Antithrombotic therapy after bioprosthetic aortic valve replacement

DOI: 10.1016/j.ejcts.2007.12.019 2008;33:531-536 Eur J Cardiothorac Surg

on behalf of ACTION Registry Investigators Dorothee Helene Lina Bail, Pascal Leprince, Bart H.M. Van Straten, Tiziano Gherli andA.J. Hyde, Domenico Pagano, Manuel Antunes, Heinrich Koertke, Sunil Kumar Ohri,

Andrea Colli, Jean-Philippe Verhoye, Robin Heijmen, Justus Thomas Strauch, Jonathan Registry survey results

Antithrombotic therapy after bioprosthetic aortic valve replacement: ACTION

This information is current as of April 16, 2008

http://ejcts.ctsnetjournals.org/cgi/content/full/33/4/531located on the World Wide Web at:

The online version of this article, along with updated information and services, is

ISSN: 1010-7940. European Association for Cardio-Thoracic Surgery. Published by Elsevier. All rights reserved. Printfor Cardio-thoracic Surgery and the European Society of Thoracic Surgeons. Copyright © 2008 by The European Journal of Cardio-thoracic Surgery is the official Journal of the European Association

by Kazimierz Suwalski on April 16, 2008 ejcts.ctsnetjournals.orgDownloaded from

www.elsevier.com/locate/ejctscic Surgery 33 (2008) 531—536

Antithrombotic therapy after bioprosthetic aortic valve replacement:ACTION Registry survey results§

Andrea Colli a,*, Jean-Philippe Verhoye b, Robin Heijmen c, Justus Thomas Strauch d,Jonathan A.J. Hyde e, Domenico Pagano f, Manuel Antunes g, Heinrich Koertke h,

Sunil Kumar Ohri i, Dorothee Helene Lina Bail j, Pascal Leprince k, Bart H.M. Van Straten l,Tiziano Gherli m, on behalf of ACTION Registry Investigators

aDepartment of Cardiovascular Surgery, Hospital Clinic, Barcelona, SpainbDepartment of Cardio-Vascular and Thoracic Surgery, University of Rennes, France

cDepartment of Cardiothoracic Surgery, St. Antonius Hospital, Nieuwegein, The NetherlandsdDepartment of Cardiac and Thoracic Surgery, University of Cologne, Germany

eDepartment of Cardiac Surgery, The Royal Sussex County Hospital, United KingdomfDepartment of Cardiothoracic Surgery, University Hospital Birmingham, United Kingdom

gDepartment of Cardiothoracic Surgery, University Hospital, Coimbra, PortugalhDepartment of Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Ruhr University of Bochum, Bad Oeynhausen, Germany

iDepartment of Cardiothoracic Surgery, Wessex Cardiothoracic Centre, Southampton General Hospital, Southampton, United KingdomjDepartment of Thoracic, Cardiac and Vascular Surgery, University of Tubingen, Germany

kDepartment of Cardiovascular Surgery, Pitie Salpetriere Hospital, University Pierre et Marie Curie, FrancelDepartment of Cardio-Thoracic Surgery, Catharina Hospital, Eindhoven, The Netherlands

mDepartment of Cardiac Surgery, University of Parma, Italy

Received 7 September 2007; received in revised form 1 December 2007; accepted 10 December 2007; Available online 18 January 2008

Abstract

Aims: A variety of antithrombotic regimens have been described for the early postoperative period after bioprosthetic aortic valvereplacement (AVR). This study reviews antithrombotic practice for patients undergoing bioprosthetic AVR with or without coronary arterybypass graft (CABG) amongst the centers participating in the ACTION (Anticoagulation Treatment Influence on Postoperative Patients) Registry.Methods and results: An antithrombotic therapy questionnaire was answered by the 49 centers participating in the ACTION Registry located inEurope, Middle East, Canada and Asia. The 43% of centers prescribe vitamin K antagonist (VKA), 20% prescribe VKA and acetyl salicylic acid (ASA),33% prescribe only ASA and 4% do not prescribe any therapy after bioprosthetic AVR. For patients undergoing bioprosthetic AVR and CABG 39% ofthe centers prescribe VKA and ASA, 37% prescribe VKA and 24% prescribe ASA. After the first three postoperative months following bioprostheticAVR, 61% of the centers prescribe only ASA, while 39% do not prescribe any therapy. Patients with bioprosthetic AVR and CABG receive ASA in 90%centers, in 2% centers VKA and ASA, and 8% centers do not prescribe any antithrombotic. Conclusion: This study demonstrates that, despiteguidelines published by several professional societies, medical practice for the prevention of thrombotic events early after bioprosthetic AVRvaries widely among cardiac surgical centers.# 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Keywords: Anticoagulants; Antiplatelet drugs; Antithrombotic therapy; Acetyl salicylic acid; Aortic bioprosthetic valve

1. Introduction

Despite improvement in valve design, patients undergoingprosthetic valve replacement are at risk of developing valvethrombosis and systemic thromboembolism. The need forlifelong anticoagulant therapy is well established in all

§ St. Jude Medical International, Inc. is the sponsor of the ACTION Registry.All authors are clinical investigators for St. Jude Medical International, Inc.* Corresponding author at: Hospital Clinic, C. Villaroel 170, 08036 Barce-

lona, Spain. Tel.: +34 687203754.E-mail address: [email protected] (A. Colli).

