Dr George KrasopoulosMD, PhD, MRCS(Eng), FRCS-CTh(Eng)

Cardiac Surgeon

www.cardiosurgeon.eu

No disclosures

Talk targets

• American & European Guidelines

• EACTS Guidelines

• Industry’s opinion

• Targeted literature review

• Conclusions

AHA Guidelines

2006 & 2008

The risk of a clinical

thromboembolism is on average

0.7% per year in patients with

biological valves in sinus rhythm

Included studies: the majority of patients were not under warfarin.

• Circulation 1970;41:1031– 41.

• N Engl J Med 1991;324:573–9.

• Ann Thorac Surg 1995;60:S65– 70.

• J Am Coll Cardiol 1995;25:1111–9.

• N Engl J Med 1996;335:407–16.

USA: Each year, 795.000 people

experience a new or recurrent stroke…

…incidence: 0,25% per year.

USA: incidence of new or recurrent

stroke is 0,25% per year.

The risk of a clinical

thromboembolism is on average

0.7% per year in patients with

biological valves in sinus rhythmIncluded studies: the majority of patients were not under warfarin.

• Circulation 1970;41:1031– 41.

• N Engl J Med 1991;324:573–9.

• Ann Thorac Surg 1995;60:S65– 70.

• J Am Coll Cardiol 1995;25:1111–9.

• N Engl J Med 1996;335:407–16.

The risk of a clinical

thromboembolism is on average

0.7% per year in patients with

biological valves in sinus rhythmIncluded studies: the majority of patients were not under warfarin.

• Circulation 1970;41:1031– 41.

• N Engl J Med 1991;324:573–9.

• Ann Thorac Surg 1995;60:S65– 70.

• J Am Coll Cardiol 1995;25:1111–9.

• N Engl J Med 1996;335:407–16.

With either type of prosthesis or valve location,

the risk of emboli is probably higher in the first

few days and months after valve insertion,

before the valve has fully endothelialized.

Included studies.

• J Am Coll Cardiol 1995;25:1111–9.

• J Am Coll Cardiol 2003;41:1633–52.

With either type of prosthesis or valve location,

the risk of emboli is probably higher in the first

few days and months after valve insertion,

before the valve is fully endothelialized.

Included studies.

• J Am Coll Cardiol 1995;25:1111–9.

• J Am Coll Cardiol 2003;41:1633–52 - American Heart

Association/American College of Cardiology Foundation guide to warfarin therapy.

With either type of prosthesis or valve location,

the risk of emboli is probably higher in the first

few days and months after valve insertion,

before the valve is fully endothelialized.

Included studies.

• J Am Coll Cardiol 1995;25:1111–9.

• J Am Coll Cardiol 2003;41:1633–52. - American Heart

Association/American College of Cardiology Foundation guide to warfarin therapy.

• In patients with a bioprosthetic valve in the mitral position, recommend VKA therapy (target INR, 2.5; range, 2.0 to 3.0) for the first 3 months after valve insertion (Grade 1B).

• In patients with aortic bioprosthetic valves, who are in sinus rhythm and have no other indication for VKA therapy, recommend aspirin (50 to 100 mg/d) [Grade 1B].

• In patients with bioprosthetic valves who have:

– a prior history of systemic embolism, recommend VKA therapy (target INR 2.5; range, 2.0 to 3.0) for at least 3 months after valve insertion, followed by clinical reassessment (Grade 1C).

– evidence of a left atrial thrombus at surgery, recommend VKA therapy (target INR, 2.5; range, 2.0 to 3.0) until documented thrombus resolution (Grade 1C).

– additional risk factors for thromboembolism, including AF, hypercoagulable state, or low ejection fraction, recommend VKA therapy (target INR, 2.5; range, 2.0 to 3.0) [Grade 1C].

ESC Guidelines

2012

The need for a three-month period of

postoperative anticoagulant therapy has been

challenged in patients with aortic bioprostheses,

with the use of low-dose aspirin is now favored

as an alternative.

• Eur J Cardiothorac Surg 2007;31:578 – 585.

• Eur J Cardiothorac Surg 2008;34:73 – 92.

The need for a three-month period of

postoperative anticoagulant therapy has been

challenged in patients with aortic bioprostheses,

with the use of low-dose aspirin is now favored

as an alternative.

