Aspirin+and+vascular

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  • Platelet activation leads to platelet aggregation. As illustrated above, various classes of antiplatelet therapies act by disparate mechanisms to reduce platelet activation and clot formation. Aspirin inhibits platelet aggregation by inhibiting the production of thromboxane A2. The thienopyridines, clopidogrel and ticlopidine, bind and inhibit adenosine diphosphate (ADP) receptors on platelets thereby inhibiting glycoprotein IIb/IIIa-receptor activation and preventing platelet aggregation. Dipyridamole interferes with platelet stimulating factors like collagen through various mechanisms including the inhibition of phosphodiesterase and inhibition of cellular uptake of adenosine. Glycoprotein IIb/IIa inhibitors directly interfere with platelet binding of fibrinogen, the final step in platelet aggregation.
  • The preparation of aspirin involves the use of two hazardous materials - concentrated sulfuric acid and acetic anhydride.
  • Aspirin inhibits the production of thromboxane A2, thereby inhibiting platelet aggregation. Thromboxane promotes platelet aggregation and vasoconstriction. During platelet activation, the hydrolysis of membrane phospholipids yields arachidonic acid, which is converted to prostaglandin H2 by the catalytic activity of the cyclooxygenase enzyme prostaglandin G/H synthase. By the selective and irreversible acetylation of a single serine residue within prostaglandin G/H synthase, aspirin causes the inactivation of cyclooxygenase activity. Aspirin also inhibits the production of endothelial-produced prostacyclin, a vasodilator and inhibitor of platelet aggregation. Unlike platelets, endothelial cells recover their ability to synthesize prostacyclin within a couple of hours. References: 1. Husain S, Andrews NP, Mulcahy D, Et al. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998;97:716-20. 2. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971;231:235-5. 3. Patrono C. Aspirin as an antiplatelet drug. NEJM 1994;330:1287-94.
  • The Physicians' Health Study was a randomized, double-blind, placebo-controlled primary prevention trial designed to determine whether aspirin (325 mg every other day) was associated with a reduction in cardiovascular disease mortality. The trial included 22,071 participants, with an average follow-up of 60 months. Aspirin use was associated with a 44% reduction in the risk of MI, however, this effect was mainly present in men >50 years of age and no reduction in total cardiovascular mortality (RR 0.96; 95% CI 0.60 to 1.54) was observed. A slightly increased risk of stroke was observed among those taking aspirin (p=NS). This trend was noted primarily in the subgroup with hemorrhagic stroke (RR 2.14; 95% CI [0.96 to 4.77]; p=0.06). The was a non-significant increased risk of gastrointestinal ulcers in the aspirin group (RR 1.22, CI [0.98 to 1.53]; p=0.08). Overall: In men (especially >50 years of age), aspirin is associated with a reduced risk of a first MI.
  • The Women's Health Study was a double-blind, placebo-controlled trial that randomized 39,876 healthy women > 45 years of age to low dose aspirin (100 mg every other day) versus placebo for a mean follow up of 10 years. There was no reduction in the primary composite endpoint of nonfatal MI, nonfatal stroke, or death from a cardiovascular cause. Aspirin use was associated with a 17% reduction in the risk of stroke (RR 0.83; 0.69-0.99; P=0.04), a 24% reduction in the risk of ischemic stroke (RR 0.76; 0.63-0.93; P=0.009), and a non-significant increase in the risk of hemorrhagic stroke (RR 1.24; 0.82-1.87; P=0.31). Aspirin had no effect on the risk of fatal or nonfatal myocardial infarction (RR 1.02; 0.84-1.25; P=0.83). Among women > 65 years of age, aspirin use was associated with a reduction of major cardiovascular events (RR 0.74; 0.59-0.92; P=0.008) and risk of ischemic stroke (RR 0.70; 0.49-1.00; P=0.05). GI bleeding requiring transfusion was more frequent in the aspirin group (RR 1.40; 1.07-1.83; P=0.02). Overall: The routine use of aspirin in low risk women (<10% 10 year risk of a CHD event) is not recommended. Aspirin use in women > 65 can reduce the risk of cardiovascular events.
