1. Title1 COMPREHENSIVE META-ANALYSIS ON ORAL ANTICOAGULANTS FOR THE SECONDARY PREVENTION OF CORONARY ARTERY DISEASE INCLUDING MORE THAN 50,000 PATIENTS Giuseppe Biondi-Zoccai, Antonio Abbate,* Marzia Lotrionte, † Davide Castagno, Claudio Moretti, Filippo Sciuto, Pierluigi Omedè, Gian Paolo Trevi, Imad Sheiban 1 University of Turin, Turin, Italy (gbiondizoccai@gmail.com); *Virginia Commonwealth University, Richmond, VA; † Catholic University, Rome, Italy

2. Title>Background2 BACKGROUND Recurrent events remain frequent among patients with coronary artery disease (CAD), despite current aggressive antithrombotic therapies, which may include antiplatelet and/or anticoagulants agents. Several trials have appraised the role of oral anticoagulants (in particular phenprocoumon and warfarin) in the secondary prevention of CAD, but with inconclusive results.

3. Title>Background>Aim3 AIM OF OUR WORK We performed a comprehensive systematic review and meta-analysis on the topic within the context of The Cochrane Collaboration. Our goal was to assess the efficacy and safety of long-term oral anticoagulant treatment in patients with established CAD, ie in the setting of secondary prevention.

4. METHODS: SEARCH STRATEGY Potentially eligible studies were searched systematically using BioMedCentral, CHID, CINHAL, The Cochrane CENTRAL register of controlled trials (CENTRAL), PubMed, metaRegister, pre-MEDLINE, and SciMed, without language restrictions. International experts and pharmaceutical firms were asked regarding uncompleted, unpublished or overlooked studies. Searches were last updated on March 2008. Title>Background>Aim>Methods4

5. METHODS: SELECTION CRITERIA Inclusion criteria were: 1) enrolment of patients with an established diagnosis of coronary heart disease, 2) randomized allocation, 3) intention-to- treat analysis, 4) treatment with oral anticoagulants for at least 4 weeks, and 5) follow- up of at least 4 weeks. Exclusion criteria were: 1) equivocal allocation, and 2) incomplete (less than 80%) follow-up within any allocation group (ie losses to pre-specified clinical follow-up 20% or more in any of the study arms). Title>Background>Aim>Methods5

6. 6 METHODS: END-POINTS The primary end-point was the composite of death from all causes, non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes were: –death (from all causes/due to cardiovascular disease), –myocardial infarction, –stroke (total/unspecified/ischemic/hemorrhagic), –repeat hospitalization for angina, –target coronary lesion revascularization. The following adverse events were also adjudicated: –bleedings (total/fatal/intracranial/major/minor/unspecified bleeding), –treatment discontinuation. Title>Background>Aim>Methods6

7. 7 METHODS: COMPARISONS AND DATA ANALYSES The comparisons of interest were: –oral anticoagulants versus placebo (in the absence of other antithrombotic drugs), –oral anticoagulants alone versus antiplatelet treatment, –oral anticoagulants plus antiplatelet treatment versus oral anticoagulants alone, –oral anticoagulants plus antiplatelet treatment versus antiplatelet treatment alone, –head-to-head comparisons of different oral anticoagulants. Odds ratios (OR) were computed at the longest available person-years of follow-up. Heterogeneity analysis was performed using a Cochran Q test. Title>Background>Aim>Methods7

8. REVIEW PROFILE Title>Background>Aim>Methods>Results8

9. 9 OVERALL RESULTS A total of 61 randomized controlled trials were retrieved, including 57,983 patients. Sample size was highly variable, ranging from 50 to 8803 patients, with a median of 284. Most studies focused on the secondary prevention following myocardial infarction (31 trials including 42576 patients), or recent unstable coronary artery disease (11 trials including 5437 patients). Other common topics were secondary prevention following coronary artery bypass grafting (11 trials including 4365) or percutaneous coronary intervention (8 trials including 4816 patients). Title>Background>Aim>Methods>Results9

