NORRED EXHIBIT 2128 - Page 1
`Medtronic, Inc., Medtronic Vascular, Inc., & Medtronic
`Corevalve, LLC v. Troy R. Norred, M.D.
`Case IPR2014-00111
`
`

`
`Ann Thorac Surg
`l991.‘51:430—7
`
`BORTOLOTTI ET AL
`HANCOCK PERICARDIAL XENOGRAFTS
`
`431
`
`Table 1. Summary of Preoperative Clim'cal Characteristics
`MAVR
`Variable
`AVR
`MVR
`
`No. of patients
`Male/female
`
`Mean age (y)
`Age range (y)
`Preoperative functional class
`NYHA II
`NYHA Ill
`NYI-IA IV
`Cause of valvar disease
`Rheumatic
`
`Calcific degeneration
`Myxoid degeneration
`Ischemic
`Endocarditis
`
`Congenital
`Prosthesis failure
`
`Cardiac rhythm
`Sinus
`Chronic atria] fibrillation
`
`Previous procedures
`AVR
`MVR
`
`Mitral valvoplasty
`Coartectomy
`Associated procedures
`MVR‘
`
`54
`33/21
`
`17
`5/12
`
`55 1 13
`13-73
`
`53 1 12
`22-70
`
`13
`10/3
`58110
`38-75
`
`.
`
`.
`
`.
`15
`2
`
`8
`
`1
`
`5
`
`2
`15
`
`2
`5
`
`3
`
`1
`40
`13
`
`16
`
`18
`7
`.
`
`.
`
`.
`
`1
`6
`
`45
`9
`
`.
`
`.
`
`6
`.
`
`3
`1
`
`10
`
`2
`Mitral valvoplasty
`1
`.
`.
`.
`Tricuspid valvoplasty
`7
`CABG
`
`
`.
`
`.
`
`.
`
`' With other bioprostheses (Hancock porcine in 3 and Liotta in 2).
`AVR = aortic valve replacement;
`CABG = coronary artery bypass
`MVR = mitral
`graft;
`MAVR = mitral-aortic valve replacement;
`valve replacement;
`NYI-IA '—' New York Heart Association.
`
`freedom from major postoperative events is expressed in
`actuarial fashion,
`including in all actuarial curves the
`operative mortality. Continuous data are presented as
`mean 1 1 standard error of the mean and categorical data
`as percent with the 70% confidence limits (CL).
`Hancock pericardial xenografts explanted at reopera-
`tion or recovered at autopsy were studied with gross,
`microradiographic, histological, and ultrastructural inves-
`tigations. Details of the results of a morphological study of
`HPX explants have been reported elsewhere [10].
`
`Results
`
`Early and Late Mortality
`There were eight hospital deaths: 4 patients died after
`AVR (7.4%; 70% CL, 3.7% to 13.0%), 1 after MVR (5.8%;
`70% CL, 0.7% to 18.6%), and 3 after MAVR (23%; 70% CL,
`10.4% to 41.0%) (Table 2). The causes of death were the
`following:
`low output state in 4 patients after AVR,
`intraoperative cerebral damage in 1 patient after MVR,
`postoperative hemorrhage in 2 patients after MAVR, and
`low output syndrome in 1 patient after MAVR. None of
`the early deaths was valve-related.
`In the entire series total follow—up is 452 pt-y; cumula-
`tive duration of follow—up is 304 pt-y after AVR (range, 0.4
`to 8.3 years; mean, 5.9 1 1.6 years); 94 pt-y after MVR
`(range, 0.6 to 8.3 years; mean, 5.8 1 2.1 years), and 54
`pt-y after MAVR (range, 0.9 to 8.0 years; mean, 5.4 1 2.1
`years). Follow—up is 100% complete in the entire series.
`Of the 76 patients discharged 21 died in the late
`postoperative period. There were 12 late deaths after AVR
`(3.9 1 1.1%/pt-y). 4 after MVR (4.2 1 2.1%/pt-y). and 5
`after MAVR (9.2 1 4.1%/pt-y). The causes of late death are
`shown in Table 3. Actuarial survival at 7 years is 66% 1
`8% after AVR, 64% 1 13% after MVR, and 41% 1 15%
`after MAVR (Fig 1).
