Thrombocytopenia After Aortic Valve Replacement With Freedom Solo Bioprosthesis: A Propensity Study

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1 Thrombocytoenia After Aortic Valve Relacement With Freedom Biorosthesis: A Proensity Study Alessandro Piccardo, MD, Dan Rusinaru, MD, Benoit Petitrez, MD, Paul Marticho, MD, Ioana Vaida, MD, Christohe Tribouilloy, MD, PhD, and Thierry Caus, MD, PhD Deartments of Cardiac Surgery, Hematology, and Cardiology, Amiens-Picardie University Hosital, Amiens, France Background. The incidence of ostoerative thrombocytoenia after aortic valve relacement with the Freedom biorosthesis remains unclear. This roensitymatched study was carried out to evaluate the incidence and clinical imact of thrombocytoenia in atients receiving the Freedom biorosthesis. Methods. Patients who underwent aortic valve relacement with a Freedom or Carentier-Edwards ericardial rosthesis at our institution between 2006 and 2008 were screened retrosectively. Exclusion criteria included double valve relacement, redo surgery, and active endocarditis. Two hundred six atients were considered eligible for this analysis. Using roensity scores 36 matched airs of atients with a Freedom or biorosthesis were obtained. The rimary end oint was the occurrence of ostoerative thrombocytoenia. Secondary end oints were ostoerative thromboembolic or hemorrhagic events and 30-day mortality. Results. Before matching, severe thrombocytoenia (< latelets/l) occurred in 22% of atients with a Freedom biorosthesis and 1% with a biorosthesis ( < ), thromboembolic or hemorrhagic events occurred in 3% and 2%, resectively ( 0.37), and 30-day mortality was 4% and 6%, resectively ( 0.48). Multivariate analysis identified reoerative latelet count ( 0.01) and Freedom ( < ) as indeendent risk factors for severe ostoerative thrombocytoenia. After matching, severe thrombocytoenia occurred in 25% and 3% of atients with Freedom and biorostheses, resectively ( < ), thromboembolic or hemorrhagic events occurred in 0%, and 30-day mortality was 3% and 6%, resectively ( 0.99). Conclusions. The risk of thrombocytoenia was high after Freedom imlantation. However, this comlication was not related to any deleterious events in our study oulation. (Ann Thorac Surg 2010;89: ) 2010 by The Society of Thoracic Surgeons In January 2006 the Freedom aortic biorosthesis was adoted as the stentless biorosthesis of choice in our institution. This rosthesis has the advantage of a single suture line, resulting in easy and fast imlantation, and has been associated with ositive ostoerative echocardiograhic findings [1]. To date, however, the biocomatibility of this rosthesis is a serious concern. Indeed, several institutional unublished observations and two retrosective studies have described a significant decrease in latelet counts during the early ostoerative days [2, 3]. To reduce the otential selection bias of revious analyses, the resent study was conducted using a roensity scores method to assemble a cohort of atients with either a Freedom or Carentier- Edwards biorosthesis who were well balanced in terms of baseline characteristics. Acceted for ublication Jan 25, Address corresondence to Dr Piccardo, Service de Chirurgie Cardiaque, CHU Amiens-Picardie, Avenue René Laennec, Amiens, France; iccardo.alessandro@chu-amiens.fr. The main objective of the study was to comare the incidence of ostoerative thrombocytoenia in atients with a Freedom or biorosthesis. Patients and Methods Study Poulation From January 2006 to December 2008, 693 atients underwent aortic valve relacement (AVR) in our institution. All atients receiving a Carentier-Edwards (Edwards Lifesciences, Irvine, CA) or Freedom (Sorin Grou, Saluggia, Italy) ericardial rosthesis were retrosectively identified. Exclusion criteria included double valve relacement, redo surgery, and active endocarditis. According to these criteria, 