“ Anticoagulation and the Heart”

M. Samir Arnaout M.DAssociate Professor of Medicine

C di l Di i iCardiology DivisionAmerican University of Beirut-Medical Center

PAFPAFThrombinThrombin ADPADP

TXATXA22

ASPIRINASPIRINEpiEpi ASPIRINASPIRIN VasopressinVasopressinPLATELETPLATELET

ASPIRINASPIRINHEPARINSHEPARINS ASPIRINASPIRIN

ASPIRINASPIRINCLOPIDOGRELCLOPIDOGREL

ASPIRINASPIRINASPIRINASPIRIN

ASPIRINASPIRIN55HTHT

GP IIb/IIIaGP IIb/IIIaThi k f liThi k f li

CollagenCollagenGP IIb/IIIaGP IIb/IIIa

GP IIb/IIIaGP IIb/IIIa

Thickness of lineThickness of lineindicates strengthindicates strength

of activatorof activator FibrinogenFibrinogenPLATELETPLATELET

Oral AnticoagulantOral AnticoagulantOral AnticoagulantOral Anticoagulant

Clotting CascadeClotting CascadeClotting CascadeClotting Cascade

Vitamin KVitamin K--DependentDependentVitamin KVitamin K Dependent Dependent Clotting FactorsClotting Factors

Vitamin KVitamin K

VIIVIISynthesis of Synthesis of Functional Functional

Coagulation Coagulation

VIIVIIIXIXXX Coagulation Coagulation

FactorsFactorsXXIIII

Warfarin Mechanism ofWarfarin Mechanism ofWarfarin Mechanism of Warfarin Mechanism of ActionAction

Vitamin KVitamin K

Antagonism VIIVIISynthesis of Synthesis of

Non Non Functional Functional

gof

Vitamin K

VIIVIIIXIXXX Functional Functional

Coagulation Coagulation FactorsFactors

XXIIII

WarfarinWarfarin

Warfarin: IndicationsWarfarin: IndicationsWarfarin: IndicationsWarfarin: Indications

Prophylaxis and/or treatment of:Prophylaxis and/or treatment of:V th b i d it t iV th b i d it t i–– Venous thrombosis and its extensionVenous thrombosis and its extension

–– Pulmonary embolismPulmonary embolismTh b b li li ti i t d ith AF dTh b b li li ti i t d ith AF d–– Thromboembolic complications associated with AF and Thromboembolic complications associated with AF and cardiac valve replacementcardiac valve replacement

P t MI t d th i k f d th t MIP t MI t d th i k f d th t MIPost MI, to reduce the risk of death, recurrent MI, Post MI, to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or and thromboembolic events such as stroke or

t i b li tit i b li tisystemic embolizationsystemic embolizationPrevention and treatment of cardiac embolismPrevention and treatment of cardiac embolism

The Fifth American College of Chest Physicians Consensus Conference

Antithrombotic Agents:Antithrombotic Agents:Antithrombotic Agents: Antithrombotic Agents: Mechanism of ActionMechanism of Action

Anticoagulants: prevent clot formation Anticoagulants: prevent clot formation and extensionand extensionAntiplatelet drugs: interfere withAntiplatelet drugs: interfere withAntiplatelet drugs: interfere with Antiplatelet drugs: interfere with platelet activityplatelet activityTh b l i di l i iTh b l i di l i iThrombolytic agents: dissolve existing Thrombolytic agents: dissolve existing thrombithrombi

Prothrombin Time (PT)Prothrombin Time (PT)( )( )

Historically, a most reliable and “relied Historically, a most reliable and “relied upon” clinical testupon” clinical testHowever:However:–– Proliferation of thromboplastin reagents with Proliferation of thromboplastin reagents with

widely varying sensitivities to reduced levels of widely varying sensitivities to reduced levels of i i Ki i K d d l i f hd d l i f hvitamin Kvitamin K--dependent clotting factors has dependent clotting factors has

occurredoccurredConcept of correct “intensity” of anticoagulantConcept of correct “intensity” of anticoagulant–– Concept of correct “intensity” of anticoagulant Concept of correct “intensity” of anticoagulant therapy has changed significantly (low intensity)therapy has changed significantly (low intensity)Problem addressed by use of INR (InternationalProblem addressed by use of INR (International–– Problem addressed by use of INR (International Problem addressed by use of INR (International Normalized Ratio)Normalized Ratio)

