Transcript BETing on the evidence

Guideline methodology
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Every topic is supported by a structured review
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Review is published as a ‘Best Evidence Topic‘ in the ICVTS
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A summary recommendation is given in the guideline
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Each recommendation is graded, based on the strength of
evidence to support that recommendation
2007 EACTS guidelines
Best Evidence Topics
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Follows a structured protocol
Answers a single narrowly phrased clinical question
Performed by Clinicians throughout Europe
Evidence supported by :
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Second author check
Information scientist search check
Journal Club evidence check
Web-based comments on ICVTS website
Then publication
2007 EACTS guidelines
2007 EACTS guidelines
2007 EACTS guidelines
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2007 EACTS guidelines
Perioperative management of anticoagulation
and anti-platelet therapy in cardiac surgery
Dose
of aspirin after coronary arterial bypass grafting
Timing
of aspirin after coronary arterial bypass grafting
Clopidogrel
for the optimisation of graft patency.
Clopidogrel
cessation prior to urgent coronary bypass
grafting.
2007 EACTS guidelines
Perioperative management of anticoagulation
and anti-platelet therapy in cardiac surgery
Anticoagulation
Warfarin
after mechanical valve replacement
after bioprosthetic valve replacement
Aspirin
in addition to warfarin for patients with a
mechanical valve replacement
Warfarin
and mitral valve repair
Anticoagulation
surgery
for patients with de novo AF after cardiac
2007 EACTS guidelines
Perioperative management of anticoagulation
and anti-platelet therapy in cardiac surgery
Aprotinin
to reduce perioperative bleeding
Aprotinin and stroke risk for cardiothoracic surgery
Tranexamic acid to reduce perioperative bleeding
Topical tranexamic acid to reduce perioperative bleeding
Protamine administration post cardiac surgery
Hepcon for minimisation of blood and blood product usage
Thromboelastography to guide blood and blood product
usage.
Recombinant Factor VIIa for intractable bleeding after
cardiac surgery
Low molecular weight heparin for deep vein thrombosis
prophylaxis
2007 EACTS guidelines
Dose of aspirin after CABG :
Recommendation
Aspirin should be given post-operatively to all patients without
contra-indications after coronary artery bypass grafting in order to
improve the long term patency of venous grafts.
The dose given should be 150-325mg.
(Grade A recommendation based on Level 1a and 1b studies)
There is no evidence to promote the use of aspirin after coronary
arterial bypass grafts to improve the patency of arterial grafts.
However aspirin may be recommended on the basis of improved
survival of patients in general who have atherosclerotic disease.
(Grade E recommendation based on expert consensus)
2007 EACTS guidelines
Dose of aspirin after CABG :
Evidence
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Fremes(1993) meta-analysis of 12 studies showing benefit of low or medium
dose aspirin over high dose aspirin
Veterans and antiplatelet trialists meta-analyses unable to differentiate between
doses of aspirin.
Mangano(2002) in 5065 CABG pts showed mortality benefit for aspirin, NNT 30
Lim(2003) comparative meta-analysis showed highest risk reduction with 300325mg compared to 75-150mg of aspirin (P=NS)
ACCP 6th consensus conference(2001) recommended 325mg of aspirin
ACCP 7th consensus conference(2004) recommended 75mg-162mg per day
(both graded as level 1a evidence)
ACC/AHA 2004 Dosing regimes from 100mg to 325mg seem efficacious
Dunning J, Das S. What is the optimal dose of aspirin after discharge following coronary
bypass surgery. ICVTS 2003;(4):427-30.
2007 EACTS guidelines
Timing of aspirin after CABG :
Recommendation
Aspirin should be commenced within 24 hours after
coronary artery bypass grafting.
(Grade A recommendation based on Level 1a and 1b studies)
There is a trend towards maximal benefit of aspirin the sooner it is
given post-operatively. Giving aspirin at 6 hours or when bleeding
has ceased may therefore be the optimal strategy.