1010-7940/$ — see front matter # 2008 European Association for Cardio-Thoracicdoi:10.1016/j.ejcts.2007.12.019

by ejcts.ctsnetjournals.orgDownloaded from

patients with mechanical heart valves and in patients withbioprosthetic heart valves in the presence of thromboem-bolic risk factors like atrial fibrillation, left ventriculardysfunction, previous thromboembolism, left atrial thrombusat surgery or hypercoagulable conditions. The use ofantithrombotic therapy in the early postoperative periodafter bioprosthetic aortic valve replacement (AVR) iscontroversial. The decision whether to use anticoagulationor antiplatelet therapy, the duration and level of antic-oagulation are all areas of debate. The 2006 guidelines issuedby the American Heart Association (AHA) and the AmericanCollege of Cardiology (ACC) for valve replacement recom-

Surgery. Published by Elsevier B.V. All rights reserved.

Kazimierz Suwalski on April 16, 2008

A. Colli et al. / European Journal of Cardio-thoracic Surgery 33 (2008) 531—536532

mend the prescription of acetyl salicylic acid (ASA) to allrecipients of bioprosthetic heart valves (Class I, Level ofevidence C) as well as the consideration to use vitamin Kantagonists (VKA) during the first 3 months after biopros-thetic AVR. The guidelines maintain an INR-range between2.0 and 3.0, as an acceptable alternative but certainly not aprimary recommendation (Class IIa, Level of evidence C) [1].The European Society of Cardiology recommends the use of aVKA for 3 months after bioprosthetic AVR [2]. The guidelinesof the American College of Chest Physicians (ACCP), updatedin 2004, recommend the use of a VKA for 3months after tissueheart valve replacement (Grade 2C) and long-term ASA(Grade 1C+) [3]. Also the guidelines issued by the CanadianCardiovascular Society (CCS) in 2004 recommend VKA for the3 months after bioprosthetic AVR (Grade 2C) [4]. The BritishSociety of Haematology (BSH) does not recommend the use oforal anticoagulants during the first 3 months for bioprostheticvalves in the aortic position if patients are sinus rhythm(Grade A, Level Ib), although it does not see the prescriptionof VKA as a contraindication, as practiced in many medicalcenters [5].

The current survey was carried out in order to review theantithrombotic regimen used by the centers participating inthe ACTION Registry located in Europe, Middle East, Canadaand Asia before the start of the enrollment.

Fig. 1. Number of centers by country.

2. Methods

Following focus group discussions between members ofthe steering committee of the ACTION Registry, a standardtherapy survey was developed with the aim to ascertain thedifferent antithrombotic management following isolatedbioprosthetic (excluding autografts and homografts) AVR(�concomitant coronary artery bypass graft; CABG.) adoptedin the recruiting centers. The participants were asked todescribe their standard antithrombotic protocol focusing onthe timing, dosage, route (intravenous, subcutaneous andoral), type of molecule (unfractioned or low-molecularweight; LMWH) of heparin. Information on the desired INRtarget or range, timing of vitamin K antagonist therapy, type,dosage and timing of antiplatelet agents was also collected.The ACTION Registry aims at collecting data on patient whoare at least 18 years of age in sinus rhythm before surgery,requiring first time aortic valve replacement with SJM EpicTM

and SJM EpicTM Supra porcine bioprosthetic heart valve.Clinical non-inclusion criteria include the presence ofprevious implanted prosthetic valve; double valve implanta-tion; concomitant CABG; intra-aortic balloon pump at anytime before, during or after intervention; use of ASA or VKAtherapy or any other antithrombotic drug; recent positivepregnancy test, breast-feeding, or the possibility of a futurepregnancy; active infective endocarditis; aortic dissection;history of cerebral ischemia; coagulopathy; history ofgastrointestinal bleeding or increased bleeding risk; vasculardisease requiring medical or surgical treatment; previouschronic anticoagulation therapy; allergy or contraindicationto ASA and/or VKA. The ACTION Registry is an open registry, inwhich every participating investigator can prescribe what-ever he/she considers appropriate in terms of postoperativeantithrombotic therapy. The sample size for the ACTION

byejcts.ctsnetjournals.orgDownloaded from

Registry is 1014 patients in total. The responses on thestandard therapy forms were collected and analyzed. Thesurvey was submitted to each participating centre startingfrom April 2006 up to February 2007.