INR: International INR: International li d ili d iNormalized RatioNormalized Ratio

A mathematical “correction” (of the PT ratio) for A mathematical “correction” (of the PT ratio) for differences in the sensitivity of thromboplastindifferences in the sensitivity of thromboplastindifferences in the sensitivity of thromboplastin differences in the sensitivity of thromboplastin reagentsreagentsRelies upon “reference” thromboplastins withRelies upon “reference” thromboplastins withRelies upon reference thromboplastins with Relies upon reference thromboplastins with known sensitivity to antithrombotic effects of oral known sensitivity to antithrombotic effects of oral anticoagulantsanticoagulantsINR i th PT ti ld h bt i d if thINR i th PT ti ld h bt i d if thINR is the PT ratio one would have obtained if the INR is the PT ratio one would have obtained if the “reference” thromboplastin had been used“reference” thromboplastin had been usedAllows for comparison of results between labs andAllows for comparison of results between labs andAllows for comparison of results between labs and Allows for comparison of results between labs and standardizes reporting of the prothrombin timestandardizes reporting of the prothrombin time

J Clin Path J Clin Path 19851985; ; 3838::133133--134134; WHO Tech Rep Ser. #; WHO Tech Rep Ser. #687 983687 983..

INR E tiINR E tiINR EquationINR Equation

(( ))Patient’s PT in SecondsPatient’s PT in Seconds ISIISI(( ))Patient’s PT in SecondsPatient’s PT in SecondsMean Normal PT in SecondsMean Normal PT in SecondsINR =INR =

ISIISI(( ))INR = International Normalized RatioINR = International Normalized RatioISI = International Sensitivity Index

Warfarin: Dosing InformationWarfarin: Dosing InformationWarfarin: Dosing InformationWarfarin: Dosing Information

Individualize dose according to patient Individualize dose according to patient response(as indicated by INR)response(as indicated by INR)response(as indicated by INR)response(as indicated by INR)Use of large loading dose not Use of large loading dose not recommended*recommended*recommended*recommended*–– May increase hemorrhagic complicationsMay increase hemorrhagic complications–– Does not offer more rapid protectionDoes not offer more rapid protectionLow initiation doses are recommended for Low initiation doses are recommended for elderly/frail/liverelderly/frail/liver--diseased/malnourished diseased/malnourished patientspatients

**Harrison L, et al. Ann Intern Med Harrison L, et al. Ann Intern Med 19971997;;126126::133133--136136..

pat e tspat e ts

Loading Dose thenLoading Dose thenLoading Dose then Loading Dose then Maintenance DoseMaintenance Dose

Daily Dose

Maintenance Dose OnlyMaintenance Dose OnlyMaintenance Dose OnlyMaintenance Dose Only

Daily Dose

Maintenance Maintenance Loading Dose thenLoading Dose then Maintenance Maintenance Dose OnlyDose Only

Loading Dose thenLoading Dose thenMaintenance DoseMaintenance Dose

Daily Dose Daily Dose

Conversion from HeparinConversion from HeparinConversion from Heparin Conversion from Heparin to Warfarinto Warfarin

May begin concomitantly with heparin May begin concomitantly with heparin thththerapytherapyHeparin should be continued for a minimum Heparin should be continued for a minimum of four daysof four days–– Time to peak antithrombotic effect of warfarin is Time to peak antithrombotic effect of warfarin is

delayed delayed 96 96 hours (despite INR)hours (despite INR)

When INR reaches desired therapeutic When INR reaches desired therapeutic range, discontinue heparin (after a range, discontinue heparin (after a minimum of four days)minimum of four days)

Relative ContraindicationsRelative ContraindicationsRelative Contraindications Relative Contraindications to Warfarin Therapyto Warfarin Therapy

Pregnancy Pregnancy Situations where the risk of Situations where the risk of hemorrhage is greater than thehemorrhage is greater than thehemorrhage is greater than the hemorrhage is greater than the potential clinical benefits of therapypotential clinical benefits of therapy

