PowerPoint Presentation

Use of Novel Anticoagulants & Antiplatlet Therapy Jong-Yoon Yi, MD, FACCPresident, Heartland Education & Research Foundation

DisclosuresSpeaker Forest Pharmaceuticals

Research ENGAGE AF-TIMI 48The Balance

BleedingClotting

4Thrombin remains active, promoting coagulation, even when bound to cross-linked fibrin within a clot.In fact, studies show that approximately 96% of thrombin is produced during the propagation phase, after the clot has formed. Clot burden in acute coronary syndromes Therapy in ACS is ComplexAnticoagulants: UFH LMWH Fondaparinux Bivalirudin

Antiplatelets: ASA Clopidogrel Prasugrel Ticagrelor

IV anitplatelets: None Abciximab Eptifibatide/Tirofiban

Cath strategy:EarlyDelayed Never

144 Different Combinations with Different effect on Bleeding and Thrombosis Risk

CollagenTXA2ADPTXA2ADPPDEADP(Fibrinogenreceptor)GP IIb/IIIaActivationCOXTiclopidineClopidogrelPrasugrelAZD6140CangrelorPRT060128ASADipyridamolecAMPTargets for antiplatelet therapies ThrombinPAR-1SCH 530348AbciximabEptifibatideTirofibanCourtesy of BM Scirica, MD.Adapted from Schafer AI.Am J Med. 1996;101:199-209.cAMP = cyclic adenosine monophosphate, COX = cyclooxygenase, PAR = protease-activated receptor, PDE = phosphodiesterase6The antiplatelet drug with the longest history of use, aspirin (ASA), inactivates cyclooxygenase-1 via irreversible acetylation, thereby blunting TxA2-dependent platelet activation.(1) Since a platelet cannot synthesize additional cyclooxygenase-1 in response, aspirin inhibits TxA2-mediated effects for the lifetime of the platelet (approximately 7 to 10 days) despite a plasma half-life for aspirin of only 20 minutes. However, aspirin is only a weak antiplatelet agent, with no effect on pathways activated in response to collagen and thrombin.Dipyridamole inhibits phosphodiesterase, thereby increasing levels of cyclic adenosine monophosphate (cAMP). However, other mechanisms may also contribute to its antiplatelet effect.(2)Clopidogrel and related compounds exert their antiplatelet effects via blockade of the platelet ADP receptor. A number of these agents are approved or under investigation.Another investigational antiplatelet drug class targets the thrombin receptor.Finally, the GP IIb/IIIa antagonists target the platelet fibrinogen receptor.Targets for antiplatelet therapies1. Selwyn AP. Am J Cardiol. 2003;91(suppl):3H-11H.2. Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-75.Prodrug:metabolized to salicylateAbsorption: affected by food, antacid buffer, enteric coating, chewingIrreversible COX-1, COX-2 inhibitionEffect within minutes, peak in 1-2 hoursAspirin Pharmacology

Beneficial in PTCA77% reduction in ischemic complications

Dosing for PCIOn ASA, then 75 to 325mg before PCINo ASA, then 325 mg >2 hrs before PCIMaintenance dose 81-162 mgLow dose has similar efficacy but decreased bleeding than with higher dosesAspirin

9Ridker et al examined the association between aspirin intake and the circadian pattern of myocardial infarction among participants in the Physicians Health Study.The investigators found that while circadian variation was lessened (primarily due to a reduction in the morning peak) it was not completely abolished.These findings support the hypothesis that increased platelet aggregability at certain times during the day contributes to the circadian variation of myocardial infarction.

Aspirin blunts but does not eliminate circadian variation of AMIAbsorption: Not affected by food or antacidsProdrug converted by liver to active metabolitesElimination half life = 8 hoursIrreversible binding: biologic effects = platelet life Clopidogrel: Thienopyridine Pharmacology

11In the CURE trial, all patients were started or continued on aspirin (recommended dose 75 mg to 325 mg daily).The primary outcome occurred in 9.3% of patients assigned to the clopidogrel group vs 11.4% in the placebo group.The development of newer oral antiplatelet agents was undertaken in the hope that more potent antiplatelet effects would translate into greater clinical benefit.Abbreviations:CV = cardiovascularMI = myocardial infarctionNSTE-ACS = non-ST elevation acute coronary syndromesCURE: Patients continue to have recurrent CV events despite dual antiplatelet therapyCREDO 28-day outcomeTime to Effect of 300mg Loading dose

300 mg has insignificant effectIf 12 hrs: 300mg

14Hochholzer et al assessed platelet aggregation by various methods in 1001 patients who were scheduled for cardiac catheterization and who received a clopidogrel loading dose of 600 mg.The data demonstrate that the full antiplatelet effects of clopidogrel were achieved after 2 hours.Clopidogrel 600 mg: Inhibition of platelet function at various timepoints

15Ho et al assessed the rate of adverse events after discontinuing clopidogrel treatment. The study population included 3137 patients discharged from 127 Veterans Affairs hospitals between October 1, 2003 and March 31, 2005.The investigators observed a clustering of adverse events in the initial 90 days after termination of clopidogrel treatment in both medically treated patients and patients treated with PCI.

