Retrograde transarterial implantation of a nonmetallic aortic valve prosthesis in high-surgical-risk patients with severe aortic stenosis: a first-in-man feasibility and safety study

Retrograde Transarterial Implantation of a NonmetallicAortic Valve Prosthesis in High–Surgical-Risk Patients With

Severe Aortic StenosisA First-in-Man Feasibility and Safety Study

Joachim Schofer, MD; Michael Schluter, PhD; Hendrik Treede, MD; Olaf W. Franzen, MD;Thilo Tubler, MD; Andrea Pascotto, MD; Reginald I. Low, MD; Steven F. Bolling, MD;

Thomas Meinertz, MD; and Hermann Reichenspurner, MD, PhD

Background—To assess the feasibility and safety of retrograde transarterial implantation of a novel nonmetallic aorticvalve prosthesis (Direct Flow Medical Inc, Santa Rosa, Calif), a prospective single-center study was performed inpatients with severe aortic stenosis at high risk for open-heart surgery.

Methods and Results—Fifteen patients (intention-to-treat cohort) with an aortic valve area �0.8 cm2, a �35-mm Hg meantransvalvular pressure gradient, and a logistic EuroSCORE �20% were enrolled. Percutaneous aortic valve replacementwas performed with the patient under general anesthesia. Hemodynamic parameters were assessed before and afterimplantation by transesophageal echocardiography. Clinical follow-up and transthoracic echocardiographic assessmentwere obtained at 30 days. Procedural success was achieved in 12 patients (80%). Surgical conversion became necessaryat day 2 in 1 patient; 11 patients (73%) were discharged with a permanent implant. In these patients, implantationresulted acutely in a significant increase in aortic valve area (median, 1.64 [interquartile range, 1.27 to 1.74] versus 0.60[0.46 to 0.69] cm2; P�0.0033) and a concomitant reduction in the mean pressure gradient (14.0 [13.2 to 16.5] versus54.0 [43.2 to 59.8] mm Hg; P�0.0033). At 30 days, 1 cardiac death (6.7%; 95% CI, 0.2% to 32.0%) and 1 major strokewere observed. The 10 surviving patients with a permanent implant showed marked hemodynamic and clinicalimprovement at this time point.

Conclusions—In this small series of patients, percutaneous implantation of the Direct Flow Medical aortic valve prosthesisin high–surgical-risk patients was feasible and associated with a reasonably low safety profile. (Circ CardiovascIntervent. 2008;1:126-133.)

Key Words: aorta � catheterization � prosthesis � stenosis � valves

Recent years have witnessed the emergence of percutane-ous treatment of valvular aortic stenosis as a clinical

entity.1–11 Initial experience in humans has focused on pa-tients deemed at high risk or unsuitable for surgery2,3,5,8–10 orpatients with end-stage aortic stenosis in whom the percuta-neous treatment modality was attempted on a compassionate-use basis.1,4,6,7 To date, investigators have used bioprostheticvalves made of equine, bovine, or porcine pericardiumattached to a balloon-expandable stainless-steel or self-expanding nitinol stent frame. Catheter-based implantation ofthese types of valve prosthesis has been achieved using anantegrade approach by way of a transseptal puncture,1–3 aretrograde transfemoral approach,3–5,8 or an antegradetransapical approach.6,9 As the failure to properly deploy a

stent-based valve prosthesis may necessitate emergent car-diac surgery, a prosthesis that allows repeated attempts at thecorrect sizing and positioning in situ is desirable. We reportour initial clinical experience with a novel nonmetallic aorticvalve prosthesis that can be retrieved and repositioned orexchanged before permanent implantation.

Clinical Perspective see p 133

MethodsStudy ProtocolAll patients were treated under an investigational plan designed toassess the feasibility and safety of permanent percutaneous implan-tation of the Direct Flow Medical (Santa Rosa, Calif) aortic valve

Received June 19, 2008; accepted August 20, 2008.From the Medical Care Center Prof Mathey, Prof Schofer and Hamburg University Cardiovascular Center (J.S., M.S., T.T., A.P.), and Departments

of Cardiovascular Surgery (H.T., H.R.) and Cardiology/Angiology (O.W.F., T.M.), University Heart Center Hamburg, Hamburg, Germany; Division ofCardiovascular Medicine, University of California, Davis Medical Center, Sacramento, Calif (R.I.L.); and University of Michigan Cardiovascular Center,Ann Arbor, Mich (S.F.B.).

