Clopidogrel When For What For How Long. T Benjanuwattra Chiang Mai Heart Cent

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1 Clopidogrel When For What For How Long T Benjanuwattra Chiang Mai Heart Cent

2 Evidence Based Medicine

3 I don t want to put you to sleep But want you to be fully alert

4 Atherothrombosis: A Generalized and Progressive Process Adapted from Stary HC et al. Circulation. 1995; 92: , and Fuster V et al. Vasc Med. 1998; 3: Unstable angina ACS MI Ischemic stroke/tia Critical leg ischemia Cardiovascularde ath Atherosclerosis Atherothrombosis Stable angina Intermittent claudication

5 Spectrum of Acute Coronary Syndromes Stable Angina Unstable Angina Non-Q wave MI Q wave MI Non ST Elevation ACS CK-MB ST Elevation MI ECG - ST ECG - ST Troponin

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7 Ticlopidine Clopidogrel ADP, Epinephrine, Collagen, Thrombin AA TxA2 Aspirin GPIIbIIIa Expression GPIIbIIIa inhibitors

8 1. CAPRIE Steering Committee. Lancet 1996; 348: CAPRIE: Design 1 Objective: to compare the efficacy and safety of clopidogrel 75 mg with active control ASA 325 mg Double-blind, blind, randomized, prospective trial Multicenter (384 centers in 16 countries) Follow-up of 19,185 patients from 1 to 3 years with: Ischemic atherothrombotic stroke Myocardial infarction (MI) Peripheral arterial disease Combined primary endpoint: cluster of ischemic stroke, MI, and vascular death

9 1. CAPRIE Steering Committee. Lancet 1996; 348: Cumulative event rate (%) CAPRIE: Long-Term Benefit of Clopidogrel Compared with ASA 1 Cumulative Event Rate (Myocardial Infarction, Ischemic Stroke or Vascular Death) p = 0.043, n = 19,185 ASA Clopidogrel 8.7% * Overall relative risk reduction *ITT analysis Months of follow-up

10 1. Gent M. Circulation 1997; 96(suppl 8): I-467. CAPRIE: Benefit of Clopidogrel over ASA in the Reduction of Myocardial Infarction 1 Cumulative event rate (%) ASA 3.6% Clopidogrel 2.9% Months of follow-up p = 0.008, n = 19,185 ASA 19.2% * Relative risk reduction Clopidogrel P *ITT analysis

11 Acute Coronary Syndromes Non ST elevation ACS (UA/NSTEMI) ST elevation ACS (AMI) Plateletes rich thrombus to stabilize plaque to prevent further thrombosis Revascularization in high risk pt Fibrin rich thrombus Revascularization

12 Platelets Fibrin Thrombin

13 Subtotal occlusion Treatment Stable plaque Re-thrombosis Embolization Spasm

14 1. The CURE Study Investigators. Eur Heart J 2000; 21: CURE: Design 1 n = 12, countries Patients with acute coronary syndrome (unstable angina or non-q-wave myocardial infarction) R Day 1 Placebo loading dose Clopidogrel 300mg loading dose Discharge visit ASA mg o.d. Double-blind treatment up to 12 months ASA mg o.d. 1 month visit 3 month visit 6 month visit 9 month visit 12 month or final visit Clopidogrel 75mg o.d. (n = 6,259) Placebo 1 tab o.d. (n = 6,303) R = Randomization

15 1. The CURE Trial Investigators. N Engl J Med 2001; 345: Data on file, 2002, p73 internal CSR-EFC CURE: Early and Long-Term Benefits of Clopidogrel 1,2 Cumulative Events (Myocardial Infarction, Stroke, or Cardiovascular Death) Cummulative hazard rate Placebo * (n = 6,303) Clopidogrel * (n = 6,259) 20% Relative risk reduction p = Months of follow-up *On top of standard therapy (including ASA)

16 MI/Stroke/CV Death within 30 Days Cumulative Hazard Rate Placebo + ASA* Clopidogrel + ASA* Benefit seen in 1 st 24Hr 34%RRR Days of Follow-Up In combination with standard therapy 21% RRR P = N = 12,562