  • This slide demonstrates a reduction in the incidence in MI among men but not women and a reduction of CVA in women but not men in the major aspirin primary prevention trials. These differences may be due to a proportionally higher incidence of CVA versus MI in women as compared to men as well as differences in total CVD risk among the men and women in these trials. However, ultimately the reasons for any sex-based differences in the efficacy of aspirin for primary prevention of CVD are unclear and require further exploration. Overall: Aspirin is recommended for men and women whose 10-year risks for a coronary-heart-disease event is > 10 percent over 10 years. Pearson TA, Blair SN, Daniels SR, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vasculardiseases. Circulation 2002;106:388-91.
  • This data was taken from the collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in high risk patients. Absolute reductions in the risk of having a serious vascular event were 36 ± 5 per 1,000 treated for 2 years among patients with previous MI; 38 ± 5 per 1,000 patients treated for 1 month among patients with acute MI; 36 ± 6 per 1000 treated for 2 years among those with previous stroke or TIA; 9 ± 3 per 1000 treated for 3 weeks among those with acute stroke; and 22 ± 3 per 1000 treated for 2 years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extra cranial bleeding. Overall: Aspirin is recommended for the secondary prevention of CVD.
  • 75 mg of aspirin per day results in almost complete inhibition of cyclooxygenase activity in platelets. This slide demonstrates that high doses of aspirin are no more effective than medium or low doses in reducing the odds of vascular events. Trials using doses of <75mg are less conclusive and, therefore, the available evidence supports daily doses of aspirin in the 75-160 mg range. Overall: For secondary prevention of CVD an aspirin dose of 75-160 mg/d is recommended.
  • ACC/AHA primary prevention guidelines for aspirin include a Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) recommendation for the use of aspirin in women with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of > 10% over the next 10 years and over the age of 65 years. A Level B, Class IIb (conflicting evidence based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) for the use of aspirin in women with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of > 10% over the next 10 years and less than 65 years old. A Level B, Class III (certainty based on single large RCT trial or several non-RCT’s suggests risk is greater than benefit) for the use of aspirin in women with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of < 10% over the next 10 years and less than 65 years old.
  • ACC/AHA primary prevention guidelines for aspirin include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation for the use of aspirin (75-162mg/d) in men with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of > 10% over the next 10 years.
  • ACC/AHA secondary prevention guidelines for aspirin include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation for the use of aspirin (75-162mg/d) in men and women with known coronary heart disease/atherosclerotic vascular disease. A Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation for the use of aspirin following coronary artery bypass grafting.
  • ACC/AHA secondary prevention guidelines for aspirin include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation for the use of aspirin (75-162mg/d) in men and women with known coronary heart disease/atherosclerotic vascular disease. A Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation for the use of aspirin following coronary artery bypass grafting.
  • CAPRIE was a randomized, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg daily) versus aspirin (325 mg daily) in reducing the risk of a composite outcome of ischemic stroke, MI, or vascular death in patients with atherosclerotic vascular disease manifested as either recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease. An intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5% risk of ischemic stroke, myocardial infarction, or vascular death compared to 6% with aspirin, resulting in a statistically significant relative risk reduction of 9% (95% Cl 0.3-16.5, P= 0.043). There were no major differences between the treatments comparing the incidence of rash, diarrhea, upper gastrointestinal discomfort, intracranial hemorrhage, and gastrointestinal hemorrhage. Overall: Clopidogrel is slightly more efficacious than aspirin for the prevention of CVD events in patients with recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease but its cost is much higher.