Correspondence to Michael Schluter, PhD, Medical Care Center Prof Mathey, Prof Schofer, Wordemanns Weg 25-27, 22527 Hamburg, Germany.E-mail [email protected]

© 2008 American Heart Association, Inc.

Circ Cardiovasc Intervent is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.108.800607

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prosthesis in high–surgical-risk patients with severe aortic valvestenosis. Feasibility was defined as procedural success (ie, correctplacement of the prosthesis in the subcoronary position with anassociated absolute reduction in the mean transvalvular pressuregradient to �25 mm Hg in the absence of severe aortic regurgita-tion). Safety was defined as the absence at 30 days of major adversecardiac and cerebrovascular events (death, myocardial infarction,emergent cardiac surgery, and minor or major stroke) or othervalve-related adverse events. High surgical risk was determined byconsensus of 2 experienced cardiac surgeons.

Patients were prospectively screened and enrolled if they met allof the following inclusion criteria: symptomatic valvular aorticstenosis with an aortic valve area �0.8 cm2 and a �35–mm Hg meanvalvular gradient; an aortic annular diameter between 19 and 23 mm;a contraindication to surgery because of concomitant comorbidities;a logistic European System for Cardiac Operative Risk Evaluation(EuroSCORE) �20%12; valvular and peripheral anatomy appropri-ate to accommodate the study device and its delivery system; and anage �70 years. Major exclusion criteria were a life expectancy �1year, contraindication to any study medication, serum creatinine�2.0 mg/dL, prior valve surgery, endocarditis in the last 18 months,myocardial infarction within the last 30 days, clinically significant(�2�) mitral insufficiency, cardiac decompensation, and stroke inthe past 6 months. The study was approved by the Ethics Committeeof the Hamburg Board of Physicians, and all patients gave writteninformed consent.

ScreeningThe screening of patients potentially suited for percutaneous aorticvalve replacement comprised a physical examination to assess theclinical history and current clinical status; transthoracic echocardi-ography to assess aortic valve dimensions, the severity of aorticstenosis and, if present, aortic regurgitation; coronary angiography toexclude clinically relevant coronary stenoses; and multislice com-puted tomography to assess cross-sectional diameters of the entireaortic valve apparatus from 15 mm below to 30 mm above theannulus in 5-mm planar increments and determine the distance of thecoronary ostia from the annulus. Multislice computed tomographywas also used to assess valvular calcification and evaluate thedelivery route for a 22-F catheter system (7.9-mm outer diameter)from the iliofemoral vasculature to the aortic root.

PatientsBetween September 20, 2007, and March 20, 2008, 20 patients werescreened for study enrollment, of whom 4 did not meet the inclusioncriteria, either because of a life expectancy of �1 year (n�3) or anaortic stenosis of only mild to moderate severity (n�1), and 1 whowithdrew consent. Thus, 15 patients (7 men, 8 women; mean age, 81years) constituted the intention-to-treat population. Pertinent patientcharacteristics are listed in Table 1. In these patients, severe calcificstenosis of the native aortic valve was reflected in a median aorticvalve area of 0.60 cm2 and a median mean transvalvular pressuregradient of 50 mm Hg. Sixty percent of patients were in New YorkHeart Association (NYHA) functional class III. The median logisticEuroSCORE in the 15 patients was 24%, and the median Society ofThoracic Surgeons predicted 30-day risk of mortality was 20%. Themajor conditions for high surgical risk are given for each patient inTable 2.

Study DeviceThe implant (Figure 1) consists of a trileaflet valve made of bovinepericardial tissue that is encased in a slightly tapered, conformable,polyester fabric cuff.13,14 Both the upper (aortic) and the lower(ventricular) margin of the cuff consist of an independently inflatableballoon ring. The rings are interconnected by a tubular bridgingsystem that is inflatable only via inflation of the aortic ring. Toposition and align the implant in the aortic valvular plane as well asseparately inflate and deflate the balloon rings, 3 detachable posi-tioning/fill lumens connect to the aortic ring of the implant at angulardistances of 120° along its perimeter. For introduction, the implant is

loaded into a flexible 22-F housing at the distal end of a 15-Fmultilumen delivery catheter. One of the lumens houses a catheterwith an olive-shaped plastic “pearl” at its distal tip, which covers thedistal end of the implant housing during advancement to allowatraumatic passage through the aorta and the native aortic valve. Thedelivery system is advanced over a 0.035-in guidewire. Incorporatedinto the delivery system is a nitinol mesh basket into which theimplant can be withdrawn and retrieved before final implantation(Figure 2). Implant deployment and retrieval is controlled by handlesat the proximal end of the delivery system; alignment of the implantagainst the native aortic annulus is achieved by pulling or pushing atthe proximal ends of the positioning/fill lumens. At present, the

