ARTICLES Therapeutic Controversies

Aspirin, Clopidogrel, and Warfarin: Is the Combination Appropriate and Effective or Inappropriate and Too Dangerous? A Janelle Hermosillo and Sarah A Spinier

O

ver the past 40 years, antiplatelet drugs have been used clinically in the treatment and preventionof cardiovascular diseases. Results of a metaanalysis of 145clinical studies reported a 25% risk reduction of vascular eventsin high-risk patients treated withantiplatelet therapy" Antiplatelet therapy aids in preventing platelet-mediated coronary thrombosis and reinfarction in patients with acute coronary syndrome(ACS) and in thoseundergoing percutaneous coronary intervention (PCI).lHowever, some patients receiving antiplatelet therapy may alsorequire long-or short-term anticoagulation with warfarin. Indications for triple antithrombotic therapy with aspirin, a thienopyridine (ticlopidine or clopidogrel),and warfarin may include atrial fibrillation for stroke prevention, mechanical heart valve replacement to avoidthrombus formation, existing leftventricular muralthrombus, or high risk of left-ventricular thrombus following an acutemyocardial infarction (MI), as well as for preventionof recurrent events in patients with venous thromboembolic disease who also have coronary artery disease.' Few data are available describing the safety and efficacy of combining dual antithrombotic therapy versus triple Authorinformation provided at the end of the text.

To review the rationale. clinical practice guideline recommendations, and clinical trial data describing bleeding and clinical outcomes associated with the use of the combination of aspirin. a thienopyridine, andwarfarin. OBJECTIVE:

DATA SOURCES: An English-language literature search was conducted using MEDLINE (1966-March 2008) and the search terms aspirin, c1opidogrel, ticlopidlne. thienopyridine, warfarin, antlplatslet, anticoagulant, myocardial infarction. atrial fibrillation, and percutaneous coronary Intervention (PCI). Additional references were Identified by reviewing reference citations of articles retrieved. STUDY SELECTION AND DATA EXTRACTION: Applicable data were extracted from published reports and studiesthat included either clinical outcomes or adverse events. DATA SYNTHESIS: Clinical guidelines recommend the combination of antlplatelets and anticoagulants based largely on writing committee consensus. Todate.only one randomized clinical trial has evaluated the safety and efficacy of adding warfarin to dual antiplatelet therapy (ie, triple antithrombotic therapy). Other published data are from case series, observational studies. and case-controlled studies primarily of patients undergoing PCI with intracoronary stent placement. Four of 12 studies reported no increased risk of major bleeding events. In the other8 studies, a 3- to 6-fold increase in bleeding events was reported with triple antithrombotic therapy. Ischemic events were reported in only 6 of the studies. Only 2 studies observed an additional benefit in the reduction of ischemic events, and 1 study reported worsened ischemic outcomes with the tripleantithrombotlc regimencompared withdual antithrombotlc therapy. CONCLUSIONS: Available guidelines pertaining to the concomitant administration of aspirin, a thienopyridine, and warfarin are based on limited trial data and consensus judgment. Overall, selectionof triple antithrombotic therapy for patients with vascular disease is considered a matter of clinical judgment for an individual patient based on the prescriber'S perceived balance between the patient's risk for recurrent ischemicevents, expected duration of treatment, and patient's risk for bleeding. KEY WORDS: acute coronary syndrome, anticoagulation, antiplatelet, aspirin. clopidogrel, percutaneous coronary intervention. warfarin.

Ann Pharmacother 2008;42:790-805. Published Online, 13 May 2008. www.theannals.com.DOI10.1345/aph.1K591

790 • The Annals ofPharmacotherapy • 2008June, Volume 42

wwwsheannalscom

antithrombotic therapy in such patients with an indication for anticoagulation. This paperdiscusses the rationale, currentavailable guidelines, results from clinical trials,as well as the controversies and intricacies associated with the selection of dual versus triple antithrombotic therapy. Clinicaltrial acronyms are defined in Appendix I.