The standard therapy forms were entered by a dedicatedteam at St. Jude Medical. Data were stored on a securedserver and was managed using Oracle Clinical. If necessary,queries were raised using Oracle Clinical. All captured datawere analyzed by quoting the frequencies and percentages.As the sample size calculation for ACTION Registry was notbased upon this separate topic, no formal statisticalcomparisons were performed.

3. Results

In total 49 standard therapy forms were received from 48centers spread over 13 countries (Belgium, Canada, Ger-many, France, India, Israel, Italy, Netherlands, Norway,Portugal, Spain, Switzerland and UK. In one center 2investigators followed a different standard therapy(Fig. 1). In Table 1 the centers were categorized into VKA/ASA or VKA or ASA or nothing according to the prescriptionbehavior between hospital discharge and the 3rd post-operative month. For patients with bioprosthetic AVRwithout CABG, 43% of centers prescribe VKA, 33% prescribeASA, 20% prescribe VKA and ASA and 4% do not prescribeanything from discharge until month 3. For patients withbioprosthetic AVR and CABG, 39% of centers prescribe bothVKA and ASA, 37% prescribe ASA, 24% prescribe VKA betweendischarge and month 3. Figs. 2 and 3 show a large variabilityin the antithrombotic therapy not only among differentcountries but also within the same country. All centers usingVKA reported an international normalized ratio (INR) targetof 2.5. After bioprosthetic AVR, 29% of centers reported theroutine use of intravenous heparin, 27% LMWH, 12%subcutaneous heparin and 16% do not prescribe any specificantiplatelet therapy. Following bioprosthetic AVR and CABG,30% of centers prescribe intravenous heparin, 29% LMWH, 29%do not prescribe anything and 12% prescribe subcutaneousheparin.

Following surgery, LMWH or heparin was reported as beingused by the most of the centers (AVR, 65%; AVR and CABG,67%). The majority of centers started LMWH or heparin on

Kazimierz Suwalski on April 16, 2008

A. Colli et al. / European Journal of Cardio-thoracic Surgery 33 (2008) 531—536 533

Table 1Summary of therapies between discharge and month 3

Without CABG N = 49 With CABG N = 49

n (%) n (%)

VKA/ASA 10 20.4 19 38.8VKA 21 42.9 12 24.5ASA 16 32.7 18 36.7Nothing 2 4.1 0 0

Fig. 3. Standard therapies at discharge for patients with CABG.

postoperative day (POD) 0 (AVR, 72%; AVR and CABG, 76%),although some centers started heparin on POD 1 (AVR, 25%;AVR and CABG, 21%). All the centers discharge patientswithout LMWH therapy. In centers prescribing ASA, itsadministration begins in the majority of cases on POD 1(AVR, 96%; AVR and CABG, 86%). The use of VKA started in themajority of centers on POD 2 (AVR, 87%; AVR and CABG, 87%).All the centers stop prescribing VKA after 3 months for allpatients with isolated AVR, 61% of them prescribe ASA long-life and 39% do not prescribe anything. For patients with AVRand CABG, 90% centers prescribe ASA after the first 3postoperative months, 2% prescribe VKA and ASA and 8% donot prescribe any antithrombotic therapy (Table 2).

In case of comparison of new onset atrial fibrillation (AF)all the centers anticoagulate patients. However, 26.5% ofcenters give VKA and ASA in patients with isolatedbioprosthetic AVR. In patients undergoing bioprostheticAVR and CABG and experiencing new onset AF we haveobserved that 63.3% of the centers give VKA and ASA, and30.6% give only VKA, 4.1% give VKA ASA and Clopidogrel, and2% gives VKA and Clopidogrel.

4. Discussion

Prosthetic valve thromboembolism is a complex phenom-enon, occurring through an interaction between prosthesistype and patient-related factors. The pathologic eventsleading to thromboembolism start immediately after surgery.Damaged paravalvular tissue and deposition of fibrinogen onthe valve surface activate platelets as soon as blood startsflowing across the valve leading to immediate plateletadhesion and aggregation [6,7]. Within 24 h after surgery,platelet deposition on the Dacron sewing ring can be imagedradiographically [8] however, these platelets are highlysensitive to shear forces and they are prone to continued

Fig. 2. Standard therapies at discharge for patients without CABG.

by ejcts.ctsnetjournals.orgDownloaded from

activation and destruction. With continuing cycles of plateletaggregation, patients with mechanical valves have shorterplatelet survival, a marker of thromboembolic risk, thanpatients with biological valves [9]. Also coagulation factorsare activated after valve implantation, leading to furtherclot formation. This is inherent to the thrombogenicity of theprosthetic material (suture material, Dacron sewing ring,struts, and hinge points) and sites of debrided tissue (valveexcision site) [10]. Transprosthetic turbulent flow leads toregional increase in shear stress, structural damage of theendocardium and causes a loss of local resistance tothrombosis. Turbulent areas on the outflow side of theprosthesis create flow stagnation, trapping damaged plate-lets and activated factors [11]. This provides an idealsubstrate for thrombus formation and subsequent emboliza-tion. Thrombin can also be formed on platelet membranesafter their activation, further promoting the organizationand growth of platelet fibrin thrombus [12].

