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North American, Prospective, Multicenterssessment of the Mitroflow Aortic Pericardialrosthesis

ohn Conte, MD, Neil Weissman, MD, Joseph A. Dearani, MD, Joseph Bavaria, MD,avid Heimansohn, MD, Walter Dembitsky, MD, and Daniel Doyle, MD

ivision of Cardiac Surgery, Johns Hopkins Hospital, Baltimore, Maryland; Medstar Research Institute, Georgetown Universitychool of Medicine, Ultrasound Core Laboratories at the Cardiovascular Research Institute, Washington Hospital Center,ashington, DC; Departments of General Surgery and Thoracic Surgery, Mayo Clinic, Rochester, Minnesota; Departments of

ardiac Surgery, Cardiothoracic Surgery, and Thoracic Surgery, Hospital of the University of Pennsylvania, Philadelphia,ennsylvania; CorVasc, St Vincent Heart Center of Indiana, Indianapolis, Indiana; Sharp Memorial Hospital, San Diego,

alifornia; and Hopital Laval, Quebec City, Quebec, Canada

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Background. The aim of the Mitroflow aortic pericardialalve study was to prospectively assess performance of theitroflow prosthesis among North American patients.Methods. The study was conducted between November

003 and December 2007 on patients requiring aortic valveeplacement. The study cohort consisted of 689 patients (391ale, 298 female), with a mean age of 74.3 � 8.4 years, and

6.6% of whom were New York Heart Association (NYHA)lass I/II preoperatively. Patients were followed at 3 to 6onths and yearly until study closure. Mean follow-up was

5.7 � 12 months, and total follow-up was 1,474.4 patient-ears, with a maximum of 48.7 months.Results. Postoperatively, more than 97% of evaluated

atients were NYHA class I/II. At 3 years, 131 patients hadied, for an actuarial survival of 79.1%; and the 3-yearctuarial freedom from valve-related death, valve explant,ll valve reoperation, and structural valve dysfunction was

7.0%, 98.1%, 97.9%, and 99.2%, respectively. Other valve-

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f Cardiac Surgery, 600 N Wolfe St, Baltimore, MD 21205; e-mail:conte@csurg.jhmi.jhu.edu.

2010 by The Society of Thoracic Surgeonsublished by Elsevier Inc

elated complications included prosthetic valve endocardi-is (1.4% per patient-year), thromboembolic episodes (1.3%er patient-year), major embolism (0.5% per patient-year),erivalvular leak (0.6% per patient-year), and major antico-gulation-related bleeding (0.6% per patient-year). Echocar-iograms at 1 year showed mean pressure gradients aver-ged from 7.3 � 1.8 mm Hg to 13.4 � 5.1 mm Hg, and peakradients averaged from 14.3 � 4.7 mm Hg to 26.0 � 9.2 mmg for valve sizes 27 to 19. Aortic regurgitation in patientsas absent/trace (90.2%) or mild (8.7%); none was severe.Conclusions. The early results of this study show a low

ncidence of valve-related adverse events and excellentemodynamic performance. Continued follow-up iseeded to determine if long-term durability in Northmerican patients is comparable to that in previous

eports on the durability of the Mitroflow valve.(Ann Thorac Surg 2010;90:144–52)

© 2010 by The Society of Thoracic Surgeons

ver the last decade, the use of bioprosthetic valveshas steadily increased owing to their enhanced

emodynamics and reduced complication rates, espe-ially bleeding, and because they do not require lifetimenticoagulant therapy. Particularly for patients morehan 60 years of age, the event-free life expectancy isetter with a bioprothesis as compared with a mechanicalrosthesis [1]. Advances in bioprostheses over the last 40ears have led to significant improvements in longevity2]. Only one bovine pericardial prosthesis (Edwardsifesciences, Irvine, CA) was available in the Unitedtates until 2007 [2, 3], when the Mitroflow aortic peri-ardial heart valve (Sorin Group Canada, Burnaby, Brit-sh Columbia) was approved by the US Food and Drugdministration. Large-scale, retrospective experienceas reported excellent hemodynamics and durability of

he Mitroflow valve [4, 5]. The purpose of this clinical

ccepted for publication Feb 26, 2010.

ddress correspondence to Dr Conte, Johns Hopkins Hospital, Division

nvestigation of the Mitroflow aortic pericardial valvetudy was to conduct a rigorous, prospective, multicenterrial of the Mitroflow valve implanted in patients requir-ng aortic valve replacement (AVR) in 28 centers in thenited States and Canada using a standardized protocol,uality controls, and a core laboratory.

aterial and Methods

atientshis trial was conducted between November 2003 andecember 2007 in patients requiring aortic valve replace-ent of a diseased or dysfunctional aortic valve or aortic

alve prosthesis. A total of 23 clinical sites in the US andclinical sites in Canada participated in this trial (see

Dr Bavaria discloses that he has a financial relationship

with Sorin.

0003-4975/$36.00doi:10.1016/j.athoracsur.2010.02.108

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ppendix*). Eligible patients were at least 18 years ofge and candidates for replacement of native aorticalves or previously implanted prosthetic aortic valves.atients included in the study required AVR with nother valve replacements. Other concomitant cardiacrocedures were allowed. Primary exclusion criteria werective endocarditis, multiple valve replacement, preg-ant or lactating, or life expectancy less than 1 year. Allandidates for isolated replacement of the aortic valve,ccording to the standard medical practice for valveelection at each center, were screened for the Mitrofloweart valve investigation; and all eligible patients at eachenter that consented to participate were enrolled. Eth-cs/Institutional Review Board approval was obtainedrom each site, and all patients gave their informedonsent to participate in the study.