U t ll d l h l/d bU t ll d l h l/d b–– Uncontrolled alcohol/drug abuseUncontrolled alcohol/drug abuse–– Unsupervised dementia/psychosisUnsupervised dementia/psychosis

Signs of WarfarinSigns of WarfarinSigns of Warfarin Signs of Warfarin OverdosageOverdosage

Any unusual bleeding:Any unusual bleeding:–– Blood in stools or urineBlood in stools or urine–– Excessive menstrual bleedingExcessive menstrual bleedingExcessive menstrual bleedingExcessive menstrual bleeding–– BruisingBruising

E i bl d /bl diE i bl d /bl di–– Excessive nose bleeds/bleeding gumsExcessive nose bleeds/bleeding gums–– Persistent oozing from superficial injuriesPersistent oozing from superficial injuries–– Bleeding from tumor, ulcer, or other Bleeding from tumor, ulcer, or other

lesionlesion

Managing Patients with High INRManaging Patients with High INRManaging Patients with High INR Managing Patients with High INR Values/Minor or No BleedingValues/Minor or No Bleeding

Clinical SituationINR >therapeutic range but <5.0,

li i ll i ifi t

GuidelinesLower the dose or omit the next dose; resume

f i th t l d h th INR no clinically significant bleeding, rapid reversal not indicated for reasons of surgical intervention

warfarin therapy at a lower dose when the INR approaches desired rangeIf the INR is only minimally above therapeutic range, d d ti t b intervention dose reduction may not be necessary

Patients with no additional risk factors for bleeding; omit the next dose or two of warfarin, monitor INR

INR >5.0 but <9.0, no clinically significant bleeding

more frequently, and resume warfarin therapy at a lower dose when the INR is in therapeutic rangePatients at increased risk of bleeding: omit the next

g g

dose of warfarin, and give vitamin K1 (1.0 to 2.5 mg orally)Patients requiring more rapid reversal before urgent

d l i i i K (2 4 surgery or dental extraction: vitamin K1 (2–4 mg orally); if the INR remains high at 24 h, an additional dose of 1–2 mg

Managing Patients with High INRManaging Patients with High INRManaging Patients with High INR Managing Patients with High INR Values/Serious BleedingValues/Serious Bleeding

Clinical Situation GuidelinesINR >9.0, no clinically significant bleeding

Vitamin K1 (3–5 mg orally); closely monitor the INR; if the INR is not substantially reduced by 24–24 h, the vitamin K1 dose can be repeatedS i bl di j f i d ( INR Serious bleeding, or major warfarin overdose (e.g., INR >20.0) requiring very rapid reversal of anticoagulant effect: Vitamin K1 (10 mg by slow IV infusion), with fresh plasma transfusion or prothrombin complex

Life threatening bleeding or

fresh plasma transfusion or prothrombin complex concentrate, depending upon urgency; vitamin K1injections may be needed q12hProthrombin complex concentrate, with vitamin K1 (10 Life-threatening bleeding or

serious warfarin overdoseProthrombin complex concentrate, with vitamin K1 (10 mg by slow IV infusion); repeat if necessary, depending upon the INR

Continuing warfarin therapy indicated after high doses of vitamin K1

Heparin, until the effects of vitamin K1 have been reversed, and patient is responsive to warfarin

Risk of Intracranial Hemorrhage in Risk of Intracranial Hemorrhage in OutpatientsOutpatients

Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin They determined that an intensity of anticoagulation expressedwith warfarin They determined that an intensity of anticoagulation expressed

Adapted from: Hylek EM, Singer DE, Ann Int Med Adapted from: Hylek EM, Singer DE, Ann Int Med 19941994;;120120::897897--902902

with warfarin. They determined that an intensity of anticoagulation expressed with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above as a prothrombin time ratio (PTR) above 22..0 0 (roughly corresponding to an (roughly corresponding to an INR of INR of 33..7 7 to to 44..33) resulted in an increase in the risk of bleeding.) resulted in an increase in the risk of bleeding.