`Currently, 27 patients are alive with their original HPX
`in place: 18 with AVR, 8 with MVR, and 1 with MAVR; 13
`are in functional class I, 9 in class II, and 5 in class III.
`
`
`Table 2. Summary of Major Postoperative Complications
`AVR
`
`MAVR
`
`MVR
`
`
`Complication
`No.
`%/pt-y
`No.
`%lpt-y
`No.
`%/pl:-y
`Late death
`12
`3.9 1 1.1
`4
`4.2 1 2.1
`5
`9.2 1 4.1
`
`Valve-related death
`Thromboembolism
`Fatal
`
`Anticoagulant-related hemorrhage
`Fatal
`Endocarditis
`
`.
`
`3
`3
`1
`
`2
`1
`6
`
`2.6 1 0.1
`0.1 1 0.1
`0.03 1 0.03
`
`0.6 1 0.4
`0.03 1 0.03
`2.0 1 0.7
`
`2
`3
`1
`
`.
`
`.
`
`1
`
`1
`
`.
`
`2.1 1 1.5 l
`3.2 1 1.8
`1.0 1 1.0
`
`1.0 1 1.0
`.
`.
`.
`1.0 1 1.0
`
`2
`
`3.7 1* 2.6
`
`.
`.
`.
`.
`.
`.
`.
`.
`0.03 1 0.03
`1
`Paraprosthetic leak
`13.0 1 5.0
`7
`4.2 1 2.1
`4
`7.5 1 1.6
`23
`Reoperation
`
`
`
`
`
`
`34 10.0 1 0.2 10 10.6 1 3.3 9Structural deterioration“ 16.6 1 5.5
`
`.
`
`.
`
`.
`
`.
`
`" Determined at reoperation, autopsy, or clinical investigation.
`AVR = aortic valve replacement;
`MAVR = mltral-aortic valve replacement;
`
`MVR = mitral valve replacement.
`
`
`
`NORRED EXHIBIT 2128 - Page 2
`NORRED EXHIBIT 2128 — Page 2
`
`

`
`432
`
`BORTOLOTTI ET AL
`HANCOCK PERICARDLAL xsnoonasrs
`
`Ann Thorac Surg
`1991,-51:-£30-7
`
`
`
`Table 3. Causes of late Death
`Cause
`
`AVR MVR MAVR
`
`Cardiac
`Valve—related
`Endocarditis
`Structural deterioration
`
`Reoperation
`Thromboembolisrn
`
`Ann'coagulant~related hemorrhages
`Sudden, unexplained
`Malignancy
`Unknown
`
`2
`
`2
`2
`
`2
`1
`
`1
`
`1
`
`1
`
`2
`
`1
`1
`
`1
`
`
`
`12 4Total 5
`
`
`
`
`
`95Free
`
`O
`
`1
`
`2
`
`3
`
`4
`
`5
`
`B
`
`7
`
`B
`
`B
`
`10
`
`Years Poatop
`
`Fig 2. Actuarial freedom from valve-related death. (Abbreviations as
`in Fig 1.)
`
`MAVR = rnitral»aortic valve replace-
`AVR = aortic valve replacement;
`ment;
`MVR = mitral valve replacement.
`
`There were eight valve-related deaths in the AVR group
`(2.6 t 0.1%/pt—y), because of endocarditis in 2 patients, at
`reoperation for HPX structural deterioration in 2, because
`of I-IPX structural deterioration without reoperation in 2,
`because of cerebral embolism in 1, and because of gastric
`hemorrhage in 1. There were two valve-related deaths
`after MVR (2.1 i 1.5%/pt—y), due to cerebral embolism in
`1 and sudden, unexplained death in the other. Finally,
`there were two valve-related deaths among patients with
`MAVR (3.7 : 2.6%/pt-y): 1 patient died of low output
`syndrome at reoperation because of structural failure of
`both HPXs and 1 died at home because of failure of both
`
`HPXs proved at autopsy. Actuarial freedom from valve-
`related deaths at 7 years is 79% 1 7% after AVR, 80% 1
`12% after MVR, and 81% i 12% after MAVR (Fig 2).