ortic Valve Prosthesis and Implantationhe Mitroflow aortic pericardial heart valve (Sorin Groupanada, Mitroflow Division, Richmond, British Colum-ia) is constructed from a glutaraldehyde-fixed bovineericardium sutured onto a polyester cloth-covered, flex-

ble, acetyl homopolymer stent. A single piece of bovineericardium placed on the outside of the stent forms theitroflow valve leaflets. The sewing ring is composed of

ungsten-impregnated silicone elastomer insert for ra-iographic opacity. This study was conducted with theurrent model (Mitroflow Model 12). This study evalu-ted valve sizes 19 through 29 (2-mm increments).Surgeons were allowed to apply their preferred cardio-

ulmonary bypass and cardioplegic methods. Standardmplantation techniques used Mitroflow sizers. Antico-gulation therapy was performed according to the stan-ard practice for biological valves at each center.

atient Follow-Upatients were evaluated prospectively at hospital discharge

or at 30 days postoperatively if the patient remainedospitalized), at 3 to 6 months, at 12 months, and annuallyntil the end of the study. Each postoperative follow-upvaluation was conducted in person and included a physicalxamination, laboratory tests, echocardiogram, and a reviewf medications, adverse events, and patient status.

oppler Echocardiographyransthoracic echocardiograms were performed using atandardized acquisition protocol by trained, experi-nced sonographers. These studies were recorded onither super-VHS video or compact disk and sent to aentral core laboratory for analysis. All echocardiogramsere interpreted following the American Society ofchocardiography guidelines for clinical trials [6] andalvular regurgitation [7]. Standard prosthetic valve mea-urements were performed including mean and peakradients, effective orifice area (EOA) and cardiac output.eft ventricular (LV) volumes and mass were measureder the Society guidelines [8]. Relevant measures were

ndexed to body surface area.

pSee note at end of article regarding e-only Appendix.

valuation of Safetydata safety monitoring committee reviewed data quar-

erly to monitor the safety of the prosthesis. A clinicalvents committee composed of four independent cardio-horacic surgeons adjudicated all study deaths, explants,nd valve dysfunctions to determine the relationshipetween the adverse event and the study valve. All casesf endocarditis were adjudicated by an independenthysician with expertise in endocarditis according to theuke Criteria [9]. Adverse events were classified accord-

ng to the definitions in The Society of Thoracic Surgeonsuidelines [10]. Explanted valves underwent indepen-ent pathologic review.

ata Analysisarly events occurred within 30 days of the implant, and

ate events occurred �30 days after implant. For adversevents occurring in the late postoperative period, linear-zed hazard rates were calculated as the number ofvents per 100 patient-years. Two-sided 95% confidencentervals (CI) of the linearized rates were calculatedased on the Cox formula. Kaplan-Meier curves weresed to illustrate the freedom from first event and com-arison of curves among patient strata was performedith the log-rank test. Asymmetrical 95% CIs for theaplan-Meier estimates were also calculated. Cox pro-ortional hazard regression analysis of preoperative anderioperative factors was used to identify patient charac-

eristics and risk factors that may contribute to an in-reased risk of death. The parametric method was used tollustrate the shape of the hazard function, or instanta-eous risk, occurring in persons not yet experiencing thevent. A repeated-measures analysis of covariance wassed to examine the change in LV mass between succes-ive follow-up periods out to 3 years, with sex, valve size,nd LV hypertrophy included as covariates. All statisticalnalyses were performed using SAS statistical analysisoftware (SAS Institute, Cary, NC). All p values less than.05 were considered statistically significant.

esults

reoperative Datarom November 2003 to December 2005, 689 patientseceived first-time isolated AVR with the Mitroflowalve. Preoperative data are summarized in Table 1. Thisatient population had a mean age of 74.3 � 8.4 years andignificant comorbidities (Fig 1). Follow-up was closed inecember 2007, with a mean follow-up of 25.7 � 12onths (maximum follow-up was 48.7 months). The total

ollow-up was 1475.4 patient-years. Seven patients wereost to follow-up, for an overall follow-up rate of 99%.

perative Dataperative clinical data and concomitant procedures are

ummarized in Table 2. The mean cross-clamp time was2 � 37 minutes (range, 29 to 270). The majority ofatients presented with aortic stenosis, with calcification

resent in 94.8%. In addition to implant of the Mitroflow

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alve, concomitant cardiac procedures were performedn 66.5% of the patients. Mitroflow aortic valve sizes 21,3, or 25 were implanted in 85.1% of patients. Most88.2%) of the valves were implanted in the supra-nnular position. Intraoperative and perioperative (24ours or less postoperation) complications includedleeding (6.0%), heart block (2.6%), cerebrovascular acci-ent/stroke (2.0%), atrial fibrillation (2.0%), and heart

ailure (1.9%).At discharge, 36% of the patients were prescribedarfarin, 53% were prescribed antiplatelet medication

aspirin or clopidogrel), and 10.8% were not prescribedny antiplatelet or anticoagulation medication. At the2-month evaluation, only 15.9% of the patients wererescribed warfarin, 76.4% were prescribed antiplateletedication, and 7.7% were not prescribed any antiplate-

et or anticoagulation therapy.

ostoperative Outcomeshe actuarial freedom from all major events at 1, 2, and 3ears is presented in Table 3. There were 131 deaths (30arly, 101 late) reported. The majority of these were notalve related (n � 111), and 20 deaths (2.9%) werelassified by the clinical events committee as valve re-

able 1. Preoperative Patient Characteristics

haracteristic Number

atients 689ge, years, mean � SD (median, range) 74.3 � 8.4 (76, 27–93)ge, years20–29 1 (0.1%)30–39 3 (0.4%)40–49 5 (0.7%)50–59 28 (4.1%)60–69 117 (17.0%)70–79 352 (51.1%)80–89 178 (25.8%)90–99 5 (0.7%)

exFemale 298 (43.3%)Male 391 (56.7%)YHA functional classI 61 (8.9%)II 260 (37.7%)III 299 (43.4%)IV 62 (9.0%)Not reported 7 (1.0%)ortic valve lesionRegurgitation 57 (8.3%)Stenosis 417 (60.5%)Mixed lesion 215 (31.2%)perative priorityElective 610 (88.5%)Urgent 62 (9.0%)Emergent 17 (2.5%)

ated (10 endocarditis, 5 sudden/unexplained, 2 stroke, t

nd 1 each of cerebral bleed, fungal sepsis, and heartailure secondary to perivalvular leak [PVL]). The actu-rial freedom from valve-related death was 97.0% at 3ears.The results of a Cox regression analysis of all deaths

ound that the statistically significant risk factors foreath were associated with the following factors: use ofn intra-aortic balloon pump, ascending aorta repair,oagulopathy, perioperative stroke, renal disease, in-reased age (80 years old or older), preoperative heartailure, longer clamp time, carotid disease, concomitantblation, New York Heart Association (NYHA) classII/IV, and mixed aortic lesion.