The insertion of an artificial device in contact with thebloodstream exposes the patient to a continuous risk ofthrombosis and thromboembolism. This risk is proportional tothe surface area of the foreign material, which is in contactwith blood, making patients with mitral valve prosthesesmore prone to thromboembolic complications [9]. In general,a recent heart valve prosthesis implantation is a strong riskfactor for thromboembolic complications [15,16], especiallyin the first 3—6months after surgery [15]. The reasons for thisare the following: first, the pathologic sequelae of thepatients’ inherent to valvular disease (atrial fibrillation,dilated left atrium, and dilated left ventricle) may predis-pose to areas of stasis and thrombus formation. Secondly, theincreased thromboembolic risk early after valve implantation

Table 2Prescribed medication at discharge and month 3

Switch from . . .! . . . Without CABGN = 49

With CABG N = 49

n (%) n (%)

VKA/ASA!VKA/ASA 0 0 1 2.0VKA/ASA! ASA 9 18.4 18 36.7VKA/ASA! nothing 1 2.0 0 0VKA! ASA 7 14.3 8 16.3VKA! nothing 14 28.6 4 8.2ASA! ASA 14 28.6 18 36.7ASA! nothing 2 4.1 0 0Nothing! nothing 2 4.1 0 0

Kazimierz Suwalski on April 16, 2008

A. Colli et al. / European Journal of Cardio-thoracic Surgery 33 (2008) 531—536534

may reflect incomplete endothelial proliferation on the rawintracardiac surfaces, sewing ring and suture knots in theinitial postoperative period [6,7,9]. The presence of anendothelial lining on the valve surface effectively preventsthrombus formation, but it may require more than one yearafter implantation for this in-growth to fully form [13,14].However, in the absence of endothelial organization, thedevelopment of a mature platelet fibrin coating on the valvesurface may also be favorable in terms of non-thrombogeni-city and explain the absence of thrombotic deposits inexplanted valves in which tissue in-growth is incomplete[13,14]. Therefore, it is believed that the lack of hostendothelial cell in-growth and mature platelet fibrin coatingon the valvular surface in the postoperative period maypromote early thrombus formation and contribute to theelevated early thromboembolic risk [17].

The optimal antithrombotic prophylaxis for aortic valvebioprostheses remains controversial. Five internationalmedical associations have addressed this issue over the last10 years in specific consensus documents. Regardless of theearlier consensus recommendations, there is widespread useof ASA as an alternative to anticoagulation for 3 months inpatients with no other indications for anticoagulation withbioprosthetic AVR. There are almost no randomized studies tosupport the safety of this management. It is yet to be clearlydetermined whether antithrombotic therapy is protectiveagainst TE events in patients with an aortic bioprosthesesduring the first 90 postoperative days after AVR.

The ESC has reported three times over the last 12 yearsrecommending to anticoagulate patients with an INR rangebetween 2.0 and 3.0 during the 3 months after surgery. The1998 ACC/AHA guidelines recommend [18] anticoagulationfor 3 months after bioprosthetic AVR with an INR target of 2.5to 3.5. The 2006 ACC/AHA guidelines [1] are now recom-mending aspirin alone in patients with AVR bioprostheses andno risk factors (Class I, Level of evidence C and also consideranticoagulation with a vitamin K antagonists (VKA) for 3months after bioprosthetic AVR with an INR target rangebetween 2.0 and 3.0; an acceptable alternative but certainlynot a primary recommendation (Class IIa, Level of evidenceC). The American College of Chest Physicians in 2001 [19] alsorecommended anticoagulation for 3 months with a reducedINR target of 2.0—3.0. In the 2004 updated release of theACCP it is recommend to use VKA for 3 months after valvereplacement (Grade 2C) followed by long-term ASA (Grade1C+) [3]. The only consensus document that did notrecommend anticoagulation was the British Society ofHaematology, reporting in 1998 [5]. The Canadian Cardio-vascular Society Consensus on Surgical Management ofValvular Heart Disease in 2004 recommend VKA during thefirst 3 months after bioprosthetic AVR (Grade 2C) [4]. There isa general consensus that anticoagulation should be utilized inthe early postoperative period and at long-term forbioprostheses patients with accompanying risk factors forTE such are atrial fibrillation, left ventricular dysfunction,previous TE and hypercoagulable condition [1—4].

