Journal of the American College of Cardiology
`© 2006 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`EXPEDITED REVIEW
`
`Vol. 47, No. 6, 2006
`ISSN 0735-1097/06/$32.00
`doi:10.1016/j.jacc.2006.01.049
`
`Treatment of Calcific Aortic
`Stenosis With the Percutaneous Heart Valve
`Mid-Term Follow-Up From the Initial
`Feasibility Studies: The French Experience
`Alain Cribier, MD, FACC,* Helene Eltchaninoff, MD,* Christophe Tron, MD,* Fabrice Bauer, MD,*
`Carla Agatiello, MD,* Deborah Nercolini, MD,* Sydney Tapiero, MD,* Pierre-Yves Litzler, MD,†
`Jean-Paul Bessou, MD,† Vasilis Babaliaros, MD*
`Rouen, France
`
`OBJECTIVES
`
`METHODS
`
`RESULTS
`
`The aim of this work was to study the feasibility, safety, efficacy, and durability of
`percutaneous heart valve (PHV) implantation in the aortic position.
`BACKGROUND We developed a PHV (equine pericardium valve in a balloon-expandable, stainless-steel
`stent) to treat patients with inoperable aortic stenosis (AS).
`Thirty-six patients (aortic valve area ⱕ0.7 cm2, New York Heart Association [NYHA]
`functional class IV, and severe comorbidities), formally declined for surgery, were recruited on
`a compassionate basis. The PHV was implanted by retrograde or antegrade trans-septal
`approach. Clinical and echocardiographic outcomes were assessed serially.
`Twenty-seven patients were implanted successfully (23 antegrade, 4 retrograde) in the
`subcoronary position with improvement in valve area (0.60 ⫾ 0.11 cm2 to 1.70 ⫾ 0.10 cm2,
`p ⬍ 0.0001) and transvalvular gradient (37 ⫾ 13 mm Hg to 9 ⫾ 2 mm Hg, p ⬍ 0.0001).
`Paravalvular aortic regurgitation was grade 0 to 1 (n ⫽ 10), grade 2 (n ⫽ 12), and grade 3
`(n ⫽ 5). One week post-procedure, improvement in left ventricular function (45 ⫾ 18% to
`53 ⫾ 14%, p ⫽ 0.02) was most pronounced in patients with ejection fraction ⬍50% (35 ⫾
`10% to 50 ⫾ 16%, p ⬍ 0.0001). Thirty-day major adverse events after successful implantation
`were 26% (pericardial tamponade, stroke, arrhythmia, urosepsis, and one death unexplained
`at autopsy). Eleven patients are currently alive with follow-up of 9 months (n ⫽ 2), 10 months
`(n ⫽ 3), 11 months (n ⫽ 1), 12 months (n ⫽ 2), 23 months (n ⫽ 1), and 26 months (n ⫽
`2). All patients experienced amelioration of symptoms (⬎90% NYHA functional class I to
`II). Percutaneous heart valve function remained unchanged during follow-up, and no deaths
`were device-related.
`CONCLUSIONS Percutaneous heart valve implantation is feasible in inoperable patients with end-stage AS
`leading to hemodynamic and clinical
`improvement. Continued advances and improved
`patient selection should decrease adverse events in the near future.
`(J Am Coll Cardiol
`2006;47:1214–23) © 2006 by the American College of Cardiology Foundation
`
`Aortic stenosis, the most common form of valvular heart
`disease in adults (1), affects thousands of patients every year,
`causing significant morbidity and mortality in those with
`advanced disease. To date, surgical valve replacement is the
`only effective therapy for these patients, improving survival
`and ameliorating symptoms (2). However, almost one-third
`of patients with severe valvular lesions who could benefit
`most from intervention are declined for operative treatment
`because of end-stage disease, advanced age, and multiple
`comorbidities with subsequent short life expectancy (1). The
`size of this untreated cohort is expected to increase in the
`next several years reflecting the aging population and
`
`From the University of Rouen, *Department of Cardiology and †Department of
`Cardiac Surgery, Charles Nicolle Hospital, Rouen, France. Financial support was
`provided by Percutaneous Valve Technologies Inc. Edwards Lifesciences (Irvine,
`California), the company that designed and provided the percutaneous valve used,
`provided funding for this clinical investigation.
`Manuscript received December 20, 2005; revised manuscript received January 19,
`2006, accepted January 24, 2006.
`
`improving therapeutic options in patients with multiple and
`advanced medical conditions.