• Eur J Cardiothorac Surg 2007;31:578 – 585.

• Eur J Cardiothorac Surg 2008;34:73 – 92 EACTS Audit and Guidelines Committee.

The need for a three-month period of

postoperative anticoagulant therapy has been

challenged in patients with aortic bioprostheses,

with the use of low-dose aspirin now favored as

an alternative.

• Eur J Cardiothorac Surg 2007;31:578 – 585.

• Eur J Cardiothorac Surg 2008;34:73 – 92. EACTS Audit and Guidelines Committee.

Review

Ant ithrombot ic therapy following bioprosthet ic aort ic valve replacement

Just in Nowell, Emma Wilton, Hugh Markus, Marj an Jahangiri *

Department of Cardiothor acic Surgery and Neurosciences, St . George’s Hospital , Universit y of London, UK

Received 19 July 2006; received in revised form 6 December 2006; accepted 14 December 2006; Available online 30 January 2007

Summary

The life expectancy of the general populat ion is increasing. This has meant that more elderly pat ients are requiring aort ic valve replacement

(AVR). The choice of valve replacement and its durability are important . Bioprost het ic (t issue) heart valves were int roduced into clinical use in

the 1960s and were developed primarily to reduce the complicat ions associated with thromboembolism (TE) and the need for lifelong oral

ant icoagulat i on, due to their low thrombogenicity compared to mechanical prostheses. This makes them suitable for use in elderly pat ients

(aged > 65 years) and in otherswhere the risksof ant icoagulat ion are higher or ant icoagulat i on iscontraindicated. There isthought to be a higher

risk of TEfor up to 90 days following bioprosthet ic AVR. Guidelines for the management of pat ients with valvular heart disease published by the

American College of Cardiology (ACC)/ American Heart Associat ion (AHA), the American College of Chest Physicians (ACCP) and the European

Society of Cardiology (ESC) all recommend the use of an ant icoagulat ion regimen for the first 3 months following bioprosthet i c AVR. However,

there is division of opinion and pract ice, despite these recommendat ions, and more recent studies have not supported the evidence for these

guidelines. In this art icle, we review the literature on the use of ant icoagulat i on in the first 90 days following bioprosthet ic AVR.

# 2007 European Associat ion for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Keywords: Bioprosthesis; Ant icoagulat i on; Aort ic valve

1. Int roduct ion

Aort ic valve replacement (AVR) is the t reatment of choice

for aort ic valve disease and is one of the most commonly

performed cardiac operat ions [1] . The nat ive valve is usually

replaced with either a bioprosthet ic or mechanical valve

prosthesis. Bioprostheses were int roduced in the 1960s as a

less thrombogenic alternat ive to mechanical prostheses.

They do, however, have less durability than mechanical

prostheses [2,3] and suffer from st ructural deteriorat ion that

may require reoperat ion and therefore increased morbidity

and mortality [4—9] . Pericardial valves were int roduced in

the 1970s to improve haemodynamics and decrease the rate

of st ructural failure [10—15] . Stent less bioprosthesis was

int roduced in 1992 with the aim to improve haemodynamic

funct ion and increase durability compared to stented t issue

valves [16—19] .

Mechanical prost heses are thrombogenic and there is

good evidence for lifelong ant icoagulat ion [20,21] . During

the first 3 months following bioprosthet ic AVR, there is

thought to be a higher risk of thromboembolism (TE) [22] .

This may be related to lack of endothelialisat ion of the

bioprosthet ic material. Many aut horit ies, including guide-

lines, recommend ant icoagulat ion during the early post -

operat ive period. However, recent ly it has been suggested

that there may be no benefi t f rom early ant icoagulat ion in

t he first 90 days af ter bioprosthet ic AVR [23] . With an

increasingly elderly populat ion more pat ients are requiring

AVR [24]. In this group, the complicat ions associated with

ant icoagulat ion are increased. In this art icle, we have

performed a systemat ic review of the lit erature and

reviewed the current guidelines.

