Slide 1

Rational For the Use of Anti-platelets Drugs in the High Risk Patient Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital Slide 2 Rational For the Use of Anti-platelets Drugs in the High Risk Patient Role of the platelets in atherosclerosis and its complicationsRole of the platelets in atherosclerosis and its complications Aspirin in secondary preventionAspirin in secondary prevention Clopidogrel in secondary preventionClopidogrel in secondary prevention The anti-IIb/IIIa glycoprotein in secondary preventionThe anti-IIb/IIIa glycoprotein in secondary prevention Aspirin in primary preventionAspirin in primary prevention Slide 3 DEVELOPMENT OF ATHEROSCLEROSIS Slide 4 Role of the Platelet in Atherosclerosis The platelet plays a key role in atherosclerosisThe platelet plays a key role in atherosclerosis Chronic activation of the vessel wall contributes to the recruitment of plateletsChronic activation of the vessel wall contributes to the recruitment of platelets Platelets secrete multiple products and chemokines which will accelerate atherosclerosis (transforming growth factor beta, platelet factor-4, RANTES, P- selectin)Platelets secrete multiple products and chemokines which will accelerate atherosclerosis (transforming growth factor beta, platelet factor-4, RANTES, P- selectin) The lack of von Willebrand factor (the principal ligand mediating platelet aggregation) slows significantly the progression of atherosclerosisThe lack of von Willebrand factor (the principal ligand mediating platelet aggregation) slows significantly the progression of atherosclerosis Slide 5 Role of the Platelets in Thrombosis UA/NQMI: Partially-occlusive thrombus (primarily platelets) Intra-plaque thrombus (platelet dominated) Plaque core ST MI: occlusive thrombus (platelets, red blood cells, and fibrin) Intra-plaque thrombus (platelet dominated) Plaque core SUDDEN DEATH Adapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46. Slide 6 Aspirin is as important as streptokinase in AMI ISIS 2: Lancet 1988;2:349 Slide 7 Platelet Adhesion, Activation, and Aggregation White HD. Am J Cardiol. 1997; 80 (4A): 2B-10B. Vessel wall Slide 8 Rational For the Use of Anti-platelets Drugs in the High Risk Patient Role of the platelets in atherosclerosis and its complicationsRole of the platelets in atherosclerosis and its complications Aspirin in secondary preventionAspirin in secondary prevention Clopidogrel in secondary preventionClopidogrel in secondary prevention The anti-IIb/IIIa glycoprotein in secondary preventionThe anti-IIb/IIIa glycoprotein in secondary prevention Aspirin in primary preventionAspirin in primary prevention Slide 9 Antiplatelet Trialists Collaboration Meta-Analysis Meta-analysis of 195 randomized trials of anti-platelet therapy Meta-analysis of 195 randomized trials of anti-platelet therapy Among 135,000 high risk patients with prior evidence of cardiovascular disease: Among 135,000 high risk patients with prior evidence of cardiovascular disease: Prior or acute MI Prior or acute stroke or TIA Other high risk groups: Unstable angina, stable angina, peripheral vascular disease, CABG, PTCA. Antiplatelet Trialists Collaboration. BMJ. 1994;308;81106. Slide 10 Other High Risk 32% Antiplatelet Trialists Collaboration Relative Reduction in Cardiovascular Events * OR = Odds reduction, a percentage reduction of an outcome measure comparing treatment to control group. Antiplatelet Trialists Collaboration. BMJ. 1994;308:81106. Antiplatelet Therapy Control % of Patients Having Stroke, MI, or Vascular Death Prior Stroke/TIA Acute MI Prior MI High Risk 0% 5% 10% 15% 20%25% 22% 29% 25% 27% All Patients Odds Reduction* Slide 11 Antiplatelet Trialists Collaboration Absolute Reduction in Cardiovascular Events CategoryNo events reducedMean duration /1000 patients therapy Prior MI36 27 months Prior MI36 27 months Acute MI38 1 month Acute MI38 1 month Previous stroke or TIA36 29 months Previous stroke or TIA36 29 months Acute stroke9 0.7 month Acute stroke9 0.7 month Other high risk features22 22 months Other high risk features22 22 months Antiplatelet Trialists Collaboration. BMJ. 1994;308;81106. Slide 12 Aspirin was the most frequent anti-platelet drug used in secondary prevention Dose tested: 75-325 mg/dayDose tested: 75-325 mg/day Doses lower than 75 mg/day showed only a trend toward benefitDoses lower than 75 mg/day showed only a trend toward benefit Doses of 75-150 mg/day were as effective as doses from 150-325 mg/day and may be less toxicDoses of 75-150 mg/day were as effective as doses from 150-325 mg/day and may be less toxic Slide 13 Rational For the Use of Anti-platelets Drugs in the High Risk Patient Role of the platelets in atherosclerosis and its complicationsRole of the platelets in atherosclerosis and its complications Aspirin in secondary preventionAspirin in secondary prevention Clopidogrel in secondary preventionClopidogrel in secondary prevention The anti-IIb/IIIa glycoprotein in secondary preventionThe anti-IIb/IIIa glycoprotein in secondary prevention Aspirin in primary preventionAspirin in primary prevention Slide 14 Currently Available Antiplatelet Agents 1 Antiplatelet Trialists Collaboration. BMJ. 1994;308:81106. 