17 CURE: Consistent Benefit on Top of Various Standard Therapies 1 Concomitant medication/therapy Events (%) N Clopidogrel * Placebo * Clopidogrel better Placebo better Heparin/LMWH No Yes ASA < 100 mg mg > 200 mg GPIIb/IIIa Antag No Yes Beta-blocker No Yes ACEI No Yes Lipid-lowering No Yes PTCA/CABG No Yes *On top of standard therapy (including ASA) 1. Clopidogrel Prescribing Information, US, February Hazard ratio (95% CI)

18 TIMI Risk Score for UA/NSTEMI 7 Independent Predictors Age 65 years 3 3 CAD risk factors ( chol, FHx,, HTN, DM, smoking) Prior CAD (cath stenosis >50%) ASA in last 7 days 2 Anginal events 24 hours ST deviation Elevated cardiac markers (CK-MB or troponin) Antman et al. JAMA ;284:835

19 RISK OF CARDIAC EVENTS (%) BY 14 DAYS IN TIMI 11B* RISK SCORE 0/ /7 DEATH OR MI DEATH, MI OR URGENT REVASC

20 URE: Effects of Clopidogrel Stratified by TIMI Risk Score at 12 Months 1. The CURE Trial Investigators. N Engl J Med 2001; 345: Budaj AJ et al J Am Coll Cardiol 2002; 39, (suppl B): 441B. MI, stroke or vascular death (%) ARR * RRR 29% 15% 27% n = 3, p = 0.03 n = 7, p = 0.02 n = 1, p = Low risk Moderate risk High risk Placebo Clopidogrel *Absolute risk reduction Relative risk reduction

21 PCI Stent

22 1. Mehtra SR et al. Lancet 2001; 358: PCI-CURE: CURE: 31% Relative Risk Reduction at Long-Term 1 Endpoint: Myocardial Infarction or Vascular Death Cumulative hazard rate Median time to PCI 31% Relative risk reduction p < Placebo * (n = 1,345) Clopidogrel * (n = 1,313) Days of follow-up *On top of standard therapy (including ASA)

23 1. The CURE Trial Investigators. N Engl J Med 2001; 345: Chesebro JH et al. Circulation 1987; 76: The GUSTO Investigators. N Engl J Med 1993; 329: Event CURE: Bleeding Episodes Placebo * (n = 6,303) Clopidogrel * (n = 6,259) p value Major bleeding 1 2.7% 3.7% Life-threatening 1.8% 2.2% NS Other major bleeding 0.9% 1.5% Transfusions of 2 units of blood 1 2.2% 2.8% 0.02 Minor bleeding 1 2.4% 5.1% < Major bleeding by TIMI definition 2 1.2% 1.1% 0.70 Major bleeding by GUSTO definition 3 1.1% 1.2% 0.48 *On top of standard therapy (including ASA)

24 The CREDO Trial Clopidogrel for the Reduction of Events During Observation

25 CREDO Objectives Objectives To evaluate the long term efficacy of prolonged (1 year) therapy with clopidogrel 75mg vs placebo in patients on top of standard therapy (including ASA) To evaluate the effect of pretreatment with a clopidogrel 300 mg loading dose on the composite of death (all-cause), MI (Q- or non-q- wave), or UTVR at Day 28, in patients who underwent PCI To evaluate the safety of clopidogrel, specifically the frequency of major bleeding events and early discontinuation of study drug UTVR= Urgent Target Vessel Revascularization Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19:

26 1 Year Endpoint CREDO Endpoints First occurrence of any component up to 1 year of the cluster of: Death,, MI, or stroke 28 Day Endpoint First occurrence of any component up to 28 days of the cluster of: Death,, MI, or urgent TVR Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19:

27 Overall Study Design Clopidogrel Arm Placebo Arm R PCI 28 Days 12 Months Pretreatment LD Clopidogrel # Clopidogrel # Clopidogrel * Clopidogrel # Placebo * LD Placebo # LD=loading dose, PT= Pretreatment, R= Randomization # on top standard therapy including ASA (325 mg) on top standard therapy including ASA ( mg)