`The initial attempts to treat non-surgical patients with
`advanced aortic stenosis began with balloon aortic valvuloplasty
`(BAV) in 1985 (3). This technique, initially met with enthu-
`siasm, was largely abandoned by clinicians as the benefits of
`valvuloplasty rarely lasted more than one year (4). The problem
`of valve restenosis after balloon dilation was finally addressed in
`1999 with the development of a bioprosthetic heart valve,
`which was sutured onto a balloon expandable stent (Percuta-
`neous Valve Technologies, Edwards Lifesciences, Irvine, Cal-
`ifornia) (Fig. 1). Though previous attempts at percutaneous
`valve replacement in the aortic position had been limited by the
`applicability to humans (5,6), this percutaneous heart valve
`(PHV) was successfully implanted on April 16, 2002, in a
`patient with inoperable aortic stenosis and life-threatening
`comorbidities (7).
`Since then,
`improvements in technique and a more
`complete comprehension of percutaneous aortic valve re-
`
`Page 1 of 10
`
`Edwards Lifesciences v. Boston Scientific Scimed
`IPR2017-00060 U.S. Patent 8,992,608
`Exhibit 2005
`
`

`

`Journal of the American College of Cardiology
`© 2006 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`EXPEDITED REVIEW
`
`Vol. 47, No. 6, 2006
`ISSN 0735-1097/06/$32.00
`doi:10.1016/j.jacc.2006.01.049
`
`Treatment of Calcific Aortic
`Stenosis With the Percutaneous Heart Valve
`Mid-Term Follow-Up From the Initial
`Feasibility Studies: The French Experience
`Alain Cribier, MD, FACC,* Helene Eltchaninoff, MD,* Christophe Tron, MD,* Fabrice Bauer, MD,*
`Carla Agatiello, MD,* Deborah Nercolini, MD,* Sydney Tapiero, MD,* Pierre-Yves Litzler, MD,†
`Jean-Paul Bessou, MD,† Vasilis Babaliaros, MD*
`Rouen, France
`
`OBJECTIVES
`
`METHODS
`
`RESULTS
`
`The aim of this work was to study the feasibility, safety, efficacy, and durability of
`percutaneous heart valve (PHV) implantation in the aortic position.
`BACKGROUND We developed a PHV (equine pericardium valve in a balloon-expandable, stainless-steel
`stent) to treat patients with inoperable aortic stenosis (AS).
`Thirty-six patients (aortic valve area ⱕ0.7 cm2, New York Heart Association [NYHA]
`functional class IV, and severe comorbidities), formally declined for surgery, were recruited on
`a compassionate basis. The PHV was implanted by retrograde or antegrade trans-septal
`approach. Clinical and echocardiographic outcomes were assessed serially.
`Twenty-seven patients were implanted successfully (23 antegrade, 4 retrograde) in the
`subcoronary position with improvement in valve area (0.60 ⫾ 0.11 cm2 to 1.70 ⫾ 0.10 cm2,
`p ⬍ 0.0001) and transvalvular gradient (37 ⫾ 13 mm Hg to 9 ⫾ 2 mm Hg, p ⬍ 0.0001).
`Paravalvular aortic regurgitation was grade 0 to 1 (n ⫽ 10), grade 2 (n ⫽ 12), and grade 3
`(n ⫽ 5). One week post-procedure, improvement in left ventricular function (45 ⫾ 18% to
`53 ⫾ 14%, p ⫽ 0.02) was most pronounced in patients with ejection fraction ⬍50% (35 ⫾
`10% to 50 ⫾ 16%, p ⬍ 0.0001). Thirty-day major adverse events after successful implantation
`were 26% (pericardial tamponade, stroke, arrhythmia, urosepsis, and one death unexplained
`at autopsy). Eleven patients are currently alive with follow-up of 9 months (n ⫽ 2), 10 months
`(n ⫽ 3), 11 months (n ⫽ 1), 12 months (n ⫽ 2), 23 months (n ⫽ 1), and 26 months (n ⫽
`2). All patients experienced amelioration of symptoms (⬎90% NYHA functional class I to
`II). Percutaneous heart valve function remained unchanged during follow-up, and no deaths
`were device-related.
`CONCLUSIONS Percutaneous heart valve implantation is feasible in inoperable patients with end-stage AS
`leading to hemodynamic and clinical
`improvement. Continued advances and improved
`patient selection should decrease adverse events in the near future.