Table 1. Baseline Characteristics of Intention-to-TreatPopulation

Patients (n�15)

Age, years, mean�SD 81�4

Age �80 years 9 (60)

Male gender 7 (47)

Hypertension 13 (87)

Diabetes mellitus 5 (33)

Prior/current smoking 3 (20)

Coronary artery disease 6 (40)

Prior coronary-artery bypass grafting 2 (13)

Prior percutaneous coronary intervention 5 (33)

Myocardial infarction in past 6 months 1 (7)

Congestive heart failure 4 (27)

Carotid artery disease 7 (47)

Peripheral arterial disease 3 (20)

Aortic regurgitation

Trivial 14 (93)

Mild 1 (7)

Atrial fibrillation 3 (20)

ASA physical status

2 (mild systemic disease) 1 (7)

3 (severe systemic disease) 13 (87)

4 (severe systemic disease, life threatening) 1 (7)

NYHA functional class

I 1 (7)

II 5 (33)

III 9 (60)

Left ventricular ejection fraction, %, median (IQR) 61 (51–67)

Logistic EuroSCORE, %, median (IQR) 23.6 (21.8–30.1)

STS predicted 30-day risk of mortality, %, median(IQR)

20.3 (17.9–22.8)

Mean pressure gradient, mm Hg, median (IQR) 50 (43–59)

Peak pressure gradient, mm Hg, median (IQR) 80 (68–95)

Aortic valve area, cm2, median (IQR) 0.60 (0.42–0.66)

Noncardiovascular concomitant comorbidities

Chronic obstructive pulmonary disease 2 (13)

Chronic renal insufficiency 6 (40)

History of cerebrovascular accident 2 (13)

Malignancy 8 (53)

Values are n (%), unless otherwise indicated.ASA indicates American Society of Anesthesiologists; NYHA, New York Heart

Association; IQR, interquartile range; STS, Society of Thoracic Surgeons.

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implant is available in heights of 16 and 17 mm and diameters of 23and 25 mm, corresponding to outer aortic ring diameters of 27 and29 mm, respectively.

Implantation ProcedureAll procedures were performed at the University Heart CenterHamburg, with the patient under general anesthesia but withoutextracorporeal circulation, in a hybrid suite equipped for both cardiaccatheterization and cardiovascular surgery. The patients had to bepremedicated with acetylsalicylic acid (aspirin, 100 mg/d) andclopidogrel (75 mg/d) for �5 days. Patients not on this regimen weregiven an intravenous bolus of 500 mg of aspirin and an oral loadingdose of 600 mg of clopidogrel immediately before the intervention.Transesophageal echocardiography was performed throughout theprocedure. A standard surgical cut-down gave access to the femoralartery with the wider dimension and the least calcification andtortuosity on preprocedural computed tomography (mostly the rightfemoral artery), while a 6-F pigtail catheter for fluoroscopic visual-ization of the ascending aorta was introduced into the contralateralfemoral artery via a 6-F introducer sheath. A pacemaker lead wasplaced in the right ventricle by way of the jugular vein. Thesurgically exposed femoral artery was fitted with a 22-F introducersheath. After sheath placement, an intravenous bolus of 5000 to10 000 U of heparin (depending on the patient’s weight) was

administered to achieve and maintain an activated clotting time of�300 seconds.