10. 10 OVERALL RESULTS Treatment regimens were also highly variable, with several types of oral anticoagulants, intensity of anticoagulation, duration of treatment and control therapy. Oral anti-vitamin K agents were used in all studies but 2. Earlier studies employed more frequently high intensity regimens (target INR equivalent>3.0) in comparison to no antithrombotic therapy, whereas recent studies compared moderate intensity regimens based on warfarin (INR 2.0-3.0) plus aspirin versus aspirin alone. In no instance oral anticoagulants plus aspirin was compared to dual antiplatelet therapy (the current standard of care following acute coronary syndromes) Title>Background>Aim>Methods>Results10

11. 11 EXCERPT OF INCLUDED STUDIES Title>Background>Aim>Methods>Results11 StudyMethodsParticipantsInterventionsOutcomes Allocation concealment AFTER 1996 Randomized, open, multicenter Patients with recent acute myocardial infarction Warfarin (target INR 2.0- 2.5) vs aspirin 150 mg/d for 3 months Death, myocardial infarction, stroke and bleeding at 3 months B APRICOT 1993 Randomized, double-blind multicenter Patients with recent myocardial infarction (randomization before discharge) Warfarin (target INR 2.8- 4.0) vs aspirin 325 mg/d vs placebo for 3 months Death, myocardial infarction and bleeding at 3 months A APRICOT-2 2002 Randomized, open, multicenter Patients with recent acute myocardial infarction Warfarin (target INR 2.0- 3.0) plus aspirin 80 mg/d vs aspirin 80 mg/d for 3 months Death, myocardial infarction and bleeding at 3 months A ASPECT 1994 Randomized, double-blind, multicenter Patients with recent acute myocardial infarction Nicoumalone or phenprocoumon (target INR 2.8-4.8) vs placebo for a mean of 37 months (range 6-76) Death, myocardial infarction, stroke and bleeding at 37 months B ASPECT-2 2002 Randomized, open, multicenter Patients with recent myocardial infarction or unstable angina Phenprocoumon or acenocoumarol (target INR 3.0-4.0) vs phenprocoumon or acenocoumarol (target INR 2.0-2.5) plus aspirin 80 mg/d vs aspirin 80 mg/d for 12 months Death, myocardial infarction, stroke and bleeding at 12 months B Aspenstroem 1964 Randomized, double-blind, single center Patients with stable or unstable coronary heart disease Dicumarol (target INR equivalent>3.0) vs placebo for 47 months Death, myocardial infarction, stroke and bleeding at 47 months B ………………

