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Original Articles |
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 of Cardiovascular 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 Schlüter, PhD, Medical Care Center Prof Mathey, Prof Schofer, Wördemanns Weg 25-27, 22527 Hamburg, Germany. E-mail schlueter{at}herz-hh.de
Received June 19, 2008; accepted August 20, 2008.
| Abstract |
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Methods and Results— Fifteen patients (intention-to-treat cohort) with an aortic valve area
0.8 cm2, a
35-mm Hg mean transvalvular pressure gradient, and a logistic EuroSCORE
20% were enrolled. Percutaneous aortic valve replacement was performed with the patient under general anesthesia. Hemodynamic parameters were assessed before and after implantation by transesophageal echocardiography. Clinical follow-up and transthoracic echocardiographic assessment were obtained at 30 days. Procedural success was achieved in 12 patients (80%). Surgical conversion became necessary at day 2 in 1 patient; 11 patients (73%) were discharged with a permanent implant. In these patients, implantation resulted 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] versus 54.0 [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 stroke were observed. The 10 surviving patients with a permanent implant showed marked hemodynamic and clinical improvement at this time point.
Conclusions— In this small series of patients, percutaneous implantation of the Direct Flow Medical aortic valve prosthesis in high–surgical-risk patients was feasible and associated with a reasonably low safety profile.
Key Words: aorta catheterization prosthesis stenosis valves
| Introduction |
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Clinical Perspective see p 126
| Methods |
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Patients were prospectively screened and enrolled if they met all of the following inclusion criteria: symptomatic valvular aortic stenosis with an aortic valve area
0.8 cm2 and a
35–mm Hg mean valvular 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 appropriate to accommodate the study device and its delivery system; and an age
70 years. Major exclusion criteria were a life expectancy <1 year, 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 in the past 6 months. The study was approved by the Ethics Committee of the Hamburg Board of Physicians, and all patients gave written informed consent.
Screening
The screening of patients potentially suited for percutaneous aortic valve replacement comprised a physical examination to assess the clinical history and current clinical status; transthoracic echocardiography to assess aortic valve dimensions, the severity of aortic stenosis and, if present, aortic regurgitation; coronary angiography to exclude clinically relevant coronary stenoses; and multislice computed tomography to assess cross-sectional diameters of the entire aortic valve apparatus from 15 mm below to 30 mm above the annulus in 5-mm planar increments and determine the distance of the coronary ostia from the annulus. Multislice computed tomography was also used to assess valvular calcification and evaluate the delivery route for a 22-F catheter system (7.9-mm outer diameter) from the iliofemoral vasculature to the aortic root.
Patients
Between September 20, 2007, and March 20, 2008, 20 patients were screened for study enrollment, of whom 4 did not meet the inclusion criteria, either because of a life expectancy of <1 year (n=3) or an aortic stenosis of only mild to moderate severity (n=1), and 1 who withdrew consent. Thus, 15 patients (7 men, 8 women; mean age, 81 years) constituted the intention-to-treat population. Pertinent patient characteristics are listed in Table 1. In these patients, severe calcific stenosis of the native aortic valve was reflected in a median aortic valve area of 0.60 cm2 and a median mean transvalvular pressure gradient of 50 mm Hg. Sixty percent of patients were in New York Heart Association (NYHA) functional class III. The median logistic EuroSCORE in the 15 patients was 24%, and the median Society of Thoracic Surgeons predicted 30-day risk of mortality was 20%. The major conditions for high surgical risk are given for each patient in Table 2.
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5 days. Patients not on this regimen were given an intravenous bolus of 500 mg of aspirin and an oral loading dose of 600 mg of clopidogrel immediately before the intervention. Transesophageal echocardiography was performed throughout the procedure. A standard surgical cut-down gave access to the femoral artery with the wider dimension and the least calcification and tortuosity on preprocedural computed tomography (mostly the right femoral artery), while a 6-F pigtail catheter for fluoroscopic visualization of the ascending aorta was introduced into the contralateral femoral artery via a 6-F introducer sheath. A pacemaker lead was placed in the right ventricle by way of the jugular vein. The surgically exposed femoral artery was fitted with a 22-F introducer sheath. After sheath placement, an intravenous bolus of 5000 to 10 000 U of heparin (depending on the patients 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 mean pressure gradient of
30 mm Hg was achieved, the delivery catheter was advanced during sinus rhythm (or atrial fibrillation in 3 patients) over a 0.035-in superstiff guidewire until the implant housing was fully contained in the left ventricle. Retraction of the housing then exposed the implant, which was subsequently expanded by injecting a 50:50 mix of saline and contrast agent into both balloon rings. Thereafter, both rings were deflated, the device aligned, and the ventricular ring inflated. At this point, the prosthetic valve was already fully functioning. The implant was then withdrawn such that the inflated ventricular ring fit against the ventricular aspect of the native 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, or completely removed and exchanged for another implant. Once the position and function of the prosthesis was deemed satisfactory, the saline/contrast mix was replaced, while maintaining a pressure of 8 to 10 atmospheres, with a polymer that becomes solid in <10 minutes and cures completely within 24 hours to keep the implant permanently in place. Contrast media added to the polymer enhanced the fluoroscopic visibility of the prosthesis rings. The positioning/fill lumens were then detached and the delivery system removed. The intervention was concluded with final aortography and transesophageal echocardiography to assess coronary patency, central aortic regurgitation and pressure gradients, aortic orifice area, and paravalvular leaks. Vascular access sites in the groin were closed by purse string sutures in 11 of 13 patients; 2 patients needed open anastomosis after careful resection of vessel margins. Wounds were closed by running sutures and covered with compression bandages. A case example of an implantation procedure is provided in Figure 3.
