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Francesco Violi

Fibrillazione Atriale. Francesco Violi. Università degli Studi di Roma “La Sapienza”. Prevalence of AF in 2 american epidemiologie studies. Fuster et al. Circulation 2001. Annual Event Rate of Stroke in Atrial Fibrillation per Age and Risk Factors.

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Francesco Violi

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  1. Fibrillazione Atriale Francesco Violi Università degli Studi di Roma “La Sapienza”

  2. Prevalence of AF in 2 american epidemiologie studies Fuster et al. Circulation 2001

  3. Annual Event Rate of Stroke in Atrial Fibrillation per Age and Risk Factors Age (yr) Event rate (%) (95% CI) <65 - 1.0 (0.3-3.1) + 4.9 (3.0-8.1) 65-75 - 4.3 (2.7-7.1) + 5.7 (3.9-8.3) >75 - 3.5 (1.6-7.7) + 8.1 (4.7-13.9) AFI. Arch. Int. Med. 1994

  4. Risk Factors for ischemic Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation Risk factors (Control Groups) Relative Risk Previous Stroke or TIA 2.5 History of hypertension 1.6 Congestive heart failure 1.4 Advanced age (continous, per decade) 1.4 Diabetes mellitus 1.7 Coronary artery disease 1.5 TIA indicates transient ischemic attack. Relative risk refers to comparison with atrial fibrillation have about a 6-fold increased risk of thromboembolism compared with patients in normal sinus rhythm. Data from collaborative analysis of five primary prevention trials. Fuster et al. Circulation 2001

  5. 50 70 90 80 60 40 70 50 60 30 40 50 tHcy, mmol/l PLP, nmol/l AGE, years 40 30 20 30 20 20 10 10 10 0 0 0 1 1 2 2 3 3 4 4 1 2 3 4 tHcy QUARTILE tHcy QUARTILE tHcy QUARTILE 2.5 40 10 9 2.0 8 30 7 1.5 6 % OF PATIENTS WITH STROKE URIC ACID, mg/dl CREATININE, mg/dl 20 5 1.0 4 3 10 0.5 2 1 0.0 0 0 1 2 3 4 1 2 3 4 1 2 3 4 tHcy QUARTILE tHcy QUARTILE tHcy QUARTILE Relationship of age, PLP levels, creatinine, uric acid levels (mean  SD) and incidence of stroke with quartiles of the tHcy distribution

  6. Logistic regression analysis in which stroke was categorical dependent variable; results of all patients (n=163)

  7. Adjusted-Dose Warfarin Compared with Placebo Relative Risk Reduction (95% CI) AFASAK I (1) SPAF (3) BAATAF (6) CAFA (7) SPINAF (8) EAFT (9) All Trials (n=6) 100% 50% 0 -50% -100% Warfarin Better Warfarin Worse Fuster et al. Circulation 2001

  8. Warfarin Compared with Aspirin Relative Risk Reduction (95% CI) AFASAK I (1) AFASAK II (2) EAFT (9) PATAF (15) SPAF II (4) All Trials (n=5) 100% 50% 0 -50% -100% Warfarin Better Warfarin Worse Fuster et al. Circulation 2001

  9. Recommendations for Antithrombotic Therapy in Patients with Atrial Fibrillation Based on Thromboembolic Risk Stratification Patient Features Antithrombotic Therapy Grade of Recommendation AGE LESS THAN 60 YEARS Aspirin (325 mg daily) or no therapy I No heart disease (lone AF) AGE LESS THAN 60 YEARS Aspirin (325 mg daily) I Heart disease but no risk factors Age greater than or equal to 60 years Aspirin (325 mg daily) I No risk factors AGE GREATER THAN OR EQUAL TO 60 YEARS Oral anticoagulation (INR 2.0–3.0) I With diabetes mellitus or CAD Addition of aspirin, 81–162 mg daily is optional IIb AGE GREATER THAN OR EQUAL TO 75 YEARS Oral anticoagulation (INR '2.0) I especially women HF Oral anticoagulation (INR 2.0–3.0) I LV ejection fraction less than or equal to 0.35 Thyrotoxicosis Hypertension Rheumatic heart disease Oral anticoagulation I (mitral stenosis) (INR 2.5-3.5 or higher may be appropriate) Prosthetic heart valves Prior thromboembolism Persistent atrial thrombus on TEE Fuster et al. Circulation 2001

  10. Reported Rates of Warfarin Use in Patients Without Contraindications Warfarin ReferenceNo. Of PatientPrescribed, Patients Population Setting NO(%) of Patients Brass 488(184) AF, aged Medicare patients 117 (38.4) et al. 1997 ≥65 y: 54% in United States were aged 65-74 y Gurwitz 413 AF, 66% Long-term care 130 (31.5) et al. 1997 aged ≥85 facility in United States Munschauer 651 (42) Chronic AF 2 Community 232 (38.1) et al. 1997 and 2 tertiary referral hospitals in United States CQIN 3575 AF, aged 19-104y 12 Canadian hospitals 852 (23.8) Investigators 1998 Whittle 172 AF, mean Medicare beneficiaries 76(44.1) et al 1997 age of 80 y at 5 hospitals in United States Bungard et al. Arch Intern Med 2000