(Grade B recommendation based on individual Level 1a and 1b
studies)
2007 EACTS guidelines
Timing of aspirin after CABG :
Evidence
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Fremes(1993) 12 study meta-analysis showed maximal risk reduction if aspirin
given <6hrs (p=NS)
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Gavaghan(1991) 237pts showed largest risk reduction with aspirin at 1hr but
increased re-operation rate
Sharma(1983) showed no benefit if aspirin started at 48hrs
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ACCP 7th consensus conference recommend aspirin at 6 hrs post-operatively
(grade 1a evidence).
ACC/AHA guidelines 2004 : Prospective controlled trials have demonstrated a
graft patency benefit when aspirin was started 1, 7, or 24 hours after operation
Musleh G, Dunning J. Does aspirin 6 h after coronary artery bypass grafting
optimise graft patency? ICVTS 2003;(4):413-5
2007 EACTS guidelines
Clopidogrel in addition to aspirin :
Recommendation 1
Clopidogrel (75mg) is an acceptable alternative to aspirin for the
optimisation of graft patency post coronary arterial bypass grafting.
(Grade B recommendation based on individual Level 1b studies)
The superiority of clopidogrel over aspirin for optimising graft
patency after coronary arterial bypass grafting has not yet been
established and thus aspirin should be regarded as the first drug of
choice.
(Grade B recommendation based on individual Level 1b studies)
2007 EACTS guidelines
Clopidogrel in addition to aspirin :
Recommendation 2
In patients having cardiac surgery for acute coronary syndrome,
clopidogrel should be considered for 9-12 months in addition to aspirin.
( Grade B recommendation based on sub-analyses of level 1b studies)
Clopidogrel may further improve the patency of saphenous vein grafts
when given in addition to aspirin, but this will be at the expense of an
increase in bleeding complications
(Grade B recommendation based on individual level 1a and 1b studies)
In patients having coronary bypass surgery with a coronary stent in
situ, clopidogrel should be continued if the stent has not been covered
by a graft.
( Grade E recommendation based on expert consensus)
2007 EACTS guidelines
Clopidogrel in addition to aspirin :
Evidence
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ACCP 7th consensus conference 2004 : Grade 1C recommendation
For patients who undergo CABG for non–ST segment elevation acute coronary
syndrome(ACS), Clopidogrel, 75 mg/d should be given for 9 to 12 months
following the procedure in addition to treatment with aspirin.
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CAPRIE ( Aspirin vs Clopidogrel 19,185pts) 1480 pts had CABG,
RRR 39% death, 38% MI.
 CURE ( Clopidogrel plus aspirin, 12,562pts) 2072pts had subsequent CABG,
11% RRR in MACE , 18% if CABG was same admission
 CREDO (Clopidogrel plus aspirin after PCI, 2116pts) 320 CABG - RRR 17%
 CASCADE(Clopidogrel After Surgery for Coronary Artery DiseasE) – 100pt RCT
Kunadian B, Babu N, Dunning J. Should High Risk Patients Receive Clopidogrel as well
as Aspirin post Coronary Arterial Bypass Grafting? ICVTS 2006 – web prepublication
Nagarajan DV, Lewis PS, Dunning J. Is clopidogrel beneficial following coronary bypass
surgery? ICVTS 2004;(2):311-3.2007 EACTS guidelines
Clopidogrel cessation pre-CABG:
Recommendation
Patients requiring urgent coronary arterial bypass grafting should
have their clopidogrel omitted for 5-7 days prior to their surgery if
their clinical condition allows.
The benefits in terms of the reduction in perioperative blood loss,
reduced risk of re-exploration and reduction of blood product usage
is at the expense of a 1% increase in the risk of MI while awaiting
surgery
(Grade B recommendation based on individual Level 1a and 1b
studies)
2007 EACTS guidelines
Clopidogrel cessation pre-CABG :
Evidence
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Purkayastha (2006) 11 study meta-analysis: Mean increase in blood loss of
323mls, a 6-fold increase in the odds of re-exploration, an increase in adverse
events and ventilation time,no difference in hospital length-of-stay or mortality
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PCI-CURE study(2001) 2,658pts having clopidogrel or placebo prior to PCI at day
6, 5.1% MI without clopidogrel , vs 3.6% with clopidogrel while waiting for PCI
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ACC/AHA guideline : stop clopidogrel 5-7 days prior to CABG (grade B)
ACCP guideline : stop clopidogrel 5-7 days prior to CABG (grade 2A)
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Kunadian B, Thornley AR, Tanos M, Dunning J. Should Clopidogrel be stopped prior to
urgent cardiac surgery? ICVTS 2006 web prepublication.
