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COMPREHENSIVE META-ANALYSIS ON ORAL ANTICOAGULANTS FOR THE SECONDARY PREVENTION OF CORONARY ARTERY DISEASE INCLUDING MOR PowerPoint Presentation
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COMPREHENSIVE META-ANALYSIS ON ORAL ANTICOAGULANTS FOR THE SECONDARY PREVENTION OF CORONARY ARTERY DISEASE INCLUDING MORE THAN 50,000 PATIENTS.

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slide1

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

background
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.
aim of our work
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.
methods search strategy
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  • International experts and pharmaceutical firms were asked regarding uncompleted, unpublished or overlooked studies.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.
methods selection criteria
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).
methods end points
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

methods comparisons and data analyses
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

overall results
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

overall results1
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

excerpt of included studies
EXCERPT OF INCLUDED STUDIES

Title>Background>Aim>Methods>Results 11

excerpt from forest plots primary end point
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

overall results2
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

subgroups results
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

subgroups results1
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

slide16

ODDS RATIOS FOR PRIMARY END-POINT

OA worse

OA better

Title>Background>Aim>Methods>Results 16

slide17

ODDS RATIOS FOR DEATH

OA worse

OA better

1,000

Title>Background>Aim>Methods>Results 17

slide18

ODDS RATIOS FOR STROKE

OA worse

OA better

Title>Background>Aim>Methods>Results 18

slide19

ODDS RATIOS FOR MAJOR BLEEDING

OA worse

OA better

Title>Background>Aim>Methods>Results 19

conclusions
CONCLUSIONS

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

conclusions1
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

conclusions2
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

slide23

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

other included studies
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 25

other included studies1
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 26

other included studies2
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 27

other included studies3
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 28

other included studies4
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 29

other included studies5
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 30

other included studies6
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 31

other included studies7
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 32

other included studies8
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 33

other included studies9
OTHER INCLUDED STUDIES

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 34

other summary data
OTHER SUMMARY DATA

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 35

other summary data1
OTHER SUMMARY DATA

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 36

other summary data2
OTHER SUMMARY DATA

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 37

other summary data3
OTHER SUMMARY DATA

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 38

other summary data4
OTHER SUMMARY DATA

Title>Background>Aim>Methods>Results>Conclusions>Extra slides 39

further forest plots death
FURTHER FOREST PLOTS: DEATH

Title>Background>Aim>Methods>Results 40

further forest plots mi
FURTHER FOREST PLOTS: MI

Title>Background>Aim>Methods>Results 41

further forest plots stroke
FURTHER FOREST PLOTS: STROKE

Title>Background>Aim>Methods>Results 42

further forest plots major bleeding
FURTHER FOREST PLOTS: MAJOR BLEEDING

Title>Background>Aim>Methods>Results 43