After multiple balloon valvuloplasties under rapid pacing (�200/min) until leaflet mobility was markedly improved and a meanpressure gradient of �30 mm Hg was achieved, the delivery catheterwas advanced during sinus rhythm (or atrial fibrillation in 3 patients)over a 0.035-in superstiff guidewire until the implant housing wasfully contained in the left ventricle. Retraction of the housing thenexposed the implant, which was subsequently expanded by injectinga 50:50 mix of saline and contrast agent into both balloon rings.Thereafter, both rings were deflated, the device aligned, and theventricular ring inflated. At this point, the prosthetic valve wasalready fully functioning. The implant was then withdrawn such thatthe inflated ventricular ring fit against the ventricular aspect of thenative annulus. The aortic ring was again inflated with the saline/contrast mix. Using fluoroscopy, transesophageal echocardiography,and aortography, the implant was checked for correct (subcoronary)position and paravalvular leaks and, if necessary, partially deflated,readvanced into the left ventricle, realigned and repositioned, orcompletely removed and exchanged for another implant. Once theposition and function of the prosthesis was deemed satisfactory, thesaline/contrast mix was replaced, while maintaining a pressure of 8to 10 atmospheres, with a polymer that becomes solid in �10minutes and cures completely within 24 hours to keep the implantpermanently in place. Contrast media added to the polymer enhanced

Figure 1. Expanded aortic valve prosthe-sis attached to positioning/fill lumens.

Table 2. High Surgical Risk Conditions

Patient Logistic EuroSCORE (%) STS Score (%) Primary Surgical Risk(s)

#1 20.0 17.2 Porcelain aorta

#2 30.2 21.6 Prior CABG; massive calcification of aortic arch

#3 19.5 12.8 Lung cancer; severe COPD

#4 23.6 28.8 Colon cancer; age 83 years

#5 21.9 22.7 Recurrent skin cancer

#6 28.9 22.9 Cervical cancer; COPD

#7 32.6 30.6 Dementia; severe ataxia with inability to walk

#8 29.8 20.6 Prior CABG; bladder cancer; COPD

#9 20.3 20.3 Breast cancer

#10 26.7 17.9 Severe renal insufficiency

#11 51.7 20.3 Prior CABG; massive calcification of aortic arch

#12 22.2 16.0 Lung cancer; intracranial aneurysm

#13 32.8 17.9 Lung cancer

#14 21.8 20.1 Pulmonary sarcoidosis

#15 23.6 23.4 Renal insufficiency; LVEF�34%; age 88 years

CABG indicates coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejectionfraction.

128 Circ Cardiovasc Intervent October 2008



the fluoroscopic visibility of the prosthesis rings. The positioning/filllumens were then detached and the delivery system removed. Theintervention was concluded with final aortography and transesoph-ageal echocardiography to assess coronary patency, central aorticregurgitation and pressure gradients, aortic orifice area, and paraval-vular leaks. Vascular access sites in the groin were closed by pursestring sutures in 11 of 13 patients; 2 patients needed open anasto-mosis after careful resection of vessel margins. Wounds were closedby running sutures and covered with compression bandages. A caseexample of an implantation procedure is provided in Figure 3.

The patients were transferred to the intensive care unit and generalanesthesia was discontinued. On day 1 after the intervention, patientswere started on a combination therapy of clopidogrel (75 mg/d for 6months) and aspirin (100 mg/d indefinitely).

Follow-UpPatients were asked to return after 30 days for an assessment of theirclinical status and a transthoracic echocardiographic examination.

StatisticsContinuous variables are presented by their median and interquartilerange (IQR). Categorical variables are presented as counts andpercentages. Exact 95% CIs were calculated based on the binomialdistribution. Changes in continuous variables between baseline andat 30 days were assessed using Wilcoxon signed rank test. Compar-isons between categorical variables were performed using thecontinuity-corrected �2 test. These analyses used the StatView 4.5

software package (Abacus Concepts Inc, Berkeley, Calif). A 2-tailedprobability value �0.05 was considered statistically significant.

The authors had full access to the data and take responsibility forits integrity. All authors have read and agreed to the manuscript aswritten.

ResultsProcedural OutcomesAfter a median of 7 (IQR, 6 to 11) balloon valvuloplastieswith mostly 2 balloons of 25-mm diameter (for the 23-mmimplant) or 28-mm diameter (for the 25-mm implant), pro-cedural success was achieved in 12 patients (80%; 95% CI,52 to 96%). In 2 patients, the introducer sheath could not beadvanced through a severely calcified iliofemoral vascula-ture. In another patient who had a functionally bicuspid nativevalve secondary to fusion of 2 leaflets at the commissures,expansion of two 23-mm implants was judged inadequateboth times and the procedure was terminated without implan-tation. The patient underwent surgical aortic valve replace-ment after 9 days because of clinical instability with severedyspnea at rest; she recovered uneventfully. The other 2patients were continued on medical treatment. In the 12successfully treated patients, procedure duration ranged from

Figure 2. Implant with retrieval basket.