206 atients were subsequently considered eligible for analysis: Carentier-Edwards (n 110) and Freedom (n 96). The study rotocol was aroved by the institutional ethics committee. All atients gave their informed consent before articiating in the study. Biorostheses were inserted by strictly following the manufacturer s recommendations. The Freedom 2010 by The Society of Thoracic Surgeons /10/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 1426 PICCARDO ET AL Ann Thorac Surg THROMBOCYTOPENIA WITH FREEDOM SOLO 2010;89: biorosthesis was directly imlanted without any rinsing rocedure whereas the Carentier-Edwards biorosthesis was rinsed before imlantation. Study End Points The rimary end oint in this study was the occurrence of ostoerative thrombocytoenia. Secondary end oints included the occurrence of thromboembolic or hemorrhagic comlications and 30-day mortality. Severe thrombocytoenia was defined as a latelet count of less than /L, and severe or moderate thrombocytoenia was defined as a latelet count of less than /L. The latelet count for all atients was systematically recorded in the electronic hosital database as a art of routine erioerative screening examinations. During the first 3 days, the latelet count was measured daily. If a latelet count of less than /L was detected, counts were measured daily until they increased to greater than /L. In all other cases the latelet count was measured every 3 days, at least, until the atient was discharged from the hosital. If more than one latelet count er atient er day was available, the lowest count was recorded. The mean total length of hosital stay (including stay in intensive care, cardiac surgery unit, and cardiology unit) was of aroximately 15 days. Platelet count at hosital discharge was available for all atients. If a latelet count of less than /L was detected, the atient was investigated for hearininduced thrombocytoenia (HIT) using a secific enzyme immunoassay (PF4 enhanced; GTI Diagnostics, Waukesha, WI). According to guidelines for reorting mortality and morbidity after heart valve interventions, thromboembolic comlications, hemorrhagic comlications, and 30-day mortality were defined, resectively, as any valve thrombosis, embolic event, bleeding event, or all-cause death that occurred within 30 days after surgery [4]. To determine the rate of thromboembolic comlications, hemorrhagic comlications, and 30- day mortality, atients were followed u at the first ostdischarge surgical consultation. The ostoerative anticoagulation rotocol was similar in all atients. If there was no bleeding during the first 6 hours, atients were treated with intravenous unfractionated hearin (artial thrombolastin time: 60 seconds), according to our rotocol. On ostoerative day 2 or 3, hearin was relaced with subcutaneous weight-adated enoxaarin. Acetylsalicylic acid at a dose of 250 mg daily was also administered systematically. Transthoracic echocardiograhy was erformed systematically before hosital discharge. The diagnosis of HIT was based on both clinical and laboratory features, as described reviously [5]. When there was reasonable clinical susicion of HIT, a laboratory test was erformed for confirmation. A retest clinical risk assessment score that included the clinical features of HIT (thrombocytoenia, timing, thrombosis, and other causes of thrombocytoenia) was used to establish the robability of HIT (high, intermediate, or low risk) [6]. The retest robability score was used as a basis to request an HIT antibody test and for theraeutic modifications. A PF 4 enzyme immunoassay was used for HIT antibody testing. This test has been shown to have high sensitivity and an excellent negative redictive value [7, 8]. Testing for HIT antibody was erformed in atients with a high (6 to 8 oints) or intermediate (4 to 5 oints) estimated risk of HIT, and only after the aroval of a monitoring hysician with exerience