12. 12 EXCERPT FROM FOREST PLOTS: PRIMARY END-POINT Title>Background>Aim>Methods>Results12 Study Oral anticoagulants Control Rx OR (random) or sub-category n/N 95% CI Borchgrevink 1960 1/103 9/100 0.10 [0.01, 0.80] Harvald 1961 64/145 78/171 0.94 [0.60, 1.47] Aspenstroem 1964 46/118 71/113 0.38 [0.22, 0.64] Conrad 1964 14/52 9/34 1.02 [0.38, 2.72] MRC 1964 66/195 122/188 0.28 [0.18, 0.42] Loeliger 1967 10/128 23/112 0.33 [0.15, 0.72] Lovell 1967 39/172 46/178 0.84 [0.52, 1.37] MRC 1969 192/712 240/715 0.73 [0.58, 0.92] Meuwissen 1969 6/68 8/70 0.75 [0.25, 2.29] Sorensen 1969 33/156 49/120 0.39 [0.23, 0.66] VA 1969 153/385 149/350 0.89 [0.66, 1.19] Drapkin 1972 212/745 286/782 0.69 [0.56, 0.86] Breddin 1980 45/320 85/626 1.04 [0.71, 1.54] Sixty Plus 1980 93/439 154/439 0.50 [0.37, 0.67] EPSIM 1982 90/652 107/651 0.81 [0.60, 1.10] McEnany 1982 2/68 6/148 0.72 [0.14, 3.65] Rothlin 1985 3/83 0/83 7.26 [0.37, 142.80] Williams 1986 3/51 7/51 0.39 [0.10, 1.61] WARIS 1990 196/607 291/607 0.52 [0.41, 0.65] Weber 1990 20/113 27/122 0.76 [0.40, 1.44] CABADAS 1993 30/307 73/605 0.79 [0.50, 1.24] ASPECT 1994 319/1700 487/1704 0.58 [0.49, 0.68] IPO-V2 1994 183/2016 255/1970 0.67 [0.55, 0.82] AFTER 1996 75/517 67/519 1.14 [0.80, 1.63] ISAR 1996 13/260 4/257 3.33 [1.07, 10.35] CARS 1997 532/5410 308/3393 1.09 [0.94, 1.27] Post CABG 1997 169/674 234/677 0.63 [0.50, 0.80] OASIS Pilot 1 1998 10/155 4/154 2.59 [0.79, 8.43] OASIS Pilot 2 1998 5/98 13/99 0.36 [0.12, 1.04] STARS 1998 12/550 21/1103 1.15 [0.56, 2.35] BAAS 2001 23/530 30/528 0.75 [0.43, 1.31] OASIS 2001 140/1848 155/1864 0.90 [0.71, 1.15] ASPECT-2 2002 33/657 31/336 0.52 [0.31, 0.87] CHAMP 2002 859/2522 860/2537 1.01 [0.90, 1.13] WARIS-2 2002 424/2424 245/1206 0.83 [0.70, 0.99] ESTEEM 2003 89/1245 68/638 0.65 [0.46, 0.90] LoWASA 2004 466/1649 473/1641 0.97 [0.84, 1.13] HELAS 2006 14/54 11/61 1.59 [0.65, 3.88] Total (95% CI)27928 24952 0.74 [0.65, 0.83] Total events: 4684 (Oral anticoagulants), 5106 (Control Rx) Test for heterogeneity: Chi² = 165.32, df = 37 (P < 0.00001), I² = 77.6% Test for overall effect: Z = 5.04 (P < 0.00001) 0.1 0.2 0.5 1 2 5 10 Favors anticoagulant Favors control

13. 13 OVERALL RESULTS Follow-up was also highly variable, ranging from 1 to 88 months, with a median of 12 months. Meta-analytic pooling, after a median follow-up of 12 months, showed that oral anticoagulants significantly reduced the risk of death, myocardial infarction or stroke in comparison to control therapy (OR=0.74 [0.65-0.83], p<0.001), as well as death from all causes (p<0.001), myocardial infarction (p<0.001), and stroke (p<0.001), despite an increase in major (p<0.001) and minor bleedings (p<0.001). Title>Background>Aim>Methods>Results13

14. 14 SUBGROUPS RESULTS Stratification for control therapy showed that benefits were maintained when anticoagulants were compared to placebo or standard therapy without any antithrombotic medication (OR for primary end- point=0.60 [0.52-0.70], p=0.05), despite significant increases in bleeding rates (OR=4.68 [3.71-5.89], p<0.001). Conversely, significant benefits occurred when comparing oral anticoagulants versus oral antiplatelet agents alone only in terms of reduction of stroke risk (OR for primary end-point=0.87 [0.76-1.01], p=0.07, OR for stroke=0.71 [0.60-0.84, p<0.001, OR for major bleeding=1.93 [1.64-2.27], p<0.001). Title>Background>Aim>Methods>Results14

15. 15 SUBGROUPS RESULTS Specifically, moderate-intensity anticoagulation (ie based on an International Normalized Ratio [INR] target between 2.0 and 3.0) appeared critical to minimize bleeding risk and maximize antithrombotic effects: –OR for primary end-point=0.71 (0.53-0.94), p=0.02, –OR for stroke=0.75 (0.54-1.04), p=0.08, –OR for major bleeding=2.79 (2.12-3.68), p<0.001. Title>Background>Aim>Methods>Results15

16. OA vs any control - overall analysis OA vs placebo - overall analysis OA vs antiplatelet Rx - overall analysis OA plus antiplatelet Rx vs antiplatelet Rx alone OA plus antiplatelet therapy vs OA alone OA at high vs low dosage OA vs any control - low risk of bias OA vs any control - moderate risk of bias OA vs any control - high risk of bias OA vs any control – ACS only OA vs any control - INR<2 OA vs any control - INR 2-3 OA vs any control - INR >3 OA better OA worse ODDS RATIOS FOR PRIMARY END-POINT 16Title>Background>Aim>Methods>Results16