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Follow-Up
Patients were asked to return after 30 days for an assessment of their clinical status and a transthoracic echocardiographic examination.
Statistics
Continuous variables are presented by their median and interquartile range (IQR). Categorical variables are presented as counts and percentages. Exact 95% CIs were calculated based on the binomial distribution. Changes in continuous variables between baseline and at 30 days were assessed using Wilcoxon signed rank test. Comparisons between categorical variables were performed using the continuity-corrected
2 test. These analyses used the StatView 4.5 software package (Abacus Concepts Inc, Berkeley, Calif). A 2-tailed probability value <0.05 was considered statistically significant.
The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the manuscript as written.
| Results |
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After implantation, 4 patients had no evidence of transvalvular insufficiency. Minor paravalvular leaks were detected in 6 patients, and central aortic regurgitation of trivial and moderate (2+) severity was present in 1 patient each.
Surgical conversion after 48 hours became necessary in patient 5, in whom the native aortic annulus turned out to be too small for the implant. The aortic ring could not be fully deployed, which subsequently caused an increase in the peak transvalvular pressure gradient to 90 mm Hg. Thus, a total of 11 of 15 patients (73%; 95% CI, 45 to 92%) received a permanent implant. Device sizes were 23 mm in 8 patients and 25 mm in 3 patients.
Hospitalization
Of the 11 patients with a permanent implant, 10 were discharged after a median of 7 days (IQR, 6 to 7 days). One patient was still hospitalized at 30 days for stroke rehabilitation.
Device Recoveries
Device recoveries were performed in 3 of 12 successfully treated patients (25%). In the first patient of our series, calcification of the native annulus prevented complete inflation of the aortic ring of a 23-mm device. It was then exchanged for a (higher) 25-mm device of which the aortic ring could be fully inflated, sealing the calcific deposit that prevented adequate inflation of the 23-mm device. In another patient, the implant, after inflation of the ventricular ring, slipped back into the ascending aorta during alignment attempts in the native annulus; it was retrieved and exchanged for another implant of the same size, which could be successfully deployed. A third patient presented with subvalvular circumferential calcification of the native annulus that impeded complete inflation of the ventricular ring of the implant; on retrieval of the device and reintroduction with different angulation relative to the native annulus, correct positioning was eventually achieved. In addition, 2 devices were recovered in the patient with a functionally bicuspid native valve who did not receive a permanent implant. The 5 device recoveries took a median of 7.5 minutes (IQR, 7 to 8 minutes).
Adverse Events
Major adverse cardiac and cerebrovascular events occurred in 3 patients (20%; 95% CI, 4% to 48%; Table 3). The patient in whom intraprocedural stenting of the left main coronary artery 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 right coronary artery at a site where a 70% stenosis had been identified preintervention that was adjudicated as being clinically not relevant. Another patient with chronic atrial fibrillation sustained a major stroke at 12 hours that resulted in dysarthria and motor weakness of the right arm and necessitated prolonged rehabilitation at an outside hospital. One patient required surgical conversion (see above).
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Acute Hemodynamic Outcomes of Patients With a Permanent Implant
In the 11 patients who received a permanent implant, the mean transvalvular pressure gradient decreased significantly from a median of 54.0 (IQR, 43.2 to 59.8) to 14.0 (13.2 to 16.5) mm Hg (P=0.0033), secondary to a fully functioning implant 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 peak aortic pressure gradient measured after implantation was also significantly reduced (median, 29.0 [24.2 to 32.8] versus 64.0 [68.2 to 98.0] mm Hg; P=0.0033).
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2 test).