in clinical hematology. Hearin was discontinued and relaced with danaaroid (high-risk atients) or fondaarinux (intermediate-risk atients) in all atients for whom HIT antibody testing was requested. Oral anticoagulants were initiated only after latelet rebound ( /L). Statistical Analyses For descritive analyses, the Pearson s 2 test, twosamle Student s t test, and Wilcoxon rank sum test were used in the rematch cohort, as aroriate. McNemar s test, aired samle Student s t test, and Wilcoxon signed rank test were used for ostmatch comarisons. Risk factors for severe or severe or moderate ostoerative thrombocytoenia were identified by univariate analysis. All variables that reached a robability value of 0.2 or less on univariate analysis were then included in a stewise logistic regression model. The imbalance in baseline covariates between the Freedom and atient grous was addressed using roensity scores, as roosed by Austin [9]. The details of this rocedure have been described reviously [10]. Briefly, roensity scores were estimated for Freedom imlantation for each of the 206 atients using a non-arsimonious, multivariate logistic regression model. Goodness-of-fit was assessed using the Hosmer-Lemeshow test ( 0.86), and discriminatory ower was determined using receiver oerating characteristics curves (area under the curve C 0.83). Using an SPSS macro and a greedy matching rotocol, each Freedom atient was matched with a atient according to the roensity score (delta 2%) [11]. Kalan-Meier curves were used to evaluate the risk of ostoerative thrombocytoenia. In the rematch cohort, curves were comared using a two-sided log-rank test. In the matched cohort, curves were comared using aroriate methods for matched data [12]. For all tests, a robability value of 0.05 or less was considered statistically significant. Statistical analysis was erformed with SPSS 16.0 (SPSS Inc, Chicago, IL). Results Prematch Cohort The rematch baseline data and balances achieved after the matching rocedure are shown in Table 1. Inthe rematch cohort, atients who received a Freedom biorosthesis were older and had a lower glomerular filtration rate and a higher estimated mortality [13].

3 Ann Thorac Surg PICCARDO ET AL 2010;89: THROMBOCYTOPENIA WITH FREEDOM SOLO 1427 Table 1. Clinical Characteristics of the Overall Poulation and Comarison Between and Freedom Patients Before and After the Matching Procedure a Before Matching (n 206) After Matching (n 72) Variable Overall (n 206) (n 110) (n 96) Age (y) b Sex (male) 120 (58) 69 (62) 51 (53) 0.16 b 17 (47) 22 (61) 0.30 Body surface (m 2 ) Preoerative latelet count ( 10 9 /L) b EuroSCORE (additive) b Glomerular filtration (ml/min) b Preoerative LVEF b Associated rocedures (%) c 86 (41) 44 (39) 42 (44) (36) 15 (42) 0.80 ECC time (min) b Aortic cross-claming (min) b a s shown are n (%) for dichotomous variables or mean SD for numeric variables. b Variables entered to calculate the roensity score. c Associated rocedures are coronary artery byass grafting, ascending aorta relacement, cryo maze, and mitral valve reair. ECC extracororeal circulation; EuroSCORE Euroean System for Cardiac Oerative Risk Evaluation; LVEF left ventricular ejection fraction. These atients also had a higher reoerative latelet count and exerienced a shorter aortic cross-claming time. However, the overall time of exosure to extracororeal circulation was similar in the two grous. After Freedom imlantation, atients had a lower ostoerative latelet count (measured at the lowest eak level), a higher occurrence of severe and severe or moderate thrombocytoenia, a greater difference between reoerative and ostoerative latelet counts, and a lower ostoerative latelet count at discharge. Postoerative thromboembolic or hemorrhagic comlications and 30-day mortality were similar in the two grous (Table 2). In the overall cohort, 56 of the 206 atients exhibited severe or moderate