`
`sequelae; the third patient, who had also a porcine valve
`in the m.itral position and was anticoagulated, sustained a
`fatal cerebral embolism after 22 months. Two patients had
`ernbolic complications after MVR (3.2 i 1.8%/pt-y): 1 of
`them, who was not anticoagulated, had a cerebral embo-
`lism after 4 years with permanent hemiparesis and the
`other, while still on anticoagulants, had two episodes of
`peripheral embolism 14 months and 5 years after MVR;
`the last one, causing acute occlusion of the aortic bifurca-
`tion, required emergency embolectomy with subsequent
`death due to acute renal failure. No thromboembolic
`
`complications were observed in patients with MAVR.
`Actuarial freedom from thromboernboli at 7 years is 93%
`1 4% after AVR, 83% : 10% after MVR, and 100% after
`MAVR (Fig 3).
`
`Thromboembolic Complications
`Thromboembolic complications occurred in 3 patients
`with AVR (0.1 : 0.1%/pt-y). Of these 2, who were not
`anticoagulated, had a cerebral embolism after 20 and 28
`months, respectively, both of which resolved without
`
`Anticoagulant-Related Hemorrhage
`Major hemorrhagic complications were observed in 3
`patients, 2 with AVR (0.6 t 0.4%/pt-y) and 1 with MVR
`(1.0 i 1.0%lpt-y). Two patients had gastric bleeding 1 and
`2 months after AVR, and 1 of these patients died; both
`
`5Survival
`
`D
`
`1
`
`2
`
`5
`
`4
`
`5
`
`5
`
`7
`
`B
`
`9
`
`10
`
`Years Pastop
`
`Fig 1. Actuarial survival after isolated aortic (AVR), mitral (MVR),
`and mitral-aortic (MAVR) valve replacement with the Hancock peri-
`cardial xenograft.
`
`100
`T
`O—O'--O-—O'*O--0 93:54
`
`\¢....—g—.——¢
`
`83110
`
`KFree
`
`D
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`E
`
`9
`
`10
`
`Years Postop
`
`Fig .3. Actuarial freedom from thromboembolic complications. (Abbre-
`viations as in Fig 1.)
`
`NORRED EXHIBIT 2128 - Page 3
`NORRED EXHIBIT 2128 — Page 3
`
`
`

`
`Ann Thorac Surg
`I991;51:43U—7
`
`100
`
`90
`
`80
`
`70
`
`ZFree
`
`o—o AVR
`o—o we
`
`50 A—-A MAVR
`
`O
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`B
`
`9
`
`10
`
`Years Postop
`
`BORTOLOTTI ET AL
`HANCOCK PERICARDLAL XENOGRAFTS
`
`433
`
`ZFree
`
`A'—A MAVR
`
`O--O AVR
`O-C MVR
`
`0
`
`1
`
`2
`
`5
`
`6
`5
`4
`Years Postop
`
`7
`
`8
`
`9
`
`1 0
`
`Fig 4. Actuarial freedom from hemorrhage related to chronic anticoag-
`ulation. (Abbreviations as in Fig 1.)
`
`Fig 6. Actuarial freedom from paraprosthetic leak. (Abbreviations as
`in Fig 1.)
`
`patients were still on anticoagulants. One patient with
`MVR had a nonfatal gastrointestinal hemorrhage after 6
`years. Actuarial freedom from anticoagulant-related hem-
`orrhages at '7 years is 98% i 2% after AVR, 88% : 11%
`after MVR, and 100% after MAVR {Fig 4).
`
`Endocarditis
`
`Endocarditis involved 6 patients with AVR (2.0 3 0.7%!
`pt-y) and 1 with MVR (1.0 i 1.0%/pt-y). Of the AVR
`patients 3 underwent successful reoperation after 7, 29,
`and 4'7 months, respectively; 2 died without reoperation
`and 1 was apparently cured with medical treatment. One
`patient with MVR underwent reoperation successfully
`after 24 months. Actuarial freedom from endocarditis at 7
`years is 85% i 7% after AVR, 93% :t 6% after MVR, and
`100% after MAVR (Fig 5).
`
`Paraprosthetic Leak
`
`Paraprosthetic leak was observed only in 1 patient with
`AVR (0.03 i 0.03%/pt—y), who underwent successful HPX
`replacement after 16 months. Actuarial freedom from this
`
`complication at 7 years is 97% : 2% after AVR and 100%
`after MVR and MAVR (Fig 6).