`(J Am Coll Cardiol
`2006;47:1214–23) © 2006 by the American College of Cardiology Foundation
`
`Aortic stenosis, the most common form of valvular heart
`disease in adults (1), affects thousands of patients every year,
`causing significant morbidity and mortality in those with
`advanced disease. To date, surgical valve replacement is the
`only effective therapy for these patients, improving survival
`and ameliorating symptoms (2). However, almost one-third
`of patients with severe valvular lesions who could benefit
`most from intervention are declined for operative treatment
`because of end-stage disease, advanced age, and multiple
`comorbidities with subsequent short life expectancy (1). The
`size of this untreated cohort is expected to increase in the
`next several years reflecting the aging population and
`
`From the University of Rouen, *Department of Cardiology and †Department of
`Cardiac Surgery, Charles Nicolle Hospital, Rouen, France. Financial support was
`provided by Percutaneous Valve Technologies Inc. Edwards Lifesciences (Irvine,
`California), the company that designed and provided the percutaneous valve used,
`provided funding for this clinical investigation.
`Manuscript received December 20, 2005; revised manuscript received January 19,
`2006, accepted January 24, 2006.
`
`improving therapeutic options in patients with multiple and
`advanced medical conditions.
`The initial attempts to treat non-surgical patients with
`advanced aortic stenosis began with balloon aortic valvuloplasty
`(BAV) in 1985 (3). This technique, initially met with enthu-
`siasm, was largely abandoned by clinicians as the benefits of
`valvuloplasty rarely lasted more than one year (4). The problem
`of valve restenosis after balloon dilation was finally addressed in
`1999 with the development of a bioprosthetic heart valve,
`which was sutured onto a balloon expandable stent (Percuta-
`neous Valve Technologies, Edwards Lifesciences, Irvine, Cal-
`ifornia) (Fig. 1). Though previous attempts at percutaneous
`valve replacement in the aortic position had been limited by the
`applicability to humans (5,6), this percutaneous heart valve
`(PHV) was successfully implanted on April 16, 2002, in a
`patient with inoperable aortic stenosis and life-threatening
`comorbidities (7).
`Since then,
`improvements in technique and a more
`complete comprehension of percutaneous aortic valve re-
`
`Page 1 of 10
`
`

`

`JACC Vol. 47, No. 6, 2006
`March 21, 2006:1214–23
`
`Cribier et al.
`Mid-Term Experience of Percutaneous Heart Valve
`
`1215
`
`Abbreviations and Acronyms
`⫽ aortic valve area
`AVA
`⫽ balloon aortic valvuloplasty
`BAV
`I-REVIVE ⫽ Initial Registry of EndoVascular
`Implantation of Valves in Europe trial
`MACCE ⫽ major adverse cardiac and cerebrovascular
`events
`⫽ myocardial infarction
`MI
`⫽ New York Heart Association
`NYHA
`⫽ percutaneous heart valve
`PHV
`RECAST ⫽ Registry of Endovascular Critical Aortic
`Stenosis Treatment trial
`⫽ transthoracic echocardiography
`
`TTE
`
`placement have been developed and partially reported in six
`patients (four patients before the onset of the protocol-
`driven study, two patients included in the current analysis)
`(8). In August 2003, we started a single-center pilot trial to
`study the feasibility and safety of compassionate percutane-
`ous valve implantation in patients with end-stage aortic
`stenosis and no surgical options (the Initial Registry of
`EndoVascular
`Implantation of Valves
`in Europe
`[I-REVIVE] trial). With the acquisition of Percutaneous
`Valve Technologies (Fort Lee, New Jersey) by Edwards
`Lifesciences, the protocol continued with minor amend-
`ments as the Registry of Endovascular Critical Aortic
`Stenosis Treatment (RECAST) trial. In the following text
`we describe our experience with the initial 36 patients
`enrolled in our institution for percutaneous aortic valve
`implantation.
`
`METHODS
`
`Thirty-six elderly patients that were able to give informed
`and signed consent were recruited for percutaneous valve
`implantation at Charles Nicolle Hospital, University of
`Rouen, France. Eligibility for entry into the study required
`the presence of severe aortic valve stenosis (ⱕ0.7 cm2) with
`associated symptoms (by New York Heart Association
`[NYHA] functional class IV dyspnea) that were expected to
`
`benefit from isolated valve replacement. Patients had to be
`refused for standard aortic valve replacement by two inde-
`pendent cardiac surgeons on the basis of their high risk for
`surgery (Parsonnet’s score ⱖ30) (9). Exclusion criteria
`included the following: vascular disease that precluded
`access, severe deformation of the chest, intracardiac throm-
`bus, unprotected stenosis of the left main coronary artery
`not amenable to percutaneous intervention, myocardial
`infarction (MI) within seven days, prosthetic heart valves,
`leukopenia (⬍3,000 white blood cells/
`active infection,
`mm3), coagulopathy, active bleeding, or acute anemia (he-
`moglobin ⬍9 mg/dl). Patients that could not be fully dilated
`with a 23-mm aortic valvuloplasty balloon (notable waist)
`and patients with a native aortic valve annulus size ⬎24 mm
`or ⬍19 mm were also excluded. The study was approved
`and performed in accordance with the regulations of our
`institutional ethics committee (CCPPRB, Comité Consul-
`tatif de Protection des Personnes dans la Recherche Bio-
`médicale) and the French government
`(AFSSAPS,
`Agence Francaise de Sécurité Sanitaire des Produits de
`Santé).