  • The CURE trial evaluated the efficacy and safety of clopidogrel and aspirin in patients with a non-ST-segment elevation acute coronary syndrome. Patients that presented within 24 hours after the onset of symptoms were randomly assigned to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients), in addition to aspirin for 3 to 12 months. A composite of death from cardiovascular causes, nonfatal MI, or stroke, occurred in 9.3% of the patients in the clopidogrel + aspirin group and 11.4% in the aspirin alone group, corresponding to a significant 20% RRR. The co- primary outcome (a composite of the first primary outcome along with refractory ischemia) occurred in 16.5% of patients in the clopidogrel + aspirin group vs. 19% of patients in the aspirin alone group, resulting in a significant 14% RR reduction. The percentage of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures was also significantly lower in the clopidogrel + aspirin group. Patients on clopidogrel + aspirin had a significantly increased risk of major bleeding as compared to patients on aspirin alone (4% vs. 3%; relative risk, 1.38; P=0.001), but no greater incidence of life-threatening bleeding (2% vs. 2%, P=0.13) or hemorrhagic strokes. Overall: The combination of aspirin + clopidogrel (for 3-12 months) is more efficacious than aspirin alone for the prevention of subsequent CVD events in patients presenting with non-ST-segment elevation acute coronary syndrome.
  • In the Clopidogrel for the Reduction of Events during Observation (CREDO) trial, 2116 patients scheduled to undergo percutaneous coronary intervention (PCI) or thought to be at high likelihood of undergoing PCI were randomized to a 300mg loading dose of clopidogrel vs. placebo 3-24 hrs prior to PCI. Following PCI, all patients received 75mg daily clopidogrel through day 28. From day 28 through 1 yr, patients in the loading dose group received 75mg of clopidogrel daily. Clopidogrel reduced the 1-year risk of MI, CVA, or death by 27% (P=.02; absolute reduction 3%). No significant difference was seen in the 28 day combined risk of MI, death, or urgent target vessel revascularization (risk reduction 19%;p=0.23).
  • The CHARISMA trial randomized 15,603 patients with multiple CV risk factors or known CVD to aspirin (75-162 mg) or aspirin (75-162 mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint of stroke, myocardial infarction, or death from cardiovascular causes occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (RR 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend for increased total events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend for benefit in those subjects with a history of prior atherothrombotic event (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046). Overall: The combination of aspirin + clopidogrel provided no benefit over aspirin alone for the prevention of CVD events in patients with multiple CV risk factors.
  • The CHARISMA trial randomized 15,603 patients with multiple CV risk factors or known CVD to aspirin (75-162 mg) or aspirin (75-162 mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint of stroke, myocardial infarction, or death from cardiovascular causes occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (RR 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend for increased total events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend for benefit in those subjects with a history of prior atherothrombotic event (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046). Overall: The combination of aspirin + clopidogrel provided no benefit over aspirin alone for the prevention of CVD events in patients with multiple CV risk factors.
  • There are no ACC/AHA primary prevention guidelines for thienopyridines. ACC/AHA secondary prevention guidelines for clopidogrel (75 mg/d), in patients intolerant of aspirin, include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation after a NSTE-ACS; Level C, Class I (generally agreed that benefit outweighs harm but only based on expert opinion or case series) following a STEMI; Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) in patients with unstable angina.
  • ACC/AHA secondary prevention guidelines for ticlopidine (75 mg/d), in patients intolerant of aspirin, include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation after a NSTE-ACS; Level C, Class I (generally agreed that benefit outweighs harm but only based on expert opinion or case series) following a STEMI. ACC/AHA secondary prevention guidelines for clopidogrel (75 mg/d for 1y), in addition to aspirin, include a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation after a NSTE-ACS.
  • ACC/AHA guidelines for clopidogrel (75 mg/d for 1y), in addition to aspirin, include a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation for a minimum of: 1 month after a bare metal, 3 months for sirolimus or 6 months for paclitaxel stents. In addition the AHA released a statement in 2006 encouraging strong consideration to extending clopidogrel in addition to aspirin for 12 months after PCI if patient is a low risk for bleeding (especially with drug eluting stent implantation).