`
`Reoperation
`A total of 34 patients required reoperation during the
`follow-up period. Reoperation was performed in 23 after
`AVR (7.5 -_t 1.6%/pt-y), because of paraprosthetic leak in 1
`and endocarditis in 3 without deaths, and because of
`structural deterioration in 19 with 2 deaths (10.5%; 70%
`CL, 3.5% to 23.2%); of the latter,
`1 had emergency
`reoperation because of acute onset of HPX regurgitation
`and 1 died at his second reoperation. Four patients
`underwent reoperation after MVR,
`1 because of en-
`docarditis and 3 because of strucmral deterioration with-
`
`‘? patients with MAVR underwent
`out deaths. Finally,
`reoperation because of structural deterioration of the
`aortic (4 patients), mitral (1 patient), or both HPXS (2
`patients) with one death (14.3%; 70% CL, 1.8% to 40.6%).
`However, in all patients but 1 both I-IPXs were explanted,
`replacing simultaneously also the one that appeared
`grossly normal. Actuarial freedom from reoperation for all
`
`o_o____8:o--o—o——-o
`‘
`o—o..,___
`
`931:5
`
`2Free
`
`0-—0 AVR
`C—C MVR
`
`A--A MAVR
`
`D
`
`1
`
`2
`
`3
`
`4-
`
`5
`
`G
`
`7
`
`8
`
`9
`
`10
`
`3Free
`
`O§8—o seen
`0 501:8
`
`O
`
`1
`
`2
`
`.3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Years Postop
`
`Years Poelop
`
`Fig 5. Actuarial freedom from prosthetic valve endocarditis. (Abbrevi-
`ations as in Fig 1.)
`
`Fig 7. Actuarial freedom from reoperation due to all causes. (Abbrevi-
`ations as in Fig 1.)
`'
`
`NORRED EXHIBIT 2128 - Page 4
`NORRED EXHIBIT 2128 — Page 4
`
`
`
`

`
`434
`
`BORTOLOTTI ET AL
`HANCOCK PERICARDIAL XENOGRAFT5
`
`Ann Thorax: Surg
`1991;51:430—7
`
`a
`
`!Free
`
`37$?
`
`D
`
`1
`
`2
`
`J
`
`4
`
`5
`
`6
`
`7
`
`B
`
`9
`
`10
`
`0 50:14-
`
`‘rear: Postop
`
`Fig 9. Actuarial freedom from valve-related death and reoperation.
`(Abbreviations as in Fig 1.)
`
`16.6 i 5.5%/pt—y after MAVR. At 7 years, actuarial free-
`dom from structural deterioration causing reoperation or
`death is 49% 2 8% after AVR, 69% i 13% after MVR, and
`18% 1 13% after MAVR (Fig 8a); actuarial freedom from
`structural deterioration, determined by reoperation, au-
`topsy, or clinical investigation, is 25% -L 7% after AVR,
`29% -_+ 14% after MVR, and 0% after MAVR (Fig 8b).
`
`Overall Valve Performance
`Actuarial freedom from valve-related death and reopen-
`tion at 7 years is 37% i 7% after AVR, 50% i 14% after
`MVR, and 13% 3 10% after MAVR (Fig 9). Actuarial
`freedom from valve—re1ated death and permanent disabil-
`ity at 7 years is 73% I 7% after AVR, 74% 1 13% after
`MVR, and 61% t 13% after MAVR (Fig 10). Actuarial
`freedom from valve-related death and morbidity at 7 years
`is 14% : 6% after AVR, 7% i 7% after MVR, and 0% after
`MAVR (Fig 11).
`
`Morphology of Hancock Pericardial Xenograft Explants
`The typical morphological substrates of I-{PX failure have
`been described in detail previously [10]. Briefly, most of
`the explants removed because of structural deterioration
`
`A____A_$
`
`100
`so \5:o—o—o—-—o—o
`o—o-—.. __
`so
`0 o._.o\I
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`73
`1 73%.?
`A—a—A-—-A—A s1s1:s
`59
`50
`l.