2007 EACTS guidelines
INR after mechanical valve replacement:
Recommendation
We recommend that European Cardiothoracic Surgeons follow the
guidelines provided by the European Society of Cardiology.
These guidelines are both up to date, detailed and will be kept up to
date by the European Society of Cardiology in the future.
2007 EACTS guidelines
Mechanical aortic
valve
ESC Guidelines
INR target 2.5
(Low risk valves : Medtronic
Hall, St Jude Medical
(without Silzone),
Carbomedics)
Mechanical aortic valve
with risk factors
Higher risk valve
types
INR Target
3.0 Low risk valve,
3.5 Medium risk valve,
4.0 High risk valve
Risk factors : AF, LA>50mm, Mitral valve
gradient, EF<35%, spontaneous echo
contrast, additional valve
replacements, hypercoagulability,
history of Thromboembolism
INR Target 3.0
(For medium risk valves Bileaflet
valves with insufficient data,
Bjork–Shiley valves.)
INR Target 3.5 ( for high risk
valves Lillehei Kaster,
Omniscience, Starr
Edwards)
AHA/ACC
guidelines
INR 2.0-3.0
INR 2.5-3.5
INR 2.5-3.5
(INR 2.5-3.5 for first 3
months)
Atrial fibrillation, LV
dysfunction, previous thromboembolism,
and hypercoagulable condition.
Aortic disk valves and StarrEdwards valves
ACCP
guidelines
INR 2.0-3.0
INR 2.5-3.5
INR 2.5-3.5
BSH guidelines
INR Target 2.5
Caged ball or caged disk valve
No additional guidance
(Bileaflet valves)
INR Target 3.0
(tilting disc)
INR Target 3.5
(Caged ball or caged disc)
SIGN guidelines
INR Target 3.0 (range
2.5-3.5)
No additional guidance
For second generation valves
such as St. Jude,
Medtronic, Monostrut
2007 EACTS guidelines
Target INR 3.5 (Range
3.0-4.5)
Starr-Edwards, Bjork Shiley
standard).
ESC Guidelines
Mechanical mitral
valve
Mechanical mitral
valve with risk
factors
INR target 3.0 (Low risk
INR Target 3.0 ( For low
valves : Medtronic Hall,
St Jude Medical (without
Silzone), Carbomedics)
AHA/ACC guidelines
INR 2.5-3.5
risk valves)
INR 2.5-3.5
Higher risk valve
types
INR Target 3.5 (For medium
risk valves Bileaflet valves
with insufficient data,
Bjork–Shiley valves.)
INR Target 4.0 ( for high risk
valves
INR 2.5-3.5
Atrial fibrillation, LV
dysfunction, previous
thromboembolism, and
hypercoagulable
condition.
ACCP guidelines
BSH guidelines
INR 2.5-3.5
INR 2.5-3.5
INR 2.5-3.5
(For tilting disc and bileaflet
valves)
AF, myocardial infarction, left
atrial enlargement,
endocardial damage,
systemic embolism and
low ejection fraction
Caged ball or caged disk valve
INR Target 3.0
No additional
guidance
INR Target 3.0
(Bileaflet valves)
(tilting disc)
INR Target 3.5 ( Caged ball
or caged disc)
SIGN guidelines
INR Target 3.0 (range
2.5-3.5) For second
No additional
guidance
generation valves such as
St. Jude,
Medtronic, Monostrut
2007 EACTS
Target INR 3.5 (Range
3.0-4.5)
Starr-Edwards, Bjork Shiley
standard).
guidelines
Warfarin after bioprosthesis:
Recommendation
Patients post-mitral bioprosthesis should have heparinisation
and warfarin for 3 months with an INR of 2-3.