Lowest Effective Intensity for Warfarin Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Therapy for Stroke Prevention in Atrial FibrillationFibrillation

INR below 2 0 results in a higher risk of

Hylek EM, et al. NEJM Hylek EM, et al. NEJM 19961996;;335335::540540--546546..Hylek EM, et al. NEJM Hylek EM, et al. NEJM 19961996;;335335::540540--546546..

INR below 2.0 results in a higher risk of stroke

Warfarin: CurrentWarfarin: CurrentWarfarin: Current Warfarin: Current Indications/IntensityIndications/Intensity

IndicationIndication INR INR RangeRange TargetTarget

Prophylaxis of venous thrombosis (highProphylaxis of venous thrombosis (high risk surgery)risk surgery) 22 00 33 00 22 55Prophylaxis of venous thrombosis (highProphylaxis of venous thrombosis (high--risk surgery)risk surgery) 22..00––33..00 22..55Treatment of venous thrombosisTreatment of venous thrombosisTreatment of PETreatment of PEP ti f t i b liP ti f t i b liPrevention of systemic embolismPrevention of systemic embolismTissue heart valvesTissue heart valvesAMI (to prevent systemic embolism)AMI (to prevent systemic embolism)Valvular heart diseaseValvular heart diseaseAtrial fibrillationAtrial fibrillation

Mechanical prosthetic valves (high risk)Mechanical prosthetic valves (high risk) 22 55––33 55 33 00Mechanical prosthetic valves (high risk)Mechanical prosthetic valves (high risk) 22..55 33..55 33..00Certain patients with thrombosis Certain patients with thrombosis and the antiphospholipid syndromeand the antiphospholipid syndromeAMI (to prevent recurrent AMI)AMI (to prevent recurrent AMI)AMI (to prevent recurrent AMI)AMI (to prevent recurrent AMI)

Bileaflet mechanical valve in aortic position, NSRBileaflet mechanical valve in aortic position, NSR 22..00––33..00 22..55

Examples of Low & High Risk InvasiveExamples of Low & High Risk InvasiveP d & Cli i l C ditiP d & Cli i l C ditiProcedures & Clinical ConditionsProcedures & Clinical Conditions

Risk of BleedingLow High

sis

Low Dental; cutaneous biopsies;open procedures; cataracts

Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy

hrom

bos

AF; valvular heart disease ±aortic prosthesis; old DVT/PE

AF; valvular heart disease ±aortic prosthesis; old DVT/PE

Risk

of T

h

Dental; cutaneous biopsies;open procedures; cataracts

Prosthetic valves esp in mitral

Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy

High

R Prosthetic valves, esp. in mitral position; AF + history of CVA; very recent DVT/PE

Prosthetic valves, esp. in mitral position;AF + history of CVA; very recent DVT/PE

Dosage Adjustment AlgorithmDosage Adjustment Algorithm

Current Daily Dose (mg)Current Daily Dose (mg)22..0 0 55..00 77..55 1010..00 1212..55

WarfarinWarfarinINRINR Dose Adjustment*Dose Adjustment* Adjusted Daily Dose (mg)Adjusted Daily Dose (mg)

11 00--22 00 Increase x Increase x 2 2 daysdays 55 00 77 55 1010 00 1212 55 1515 0011..00 22..00 Increase x Increase x 2 2 daysdays 55..00 77..55 1010..00 1212..55 1515..0022..00--33..00 No changeNo change —— —— —— —— ——33..00--66..00 Decrease x Decrease x 2 2 daysdays 11..2525 22..55 55..00 77..55 1010..00

66..00--1010..00†† Decrease x Decrease x 2 2 daysdays 00 11..2525 22..55 55..00 77..5566..00 1010..00 Decrease x Decrease x 2 2 daysdays 00 11..2525 22..55 55..00 77..551010..00--1818..00§§ Decrease x Decrease x 2 2 daysdays 00 00 00 00 22..55

>>1818..00§§ Discontinue warfarinDiscontinue warfarin and consider hospitalization/reversaland consider hospitalization/reversalof anticoagulationof anticoagulationgg

† † Consider oral vitamin K, Consider oral vitamin K, 22..55––5 5 mgmg§§ Oral vitamin K, Oral vitamin K, 22..55––5 5 mgmg* Allow * Allow 2 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 2 days after days after increasing or decreasing warfarin dosage and use new guide to management (INR = International Normalized increasing or decreasing warfarin dosage and use new guide to management (INR = International Normalized increasing or decreasing warfarin dosage and use new guide to management (INR International Normalized increasing or decreasing warfarin dosage and use new guide to management (INR International Normalized Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 55..0 0 qd, qd, alternate alternate 55..00//77..55; if alternate ; if alternate 22..55//55..00, increase to , increase to 55..0 0 qd).qd).