2. Review methodology

We have searched Medline, Embase, CINAHL and

Cochrane databases (1966 to July 2006). We combined

t hree MeSH terms: heart valve prosthesisor bioprosthesisor

aort ic valve and thromboembolism and ant icoagulants. The

search was limited to studies of humans and art icles in

English. For search complet ion, references of art icles,

which fulfi l led the inclusion and exclusion crit eria, were

hand searched. Ident ified studies were independent ly

assessed by two reviewers (EW and JN). Art icles were

included if they provided data on at least five pat ients aged

over 18 years. Where art icles included t issue aort ic valve

www.elsevier.com/ locat e/ ej cts

European Journal of Cardio-t horacic Surgery 31 (2007) 578—585

* Corresponding author. Address: Department of Cardiothoracic Surgery, St .

George’s Hospital, Blackshaw Road, London, SW17 0QT, UK.

Tel.: +44 208 725 3565; fax: +44 208 725 2049.

E-mail address: marj an.j ahangiri@stgeorges.nhs.uk (M. Jahangiri).

1010-7940/ $ —see front mat ter # 2007 European Associat ion for Cardio-Thoraci c Surgery. Published by Elsevier B.V. All rights reserved.

doi:10.1016/ j .ej cts.2006.12.017

EACTS

Audit & Guidelines

Committee.

Industry's opinion

Targeted

literature review

Antithrombotic and Thrombolytic Therapy for

Valvular Disease, 9th ed: ACCP Evidence-

Based Clinical Practice GuidelinesCHEST. 2012;141(2_suppl):7S-47S

• In the first 3 months after bioprosthetic valve implantation:

• Warfarin therapy with a target international normalized

ratio (INR) of 2.5 for mitral valves (Grade 2C).

• Aspirin for aortic valves (Grade 2C)

• Aspirin and clopidogrel for transcatheter aortic valves

(Grade 2C),

• After 3 months from bioproasthetic valve implantation:

aspirin mono-therapy (Grade 2C).

• In valve repair the recommendation is aspirin mono-

therapy (Grade 2C).

Association of Warfarin Therapy Duration After

Bioprosthetic AVR With Risk of Mortality,

Thromboembolic Complications, and BleedingJAMA. 2012;308(20):2118-2125

• Question: Assess the risk of warfarin treatment after bio-AVR

• Danish National Patient Registry

• Retrospective analysis of a National Registry

• 4075 patients, 3186 on Warfarin and 881 on Aspirin

• January 1, 1997, and December 31, 2009

• Median duration of follow-up was 6.57 person-years.

Association of Warfarin Therapy Duration After

Bioprosthetic AVR With Risk of Mortality,

Thromboembolic Complications, and BleedingJAMA. 2012;308(20):2118-2125

• Question: Assess the risk of warfarin treatment after bio-AVR

• Danish National Patient Registry

• Retrospective analysis of a National Registry

• 4075 patients, 3186 on Warfarin and 881 on Aspirin

• January 1, 1997, and December 31, 2009

• Median duration of follow-up was 6.57 person-years.

• Results: Warfarin is of benefit for 3 months after bio-AVR

and its benefit appears to persist for up to 6 months (fewer

strokes, thromboembolic events & cardiovascular deaths per

100 person-years)

Cerebral microembolization after bioprosthetic

aortic valve replacement: comparison of warfarin

plus aspirin versus aspirin only.Circulation. 2012 Sep 11;126:S239-44

• Prospective randomized study after bio-AVR.

• 28 patients Warfarin + 81mg Aspirin & 28 patients Aspirin

325mg.

• Cerebral microembolization was quantified at 4 hours and 1

month postoperatively, by recording 1-hour bilateral middle

cerebral artery (MCA) microembolic signals (MES).

• Platelet-function analysis (PFA) performed.

• Follow-up to 1 year was complete.

Cerebral microembolization after bioprosthetic

aortic valve replacement: comparison of warfarin

plus aspirin versus aspirin only.Circulation. 2012 Sep 11;126:S239-44

• Prospective randomized study after bio-AVR.

• 28 patients Warfarin + 81mg Aspirin & 28 patients Aspirin

325mg.

• Cerebral microembolization was quantified at 4 hours and 1

month postoperatively, by recording 1-hour bilateral middle

cerebral artery (MCA) microembolic signals (MES).

• Platelet-function analysis (PFA) performed.