Hazard of death or MI after clopidogrel discontinuation post-ACS

16Using light transmittance to measure ADP-induced platelet aggregation, Gurbel et al demonstrated that there was a normal distribution of clopidogrel responsiveness.The distribution is shifted rightward for patients receiving a 600 mg vs a 300 mg dose, indicating greater antiplatelet effect.Clopidogrel nonresponsiveness was defined as an absolute change in ADP-induced platelet aggregation of 75 or weight benefitASA 162-325 mg/d for 1mo then 75-100mg/d indefinitely+Clodpidogrel 75mg/d or Prasugrel 10mg/d or Ticagrelor 90mg BID for at 6-12 months

Shorter duration if bleeding risk >benefit

26The slides in this section will address the last three bullets (highlighted).Antiplatelet therapy: The changing landscapeASA, CV events & is foundation of acute & long-term therapyAll ADP antagonists should be given 2-6 hours before PCIRoutine genetic testing & POC platelet function testing unnecessary2nd Generation ADP antagonists are superior to clopidogrel*Reduced MACE & mortality*Increased Bleeding*Novel adverse effects, restrictions.ConclusionsNew Data on Prevention of Stroke in Nonvalvular AF

AF in the USAApprox 5 million peopleIncrease with ageIncreasing incidence & prevalence

Life time Risk:25%Independent predictor of mortalityRisk of stroke 3-7%/yearIncrease with ageAlmost half of all embolic strokesAbout 100,000 strokes/yearA growing EpidemicAppox 15M by 2050Stroke Risk StratificationCHADS2 Risk ScoreCHF 1 Hypertension 1 Age >75 1DM 1CVA or TIA 2Total 6CHADS2-VASc ScoreCHF 1Hypertension 1Age>75 2DM 1CVA/TIA 2Vascular Ds 1(MI, PAD)Aged 65-74 1Female 1Total 9Score CVA (%/Yr) 0 1.9% 1 2.8 % 2 4.0% 3 5.9% 4 8.5% 5 12.5% 6 18.2%Score CVA (%/Yr) 0 0% 1 1.3% 2 2.2% 3 3.2% 4 4.0% 5 6.7% 6 9.8% 7 9.6% 8 6.7% 9 15.2%Prevention of Stroke in pt with AF Trials (no.)ASA > Placebo7

ASA + Clopidogrel > aspirin1Warfarin > placebo5Warfarin > ASA9Warfarin > ASA = clopidogrel1Adjusted-dose warfarin > low-dose (fixed) warfarin + ASA1

32The efficacy of warfarin in preventing stroke in patients with AF was demonstrated in 3 prospective randomized trials:Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation (AFASAK)Stroke Prevention in Atrial Fibrillation (SPAF)Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)Summation of the data from these clinical trials demonstrated a 69% reduction in stroke risk with warfarin compared with control (either placebo or aspirin), decreasing the incidence of stroke from 4.5 per 100 person-years to 1.4 per 100 person-years. This represented 31 fewer strokes for every 1000 patients treated.The rate of major bleeding or intracranial hemorrhage was nearly identical in warfarin-treated patients and in controls. Only 1 warfarin-treated patient in each study had an intracranial bleed.This represents an overall substantially positive risk/benefit ratio for intervention.Anticoagulation for nonvalvular AFLimitations of Vit K AntagonistsLimitationsSlow Onset & Offset of actionNarrowTherapeutic RangeGenetic polymorphism Food & drug interactionsConcurrent diseaseNeed for monitoring of A/C effect & dose adjustmentsVariable & Unpredictable anticoagulation effect

34Warfarin has a narrow therapeutic window.An INR below 2.0 is associated with incomplete anticoagulation.An INR above 3.0 is associated with too much anticoagulation and an increased risk of hemorrhage.Warfarin risk/benefit balance

DabigatranRivaroxabanApixaban35The cascade comprises a regulated series of linked reactions involving the sequential activation of coagulation factors.The primary (extrinsic) pathway is triggered by exposure or expression of tissue factor (TF) to form a complex with factor VIIa. This complex converts factor X to factor Xa. Factor Xa (in complex with factor Va) then converts prothrombin (factor II) to thrombin (factor IIa), the most important protein in the coagulation cascade. Thrombin converts fibrinogen to fibrin, which polymerizes to form a 3-dimensional matrix. Thrombin also activates factor XIII, which catalyzes formation of this matrix. Cross-linking of platelets with fibrinogen recruits circulating platelets to the growing thrombus.Thrombin then binds to fibrin, remaining in the growing clot, where it remains active. The intrinsic pathway plays an accessory role in amplification of the cascade. The VIIIa/IXa complex formed by this pathway is approximately 50 times more efficient than the VIIa/TF complex.The large arrows indicate points in the cascade that are targeted by new anticoagulant therapies.Coagulation cascadeDabigatran

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Dabigatran: Advantages & Disadvantages

Stroke ICH No INR monitoringConvenientInability to assess efficacyRapid onset of effectTwice-daily dosing Effect on compliance?IrreversibilityDose in pt with renal dysfunction & age >75yr ConfusingDyspepsia (11-12%) Costs SocieetalPt related impact on compliance MI:Play of chanceDirect causeWrfarin effectLack of ASAUse in pts on dual antiplatelet therapy?AdvantageDisadvantage

Rivaroxaban

Rates of Major BleedingNo./100 patient-yearRivaroxabanWarfarinPANY 2.13 3.09