ostoerative thrombocytoenia. These atients exerienced a shorter extracororeal circulation time and a shorter cross-claming time, and were more likely to have received a Freedom ros- Table 2. Postoerative Clinical and Biologic Outcomes of the Overall Poulation and Comarison Between and Freedom Patients Before and After the Matching Procedure a Before Matching (n 206) After Matching (n 72) Variable Overall (n 206) (n 110) (n 96) During the hosital stay Lowest ostoerative latelet count ( 10 9 /L) Postoerative latelet count /L 56 (27) 8 (7) 48 (50) (8) 21 (58) Postoerative latelet count /L 22 (11) 1 (1) 21 (22) (3) 9 (25) Delta latelet count b ( 10 9 /L) HIT 4 (2) 2 (2) 2 (2) (3) 1 (3) 1.00 Mean early gradient (mm Hg) Hemodialysis 1 (1) 1 (1) Thromboembolic/hemorrhagic events 5 (2) 2 (2) 3 (3) day mortality 11 (5) 7 (6) 4 (4) (6) 1 (3) 1.00 At hosital discharge Platelet count at hosital discharge ( 10 9 /L) Platelet count at hosital discharge /L 1 (0.5) 0 1 (1) Platelet count at hosital discharge /L 1 (0.5) 0 1 (1) Platelet count at hosital discharge /L 188 (92) 106 (97) 82 (85) (91) 29 (80) 0.21 a s shown are n (%) for dichotomous variables or mean standard deviation for numeric variables. between the reoerative latelet count and the lowest ostoerative latelet count. HIT hearin-induced thrombocytoenia. b Delta latelet count is the difference

4 1428 PICCARDO ET AL Ann Thorac Surg THROMBOCYTOPENIA WITH FREEDOM SOLO 2010;89: Table 3. Predictors of Severe or Moderate Thrombocytoenia by Univariate Analysis in 206 Patients With a Freedom or Carentier-Edwards Biorosthesis a,b Variable No Severe Thrombocytoenia (n 184) Severe Thrombocytoenia (n 22) No Severe or Moderate Thrombocytoenia (n 150) Severe or Moderate Thrombocytoenia (n 56) Age (y) Sex (male) 110 (60) 10 (45) (62) 48 (27) 0.07 Body surface (m 2 ) Preoerative latelet count ( 10 9 /L) EuroSCORE (additive) Glomerular filtration rate (ml/min) Preoerative LVEF Associated rocedures (%) 77 (42) 8 (46) (40) 25 (45) 0.54 Freedom biorosthesis 75 (41) 21 (95) (32) 48 (85) Prosthesis size ECC time (min) Aortic cross claming (min) a s shown are n (%) for dichotomous variables or mean standard deviation for numeric variables. b Severe ostoerative thrombocytoenia is defined as less than latelets/l; severe or moderate ostoerative thrombocytoenia is defined as less than latelets/l. ECC extracororeal circulation; EuroSCORE Euroean System for Cardiac Oerative Risk Evaluation; LVEF left ventricular ejection fraction. thesis (Table 3). Multivariate logistic regression identified reoerative latelet count and Freedom biorosthesis as indeendent risk factors for severe ( 0.01 and , resectively) and severe or moderate (both ) thrombocytoenia. Twenty-two of 206 atients exerienced severe ostoerative thrombocytoenia. All these atients received a latelet transfusion during hositalization. During hositalization, severe or moderate thrombocytoenia occurred in 50% 2% and 7% 2% of atients with Freedom or rosthesis, resectively ( ). Severe thrombocytoenia occurred in 22% 4% and 1% 1% of atients with Freedom or rosthesis, resectively ( ) (Fig 1). At hosital discharge (mean hosital stay: 13 2 days), 1 atient still exhibited a latelet count less than /L. He was an 82-year-old man resenting with a reoerative chronic renal failure who received a Freedom rosthesis. Presence of HIT was excluded, and at ostoerative day 21 there was evidence of intravascular hemolysis. Desite corticoid theray, thrombocytoenia was ersistent and he was discharged at ostoerative day 45 with a latelet count of /L. However, during the hosital stay he did not exerience thromboembolic or hemorrhagic comlications. Fig 1. Develoment of severe thrombocytoenia after Freedom or Carentier-Edwards biorosthesis imlantation, before the matching rocedure (n 206). Dotted line is atients who received a Freedom rosthesis. Solid line is atients who received a rosthesis.