Rationale for Dual Antiplatelet Therapy: Aspirin plus a Thienopyridine Aspirin and thienopyridines inhibitplateletaggregation in different manners and thereby may exert a complementary effectin prevention of vascular ischemic events.Dual antiplatelet therapy with aspirin and clopidogrel has been proven to be beneficial in patients with eithernon-S'T-segmemelevation (NSTE) ACS,4 ST-segment elevation MI (STEMI),s and in patients undergoing PCI.6,7 Evidence for an increased risk of major bleedingwith combineduse of aspirin and clopidogrel has been noted in the CURE trial.' In CURE, the rate of major bleeding in patients with NSTE ACS takingclopidogrel plusaspirin for up to a year was 3,7% compared with 2,7% in patients taking aspirin alone (RR 1.4[95% CI 1.1 to 1.7]). In contrast, no increased riskof majorbleeding was found in COMMIT,s the CREDO study,' and the CHARISMA study," In COMMIT, clopidogrel plus aspirin administered for a mean of about 15days in patients with STEMI showedno increased risk of major bleeding (0.58% vs 0.55%; p = 0.59).5 In the CREDO study,major bleeding rates did not differ significantlybetween monotherapy with aspirin and the combinationof aspirin and clopidogrel after 9-12 months follOWing PCI (8.8% vs 6.7%; P = 0.07).7 In CHARISMA, long-term administration of clopidogrel plus aspirinfor a median of 28 months in patientswith atherosclerotic vascular disease showed no significant increase in severe bleeding (1.7%vs 1.3%,RR 1.25 [95%CI 0.97 to 1.61]).8 Overall, current data support the administration of dual antithmmbotic therapy in ACS and PCI. Aspirin plusclopidogrel treatment has not been foundto be beneficial in patients withrecentischemic strokeor atrial fibrilIation.9,lo In the MATCH trial, a nonsignificant reduction in majorvascular eventswas observed whenclopidogrel was added to aspirin (15.7%) versus clopidogrel alone (16.7%), with absolute riskreduction of 1% (95%CI -0.6 to 2.7) in patients with ischemic strokeor transient ischemic attack," Conversely, the risk of majorbleeding was increaSed in the dual antiplatelet group versusclopidogrel alone when administered for a meanof 18 months(2% vs 1%; p < 0.0001,respectively). In the ACTIVE-W trial,the Combination of aspirin 75-100 mg daily plus clopidogrel 75 mg dailydemonstrated inferiority against warfarin (target international normalized ratio [INR] 2.0-3.0) for stroke prevention in patients with atrialfibrillation and one Or mOre risk factors for stroke," The studywas stopped on lVwwJheannals.com

the recommendation of the Data Safety and Monitoring Board before the planned follow-up was completed because of the clear evidence of superiority of oral anticoagulation. A signific~t reduction in the numberof a first occurrence of stroke, non-central nervous system systemic embolus, MI, or vascular death with warfarin compared with dual antiplatelet therapy was observed (annual risk 3.93% vs 5.60%, respectively; RR 1.44 [95% CI 1.18 to 1.76]). However, the risk of major hemorrhage was not significantly different between the groups (aspirin plus clopidQgreI2.42% vs warfarin 2.21%; RR 1.10 [95% CI 0.83 to 1.5]). Warfarin demonstrated superiority to dualantiplatelet therapy in clinical outcomes without an increased riskof majorbleeding.

