Virchow s triad in AF

Transcription

1 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence Consequences 4- PCI (with stents) PCI and antithrombotic treatment 5- Overview of published anticoagulated or AF patients undergoing PCI 6- Guidelines

2 Virchow s triad in AF ABNORMAL BLOOD FLOW; STASIS Atrial tissue changes (myocytes, fibrosis) Left atrial dilatation / dysfunction LA SEC / thrombus Left ventricular dysfunction STRUCTURAL HEART DISEASE Mitral stenosis MV prosthesis Heart Failure CAD (WMA) BLOOD CONSTITUENTS HYPERCOAGULABLE (PROTHROMBOTIC) STATE Haemoconcentration Abnormal Hemostasis (coagulation cascade activation) Platelet activation Defective fibrinolysis Inflammation (CRP, IL6, vwf) Growth factors Watson T. Lancet 2009;373:

3 Virchow s triad in ACS RHEOLOGY/FLUID DYNAMICS Plasma viscosity Shear stress Circumferential tensile stress Local stasis BLOOD CONSTITUENTS BLOOD CONSTITUENTS Thrombogenic factors Defective fibrinolysis Hyperlipidemia Lipoprotein (a), Hyperglycemia Cell aggregation VESSEL WALL Endothelial dysfunction TF rich lipid core Inflammation infiltration Weakening fibrous cap Remodelling Vasoconstriction Lee KW. Blood Coagulation and Fibrinolysis 2003, 14:

4 Thrombo-embolic risk: AF vs CAD CAD AF MACE after an ACS : 9 10 %/year (first 3 months) Stent thrombosis: %/year Early stent thrombosis: (<30 days) :1.4%. MACE in stable CAD : 2%/year Stroke : 1 %/year (lone AF) Low risk (CHADS 2 1) 1-5 %/year Moderate/high risk : 8-12 %/year SJM (Mitral valve) : 20 %/year Type of thrombus: platelet-driven Platelets play the main role APA >> OAC (Wf) Type of thrombus: fibrin rich Platelets play a smaller role OAC (Wf) >> APA

5 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence Consequences 4- PCI (with stents) PCI and antithrombotic treatment 5- Overview of published anticoagulated or AF patients undergoing PCI 6- Guidelines

6 CHADS 2 score CHADS 2 score and risk of stroke ( ) 2.8 ( ) 4.0 ( ) 5.9 ( ) CHADS 2 score +1 for CHF, +1 for HT, +1 for age > 75y, +1 for diabetes, +2 for prior stroke/tia ( ) ( ) ( ) Error bars = 95% CI Annual stroke rate, per 100 patient-years (%, CI) Gage B. JAMA ; 285 :

7 Risk stratification for stroke and thromboembolism in non valvular AF Risk factor Score CHA2DS2- VASc score Adjusted Stroke Rate (%/y) Congestive heart failure/lv dysfunction Hypertension Age Diabetes mellitus Stroke/TIA/TE Vascular disease [prior myocardial infarction, peripheral artery disease, aortic plaque] Age Sex category [ie Female gender] Maximum score Camm J. Eur Heart J. doi: /eurheartj/ehq278

8 Approach to thromboprophylaxis in patients with atrial fibrillation Risk category CHA2DS2- VASc score Recommended antithrombotic therapy One major risk factor or 2 clinically relevant non-major risk factors One clinically relevant nonmajor risk factor 2 Oral anticoagulation 1 Antithrombotic therapy, either as OAC or aspirin mg daily. We suggest OAC rather than aspirin. No risk factors 0 Aspirin mg daily or no antithrombotic therapy. We suggest no antithrombotic therapy rather than aspirin. Camm J. Eur Heart J. doi: /eurheartj/ehq278

9 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence Consequences 4- PCI (with stents) PCI and antithrombotic treatment 5- Overview of published anticoagulated or AF patients undergoing PCI 6- Guidelines

10 Meta-analysis of the efficacy of antithrombotic therapies for stroke prevention in patients who have AF Comparison Adjusted dose Wf vs control Antiplatelet agents vs control Adjusted dose Wf vs antiplatelet agents Trials, n Patients, n Strokes, n Relative risk reduction % Hypothetical NNT primary prevention Hypothetical NNT secondary prevention NNT number needed to treat : prevent 1 stroke for 1 year Hart RG. Ann Intern Med. 2007;146:

11 Cumulative event rate (% per year) Stroke Prevention in Atrial Fibrillation III Cumulative rate of ischaemic stroke or systemic embolism (primary events) eligible patients randomised - Standard adjusted-dose wafarin (n=523) - Low-intensity fixed-dose warfarin + aspirin (n=521) Combination therapy ((Wf ld +asp) RRR 74% (95% CI 50-87, p< Adjusted-dose warfarin Days from randomisation Trial stopped after a mean follow-up of 1 1 years : rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7 9% per year) significantly higher than in those given adjusteddose warfarin (1 9% per year) at interim analysis Lancet. 1996;348:633-8.

12 ACTIVE trials : overall design Documented AF + 1 risk factor for Stroke Unsuitable for VKA ACTIVE W Clopidogrel + aspirin versus VKA (N = 6507) ACTIVE A Clopidogrel + aspirin versus ASA (N = 7554) No Exclusion Criteria for ACTIVE I ACTIVE I Irbesartan versus Placebo (N = 9016) Partial Factorial Design Risk factor for Stroke : age 75 y, HT, prior stroke/tia, LVEF<45%, PAD, age CAD or diabetes

13 ACTIVE W: OAC vs dual APA for SPAF Clinical outcomes vs use of oral anticoagulation therapy at study entry Risk (% per year) Clopidogrel+aspirin vs oral anticoagulation) Primary outcome 1 Oral anticoagulation therapy at entry No oral anticoagulation therapy at entry Major haemorrhage Oral anticoagulation therapy at entry No oral anticoagulation therapy at entry Net benefit 2 Oral anticoagulation therapy at entry No oral anticoagulation therapy at entry Clopidogrel + aspirin Oral anticoagulation therapy RR (95 % Cl p p (interaction) ( ) ( ) ( ) ( ) ( ) < ( ) Stroke, MI, vascular death, non-cns systemic embolism 2 Stroke, MI, vascular death, non-cns systemic embolism, major bleed ACTIVE Investigators. Lancet 2006;151:

14 Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W - Vitamin K antagonists (VKAs) are superior to clopidogrel + aspirin in the prevention of all strokes [RR) 1.72; 95% CI ; P = 0.001]. - VKAs did not significantly reduce the risk of all-cause mortality (RR 1.01; 95% CI, ; P = 0.91, vascular death (RR 1.14; 95% CI ; P = 0.34, non-vascular death (RR 0.76; 95% CI ; P = VKAs were significantly associated with -fewer bleeding events (RR 1.21; 95% CI ; P = 0.001) -net clinical benefit (primary outcome, major bleed, and death) (RR 1.31; 95% CI ; P = ). - VKAs did not significantly reduce the risk of disabling stroke [ RR 1.47; 95% CI ; P = 0.06] fatal stroke [ RR 0.93; 95% CI ; P = 0.85 ] VKAs >> clopidogrel + aspirin in the prevention of all strokes VKAs >> clopidogrel + aspirin in the rate of bleeding events VKAs associated with a net clinical benefit De Caterina R. Eur Heart J doi: /eurheartj/ehq250

15 ACTIVE A: dual APA vs aspirin alone for SPAF Primary Outcome Components and Bleeding Outcome Clopidogrel + Aspirin # rate/ year Aspirin # rate/ year Clopidogrel + Aspirin versus Aspirin RR 95% CI P Primary endpoint Ischemic/Und. stroke <0.001 Hemorrhagic stroke Major bleeding < Stroke, MI, vascular death, non-cns systemic embolism ACTIVE Investigators. N Engl J Med 2009;360:

16 ACTIVE A: bleeding risk with dual APA therapy compared with aspirin alone Bleeding Clopidogrel + aspirin (N = 3772) Aspirin alone (N = 3782) RR (95% CI) P value Events, n %/yr Events, n %/yr Major bleeding ( ) <0.001 Severe ( ) <0.001 Fatal ( ) 0.07 Minor bleeding ( ) <0.001 Any bleeding ( ) <0.001 Site of major bleeding* Gastrointestinal ( ) <0.001 Gastrointestinal, with transfusion ( ) <0.001 Intracranial ( ) Extracranial ( ) <0.001 Dosing: clopidogrel 75 mg/d; aspirin mg/d *Four patients had both intracranial and extracranial bleeding. RR = relative risk ACTIVE Investigators. N Engl J Med 2009;360:

17 OAC vs APA and dual APA vs single APA in AF Thromboembolic risk Bleeding risk Warfarin vs aspirin + clopidogrel Aspirin + clopidogrel vs aspirin Warfarinld + aspirin SPAFIII Thrombin inhibitors vs aspirin Re-LY?? ACTIVE Investigators. Lancet 2006;151: ACTIVE Investigators. N Engl J Med 2009;360:

18 Risks and benefits of combining aspirin with anticoagulant in patients with AF An analysis of stroke prevention using an oral thrombin inhibitor : SPORTIF trials Major events occurring when aspirin given in association with warfarin or ximelagatran Stroke Ximel + ASA Warf + ASA Stroke/SEE MI Death Major bleeds All bleeds HR (95% CI) Flaker GC. Am Heart J 2006;152:967-73

19 Does Warfarin for Stroke Thromboprophylaxis Protect Against MI in Atrial Fibrillation Patients? Myocardial Infarction Events in Warfarin Group versus Non-Warfarin Comparator Anticoagulant Group in Patients with AF Warfarin Comparator Risk ratio M-H, Fixed, 95 % Cl) Study Events Total Events Total Weight Risk ratio M-H, Fixed, 95 % Cl ACTIVE-W % 0.63 [ ] AMADEUS % 0.74 [ ] RE-LY % 0.72 [ ] SPORTIF-III % 0.54 [ ] SPORTIF-IV % 1.42 [ ] Total (95 % Cl) % 0.77 [ ] Heterogeneity : Chi² = 7.63, df = 4 (p = 0.11), l² = 48 % Test for overall effect : Z = 2.51 (p = 0.01) Favours warfarin Favours comparator Lip GYH. Am J Med 2010 (in press)

20 Cumulative hazard rates Intracranial Bleeds 0.02 Warfarin Dabigatran 110 mg Dabigatran 150 mg 0.01 RR 0.40 (95% CI: ) p<0.001 RRR 60% RRR 69% 0.0 RR 0.31 (95% CI: ) p< Years N Engl J Med 2009; 361

21 Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Point awarded H Hypertension* 1 A Abnormal renal** and liver funtion*** 1 or 2 S Stroke 1 B Bleeding*** 1 L Labile INRs 1 E Elderly (>65) 1 D Drugs or alcohol 1 or 2 * Define as SBP>160mmHg ** creatinine >200µmol *** Bilirubin<2 UNL with APL>3 UNL **** Bleeding refers to prior history of bleeding or predisposition to bleed ***** Drugs refers to other antithrombotic drugs and to NSAID Maximum 9 points

22 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence Consequences 4- PCI (with stents) PCI and antithrombotic treatment 5- Overview of published anticoagulated or AF patients undergoing PCI 6- Guidelines

23 Incidence and prognostic implication of AF in acute MI Study/author AF incidence OR [95 % Cl] after AMI (%) In-hospital mortality Long-term mortality Behar/Sprint Prognosis (1992) 9.9 no 1.28 [ ] Madias (1996) 11.2 no n.a. Crenshaw/GUSTO I (1997) [ ] n.a. Eldar/Sprint (1998) [ ] 1.33 [ ] Pedersen/TRACE (1999) [ ] 1.3 [ ] Rathore (2000) ] 1.34 [ ] Wong/GUSTOIII (2000) [ ] 1.64 [ ] Pizzetti/GISSI III (2001) 6.1 yes yes Goldberg (2002) ] 1.23 [ ] Kinjo/OACIS (2003) 7.7 no 1.64 [ ] Lehto/OPTIMAAL(2005) [ ] 1.82 [ ] Pedersen/TRACE CHF (2005) - n.a. n.a. Stenenstrand/RIKS-HIA (2005) 1.7 n.a. n.a. MCMurray/CAPRICORNS (2005) n.a. n.a. Laurent/RICO (2005) 7.6 n.a [ ] Kober/VALIANT (2006) 12.3 n.a [ ] Schmitt J. Eur Heart J 2009:30:

