1 Antiplatelet / Anticoagulant Therapy Evidence and Guidelines Ty J. Gluckman, Andrew P. DeFilippis, James Mudd, Catherine Campbell, Gregg Fonarow, & Roger S. Blumenthal

2 Antiplatelet Therapy Evidence and Guidelines

3 Antiplatelet Therapy: Targets Collagen Thrombin TXA 2 ADP (Fibrinogen Receptor) ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA 2 =Thromboxane A 2 clopidogrel bisulfate TXA 2 phosphodiesterase ADP Gp IIb/IIIa Activation COX ticlopidine hydrochloride aspirin Gp 2b/3a Inhibitors dipyridamole Schafer AI. Am J Med 1996;101:199–209

4 Antiplatelet Therapy: Common Oral Agents Acetylsalicylic acid (ASA) Clopidogrel bisulfate* Ticlopidine hydrochloride* Trade NameAspirinPlavix®Ticlid® ClassSalicylateThienopyridine FormulationActive DrugPro-DrugActive Drug Maintenance Dose mg daily75 mg daily250 mg twice daily Major Bleeding Risk (%) 2-3% 1 1-4% alone 2,3 3-5% w/ ASA 4 1% alone 5 2-6% w/ ASA 6,7 1 Topol EJ et al. Circulation 2003;108: Diener HC et al. Lancet 2004;364; Plavix® package insert. 4 Peters RJ et al. Circulation 2003;108: Hass WK. NEJM 1989;321: Urban P. Circulation 1998;98: Ticlid® package insert. * Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

5 Aspirin: Mechanism of Action Membrane Phospholipids Arachadonic Acid Prostaglandin H 2 COX-1 Thromboxane A 2  Platelet Aggregation Vasoconstriction Prostacyclin  Platelet Aggregation Vasodilation Aspirin

6 Aspirin Evidence: Primary Prevention in Men Physicians’ Health Study (PHS) 22,071 men randomized to aspirin (325mg every other day) followed for an average of 5 years Aspirin significantly reduces the risk of MI in men Physicians’ Health Study Research Group. NEJM 1989;321: CI=Confidence interval, MI=Myocardial infarction

7 Aspirin Evidence: Primary Prevention in Women Womens’ Health Study (WHS) Placebo Aspirin Ridker P et al. NEJM 2005;352: MI=Myocardial infarction 39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years Aspirin did not reduce the risk of MI, CVA & CV death

8 Aspirin Evidence: Primary Prevention BDT, 1988 Combined PPP, 2001 HOT, 1998 TPT, 1998 PHS, 1989 RR of MI in Men RR = 0.68 ( ) P= RR = 1.13 ( ) P=0.15 HOT, 1998 Combined WHS, 2005 PPP, Aspirin BetterPlacebo Better RR = 0.99 ( ) P= Aspirin BetterPlacebo Better RR = 0.81 ( ) P=0.01 RR of CVA in Men RR of MI in Women RR of CVA in Women Ridker P et al. NEJM 2005;352: CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk

9 Aspirin Evidence: Secondary Prevention Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86 Category % Odds Reduction Acute MI Acute CVA Prior MI Prior CVA/TIA Other high risk CVD (e.g. unstable angina, heart failure) PAD (e.g. intermittent claudication) High risk of embolism (e.g. Afib) Other (e.g. DM) All trials Control better Antiplatelet better Effect of antiplatelet treatment* on vascular events** *Aspirin was the predominant antiplatelet agent studied **Include MI, stroke, or death

10 Aspirin Evidence: Dose and Efficacy mg mg mg12 32 <75 mg 3 13 Any aspirin65 23 Antiplatelet Better Antiplatelet Worse Aspirin Dose No. of Trials (%) Odds Ratio for Vascular Events 0 P<.0001 Indirect comparisons of aspirin doses on vascular events in high-risk patients Antithrombotic Trialist Collaboration. BMJ 2002;324:71-86

11 Aspirin (81 mg daily or 100 mg every other day) in at risk women >65 years of age Aspirin in at risk women <65 years of age for ischemic stroke prevention Aspirin in optimal risk women <65 years of age Primary Prevention (Women) CHD=Coronary heart disease Aspirin Recommendations

12 Aspirin Recommendations Aspirin ( mg daily) in those at intermediate risk (10 year risk of CHD >10%) Primary Prevention (Men*) CHD=Coronary heart disease *Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines

13 Aspirin Recommendations (Continued) Aspirin ( mg daily) if known CHD/ASVD Aspirin ( mg daily) for at least 3 months after sirolimus-eluting stent implantation and at least 6 months after paclitaxel-eluting stent implantation after which aspirin ( mg daily) should be continued indefinitely Secondary Prevention ASVD=Atherosclerotic vascular disease, CABG=Coronary artery bypass graft, CHD=Coronary heart disease