Clinical Practice Guidelines: Dual Antiplatelet Therapy Practice guideline recommendations from the American College of Cardiology (ACC) and the American HeartAssociation (AHA) for using dualantiplatelet therapy withaspirinand clopidogrel in patients with NSTEACS,STEMI, and PCI are shown in Table 1.11•17The ACC/AHA recommend clopidogrelfor preventionof recurrent myocardial ischemic events and strokein patients with NSTE ACS or STEMIand in thoseundergoing elective PCI or PCI in the settingof NSTE ACS or STEMl.ll,11,14 In patients not undergoing intracoronary stenting, treatment withclopidogrel shouldbe givenfor at least2 weeksfor patients withSTEMIl1 and up to 1 year in patients with NSTE ACS,14 In patients undergoing elective PCI or PCI in the setting of ACS, the duration of clopidogrel treatment should be at least 30 days in patientsreceivinga bare metal intracoronary stent (ideally 1 y) and for at least 12 months in patientsreceiving a drug-eluting intracoronary stentif the patient is not at high risk of bleeding." For patients at high risk of bleeding,clopidogrel should be administered for a minimumof2 weeks,"

Rationale for Combining Antiplatelets and Anticoagulants Warfarinmonotherapy has been proven beneficial for stroke prevention in patients with valvular heart disease, atrial fibrillation, atrial flutter, and patients with reduced left-ventricular function or left-ventricular thrombus followingMI.ll.17 Currentrecommendations, dosing,and duration for combining warfarinand antiplatelet therapy are included in Table 1. Oral anticoagulants are routinely indicated as monotherapy for prophylaxis and/or treatment of venous thromboembolism and stroke prevention in atrial fibrillation or in patients with mechanical or certain bioprosthetic heart valves,1S,J6 Warfarin, in combination withlow-doseaspirin,

The Annals ofPharmacotherapy • 2008June, Volume 42 • 791

Ai Hermosillo and SA Spinier

Table 1. United States Guideline Recommendations for Combining Warfarin and Antiplatelet Therapy Guideline ACC/AHA/SCAI 2007 Guideline Updatefor Percutaneous Coronary Intervention11

ACC/AHA 2007 Guidelines for the Management of Patients with STElevation Myocardiallnfarction 12

Recommendation use warfarin + clopidogrel + low-dose aspirin, with greatcaution, monitorINR (2.Q-3.0) carefully paroxysmal or chronicAF and post-MI pts. whenclinicallyindicated (eg, AF, LV thrombus) use of warfarin in conjunction with aspirinand/orclopidogrel is associated with an increased risk of bleeding and should be monitored closely in pts.requiring warfarin, clopidogrel, andaspirin afterPCI,targetINRof 2.0-2.5 is recommended with low-dose aspirin(75-81 mg) and a 75-mgdose of clopidogrel medical management alone or PTCAwithoutintracoronary stentb if indication for anticoagulation, add warfarin (INR2.Q-3.0) to aspirin PCI with stentwithoutaspirin resistance, allergy, or increased risk of bleeding if indication for anticoagulation, add warfarin (INR2.Q-3.0) use of warfarinin combination with aspirinand/orclopidogrel is associated with increased risk of bleeding and shouldbe monitored closely in pts. requiring warfarin, clopidogrel, and aspirin, an INRof 2.0-2.5 is recommended with low-dose aspirin(75-81 mg) and a 75-mgdoseof clopidogrel MI with AF, atrialflutter, or LVthrombus warfarin plus antiplatelet (INR2.0-3.0)

AHA/ASA 2006 Guidelines for Prevention of Strokein Patients with Ischemic Strokeor Transient Ischemic Attack13

acuteMI with LVthrombus warfarin (INR2.Q-3.0) + aspirins:162 mg daily rheumatic mitralvalvedisease, with or withoutAF, in pts. who havea recurrent embolism while receiving warfarin warfarin (INR 2.Q-3.0) + aspirin81 mg daily