Survival for isolated AVR patients was significantlyetter (p � 0.01) than for patients with AVR and coronaryrtery bypass grafts. Kaplan-Meier survival for isolatedVR was 90.2%, 89.2%, and 84.5% at 1, 2, and 3 years,

espectively (Fig 2); survival of patients with AVR andoronary artery bypass grafts was 83.5%, 81.0%, and3.9% at 1, 2, and 3 years, respectively.

alve-Related EventsALVE REOPERATION AND EXPLANT. Of the 12 patients withtudy valve reoperations, all except 1 underwent valvexplant. Endocarditis was the leading cause of valve explantn � 7). Less common causes of reoperation were valveysfunction (n � 3) and PVL (n � 2). All valve reoperationsccurred between 48 days and 36 months after implant ofhe Mitroflow valve. Two patients died before hospitalischarge after explant for endocarditis.

TRUCTURAL VALVE DYSFUNCTION. Structural valve dysfunc-ion (SVD) was diagnosed by echocardiographic exami-ation in 4 patients. Three patients had their valvesuccessfully replaced between 32 and 36 months aftermplant. The fourth patient was diagnosed with aortictenosis at 9 months due to calcification of the valveeaflets. This patient had acute renal failure requiringialysis and was not considered a candidate for reopera-

ion. The patient refused to continue dialysis and died ofenal failure 8 days later. The three explanted valves werenalyzed by an independent pathologist. The pathologisteported that in 2 cases, the explanted valves revealedalcification along the commissures. However, pathologynalysis showed that failure in the third valve was dueolely to pannus formation along the base of one leaflet.here was no evidence of leaflet tearing or perforation in

he explanted valves.ROSTHETIC VALVE ENDOCARDITIS. Of the 21 cases of pros-hetic valve endocarditis (PVE) reported (Table 3), 20ases occurred more than 30 days (range, 27 to 694) aftermplant. One case of PVE was attributed to fungal sepsis.leven patients with PVE died, thus making PVE the

eading valve-related mortality event. Seven of the 21VE cases had the infected valve explanted, and of these,patients died. The remaining 5 patients were treatedith antibiotic therapy and subsequently recovered orere still undergoing treatment at their last evaluations.arametric analysis of the hazard function showed that

he risk of endocarditis was highest in the first 3 months

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fter implant (Fig 3). Afterwards, the hazard rate declinedapidly to a constant hazard rate of 0.27% per patient-ear after 12 months.Thirteen 13 cases of sterile PVL were reported in 13

atients (4 early, 9 late). Three cases resulted in reopera-ion or death. One patient died of heart failure secondaryo PVL before reoperation, 1 patient had the valve ex-lanted, and 1 patient had a reoperation to repair the

eak.HROMBOEMBOLISM. A total of 36 embolic events (17 early,9 late) occurred in 35 patients. Of these, 13 were majorvents (6 early, 7 late) and 23 were minor events (11 early,2 late). There were 25 cerebral embolisms (9 major, 16inor), 9 peripheral or systemic embolisms, and 2 coro-

ary embolisms. In this study, 24.5% of the patients hadhistory of atrial fibrillation or had persistent atrial

brillation after surgery. These patients had a signifi-antly higher incidence (p � 0.001) of thromboembolicvents (Fig 4). Warfarin use was not associated with aignificantly lower incidence of thromboembolism (p �.23). One case of transient valve thrombosis (identifiedn a routine echocardiogram performed 35 months after

mplant) was successfully treated with 3 months of war-arin therapy.EMOLYSIS. No clinically significant hemolysis related to

he Mitroflow valve was reported. An analysis of theematology data showed no trend of increasing hemoly-is after implant of the Mitroflow valve. Although hema-ologic changes from the surgery (elevated lactic dehy-rogenase and reticulocytes and decreased haptoglobin,ematocrit, and hemoglobin) occurred, these all returned

o preoperative levels by 3 to 6 months.YHA FUNCTIONAL CLASSIFICATION. At the time of surgery,2.9% of patients were in NYHA class III or IV functional

tatus. By the 3- to 6-month follow-up, 97.7% of evaluated p

atients were in NYHA class I or II. By 12 months, 98.8%f the patients were NYHA class I or II, a rate that wasaintained at 2 years (97.7% were in class I or II).

chocardiographyemodynamic results at 1 year are presented in Table 4

or each valve size from 19 through 27. Peak aorticelocities averaged 2.1 � 0.3 to 2.8 � 0.4 m/s. Meanressure gradients averaged from 7.3 � 2.7 mm Hg to3.4 � 5.0 mm Hg, and peak gradients averaged from4.3 � 4.7 mm Hg to 26.0 � 9.2 mm Hg. Effective orificerea averaged from 1.05 � 0.17 cm2 to 1.82 � 0.34 cm2. Athe 12-month evaluation, aortic regurgitation was absentr trace among 90.4%, mild in 8.8%, and moderate in 0.2%f patients. There were no patients with severe aorticegurgitation.

