

Postpone intervention 6 months to 1 year after stent positioning If impossible: maintain aspirin, stop clopidogrel 5 days Maintain aspirin, stop clopidogrel 5 days

Maintain aspirin and clopidogrel

If impossible: stop aspirin–clopidogrel 5 days, or stop aspirin–clopidogrel 10 days (max) and substitute Stop aspirin–clopidogrel 5 days, or stop aspirin–clopidogrel 10 days (max) and substitute

Maintain aspirin and clopidogrel, or maintain aspirin and stop clopidogrel 5 days

Adapted with permission from Oxford University Press. From Albaladejo et al., Br J Anaesth 2006;97:580–582; permission conveyed through Copyright Clearance Center, Inc. a Risk of stent thrombosis—major: stent in place ,6 months to 1 year or patient requiring aspirin and clopidogrel or patient with risk factor; moderate: stent in place .6 months to 1 year. b Haemorrhagic risk – major: intervention cannot proceed on antiplatelet agent; intermediate: intervention can proceed on aspirin alone; minor: intervention can proceed on aspirin and clopidogrel.

When and how to discontinue antiplatelet therapy

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mechanical means, discontinuation of antiplatelet agents may not be necessary, especially in patients at high risk for thrombosis.20

Antiplatelet therapy in patients on anticoagulation undergoing percutaneous coronary intervention with stenting

not to prolong aspirin and clopidogrel therapy beyond that recommended in clinical guidelines. Use of a baremetal stent, rather than a DES, will shorten the required period of dual antiplatelet therapy, and a radial approach, rather than a femoral approach, will reduce the risk of bleeding.

The role of emerging antiplatelet therapies Anticoagulants are routinely prescribed for patients with atrial fibrillation or prosthetic heart valves, who may also have coronary atherosclerosis treated with antiplatelet agents. Given concomitantly, warfarin and antiplatelet agents confer a high risk of bleeding.46,47 How these patients should be managed if they require PCI with stenting is uncertain, and there is much variability in their care.48,49 Various recommendations have been made, most of them based on an evaluation of the patient’s relative risks of ischaemic events and bleeding and the need to provide antiplatelet agents in sufficient doses for a long-enough period to prevent the former without triggering the latter (Table 2).46,49,50 If warfarin is to be continued, it would at least seem reasonable

The practicality of clopidogrel therapy is limited by its irreversible effects and slow onset of action. If discontinuation is necessary, platelet function does not fully recover for at least several days; when therapy is resumed, protection against thrombosis is delayed. Newer antiplatelet agents may help overcome some of these limitations. AZD6140 and cangrelor are reversible antiplatelet agents that could be discontinued much sooner prior to surgery than clopidogrel, thus easing patient management and reducing the risk of bleeding when surgery is urgent.51,52 Prasugrel, a thienopyridine with irreversible antiplatelet effects, has a faster onset of action, greater potency, and less variability in response than clopidogrel and

Table 2 Suggested management strategy for patients with non-valvular atrial fibrillation requiring anticoagulation and percutaneous coronary intervention (PCI) with stenting49a Stroke risk category

Usual strategy recommended

Low

Aspirin

High

Warfarin

High

Warfarin

Perceived potential bleeding risk

Acute coronary syndrome (ACS) presentation

Low

No

Low

Yes

Highb

No

Highb

Yes

Post-PCI management

BMS: aspirin plus clopidogrel for 4 weeks, then aspirin DES: aspirin plus clopidogrel for 6–12 months, then aspirin BMS if possible BMS: triple therapy with warfarin, aspirin, and clopidogrel for 2–4 weeks; then warfarin plus clopidogrel up to month 12; then warfarin alone DES: triple therapy with warfarin, aspirin, and clopidogrel for 3–6 months or more; then warfarin plus clopidogrel up to month 12; then warfarin alone BMS or DES: triple therapy with warfarin, aspirin, and clopidogrel for 3–6 months or more; then warfarin plus clopidogrel up to month 12; then warfarin alone BMS if possible BMS: triple therapy with warfarin, aspirin, and clopidogrel for 4 weeks, then warfarin alone DES: triple therapy with warfarin, aspirin, and clopidogrel for 4 weeks; then warfarin plus clopidogrel up to month 12; then warfarin alone BMS or DES: triple therapy with warfarin, aspirin, and clopidogrel for 4 weeks; then warfarin plus clopidogrel up to month 12; then warfarin alone

BMS, bare metal stent; DES, drug-eluting stent. Adapted with permission from American College of Chest Physicians. From Lip, Karpha, Chest 2006;130:1823–1827; permission conveyed through Copyright Clearance Center, Inc. a Doses: aspirin, 75–81 mg/day; clopidogrel, 75 mg/day. Warfarin is dose adjusted to target international normalized ratio (INR) of 2.0–2.5. b Particular attention should be paid to patients with any of the following risk factors: (i) aged .75 years; (ii) receiving non-steroidal antiinflammatory drugs; (iii) receiving multiple other drug treatments; (iv) uncontrolled hypertension; (v) history of bleeding (e.g. peptic ulcer, cerebral haemorrhage); and (vi) history of poorly controlled anticoagulation therapy.

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might be expected to provide more rapid protection against thrombosis when therapy is resumed.53 The recent TRITON-TIMI 38 trial, which compared prasugrel with clopidogrel in patients with moderate- to high-risk ACS, found that prasugrel therapy was associated with a lower rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke and a higher rate of major bleeding, including fatal bleeding.54 The ongoing PRINCIPLE55 and ACAPULCO56 trials will further define the differences in these drugs’ clinical effects.

Conclusion The decision whether to discontinue antiplatelet therapy in a coronary patient who needs surgery or a diagnostic procedure is based on an evaluation of the patient’s risk for bleeding and risk for ischaemic events. Unfortunately, with a few exceptions, each case must be decided individually because there is insufficient clinical evidence to establish comprehensive guidelines. Discontinuation of antiplatelet therapy appears to carry real challenges and continuation of antiplatelet therapy should be the rule when the risk of bleeding is low or haemostasis is controllable. If a procedure is associated with a high risk of bleeding, consideration should be given to postponing it; if that is not possible, antiplatelet agents should be discontinued only if necessary and reinstated promptly. There is an urgent need for research on this issue with the goal of establishing a comprehensive set of recommendations. Conflict of interest: None declared.

Funding Sponsored by an educational grant from Daiichi Sankyo Europe GmbH and Eli Lilly and Company.

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