5 Ann Thorac Surg PICCARDO ET AL 2010;89: THROMBOCYTOPENIA WITH FREEDOM SOLO 1429 Table 4. Comarison of Mean Postoerative Platelet Count Before and After the Matching Procedure in a Day-by-Day Analysis a Before Matching (n 206) After Matching (n 72) Day (n 110) (n 96) POD 0 (number of atients) (110) (96) (36) (36) 0.59 POD 1 (number of atients) (110) (96) (36) (36) 0.01 POD 2 (number of atients) (110) (96) (36) (36) POD 3 (number of atients) (91) (83) (28) (32) POD 4 (number of atients) (66) (68) (20) (21) POD 5 (number of atients) (54) (55) (19) (21) 0.01 POD 6 (number of atients) (45) (52) (15) (17) 0.20 a Platelet counts are exressed as 10 9 /L; mean standard deviation. POD ostoerative day. Postmatch Cohort In the ostmatch cohort (Table 2), the difference in ostoerative latelet count remained highly significant. More than half of the atients had severe or moderate thrombocytoenia after Freedom imlantation, and 25% had severe thrombocytoenia. Postoerative HIT was observed in 1 atient in each grou (Table 2). In a day-by-day comarison, from ostoerative day 1 to ostoerative day 5, atients with the Freedom biorosthesis had significantly lower ostoerative latelet counts comared with atients with the biorosthesis (Table 4). However, thromboembolic or hemorrhagic ostoerative comlications and 30-day mortality rates were similar in both grous (Table 2). During hositalization, severe or moderate thrombocytoenia occurred in 58% 8% and 8% 4% of atients with Freedom or biorosthesis, resectively ( ). Severe thrombocytoenia occurred in 26% 8% and 3% 3% of atients with Freedom or biorosthesis, resectively ( 0.006; Fig 2). At hosital discharge, after Freedom imlantation, no atient exhibited a latelet count less than /L, and 80% of atients had achieved a latelet count of more than /L. Comment The results of this study show the occurrence of significant thrombocytoenia after imlantation of the Freedom rosthesis [2, 3]. The Freedom biorosthesis emerged as the strongest indeendent risk factor for ostoerative thrombocytoenia. Furthermore, in a roensity scores-matched cohort of atients comaring Freedom and rostheses, the resence of the Freedom was associated with an increased risk of ostoerative thrombocytoenia. However, thrombocytoenia was transient in the majority of cases because 80% of atients had recovered a latelet count of more than /L by hosital discharge. The henomenon of thrombocytoenia resented a eculiar attern because, in the majority of cases, it aeared early (between ostoerative days 2 and 5), ersisted for 2 to 3 days, and then disaeared from ostoerative day 5 to 7. In this series, thrombocytoenia was not associ- Fig 2. Develoment of severe thrombocytoenia after Freedom or Carentier-Edwards biorosthesis imlantation, after the matching rocedure (n 72). Dotted line is atients who received a Freedom rosthesis. Solid line is atients who received a rosthesis.

6 1430 PICCARDO ET AL Ann Thorac Surg THROMBOCYTOPENIA WITH FREEDOM SOLO 2010;89: ated with a higher occurrence of ostoerative thromboembolic or hemorrhagic events. On univariate analysis, the larger size of the Freedom rosthesis as well as the shorter oerative time seemed to favor ostoerative thrombocytoenia. Although thrombocytoenia might be related to various atient characteristics, the occurrence of thrombocytoenia was higher in the matched cohort, suggesting a mechanism that was not atient related. In this single center study, atients were exosed to the same ostoerative treatment rotocols; thus the incidence of ostoerative thrombocytoenia of 25% to 50% could not be exlained by variations in treatment rotocols. It is believed that this henomenon could be valve-related, therefore raising the question of an imerfect biocomatibility of the Freedom biorosthesis. Yerebakan and associates [2] suggested a transient direct toxic effect of the Freedom biorosthesis on latelets. This toxic effect may be caused by the storage solution. The Freedom biorosthesis is comosed of two sheets of bovine ericardium. As in the rosthesis, the ericardium is fixed in a glutaraldehyde-based rocess. The rosthesis is then reserved in a buffered glutaraldehyde solution and requires rinsing before imlantation. On the other hand, the Freedom biorosthesis is detoxified with homocysteic acid, treated