`Definitions and baseline measurements. The primary
`objectives of this study were to evaluate the feasibility and
`safety of PHV implantation. Feasibility was evaluated by
`procedural success defined as accurate placement of the
`PHV in the subcoronary position with associated improve-
`ment of hemodynamic parameters (ⱖ30% reduction in
`mean transvalvular aortic gradient) and absence of severe
`aortic regurgitation (grade 4) (10). Safety was evaluated by
`the occurrence of major adverse cardiac and cerebrovascular
`events (MACCE) or other valve-related adverse events.
`Major adverse cardiac and cerebrovascular events were
`defined as death, MI, emergent cardiac surgery, and cere-
`brovascular accident. Any MACCE that occurred either
`during or within 30 days of PHV implantation was consid-
`ered a procedure-related complication. Any adverse event
`that was secondary to PHV malfunction after implantation
`was considered a device-related complication. Safety was
`
`Figure 1. (A) Top view of the percutaneous heart valve in the closed position showing the three pericardial leaflets sutured to the stainless-steel stent. (B)
`Side view of the percutaneous heart valve crimped over a 3-cm ⫻ 22-mm balloon catheter. (C) Side view of the percutaneous heart valve after being
`expanded by the delivery balloon.
`
`Page 2 of 10
`
`

`

`1216
`
`Cribier etal.
`Mid-Term Experience of Percutaneous Heart Valve
`
`assessed at 1, 3, 6, and 12 months; after 1 year, patients were
`followed every 6 months.
`The secondary objectives of the study were to obtain data
`regarding the efficacy and durability of the PHV. Efficacy
`and durability were assessed by NYHA functional classifi-
`cation and hemodynamic improvement (measured by echo-
`cardiography). Hemodynamic variables, such as native and
`prosthetic aortic valve gradient, area, and regurgitation
`(valvular or paravalvular, graded from 0 to 4) (10), were
`evaluated by standard methods of echocardiographic mea-
`surement. Clinical evaluation and echocardiographic exam-
`ination were performed immediately post-procedure, on day
`1, day 7, 1 month, 3 months, 6 months, and 12 months;
`afterwards, patients were followed every 6 months.
`Valve anatomy and function were determined in all
`patients by transesophageal echocardiography and transtho-
`racic echocardiography (TTE) pre-procedure; coronary
`anatomy was also evaluated pre-procedure. In addition to
`echocardiographic measurements, right-sided heart pres-
`sures, cardiac output, oxygen saturations, and aortic trans-
`valvular pressure gradient were measured on the day of
`implantation by invasive methods. Valve calcification was
`assessed qualitatively by fluoroscopic evaluation.
`Procedure. The materials and technique for implantation
`have been previously described in detail (7,8,11). Briefly,
`each procedure was performed under mild sedation and
`local anesthesia. All patients received aspirin (160 mg) and
`clopidogrel (300 mg) 24 h before valve placement; antibi-
`otics for procedural prophylaxis (first generation cephalo-
`sporin) were given 1 h before. After measurement of
`baseline hemodynamics, supra-aortic angiography and
`placement of a right ventricular pacing lead were performed.
`Heparin 5,000 IU was given intravenously before retrograde
`catheterization of the aortic valve. Retrograde pre-dilation
`of the aortic valve was done in all patients (except two who
`
`JACC Vol. 47, No. 6, 2006
`March 21, 2006:1214–23
`
`were dilated antegrade) with a 23-mm Z-MED balloon
`(NuMED Inc., Hopkinton, New York) during rapid ven-
`tricular pacing (200 to 220 stimulations/min) (Fig. 2).
`Delivery of the valve was performed by an antegrade
`trans-septal or retrograde approach.