  • Aspirin+and+vascular

    1. 1. Antiplatelet Therapy Evidence and Guidelines
    2. 2. Ischemic heart disease Definition <ul><li>An imbalance between the supply of oxygen and the myocardial demand resulting in myocardial ischaemia. </li></ul><ul><li>Angina pectoris </li></ul><ul><li>Symptom not a disease </li></ul><ul><li>Chest discomfort associated with abnormal myocardial function in the absence of myocardial necrosis </li></ul>
    3. 3. Manifestations <ul><li>Sudden death </li></ul><ul><li>Myocardial infarction </li></ul><ul><li>Acute coronary syndrome </li></ul><ul><li>Stable angina pectoris </li></ul><ul><li>Heart failure </li></ul><ul><li>Arrhythmia </li></ul><ul><li>Asymptomatic </li></ul>
    4. 4. Epidemiology <ul><li>Commonest cause of death in the Western world. (up to 35% of total mortality) </li></ul><ul><li>Over 20% males under 60 years have IHD </li></ul>
    5. 5. Aetiology <ul><li>Fixed </li></ul><ul><ul><li>Age, Male, +ve family history </li></ul></ul><ul><li>Modifiable – strong association </li></ul><ul><ul><li>Dyslipidaemia, smoking, diabetes mellitus, obesity, hypertension </li></ul></ul><ul><li>Modifiable - weak association </li></ul><ul><ul><li>Lack of exercise, high alcohol consumption, type A personality, OCP, soft water </li></ul></ul>Atherosclerosis
    6. 6. Pathophysiology <ul><li>Response to injury hypothesis </li></ul><ul><li>ATHEROSIS </li></ul><ul><li>Accumulation of cholesterol within the vessel wall intima. Smooth muscle cell proliferation </li></ul><ul><li>SCLEROSIS </li></ul><ul><li>Expansion of fibrous tissue </li></ul><ul><li>INFLAMMATION </li></ul><ul><li>Chronic inflammatory cells migrate into wall, release cytokines </li></ul><ul><li>GROWTH FACTORS/INFLAMMATORY MEDIATORS </li></ul>
    7. 7. Pathophysiology
    8. 8. Ischemic heart disease Acute coronary syndromes Atherosclerosis Fatal / non-fatal AMI Unstable angina Coronary Artery spasm
    9. 9. Acute coronary syndromes <ul><li>Fatal AMI </li></ul><ul><li>Small, fat rich plaques. Plaque RUPTURE. Thrombus in lipid core and on plaques surface. Vessel lumen OCCLUDED. </li></ul><ul><li>Non - fatal AMI </li></ul><ul><li>Plaque EROSION rather than rupture. OCCLUSIVE thrombus. </li></ul><ul><li>Unstable angina </li></ul><ul><li>Usually mod-severe stenosis. Multiple vessels. Collaterals often formed. Thrombus formation and vasoconstriction. Myocardial infarction may ensue. </li></ul>
    10. 10. Ischemic heart disease Risk factors and prevention <ul><li>Family History </li></ul><ul><li>Smoking </li></ul><ul><li>Hypertension </li></ul><ul><li>Diabetes Mellitus </li></ul><ul><li>Hypercholesterolemia </li></ul><ul><li>Lack of exercise </li></ul><ul><li>PRIMARY PREVENTION </li></ul>
    11. 11. Chest Pain Myocardial ischemia <ul><li>Site </li></ul><ul><li>Jaw to navel, retrosternal, left submammary </li></ul><ul><li>Radiation </li></ul><ul><li>Left chest, left arm, jaw….mandible, teeth, palate </li></ul><ul><li>Quality / severity </li></ul><ul><li>tightness, heaviness, compression…clenched fists </li></ul>
    12. 12. Chest Pain Myocardial ischaemia <ul><li>Precipitating/relieving factors </li></ul><ul><li>Physical exertion, cold windy weather, emotion </li></ul><ul><li>rest, sublingual nitrates </li></ul><ul><li>Autonomic symptoms </li></ul><ul><li>Sweating, pallor, peripheral vasoconstriction, nausea and vomiting </li></ul>
    13. 13. Chest Pain Differential diagnosis <ul><li>Cardiac pathology </li></ul><ul><ul><li>Pericarditis, aortic dissection </li></ul></ul><ul><li>Pulmonary pathology </li></ul><ul><ul><li>Pulmonary embolus, pneumothorax, pneumonia </li></ul></ul><ul><li>Gastrointestinal pathology </li></ul><ul><ul><li>Peptic ulcer disease, reflux, pancreatitis, ‘café coronary’ </li></ul></ul><ul><li>Musculoskeletal pathology </li></ul><ul><ul><li>Trauma, Tietze’s Syndrome </li></ul></ul>