At 3 to 6 months, mean left ventricular mass (193.4 �7.5 g) decreased 7.4% from discharge (208.9 � 65.6 g),nd LV mass at 12 months (188.2 � 51.7 g) decreased 10%rom discharge. The decrease in LV mass was significantetween discharge and all follow-up periods out to 3ears (p � 0.001); results based on LV mass index (LVass divided by body surface area) were the same. The

V mass index was 111.4 � 31.1 g/m2, 103.7 � 27.3 g/m2,nd 100.3 � 24.4 g/m2 at discharge, 3 to 6 months, and 12onths, respectively. The LV mass remained stable at

he 2-year and 3-year follow-up. Regression of LV massas independent of sex, valve size, and preoperative LVypertrophy.

omment

his prospective, multicenter study demonstrated theafety and efficacy of the Mitroflow aortic heart valve in a

Fig 1. Medical history. (BMI � body massindex; CVA � cerebrovascular accident; LV �left ventricular; Preop � preoperative.)

redominantly US patient cohort. Despite valve implan-

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ation in patients with significant comorbidities, overallurvival was high (85.8% at 1 year) and freedom fromxplant was high (98.1% at 3 years). Furthermore, thealve had good hemodynamics at 1 year with a low ratef valvular regurgitation. The valve-related event ratesere equivalent to other bioprosthetic valves.The Mitroflow aortic heart valve was introduced in

urope in 1982 and has demonstrated excellent long-erm durability, sustained improvement in freedom fromalcification and thromboembolism, and safety in allatients and particularly in elderly patients aged 70 yearsnd older [5, 11–15]. Two recent studies report the resultsrom long-term experience. Benhameid and associates [11]erformed a retrospective analysis of 161 patients (meange 69.5 years) and reported early mortality rates of 4.8%or patients 60 to 69 years old and 10.4% for patients morehan 70 years old, with a low rate of structural valveeterioration (less than 3%). Actuarial freedom fromtructural valve deterioration at 15 years for patients

able 2. Operative Characteristics

tiologya

Calcification 653 (94.8%)Congenital anomalies 96 (13.9%)Rheumatic heart disease 29 (4.2%)Collagen vascular disease 8 (1.2%)Leaflet prolapse 2 (0.3%)Failed valve repair 1 (0.1%)Marfan syndrome 1 (0.1%)

mplant valve size, mm19 43 (6.2%)21 191 (27.7%)23 238 (34.5%)25 158 (22.9%)27 54 (7.8%)29 5 (0.7%)

alve placement in the annulusSupra-annular 608 (88.2%)Intra-annular 80 (11.6%)Subannular 1 (0.1%)

oncomitant proceduresa

Concomitant procedures performed 458 (66.5%)Coronary artery bypass graft surgery 366 (53.1%)Ablation/maze procedure 48 (7.0%)Ascending aorta repair 38 (5.5%)Mitral/tricuspid valve repair 34 (4.9%)Intra-aortic balloon pump insertion 18 (2.6%)Patch closure of aortotomy 13 (1.9%)ASD/PFO closure 13 (1.9%)Aortic annulus enlargement 9 (1.3%)Carotid endarterectomy 8 (1.2%)Permanent pacemaker insertion 4 (0.6%)Myectomy/myotomy 4 (0.6%)

Patients may have several etiologies or concomitant surgical procedures.

SD � atrial septal defect; PFO � patent foramen ovale.

ore than 70 years old was 81%. Yankah and associates n

5] accumulated data from 1,513 patients with isolatedVR and follow-up to 21 years. Hospital mortality was

.5%, and the reoperation rate was 5.7%, with a low ratef valve deterioration (4.2%) and endocarditis (1.1%).wenty-year actual freedom from reoperation for struc-

ural valve deterioration was 88.6% for all patients and6.6% for patients aged 70 years or more. These investi-ators concluded that “with 2 decades of follow-up, theitroflow pericardial aortic valve continues to be a valve

f choice with a predictable low rate of valve-relatedvents, particularly for patients over the age of 65 to 70ears and others with comorbidities [5].”The current study of North American patients expands

pon the previously reported experience with the Mitro-ow valve outside of the United States and confirms the

avorable results in a prospective, multicenter studysing a standardized clinical protocol, clinical trial qual-

ty-control monitoring, centralized clinical event adjudi-ation, and core laboratory analysis. In this investigation,early 700 patients were enrolled and followed withniform examinations, laboratory analyses, and echocar-iograms. This study population was similar to that ofankah and associates [5] in terms of age, comorbidities,nd concomitant procedures, and had similar or lowerdverse event rates. Overall, Yankah and colleagues [5]eported 157 early deaths (10.4%, versus 4.5% in theurrent report). Hemodynamic data were similar, withean pressure gradients ranging from 8 mm Hg to 12m Hg. Although it is impossible to directly compare

azard rates to the Yankah report (because of a longerverage follow-up period of 49 months as compared to 26onths in this study), the reoperation rates (1.4% versus

.85% per patient-year) and structural valve deteriorationates (4.2% versus 0.6%) in this cohort of patients suggesthat the long-term safety of the Mitroflow valve in Northmerican patients is as good as that reported in earlier

tudies. Further continuation of the prospective evalua-ion of these patients will confirm if reoperation andtructural valve deterioration rates remain low.

The Mitroflow valve has some advantageous featureshat contribute to ease of implant. The Mitroflow valvean be implanted in either the annular or supra-annularosition. The low profile has the advantage of reducing

he risk of obstructing the coronary ostia. Both the thinewing cuff and low profile of the Mitroflow valve mayrove favorable over other bioprosthesis for implantation

n the small aortic root.Survival in this study was typical for an elderly popu-

ation with significant comorbidities. Kaplan-Meier anal-sis showed valve-related survival of 97.0% at 1, 2, and 3ears. The survival rates for the Mitroflow valve areomparable to those in other recent AVR studies usingericardial tissue valves [16–18]. Survival rates in con-

emporary studies reflect the changing practice of per-orming more cardiovascular surgery with older patientge and significant patient comorbidities. This is evidenthen examining the 1-year data in our study that indi-

ated that, despite the inclusion criteria of life expectancyreater than 1 year, 77 patients (11.2%) had died of

onvalve-related causes in the first year after implant.