for the elimination and neutralization of aldehyde residues, and stored in an aldehyde-free solution. As a consequence, the Freedom biorosthesis does not require rinsing before imlantation. However, no toxic effect was identified during remarket laboratory tests. Although it may be related to a don t-look-don t-find henomenon, ostoerative thrombocytoenia has not been reorted after imlantation of biorostheses that share the same storage solution. Isolated mechanical stress on latelets seems unconvincing if the suerior hemodynamics and lower gradients after imlantation of the Freedom biorosthesis are considered. This study has several limitations. It was a retrosective study and therefore may have included some bias in data collection. Desite the fact that it is the largest study to focus on ostoerative thrombocytoenia after Freedom imlantation, the number of atients in the matched cohort remains relatively small. The results could have been affected by unmeasured or hidden covariates. In conclusion, this study shows that transient thrombocytoenia may occur after imlantation of the Freedom ericardial rosthesis and raises the concern of biocomatibility. However, this henomenon was not related to any serious deleterious event in our study oulation. A large multicenter, randomized, rosective trial is warranted to confirm the existence, mechanism, and clinical imact of this henomenon. References 1. Beholz S, Liu J, Dushe S, Konertz WF. The Freedom valve: suerior hemodynamic results with a new stentless ericardial valve in aortic valve relacement. J Heart Valve Dis 2007;16: Yerebakan C, Kaminski A, Westhal B, et al. Thrombocytoenia after aortic valve relacement with the Freedom stentless biorosthesis. Interact Cardiovasc Thorac Surg 2008;7: Hilker L, Wodny M, Ginesta M, Wollert HG, Eckel L. Difference in the recovery of latelet counts after biological aortic valve relacement. Interact Cardiovasc Thorac Surg 2009;8: Akins CW, Miller DC, Turina MI, et al. Guidelines for reorting mortality and morbidity after cardiac valve interventions. Ann Thorac Surg 2008;85: Warkentin TE. New aroaches to the diagnosis of hearininduced thrombocytoenia. Chest 2005;127(Sul):35S 45S. 6. Warkentin TE. Hearin-induced thrombocytoenia: diagnosis and management. Circulation 2004;110:e Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of retest clinical score (4 T s) for the diagnosis of hearin-induced thrombocytoenia in two clinical settings. J Thromb Haemost 2006;4: Poulard C, Amiral J, Borg JY, Laorte-Simitsidis S, Delahousse B, Gruel Y. Decision analysis for use of latelet aggregation test, carbon 14-serotonin release assay, and hearin-latelet factor 4 enzyme-linked immunosorbent assay for diagnosis of hearin-induced thrombocytoenia. Am J Clin Pathol 1999;111: Austin PC. Proensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for imrovement. J Thorac Cardiovasc Surg 2007;134: Tribouilloy C, Levy F, Rusinaru D, et al. Outcome after aortic valve relacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiograhy. J Am Coll Cardiol 2009;20: Levesque R. Macro. In: Levesque R, ed. SPSS Programming and Data Management. 2nd ed. A Guide for SPSS and SAS Users. Chicago: SPSS Inc. Available online at: htt:// Accessed on July 1, Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. New York: Sringer- Verlag, Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. Euroean system for cardiac oerative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16: INVITED COMMENTARY Stentless biorostheses for the aortic osition have shown suerior hemodynamics comared with stented valves and have imroved reverse remodeling. A number of studies have reorted imroved long-term survival in atients with stentless aortic valves comared with stented valves [1]. The Freedom (FS) stentless valve is a modification of the Pericarbon Freedom stentless valve (Sorin Grou, Saluggia, Italy), which demonstrated excellent results in both short-term and medium-term follow-u studies. This modification was imlemented to facilitate its imlantation in the suraannular osition with a single continuous suture line using a small ericardial skirt of the outer layer of the ericardium. Multile reorts 2010 by The Society of Thoracic Surgeons /10/$36.00 Published by Elsevier Inc doi: /j.athoracsur