ACC/AHA 2007 Guidelines for the Management of Patients with Unstable AnginalNon-ST·Elevation Myocardial Infarction14

medicaltherapywith no intracoronary stent if indication for anticoagulation, add warfarin (INR2.Q-3.0) PCI with intracoronary stent (eitherdrug-eluting or bars-metaf)" if indication for anticoagulation, add warfarin(INR2.Q-3.0) high CAD riskwith a low bleeding risk in pts. who do not require or are intolerant of clopldogrel low-dose aspirin75-81 mg dally + warfarin (INR 2.0-2.5) warfarin addedto aspirin + clopldogrel; INR 2.0-2.5 recommended especially in older pts. and pts, with risk factorsfor bleeding

ACC/AHAIESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation 15

PCI in pt. with AF may holdwarfarintemporarily duringhospitalization for PCI; resume warfarin as soonas possible to achieve target INR;aspirinmay be given temporarily duringtime warfarin held:maintenance regimen shouldconsistof clopidogrel 75 mg daily" + warfarin (INR2.Q-3.0) for durationspecified by the stent,then clopidogrel shouldbe discontinued whenwarfarin is givenIn combination with clopidogrel or low-dose aspirin, dose intensity must be carefully regulated

Grade Recommendation! Level of Evidence" no grade recommendation

Class IB Class IC

Class IB Class IA Class IB Class IC

Class IA Class llaA

Class llaA ClassIIbB Class lib

ClassllbB no grade recommendation ClassIIbC

ClassIIbC

ACC = American College of Cardiology; AF = atrialfibrillation; AHA = American HeartAssociation; ASA = American StrokeAssociation; BMS = bare metalstent;CAD = coronary arterydisease; ESC = European Society of Cardiology; INA = international normalized ratio; LV = left ventricular; MI = myocardia/Infarction; PCI = percutaneous coronary Intervention; PTCA = percutaneous transluminal coronary angioplasty; SCAI = Society forCardiovascular Angiography and Interventions. "ACC/AHA Recommendation Grades.Class I: conditions for which there is evidenceand/or general agreement that a given procedureltherapy is beneficial. useful. andeffective. Class II:conditions for which thereis conflicting evidence and/ora divergence of opinion abouttheusefulness/ efficacy of performing the procedureltherapy. ClasslIa: weightof evidence/opinion is in favorof usefulness/efficacy. Classlib: usefulness/efficacy is lesswell established by evidence/opinion. ClassIII:conditions for whichthereis evidence and/orgeneral agreement that a procedureltherapy is not usefulor effectiveand In somecases maybe harmful. Levelof evidence. The weightof evidenca was ranked from highest(A) to lowest(C),as follows: levelof evidence A: dataderivedfrom mUltiple randomized clinicaltrialsor meta-analyses; levelof evidence B: dataderived froma singlerandomized trial or nonrandomlzed studies; levelof evidence C: only consensus opinionof experts. case studies, or standard-of-care. bContinue aspirinindefinitely and warfarin longerterm as indicated for specificconditions such as AF; LVthrombus; cerebral, venous, or pulmonary embolism. c'n pts, with a drug·eluting stent,administer for :t12mo If pt. is not at high risk of bleeding; for pts. with BMS,clopidogrel shouldbe givenfor:t1 rno, Ideally12 mo, unlessthe pt. is at increased risk of bleeding; then It shouldbe givenfor a minimum of 2 wk. (continued on page793)

792 • The Annals ofPharmacotherapy • 2008 June, Volume 42

wwwtheannalscom

Combination Treatment withAspirin,Clopidogrel, and Warfarin

has alsobeen provenbeneficial in patients with ACS.The

WARIs II trial showeda reduction in death, nonfatal reinfarction, or thromboembolic stroke in patients receiving aspirin 75 mg daily plus warfarin (target INR 2-2.5) comparedwith aspirin 160 mg daily alone (15% vs 20%; p = 0.001).18 The APRICOT II trial (aspirin 80 mg daily and median INR 2.6; targetINR 2.0-3.0) demonstrated a significant reduction in coronary arteryreocclusions, defined as the presence of Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow or less at angiographic follow-up (28% aspirin alone vs 15%dual antithrombotic therapy; p