`In the antegrade approach, atrial trans-septal catheteriza-
`tion was performed, and a 7-F Swan-Ganz catheter (Ed-
`wards LifeSciences, Irvine, California) was used to cross the
`mitral valve and direct a guidewire across the aortic valve
`(Fig. 3A). Using the pigtail catheter as a conduit, this
`guidewire was exchanged for an extra stiff guidewire, which
`was snared and externalized through the left femoral artery
`sheath. The septum was then dilated with a 10-mm sep-
`tostomy balloon. The PHV was advanced over the guide-
`wire through a 24-F sheath (COOK, Bjaeverskov, Den-
`mark) in the right femoral vein. A 7-F Sones catheter
`(Cordis, Miami, Florida) was advanced over the same
`guidewire from the left femoral artery to facilitate valve
`placement (Fig. 3B).
`In the retrograde approach, pre-closure of the common
`femoral artery puncture site was done before introduction of
`the 24-F sheath (four patients) using two 10-F Prostar XL
`devices (Abbott Vascular Devices, Redwood City, Califor-
`nia) (12). After retrograde catheterization of the aortic
`valve, the crossing catheter was exchanged for an extra stiff
`guidewire, and pre-dilation of the aortic valve was done as
`described previously. The femoral artery was then pre-
`dilated with a series of dilators of increasing size (18-, 20-,
`and 22-F) in order to facilitate entry of the 24-F sheath.
`Regardless of the approach used, the final steps of
`PHV implantation were similar for both methods. The
`PHV was mounted onto a 22-mm Z-MED II balloon
`(NuMed Canada Inc., Cornwall, Ontario, Canada) using
`a specially designed crimper. The supra-aortic angiogram
`and native valve calcifications were used as anatomical
`
`Figure 2. Electrocardiogram and aortic pressure curve depicting the effect of rapid stimulation (arrows) of the right ventricle (200 to 220 stimulations/min).
`
`Page 3 of 10
`
`

`

`JACC Vol. 47, No. 6, 2006
`March 21, 2006:1214–23
`
`Cribier et al.
`Mid-Term Experience of Percutaneous Heart Valve
`
`1217
`
`Figure 3. (A) Swan-Ganz (SG) catheter is used to direct a guidewire (GW) across the native aortic valve in the antegrade approach. (B) Guidewire loop in the
`left ventricle is tracked by the percutaneous heart valve from the right femoral vein (antegrade approach). Sones catheter (SC) from the left femoral artery is used
`to help position the percutaneous heart valve. Native aortic valve calcifications (arrows) in the anteroposterior projection transect the mid-line of the length of the
`stent valve. (C) Deployment of the percutaneous heart valve using the antegrade approach. (D) Valve deployment via the retrograde method. (E) Supra-aortic
`angiogram showing no aortic regurgitation and the subcoronary position of the percutaneous heart valve (arrow: filling of the left coronary artery). (F) Cranial view
`of the percutaneous heart valve showing symmetrical and complete expansion of the stent frame. MS ⫽ Mullins sheath; PL ⫽ pacing lead.
`
`landmarks for valve placement in the anteroposterior
`projection (mid-line of the stent frame was placed at the
`level of the calcifications). All valves were deployed (Figs.
`3C and 3D) during rapid pacing except two patients that
`were implanted during cardiac arrest. Hemodynamic
`improvement was measured immediately afterwards, and
`a supra-aortic angiogram was performed in patients
`without renal insufficiency to verify placement as well as
`the presence of aortic regurgitation (Fig. 3E). A cranial
`view of the stent-valve was used to evaluate uniform
`expansion of the PHV (Fig. 3F). Arterial access was
`managed using closure devices and/or surgical repair
`
`before device use or in cases of device failure. Venous
`access was managed by manual compression. Antibiotics
`were given up to 48 h after the procedure. Subcutaneous
`enoxaparin (40 mg/day) was administered until the day of
`discharge. Clopidogrel (75 mg/day) was continued for one
`month, and aspirin (160 mg/day) was continued indefinitely.
`Statistical analysis. Comparison of clinical and echocar-
`diographic variables with baseline values was performed
`using the non-parametric Wilcoxon rank sum test. Compar-
`ison of procedural times was done by the Mann-Whitney U
`test. Differences were considered statistically significant for
`p ⬍ 0.05. All values were expressed as mean ⫾ SD.
`
`Page 4 of 10
`
`

`

`1218
`
`Cribier etal.
