Sticky Issues with Antiplatelet Therapy

Goal Have an understanding, based on a review of current literature, on how to manage patients on antiplatelet therapy who present with hemorrhage or need for surgery.

Specific Objectives For Aspirin, Clopidogrel, and dual antiplatelet therapy with both agents, understand: Indications for and duration of use Risks of hemorrhage Risks of stopping therapy Current evidence regarding perioperative management of these therapies

Case 1 You are asked to do a pre-op consult on a 78 M presenting for elective hip arthroplasty with hx STEMI 4 months prior, no stent placed, taking plavix and ASA since. a.Advise continue the aspirin only b.Advise continue both asa and plavix c.Advise continue the plavix only d.Advise stop both and restart morning after surgery mentioning ideally meds would be stopped 5, preferably 10 days prior surgery

Case 2 74 F admitted with black stools for 1 week, stable vitals, H/H 8/24, with hx of ischemic stroke 2 years prior and taking aspirin. a. for admit orders, you continue aspirin b. for admit orders, you stop aspirin

Case 3 65 M admitted to 4W for UGIB with hx many years daily NSAID use for osteoarthritis, no hx Etoh, with hx admit 9 months ago for unstable angina for which he had a drug-eluting stent placed and for which he takes both plavix and aspirin. a. you stop plavix, continue aspirin b. you stop both plavix and aspirin c. you continue both plavix and aspirin

Case 4 83 M admit for planned carotid endarterectomy, with hx DM Type 2, and you are asked to do a pre-op assessment. a.You advise the surgeons to start aspirin the morning after surgery b.You advise the surgeons to start aspirin before the surgery and continue daily

Indications Aspirin mg QD Primary Prevention moderate risk coronary event (2A) [avoid DAT (1A)] Female <65 at risk ischemic stroke, low risk bleeding (2A) Female > 65 at risk ischemic stroke and MI, low risk bleeding (2A) Secondary Prevention Prior NSTEMI (1A) [ACC/AHA ‘07+plavix 1-12 mo] CABG (1A) [note if IMA graft, dose mg (1A)] Prior ischemic stroke or TIA (1A) [2 nd choice,1 st Plavix (2B)or Aggrenox(1A), avoid DAT(1B)] PAD w/ clinical CAD or CVA (1A) [or Plavix] PAD w/o clinical CAD or CVA (2B) [1 st choice] PAD undergoing infrainguinal arterial reconstruction, autogenous vein bypass, angioplasty w or w/o stent, and routine prosthetic bypass (1A) [start pre-op] CAS asymptomatic, nonoperable,primary or recurrent (1C) [Avoid DAT (1B)] CAS to undergo CEA (1A) [start pre-op] Acute Use NSTE ACS (1A) [Load dose mg] Acute stroke not receiving thrombolysis [initial dose mg] Plavix 75 mg QD Prior TIA (1A) [1 st choice, = ASA/Dipyridamole] PAD w/ clinical CAD or CVA (1A) [=choice to ASA] PAD w/o clinical CAD or CVA [2 nd choice to ASA] Dual Anitplatelet Therapy (DAT) [Asa mg + Plavix 75 mg QD] Secondary Prevention Prior STEMI regardless if received fibrinolytics (1A) [min 28 days, up to 1 yr (2B)] Symptomatic CAD/ Unstable Angina (2B) PCI w/ Bare Metal Stent (1A) [min 4 wk duration for plavix (2C)] PCI w/ Bare Metal Stent after ACS (1A) [duration 12 months] PCI w/ Drug Eluting Stent [3 to 4 mo (1A), 4-12 mo (1B), > 1 yr if tolerated (2C)] CABG following NSTE ACS [9-12 mo plavix (2B)] Triple Therapy [asa +plavix+coumadin] Stent placement and strong concomitant indication coumadin (2C)

Hemorrhagic Risks Aspirin 1.Antithrombotic Trialists Collaboration Lancet 2009 Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials -aspirin increased major gastrointestinal and extracranial bleeds by about half in the primary prevention trials (0.10% vs 0.07% per year; RR 1.54) -the excess risk was chiefly of non-fatal bleeds -main risks for coronary events also associated with hemorrhagic events, though, for most the associations were slightly weaker for bleeding than for occlusive events -For comparison, 2008 Antithrombotic and Thrombotic Therapy 8 th Ed: ACCP Guidelines, regarding risk of bleeding with VKAs, concludes, in clinical studies charaterized by careful monitoring of anticoagulant intensity, VKAs increase risk of major bleeding by 0.3%-0.5%/yr and the risk of ICH by approximately 0.2%/yr compared to controls. 2.Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ online Sept cases of serious UGIB identified during Adjusted odds ratios(95% CI) between use of drug and serious UGIB Aspirin use alone1.8 Clopidogrel alone1.1 VKA alone 1.8 Aspirin and Clopidogrel7.4