For patients post-aortic bioprosthesis without additional risk
factors, antiplatelet therapy alone is adequate.
(Grade B recommendation based on Level 2b and 3b studies)
2007 EACTS guidelines
Warfarin after bioprosthesis :
Evidence
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ESC(2005) due to the absence of studies that demonstrate the safety of omitting
anticoagulation for 3-months post-bioprosthesis, warfarinisation with a target INR of 2.5 or
3.0 in higher risk patients should be given.
ACCP(2004) Bioprosthetic valves in the mitral position should receive warfarin for the first 3
months ( Grade 1C+) and also in the aortic position( grade 2C)
ACC/AHA (1998) warfarin is recommended although in several centres only aspirin is used.
SIGN(1999) 3 months of warfarin in the aortic position( grade C) and the mitral position
(grade A)
BSH (1998, 2005) warfarin in the aortic position is not required although many centres
anticoagulate for 3-6 months. Mitral bioprosthesis should receive warfarin for 3-6 months
(grade A)
Surveys in UK and USA show that 60% of surgeons do not anticoagulate aortic
bioprostheses
No primary studies show convincing evidence in favour of anticoagulating aortic valves.
El-Husseiny M, Salhiyyah K, Raja SG, Dunning J. Should warfarin be routinely prescribed for the
first three months after a biprosthetic valve replacement? ICVTS 2006 web prepublication
2007 EACTS guidelines
Aspirin in addition to warfarin for
mechanical valves: Recommendation
Low dose aspirin (80-100 mg daily) in addition to warfarin in
patients with prosthetic heart valves reduces all cause mortality
(NNT=19), with significant reductions in thromboembolism despite
an increase in bleeding.
(Grade A recommendation based on Level 1a and 1b studies)
2007 EACTS guidelines
Aspirin in addition to warfarin for
mechanical valves: Evidence
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11 trials found and 12 meta-analyses or guidelines
Massel (2001) meta-analysis of 11 studies 2428 patients.
significant reduction of all cause mortality from 9% to 5.2%
significant increase in major bleeding of 5.4% to 8.5%
ACC/AHA (1998) 80mg-100mg aspirin in addition to warfarin (Grade 2A)
ACCP(2004) patients who suffer systemic embolism despite warfarin
aspirin should be added ( Grade 1C)
ESC (2005) Aspirin in addition to warfarin only for patients with arterial
disease, systemic embolisation or stenting.
Nagarajan DV, Lewis PS, Botha P, Dunning J. Is addition of anti-platelet therapy to warfarin
beneficial to patients with prosthetic heart valves? ICVTS 2004;(3):450-5
2007 EACTS guidelines
Warfarin for mitral valve repair:
Recommendation
There is an absence of studies demonstrating the safety of omitting
warfarin for patients undergoing mitral valve repair.
In addition, due to higher atrial fibrillation and thromboembolic
episodes in the early postoperative period a period of 6 weeks to 3
months of anticoagulation may be regarded as current best practise.
(Grade C recommendation based on an absence of studies
demonstrating the safety of omission and level 2b and 3b studies )
2007 EACTS guidelines
Warfarin for mitral valve repair:
Evidence
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The European Society of Cardiology state that there are no randomized
controlled trials to support the safety of omitting warfarin after mitral repair.
They recommend 3 months of warfarin at a target INR of 2.5 or 3.0.
No other guidelines make recommendations
Vaughan UK survey – 64% of consultants use warfarin post-mitral valve repair
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Carpentier 29 year follow up series demonstrate very low rates of
thromboembolism ( Warfarin for 2 months)
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Jovin – of 181 patients post-repair who were discharged in sinus rhythm, 36%
had an episode of AF post discharge.
Asopa S, Patel A, Dunning J. Is short term anticoagulation necessary after mitral valve repair?
ICVTS 2006;Accepted for publication.
2007 EACTS guidelines
DVT prophylaxis for cardiac surgery:
Recommendation
The incidence of thromboembolism after cardiac surgery is similar to
the incidence in patients undergoing high risk general surgery.