In 2004 a survey conducted and reported on the Cardio-thoracic Surgery Network web page (<http://www.ctsnet.org/file/AnticoagulationSurveyFinalResultsSlidesPDF.pdf>,‘Anticoagulation therapy after aortic tissue valve replace-ment’, accessed June 26, 2007) demonstrated that ASA is

byejcts.ctsnetjournals.orgDownloaded from

considered by many surgeons a good alternative to antic-oagulation in patients who are in sinus rhythm having abiological AVR and without demonstrable risk factors. Thesurvey intended toestablish the level of awareness of theACC/AHA guidelines among the 726 participating surgeons and theadherence to the guidelines in their daily practice. In eachcountry (mainly theUnited States andEurope), thepercentageof respondents acquainted with or unaware of the guidelineswas equally distributed, with an overall prevalence ofawareness (79% versus 21%). Three main issues emerged fromthe study: (1) more than 60% of surgeons are convinced thatoral anticoagulation therapy administration prolongs hospitalstay with approximately 2—3 days; (2) more than 60% believethat antiplatelet therapy alone represents a valuable alter-native, in absence of comorbidities, granting patients’ safetyand reducing overall stay and cost of care; they no longerconsider VKA to be the gold standard of early antithrombotictherapy for biologic valves; and (3) approximately 50% ofsurgeons adopt antiplatelet therapy in their current practiceinstead of VKA and use it in 90% of patients withoutcomorbidities. At the opposite end of the spectrum, morethan 25% of surgeons do not only administer VKA after aortictissue valve replacement but also maintain long-term antic-oagulant therapy, even in the absence of comorbidities.

A survey reviewing the anticoagulation practice amongcardiac surgeons consultants members of the Society ofCardiothoracic Surgeons of Great Britain and Ireland waspublished in September 2005. The authors showed that 53% ofconsultants never use VKA after bioprosthetic AVR and that47% of the consultants treated their patients with VKA for thefirst 3 months [20]. Brueck et al. [21] presented the results ofa retrospective double institutional study comparing thenecessity of antiplatelet treatment by ASA with no post-operative antiplatelet therapy in terms of survival, majorbleedings and cerebral thromboembolism for patients under-going biological AVR without thromboembolic risk factors.Two hundred and eighty-eight patients were evaluated anddivided into two groups, 132 patients received ASA and 156patients did not receive antiplatelet therapy. There were nostatistically significant differences for cerebral ischemiawithin 3 months after AVR (ASA 0.8% vs no ASA 1.3%;p = 0.884) and 3—12months after AVR (ASA 0.8% vs no ASA 0%;p = 0.933). Major bleeding occurred in two ASA treatedpatients and in one patient without antiplatelet therapy( p = 0.884). The authors concluded that in patients withoutthromboembolic risk factors undergoing biological AVRadministration of ASA no advantage was conferred comparedto the absence of antiplatelet therapy. Functional status,thromboembolic events and survival were not adverselyaffected by withholding any antiplatelet therapy. Di Marcoet al. [22] who analyzed the presence vs absence ofmicroembolic signals, showed a correlation between absenceof neurologic complications and absence of microembolicsignals on transcranial Doppler examination in a smallsubgroup of aortic valve bioprostheses recipients who weretreated with ASA instead of VKA in the early postoperativeperiod (0% microembolic signals).

Recently two complete systematic reviews on the topic ofantithrombotic management after bioprosthetic aortic valvereplacement have been published [23,24]. Both reviewsconclude that due to the lack of data from prospective

Kazimierz Suwalski on April 16, 2008

A. Colli et al. / European Journal of Cardio-thoracic Surgery 33 (2008) 531—536 535

randomized trials, the optimal antithrombotic or antic-oagulation regimen in patients following bioprosthetic aorticvalve replacement remains unclear. It is evident that severalstudies have shown equivalence between antiplatelettherapy and anticoagulation whilst no studies have demon-strated that anticoagulation leads to a reduction or increasein adverse outcomes. However, some of the current guide-lines are still weighted in favor of oral anticoagulant therapybased on observational studies previously discussed.

VKAs are used to treat a variety of conditions includingdeep venous thrombosis, pulmonary embolism, atrial fibrilla-tion and patients undergoing valve replacement. Due to thenarrow therapeutic window of all anticoagulants, thedecision to anticoagulate a patient using VKA can bemultifactorial, especially for bioprosthetic valve replace-ment and is generally based on such factors as age, thepresence or absence of atrial fibrillation, left ventricledysfunction, left atrial dimensions, previous thromboembo-lism, and hypercoagulable state.

In the ACTION Registry we decided to include only patientsundergoing isolated biological AVR or biological AVR com-bined with CABG but without thromboembolic risk factors.The participating centers were asked to explain preciselytheir routine antithrombotic strategies for patients under-going a bioprosthetic AVR without considering all the specialconditions in which anticoagulation or antiplatelet therapywould have absolutely indicated or contraindicated for therisk of thromboembolism or hemorrhage, respectively.