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In our study cohort, only 12 patients (1.7%) wereeported with study valve reoperations and, as with otherissue valves, SVD and endocarditis were the primaryeasons for valve explants, comparable to other recenteports on pericardial tissue valves [18, 19]. Structuralalve dysfunction was reported in four valves. The actu-rial freedom from SVD was similar to the report ofericardial valves by Aupart and coworkers [20] who

ound 4 patients among 589 patients with SVD, all due toalcification of the valve leaflets. Given the short duration ofhis study, the reports of early failure are not indicative of

ig 2. Kaplan-Meier survival in patients with isolated aortic valveeplacement (AVR) versus AVR and coronary artery bypass grafturgery (CABG). Patients with isolated AVR have higher rates ofurvival and are displayed in the upper curve. Patients with AVRnd coronary artery bypass graft procedures have lower rates of sur-ival and are displayed in the lower curve. The number of patientst risk is listed at 6-month milestones. Patients with AVR and otherrocedures excluding coronary artery bypass grafts are not included

able 3. Linearized Hazard Rates

dverse EventLate Events

(No. of Patients)Hazar

(95%

tructural valve dysfunction 3 (3) 0.21 (0.0nticoagulant-related bleedb 8 (8) 0.56 (0.2hromboembolism 19 (18) 1.34 (0.8ajor embolism 7 (7) 0.49 (0.2erebral embolism 12 (12) 0.85 (0.4ndocarditis 20 (20) 1.41 (0.8erivalvular leak 9 (9) 0.63 (0.3alve reoperationc 12 (12) 0.85 (0.4alve explants 11 (11) 0.77 (0.4ll mortality 101 (101) 7.11 (5.8ardiovascular mortality 26 (26) 1.83 (1.2alve-related mortality 18 (18) 1.27 (0.7

inearized hazard rates (% per patient-year) based on events and follow-up gf each event at 1, 2, and 3 years after implant of the Mitroflow aortic peri8.7) a Kaplan-Meier freedom from first occurrence of each event.11) and valve reoperation to repair perivalvular leak (1).

I � confidence interval.

n the graphs. o

he long-term durability of the Mitroflow valve, which haseen well established out to 20 years [5]. The occurrence ofarly SVD in some patients is consistent with previouseports for other bioprosthetic valves [3, 18, 21, 22].

In the current study, 21 cases of PVE were reported,epresenting an overall incidence of 3.0%. One study siteeported a significantly higher (p � 0.03) percentage ofVE cases (5 of 60 patients; 8.3%) than the remaining sitesombined (16 of 629 patients; 2.5%). A Cox regressionnalysis found that the highest risk of endocarditis in thisohort was attributed to implants at this institution (haz-rd ratio � 9.4). No explanations are known for this.ther significant risk factors for endocarditis in this

tudy were concomitant repair of ascending aorta, aortictenosis, NYHA class III or IV, and older age (70 years or

ig 3. Parametric survivorship (top line) and hazard function (bot-om line) for endocarditis. Dashed lines represent approximate 70%onfidence limits (�1 SE) of the parametric estimates. The number

te% Freedoma (95% CI)

1 Year 2 Years 3 Years

6) 99.8 (98.8–99.9) 99.8 (98.8–99.9) 99.2 (97.4–99.7)6) 98.1 (96.7–98.9) 97.8 (96.3–98.7) 97.8 (96.3–98.7)5) 95.2 (93.2–96.6) 95.0 (93.0–96.4) 94.0 (91.7–95.8)7) 98.5 (97.2–99.2) 98.3 (96.9–99.0) 97.6 (95.9–98.7)3) 96.6 (94.8–97.7) 96.4 (94.6–97.6) 96.1 (94.2–97.4)3) 96.9 (96.2–97.6) 96.8 (96.0–97.4) 96.8 (96.0–97.4)6) 98.4 (97.1–99.1) 98.0 (96.5–98.9) 97.7 (95.9–98.7)3) 98.5 (97.2–99.2) 98.5 (97.2–99.2) 97.9 (96.2–98.9)4) 98.7 (97.5–99.4) 98.7 (97.5–99.4) 98.1 (96.4–99.0)1) 85.8 (82.9–88.2) 83.9 (80.9–86.5) 79.1 (75.5–82.3)4) 92.0 (89.7–93.8) 91.7 (89.3–93.6) 90.2 (87.5–92.4)6) 97.0 (95.3–98.1) 97.0 (95.3–98.1) 97.0 (95.3–98.1)

than 30 days after surgery and Kaplan-Meier freedom from first occurrencel valve (n � 689; 1,474.4 patient-years; mean 25.7 � 12 months, maximumjor bleeding attributed to warfarin therapy. c Includes valve explant

d RaCI)

6–0.57–1.03–2.02–0.96–1.49–2.11–1.16–1.41–1.33–8.62–2.68–1.9

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150 CONTE ET AL Ann Thorac SurgMITROFLOW PROSTHESIS ASSESSMENT STUDY 2010;90:144–52

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ore). Endocarditis was the leading cause of valve-elated death (11 of 20 cases), the leading cause ofeoperation (7 of 12 cases), and the leading cause ofxplant (7 of 11 cases). It is well known that the risk

ig 4. Kaplan-Meier freedom from thromboembolic events (TE)mong patients with or without history of atrial fibrillation (fib).atients with atrial fibrillation who had a preoperative history oftrial fibrillation or who had persistent atrial fibrillation after valvemplant have lower TE rates and are displayed in the lower curve.ne patient had a TE before atrial fibrillation develop, and then had

nother a TE after having atrial fibrillation. Therefore, that patients counted in both groups for the separate TE events. Patients with-ut atrial fibrillation have higher TE rates and are displayed in thepper curve. Number of patients at risk is listed at 6-monthilestones.

able 4. Postoperative Hemodynamic Data by Valve Size

emodynamic Data

19 (n � 33) 21 (n � 146)

n Mean � SD n Mean �

eart rate, beats perminute

33 65.2 � 7.1 146 65.5 � 1

ody surface area, m2 33 1.6 � 0.2 146 1.8 � 0eft ventricular ejectionfraction, %

22 62.3 � 6.1 95 55.8 � 7

ardiac output, L/min 30 4.2 � 0.9 135 4.3 � 1ardiac index, L/min/m2 30 2.6 � 0.5 135 2.4 � 0ortic velocity, VA 33 2.8 � 0.4 144 2.6 � 0VOT velocity, VL 32 1.2 � 0.2 140 1.1 � 0ean pressure gradient,mm Hg

32 13.4 � 5.0 139 11.5 � 4

eak pressure gradient4, V2

A�V2L

32 26.0 � 9.2 139 22.6 � 8

ffective orifice area,cm2

30 1.05 � 0.17 134 1.22 � 0

ffective orifice areaindex, cm2/m2

30 0.67 � 0.12 134 0.70 � 0

ostoperative hemodynamic data by valve size collected at 12-month foll� 547).

