COMPREHENSIVE META-ANALYSIS ON ORAL ANTICOAGULANTS FOR THE SECONDARY PREVENTION OF CORONARY ARTERY DISEASE INCLUDING MOR

1. 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 1University ofTurin, Turin, Italy (gbiondizoccai@gmail.com); *Virginia Commonwealth University, Richmond, VA; †CatholicUniversity, Rome, Italy

2. 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. 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 • International experts and pharmaceutical firms were asked regarding uncompleted, unpublished or overlooked studies.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.

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).

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>Methods 6

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>Methods 7

8. REVIEW PROFILE

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>Results 9

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>Results 10

11. EXCERPT OF INCLUDED STUDIES Title>Background>Aim>Methods>Results 11

12. EXCERPT FROM FOREST PLOTS: PRIMARY END-POINT Study Oral anticoagulants Control Rx OR (random) OR (random) or sub-category n/N n/N 95% CI 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 Title>Background>Aim>Methods>Results 12

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>Results 13

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>Results 14

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>Results 15

16. ODDS RATIOS FOR PRIMARY END-POINT OA worse OA better Title>Background>Aim>Methods>Results 16

17. ODDS RATIOS FOR DEATH OA worse OA better 1,000 Title>Background>Aim>Methods>Results 17

18. ODDS RATIOS FOR STROKE OA worse OA better Title>Background>Aim>Methods>Results 18

19. ODDS RATIOS FOR MAJOR BLEEDING OA worse OA better Title>Background>Aim>Methods>Results 19

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

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>Conclusions 21

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>Conclusions 22

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24. EXTRA SLIDES

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

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

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

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