28 Long-term Benefits of Clopidogrel in PCI Patients 15 1 year results (MI, Stroke, or Death) COMBINED ENDPOINT OCCURRENCE (%) 10 5 Placebo* # Clopidogrel* 11.5% 8.5% 27% RRR p = MONTHS FROM RANDOMIZATION * On top of standard therapy including ASA # All patients received clopidogrel post PCI up to day 28 Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19:

29 Early Effects of Pretreatment with Clopidogrel: Per - Protocol 28 Days results (Death, MI, UTVR) COMBINED ENDPOINT OCCURRENCE (%) PT- Clopidogrel* No-PT Clopidogrel* 8.3% 6.8% 18.5 % RRR p = DAYS FROM RANDOMIZATION *From PCI to 28 days, on top of standard therapy including ASA (325mg from randomization to Day 28) PT= Pretreatment UTVR: Urgent Target Vessel Revascularization

30 Timing of Loading Dose - 28 Days Events (%) PT-Clopidogrel* No-PT Clopidogrel* n PT-Clopidogrel Better No-PT Clopidogrel Better < 6 hrs to 24 hr RRR p=ns RRR 38.6 p=0.05 Overall CREDO Results RRR 18.5 p= Hazard ratio (95% CI) * On top of standard therapy including ASA, PT= Pretreatment Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19:

31 Increased Risk in Other Vascular Beds After an Atherothrombotic Event 1 4 Increased risk of MI Increased risk of stroke Post-MI Post-stroke PAD 5 7 X greater risk (includes death) 2 3 X greater risk (includes angina and sudden death) 4 X greater risk (includes only fatal MI and other CHD death) 3 4 X greater risk (includes TIA) 9 X greater risk 2 3 X greater risk (includes TIA) CHD=coronary heart disease Adult Treatment Panel II. Circulation 1994; 89: Kannel WB. J Cardiovasc Risk 1994; 1: Wilterdink JI et al. Arch Neurol 1992; 49:

32 Clopidogrel in Patients with ST-Segment Segment Elevation Myocardial Infarction (STEMI) N Engl J Med 2005;352:117

33 occlusion Fibrinolytic, PCI Lysed clot Exposed clot-bound thrombin Activated platelets Platelet & thrombus emboli TxA 2 Reperfusion Re-thrombosis Embolization Spasm

34 Pathophysiology of STEMI 1 Generally caused by a completely occlusive thrombus in a coronary artery Results from stabilization of a platelet aggregate at site of plaque rupture by fibrin mesh Platelet RBC Fibrin mesh GPIIb/IIIa RBC=red blood cell dapted from Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII.

35 High Risk of Mortality Following Acute MI NRMI 3 4 (n=153,486) 1 GRACE Registry (n=5476) 2 In-hospital mortality Reperfused Not reperfused 6-month* mortality 12.3% 6.6% 18.7% 7.8% 4.8% Despite current therapy, 10% of STEMI patients die within one month after hospital discharge 2 Within 6 years 18% of men and 35% of women will have another heart attack 3 ost-discharge; GRACE=The Global Registry of Acute Coronary Events; NRMI=National Registry or Acute Myocardial Infarction NRMI-4. J Am Coll Cardiol 2003; 41: 365A 366A. ๐๕/๐๘ ๐๘/๔๘ 35 Goldberg RJ et al. Am J Cardiol 2004; 93:

36 Assessing Reperfusion Options for Patients with STEMI 1 STEP 1: Assess time and risk (time from symptom onset, risk of STEMI, risk r of thrombolysis, time for transport to PCI lab) STEP 2: Determine whether fibrinolysis or invasive strategy is preferred* Fibrinolysis preferred if: Early presentation (<3 hours) Delay to invasive strategy Invasive strategy preferred if: Skilled PCI lab with surgical backup available High risk (i.e. cardiogenic shock) Contraindications to fibrinolysis Late presentation (>3 hours) Diagnosis of STEMI is in doubt *If presentation is <3 hours from onset and there is no delay to an invasive strategy, there is no preference for either strategy

37 Thrombolysis and ASA in Acute STEMI: ISIS %* p < %* p < %* p < % % 11.8% 5-week mortality (%) % 9.4% 8.0% 2 0 Placebo versus streptokinase Placebo versus ASA 162 mg Neither versus both *Odds reduction; ASA=acetylsalic acid