`Mid-Term Experience of Percutaneous Heart Valve
`
`JACC Vol. 47, No. 6, 2006
`March 21, 2006:1214–23
`
`Table 1. Baseline Characteristics of Patients
`Characteristics
`
`n (%)
`80 ⫾ 7 (range 62–91)
`9 (24)
`21 (57)
`
`Age, yrs
`ⱖ85 yrs
`Gender, male
`Ejection fraction
`⬎50%
`11 (30)
`15 (42)
`31%–50%
`ⱕ30%
`10 (28)
`2 (5)
`Cardiogenic shock
`28 (76)
`Coronary artery disease
`8 (22)
`CABG surgery
`7 (19)
`Previous MI
`12 (32)
`Diabetes mellitus
`26 (70)
`Hypertension
`14 (38)
`Renal failure*
`15 (41)
`Severe lung disease
`14 (38)
`Pulmonary hypertension†
`10 (27)
`Peripheral vascular disease
`2 (5)
`Porcelain aorta
`4 (11)
`Carotid disease
`3 (8)
`Previous stroke
`12 (32)
`Mitral valve disease
`ⱖ grade 3 regurgitation
`10 (27)
`ⱖ moderate stenosis
`2 (5)
`2 (5)
`Active cancer
`4 (11)
`Previous chest irradiation
`22 (59)
`Other comorbidity
`47 ⫾ 9
`Parsonnet’s score
`12 ⫾ 2
`EuroSCORE
`*Serum creatinine ⬎2 mg/dl or creatinine clearance ⱕ30 ml/min. †Mean pulmonary
`artery pressure ⬎30 mm Hg or systolic pulmonary artery pressure ⬎60 mm Hg.
`CABG ⫽ coronary artery bypass grafting.
`
`RESULTS
`
`Patient characteristics. Characteristics of the patients re-
`cruited are shown in Table 1. In addition to their age and
`
`end-stage aortic stenosis, these patients had extensive and
`multiple comorbid conditions (ⱖ3 per patient). Other
`significant comorbid conditions not detailed in the table
`included severe kyphoscoliosis, severe osteoporosis, hepatic
`cirrhosis, systemic scleroderma, angiodysplasia of the colon
`with chronic anemia (hematocrit ⬍30%), myelodysplastic
`syndrome with chronic anemia, chronic steroid use, an-
`tiphospholipid syndrome with previous thrombotic history,
`peripheral neuropathy, severe obesity, severe right heart
`failure, and Parkinson’s disease. One patient was a Jehovah’s
`Witness. All native aortic valves were tricuspid and calcified
`(12 heavy, 17 moderate, 7 mild).
`Procedural success. Of the 36 patients enrolled, 35 pa-
`tients were taken to the catheterization laboratory (Fig. 4):
`1 patient died of sudden cardiac death while awaiting his
`procedure. After pre-dilation, one procedure was cancelled
`because the annulus size was inappropriately large for a
`23-mm PHV (the 23-mm balloon could not be stabilized in
`the native valve during valvuloplasty). One patient
`in
`cardiogenic shock arrested during pre-dilation of the aortic
`valve and had an unsuccessful resuscitation. Among 33
`patients, the antegrade trans-septal approach was used in 26
`cases, and retrograde implantation was attempted in the
`remaining 7 cases. Twenty-two of the antegrade implanta-
`tions were performed successfully with four technical fail-
`ures. Two of these patients could not hemodynamically
`tolerate the guidewire across the mitral valve, and the
`procedure was aborted before proceeding to valve implan-
`tation. In the other two patients, PHV migration occurred
`immediately after implantation. In one case of migration,
`the PHV was positioned too high, and in the other case, the
`native valve was only mildly calcified with a large annulus
`
`Figure 4. Schematic representation of patient enrollment and procedural success (*Patient #16 was implanted successfully by the antegrade approach after
`initial retrograde failure). PHV ⫽ percutaneous heart valve.
`
`Page 5 of 10
`
`

`

`JACC Vol. 47, No. 6, 2006
`March 21, 2006:1214–23
`
`Cribier et al.
`Mid-Term Experience of Percutaneous Heart Valve
`
`1219
`
`(23 mm). In both situations, the PHV was deployed in the
`aorta (thoracic descending aorta in one, and between the left
`common carotid and left subclavian artery in the other)
`without sequelae. In all cases of technical
`failure, the
`patients were discharged from the catheterization laboratory
`in stable condition.
`Four of seven patients were successfully implanted using
`the retrograde method. Of the three technical failures, one
`patient could not be implanted because the stent-mounted
`catheter was too short to reach the aortic valve (PHV
`removed surgically from the femoral artery). Two of the
`patients’ valves could not be crossed retrograde with the
`delivery system because of extensive calcification, and the
`PHV was implanted in the descending aorta without
`sequelae. In one of these cases, the PHV was successfully
`implanted by the antegrade approach in the same session. A
`total of 27 (75%) patients were implanted successfully.