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| Discussion |
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Advantages of the Nonmetallic Implant
The most obvious advantage of the nonmetallic aortic valve prosthesis is that it gives the operator unprecedented freedom of handling the device during implantation. It is nonmetallic and, in its unexpanded state, highly flexible and can be easily negotiated, even through a calcified aortic arch; it allows repeated advancement and retraction across the native annulus for proper positioning; it immediately functions on expansion and thus requires no rapid pacing during the actual implantation; and it can be checked for competent sealing of the annulus and adequate valve performance before permanent implantation. The implant can be readily retrieved and exchanged for another implant of the same or a different size should it slip back into the ascending aorta from its intended position or in cases where correct placement cannot be achieved. Thus, the characteristics of the nonmetallic implant render intraprocedural migration into the ascending or descending aorta3 virtually impossible and reduce the likelihood of emergent surgical conversion.8
The design of the implant allows fixation of the aortic ring in a subcoronary position without encroachment on the coronary ostia and fixation of the ventricular ring in a subannular position without 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 events observed in the present series. It cannot be determined if the stroke that occurred 12 hours after the intervention was related to the procedure or to the patients chronic atrial fibrillation.
Potential Disadvantages of the Nonmetallic Implant
Balloon-expandable as well as self-expanding stent-based aortic valve prostheses exert pronounced radial force on the surrounding tissue, thereby sealing the native aortic annulus and ensuring prosthesis function. With the nonmetallic implant, annular sealing is accomplished by the prosthesis rings, while the "passive" polymer-filled bridging system connecting the rings must withstand circumferential outer forces. It is therefore necessary to possibly reduce such forces and create an adequate, preferably circular, opening of the native annulus by multiple valvuloplasties (a median of 7 in our series) during rapid pacing before implantation is attempted. A circular opening and, subsequently, implantation could not be achieved in the patient with a functionally bicuspid native valve; in another patient, full expansion of the aortic prosthesis ring was prevented by a native annulus too small for the implant. Both patients underwent surgical valve replacement. Repeated rapid pacing in patients with severe aortic stenosis may result in global and irreversible myocardial ischemia. Also, it is not known if progression of sclerotic disease will eventually cause a reduction in effective aortic valve area in patients with a permanent percutaneous implant.
Impact of the Learning Curve
As is generally the case with new therapeutic technologies, increased operator experience will likely reduce the incidence of screening failures, avoid adverse events, and "streamline" the various procedural steps. In 2 patients of our series, the 22-F introducer sheath could not be advanced through severely calcified iliac arteries, and the intervention had to be aborted. More experience in the interpretation of the calcification status of the iliofemoral vasculature on the screening computed tomograms may have avoided these screening, and ultimately procedural, failures. It is expected that the development of an 18-F device will also help to reduce the number of screening failures. In patient 5, the intervention was concluded supposedly successful even though the aortic ring of the implant appeared indented and nonplanar on fluoroscopy (Figure 7) and the mean transvalvular pressure gradient was 30 mm Hg. Within 2 days, the gradient increased significantly and the patient underwent surgical conversion. Thus, a perfectly circular and planar appearance of the prosthesis rings on fluoroscopy seems to be mandatory before an intervention can be concluded.
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| Conclusions |
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| Acknowledgments |
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This study was sponsored by Direct Flow Medical Inc, Santa Rosa, Calif.
Disclosures
Drs Low and Bolling serve as consultants to Direct Flow Medical Inc, and Dr Bolling owns stock options in Direct Flow Medical Inc. Drs Schofer and Tübler have received reimbursement from Direct Flow Medical Inc for travels to scientific meetings. The other authors report no conflicts of interest.
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CLINICAL PERSPECTIVE
We performed a first-in-man study of percutaneous implantation of a novel nonmetallic aortic valve prosthesis in a small series of 15 patients with severe aortic valve stenosis who were at high risk for open-heart surgery. Implantation was acutely successful in 12 patients (80%) in whom a significant increase in aortic valve area and a concomitant reduction in the mean transvalvular pressure gradient was achieved. One patient had to undergo surgical conversion at day 2, thus 11 patients (73%) were discharged with a permanent implant. At 30 days, 1 cardiac death (6.7%; 95% CI, 0.2% to 32.0%) and 1 major stroke were observed. The 10 patients surviving 30 days with a permanent implant showed marked hemodynamic and clinical improvement. The major advantage of the highly flexible prosthesis is that it gives the operator unprecedented freedom of handling the device during implantation; it can be easily negotiated even through a calcified aortic arch, allows repeated advancement and retraction across the native annulus for proper positioning, and functions immediately upon expansion. A greater number of patients and longer follow-up are necessary for a more confident assessment of procedural success as well as long-term mortality and morbidity.
Circ Cardiovasc Intervent 2008 1: 126-133.
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