38 Study Design 1 Double-blind, randomized, placebo-controlled trial in patients aged years with STEMI 12 hours Clopidogrel 300 mg loading dose / 75 mg QD n=1752 Thrombolysis, heparin and ASA* Time-lysis 2.7Hr R Study treatment until angiography (2 8 days) or hospital discharge (maximum 8 days) Clinical Follow-up at 30 days n=1739 Placebo Primary endpoint: occluded artery (TIMI flow grade [TFG] 0/1), death/mi by time of angiography A= mg (if no ASA within prior 24 hours) as loading dose. Patients received heparin if they eived a fibrin specific thrombolytic l patients received ASA mg/day plus other standard care

39 Study Endpoints 1 Primary endpoint: Composite of occluded infarct related artery (TFG 0/1) on pre-discharge angiogram, or death or MI before angiography Death or MI by hospital discharge (maximum 8 days) if no angiography performed Secondary endpoints: Angiographic (TFG 0/1) Clinical (death, recurrent MI or recurrent ischemia) Clinical events* at 30 days Safety endpoints: Primary: TIMI major bleeding Secondary: TIMI minor bleeding, ICH *CV death, MI, stroke or recurrent ischemia leading to urgent target vessel revascularization

40 TIMI Flow Grade Definitions 1 TIMI flow grade describes epicardial blood flow: Grade 0: complete occlusion Grade 1: penetration of obstruction with no distal perfusion Grade 2: perfusion of artery with delayed flow Grade 3: full perfusion with normal flow TFG 0 Occlusion TFG 1 Penetration TFG 2 Slow flow TFG 3 Normal flow

41 TIMI Myocardial Perfusion Grade Definitions 1 TIMI Myocardial Perfusion Grade (TMPG) or blush score describes blood flow in the microvasculature: Grade 0: no dye enters Grade 1: dye slowly enters but fails to exit Grade 2: delayed entry and exit of dye Grade 3: normal entry and exit of dye TMPG 0 TMPG 1 TMPG 2 TMPG 3

42 Relationship Between Angiographic Outcomes and Long-term Mortality 1 2-year mortality (%) HR: 0.41 (p=0.001) 14.5% TFG 0/1 6.4% TIMI flow grade HR: 0.51 (p=0.038) 9.1% 4.8% TFG 2/3 TMPG 0/1 TMPG 2/3 TIMI myocardial perfusion grade* *Assessed on 90 minute angiogram in TIMI 10b trial; HR=hazard ratio

43 Concomitant Medications 1 Clopidogrel Placebo Characteristic (n=1752) (n=1739) Fibrin-specific thrombolytic (%): Tenecteplase Reteplase Alteplase Non-fibrin specific thrombolytic (%): Streptokinase No thrombolytic given (%) ASA (%) Heparin (%): UFH LMWH

44 Patient Management 1 Clopidogrel Placebo Parameter (n=1752) (n=1739) Symptom onset to fibrinolytic (hours) Fibrinolytic to study drug (minutes) Median doses of study medication 4 4 Angiography performed (%) Time to angiography (hours) Coronary revascularization (%): PCI CABG 6 6

45 Clopidogrel Improved Coronary Perfusion 1 Primary endpoint* (%) % reduction* p < Clopidogrel (n=1752) Placebo (n=1739) *Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel versus placebo (OR: 0.64 [0.53 to 0.76]; p <0.001)

46 Clopidogrel Reduced Primary Endpoint by 36% 1 Clopidogrel Placebo Odds ratio (n=1752) (n=1739) (95% CI) p value Primary composite endpoint (%) TFG 0/1, MI or death ( ) <0.001 Individual components of primary endpoint (%) TFG 0/ ( ) <0.001 Recurrent MI ( ) 0.08 Death ( ) 0.49

47 Consistent Results for Primary Endpoint Across Subgroups 1 Number of Odds Event rates (%) Characteristic patients reduction Clopidogrel Placebo OVERALL Age <65 years years Gender Male Female Infarct location Anterior Non-anterior Fibrinolytic Fibrin-specific Non-fibrin specific Predominant heparin LMWH UFH None Clopidogrel better Placebo better