(Grade B recommendation based on Level 2b studies)
The ACCP guidelines recommend heparin prophylaxis for this risk
group and we conclude that patients post-cardiac surgery should be
treated equivalently, with prophylaxis using heparin or LMWH
starting on the first post-operative day.
(Grade B recommendation based on Level 1b and 2b studies)
2007 EACTS guidelines
DVT prophylaxis for cardiac surgery:
Evidence
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Shammas(2000) review of 8 studies including over 18,000 patients post cardiac
surgery. Incidence of proximal DVT was 18%, PE 0.8%, 29 fatal PEs identified.
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Ramos(1996) PRCT of 2551 patients undergoing cardiac surgery using heparin
5000sc +/- TEDS. Incidence of PE was 3%
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Systematic reviews in many specialties demonstrate the efficacy of LMWH and
the safety with regard to bleeding complications
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Malouf et al – patients with immediate heparin and warfarinisation post surgery
had a 32% pericardial effusion rate with 12 delayed tamponades.
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Kulik(2006) systematic reviews of anticoagulation strategies- 4% bleed rate with
LMWH, 8% with full dose heparin.
Close V, Purohit M, Tanos M, Hunter S. Should patients post cardiac surgery be given low
molecular weight heparin for deep vein thrombosis prophylaxis? ICVTS 2006;In press
2007 EACTS guidelines
Aprotinin to reduce perioperative bleeding:
Recommendation
Aprotinin clearly reduces blood loss, requirement for blood
transfusion, and the risk of reoperation for bleeding, but probably
does increase the risk of saphenous vein graft occlusion.
(Grade A recommendation based on Level 1a and 1b studies)
2007 EACTS guidelines
Aprotinin to reduce perioperative bleeding:
Evidence
Odds ratio
(95% CI)
Study
% Weight
Alderman [3]
1.61 (1.07,2.41)
51.2
Havel [4]
0.67 (0.11,4.22)
3.8
Lemmer [5]
1.67 (0.68,4.10)
10.2
Lass [6]
0.80 (0.35,1.82)
17.1
Kalangos [7]
1.97 (0.18,21.99)
1.3
Bidstrup [8]
1.33 (0.35,5.06)
5.0
Van der Meer [9]
1.88 (0.88,4.03)
10.7
Laub [10]
11.00 (0.59,205.86)
Overall (95% CI)
1.52 (1.14,2.03)
.004858
1
0.6
205.864
Odds ratio
Kalkat M, Levine A, Dunning J. Does use of aprotinin in coronary artery bypass graft surgery
affect graft patency? ICVTS 2004;(1):124-8.
Ronald A, Dunning J. Does use of Aprotinin decrease the incidence of stroke and neurological
complications in adult patients undergoing Cardiac Surgery? ICVTS 2006 web pre-publication
2007 EACTS guidelines
Tranexamic acid to reduce perioperative
bleeding: Recommendation
Tranexamic acid reduces blood loss, requirement for blood
transfusion, and the risk of reoperation for bleeding
(Grade A recommendation based on Level 1b studies)
No study has yet looked directly at vein graft patency with
tranexamic acid, but equally no randomized studies have raised
concerns over its safety
(Grade B recommendation based on individual Level 1b studies)
2007 EACTS guidelines
Tranexamic acid to reduce perioperative
bleeding: Evidence
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10 PRCTs and one meta-analysis found
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5 PRCTS of Tranexamic acid versus placebo – 4/5 demonstrated
significant reductions in bleeding
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Casati 2001 (Aprotinin vs Tranexamic acid) 1040 primary elective CABG
patients. No difference in bleeding, re-operation for bleeding, transfusion
or outcome.
Thiagarajamurthy S, Levine A, Dunning J. Does prophylactic tranexamic acid safely reduce
bleeding without increasing thrombotic complications in patients undergoing cardiac surgery?
ICVTS 2004;(3):489-94
.
