Hemodynamics and Early Clinical Performance of the St. Jude Medical Regent Mechanical Aortic Valve

Transcription

1 Hemodynamics and Early Clinical Performance of the St. Jude Medical Regent Mechanical Aortic Valve David S. Bach, MD, Marc P. Sakwa, MD, Martin Goldbach, MD, Michael R. Petracek, MD, Robert W. Emery, MD, and Friedrich W. Mohr, MD Department of Medicine, Division of Cardiology, University of Michigan, Ann Arbor, Michigan; Section of Cardiothoracic Surgery, Department of Surgery, William Beaumont Hospital, Royal Oak, Michigan; Section of Cardiothoracic Surgery, Department of Surgery, London Health Sciences Center, London, Ontario, Canada; Section of Cardiothoracic Surgery, Department of Surgery, St. Thomas Hospital, Nashville, Tennessee; and Section of Cardiothoracic Surgery, Department of Surgery, Herzzentrum Universitat Leipzig, Leipzig, Germany Background. The St. Jude Medical Regent valve is the next-generation bileaflet aortic prosthesis, modified from the currently marketed St. Jude Medical mechanical valve to achieve a larger geometric orifice without changing the existing design of the pivot mechanism or bloodcontact surface areas. The present study reports the hemodynamic and early clinical results of an ongoing multicenter trial investigating the performance of the Regent valve. Methods. Between July 1998 and July 2001, 361 patients at 17 centers in North America and Europe underwent implantation of a Regent mechanical aortic valve prosthesis. Clinical status was prospectively recorded, and echocardiography with Doppler was performed at discharge and at 2 months, 6 months, 1 year, and 2 years after operation. Results. Follow-up to date is 300 patient-years (average, years per patient; range, 0.0 to 2.7 years). There The St. Jude Medical Regent valve is the nextgeneration bileaflet mechanical prosthetic aortic valve, constructed of pyrolytic carbon and modified from the currently marketed St. Jude Medical mechanical valve. The currently marketed Standard and HP valve prostheses have excellent in vitro and in vivo hemodynamics [1], with an excellent record for safety and freedom from adverse events [2]. The Regent valve has a modified external profile that achieves a larger geometric orifice area without changing the existing design of the pivot mechanism or blood-contact surface areas. The prosthesis is presently in clinical use in Europe and Canada, and is undergoing evaluation for clinical use by the US Food and Drug Administration. The purpose of the present study is to report the hemodynamic and early clinical results of an ongoing prospective, observational, multicenter, international trial investigating the clinical Presented at the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 30, Address reprint requests to Dr Bach, University of Michigan, L3119 Women s 0273, Ann Arbor, MI 48109; dbach@umich.edu. were low rates of clinical adverse events. Mean gradient at 6 months was mm Hg, mm Hg, mm Hg, mm Hg, and mm Hg, respectively, for 19-mm, 21-mm, 23-mm, 25-mm, and 27-mm valves; effective orifice area was cm 2, cm 2, cm 2, cm 2, and cm 2, respectively. Indexed effective orifice area was equal to or greater than 1.0 cm 2 /m 2 for all valve sizes. Left ventricular mass index decreased significantly between early postoperative ( g/m 2 ) and 6-month follow-up ( g/m 2 ; g/m 2 ; p < ). Conclusions. The St. Jude Medical Regent aortic valve has excellent hemodynamics and early clinical results, with rapid and significant left ventricular mass regression. Long-term clinical assessment is ongoing. (Ann Thorac Surg 2002;74:2003 9) 2002 by The Society of Thoracic Surgeons performance of the Regent mechanical aortic valve prosthesis. Patients and Methods Study Population Between July 1998 and July 2001, 361 patients at 17 centers in North America and Europe underwent implantation of a Regent mechanical aortic valve prosthesis (St. Jude Medical, Inc., St. Paul, MN). Participating centers and principal investigators are listed in the Appendix. Patients included 253 (70%) men and 108 (30%) women. Mean age at the time of operation was years (range, 28.8 to 84.9 years). The predominance of patients (235, 65.1%) were 50 to 69 years (147 patients, 40.7%, were 60 to 69 years), and 45 (12.5%) were at least 70 years at the time of operation. Preoperative left ventricular (LV) ejection fraction was 56.4% 13.7% (range, 18% to 83%). History of arrhythmia was present in 58 patients (16%), including 40 (11%) with atrial fibrillation. Carotid artery disease was present in 15 patients (4%). Preoperative valve dysfunction was aortic stenosis in 182 (50.4%) patients, aortic regurgitation in 68 (18.8%), 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)