14 Aspirin Recommendations (Continued) Aspirin ( mg daily) as the initial dose after stent implantation in those at higher bleeding risk Aspirin ( mg daily) following CABG surgery* Secondary Prevention *To be administered within the first 48 hours after surgery in order to reduce the risk of saphenous vein graft failure. Doses >162 mg/day may be continued for up to one year

15 Thienopyridine: Mechanism of Action ADP / ATP P2Y 1 P2X 1 P2Y 12 Gi 2 coupled Gq coupled Ca 2+ cAMP Platelet shape change Transient aggregation No effect on fibrinogen receptor Cation influx Calcium mobilization Fibrinogen receptor activation Thromboxane A 2 generation Sustained Aggregation Response Savi P et al. Biochem Biophys Res Commun 2001; 283:379–83 and Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000: pp.15–35 Clopidogrel or Ticlopidine

16 Clopidogrel Evidence: Secondary Prevention Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial Months Treated Event Rate for MI (%) (fatal or nonfatal) Aspirin Clopidogrel 4 P = CAPRIE Steering Committee. Lancet 1996;348: CVA=Cerebrovascular accident, MI=Myocardial infarction, PAD=Peripheral arterial disease 19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin (325 mg) or clopidogrel (75 mg) for 2 years Clopidogrel provides slightly greater risk reduction

17 Clopidogrel Evidence: Secondary Prevention Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Rate of death, myocardial infarction, or stroke P<0.001 Months of Follow Up The CURE Trial Investigators. NEJM 2001;345: NSTE-ACS=Non ST-segment elevation acute coronary syndrome Aspirin + Clopidogrel Aspirin + Placebo 12,562 patients with a NSTE-ACS randomized to daily aspirin ( mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin ( mg) for 9 months Dual antiplatelet therapy is more efficacious in NSTE-ACS

18 Steinhubl S et al. JAMA 2002;288: Clopidogrel for the Reduction of Events during Observation (CREDO) Trial Clopidogrel Evidence: Secondary Prevention DAP=Dual antiplatelet therapy, PCI=Percutaneous coronary intervention, RRR=Relative risk reduction *Dual antiplatelet therapy=Aspirin ( mg daily) plus Clopidogrel (300 mg load followed by 75 mg daily) Risk of MI, Stroke, or Death (%) 27% RRR, P= weeks of DAP 1 year of DAP Months from Randomization 2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin ( mg) monotherapy vs persistent DAP* for 1 year DAP* produces continued benefit when used for 1 year

19 Bhatt DL et al. NEJM 2006;354: Months Placebo Clopidogrel Incidence of CV Death, MI, or CVA (%) Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial Clopidogrel Evidence: Secondary Prevention P = 0.22 CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction 15,603 patients with multiple CV risk factors or known CVD randomized to aspirin ( mg) or aspirin ( mg) & clopidogrel (75 mg) for a mean of 30 months Routine DAP therapy offers little long-term benefit

20 Bhatt DL et al. NEJM 2006;354: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial Clopidogrel Evidence: Secondary Prevention 15,603 patients with multiple CV risk factors or known CVD randomized to aspirin ( mg) or aspirin ( mg) & clopidogrel (75 mg) for a mean of 30 months Long-term DAP provides benefit to those with CV disease Population RR (95% CI) p value Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.04 Multiple Risk Factors 1.20 (0.91, 1.59) 0.20 Overall Population 0.93 (0.83, 1.05) CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction

21 Thienopyridine Recommendations No data to support the use of thienopyridines in primary prevention Clopidogrel (75 mg daily) if aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI; Class IIa, Level B in those with stable angina) Primary Prevention Secondary Prevention NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI

22 Ticlopidine* (250 mg twice daily) for aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI) Clopidogrel* (75 mg daily) in addition to aspirin for a minimum of 1 month (Class I, Level A) and ideally 1 year (Class I, Level B) after a NSTE-ACS Secondary Prevention NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI Thienopyridine Recommendations (Continued) * Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

23 Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 14 days (Class I, Level A) and up to 1 year (Class IIa, Level C) in those treated with fibrinolytic therapy or no reperfusion therapy after a STEMI Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 1 month and ideally for 12 months after bare metal stent implantation and for at least 12 months after drug-eluting stent implantation in those at low bleeding risk Secondary Prevention STEMI=ST-segment elevation myocardial infarction Thienopyridine Recommendations (Continued)

24 Anticoagulant Therapy Evidence and Guidelines

25 Warfarin Synthesis of Non- Functional Coagulation Factors Antagonism of Vitamin K VII IX X II Warfarin: Mechanism of Action Ansell J et al. Council on Clinical Cardiology.