Figure 3. Case example. A, Baseline aortogram. B, Crossing of the native annulus with implant in its housing (distal radiopaque markervisible). C, Ventricular ring of implant in the subvalvular position; 3 positioning/fill lumens visible. D, Implant in final position with bothrings inflated. E, Aortogram with implant in final position, before exchange of inflation media. F, Final aortogram after exchange of infla-tion media.




315 minutes (first procedure) to 118 minutes (last procedure),with an average of 193 minutes. The actual implantation ofthe prosthesis (from insertion of the delivery catheter to thetime the inflation media reached its cured state in the syringe)lasted for a median of 36 minutes, with an IQR of 33 to 45minutes. Implantation time was markedly prolonged to 102minutes in patient 12, in whom an occlusion of the left maincoronary artery that was noted after successful deployment ofthe implant had to be dilated and stented. Fluoroscopy timeamounted to a median of 34 minutes (IQR, 28.5 to 58.0minutes).

After implantation, 4 patients had no evidence of transval-vular insufficiency. Minor paravalvular leaks were detectedin 6 patients, and central aortic regurgitation of trivial andmoderate (2�) severity was present in 1 patient each.

Surgical conversion after 48 hours became necessary inpatient 5, in whom the native aortic annulus turned out to betoo small for the implant. The aortic ring could not be fullydeployed, which subsequently caused an increase in the peaktransvalvular pressure gradient to 90 mm Hg. Thus, a total of11 of 15 patients (73%; 95% CI, 45 to 92%) received apermanent implant. Device sizes were 23 mm in 8 patientsand 25 mm in 3 patients.

HospitalizationOf the 11 patients with a permanent implant, 10 weredischarged after a median of 7 days (IQR, 6 to 7 days). Onepatient was still hospitalized at 30 days for strokerehabilitation.

Device RecoveriesDevice recoveries were performed in 3 of 12 successfullytreated patients (25%). In the first patient of our series,calcification of the native annulus prevented complete infla-tion of the aortic ring of a 23-mm device. It was thenexchanged for a (higher) 25-mm device of which the aorticring could be fully inflated, sealing the calcific deposit thatprevented adequate inflation of the 23-mm device. In anotherpatient, the implant, after inflation of the ventricular ring,slipped back into the ascending aorta during alignmentattempts in the native annulus; it was retrieved and exchangedfor another implant of the same size, which could besuccessfully deployed. A third patient presented with subval-vular circumferential calcification of the native annulus thatimpeded complete inflation of the ventricular ring of theimplant; on retrieval of the device and reintroduction withdifferent angulation relative to the native annulus, correctpositioning was eventually achieved. In addition, 2 deviceswere recovered in the patient with a functionally bicuspidnative valve who did not receive a permanent implant. The 5device recoveries took a median of 7.5 minutes (IQR, 7 to 8minutes).

Adverse EventsMajor adverse cardiac and cerebrovascular events occurred in3 patients (20%; 95% CI, 4% to 48%; Table 3). The patientin whom intraprocedural stenting of the left main coronaryartery was performed died at 36 hours after an inferior (ie,right coronary artery–related) myocardial infarction. Autopsy

revealed a patent stent but a total occlusion of the distal rightcoronary artery at a site where a 70% stenosis had beenidentified preintervention that was adjudicated as being clin-ically not relevant. Another patient with chronic atrial fibril-lation sustained a major stroke at 12 hours that resulted indysarthria and motor weakness of the right arm and necessi-tated prolonged rehabilitation at an outside hospital. Onepatient required surgical conversion (see above).

A minor adverse event was the intraprocedural occurrenceof a groin hematoma that required immediate surgical re-moval. Atrioventricular conduction block was not induced inany patient.