VOT � left ventricular outflow tract.

f PVE, like most valve-related events, is highest in therst year after implant and typically decreases over time.

n this study, the risk of endocarditis was highest in the firstmonths after implant, and then the hazard rate decreased

apidly to a low constant hazard rate of 0.27% per patient-ear after 12 months. This pattern has been describedreviously with other prosthetic valves [23]. The incidencef PVE in our study, which was high at one center, isonsistent with epidemiologic data that report an increasen endocarditis in elderly patients with comorbidities andncreased exposure to health care interventions [24].

Early PVL after implant of a prosthetic valve is consid-red a technical issue not related to the device, but ratherelated to other patient factors. In this study, the inci-ence of PVL (early PVL 0.6%, late PVL 0.63% peratient-year) was similar to that reported for other tissuealves [16, 25]. The low rate of PVL for the Mitroflowalve, with the use of a thin sewing cuff, is notable.The rate of late thromboembolism (1.3% per patient-

ear) is well within the range of those reported for otherioprosthetic valves (0.6% to 2.6% per patient-year) [17–0, 26–29]. In addition, linearized rates for nonstructuralysfunction (0.7% per patient-year), valve thrombosis

0.07% per patient-year), and hemolysis (0.0% per pa-ient-year) all compared favorably to the other pericar-ial valve studies. Although some bioprosthetic valvetudies reported cases of hemolysis [16], hemolysis isncommon with bioprosthetic valves.Hemodynamics of the Mitroflow valve compared fa-

orably to those reported by other recent stented peri-ardial valve studies [18, 20, 27, 30, 31]. Rajani andssociates [31] recently conducted an extensive review of

Mitroflow Valve Size

23 (n � 194) 25 (n � 130) 27 (n � 44)

n Mean � SD n Mean � SD n Mean � SD

194 63.9 � 10.7 130 63.9 � 12.4 43 65.0 � 12.8

194 1.9 � 0.2 130 2.0 � 0.2 44 2.0 � 0.2138 55.4 � 9.0 94 55.2 � 7.0 33 51.8 � 10.1

186 4.5 � 1.0 125 4.7 � 1.0 41 5.0 � 1.0186 2.4 � 0.5 125 2.3 � 0.5 41 2.5 � 0.6192 2.5 � 0.4 126 2.3 � 0.3 41 2.1 � 0.3191 1.1 � 0.2 126 1.1 � 0.2 43 1.0 � 0.2190 10.6 � 4.2 124 8.6 � 3.3 41 7.3 � 2.7

190 20.8 � 7.7 124 17.0 � 5.9 41 14.3 � 4.7

186 1.37 � 0.29 123 1.60 � 0.31 39 1.82 � 0.34

186 0.73 � 0.17 123 0.79 � 0.16 39 0.90 � 0.17

(total patients, n � 689; evaluable patients for valve sizes 19 to 27 mm,

SD

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29 studies with peak gradient, mean gradient, effectiverifice area (EOA) and EOA index in normal functioningrosthetic aortic valves. Comparison of those results with

he hemodynamic data of the Mitroflow valve in theresent study also suggest favorable hemodynamic re-ults. The study by Yankah and colleagues [5] involving,513 patients presented mean pressure gradient data onsubset (n � 121) who received the Mitroflow valve. Theresent study considerably expands the hemodynamicata on the Mitroflow valve. The mean pressure gradi-nts for sizes 19 through 23 Mitroflow valves were asood or better than those reported in several othertudies of pericardial valves [16, 20, 27, 30–32] The EOAslso were similar to other studies [20, 27, 30, 32]. As anxample, the EOA for the size 23 Mitroflow valve was.4 � 0.3 cm2 in this study as compared with 1.1 to 1.5 cm2

or other pericardial valve studies. For the size 21 valve,n EOA of 1.2 cm2 compares to that of Pelletier andoworkers [32] of 1.1 cm2; Aupart and associates [2]eported 1.3 cm2, Dellgren and colleagues [27] reported.1 cm2, and McDonald and coworkers [30] reported.49 � 0.37 cm2.In conclusion, our results with the Mitroflow valve

emonstrate favorable hemodynamic performance andafety that is similar to or better than other tissue valvesnd the Carpentier-Edwards pericardial valve. This studyeported low rates of valve-related deaths, structuralalve dysfunction, and PVLs. This study, conducted withorth American patients using a standardized clinical

rial protocol with rigorous quality controls, extends ournowledge about the favorable results of this valve fromrior European experience. Continued follow-up iseeded to determine whether long-term durability inorth American patients is comparable to that in previ-

us reports on the durability of the Mitroflow valve.

he authors wish to acknowledge and thank William B. Dolmanor the statistical analysis of the data and the preparation of thegures. The authors also wish to acknowledge Sorin Groupanada, Burnaby, British Columbia. The authors state they haveo conflicts of interest based on the study. The authors had fullccess to all the data in the study and take full responsibility forhe integrity of the data and the accuracy of the data analysis.unds for this project were provided by the manufacturer of theitroflow valve.

eferences

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2. Desai ND, Christakis GT. Bioprosthetic aortic valve replace-ment: stented pericardial and porcine valves. Cohn LH, ed.Cardiac surgery in the adult. New York: McGraw-Hill,2008:857–94.

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7. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommen-dations for evaluation of the severity of native valvularregurgitation with two-dimensional and Doppler echocardi-ography. J Am Soc Echocardiogr 2003;16:777–802.