24 Short- and long-term outcomes following AF in patients with ACS with or without ST-segment elevation Pooled database Parameters Patients with STEMI Patients with NSTE-ACS No AF (n = 77440) AF (n = 6721) P Value No AF (n = 34089) AF (n = 2316) P value p value Interaction* Mortality 1-7 days < < Mortality days < < Stroke 1-7 days < < Stroke > 7 days < < Pooled database ST-segment elevation myocardial infarction (n = STEMI) : (GUSTO I, GUSTO IIb, GUSTO III, ASSENT 2, ASSENT 3, ASSENT 3 Plus. NSTE-ACS Non- ST-segment elevation (NSTE) ACS (n=36 405) : GUSTO IIb (22%), PURSUIT, PARAGONA, PARAGON-B, SYNERGY Lopes RD Heart 2008; 94:

25 Short- and long-term outcomes following AF in patients with ACS with or without ST-segment elevation Parameters Patients with STEMI Patients with NSTE-ACS No AF (n = ) Pooled database AF (n = 6721) P Value No AF (n = 34089) AF (n = 2316) P value p value Interaction* MI-1-7 days < < Death/MI 1-7 days < < In-hospital ischaemic stroke 1-7 days Any moderate or severe bleeding In-hospital haemorrhagic stroke < < < < < < Pooled database ST-segment elevation myocardial infarction (n = STEMI) : (GUSTO I, GUSTO IIb, GUSTO III, ASSENT 2, ASSENT 3, ASSENT 3 Plus. NSTE-ACS Non- ST-segment elevation (NSTE) ACS (n=36 405) : GUSTO IIb (22%), PURSUIT, PARAGONA, PARAGON-B, SYNERGY Lopes RD Heart 2008; 94:

26 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence / prognosis Consequences

27 Adjusted Indirect Meta-Analysis of Aspirin Plus Warfarin at INR 2 to 3 Versus Aspirin Plus Clopidogrel After ACS Adjusted indirect comparison of ASA + Wf versus ASA + Clopidogrel. 13 studies 1 69,741 patients OR (95% CI) Major Adverse Events All cause death Non-fatal AMI T.E. stroke Major Bleed Intracranial bleeds Extracranial bleeds OR 1.9, 95% CI 1.2 to 2.8, p = OR 3.14, 95% CI 0.6 to 16.1, p = 0.7 OR 1.8, 95% CI 1.02 to 3.2, p = 0.04 OR 0.84, 95% CI 0.71 to 1.20, p = 0.2 OR 1.06, 95% CI 0.85 to 1.31, p = 0.5 OR 0.9, 95% CI 0.66 to 1.24, p = 0.6 OR 0.53, 95% CI 0.31 to 0.88, p = compared aspirin plus dose-adjusted warfarin versus aspirin alone 3 compared aspirin plus clopidogrel versus aspirin alone Favours ASA+Wf Favours ASA + Clopidogrel Testa L. Am J Cardiol 2007;99:

28 Adjusted Indirect Meta-Analysis of Aspirin Plus Warfarin at INR 2 to 3 Versus Aspirin Plus Clopidogrel After ACS After ACS, allocating 100 patients to aspirin plus dose-adjusted warfarin (at INR 2 to 3) versus aspirin plus clopidogrel could prevent 17 thromboembolic strokes while causing 3 major bleeds Testa L. Am J Cardiol 2007;99:

29 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence Consequences 4- PCI (with stents) ACS / PCI and antithrombotic treatment 5- Overview of published anticoagulated or AF patients undergoing PCI 6- Guidelines

30 Death or MI Rates Warfarin Use and Outcomes in Patients with AF complicating ACS Adjusted 6-month death or MI curves according to warfarin use at discharge 15 % No Warfarin Warfarin 10 % Adjusted HR 0.39; 95% CI, % P = % Discharge (Days) 23,208 patients enrolled in the PURSUIT, PARAGON-A, and SYNERGY trials, 5.8% (1346 patients) had AF as an in-hospital complication 4.0% (917 patients) had AF discharged alive Lopes RD. Am J Med 2010; 123:

