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Sticky Issues with Antiplatelet Therapy

GoalHave 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 ObjectivesFor Aspirin, Clopidogrel, and dual antiplatelet therapy with both agents, understand:

Indications for and duration of useRisks of hemorrhageRisks of stopping therapyCurrent evidence regarding perioperative management of these therapies

Case 1You 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.

Advise continue the aspirin onlyAdvise continue both asa and plavixAdvise continue the plavix onlyAdvise stop both and restart morning after surgery mentioning ideally meds would be stopped 5 , preferably 10 days prior surgery

Case 274 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 aspirinb. for admit orders, you stop aspirin

Case 365 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 aspirinb. you stop both plavix and aspirinc. 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.

You advise the surgeons to start aspirin the morning after surgeryYou advise the surgeons to start aspirin before the surgery and continue daily

IndicationsAspirin 75-100 mg QDPrimary Prevention

moderate risk coronary event (2A) [avoid DAT (1A)]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 75-162 mg (1A)]Prior ischemic stroke or TIA (1A) [2nd choice,1stPlavix (2B)or Aggrenox(1A), avoid DAT(1B)]PAD w/ clinical CAD or CVA (1A) [or Plavix]PAD w/o clinical CAD or CVA (2B) [1st 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 UseNSTE ACS (1A) [Load dose 162-325 mg]Acute stroke not receiving thrombolysis [initial dose 150-325 mg]

Plavix 75 mg QDPrior TIA (1A) [1st choice, = ASA/Dipyridamole]PAD w/ clinical CAD or CVA (1A) [=choice to ASA]PAD w/o clinical CAD or CVA [2nd choice to ASA]

Dual Anitplatelet Therapy (DAT)[Asa 75-100 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 AspirinAntithrombotic 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 8th 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.Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ online Sept 2006-1443 cases of serious UGIB identified during 2000 -2004Adjusted odds ratios(95% CI) between use of drug and serious UGIBAspirin use alone1.8Clopidogrel alone1.1VKA alone 1.8 Aspirin and Clopidogrel7.4

Hemorrhagic Risks Aspirin1.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 2005 - 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

Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin. Lancet 2000.-when pts , undergoing THR or hip-fracture surgery given aspirin pre-operatively, increase in bleeding was minor

Patients under anti-platelet therapy. Best Practice & Research Clinical Anaesth 2010 Is global international trend in maintaining aspirin preoperatively in majority of surgical settingsopinion espoused by 2002 French Expert conference on anti-platelet therapy and by ORiordan in Archives of Surgery 2009 in Antiplatelet agents in the perioperative period

Hemorrhagic Risks with Clopidogrel and Dual Antiplatelet Therapy (DAT)A randomized, blinded, trial of clopidogrel vs. aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996overall incidence of hemorrhagic events was identical in the aspirin and clopidogrel groups (9.3%)

CURE Trial: Effects of clopidogrel in addition to aspirin in pts with acute coronary syndromes w/o ST-segment elevation. NEJM 2001there 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 8th Ed: Antithrombotic and Thrombolytic Therapy regarding dual antiplatelet therapy:Clopidogrel and Metoprolol Myocardial Infarction Trial (COMMIT) Lancet 2005 no excess riskMgt Atherothrombosis w/ Clopidogrel in High-risk Pt (MATCH) Lancet 2004 yes excess riskClopidogrel High Atherothrombotic Risk Ischemic Stab,Mgt,Avoid (CHARISMA) NEJM 2006- yes riskNatl Estimates ED Visits for Hemorrhage-Related Adverse Events from Clopidogrel plus Aspirin and From Warfarin. Archives of Internal Medicine Nov 2010when 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 therapyfor every 815 outpt prescription for DAT , 1 went to ED for evaluation bleedingfor every 274 outpt prescription for warfarin, 1 went to ED for evaluation bleeding

Risk of Withdrawing Antiplatelet TherapyCoronary syndromes following aspirin withdrawal. Jrl of Am Col Cardiology 20051236 pt admitted for ACS queried regarding aspirin use13.3 % recurrences, had stopped ASA within 1 month priorEffect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch of Neurology 2005Case control study of 309 pt admitted with stroke or TIA24% had stopped ASA, resulting in odds ratio of 3.4 for stroke or TIAAspirin withdrawal and acute lower limb ischemia. Anesth and Analgesia 2004Retrospective cohort of 181 admits for acute lower limb ischemia16.4% had stopped ASA with median time between ASA withdrawal and ischemic event being 23 daysSystematic review to appraise hazards ASA withdrawal in pt at risk for or with CAD. European Heart Journal 20066 studies selected looking at over 50,000 pts.Found 3 fold higher risk major cardiac eventIncidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents (DES). JAMA 2005multiple risks for stent thrombosis found, including DM, CKD, pertaining to coronary anatomy, yet most important risk was withdrawal of antiplatelet therapy

Current Peri-Operative GuidelinesAntithrombotic and Thrombolytic Therapy 8th 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 priorIf 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 surgeryClopidogrel should be withdrawn no more than 5 days in case of increased bleeding riskAntiplatelet treatment discontinuation increases thrombotic risk and should always be discussedIn case BMS, postpone surgery at least 6 wksIn case DES, postpone surgery 1 yearIn case DES, perform surgery under the aspirin-clopidogrel combination if possible or, at least aspirin. Multidisciplinary team meeting must take place to decideRegarding neuraxial aneasthesia, can be performed with aspirin treatment, but should be discouraged with clopidogrelAntiplatelet 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