`40
`30
`20
`10
`
`5Free
`
`0
`
`1
`
`2
`
`3
`
`6
`5
`4
`Years Pustop
`
`7
`
`8
`
`9
`
`10
`
`Fig 10. Actuarial freedom from valve-related death and permanent
`disability. (Abbreviations as in Pig 1.)
`
`NORRED EXHIBIT 2128 - Page 5
`NORRED EXHIBIT 2128 — Page 5
`
`01234563910
`
`‘I'eorsPostop
`
`la) Actuarial freedom from prosthesis structural deterioration
`Fig 8.
`requiring reoperation or causing death. (b) Actuarial freedom from
`structural deterioration determined at reoperation, autopsy, or clinical
`investigation. (Abbreviations as in Fig 1.)
`
`causes at 7 years is 50% : 8% after AVR, 69% i 14% after
`MVR, and 20% I 14% after MAVR (Fig 7).
`
`Structural Deterioration
`
`A total of 32 patients underwent reoperation or died
`because of I-IPX structural deterioration, 21 after AVR (7.0
`1 1.5%lpt-y), 3 after MVR (3.1 : 1.8%/pt-y), and 8 after
`MAVR (14.8 t 5.2%ipt-y). After AVR 19 patients under-
`went reoperation and 2 died without reoperation after a
`mean interval of 5.0 t 1.4 years (range, 2.9 to 7.7 years).
`All patients with MVR underwent reoperation after a
`mean interval of 4.2 t 0.9 years (range, 3.2 to 5.1 years).
`After MAVR 7 patients underwent reoperation and 1 died
`without reoperation after a mean interval of 4.6 : 1.3
`years (range, 2.8 to 6.5 years).
`In 21 (78%) of the current survivors, 13 with AVE, 7
`with MVR, and 1 with MAVR, clinical and echocardio-
`graphic signs of HPX dysfunction have been documented
`at a mean of 5.8 i 1.5 years after operation (range, 1.8 to
`7.9 years), with predominant incompetence in 87% and
`stenosis in 13%. Including these patients the overall
`linearized incidence of HPX structural deterioration is 10.0
`
`2': 0.2%/pt-y after AVR, 10.6 i 3.3%lpt-y after MVR, and
`
`
`
`E 25i I5E
`
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`
`

`
`Ann Thorac Surg
`l99I;5l:430—7
`
`BORTOLOTH ET AL
`HANCOCK PERICARDEAL XENOGRAFFS
`
`435
`
`55Free
`
`01234553910
`‘rearsPostop
`
`Fig 11. Actuarial freedom from valve-related death and morbidity.
`(Abbreviations as in Fig 1.)
`
`showed tears of one or more cusps starting at the com-
`missures and extending downward causing cusp prolapse
`and various degrees of regurgitation (Figs 12, 13); valve
`incompetence was the predominant mode of failure in
`more than 80% of explants studied and it was similar for
`HPXS implanted in mitral and aortic position. With the
`exception of infected valves, which showed severe calcific
`deposits, calcification was absent in most HPXs explanted
`for structural deterioration.
`
`Comment
`
`Biological prostheses have been extensively employed in
`the past, mainly to overcome the problems related to the
`use of mechanical devices, such as thromboembolic com-
`plications or hemorrhage related to the indefinite use of
`anticoagulants, which is mandatory in patients with me-
`chanical prostheses but may be avoidable in many of
`those with tissue valves [11—13].
`Bioprostheses manufactured with bovine pericardium
`have gained worldwide acceptance particularly because
`they combine the biocompatibility of biological tissue with
`a Superior hemodynamic performance, when compared
`with porcine valves [14]. However, despite this advan-
`tage, there have been reports that, with increasing fre-
`quency, have called attention to the high incidence of
`early failures of pericardial xenografts. Gabbay and col-
`leagues [2], in 1984, demonstrated the similarity between
`the lesions observed in Ionescu—Shiley pericardial xe-
`nografts and those noted in the same valves removed
`from a fatigue test system, showing also a poor durability
`of this device within 6 years after clinical MVR [3]. The
`same conclusions were reached by other groups, includ-
`ing ourselves, who experienced a high incidence of early
`failures of peiicardial xenografts, either Ionescu—Shiley or
`Hancock, regardless of the site of valve implantation [4, 6,
`15, 16].