8. Lang RL, Bierig M, Devereux RB, et al. Recommendations forchamber quantification: a report from the American Societyof Echocardiography’s Guidelines and Standards Commit-tee and the Chamber Quantification. J Am Soc Echocardiogr2005;18:1440–63.

9. Durack DT, Lukes AS, Bright DK. New criteria for diagnosisof infective endocarditis: utilization of specific echocardio-graphic findings. Duke endocarditis service. Am J Med1994;96:200–9.

0. Edmunds LH, Clark RE, Cohn LH, et al. Guidelines forreporting morbidity and mortality after cardiac valvularoperations. Ann Thorac Surg 1996;62:932–5.

1. Benhameid O, Jamieson WRE, Castellan M, et al. CarbomedicsMitroflow pericardial aortic bioprothesis—performance in pa-tients aged 60 years and older after 15 years. Thorac CardiovascSurg 2008;56:195–9.

2. Mazzucotelli JP, Bertrand PC, Loisance DY. The Mitroflowpericardial valve: clinical performance to 10 years. J HeartValve Dis 1995;4:407–13.

3. Pomar JL, Jamieson WR, Pelletier LC, Castella M, GermannE, Brownlee RT. Mitroflow pericardial bioprosthesis experi-ence in aortic valve replacement at �60 years of age. AnnThorac Surg 1998;66(Suppl):53–6.

4. Sjögren J, Gudbjartsson T, Thulin LI. Long-term outcome ofthe Mitroflow pericardial bioprosthesis in the elderly afteraortic valve replacement. J Heart Valve Dis 2006;15:197–202.

5. Thulin LI, Thilen UJ, Kymle KA. Mitroflow pericardial bio-prosthesis in the aortic position. Low incidence of structuralvalve deterioration in elderly patients during an 11-yearfollow-up. Scand Cardiovasc J 2000;34:192–6.

6. Frater RW, Furlong P, Cosgrove DM, et al. Long-termdurability and patient functional status of the Carpentier-Edwards Perimount pericardial bioprosthesis in the aorticposition. J Heart Valve Dis 1998;7:48–53.

7. Le Tourneau T, Savoye C, McFadden EP, et al. Mid-termcomparative follow-up after aortic valve replacement withCarpentier-Edwards and Pericarbon pericardial prostheses.Circulation 1999;100(Suppl 2):11–6.

8. Poirer NC, Pelletier LC, Pellerin M, Carrier M. 15-yearexperience with the Carpentier-Edwards pericardial bio-prosthesis. Ann Thorac Surg 1998;66(Suppl):57–61.

9. Gao G, Wu Y, Grunkemeier GL, Furnary AP, Starr A.Durability of pericardial versus porcine aortic valves. J AmColl Card 2004;44:384–8.

0. Aupart MR, Sirinelli AL, Diemont FF, Meurisse YA, XavierBD, Marchand MA. The last generation of pericardial valvesin the aortic position: ten-year follow-up in 589 patients. AnnThorac Surg 1996;61:615–20.

1. Banbury MK, Cosgrove DM, White JA, Blackstone EH, FraterRW, Okies JE. Age and valve size effect on the long-termdurability of the Carpentier-Edwards aortic pericardial bio-prosthesis. Ann Thorac Surg 2001;72:753–7.

2. Smedira NG, Blackstone EH, Roselli EE, Laffey CC, Cos-grove DM. Are allografts the biologic valve of choice foraortic valve replacement in nonelderly patients? Compari-

son of explantation for structural valve deterioration of

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allograft and pericardial prostheses. J Thorac CardiovascSurg 2006;131:558–64.

3. Agnihotri AK, McGiffin DC, Galbraith AJ, O’Brien MF. Theprevalence of infective endocarditis after aortic valve re-placement. J Thorac Cardiovasc Surg 1995;110:1708–20.

4. Wang A, Athan E, Pappas PA, et al. Contemporary clinicalprofile and outcome of prosthetic valve endocarditis. JAMA2007;297:1354–61.

5. Bottio T, Rizzoli G, Thiene G, Nesseris G, Casarotto D,Gerosa G. Hemodynamic and clinical outcomes with theBiocor valve in the aortic position: an 8-year experience.J Thorac Cardiovasc Surg 2004;127:1616–23.

6. Cosgrove DM, Lytle BW, Taylor PC, et al. The Carpentier-Edwards pericardial aortic valve: ten-year results. J ThoracCardiovasc Surg 1995;110:651–62.

7. Dellgren G, David TE, Raanani E, Armstrong S, Ivanov J,Rakowski H. Late hemodynamic and clinical outcomes ofaortic valve replacement with the Carpentier-Edwards Peri-mount pericardial bioprosthesis. J Thor Cardiovasc Surg

8. Meyns B, Szecsi J, Flameng W, Daenen W. Aortic and mitralvalve replacement with the Carpentier-Edwards pericardialbioprosthesis: mid-term clinical results. J Heart Valve Dis1993;2:66–70.

9. Mistiaen W, Van Cauwelaert PH, Sys SU, Muylaertz PH,Harrison F, Bortier H. Role of age, gender and association ofCABG on long-term results after aortic valve replacementwith a Carpentier-Edwards bioprosthesis in the elderly.J Cardiovasc Surg 2003;44:701–6.

0. McDonald ML, Daly RC, Schaff HV, et al. Hemodynamicperformance of small aortic valve bioprostheses: is there adifference? Ann Thorac Surg 1997;63:362–6.

1. Rajani R, Mukherjee D, Chambers JB. Doppler echocardiog-raphy in normally functioning replacement aortic valves: areview of 129 studies. J Heart Valve Dis 2007;16:519–35.

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2002;124:146–54. Surg 1988;3:405–12.

The Appendix is available online only. To access it, please visit: http://ats.ctsnetjournals.org and search for thearticle by Conte, Vol. 90, pages 144–152.