26 WA* N=1277 W* N=1268 A* N=1268 P* N=1272 MI and coronary death (primary end point) 71 (0.87%) 83 (1.03%) 83 (1.02%) 107 (1.33%) Stroke29 (0.36%) 22 (0.27%) 18 (0.22%) 26 (0.32%) All cause mortality103 (1.24%) 95 (1.14%) 113 (1.36%) 110 (13.1%) RRR of primary end point compared to placebo 34% (p=0.006) 21% (p=0.02) 20% (p=0.04) N/A Warfarin Evidence: Primary Prevention Thrombosis Prevention Trial (TPT) TPT Investigators. Lancet 1998;351: *WA=Warfarin and aspirin, W=Warfarin, A=Aspirin, P=Placebo 5,499 men at high risk for CHD randomized to aspirin (75 mg), warfarin (mean INR=1.5), warfarin and aspirin, or placebo for 6.4 years Warfarin has similar efficacy to aspirin

27 Warfarin Evidence: Secondary Prevention Meta-analysis of 31 trials comparing the effects of oral anticoagulation with and without aspirin on CV outcomes Anand SS et al. JAMA 1999;282: Events prevented per 1000 patients treated (95% CI) Major bleeds per 1000 patients treated (95% CI) High intensity OA vs. control 98 (73-123)39 (35-43) Moderate intensity OA vs. control 24 (22-26)35 (21-49) Moderate to high intensity OA and ASA vs. ASA 54 (43-65)16 (10-22) Moderate to high intensity OA vs. ASA 13 (11-14)14 (12-16) Low intensity OA and ASA vs. ASA 7 (6-8)5 (4-6) ASA=Aspirin, CI=Confidence interval, CV=Cardiovascular, OA=Oral anticoagulation

28 Outcome Aspirin (n=523) Warfarin (n=540) Clopidogrel (n=524) Death, MI, or stroke (%) HF hospitalizations (%) Major bleeding (number of episodes) * *p=0.012 vs warfarin Massie BM. American College of Cardiology 2004 Scientific Sessions; Mar 7-10, 2004; New Orleans, LA Warfarin Evidence: Secondary Prevention Warfarin and Antiplatelet Therapy in Heart Failure (WATCH) Trial EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction 1,587 patients with HF and LVSD (EF <0.35) randomized to aspirin (162 mg), clopidogrel (75 mg), or warfarin (mean INR=2.6) for 23 months There is no significant benefit to clopidogrel or warfarin over aspirin in LVSD for reduction of hard end points

29 Warfarin Recommendations Warfarin (INR ) if aspirin intolerance or a true aspirin allergy* Warfarin either without (INR ) or with aspirin (75-81 mg; INR ) may be reasonable for patients at high CAD risk and low bleeding risk who are intolerant of clopidogrel following a NSTE-ACS Warfarin (INR <2.0) in addition to aspirin in those with stable angina Primary Prevention Secondary Prevention NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI *No guideline recommendation exists

30 Warfarin Recommendations (Continued) Warfarin (INR ) following a STEMI without stent implantation in those with aspirin intolerance or aspirin allergy. Use clopidogrel preferentially if no indication for anticoagulation* Warfarin (INR ) in addition to clopidogrel (75 mg daily) following a STEMI with stent implantation in those with an indication for anticoagulation* and either aspirin intolerance or aspirin allergy Secondary Prevention *Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities

31 Warfarin Recommendations (Continued) Warfarin (INR ) following a STEMI without stent implantation as an alternative to aspirin in those with (Class I, Level B) and without (Class IIa, Level B) indication for anticoagulation* Warfarin (INR ) in addition to aspirin ( mg daily) following a STEMI without stent implantation in those with (Class I, Level A) and without (Class IIa, Level B) indication for anticoagulation* Secondary Prevention *Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities

32 Warfarin Recommendations (Continued) Warfarin (INR ) in addition to aspirin ( mg daily) and clopidogrel (75 mg daily) following a STEMI with stent implantation in those with indication for anticoagulation* Warfarin (INR ) in those with HF or LVSD with indication for anticoagulation* Secondary Prevention *Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities HF=Heart failure, LVSD=Left ventricular systolic dysfunction

33 Warfarin Recommendations (Continued) Warfarin (INR ) in those with HF or LVSD, but without indication for anticoagulation* Close monitoring of anticoagulation in those receiving warfarin along with aspirin and/or clopidogrel because of increased risk of bleeding Secondary Prevention *Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities HF=Heart failure, LVSD=Left ventricular systolic dysfunction