  11. Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity 20 15 Odds ratio 10 5 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 International Normalized Ratio Fuster et al. Circulation 2001

  12. Characteristics of Elderly and Control Groups: Long vs Short Duration of Therapy Both Groups Short Duration All long All Short Control Elderly Duration Duration Group Group >12 mo ≤12 mo Aged 60-69y Aged>75y (n=227) (n=101) (n=65) (n=36) 357 (18.9) 101 (12.1) 67 (12.4) 34 (11.4) 2110 (5.9) 900 (8.8) 593 (8.8) 307 (8.9) 478 (1.4) 181 (1.8) 137 (2.0) 44 (1.3) 127 (0.4) 132 (1.3) 81 (1.2) 51 (1.5) 29.1 38.0 40.2 33.9 70.9 62.0 59.8 66.1 12 (3.4) 8 (7.9) 5 (7.5) 3 (8.8) 6 (1.7) 7 (6.9) 5 (7.4) 2 (5.9) Total follow-up, y (average No. of mounths/patient) No. Of INRs* (No. Of INRs per patient-year) checked High INRs Low INRs %of INR Out of target In target No. Of episodes with INR>7 (%per patient-year) No. Of hemorrhages (% per patient-year) Copland et al. Arch Intern Med 2001

  13. Number of cardiovascular events (event rate per patient year) Pengo et al. Thromb Haemost 2001

  14. INR measurement temporally related a severe cardiovascular complication. The points inside the circle refer to fatal cerebral bleedings. 5 4 3 2 1 Trombosis-related Vascular death Stroke Major (Primary) Bleeding Pengo et al. Thromb Haemost 2001

  15. Aspirin Compared with Placebo Relative Risk Reduction (95% CI) AFASAK I (1) SPAF I (3) EAFT (9) ESPS II (14) LASAF (13) UK-TIA (16) All Trials (n=5) 100% 50% 0 -50% -100% Aspirin Better Aspirin Worse Fuster et al. Circulation 2001

  16. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients Antithrombotic Trialists’ Collaboration Category of trial # trial Previous myocardial infarction 12 Acute myocardial infarction 15 Previous stroke/ transient ischaemic attack 21 Acute stroke 7 Other high risk 140 Subtotal: all except acute stroke 188 All trials 195 BMJ 2002; 324: 71-86

  17. Resistance Evidences 1978 Ather 31;169 30% no reduction PA 650 mg 1988 Scan Card J 32;233 14/143 no reduction PA 70-160mg 1995 Can J Card 11;221 only 23/40 BT  325 mg 1997 Th Haemost 78;103 40% reduction PA 100 mg Clinical 1991 Thromb Res 63;587 Stroke Pat in 2yrs Risk F. 500 mg 1997 Th Haemost 78;103 87%  arterial re-occlusion 100 mg

  18. Prior aspirin use predicts worse outcomes in patients with non-ST-elevation acute coronary syndromesPursuit investigatorsAm J Cardiol 1999, 83 pg 1147 • 9461 patients • ASA 80-325 mg/die • 6039 patients (63,8%) took ASA at the time of the enrollement • 3422 patients (36,2%) did not take ASA at the time of the enrollement

  19. Alexander et al. The American Journal of Cardiology, 1999

  20. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events 11-dehydroTxB2 <15 15-21 21-33 >33 MI 1.0 1.3 1.5 2.0 CV death 1.0 2.0 2.5 3.5 MI/stroke/CV death 1.0 1.3 1.4 1.8 Circulation 2002, 105 pg 1650HOPE study (5529 su 9541)

  21. Profile and prevalence of aspirin resistance in patients with cardiovascular diseaseAm J Cardiol 2001, 88 pg.230 • 328 patients enrolled • > 21 years old • 325 mg/die aspirin for 7 days before entering the study • No concomitant assumption of anti-inflammatory or antiplatelet drugs

  22. Resistance as defined by aggregometric studies: a) ADP 10 mM > al 70%b) Arachidonic Acid 0.5 mg/ml >20% Resistant Semiresponder Sensitives Both prerequisites One prerequisite None of the satisfied satisfied prerequisites satisfied 18 78 232 7,6% 23,8% 68,6%

  23. Gum et al. Jacc, 2003

  24. ADP induced platelet aggregation *p<0,005 JACC 2004

  25. Collagen induced platelet aggregation(maximum percentage) *p<0,005 JACC 2004

  26. Collagen induced platelet aggregation(lag-phase) *p<0,005 JACC 2004

  27. Aggregometric tests in Ticlopidine treated patients *p<0,05 **p<0.005 JACC 2004

  28. Conclusion • Platelets of patients treated with aspirin become progressively less sensitive to its antiplatelet effect; • Open issues: a) relevance with clinical outcome b) intrinsic mechanism

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