`The procedural time for the antegrade approach was 164
`⫾ 38 min in the I-REVIVE trial and 130 ⫾ 30 min in
`the RECAST trial (p ⫽ 0.047). No detectable atrial
`shunt could be measured by oximetry at the end of the
`procedure. Procedural time for the retrograde approach
`(only I-REVIVE patients) was 96 ⫾ 23 min.
`Echocardiographic data. A statistically significant increase
`in aortic valve area (AVA) was seen in the group of patients
`with successful implantation. Twenty-four hours after the
`procedure, the AVA, measured by TTE, increased from
`0.60 ⫾ 0.09 cm2 to 1.70 ⫾ 0.11 cm2 (p ⬍ 0.0001, n ⫽ 25
`
`surviving patients). At 1, 3, 6, 12, and 24 months, the AVA
`remained stable at 1.68 ⫾ 0.11 cm2 (n ⫽ 16), 1.66 ⫾ 0.09
`cm2 (n ⫽ 12), 1.63 ⫾ 0.07 cm2 (n ⫽ 7), 1.75 ⫾ 0.18 cm2
`(n ⫽ 3), and 1.64 ⫾ 0.04 cm2 (n ⫽ 2), respectively (p ⫽ NS)
`(Fig. 5A). Similarly, the mean aortic gradient decreased
`from 37 ⫾ 13 mm Hg to 9 ⫾ 2 mm Hg post-procedure
`(p ⬍ 0.0001, n ⫽ 25), and remained 10 ⫾ 2 mm Hg, 11 ⫾
`2 mm Hg, 11 ⫾ 2 mm Hg, 10 ⫾ 1 mm Hg, and 12 ⫾ 1 mm
`Hg (1, 3, 6, 12, and 24 months, respectively) during
`follow-up (p ⫽ NS) (Fig. 5B). Peak velocity across the
`aortic valve decreased from 4.01 ⫾ 0.60 m/s to 2.25 ⫾ 0.40
`m/s post-implantation (p ⬍ 0.0001), and was 2.36 ⫾ 0.25
`m/s, 2.45 ⫾ 0.25 m/s, 2.42 ⫾ 0.31 m/s, 2.33 ⫾ 0.11 m/s,
`and 2.36 ⫾ 0.17 m/s upon follow-up (p ⫽ NS).
`The ejection fraction also improved significantly in the
`patient group with a successful implantation. Left ventric-
`ular function was 45 ⫾ 18% pre-procedure and 53 ⫾ 14%
`(Fig. 6A) one week post-procedure (n ⫽ 22, p ⫽ 0.02). The
`most dramatic improvements were seen in patients that had
`depressed function at baseline (Fig. 6B). In these 15
`patients, the ejection fraction (35 ⫾ 10%) increased to 50 ⫾
`16% (p ⬍ 0.0001) at one week.
`Aortic regurgitation in patients after implantation was
`always paravalvular in origin. In 10 patients, the regurgita-
`tion was mild (grade 0 to 1). In 10 patients, moderate (grade
`2) paravalvular leak was observed, and in 5, moderate-to-
`severe regurgitation was noted (grade 3). In the two patients
`without post-procedure echocardiography, aortic insuffi-
`
`Figure 5. (A) Improvements in aortic valve area in patients 24 h, 1, 3, 6, 12, and 24 months after successful implantation. (B) Decrease in mean aortic
`gradient in patients 24 h, 1, 3, 6, 12, and 24 months after successful implantation.
`
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`1220
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`Cribier etal.
`Mid-Term Experience of Percutaneous Heart Valve
`
`JACC Vol. 47, No. 6, 2006
`March 21, 2006:1214–23
`
`Figure 6. (A) Improvement in ejection fraction one week after successful implantation (n ⫽ 22). (B) Improvement in ejection fraction comparing baseline
`values with values one week after successful implantation in patients with left ventricular function ⬍50% (n ⫽ 15).
`
`ciency was grade 2 by angiography. The amount of para-
`valvular leak was unchanged in most patients during follow-
`up. In two patients, an improvement of paravalvular leak by
`one grade was seen three months after the procedure. In two
`patients, an increase of paravalvular leak by one grade was
`seen after one week. No atrial shunt was visualized by TTE
`at three-month follow-up.