2 Diener HC et al. J Neurol Sci. 1996;143:113. 3 Schafer AI. In: Smith TW, ed. Cardiovascular Therapeutics. Philadelphia, PA: WB Saunders; 1996:chap 27. 4 Schafer AI. Am J Med. 1996;101:199209. Aspirin Ticlopidine/clopidogrel Dipyridamole Mechanism of Action TXA 2 ADP binding to receptor cAMP Efficacy 25% 1 33% 1 16% 2 Significant Side Effects GI bleeding, GI intolerance 3 Severe neutropenia, rash, diarrhea 4 GI distress, headache 4 Slide 15 Oral Antiplatelet Agents Mechanism of Action Collagen Thrombin TXA 2 ADP (FibrinogenReceptor) ADP = adenosine diphosphate, TXA 2 = thromboxane A 2, COX = cyclooxygenase. Schafer AI. Am J Med. 1996;101:199209. clopidogrel bisulfate TXA 2 ADP dipyridamole phosphodiesterase ADP Gp IIb/IIIa Activation COX ticlopidine HCl aspirin Slide 16 Ticlopidine (ticlid) and clopidogrel (plavix) TiclopidineClopidogrel twice / dayonce / day NeutropeniaNo neutropenia CBC monitoringNo need for CBC monitoring Skin reactions (rash)No skin reactions Delayed onset of effectRapid onset of effect Slide 17 Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events CAPRIE Slide 18 CAPRIE Study Rationale Patients who have atherosclerotic disease (recent MI, recent ischemic stroke, or established PAD) are at risk for subsequent ischemic events and will benefit from antiplatelet therapy Patients who have atherosclerotic disease (recent MI, recent ischemic stroke, or established PAD) are at risk for subsequent ischemic events and will benefit from antiplatelet therapy Clopidogrel was hypothesized to provide approximately 10% reduction in events vs aspirin based on the results of the Antiplatelet Trialists Collaboration Clopidogrel was hypothesized to provide approximately 10% reduction in events vs aspirin based on the results of the Antiplatelet Trialists Collaboration CAPRIE Steering Committee. Lancet. 1996;348:13291339. Slide 19 CAPRIE Study Methodology Study Design Number of Patients Patient Types Included Study Drugs Treatment Duration Investigational Centers Prospective, randomized, blinded 19,185 patients with atherosclerotic vascular disease Recent ischemic stroke ( 6 mo) Recent MI ( 35 d) Established peripheral arterial disease Clopidogrel bisulfate: 75 mg qd Aspirin: 325 mg qd Up to 3 yrs (mean 1.6 yr) 304 in 16 countries, including the US Slide 20 CAPRIE Study MI, Ischemic Stroke, or Vascular Death Months of Follow-Up Cumulative Event Rate, % 0 4 8 12160369121518212427303336 5.83% Clopidogrel Aspirin 5.33% Overall Risk Reduction 8.7% Event Rate per Year P = 0.045 Slide 21 CAPRIE Study Safety Low incidence of GI hemorrhage191(2.0%)255(2.7%)(P < 0.05) Low incidence of hospitalization due to GI hemorrhage71(0.7%)104(1.1%)(P = 0.012) Low incidence of GI ulcers 65(0.7%)110(1.2%)(P < 0.001) Low incidence of intracranial hemorrhage34(0.4%)47(0.5%)(P = NS) Clopidogrel Aspirin (n = 9599)(n = 9586) Clopidogrel Aspirin (n = 9599)(n = 9586) Slide 22 IS IS MI MI PAD PAD Total Total Aspirin better Clopidogrel better Aspirin better Clopidogrel better IS (fatal or non-fatal) MI (fatal or non-fatal) (fatal or non-fatal) Vascular death Total Aspirin better Clopidogrel better CAPRIE Study MI Paradox: Subgroups vs. Outcomes -40 -20 -10 0 10 20 30 40 Relative Risk Reduction* by Qualifying Subgroup 1 Relative Risk Reduction of Individual Outcomes in Total Population 7.3% 5.2% 2 19.2% 3 7.6% 1 -3.7% 23.8% 8.7% 1 *Cluster of IS, MI, or vascular death p=0.043 p=0.008 1 CAPRIE Steering Committee. Lancet.1996; 348:1329-1339 2 Easton JD. Neurology. 1998 July; P03.081 Abstract. 3 Gent M. Circulation. 1997; 96(8 supple): I-467 Abstract. 8.7% 1 Slide 23 Clopidogrel + ASA* 369 Placebo + ASA* Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 0 12 * In combination with standard therapy The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. CURE Study: Clopidogrel on the top of aspirin Primary End Point - MI/Stroke/CV Death Slide 24 Rational For the Use of Anti-platelets Drugs in the High Risk Patient Role of the platelets in atherosclerosis and its complicationsRole of the platelets in atherosclerosis and its complications Aspirin in secondary preventionAspirin in secondary prevention Clopidogrel in secondary preventionClopidogrel in secondary prevention The anti-IIb/IIIa glycoprotein in secondary preventionThe anti-IIb/IIIa glycoprotein in secondary prevention Aspirin in primary preventionAspirin in primary prevention Slide 25 Mechanism of Action: GP IIb-IIIa Inhibitors White HD. Am J Cardiol. 