Acute Hemodynamic Outcomes of Patients With aPermanent ImplantIn the 11 patients who received a permanent implant, themean transvalvular pressure gradient decreased significantlyfrom a median of 54.0 (IQR, 43.2 to 59.8) to 14.0 (13.2 to16.5) mm Hg (P�0.0033), secondary to a fully functioningimplant with a significantly increased effective orifice area(median, 1.64 [1.27 to 1.74] versus 0.60 [0.46 to 0.69] cm2;P�0.0033; Table 4 and Figure 4). Accordingly, the peakaortic pressure gradient measured after implantation was alsosignificantly reduced (median, 29.0 [24.2 to 32.8] versus 64.0[68.2 to 98.0] mm Hg; P�0.0033).

Follow-UpClinical and transthoracic echocardiographic follow-up wasobtained at a median of 35 days (IQR, 29 to 36 days) from 10patients with a permanent implant. A clinical improvement by2 NYHA functional classes was observed in 4 patients and by1 NYHA functional class in 5 patients; 1 patient remained inNYHA functional class I (Figure 5). The difference in thedistribution of NYHA functional class between baseline and30 days was statistically significant (P�0.0029 by continuity-corrected �2 test).

Transthoracic echocardiography revealed adequate posi-tion and function of the implant in all 10 patients. Thepresence of paravalvular leaks and central aortic regurgitationwas unchanged with respect to postimplantation except for 1patient in whom 2� aortic regurgitation on transesophagealechocardiography was now measured as 1�. Aortic orificearea was essentially unchanged, and the slight increase inmean aortic pressure gradient from a median of 14.0 mm Hg

Table 3. Adverse Events Within 30 days

Major events

Death 1 (6.7,0.2–32.0)

Stroke 1

Myocardial infarction 1

Surgical conversion 1

Total (hierarchical) 3 (20.0,4.3–48.1)

Other events

Atrioventricular conduction block 0

Intraprocedural groin hematomanecessitating surgical removal

1

Values are n (%, 95% CI).




to a median of 17.0 mm Hg did not reach statistical signifi-cance (Figure 4 and Table 4). Left ventricular ejectionfraction increased relative to baseline in 8 patients butdecreased in 2; the overall difference of 68% (54% to 74%)at 30 days versus 61% (46% to 67%) at baseline wasstatistically not significant (P�0.0829; Figure 6).

DiscussionThis report demonstrates the feasibility and safety of retrogradetransfemoral implantation of a nonmetallic aortic valve prosthe-sis in a first-in-man series of 15 high–surgical-risk patients withsevere aortic stenosis. Acute procedural success was achieved in12 patients (80%) of whom 11 (73%) were discharged with apermanent implant. In the latter patients, successful implantationresulted in a significant reduction of the mean transvalvularpressure gradient secondary to a significant increase in effectiveaortic valve area. After implantation, no patient exhibited aorticinsufficiency, neither central nor paravalvular, of hemodynamicrelevance, attesting to adequate sealing of the native aorticannulus by the implant. Coronary compromise during the inter-vention occurred in only 1 patient in whom correct deploymentof the implant in the subcoronary position caused the displace-ment of an aortic-wall plaque, impeding inflow into the left maincoronary artery; the condition was remedied by ostial stenting.Major in-hospital cardiovascular and cerebral events occurred in2 of the 15 patients (13%) and comprised 1 cardiac death after amyocardial infarction and 1 major stroke; this incidence seemsnot to be different from that reported in first-in-man studies ofstent-based percutaneous valve prostheses.3–6 One patient of our

Table 4. Echocardiography in Patients Who Received a Permanent Implant

ParameterBaseline*(n�11) Post Procedure† (n�11) Change vs Baseline (n�11)

30 days*(n�10) Change vs Post Proc. (n�10

Mean pressure gradient, mm Hg 54.0 (43.2–59.8) 14.0 (13.2–16.5) �40 (�45–�30) 17.0 (15–20) 2.5 (0–9)

Peak pressure gradient, mm Hg 64.0 (68.2–98.0) 29.0 (24.2–32.8) �52 (�68–�48) 34.5 (27–38) 4 (�3–10)

Aortic valve area, cm2 0.60 (0.46–0.69) 1.64 (1.27–1.74) 0.89 (0.81–1.07) 1.58 (1.5–1.8) 0.02 (�0.09–0.23)

Change vs Baseline

LVEF, % 61 (46–67) 68 (54–74) 8.5 (�1–15)

Values are medians and (in parentheses) interquartile ranges.LVEF indicates left ventricular ejection fraction.*By transthoracic echocardiography.†By transesophageal echocardiography.