The present results clearly show that there is a greatvariability in antithrombotic management after biopros-thetic AVR. This variability can be observed among differentcountries and inside the same country as well: we could notidentify a geographical factor resulting in a commonpractice. There are centers who anticoagulate the patients(43%), others give anticoagulants and antiplatelet therapy(20%), others prescribe only ASA (33%) and finally somecenters do not prescribe any specific therapy (4%). Thesedifferences are observed and amplified for patients under-going biological AVR and CABG also. For this specific group ofpatients there are centers that give only VKA for the first 3postoperative months (24%) where the 33% of these do notgive any antithrombotic therapy for the rest of the patient’slife. This particular finding is very different from the commongeneral practice in patients with coronary artery disease.The ACCP and ESC guidelines [2,3] recommend the use of ASA(Grade 1A) for all patients with coronary artery disease andwho undergo CABG, also in presence of a prosthetic heartvalve. The same guideline also underlines that the use ofclopidogrel is recommended only for patients who areallergic to ASA or in patients with a coronary drug-elutingstent. Nevertheless, despite strong evidence supporting itsadministration after CABG, ASA continues to be underused bymany surgeons worldwide. This chaos is reflected also in thepresence of many different guidelines with differentsuggestions for isolated bioprosthetic AVR and without clearspecific recommendations for combined bioprosthetic AVRand CABG. Given the high grade of variability in antithrom-botic therapy after biological valve implant, we think thatthe ACTION Registry, with all its limitations (no randomiza-tion, lack of preoperative and follow-up cerebral CT scan forall patients) will collect early clinical postoperative informa-

by ejcts.ctsnetjournals.orgDownloaded from

tion on the use of a specific antithrombotic regimen offeringan important opportunity to examine for the first time, in aninternational population, which therapy confers the highestlevel of protection against thromboembolism. We also hopethat future results of the ACTION Registry will provide thebasis for an international randomized trial comparingantiplatelet therapy versus anticoagulation versus no antith-rombotic therapy, hopefully supported by professionalorganizations.

Acknowledgements

The authors thank Silvia Mora and Karina Engels for theirtechnical assistance.

References

[1] Bonow RO, Carabello B, de Leon Jr AC, Faxon DP, Freed MD, Gaasch WH,Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM,Shanewise JS, Smith Jr SC, Jacobs AK, Adams CD, Anderson JL, AntmanEM, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R,Page RL, Riegel B. ACC/AHA 2006 guidelines for the managementof patients with valvular heart disease. J Am Coll Cardiol 2006;48:598—675.

[2] Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G,Flachskampf F, Hall R, lung B, Kasprzak J, Nataf P, Tornos P, Torracca L,Wenink A, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J,Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A,Tamargo J, Zamorano JL, Zamorano JL, Angelini A, Antunes M, FernandezMA, Gohlke-Baerwolf C, Habib G, McMurray J, Otto C, Pierard L, Pomar JL,Prendergast B, Rosenhek R, Uva MS, Tamargo J. Guidelines on themanagement of valvular heart disease: The Task Force on the Manage-ment of Valvular Heart Disease of the European Society of Cardiology. EurHeart J 2007;28:230—68.

[3] Salem DN, Stein PD, Al-Ahmad A, Bussey HI, Horstkotte D, Miller N, PaukerSG. Antithrombotic therapy in valvular heart disease — native andprosthetic: the seventh ACCP conference on antithrombotic and throm-bolytic therapy. Chest 2004;126(3 Suppl.):457S—82S.

[4] JamiesonWR, Cartier CP, Allard M. Surgical management of valvular heartdisease. Can J Cardiol 2004;20(Suppl. E):15.

[5] British Committee for Standards in Haematology. Guidelines on oralanticoagulation: third edition. Br J Haematol 1998;101:374—87.

[6] LeGuyader A, Watanabe R, Berbe J, Boumediene A, Cogne M, Laskar M.Platelet activation after aortic prosthetic valve surgery. InteractiveCardiovasc Thorac Surg 2006;5:60—4.

[7] Chesebro JH, Adams PC, Fuster V. Antithrombotic therapy in patients withvalvular heart disease and prosthetic heart valves. J Am Coll Cardiol1986;8(Suppl. B):41B—56B.

[8] Dewanjee MK, Trastek VF, Tago M, Kaye MP. Radioisotopic techniques fornoninvasive detection of platelet deposition in bovine-tissue mitral-valveprostheses and in vitro quantification of visceral microembolism in dogs.Invest Radiol 1984;19:535—42.

[9] Harker LA, Slichter SJ. Studies of platelet and fibrinogen kineticsin patients with prosthetic heart valves. N Engl J Med 1970;283:1302—5.

[10] Stein B, Fuster V, Halperin JL, Chesebro JH. Antithrombotic therapy incardiac disease. An emerging approach based on pathogenesis and risk.Circulation 1989;80:1501—13.