1997; 80(4A):2B-10B. Vessel wall Slide 26 Platelet-fibrinogen interaction Slide 27 EPIC: Improved 3-year outcome with the IIb/IIIa receptor blocker abciximab following PTCA JAMA 1997;278:478 Slide 28 Abciximab in primary PTCA for acute MI improves event free survival (death, acute coronary syndromes, TVR) Azar et al. J Am Coll Cardiol 1998;32:1996 Slide 29 P < 0.0000000011356 0.5 1.02 Risk ratio & 95% confidence interval for death or MI at 30 days GP IIb-IIIa inhibitor betterPlacebo better Trials of GP IIb-IIIa inhibitors (n=32,735) Topol EJ. Circulation. 1998; 97: 211-218. Odds Ratio Plot for Death/Re-MI in Patients Receiving GP IIb-IIIa Inhibitor Therapy Slide 30 (and www.circ.ahajournals.org r23-r35). A Phase 3 International, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety Of Orbofiban in Patients with Unstable Coronary Syndromes Cannon CP et al. Circulation 2000;102:149-156 Slide 31 Study Design ASA 150-162 mg daily Orbofiban 50 mg BID Orbo 50 mg BID x 30 days then Orbo 30 mg BID Placebo BID Other Meds, Cath/Revasc per MD F/U Day 14, Day 30 Follow-up visit every 3 months Primary endpoint to 30 days + follow-up Death, MI Urgent Revasc, Ischemia -> Rehosp, or Stroke Randomize 1:1:1 Patient with Unstable Coronary SyndromeSlide 32 10 Month Outcomes Cannon CP et al. Circulation 2000;102:149-156 Slide 33 Bleeding - 10 Months Cannon CP et al. Circulation 2000;102:149-156 Slide 34 Rational For the Use of Anti-platelets Drugs in the High Risk Patient Role of the platelets in atherosclerosis and its complicationsRole of the platelets in atherosclerosis and its complications Aspirin in secondary preventionAspirin in secondary prevention Clopidogrel in secondary preventionClopidogrel in secondary prevention The anti-IIb/IIIa glycoprotein in secondary preventionThe anti-IIb/IIIa glycoprotein in secondary prevention Aspirin in primary preventionAspirin in primary prevention Slide 35 Anti-platelets Therapy in Primary Prevention Aspirin reduces the risk of cardiovascular events: RR= 0.85; CI= 0.78-0.94Aspirin reduces the risk of cardiovascular events: RR= 0.85; CI= 0.78-0.94 But increase the risk of major non cerebral bleeding: RR= 1.69; CI= 1.38-2.07But increase the risk of major non cerebral bleeding: RR= 1.69; CI= 1.38-2.07 The potential benefit of aspirin is highly dependable on the absolute risk of MI at baselineThe potential benefit of aspirin is highly dependable on the absolute risk of MI at baseline Risk < 0.5%/year, aspirin not recommendedRisk < 0.5%/year, aspirin not recommended Risk > 1.5%/year, aspirin usefulRisk > 1.5%/year, aspirin useful Heart 2001;85:265-71 Slide 36 Effect of baseline risk on the number of patients who would need to be treated with aspirin in order to prevent one myocardial infarction over a period of five years Baseline risk of MINumber needed to treat for 5 years To prevent 1 MITo prevent 1 MI without a major bleeding episode 0.5%/year133256 1%/year6788 1.5%/year4453 Heart 2001;85:265-71 Slide 37 Algorithm for the Use of Aspirin in Primary Prevention Slide 38 Aspirin in Primary and Secondary Prevention Trials Slide 39 CONCLUSIONS Aspirin in the drug of choice and should be used for all patients in secondary preventionAspirin in the drug of choice and should be used for all patients in secondary prevention Clopidogrel is as good than aspirin in secondary prevention and should be used in all patients who are intolerant to aspirinClopidogrel is as good than aspirin in secondary prevention and should be used in all patients who are intolerant to aspirin Clopidogrel in association to aspirin is superior to aspirin alone, especially after unstable angina or non Q wave MI or after elective coronary angioplastyClopidogrel in association to aspirin is superior to aspirin alone, especially after unstable angina or non Q wave MI or after elective coronary angioplasty The IIb/IIIa receptor blockers are useful when used IV in the acute setting. Oral therapy is not recommendedThe IIb/IIIa receptor blockers are useful when used IV in the acute setting. Oral therapy is not recommended In primary prevention, the only drug studied is aspirin. It should be used only in selective cases (high risk)In primary prevention, the only drug studied is aspirin. It should be used only in selective cases (high risk)