31 Warfarin Use and Outcomes in Patients with AF complicating ACS Predictors of 6-month Death or MI in Patients with AF and ACS Variable HR (95 % Cl) Chi-square p Value In-hospital CABG 0.30 ( ) < 0.01 CHADS 2 score ( ) < 0.01 Warfarin at discharge 0.39 ( ) Aspirin at discharge 0.47 ( ) ,208 patients enrolled in the PURSUIT, PARAGON-A, and SYNERGY trials, 5.8% (1346 patients) had AF as an in-hospital complication 4.0% (917 patients) had AF discharged alive Lopes RD. Am J Med 2010; 123:

32 Warfarin Use and Outcomes in Patients with AF complicating ACS Antithrombotic use according to CHADS2 score risk 100 % 90 % 80 % 70 % 60 % 50 % 40 % 30 % 20 % 10 % 0 % CHADS 2 = 0 CHADS 2 = 1 CHADS 2 = 2 Warfarin Aspirin Ticlopidine/Clopidogrel 23,208 patients enrolled in the PURSUIT, PARAGON-A, and SYNERGY trials, 5.8% (1346 patients) had AF as an in-hospital complication 4.0% (917 patients) had AF discharged alive Lopes RD. Am J Med 2010; 123:

33 Warfarin Use and Outcomes in Patients with AF complicating ACS Antithrombotic use according to bleeding risk 100 % 90 % 80 % 70 % 60 % 50 % 40 % 30 % 20 % 10 % 0 % Risk of bleeding 1 Low Intermediate High 1* 2* 4* 1* 2* 4* 1* 2* 4* Warfarin Aspirin Ticlopidine/Clopidogrel 23,208 ACS patients (3 trials) In-hospital AF: 5.8 % AF at discharge: 4.0 % * Median CHADS 2 score 1 Bleeding risk factors : age > 65 years or more, history of stroke, history of gastrointestinal bleed, recent hematocrit < 30%, serum creatinine > 1.5 mg/dl, history of diabetes mellitus Low risk: no risk factors ; Intermediate risk: 1 to 2 risk factors ; High risk: 3 to 4 risk factors Beyth RJ. Am J Med. 1998;105:91-99 Lopes RD. Am J Med 2010; 123:

34 Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting at 1 year F.U. Primary endpoints: death, MI, target vessel revascularization, stent thrombosis at 12 months Secondary endpoints : major bleeding and stroke at 12 months Warfarin patients (n=219) Control patients (n=227) OR (95 % CI) Primary endpoint at discharge Primary E.P., n (%) 6 (2.7) 3 (1.3) 2.1 ( ) 0.30 Primary endpoint at 12 months Primary E.P., n (%) 48 (21.9) 25 (11.0) 2.3 ( ) Secondary endpoints Major bleeding, n (%) 18 (8.2) 6 (2.6) 3.3 ( ) Stroke, n (%) 7 (3.2) 5 (2.2) 1.5 ( ) 0.52 Overall, n (%) 25 (11.4) 11 (4.8) 2.5 ( ) p Karjalainen PP. Eur Heart J. 2007; 28,

35 Bleeding event free survival Long-Term Outcomes in Patients Undergoing Coronary Stenting on Dual Oral Antiplatelet Treatment Requiring OAC Therapy Cumulative event-free survival from overall bleeding in patients on dual therapy, or triple therapy within targeted INR values (2.0 to 2.5), and those who were not (> 2.5) % % 95.1 % 80 Log Rank, p < vs dual therapy Log Rank, p < vs triple therapy (INR : ) Dual therapy (n = 102, control group) Triple therapy (INR : ) (n = 81) Triple therapy (INR > 2.5) (n = 21) Days Prospective study, 102 consecutive patients undergoing coronary stenting Dual antiplatelet therapy and oral anticoagulation (INR therapeutic range (2.0 to 2.5)). F.U. = 18 months, TIMI bleeding criteria, 66.7 % Rossini R. Am J Cardiol 2008;102: mean duration : 157±134 days