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152.e1Ann Thorac Surg CONTE ET AL2010;90:152.e1–3 MITROFLOW PROSTHESIS ASSESSMENT STUDY

ppendix

nvestigator List

ame and Address of Investigational Site Name and Address of Investigator

entara Norfolk General Hospital00 Gresham Drorfolk, VA 23507

Michael McGrath, MDMid-Atlantic Cardiothoracic Surgeons, Ltd400 W Brambleton AveSte 200Norfolk, VA 23510

t. Joseph’s Medical Center601 Osler Drowson, MD 21204

Jeffrey Sell, MDMidAtlantic Cardiovascular Assoc7505 Osler DrSte 410Towson, MD 21204

ohns Hopkins Hospital00 North Wolfe Staltimore, MD 21287

John Conte, MDJohns Hopkins Division of Cardiac SurgeryBlalock 618600 N Wolfe StBaltimore, MD 21287

ospital of University of PA400 Spruce Sthiladelphia, PA 19104

resbyterian Medical Center9th & Market Stshiladelphia, PA 19104

Joseph E. Bavaria, MDAssociate Professor of SurgeryCardiovascular & Thoracic Surgery3400 Spruce St6 Silverstein PavilionPhiladelphia, PA 19104

eart Center of Indiana0580 N Meridian Stndianapolis, IN 46290

t. Vincent Hospital001 West 86th Stndianapolis, IN 46240

David Heimansohn, MD10590 N Meridian StSte 105Indianapolis, IN 46290

ershey Medical Center00 University Drershey, PA 17033

Walter Pae, MDDepartment of Cardiothoracic SurgeryMilton S. Hershey Medical Center500 University DrMail Code H165Hershey, PA 17033

ethodist Hospital65 at 21st StO Box 1367

ndianapolis, IN 46206

Arthur Coffey, MDMethodist Professional Center1801 N Senate Blvd, #755Indianapolis, IN 46202

ewark Beth Israel Medical Center01 Lyons Ave at Osborne Terraceewark, NJ 07112

Craig Saunders, MDNewark Beth Israel Medical Center G5Department of Cardiothoracic Surgery201 Lyons Ave at Osborne TerraceNewark, NJ 07112

harp Memorial Hospital901 Frost Stan Diego, CA 92123

Walter Dembitsky, MD7910 Frost StSte 330San Diego, CA 92123

t. Luke’s Hospital4th and Wornall Rdansas City, MO 64111

Michael Borkon, MD4320 Wornall Rd, Ste 50-IIKansas City, MO 64111

t. Luke’s Medical Center900 W Oklahoma Aveilwaukee, WI 53215

Leonard Kleinman, MDCardiovascular Surgery Assoc2901 W Kinnickinnic River PkwySte 310Milwaukee, WI 53215

Continued

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152.e2 CONTE ET AL Ann Thorac SurgMITROFLOW PROSTHESIS ASSESSMENT STUDY 2010;90:152.e1–3

ppendix Continued

ame and Address of Investigational Site Name and Address of Investigator

estchester County Medical Center5 Grasslands Rdalhalla, NY 10595

Arlen G. Fleisher, MDWestchester County Medical CenterDepartment of Cardiothoracic SurgeryMacy Pavilion, Ste 128WValhalla, NY 10595

ankenau Hospital00 Lancaster Ave

ynnewood, PA 19096

Francis Ferdinand, MDLankenau Hospital280 Lankenau Medical Science Bldg100 Lancaster AveWynnewood, PA 19096

enton Regional Medical Center535 South Interstate 35enton, TX 76210

edical Center of Plano901 West 15th Stlano, TX 75075

Tea E. Acuff, MD209 N Bonnie BraeSte 303Denton, TX 76201

ayo Clinic00 First St SWochester, MN 55905

Joseph Dearani, MDMayo ClinicCardiovascular Surgery200 First St SWRochester, MN 55905

anner Good Samaritan Hospital111 E McDowell Rdhoenix, AZ 85006

Kenith Fang, MD1144 E McDowell RdSte 400Phoenix, AZ 85006

aylor University Medical Center600 Gaston Aveallas, TX 75246

Baron Hamman, MD621 N Hall StSte 500Dallas, TX 75226

rovidence St. Vincent Medical Center205 SW Barnes Rdortland, OR 97225

Jeffrey Swanson, MDSwanson Gately Cardiothoracic Surgeons, LLC9427 SW Barnes RdPortland, OR 97225

niversity of Arizona Health Sciences Center501 N Campbell AveO Box 245018ucson, AZ 85724

Jack Copeland, MD1501 N Campbell AveSte 4402Tucson, AZ 85724

aint Michael’s Medical Center68 Dr Martin Luther King Jr Blvdewark, NJ 07102

Mark Connolly, MD268 Dr Martin Luther King Jr BlvdNewark, NJ 07102

oothills Medical Centre403 29 St NWalgary, Albertaanada T2N 2T9

Dr Andrew MaitlandRm C880Foothills Medical Centre1403 29 St NWCalgary, AlbertaCanada T2N 2T9

ueen Elizabeth II Health Sciences Centre796 Summer Stalifax, Nova Scotiaanada B3H 3A7

Dr Camille Hancock-Friesen1796 Summer St, Rm 2268Halifax, Nova ScotiaCanada B3H 3A7

opital Laval725 Chemin Ste-Foyuebec City, Quebecanada G1V 4G5

Dr Daniel DoyleHopital LavalCardiac Surgery Department2725 Chemin Ste-FoyQuebec City, QuebecCanada G1V 4G5

Continued

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152.e3Ann Thorac Surg CONTE ET AL2010;90:152.e1–3 MITROFLOW PROSTHESIS ASSESSMENT STUDY

ppendix Continued

ame and Address of Investigational Site Name and Address of Investigator

unnybrook and Women’s College Health Sciences Centre075 Bayview Aveoronto, Ontarioanada M4N 3M5

Dr George ChristakisSunnybrook Health Sciences Centre2075 Bayview Ave, H406Toronto, OntarioCanada M4N 3M5

ontreal Heart Institute000 Est rue Belangerontreal, Quebecanada H1T 1C8

Dr Michel Pellerin5000 Est rue BelangerMontreal, QuebecCanada H1T 1C8

total of 23 clinical sites in the United States and 5 clinical sites in Canada, for a total of 94 surgeons, participated in this trial.