    14. 14. Management
    15. 15. 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
    16. 16. Antiplatelet Therapy: Common Oral Agents 1 Topol EJ et al. Circulation 2003;108:399-406 2 Diener HC et al. Lancet 2004;364;331-7 3 Plavix® package insert. www.sanofi-synthelabo.us 4 Peters RJ et al. Circulation 2003;108:1682-7 5 Hass WK. NEJM 1989;321:501-7 6 Urban P. Circulation 1998;98:2126-32 7 Ticlid® package insert. www.rocheusa.com * Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile Acetylsalicylic acid (ASA) Clopidogrel bisulfate* Ticlopidine hydrochloride* Trade Name Aspirin Plavix® Ticlid® Class Salicylate Thienopyridine Thienopyridine Formulation Active Drug Pro-Drug Active Drug Maintenance Dose 75-325 mg daily 75 mg daily 250 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
    17. 17. The formula of aspirin is C 9 H 8 O 4
    18. 18. Synthesis of Acetylsalicylic acid
    19. 19. Aspirin: Mechanism of Action Membrane Phospholipids Arachadonic Acid Prostaglandin H 2 COX-1 Thromboxane A 2  Platelet Aggregation Vasoconstriction Prostacyclin  Platelet Aggregation Vasodilation Aspirin
    20. 20. Pharmacokinetics Of Aspirin <ul><li>Aspirin is rapidly absorbed from the gastrointestinal tract and peak plasma concentration are achieved in 30 to 40 minutes. </li></ul><ul><li>Significant platelet inhibition is noted within 60 minute of ingestion and a single dose of 100mg of aspirin can completely block TXA2 production for the life of the platelet in most individual. </li></ul><ul><li>The plasma half-life of aspirin is only 20 minutes but the irreversible nature function makes once-daily dosing sufficient to maintain its antithrombotic benefit. </li></ul>
    21. 21. Physicians’ Health Study (PHS) Aspirin Evidence: Primary Prevention in Men 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;321:129-35 CI=Confidence interval, MI=Myocardial infarction
    22. 22. Womens’ Health Study (WHS) Aspirin Evidence: Primary Prevention in Women Placebo Aspirin Ridker P et al. NEJM 2005;352:1293-304 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
    23. 23. Aspirin Evidence: Primary Prevention BDT, 1988 Combined PPP, 2001 HOT, 1998 TPT, 1998 PHS, 1989 RR of MI in Men 1.0 2.0 5.0 0.5 0.2 RR = 0.68 (0.54-0.86) P=0.001 1.0 2.0 5.0 0.5 0.2 RR = 1.13 (0.96-1.33) P=0.15 HOT, 1998 Combined WHS, 2005 PPP, 2001 1.0 2.0 5.0 0.5 0.2 Aspirin Better Placebo Better RR = 0.99 (0.83-1.19) P=0.95 1.0 2.0 5.0 0.5 0.2 Aspirin Better Placebo Better RR = 0.81 (0.69-0.96) P=0.01 RR of CVA in Men RR of MI in Women RR of CVA in Women Ridker P et al. NEJM 2005;352:1293-304 CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk
    24. 24. Aspirin Evidence: Secondary Prevention Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86 Control better Antiplatelet better Effect of antiplatelet treatment* on vascular events** *Aspirin was the predominant antiplatelet agent studied **Include MI, stroke, or death 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 1.0 0.5 0.0 1.5 2.0
    25. 25. Aspirin Evidence: Dose and Efficacy 0.5 1.0 1.5 2.0 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 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
    26. 26. 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 I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III B
    27. 27. Aspirin Recommendations Aspirin (75-162 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