Drug Interactions withDrug Interactions withDrug Interactions with Drug Interactions with Warfarin: PotentiationWarfarin: Potentiation

Level of Evidence Potentiation

Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600 mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam propafenone propranolol † sulfinpyrazone (biphasic with later

Ipiroxicam, propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, di lfi it l i idi h t i (bi h i ith l t i hibiti )

IIdisulfiram, itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen, tetracycline, flu vaccineAcetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen, i t ti t l i i i lidi i id fl i fl i III iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylatesCefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole

III

IV

†In a small number of volunteer subjects, an inhibitory drug interaction occurred.

Drug Interactions withDrug Interactions withDrug Interactions with Drug Interactions with Warfarin: InhibitionWarfarin: Inhibition

Level of Evidence Inhibition

Barbiturates, carbamazepine, chlordiazepoxide, Icholestyramine, griseofulvin, nafcillin, rifampin, sucralfateDi l illi A hi i l i i

IIDicloxacillin Azathioprine, cyclosporine, etretinate, trazodone

III

IVIV

Drug Interactions withDrug Interactions withDrug Interactions with Drug Interactions with Warfarin: No EffectWarfarin: No Effect

Level of Evidence No Effect

Alcohol, antacids, atenolol, bumetadine, enoxacin, I famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine‡

Ib f k l

I

Ibuprofen, ketoconazoleIIIII

Diltiazem, tobacco, vancomycinIV

Effective PatientEffective PatientEffective Patient Effective Patient EducationEducation

Teach basic concepts of safe, Teach basic concepts of safe, effective anticoagulationeffective anticoagulationDiscuss importance of regular INRDiscuss importance of regular INRDiscuss importance of regular INR Discuss importance of regular INR monitoringmonitoringC l f h di iC l f h di iCounsel on use of other medications, Counsel on use of other medications, alcoholalcoholDevelop creative strategies for Develop creative strategies for improving complianceimproving complianceimproving complianceimproving compliance

Factors InfluencingFactors InfluencingFactors Influencing Factors Influencing VariabilityVariability

Patient/Disease State

Process of Care Warfarin: drug with a narrow therapeutic i dindex

Antithrombotic agents in CHFAntithrombotic agents in CHFAntithrombotic agents in CHFAntithrombotic agents in CHF

AntiAnti--coagulation is firmly indicated in CHF coagulation is firmly indicated in CHF with atrial fibrillation a previouswith atrial fibrillation a previouswith atrial fibrillation, a previous with atrial fibrillation, a previous thromboembolic event or a mobile LV thromboembolic event or a mobile LV thrombusthrombusthrombusthrombusAfter a prior MI. either aspirin or oral antiAfter a prior MI. either aspirin or oral anti--cc00agulation are recommended as aagulation are recommended as acc00agulation are recommended as a agulation are recommended as a secondary prophylaxix.secondary prophylaxix.Aspirin should be avoide I patient withAspirin should be avoide I patient withAspirin should be avoide I patient with Aspirin should be avoide I patient with recurrent hospitalization because df recurrent hospitalization because df worsening heart failure.worsening heart failure.gg

Anticoagulation is recommende Anticoagulation is recommende ggin the following situationsin the following situations

Lifelong for all patients with Lifelong for all patients with mechanical valves and for patients mechanical valves and for patients with bioprosthesis who have other with bioprosthesis who have other ppindicastion for antiindicastion for anti--coagulationcoagulationFor the firstFor the first 33 months after insertion inmonths after insertion inFor the first For the first 3 3 months after insertion in months after insertion in all patients with bioprosthesis with a all patients with bioprosthesis with a target INR of target INR of 22..55