36 Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: A systematic review and meta-analysis of randomized trials Summary of outcomes of radial versus femoral access for coronary angiography or intervention No / total (%) Radial Femoral Odds ratio p (95 % Cl) Major bleeding 13/2390 (0.05) 48/2068 (2.3) 0.27 (0.16, 0.45) <.001 Dealth MI, or stroke 56/2209 (2.5) 71/1874 (3.8) 0.71 (0.49, 1.01).058 Dealth 22/1906 (1.2) 28/1565 (1.8) 0.74 (0.42, 1.30).29 Myocardial infarction 39/1931 (2.0) 46/1595 (2.9) 0.76 (0.49, 1.17).21 Stroke 2/1428 (0.1) 5/1107 (0.5) 0.39 (0.09, 1.75).22 Access site crossover 150/2542 (5.9) 34/2460 (1.4) 3.82 (2.83, 5.15) <.001 Inhability to cross the lesion with a wire, balloon or stent during PCI 60/1274 (4.7) 40/1186 (3.4) 1.31 (0.87, 1.96) randomized trials (from 1980 to April 2008) Jolly SS. Am Heart J 2009; 157:

37 Efficacy and safety of drug-eluting stent use in patients with atrial fibrillation Events during follow-up DES BMS HR 95 % Cl P-Value n 206/207(99.5 % ) 191/207 (92.3 %) Median follow-up (days) < 0.01 Embolism (%) Death MACE (%) Major adverse events (%) Safety endpoints Major bleeding (%) Minor bleeding (%) Subacute or late thrombosis (%) (definitive or probable) patients with AF who had undergone PCI with stent over 7 years ( ). The routine use of DES in patients with AF does not seem to be justified. Ruiz-Nodar JM. Eur Heart J 2009; 30: 932 9

38 Antithrombotic therapy and outcomes of patients with AF following primary PCI: results from the APEX-AMI trial Antithrombotic therapy in patients with AF at discharge according to CHADS2 score CHADS 2 = 0 CHADS 2 = 1 CHADS 2 = Warfarin only Aspirin only 5745 STEMI At discharge, No OAC in 55% of AF patients OAC at discharge in AF: morbi-mortality Warfarin + Aspirin 26.7 Aspirin + Clopidogrel Triple Therapy Lopes RD. Eur Heart J 2009; 30:

39 Factors associated with increased bleeding risk - Triple therapy using an OAC and dual platelet inhibition (aspirin and clopidogrel/ ticlopidine) - OAC vs non-anticoagulated patients - Use of a GP IIb/IIIa inhibitor - Left main or three-vessel disease - Older age (e.g. >75 years) - Female gender - Smoking - Chronic kidney disease - High INR value (> 2.6) - Femoral access vs radial access Lip GYH. Thromb Haemost 2010; 103: and Eur Heart J 2010;31:1311 8

40 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence Consequences 4- PCI (with stents) PCI and antithrombotic treatment 5- Overview of published anticoagulated or AF patients undergoing PCI 6- Guidelines

41 Per cent Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events (GRACE): Is it safe and effective to use just one antiplatelet agent? Geographical variation in combination regimen at discharge 100 Warfarin/dual antiplatelet (n = 580) Warfarin/single antiplatelete (n = 220) Australia/New Zealand/Canada Europe Argentina/Brazil Four-way p-value < USA Retrospective analysis, 800 patients with an ACS with coronary stenting (130 patients received a drug-eluting stent) Discharge on warfarin and either dual (n = 580) or single (n = 220) antiplatelet therapy Nguyen MC. Eur Heart J 2007; 28:

42 Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events (GRACE): Is it safe and effective to use just one antiplatelet agent? 6-months outcomes, among the cohort who received a drug-eluting stent Combination discharge therapy Warfarin /dual antiplatelet Warfarin/single antiplatelet P value Six-month outcomes n (%) n = 102 n = 28 Death 5/67 (7.5) 3/25 (12) 0.67 Stroke 0/62 (0) 0/21 (0) - Unscheduled PCI 14/62 (23) 3/22 (14) 0.54 Myocardial infarction 2/63 (3.2) 0/23 (0) 1.0 Nguyen MC. Eur Heart J 2007; 28:

43 Recommended antithrombotic strategies following coronary artery stenting in patients with AF at moderate-to-high thromboembolic risk (in whom oral anticoagulation therapy is required). Expert consensus recommendations of a practical, pragmatic approach to management of patients with AF who need anticoagulation with Vitamin K antagonists Summary of the published clinical, procedural and outcome information on anticoagulated patients or AF patients undergoing PCI Report on PCI in anticoagulated patients (n=18 publications) Percent of patients Number of studies reporting data Patients on OAC Patients with AF ACS Radial access 20 7 Femoral access 80 7 Closure device 31 4 GPI inhibitor Stent Drug-eluting stent (DES) Lip GYH. Thromb Haemost 2010; 103: and Eur Heart J 2010;31:1311 8

44 Recommended antithrombotic strategies following coronary artery stenting in patients with AF at moderate-to-high thromboembolic risk (in whom oral anticoagulation therapy is required). Summary of the published clinical, procedural and outcome information on anticoagulated patients or AF patients undergoing PCI. Report on PCI in anticoagulated patients (n=18 publications) % of patients Number of studies with an event reporting data Death 12 9 Major bleed 6 13 Stent thrombosis 2 10 Stroke 4 8 MI 7 9 Lip GYH. Thromb Haemost 2010; 103: and Eur Heart J 2010;31:1311 8

45 1- Pathophysiology 2- Atrial Fibrillation Thrombogenesis Prevention (OAC / APA) 3- Thrombogenesis in AF complicating ACS Prevalence Consequences 4- PCI (with stents) PCI and antithrombotic treatment 5- Overview of published anticoagulated or AF patients undergoing PCI 6- Guidelines

46 Recommended antithrombotic strategies following coronary artery stenting in patients with AF at moderate-to-high thromboembolic risk (in whom oral anticoagulation therapy is required). Expert consensus recommendations of a practical, pragmatic approach to management of patients with AF who need anticoagulation with Vitamin K antagonists Haemorrahage risk Clinical setting Stent implanted Recommendations Elective Bare metal 1 month. Triple therapy of WF (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d + gastric protection Lifelong. WF (INR ) alone. Low or intermediate Elective Drug eluting 3 (olimus group) to 6 (paclitaxel) months. Triple therapy of WF (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d Up to 12 th month. Combination of WF (INR ) + clopidogrel 75 mg/d* (or aspirin 100 mg/d). Lifelong. WF (INR ) alone. * warfarin (INR ) + aspirin = 100 mg/day (with PPI, if indicated) considered as an alternative. Lip GYH. Thromb Haemost 2010; 103: and Eur Heart J 2010;31:1311 8

47 Recommended antithrombotic strategies following coronary artery stenting in patients with AF at moderate-to-high thromboembolic risk (in whom oral anticoagulation therapy is required). Expert consensus recommendations of a practical, pragmatic approach to management of patients with AF who need anticoagulation with Vitamin K antagonists Haemorrahage risk Low or intermediate Clinical setting Elective Elective Stent implanted Bare metal Drug eluting Recommendations * warfarin (INR ) + aspirin = 100 mg/day (with PPI, if indicated) considered as an alternative. Lip GYH. Thromb Haemost 2010; 103: and Eur Heart J 2010;31: month. Triple therapy of WF (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d + gastric protection Lifelong. WF (INR ) alone. 3 (olimus group) to 6 (paclitaxel) months. Triple therapy of WF (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d Up to 12 th month. Combination of WF (INR ) + clopidogrel 75 mg/d* (or aspirin 100 mg/d). Lifelong. WF (INR ) alone.