`Clinical follow-up. Six of the 27 patients with PHV
`implantation had a complication during the procedure. Two
`patients died as a consequence of cardiac tamponade. One
`of these patients, with severe dextrorotation of the heart,
`had a complicated trans-septal puncture. The other patient,
`on chronic steroid therapy for pulmonary fibrosis, had a
`slow bleeding perforation of the right ventricle from the
`pacing lead; infection and subsequent sepsis developed after
`surgical repair. Another patient on chronic steroids for
`treatment of rheumatologic disease developed urosepsis
`three days after the procedure and died two days later.
`Complete heart block with temporary loss of pacing lead
`contact occurred in one case; despite successful PHV im-
`plantation, prolonged resuscitation lead to irreversible brain
`damage. One patient developed a stroke during retrograde
`catheterization of the aortic valve. She expired at 33 days
`secondary to multi-organ failure. Intractable hypotension in
`
`the procedure room after removal of the 24-F sheath from
`the femoral artery was the cause of another death. No
`etiology was found at autopsy; the PHV appeared normal
`and appropriately positioned (Table 2).
`The remaining 21 patients with successful PHV implan-
`tation experienced remarkable amelioration of symptoms
`with improvements in functional class. Five patients im-
`proved to NYHA functional class I; 14 improved to NYHA
`class II, and 2 improved to NYHA class III (limited by
`severe lung disease). Despite their improvements, however,
`their advanced comorbid conditions limited the extent of
`their survival. One patient with severe right and left ven-
`tricular dysfunction died of a ventricular arrhythmia at day
`18 post-procedure. Three patients died of progressive renal
`failure at two months. Three patients died of a non-cardiac
`cause during a prolonged and complicated postoperative
`course (toe amputation at 2 months, revascularization of the
`lower extremities at 3 months, and orthopedic surgery at 5.5
`months). Third-degree heart block developed in one patient
`three months after the procedure. Pacemaker implantation
`was complicated by pulmonary embolus, sepsis, and death.
`Another patient expired at three months secondary to pneu-
`monia. One patient with underlying metastatic breast cancer,
`died with a morphine overdose (3.5 months), (Table 2).
`
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`JACC Vol. 47, No. 6, 2006
`March 21, 2006:1214–23
`
`Cribier et al.
`Mid-Term Experience of Percutaneous Heart Valve
`
`1221
`
`6
`2
`1
`1
`1
`1
`1
`0
`0
`7 (26)
`
`Table 2. Major Adverse Cardiac and Cerebrovascular
`Events (MACCE) at 30 Days and 6 Months After
`Successful Implantation
`MACCE at 30 days
`Death
`Tamponade
`Sepsis
`Brain death post resuscitation
`Unknown etiology
`Ventricular arrhythmia
`Stroke
`Myocardial infarction
`Emergent cardiac surgery
`Total
`MACCE at 6 months*
`10
`Death
`3
`Renal failure
`3
`Postoperative
`1
`Pulmonary embolus
`1
`Pneumonia
`1
`Cancer
`1
`Multi-organ failure†
`0
`Stroke
`0
`Myocardial infarction
`0
`Emergent cardiac surgery
`10 (37)
`Total
`Values are n (%). *MACCE ⬍30 days not included. †Multi-organ failure death
`occurred at 33 days in the patient who suffered a procedural stroke.
`
`Device-related complications (0% occurrence in this study)
`were not a cause of death in any of these cases.
`To date, 11 patients are alive (3 from the I-REVIVE
`trial, 8 from the RECAST trial) and have returned to a
`normal life, limited only by their previous medical condi-
`tions (NYHA functional class I in 4 patients, class II in 6
`patients, class III in 1 patient). Their follow-up is 9 months
`(n ⫽ 2), 10 months (n ⫽ 3), 11 months (n ⫽ 1), 12 months
`(n ⫽ 2), 23 months (n ⫽ 1), and 26 months (n ⫽ 2). The
`valve function by the most recent echocardiographic exam
`(valve area 1.69 ⫾ 0.10 cm2, mean transvalvular gradient
`11 ⫾ 3 mm Hg, measured at 3 to 24 months post-
`procedure) is unchanged compared to the day of implanta-
`tion (valve area 1.72 ⫾ 0.13 cm2, mean transvalvular
`gradient 9 ⫾ 3 mm Hg, p ⫽ NS). The amount of
`paravalvular leak in these patients is grade 0 to 1 (n ⫽ 7) and
`grade 2 (n ⫽ 4). Ejection fraction in this group is 53 ⫾ 12%
`(baseline 51 ⫾ 15%, p ⫽ NS). One patient has not returned
`for repeat TTE, but remains clinically improved.
`Seven patients who underwent BAV without a successful
`valve implantation or attempte