Target INR for Mechanical ProsthesisTarget INR for Mechanical ProsthesisTarget INR for Mechanical ProsthesisTarget INR for Mechanical ProsthesisPatient -related risk factors

Prosthesis Prosthesis thrombogenicitythrombogenicity

No risk factorNo risk factor > > 1 1 risk factorrisk factor

Patient related risk factors

thrombogenicitythrombogenicity

LowLow 22..55 33..00

MediumMedium 33 00 33 55MediumMedium 33..00 33..55

HighHigh 33..55 44..00

Patient Characteristics RecommendationBileaflet mechanical valve in the aortic position, Goal INR 2.5; range, 2.0–3.0left atrium of normal size NSR normal ejection fractionleft atrium of normal size, NSR, normal ejection fractionTilting disk valve or bileaflet mechanical valve in Goal INR 3.0; range, 2.5–3.5*the mitral positionBileaflet mechanical aortic valve and AF Goal INR 3.0; range, 2.5–3.5*Caged ball or caged disk valves Goal INR 3.0; range, 2.5–3.5(+)

aspirin therapy (80–100 mg/d)aspirin therapy (80 100 mg/d)Additional risk factors Goal INR 3.0; range, 2.5–3.5;

and aspirin therapy (81 mg/d)Systemic embolism, despite adequate therapy Goal INR 3.0; range, 2.5–3.5;with oral anticoagulants and aspirin therapy (81 mg/d)* Alternative: goal INR 2.5; range, 2.0–3.0; and aspirin therapy (80–100 mg/d)

The Warfarin, Aspirin, The Warfarin, Aspirin, Reinfarction Study (WARIS II)Reinfarction Study (WARIS II)

Was a randomised , multicenter trial conducted in Was a randomised , multicenter trial conducted in 3630 3630 patients with recent MI (WHO criteria)patients with recent MI (WHO criteria)patients with recent MI (WHO criteria) . patients with recent MI (WHO criteria) . 1216 1216 patients received warfarin (target INR patients received warfarin (target INR 22..88--44..22), ), 1206 1206 received received 160 160 mg aspirin dailymg aspirin dailyg p yg p y1208 1208 received received 75 75 mg aspirin daily plus warfarin (target mg aspirin daily plus warfarin (target INR INR 22..00--22..55). T). TThe treatment was started before discharge from the The treatment was started before discharge from the hospital. Patients were all below hospital. Patients were all below 75 75 years and were years and were followed for approximatelyfollowed for approximately 44 years (average)years (average)followed for approximately followed for approximately 4 4 years (average).years (average).Approximately Approximately 59 59 % of the patients had a Q% of the patients had a Q--wave wave infarction and infarction and 54 54 % were treated with thrombolysis % were treated with thrombolysis yyMean ejection fraction was Mean ejection fraction was 52 52 %. %. 77 77 % received statins % received statins and and 74 74 % beta% beta--blockers.blockers.

Primary EndpointsPrimary Endpointsy py pcomposite of death, reinfarction of thromboembolic composite of death, reinfarction of thromboembolic stroke occurred in:stroke occurred in:stroke occurred in: stroke occurred in: 2020..0 0 %% in the in the aspirin groupaspirin group ( p value NS)( p value NS)1616 77 %% i hi h f if i ( l NS)( l NS)1616..7 7 %% in the in the warfarin groupwarfarin group ( p value NS)( p value NS)1515..0 0 %% in the in the warfarin+aspirin group warfarin+aspirin group ( p value s)( p value s)Episodes of major, nonEpisodes of major, non--fatal bleeding were seen fatal bleeding were seen significantly more often in the two warfarin groups significantly more often in the two warfarin groups

d t th i i ld t th i i lcompared to the aspirin alone group.compared to the aspirin alone group.There was no difference in mortality between the There was no difference in mortality between the

Th diff i th i d i tTh diff i th i d i tgroups. The difference in the primary endpoint was groups. The difference in the primary endpoint was driven by a significant reduction in reinfarction and driven by a significant reduction in reinfarction and thromboembolic stroke in the warfarin groupsthromboembolic stroke in the warfarin groupsthromboembolic stroke in the warfarin groups.thromboembolic stroke in the warfarin groups.

Th kTh kThank youThank youyy