Hemorrhagic Risks Aspirin 1.Low-dose aspirin for secondary cardiovascular prevention-cardiovascular risks after its perioperative withdrawal vs bleeding risks with its continuation-review and meta-analysis. Journal of Internal medicine frequency of bleeding complications varied between 0% (e.g.,skin lesion excision and cataract surery) and 75% (e.g.,transrectal prostte biopsy - however, while aspirin increased the rate of bleeding compications by a factor of 1.5, it did not lead to a higher level of the severity of bleeding complication (exception; intracranial surgery and possibly TURP 2.Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin. Lancet when pts, undergoing THR or hip-fracture surgery given aspirin pre- operatively, increase in bleeding was minor 3.Patients under anti-platelet therapy. Best Practice & Research Clinical Anaesth 2010 ”Is global international trend in maintaining aspirin preoperatively in majority of surgical settings” opinion espoused by 2002 French Expert conference on anti-platelet therapy and by O’Riordan in Archives of Surgery 2009 in Antiplatelet agents in the perioperative period

Hemorrhagic Risks with Clopidogrel and Dual Antiplatelet Therapy (DAT) 1.A randomized, blinded, trial of clopidogrel vs. aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996 overall incidence of hemorrhagic events was identical in the aspirin and clopidogrel groups (9.3%) 2.CURE Trial: Effects of clopidogrel in addition to aspirin in pts with acute coronary syndromes w/o ST-segment elevation. NEJM 2001 there were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7% vs. 2.7%; p=0.001) 3.Brief synopsis trials reviewed in the ACCP 8 th Ed: Antithrombotic and Thrombolytic Therapy regarding dual antiplatelet therapy: Clopidogrel and Metoprolol Myocardial Infarction Trial (COMMIT) Lancet 2005 – no excess risk Mgt Atherothrombosis w/ Clopidogrel in High-risk Pt (MATCH) Lancet 2004 – yes excess risk Clopidogrel High Atherothrombotic Risk Ischemic Stab,Mgt,Avoid (CHARISMA) NEJM yes risk 4.Natl Estimates ED Visits for Hemorrhage-Related Adverse Events from Clopidogrel plus Aspirin and From Warfarin. Archives of Internal Medicine Nov 2010 when adjusted for prescribing frequency, estimated rate of ED visits for hemorrhage-related AEs overall was 3.7 per 1000 outpt prescription visits for warfarin vs. 1.2 for clopidogrel+aspirin therapy for every 815 outpt prescription for DAT, 1 went to ED for evaluation bleeding for every 274 outpt prescription for warfarin, 1 went to ED for evaluation bleeding

Risk of Withdrawing Antiplatelet Therapy 1.Coronary syndromes following aspirin withdrawal. Jrl of Am Col Cardiology pt admitted for ACS queried regarding aspirin use 13.3 % recurrences, had stopped ASA within 1 month prior 2.Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch of Neurology 2005 Case control study of 309 pt admitted with stroke or TIA 24% had stopped ASA, resulting in odds ratio of 3.4 for stroke or TIA 3.Aspirin withdrawal and acute lower limb ischemia. Anesth and Analgesia 2004 Retrospective cohort of 181 admits for acute lower limb ischemia 16.4% had stopped ASA with median time between ASA withdrawal and ischemic event being 23 days 4.Systematic review to appraise hazards ASA withdrawal in pt at risk for or with CAD. European Heart Journal studies selected looking at over 50,000 pts. Found 3 fold higher risk major cardiac event 5.Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents (DES). JAMA 2005 multiple risks for stent thrombosis found, including DM, CKD, pertaining to coronary anatomy, yet most important risk was withdrawal of antiplatelet therapy

Current Peri-Operative Guidelines Antithrombotic and Thrombolytic Therapy 8 th Ed: ACCP Guidelines Gen: Stop antiplatelet Rx 7-10 day prior over stopping closer to procedure (2C) Specifics: If not high risk cardiac event, stop therapy If high risk cardiac event (excl. stents), cont ASA up to and beyond procedure (2C), stop Plavix 5-10 day prior If within 6 wk Bare Metal Stent (BMS) placement, continue ASA and Plavix (1C) If within 12 months DES, continue ASA and Plavix (1C) If ASA stopped, resume 24 hr or next AM over closer to surgery (2C) If Plavix stopped, resume 24 hr or next AM over closer to surgery (2C) Note: no validated perioperative risk stratification; ACCP used hx related to mechanical heart valves, AF CHADS2 score, and VTE to determine. Recommendation of French Task Force 2006 Continue ASA in most surgical settings, and for sure, in cardiac surgery Clopidogrel should be withdrawn no more than 5 days in case of increased bleeding risk Antiplatelet treatment discontinuation increases thrombotic risk and should always be discussed In case BMS, postpone surgery at least 6 wks In case DES, postpone surgery 1 year In case DES, perform surgery under the aspirin- clopidogrel combination if possible or, at least aspirin. Multidisciplinary team meeting must take place to decide Regarding neuraxial aneasthesia, can be performed with aspirin treatment, but should be discouraged with clopidogrel Antiplatelet therapy should be resumed post- operatively as soon as possible to prevent platelet activation. First dose should be a loading dose, and given no later than 24 hr after skin closure