    28. 28. Aspirin Recommendations (Continued) Aspirin (75-162 mg daily) if known CHD/ASVD Aspirin (162-325 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 (75-162 mg daily) should be continued indefinitely Secondary Prevention ASVD=Atherosclerotic vascular disease, CABG=Coronary artery bypass graft, CHD=Coronary heart disease
    29. 29. Aspirin Recommendations (Continued) Aspirin (75-162 mg daily) as the initial dose after stent implantation in those at higher bleeding risk Aspirin (100-325 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 I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III C
    30. 30. Definition(s) of “APT Resistance?” <ul><li>The fact that some patients may experience recurrent vascular events despite the use of APT should be properly defined as “treatment failure” rather than “APT resistance” (multiple pathways mediate thrombotic events). </li></ul><ul><li>APT Resistance/Non-responsiveness=failure to inhibit the target </li></ul><ul><li>APT Resistance/Non-responsiveness≠clinical failure </li></ul>
    31. 32. 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) 0 1 2 3 5 3 6 9 12 15 18 21 24 27 30 33 36 Aspirin Clopidogrel 4 P = 0.008 CAPRIE Steering Committee. Lancet 1996;348:1329-39 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
    32. 33. Clopidogrel Evidence: Secondary Prevention Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial 3 6 9 0 12 Rate of death, myocardial infarction, or stroke P<0.001 Months of Follow Up The CURE Trial Investigators . NEJM 2001;345:494-502 NSTE-ACS=Non ST-segment elevation acute coronary syndrome Aspirin + Clopidogrel Aspirin + Placebo 12,562 patients with a NSTE-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg) for 9 months Dual antiplatelet therapy is more efficacious in NSTE-ACS
    33. 34. Steinhubl S et al. JAMA 2002;288:2411-20 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 (75-325 mg daily) plus Clopidogrel (300 mg load followed by 75 mg daily). 0 12 3 6 9 0 Risk of MI, Stroke, or Death (%) 27% RRR, P=0.02 10 5 15 4 weeks of DAP 1 year of DAP Months from Randomization 2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin (75-325 mg) monotherapy vs persistent DAP* for 1 year DAP* produces continued benefit when used for 1 year
    34. 35. Bhatt DL et al. NEJM 2006;354:1706-17 Months 8 6 4 2 0 0 6 12 18 24 30 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 (75-162 mg) or aspirin (75-162 mg) & clopidogrel (75 mg) for a mean of 30 months Routine DAP therapy offers little long-term benefit
    35. 36. Bhatt DL et al. NEJM 2006;354:1706-17 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 (75-162 mg) or aspirin (75-162 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) 0.22 0.6 0.8 1.4 1.2 1.6 0.4 CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction
    36. 37. 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 I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III B
    37. 38. 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
    38. 39. 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) I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III C
    39. 40. Summary <ul><li>Variability in individual responsiveness to antiplatelet agents is an emerging clinical problem: poor responsiveness has been associated with an increased risk of ischemic events, including stent thrombosis. </li></ul><ul><li>WHAT and HOW to measure antiplatelet drug responsiveness still needs to be fully defined. </li></ul><ul><li>Responsiveness to antiplatelet therapy should be evaluated for mainly investigation purposes!!! </li></ul>
    40. 41. Thank You
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