17. OA better OA worse OA vs any control - overall analysis OA vs placebo - overall analysis OA vs antiplatelet therapy - overall analysis OA plus antiplatelet therapy vs antiplatelet therapy alone OA plus antiplatelet therapy vs OA alone OA at high vs low dosage OA vs any control - ACS OA vs any control - INR<2 OA vs any control - INR 2-3 OA vs any control - INR >3 ODDS RATIOS FOR DEATH 1,000 Title>Background>Aim>Methods>Results17

18. OA better OA worse OA vs any control - overall analysis OA vs placebo - overall analysis OA vs antiplatelet therapy - overall analysis OA plus antiplatelet therapy vs antiplatelet therapy alone OA plus antiplatelet therapy vs OA alone OA at high vs low dosage OA vs any control - ACS OA vs any control - INR<2 OA vs any control - INR 2-3 OA vs any control - INR >3 ODDS RATIOS FOR STROKE Title>Background>Aim>Methods>Results18

19. OA better OA worse OA vs any control - overall analysis OA vs placebo - overall analysis OA vs antiplatelet therapy - overall analysis OA plus antiplatelet therapy vs antiplatelet therapy alone OA plus antiplatelet therapy vs OA alone OA at high vs low dosage OA vs any control - ACS OA vs any control - INR<2 OA vs any control - INR 2-3 OA vs any control - INR >3 ODDS RATIOS FOR MAJOR BLEEDING Title>Background>Aim>Methods>Results19

20. 20 CONCLUSIONS Title>Background>Aim>Methods>Results>Conclusions20

21. 21 CONCLUSIONS Oral anticoagulants significantly prevent adverse events in patients with established CAD in comparison to standard therapy without any antithrombotic medication. Title>Background>Aim>Methods>Results>Conclusions21

22. 22 CONCLUSIONS Oral anticoagulants significantly prevent adverse events in patients with established CAD in comparison to standard therapy without any antithrombotic medication. Comparisons of oral antiplatelet agents versus oral anticoagulants alone or oral anticoagulants plus oral antiplatelet agents showed conversely that oral anticoagulant therapy can achieve a favorable risk-benefit balance only when subjects with low bleeding risk are selected and INR is maintained between 2.0 and 3.0. Title>Background>Aim>Methods>Results>Conclusions22

23. Thanks for your attention! For further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html

24. EXTRA SLIDES

25. 25 OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides25 StudyMethodsParticipantsInterventionsOutcomesAllocation concealment ATACS 1994 Randomized, open, multicenter Patients with recent myocardial infarction or unstable angina Warfarin (target INR 2.0- 3.0) plus aspirin 162.5 mg/d vs aspirin 162.5 mg/d for 12 weeks Death, myocardial infarction and bleeding at 3 months B ATACS Pilot 1990 Randomized, open, multicenter Patients with recent myocardial infarction or unstable angina Warfarin (target INR 3.0- 4.5) vs warfarin (target INR 3.0-4.5) plus aspirin 80 mg/d vs aspirin 325 mg/d for 12 weeks Death, myocardial infarction and bleeding at 3 months B BAAS 2001 Randomized, open, single center Patients with stable or unstable coronary syndromes referred for percutaneous transluminal coronary angioplasty (PTCA) Warfarin (target INR 2.1- 4.8) plus aspirin 100 mg/d vs aspirin for 12 months Composite of death, myocardial infarction, revascularization, or stroke at 12 months B Borchgrevink 1960 Randomized, open, multicenter Patients with stable angina pectoris or recent myocardial infarction Dicoumarol, phenindione, or warfarin (target INR equivalent>3.0) vs standard therapy for 12 months Death, myocardial infarction and bleeding at 12 months B Borchgrevink 1968 Randomized, open, multicenter Patients with recent acute myocardial infarction Dicoumarol, phenindione, or warfarin (target INR equivalent>3.0) vs standard therapy for 12 months Death, myocardial infarction and bleeding at 12 months D Breddin 1980Randomized, double-blind, multicenter Patients with recent myocardial infarction (randomization before discharge) Phenprocoumon (target INR equivalent>3.0) vs aspirin 1500 mg/d vs placebo for 24 months Death, myocardial infarction, stroke and bleeding at 24 months B

26. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment CABADAS 1993 Randomized, open, multicenter Patients undergoing coronary artery bypass grafting (CABG) for stable coronary disease (randomization before CABG) Acenocoumarol or phenprocoumon (target INR 2.8-4.8) vs aspirin 50 mg/d vs aspirin 50 mg/d plus dipyridamolo 400 mg/d for 12 months Death, myocardial infarction, stroke and bleeding at 12 months A CARS 1997 Randomized, double-blind, multicenter Patients with recent acute myocardial infarction Warfarin 3 mg/d (median INR 1.5 [25-75% range 1.2- 2.1]) plus aspirin 80 mg/d vs warfarin 1 mg/d (median INR 1.3 [25-75% range 1.1- 1.6]) plus aspirin 80 mg/d vs aspirin 160 mg/d for 14 months Death, myocardial infarction and bleeding at 14 months A CHAMP 2002 Randomized, open, multicenter Patients with recent myocardial infarction Warfarin (target INR 1.5- 2.5) plus aspirin 81 mg/d vs aspirin 162 mg/d for 2.7 years Death, myocardial infarction, stroke and bleeding at 32 months A Clausen 1961 Randomized, open, multicenter Patients with recent myocardial infarction (randomization before discharge) Dicoumarol, phenindione, or warfarin (target INR equivalent>3.0) vs standard therapy for 12 months Death, myocardial infarction and bleeding at 12 months B Conrad 1964 Randomized, double-blind, single center Death, myocardial infarction and bleeding at 60 months Phenprocoumon (target INR equivalent>3.0) vs placebo for 60 months Patients with recent myocardial infarction A Drapkin 1972Randomized, double-blind, single center Patients with recent myocardial infarction (randomization before discharge) Phenidione, warfarin or dicumarol (target INR equivalent>3.0) vs standard therapy for 48 months Death, myocardial infarction, stroke and bleeding at 48 months A OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides26

27. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment EPSIM 1982 Randomized, open, multicenter Patients with recent myocardial infarction Acenocoumarol or other oral anticoagulants (target INR equivalent 2.0-3.0) vs aspirin 1500 mg/d for 29 months Death, myocardial infarction, stroke and bleeding at 29 months A Eritsland 1996 Randomized, open, single center Patients with recent non- ST-elevation acute coronary syndromes and recent coronary artery bypass grafting Warfarin (target INR 2.4- 4.2) vs aspirin 300 mg/d for 12 months Death and bleeding at 12 months B ESTEEM 2003 Randomized, double-blind, multicenter Patients with recent myocardial infarction Ximelagatran 24-60 mg/d plus aspirin 160 mg/d vs aspirin 160 mg/d for 6 months Death, myocardial infarction, stroke and bleeding at 6 months B FANTASTIC 1998 Randomized, open, multicenter Patients undergoing successful percutaneous transluminal coronary angioplasty (PTCA) with stent implantation for stable or unstable coronary syndromes (randomization before PCI) Warfarin (target INR 2.5- 3.0) plus aspirin 100-325 mg/d vs aspirin 100-325 mg/d plus ticlopidine 500 mg/d for 1.5 months Death, myocardial infarction and bleeding at 6 months A Garachemani 2002Randomized, open, single center Patients undergoing successful percutaneous transluminal coronary angioplasty for stable or unstable coronary syndromes (randomization after PTCA) Warfarin (target INR 2.5- 4.0) plus aspirin 100 mg/d vs aspirin 100 mg/d for 6 months Death, myocardial infarction, stroke and bleeding at 6 months B OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides27

28. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment Gohlke 1981 Randomized, open, single center Patients undergoing coronary artery bypass grafting (CABG) for stable or unstable coronary syndromes (randomization before CABG) Phenprocoumon (target INR equivalent >3.0) vs standard treatment for 2 months Bleeding at 2 monthsB Harvald 1961 Randomized, open, multicenter Patients with recent myocardial infarction (randomization before discharge) Dicoumarol, phenindione, or warfarin (target INR equivalent>3.0) vs standard therapy for 36 months Death, myocardial infarction and bleeding at 36 months B HELAS 2006 Randomized, double-blind, multicenter Patients with heart failure and prior myocardial infarction Warfarin (target INR 2.0- 3.0) vs aspirin 325 mg/d Death, myocardial infarction, stroke and bleeding at 24 months A Huynh 2001 Randomized, double-blind, multicenter Patients with recent non- ST-elevation acute coronary syndromes and previous coronary artery bypass grafting Warfarin (target INR 2.0- 2.5) plus placebo vs aspirin 80 mg/d plus placebo vs warfarin plus aspirin 80 mg/d for 12 months Death, myocardial infarction and bleeding at 12 months B IPO-V2 1994 Randomized, open, multicenter Patients with recent acute myocardial infarction Sulodexide (initially intramuscularly and then orally) vs standard therapy for 12 months Death, myocardial infarction and stroke at 12 months B ISAR 1996Randomized, open, single center Patients undergoing successful percutaneous coronary intervention (PCI) with stent implantation for stable or unstable coronary syndromes (randomization after PCI) Phenprocoumon (target INR 3.5-4.5) plus aspirin 200 mg/d vs ticlopidine 500 mg/d plus aspirin 200 mg/d for 1 month Death, myocardial infarction, stroke and bleeding at 1 month A OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides28

29. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment Kraska 1981 Randomized, open, single center Patients with recent myocardial infarction Dicoumarol (target INR equivalent>3.0) vs aspirin 325 mg/d for 6 months Death, myocardial infarction, stroke and bleeding at 6 months B Loeliger 1967 Randomized, double-blind, single center Male patients with prior myocardial infarction Pheprocoumon (target INR equivalent>3.0) vs placebo for 48 months Death, myocardial infarction, stroke and bleeding at 48 months B Lovell 1967 Randomized, open, single center Male patients with recent myocardial infarction (randomization before discharge) Pheprocoumon (target INR equivalent>3.0) vs phenprocoumon (target INR equivalent<2.0) for 36 months Death, myocardial infarction, stroke and bleeding at 36 months B LoWASA 2004 Randomized, open, multicenter Patients with recent myocardial infarction Warfarin 1.25 mg/d plus aspirin 75 mg/d vs aspirin 75 mg/d for 60 months Death, myocardial infarction, stroke and bleeding at 60 months A Machraoui 1999 Randomized, open, single center Patients undergoing successful percutaneous coronary intervention (PCI) with stent implantation for stable or unstable coronary syndromes (randomization after PCI) Warfarin (target INR 3.5- 4.5) plus aspirin 100 mg/d vs aspirin 100 mg/d for 3 months Death, myocardial infarction and bleeding at 3 months B MacMillan 1960Randomized, double-blind, single center Patients with recent myocardial infarction Dicoumarol at high dosage (target INR equivalent>3.0) vs dicoumarol at low dosage (target INR equivalent<2.0) for 12 months Death and myocardial infarction at 12 months B OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides29

30. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment MATTIS 1998 Randomized, open, multicenter Patients undergoing successful percutaneous coronary intervention (PCI) with stent implantation for stable or unstable coronary syndromes (randomization after PCI) Oral anticoagulants (agent not specified; target INR 2.5-3.0) plus aspirin 250 mg/d vs ticlopidine 500 mg/d plus aspirin 250 mg/d for 1 month Death, myocardial infarction and bleeding at 6 months A McEnany 1982 Randomized, double-blind, single center Patients undergoing coronary artery bypass grafting (CABG) with patent saphenous vein grafts stable or unstable coronary syndromes Warfarin (target INR equivalent 2.0-3.0) vs aspirin 600 mg/d vs placebo for 24 months Death, myocardial infarction, stroke and bleeding at 24 months B Meuwissen 1969 Randomized, double-blind, single center Patients with recent or prior myocardial infarction Phenprocoumon (target INR equivalent>3.0) vs placebo for 20 months Death, myocardial infarction, stroke and bleeding at 20 months C MRC 1964 Randomized, open, multicenter Patients with recent myocardial infarction Phenindione at moderate dosage (target INR equivalent 2.0-3.0) vs phenindione at low dosage (target INR equivalent<2.0) for 1 month Death, myocardial infarction, stroke and bleeding at 13 months A MRC 1969Randomized, open, multicenter Patients with recent myocardial infarction Phenindione at moderate dosage (target INR equivalent 2.0-3.0) vs phenindione at low dosage (target INR equivalent<2.0) for 1 month Death and stroke at 1 month A OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides30

31. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment OASIS 2001 Randomized, open, multicenter Patients with recent unstable angina Warfarin or dicoumarol (target INR 2.0-2.5) vs standard therapy (95% of both groups on aspirin) for 5 months Cardiovascular death, myocardial infarction, stroke and bleeding at 5 months A OASIS Pilot 1 1998 Randomized, open, multicenter Patients with recent non- ST-elevation acute coronary syndromes Warfarin 3 mg/d (INR 1.5+- 0.6) vs standard therapy (87% of both groups on aspirin) for 6 months Cardiovascular death, myocardial infarction, stroke and bleeding at 6 months B OASIS Pilot 2 1998 Randomized, open, multicenter Patients with recent non- ST-elevation acute coronary syndromes Warfarin (target INR 2.0- 2.5) vs standard therapy (87% of both groups on aspirin) for 3 months Cardiovascular death, myocardial infarction, stroke and bleeding at 3 months B Pantely 1979 Randomized, open, single center Patients undergoing coronary artery bypass grafting (CABG) with patent saphenous vein grafts stable or unstable coronary syndromes Warfarin (target INR equivalent >3.0) vs aspirin 975 mg/d plus dipyridamole 225 mg/d vs standard therapy Death, stroke and bleeding at 6 months A Pfisterer 1989Randomized, open, single center Patients undergoing coronary artery bypass grafting (CABG) with patent saphenous vein grafts stable or unstable coronary syndromes Phenprocoumon (target INR 2.5-5.0) vs aspirin 50 mg/d plus dipyridamole 400 mg/d for at least 3 months Death, myocardial infarction and bleeding at 12 months A OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides31

32. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment Post CABG 1997 Randomized, double-blind, multicenter Patients with prior coronary artery bypass grafting (CABG) with patent saphenous vein grafts stable or unstable coronary syndromes (randomization after CABG) Warfarin (INR<2.0) vs placebo (77% of both groups on aspirin) for 4 years Death, myocardial infarction and stroke at 88 months A Rothlin 1985 Randomized, open, single center Death, myocardial infarction and bleeding at 3 months Acenocoumarol (target INR equivalent>3.0) vs ticlopidine 500 mg/d for 3 months Patients undergoing coronary artery bypass grafting (CABG) with patent saphenous vein grafts stable or unstable coronary syndromes B Seaman 1969 Randomized, open, single center Patients with recent or prior myocardial infarction Phenindione (target INR equivalent>3.0) vs placebo vs standard therapy Death at 84 monthsB Sixty Plus 1980 Randomized, double-blind, multicenter Patients over 60 years of age with prior myocardial infarction and already on treatment with oral anticoagulants Acenocoumarin or phenprocoumon (target INR 2.7-4.5) vs placebo for 24 months Death, myocardial infarction, stroke and bleeding at 24 months B Sorensen 1969Randomized, double-blind, single center Patients with recent myocardial infarction (randomization before discharge) Dicoumarol (target INR equivalent>3.0) vs placebo for 17 months Death, myocardial infarction, stroke and bleeding at 17 months C OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides32

33. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment STARS 1998 Open, multicenter, randomized 3-arm controlled Patients with successful percutaneous coronary intervention (PCI) with stent implantation for stable or unstable coronary syndromes Warfarin (target INR 2.0- 2.5) plus aspirin 325 mg daily versus aspirin 325 mg daily versus aspirin 325 mg daily plus ticlopidine 500 mg daily for 1 month Death, myocardial infarction, stroke and bleeding at 1 month B Urban 1988 Randomized, open, single center Patients undergoing successful percutaneous transluminal coronary angioplasty (PTCA) with stent implantation for stable or unstable coronary syndromes (randomization before PCI) Warfarin (target INR?2.5) vs standard therapy for 6 months Bleeding at 5 monthsB VA 1969 Randomized, open, multicenter Patients with recent myocardial infarction Byshydroxycoumarin (target INR equivalent 2.0- 3.0) vs standard therapy for 60 months Death, myocardial infarction, stroke and bleeding at 60 months B WARIS 1990 Randomized, double-blind, multicenter Patients with recent myocardial infarction (randomization before discharge) Warfarin (target INR 2.8- 4.8) vs placebo for 37 months Death, myocardial infarction, stroke and bleeding at 37 months A WARIS-2 2002Randomized, open, multicenter, 3-arm controlled trial Patients with recent acute myocardial infarction Warfarin (target INR 2.8- 4.2) versus aspirin 160 mg daily versus warfarin (target INR 2.0-2.5) plus aspirin 75 mg daily for at least 2 years Death, myocardial infarction, stroke and bleeding at 48 months A OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides33

34. StudyMethodsParticipantsInterventionsOutcomesAllocation concealment Wasserman 1966 Randomized, open, single center Patients with recent myocardial infarction (randomization before discharge) Warfarin (target INR equivalent>3.0) vs standard therapy for 12 months Death and bleeding at 12 months C Weber 1990 Randomized, open, multicenter Patients undergoing coronary artery bypass grafting (CABG) with patent saphenous vein grafts stable or unstable coronary syndromes Phenprocoumon (target INR equivalent 2.0-3.0) vs aspirin 100 mg/d for 2 months Death, myocardial infarction, stroke and bleeding at 3 months A Williams 1986 Randomized, open, single center Patients with recent unstable angina Warfarin (target INR equivalent 2.0-3.0) vs standard therapy for 6 months Death, myocardial infarction and stroke at 6 months B Williams 1997 Randomized, double-blind, single center Patients with recent myocardial infarction or unstable angina Warfarin (target INR 2.0- 2.5) plus aspirin 150 mg/d vs aspirin 150 mg/d for 2.5 months Death, myocardial infarction and bleeding at 3 months B Yli-Mayry 1992 Randomized, open, single center Patients undergoing coronary artery bypass grafting (CABG) Warfarin (target INR equivalent>3.0) vs dypyridamole 225 mg/d and aspirin 250 mg/d Death, myocardial infarction, stroke and bleeding at 3 months B Zibaeenezhad 2004Randomized, open, single center Patients with recent myocardial infarction (randomization before discharge) Warfarin (target INR 2.0- 3.0) plus aspirin 100 mg/d vs aspirin 100 mg/d for 12 months Death, myocardial infarction and bleeding at 12 months B OTHER INCLUDED STUDIES Title>Background>Aim>Methods>Results>Conclusions>Extra slides34

35. OTHER SUMMARY DATA Title>Background>Aim>Methods>Results>Conclusions>Extra slides35

36. OTHER SUMMARY DATA Title>Background>Aim>Methods>Results>Conclusions>Extra slides36

37. OTHER SUMMARY DATA Title>Background>Aim>Methods>Results>Conclusions>Extra slides37

38. OTHER SUMMARY DATA Title>Background>Aim>Methods>Results>Conclusions>Extra slides38

39. OTHER SUMMARY DATA Title>Background>Aim>Methods>Results>Conclusions>Extra slides39

40. 40 FURTHER FOREST PLOTS: DEATH Title>Background>Aim>Methods>Results40

41. 41Title>Background>Aim>Methods>Results41 FURTHER FOREST PLOTS: MI

42. 42Title>Background>Aim>Methods>Results42 FURTHER FOREST PLOTS: STROKE

43. 43Title>Background>Aim>Methods>Results43 FURTHER FOREST PLOTS: MAJOR BLEEDING