Figure 4. Box-and-whiskers plots of mean transvalvular aorticpressure gradient (A) and effective aortic orifice area (B) at base-line, postimplantation, and at 30-day follow-up in patients with apermanent implant. Horizontal bar within box represents median(numeric value next to it); top and bottom of box represent 75thand 25th percentile, respectively; ends of top and bottom whis-ker represent 90th and 10th percentile, respectively. Post mea-surements were taken with transesophageal echocardiography,whereas baseline and 30-day measurements were taken withtransthoracic echocardiography. Probability values representpaired comparisons (n�11 patients for the comparison of base-line versus post; n�10 patients for the comparison of post ver-sus 30 days).

Figure 5. Change in NYHA functional class from baseline to 30days in 10 patients with a permanent implant. Improvements byat least 1 functional class were observed in all patients but 1.The difference in the distributions at baseline and 30 days wasstatistically highly significant (P�0.0029).




series required a surgical conversion; the total rate of majorprocedure-related adverse events was 20%. At 30 days, prosthesisperformance was maintained in all surviving patients with a perma-nent implant. Left ventricular ejection fraction had an averageincreased and symptomatic relief, as reflected by an overall signif-icant reduction in NYHA functional class in all but 1 patient, whowas already in NYHA functional class I at baseline.

Advantages of the Nonmetallic ImplantThe most obvious advantage of the nonmetallic aortic valveprosthesis is that it gives the operator unprecedented freedom ofhandling the device during implantation. It is nonmetallic and, inits unexpanded state, highly flexible and can be easily negoti-ated, even through a calcified aortic arch; it allows repeatedadvancement and retraction across the native annulus for properpositioning; it immediately functions on expansion and thusrequires no rapid pacing during the actual implantation; and itcan be checked for competent sealing of the annulus andadequate valve performance before permanent implantation. Theimplant can be readily retrieved and exchanged for anotherimplant of the same or a different size should it slip back into theascending aorta from its intended position or in cases wherecorrect placement cannot be achieved. Thus, the characteristicsof the nonmetallic implant render intraprocedural migration intothe ascending or descending aorta3 virtually impossible andreduce the likelihood of emergent surgical conversion.8

The design of the implant allows fixation of the aortic ring ina subcoronary position without encroachment on the coronaryostia and fixation of the ventricular ring in a subannular positionwithout impairing the mobility of the anterior mitral leaflet.

The atraumatic advancement of the implant delivery system,particularly through the aortic arch and the native aortic annulus,may account for the low incidence of cerebrovascular eventsobserved in the present series. It cannot be determined if thestroke that occurred 12 hours after the intervention was related tothe procedure or to the patient’s chronic atrial fibrillation.

Potential Disadvantages of theNonmetallic ImplantBalloon-expandable as well as self-expanding stent-based aorticvalve prostheses exert pronounced radial force on the surround-ing tissue, thereby sealing the native aortic annulus and ensuringprosthesis function. With the nonmetallic implant, annular seal-

ing is accomplished by the prosthesis rings, while the “passive”polymer-filled bridging system connecting the rings must with-stand circumferential outer forces. It is therefore necessary topossibly reduce such forces and create an adequate, preferablycircular, opening of the native annulus by multiple valvuloplas-ties (a median of 7 in our series) during rapid pacing beforeimplantation is attempted. A circular opening and, subsequently,implantation could not be achieved in the patient with afunctionally bicuspid native valve; in another patient, full ex-pansion of the aortic prosthesis ring was prevented by a nativeannulus too small for the implant. Both patients underwentsurgical valve replacement. Repeated rapid pacing in patients withsevere aortic stenosis may result in global and irreversible myocar-dial ischemia. Also, it is not known if progression of scleroticdisease will eventually cause a reduction in effective aortic valvearea in patients with a permanent percutaneous implant.