[11] Nemerson Y, Turitto VT. The effect of flow on hemostasis and thrombosis.Thromb Haemost 1991;66:272—6.

[12] Pengo V, Peruzzi P, Baca M, Marzari A, Zanon F, Schivapappa L, Dalla VoltaS. The optimal therapeutic range for oral anticoagulant treatment assuggested by fibrinopeptide A (FpA) levels in patients with heart valveprostheses. Eur J Clin Invest 1989;19:181—4.

[13] Brais M, Braunwald NS. Acceleration of tissue in-growth on materialsimplanted in the heart. Ann Thorac Surg 1976;21:221—9.

[14] Bull B, Braunwald NS. Human histopathologic response to acompletely fabric-covered prosthetic heart valve. Ann Surg 1971;174:755—61.

Kazimierz Suwalski on April 16, 2008

A. Colli et al. / European Journal of Cardio-thoracic Surgery 33 (2008) 531—536536

[15] Heras M, Chesebro JH, Fuster V, Penny WJ, Grill DE, Bailey KR, DanielsonGK, Orszulak TA, Pluth JR, Puga FJ, Schaff HV, Larsonkeller JJ. High risk ofthromboemboli early after bioprosthetic cardiac valve replacement. JAm Coll Cardiol 1995;25:1111—9.

[16] Blair KL, Hatton AC, White DW, Blair KL, Hatton AC, White WD,Smith LR, Lowe JE, Wolfe WG, Young WG, Oldham HN, Douglas Jr JM,Glower DD. Comparison of anticoagulation regimens after Carpentier-Edwards aortic or mitral valve replacement. Circulation 1994;90(5 Pt 2):II214—9.

[17] Kulik A, Rubens FD, Mesana TG, Lam BK. Early postoperative anticoagula-tion: more questions than answers? Ann Thorac Surg 2006;82:1573—4.

[18] Bonow RO, Carabello B, de Leon Jr AC, Edmunds Jr LH, Fedderly BJ,Freed MD, Gaasch WH, McKay CR, Nishimura RA, O’Gara PT, O’Rourke RA,Rahimtoola SH, Ritchie JL, Cheitlin MD, Eagle KA, Gardner TJ, Garson JrA, Gibbons RJ, Russell RO, Ryan TJ, Smith Jr SC. Guidelines forthe management of patients with valvular heart disease: executivesummary: a report of the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines (Committee on Manage-ment of Patients With Valvular Heart Disease). Circulation 1998;98:1949—84.

[19] Stein PD, Alpert JS, Bussey HI, Dalen JE, Turpie AGG. Antithrombotictherapy in patients with mechanical and biological prosthetic heartvalves. Chest 2001;119(1 Suppl.):220S—7S.

[20] Vaughan P, Waterworth PD. An audit of anticoagulation practice amongUK cardiothoracic consultant surgeons following valve replacement/repair. J Heart Valve Dis 2005;14:576—82.

[21] Brueck M, Kramer W, Vogt P, Steinert N, Roth P, Gorlach G, Schonburg M,Heidt MC. Antiplatelet therapy early after bioprosthetic aortic valvereplacement is unnecessary in patients without thromboembolic riskfactors. Eur J Cardiothorac Surg 2007;32:108—12.

[22] di Marco F, Grendene S, Feltrin G, Meneghetti D, Gerosa G. Antiplatelettherapy in patients receiving aortic bioprostheses: a report of clinical andinstrumental safety. J Thorac Cardiovasc Surg 2007;133:1597—603.

[23] Nowell J, Wilton E, Markus H, Jahangiri M. Antithrombotic therapyfollowing bioprosthetic aortic valve replacement. Eur J CardiothoracSurg 2007;31:578—85.

[24] Colli A, Verhoye JP, Leguerrier A, Gherli T. Anticoagulation or antiplatelettherapy of bioprosthetic heart valves recipients: an unresolved issue. EurJ Cardiothorac Surg 2007;31:573—7.

Appendix A. Participating centers and investigators

BelgiumVirga Jesseziekenhuis, Hasselt (Mees, Urbain)Clinique Universitaires Saint Luc, Brussels (Noirhomme, Philippe)Onze Lieve Vrouwziekenhuis, Aalst (Casselman, Filip)

CanadaSt. John’s Regional hospital, St. John (Brown, Craig)St. Pauls Hospital, Vancouver (Jamieson, Eric/Shillitto, Kevin)Vancouver General Hospital, Vancouver (Jamieson, Eric)