• Follow-up to 1 year was complete.

• Results: no differences in mortality, stroke, transient ischemic

attack or proportion of patients with MES at 1 year, in either

group.

Low-dose acetyl salicylic acid versus oral

anticoagulation after bioprosthetic aortic valve

replacement. Final report of the ACTION registry.International Journal of Cardiology, online 11 December 2012

• Safety and efficacy of anticoagulation with warfarin versus

low-dose aspirin, up to 6 months after bio-AVR.

• 47 medical centers in Europe, Canada and India

• January 2006 and June 2009, 1118 patients underwent

AVR alone or AVR+CABG, 500 received VKA and 618

received ASA.

Low-dose acetyl salicylic acid versus oral

anticoagulation after bioprosthetic aortic valve

replacement. Final report of the ACTION registry.International Journal of Cardiology, online 11 December 2012

Results: Warfarin

was associated with

higher morbidity

within 6 months after

bioprosthetic AVR,

suggesting that,

particularly after

concomitant CABG

surgery Aspirin is the

better option.

Dual antiplatelet therapy versus aspirin alone in

patients undergoing transcatheter aortic valve

implantation (TAVI).Am J Cardiol. 2011 Dec 15;108(12):1772-6.

• 2009 - 2010, prospective randomized study

• 300-mg loading dose of clopidogrel on the day before TAVI

followed by a 3-month maintenance daily dose of 75 mg plus

aspirin 100 mg lifelong (DAPT group) or aspirin 100 mg alone

(ASA group).

• The primary end point was the composite of major adverse

cardiac and cerebrovascular events, defined as death from

any cause, myocardial infarction, major stroke, urgent or

emergency conversion to surgery, or life-threatening

bleeding.

Dual antiplatelet therapy versus aspirin alone in

patients undergoing transcatheter aortic valve

implantation (TAVI).Am J Cardiol. 2011 Dec 15;108(12):1772-6.

• 2009 - 2010, prospective randomized study

• 300-mg loading dose of clopidogrel on the day before TAVI

followed by a 3-month maintenance daily dose of 75 mg plus

aspirin 100 mg lifelong (DAPT group) or aspirin 100 mg alone

(ASA group).

• The primary end point was the composite of major adverse

cardiac and cerebrovascular events, defined as death from

any cause, myocardial infarction, major stroke, urgent or

emergency conversion to surgery, or life-threatening

bleeding.

• Results: No significant difference amongst the groups

For patients with

bioprosthetic cardiac valves:

We have no data to support the

motion of “no need for treatment”

and no data to reject such a motion

either!!!!

However…

• For patients with bio-AVR: Aspirin is equally good and possibly better than warfarin.

• For patients with bio-MVR: very weak data to support either motion. These patient may also have other reasons to warrant warfarin treatment.

• For patients with bio-PVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TAVI: early practice and published results support antiplatelet treatment with aspirin.

• For patients with bio-AVR: Aspirin is equally good and possibly better than warfarin.

• For patients with bio-MVR: very weak data to support either motion. These patient may also have other reasons to warrant warfarin treatment.

• For patients with bio-PVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TAVI: early practice and published results support antiplatelet treatment with aspirin.

• For patients with bio-AVR: Aspirin is equally good and possibly better than warfarin.

• For patients with bio-MVR: very weak data to support either motion. These patient may also have other reasons to warrant warfarin treatment.

• For patients with bio-PVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TAVI: early practice and published results support antiplatelet treatment with aspirin.

• For patients with bio-AVR: Aspirin is equally good and possibly better than warfarin.

• For patients with bio-MVR: very weak data to support either motion. These patient may also have other reasons to warrant warfarin treatment.

• For patients with bio-PVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TAVI: early practice and published results support antiplatelet treatment with aspirin.

• For patients with bio-AVR: Aspirin is equally good and possibly better than warfarin.

• For patients with bio-MVR: very weak data to support either motion. These patient may also have other reasons to warrant warfarin treatment.

• For patients with bio-PVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TVR: no data to support either motion. Extrapolation of data from bio-AVR and the absence of the risk of stroke may warrant aspirin treatment.

• For patients with bio-TAVI: early practice and published results support antiplatelet treatment with aspirin.

Thank you very much for your attention

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