2007 EACTS guidelines
Topical Tranexamic acid to reduce
perioperative bleeding: Recommendation
Only 1 RCT exists to answer this question, which demonstrated
a clinically small benefit in favour of topical tranexamic acid in
low risk patients. Further RCTs should be performed prior to any
further use of topical tranexamic acid as a strategy to reduce
postoperative bleeding.
(Grade B recommendation based on a single Level 1b study)
2007 EACTS guidelines
Topical Tranexamic acid to reduce
perioperative bleeding: Evidence
De Bonis (2001) 40 patients undergoing CABG. 36% reduction in
bleeding at 2 hours, 25% at 24 hours.
NB new abstract presented at this meeting – to await full paper
Hanif M, Nourei SM, Dunning J. Does the use of topical tranexamic acid in cardiac surgery reduce
the incidence of post-operative mediastinal bleeding? ICVTS 2004;(4):603-5
2007 EACTS guidelines
Protamine post-cardiac surgery:
Recommendation
High doses of protamine can cause increased bleeding and impaired
platelet function, but these effects have never been demonstrated
below a ratio of 2.6:1 protamine to heparin.
(Grade B recommendation based on Level 1b and 2b studies)
2007 EACTS guidelines
Protamine post-cardiac surgery:
Evidence
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Carr (1994) and Moshizuki(1998) provide convincing evidence that at
protamine to heparin ratios above 5:1 cause platelet aggregation and
function does become impaired.
Moshizuki - levels above 2.6:1 the ACT significantly increases
Butterworth(2002)– protamine half life is 7 mins and is fully eliminated in
20-30 mins
Mclaughlin KE, Dunning J. In patients post cardiac surgery do high doses of protamine cause
increased bleeding? ICVTS 2003;(4):424-6
2007 EACTS guidelines
Hepcon to reduce blood product usage:
Recommendation
Hepcon monitoring is associated with higher heparin and lower
protamine doses and may decrease activation of the coagulation and
inflammatory cascades. Some studies have shown this may be
associated with decreased postoperative bleeding and blood
component therapy requirement. Larger trials are required to
investigate this further.
(Grade B recommendation based on Level 1b and 2b studies)
Aziz KAA, Masood O, Hoschtitzky A, Ronald A. Does use of the Hepcon decrease bleeding and
blood and blood product requirements in patients undergoing cardiac surgery? ICVTS
2006;5:469-82.
2007 EACTS guidelines
TEG to guide blood product usage:
Recommendation
Thromboelastography may be used to guide transfusion in the postoperative period and studies have demonstrated a reduction in blood
and blood product usage if used in conjunction with a treatment
algorithm.
Further studies are required before Thromboelastography can be
recommended as the standard of care for post-operative transfusion
management.
(Grade B recommendation based on Level 2b studies)
Ronald A, Dunning J. Can the use of thromboelastography predict and decrease bleeding and
blood and blood product requirements in adult patients undergoing cardiac surgery? ICVTS
2005;(5):456-63.
2007 EACTS guidelines
Factor VIIa for intractable bleeding:
Recommendation
For patients with intractable bleeding post cardiac surgery refractory
to conventional haemostatic interventions, factor VIIa is
recommended and its complication rates are low.
(Grade C recommendation based on Level 2b, 3b and level 4 studies)
2007 EACTS guidelines
Factor VIIa for intractable bleeding:
Evidence
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Roberts(2004) over 400,000 usages of Factor VIIa across all specialties recorded
adverse event risk around 1%
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Diprose – PRCT in cardiac surgery 20pts, halved blood loss
At least 160 case reports of use in Cardiothoracic surgery,
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 with a 1% risk of serious thrombosis
Tanos M, Dunning J. Is recombinant activated factor VII useful for intractable bleeding after
cardiac surgery? ICVTS 2006;5:493-8.
2007 EACTS guidelines
Future EACTS guidelines
2008 Guidelines :
The Indications for Coronary
Artery Bypass Grafting
2007 EACTS guidelines
Any Questions ?
To get involved in writing the 2008 EACTS
guidelines and Best Evidence Topics :
www.icvts.org
[email protected]
2007 EACTS guidelines