48 Clopidogrel Improved Angiographic Outcomes 1 Clopidogrel Placebo Odds ratio (n=1752) (n=1739) (95% CI) p value Angiographic outcomes (%) TFG 3* ( ) <0.001 TMPG ( ) Thrombus ( ) <0.001 *TFG= TIMI Flow Grade TPMG= TIMI Myocardial Perfusion Grade

49 Clopidogrel Reduced Clinical Events by 20% at 30 Days 1 Incidence of clinical endpoints (%) Placebo Clopidogrel 20%* p= Time (days) Odds Ratio (OR) in CV death, MI or recurrent ischemia leading to rgent revascularization

50 Consistent Benefit Across 30-Day Endpoints 1 Endpoint Odds ratio (95% CI) Odds reduction Percentage of patients with event Clopidogrel Placebo CV death Recurrent MI Recurrent ischemia leading to urgent revascularization Stroke CV death or MI CV death, MI or stroke CV death, MI or recurrent ischemia leading to urgent revascularization CV death, MI, stroke or recurrent ischemia leading to urgent revascularization Clopidogrel better Placebo better

51 Safety 1 Clopidogrel Placebo (n=1733) (n=1719) p value Primary bleeding endpoint (%) TIMI major 23 (1.3) 19 (1.1) 0.64 Secondary bleeding endpoints (%) TIMI minor 17 (1.0) 9 (0.5) 0.17 TIMI major or minor 40 (2.3) 28 (1.6) 0.18 Intracranial hemorrhage 8 (0.5) 12 (0.7) 0.38 Bleeding through 30 days (%) TIMI major 33 (1.9) 30 (1.7) 0.80 TIMI minor 27 (1.6) 16 (0.9) 0.12 TIMI major or minor 59 (3.4) 46 (2.7) 0.24

52 Summary 1 In patients aged 75 years with STEMI, receiving ASA and standard fibrinolytic therapy, a loading dose of 300 mg of clopidogrel followed by 75 mg daily resulted in: A 36% reduction (p <0.001) in the odds of an occluded infarct-related related artery, or death or MI by time of pre-discharge angiography or hospital discharge (maximum 8 days) ( 41% reduction occluded infarct-related related MI) Consistent results across all major subgroups At 30 days, a 20% reduction (p=0.03) in CV death, MI or recurrent ischemia leading to urgent revascularization ( 31% reduction in recurrent MI) No significant excess in TIMI major bleeding or ICH

53 Slide Source: Lipids Online

54 Take home message Previous MI : Aspirin intolerance Use Clopidogrel ACS : Cool down Tx Clopidogrel 300 mg ASA 325 mg/d LMWH/Heparin 75 mg/d +/- Statin, +/- Gp II b /III a IV PCI : Clopidogrel 300 mg 6-24 hr. prior to PCI Post PCI Clopidogrel 75 mg/d & low dose ASA 1 year

55 Drugs Prescriptions for Mr. Had-enough? 1. Enalapril (20) ½ tab bid pc. 6. Glibencarmide(5) 1½1 tab bid ac 2. Bisoprolol (5) 1 tab OD. 7. Metformin (500) 1 tab tid pc 3. Spironolactone (25) 1 tab OD. 4. Digoxin POLYPHARMACY (0.25) ½ tab E.O.D. 8. Aspirin (300) 1 tab OD. 5. Furosemide (40) 1 tab prn for dyspnea,edema or weight 9. ISDN (10) 2 tab tid ac gain > 1 kg in 2 days 10. Isordil (5) 1 tab SL prn 13. Warfarin (3) ½ tab o OD. 14. Warfarin (5) ½ tab o OD. 15. Lorazepam 1 tab prn hs. 11. Amlodipine (10) 1 tab OD. 12. Atrovastatin (20) 1 tab pc evening

56 The Polypill Prevention of Cardiovascular Complications

57 Empirical Drug For Life One combination One dose All patient

58 The Polypill mg of atorvastatin& 10mg zetrol 12.5 mg of hydrochlorthiazide 2.5mg amlodipine 75 mg of aspirin & 75 mg clopidogrel 10 mg of lisinopril 50mg atenolol

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