Impact of the Learning CurveAs is generally the case with new therapeutic technologies,increased operator experience will likely reduce the incidence ofscreening failures, avoid adverse events, and “streamline” thevarious procedural steps. In 2 patients of our series, the 22-Fintroducer sheath could not be advanced through severelycalcified iliac arteries, and the intervention had to be aborted.More experience in the interpretation of the calcification statusof the iliofemoral vasculature on the screening computed tomo-grams may have avoided these screening, and ultimately proce-dural, failures. It is expected that the development of an 18-Fdevice will also help to reduce the number of screening failures.In patient 5, the intervention was concluded supposedly success-ful even though the aortic ring of the implant appeared indentedand nonplanar on fluoroscopy (Figure 7) and the mean transval-vular pressure gradient was 30 mm Hg. Within 2 days, thegradient increased significantly and the patient underwent sur-

Figure 6. Left ventricular ejection fraction at baseline and 30days in 10 patients with a permanent implant. Large dots indi-cate means; error bars indicate SD.

Figure 7. Fluoroscopic image of implant in patient 5 beforeexchange of inflation media. Ventricular ring appears circular,but aortic ring appears indented and nonplanar (arrow).




gical conversion. Thus, a perfectly circular and planar appear-ance of the prosthesis rings on fluoroscopy seems to be manda-tory before an intervention can be concluded.

LimitationsThe patients in this study represent a highly selected cohort.They were all elderly with a high–surgical-risk profile due tosignificant comorbidities. Therefore, our results may not beextrapolated to younger patients with severe aortic stenosis butless critical surgical risk conditions. The number of patients wassmall and, thus, all percentages were associated with wide 95% CIs.More confident estimates of success and complicates rates will begained with more patients. Follow-up in this study was restricted to30 days. Thus, no statements can yet be made on the long-termdurability of the implant and clinical outcome of the patients.

ConclusionsThis single-center first-in-man study has shown that retrogradetransarterial implantation of the Direct Flow Medical nonmetal-lic aortic valve prosthesis is feasible in the majority of patients.Patients discharged with a permanent implant showed markedhemodynamic and significant clinical improvement at 30 days.The incidence of major periprocedural events was reasonablylow, with 1 death, 1 stroke, and 1 surgical conversion. A greaternumber of patients and longer follow-up are necessary for amore confident assessment of procedural success as well aslong-term mortality and morbidity.

Sources of FundingThis study was sponsored by Direct Flow Medical Inc, Santa Rosa, Calif.

DisclosuresDrs Low and Bolling serve as consultants to Direct Flow MedicalInc, and Dr Bolling owns stock options in Direct Flow Medical Inc.Drs Schofer and Tubler have received reimbursement from DirectFlow Medical Inc for travels to scientific meetings. The other authorsreport no conflicts of interest.

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CLINICAL PERSPECTIVEWe performed a first-in-man study of percutaneous implantation of a novel nonmetallic aortic valve prosthesis in a smallseries of 15 patients with severe aortic valve stenosis who were at high risk for open-heart surgery. Implantation wasacutely successful in 12 patients (80%) in whom a significant increase in aortic valve area and a concomitant reduction inthe mean transvalvular pressure gradient was achieved. One patient had to undergo surgical conversion at day 2, thus 11patients (73%) were discharged with a permanent implant. At 30 days, 1 cardiac death (6.7%; 95% CI, 0.2% to 32.0%) and1 major stroke were observed. The 10 patients surviving 30 days with a permanent implant showed marked hemodynamicand clinical improvement. The major advantage of the highly flexible prosthesis is that it gives the operator unprecedentedfreedom of handling the device during implantation; it can be easily negotiated even through a calcified aortic arch, allowsrepeated advancement and retraction across the native annulus for proper positioning, and functions immediately uponexpansion. A greater number of patients and longer follow-up are necessary for a more confident assessment of proceduralsuccess as well as long-term mortality and morbidity.




Pascotto, Reginald I. Low, Steven F. Bolling, Thomas Meinertz and Hermann ReichenspurnerJoachim Schofer, Michael Schlüter, Hendrik Treede, Olaf W. Franzen, Thilo Tübler, Andrea

StudySurgical-Risk Patients With Severe Aortic Stenosis: A First-in-Man Feasibility and Safety

−Retrograde Transarterial Implantation of a Nonmetallic Aortic Valve Prosthesis in High

Print ISSN: 1941-7640. Online ISSN: 1941-7632 Copyright © 2008 American Heart Association, Inc. All rights reserved.

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Retrograde transarterial implantation of a nonmetallic aortic valve prosthesis in high-surgical-risk patients with severe aortic stenosis: a first-in-man feasibility and safety study