48 Recommended antithrombotic strategies following coronary artery stenting in patients with AF at moderate-to-high thromboembolic risk (in whom oral anticoagulation therapy is required). Expert consensus recommendations of a practical, pragmatic approach to management of patients with AF who need anticoagulation with Vitamin K antagonists Haemorrahage risk Clinical setting Stent implanted Recommendations Low or intermediate ACS Bare metal/drug eluting 6 months. Triple therapy of WF (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d Up to 12 th month. Combination of WF (INR ) + clopidogrel 75 mg/d* (or aspirin 100 mg/d). Lifelong. Warfarin (INR ) alone. * warfarin (INR ) + aspirin = 100 mg/day (with PPI, if indicated) considered as an alternative. Lip GYH. Thromb Haemost 2010; 103: and Eur Heart J 2010;31:1311 8

49 Recommended antithrombotic strategies following coronary artery stenting in patients with AF at moderate-to-high thromboembolic risk (in whom oral anticoagulation therapy is required). Expert consensus recommendations of a practical, pragmatic approach to management of patients with AF who need anticoagulation with Vitamin K antagonists Haemorrahage risk Clinical setting Stent implanted Recommendations High Elective ACS Bare metal** Bare metal** 2 to 4 weeks. Triple therapy of warfarin (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d. Lifelong. Warfarin (INR ) alone. 4 weeks. Triple therapy of WF (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d. Up to 12 th month. Combination of warfarin (INR ) + clopidogrel 75 mg/d* (or aspirin 100 mg/d). Lifelong. Warfarin (INR ) alone. *Combination of warfarin (INR ) + aspirin = 100 mg/d (with PPI, if indicated) may be considered as an alternative. Lip GYH. Thromb Haemost 2010; 103: ** drug eluting stents should be avoided. and Eur Heart J 2010;31:1311 8

50 Recommended antithrombotic strategies following coronary artery stenting in patients with AF at moderate-to-high thromboembolic risk (in whom oral anticoagulation therapy is required). Expert consensus recommendations of a practical, pragmatic approach to management of patients with AF who need anticoagulation with Vitamin K antagonists Haemorrahag e risk Clinical setting Stent implanted Recommendations Elective Bare metal** 2 to 4 weeks. Triple therapy of warfarin (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d. Lifelong. Warfarin (INR ) alone. High ACS Bare metal** 4 weeks. Triple therapy of WF (INR ) + aspirin 100 mg/d + clopidogrel 75 mg/d. Up to 12 th month. Combination of warfarin (INR ) + clopidogrel 75 mg/d* (or aspirin 100 mg/d). Lifelong. Warfarin (INR ) alone. *Combination of warfarin (INR ) + aspirin = 100 mg/d (with PPI, if indicated) may be considered as an alternative. Lip GYH. Thromb Haemost 2010; 103: ** drug eluting stents should be avoided. and Eur Heart J 2010;31:1311 8

51 Atrial fibrillation + coronary artery stent High Risk of Stroke (CHADS 2 >1) Yes High Risk of Bleeding? No Yes No Dual APA Tt Triple Therapy Paikin JS. Circulation 2010;121;

52 Conclusion 1- Thrombogenesis Atrial Fibrillation (fibrin rich) : peripheral thromboembolism ACS (platelet activation) : coronary thrombus, MACE CAD (stent) : early (< 30 days) thrombosis, MACE Atrial Fibrillation in ACS : increased morbi-mortality 2- Prevention Atrial Fibrillation : OAC >> APA (bleeding risk) ACS/PCI : APA (dual) >> OAC (bleeding risk) Risk stratification : balance thromboembolism vs. Bleeding 3- Clinical factors associated with bleeding or thrombotic events PCI in the setting of ACS, use of a GPI, no use of OAC, use of DES, femoral access site, use of a closure device for femoral access patients 4- Guidelines (ESC, 2010) In elective PCI, DES should be avoided Triple therapy : variable durations 1-6M, (CAD/ACS, type of stent) > 1 year post ACS/stent : OAC alone 5- Areas of investigation (AFCAS, ISAR-TRIPLE, WOEST studies )

53 WOEST trial 496 patients on OAC undergoing stent (DES/BMS) implantation randomization oral anticoagulants* oral anticoagulants* + + clopidogrel 75 mg qd** clopidogrel 75 mg qd** + aspirin 80 mg qd Follow-up: Primary endpoint: Secondary endpoint: 1 year bleeding ischemic events * INR as originally indicated ** BMS 1 month DES 1 year Dewilde,W. Am Heart J 2009;158:713-8