FranceCHRU Rennes — Hopital de Pontchaillou, Rennes (Verhoye, Jean-Philippe)CHU Strasbourg — Hopital de Hautepierre (Kindo, Michel)Groupe Hospitalier Bichat, Paris (Nataf, Patrick)Hopital La Pitie Salpetiere, Paris (Leprince, Pascal)

byejcts.ctsnetjournals.orgDownloaded from

GermanyMartin Luther Universitatsklinikum, Halle (Friedrich, Ivar)Herz- und diabeteszentrum Nordrhein-Westfalen, Bad Oeynhausen (Kortke,Heinrich)Herzzentrum Brandenburg Evangelisches Freikirchliches Krankenhaus,Bernau (Stock, Ulrich)Klinikum der Eberhard-Karls-Universitat, Tubingen (Bail, Dorothee)Medizinische Einrichtungen der Universitat zu Koln, Koln (Strauch, Justus)Universitatsklinikum, Freiburg (Schlensak, Christian)Deutches Herzzentrum, Lahr (Ennker, Jurgen)Friedrich-Alexander-University, Erlangen (Feyrer, Richard)Herzzentrum, Cottbus (Sanger, Stefan)

IndiaSri Ramachandra Medical College & Hospital, Chennai (Balakrishnan,Komarakshi)G. Kuppuswamy Naidu, Coimbatore (Muralidharan, Srinivasan)Wockhardt Hospital, Mumbai (Pandey, Kaushal)P.D. Hinduja National Hospital, Mumbai (Pandey, Kaushal)SAL Hospital, Ahmedabad (Jain, Anil)

IsraelRabin Medical Center, Petah Tikva (Porat, Eyal)Soroka Medical Center, Beer Shiva (Sahar, Gideon)

ItalyOspedale Cardiologico — G.M. Lancisi, Ancona (Jacobone, Gianfranco)Ospedale Maggiori, Parma (Gherli, Tiziano)Ospedale San Filippo Neri, Roma (Gentili, Carlo)Ospedale Civile Ss. Antonio e Bagio, Alessandria (Medici, Dante)

NetherlandsOnze Lieve Vrouw Gasthuis, Amsterdam (Maquelain, Kyra)St. Antonius Ziekenhuis, Nieuwegein (Heijmen, Robin)Catharina Ziekenhuism, Eindhoven (Van Straten, Bart)

NorwaySt. Olavs University Hospitalm, Trondheim (Haaverstad, Rune)

PortugalCentro de Cirurgica Cardiotoracica dos hospitais Universidade, Coimbra(Antunes, Manuel)

SpainHospital Universitari Clinic y Provencial, Barcelona (Colli, Andrea)Hospiten Rambla, Santa Cruz de Tenerife (Llorens Leon, Rafael)Hospital do Meixoeiro, Vigo (Pradas Montilla, Gonzalo)

SwitzerlandBasel University Hospital, Basel (Matt, Peter)Inselspital, Bern (Eckstein, Friedrich)

United KingdomQueen Elisabeth Hospital, Birmingham (Pagano, Domenico)Hammersmith Hospital, London (Punjabi, Prakash)Southampton University Hospital, Southampton (Ohri, Sunil Kumar)Derriford Hospital, Plymouth (Unsworth-White, Michael Jonathan)The Royal Sussex Country Hospital, Brighton (Hyde, Jonathan)Blackpool Victoria Hospital, Blackpool (Tang, Augustine)Walsgrave Hospital, Coventry (Patel, Ramesh)St. Georges Hospital, London (Chandrasekaran, Venkatachalam)

Kazimierz Suwalski on April 16, 2008

DOI: 10.1016/j.ejcts.2007.12.019 2008;33:531-536 Eur J Cardiothorac Surg

on behalf of ACTION Registry Investigators Dorothee Helene Lina Bail, Pascal Leprince, Bart H.M. Van Straten, Tiziano Gherli andA.J. Hyde, Domenico Pagano, Manuel Antunes, Heinrich Koertke, Sunil Kumar Ohri,

Andrea Colli, Jean-Philippe Verhoye, Robin Heijmen, Justus Thomas Strauch, Jonathan Registry survey results

Antithrombotic therapy after bioprosthetic aortic valve replacement: ACTION

This information is current as of April 16, 2008

& ServicesUpdated Information

http://ejcts.ctsnetjournals.org/cgi/content/full/33/4/531including high-resolution figures, can be found at:

References

http://ejcts.ctsnetjournals.org/cgi/content/full/33/4/531#BIBL

This article cites 23 articles, 10 of which you can access for free at:

Citations

shttp://ejcts.ctsnetjournals.org/cgi/content/full/33/4/531#otherarticleThis article has been cited by 1 HighWire-hosted articles:

Subspecialty Collections

http://ejcts.ctsnetjournals.org/cgi/collection/valve_disease Valve disease

following collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://ejcts.ctsnetjournals.org/misc/Permissions.shtmlor in its entirety can be found online at: Information about reproducing this article in parts (figures, tables)

Reprints http://ejcts.ctsnetjournals.org/misc/reprints.shtml

Information about ordering reprints can be found online:

by Kazimierz Suwalski on April 16, 2008 ejcts.ctsnetjournals.orgDownloaded from