`Morphological studies have demonstrated that pericar-
`dial xenografts fail mostly because of cusp laceration,
`unlike porcine bioprostheses, in which structural deterio-
`ration is almost exclusively caused by tissue mineraliza-
`
`tion [17]. Cusp tears in pericardial xenografts are almost
`never calcium—related; they usually start at the commis-
`sures and are the result of the Continuous bending stress
`or tissue abrasion on the Dacron cloth that covers the
`
`prosthetic stem’: [2, 10]. Repeated observations on surgical
`or autopsy specimens have conclusively shown that such
`mode of failure is typical of these devices, appears highly
`predictable, and is clearly related to a faulty prosthetic
`design [2, 5, 10, 18, 19]. Furthermore, small cusp rupture,
`which may initially cause only trivial prosthetic regurgi-
`tation, may acutely progress, seriously jeopardizing pa-
`tient survival [7, 8].
`We [6j have previously reported our medium-term
`
`Fig 12. Cross view ofan aortic (:1) and a mitral (bl Hancock pericar-
`dial Icrlogmfl explauicd from 2 dijfcrent patients because of severe
`regurgitation after 75 and 58 months, respectively. Both explarils
`showed typical features of pericardial valve failure represented by cusp
`tears starting at the commissural level.
`
`NORRED EXHIBIT 2128 - Page 6
`NORRED EXHIBIT 2128 — Page 6
`
`
`
`

`
`436
`
`BORTOLOTTI ET AL
`HANCOCK PERICARDIAL xsnooamrrs
`
`Ann Thorac Surg
`1991,'51:43[)—7
`
`Fig 13. View afar: aortic (left) and a mi-
`tral {right) Hancock pericardial xenograft
`explanted from the same patient after 72
`months. The mitral valve showed tears at
`
`two cammissures causing severe incompe-
`teflct‘: the aortic valve, which appeared
`grossly normal, was replaced prophylacti-
`ca-lly.
`
`
`
`results with the HPX in a limited series of patients in
`whom this device was used as alternative to the Hancock
`
`porcine bioprosthesis, the latter having been the tissue
`valve of choice in our center for almost two decades [20].
`The purpose of this study was to assess the real incidence
`of structural deterioration of I-IPX at a longer follow-up,
`and to determine whether asymptomatic HPX recipients
`with or without clinical evidence of valve failure should
`
`undergo a planned, prophylactic HPX replacement.
`Reevaluation of patients with an HPX have confirmed
`the extremely poor durability of this device at 7 years,
`which still cannot be considered a long-terrn postopera-
`tive interval, as indicated by the high incidence of struc-
`tural deterioration particularly after AVR and MAVR.
`Moreover, if we gather all cases of HPX structural deteri-
`oration observed at reoperation or autopsy with those
`determined at clinical investigation, as currently recom-
`mended [9], only 25% of patients with AVR, 29% of those
`with MVR, and none of those with MAVR are free from
`this complication at '7 years. These results, together with
`the morphological reports from our and other groups [10,
`18, 19], confirm that bioprostheses obtained by individu-
`ally sewing to a stent three separate leaflets of pericar-
`dium did not provide a durable valve substitute, as also
`witnessed by the retrieval from the market of some of
`these devices.
`Transthoracic two—dimensional eglrocardiography,
`which allows frequent monitoring of prosthetic function,
`showed clear signs of valve failure in 78% of our current
`survivors with their original I-IPX still in place. Further-
`more, 3 of our "patients died because of I-IPX structural
`deterioration before reoperation could be performed, and
`in 1, sudden onset of massive aortic regurgitation
`prompted emergency, unsuccessful reoperation. Finally,
`in our experience reopera tion for structural deterioration
`of bioprosthetic valves, when performed on an elective
`basis, is associated with an acceptable risk [21, 22].
`
`these considerations not only
`In our opinion, all
`strongly support the need for a continuous and closer
`reevaluation of HPX recipients by noninvasive methods,
`but also justify an early prophylactic replacement of an
`HPX even in asymptomatic patients with oniy initial signs
`of prosthetic failure who, therefore, should be scheduled
`for an elective reoperation.
`
`We thank Paola Melacini, MD, for the echocardiographic fol-
`low-up of some patients included in this study and Gian Carlo
`Pengo and Agostino Leorin for their technical assistance.
`
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