2 2004 BACH ET AL Ann Thorac Surg REGENT AORTIC VALVE 2002;74: Clinical Follow-Up All patients underwent regular clinical follow-up at the investigational center at which the aortic valve operation was performed. Adverse clinical events were recorded prospectively, including evidence of embolization (any; and reversible ischemic neurological deficit, cerebrovascular accident, or peripheral), nonstructural valve dysfunction (paravalvular leak), structural deterioration, endocarditis, major bleeding event, clinically significant hemolytic anemia, thrombosis, reoperation, and death (all-cause, cardiac, and valve-related). Definitions for adverse events were based on published guidelines [3, 4]. Early events were defined as those occurring on or before 30 days after valve implantation. Patient-years at risk for late events were determined from 31 days after operation to either occurrence of the primary event or to the censoring event. Fig 1. Valve sizes implanted among patients undergoing Regent aortic valve replacement. and mixed stenosis and regurgitation in 111 (30.7%). The cause of disease (more than one cause could be included for each patient) was degenerative in 212 (58.7%) patients, congenital in 124 (34.3%), rheumatic in 48 (13.3%), infective in 8 (2.2%), and other causes in 41 (11.4%). Surgical inspection of valve disease (patients could be counted more than once) revealed leaflet calcification in 260 (72.0%), annular calcification in 207 (57.3%), leaflet thickening in 102 (28.3%), commissural fusion in 84 (23.3%), annular dilation in 27 (7.5%), leaflet perforation in 12 (3.3%), and other diseases in 34 (9.4%). Aortic valve repair or replacement had been previously performed in 12 (3.3%) patients; prior coronary artery bypass grafting had been performed in 16 (4.4%). The distribution of aortic valve sizes implanted is shown in Figure 1. Concomitant surgical procedures were performed in 138 (38.2%) of 361 patients, and included coronary artery bypass grafting in 109 (30.2%) patients, mitral valve repair in 6 (1.7%), and aortic root enlargement in 4 (1.1%). Postoperative anticoagulation schemes were determined by individual physicians and study sites. The preponderance of sites used a target international normalized ratio range of 2.0 to 3.0 or 3.5. Echocardiography By protocol, transthoracic echocardiography with Doppler was performed at specified times, including before hospital discharge and at 2 months, 6 months, and 1 year postoperatively, and yearly thereafter. Imaging included two-dimensional and M-mode echocardiography, pulsed-wave and continuous-wave spectral Doppler, and color flow Doppler imaging. The aortic valve prosthesis was interrogated for regurgitation using parasternal and apical windows. Echocardiographic images were recorded on standard or super VHS videotape for subsequent analysis. All echocardiograms were analyzed at a central, core echocardiography laboratory by observers highly trained in qualitative and quantitative echocardiography and Doppler. Observers had no knowledge of clinical information at the time of echocardiographic analysis. Echocardiographic analysis included two-dimensional echocardiographic measurement of LV dimensions and ejection fraction, measurement of mean and peak aortic gradients using the modified Bernoulli equation P 4(V 2 2 V 1 2 ) [5], and calculation of aortic valve effective orifice area using the continuity equation [5]. Left ventricular mass was calculated using the modified American Society of Echocardiography cube method [6]: Surgical Technique The Regent valve is shown in Figure 2. Surgical procedure was performed in accordance with clinical practice at each investigative site, using cardiopulmonary bypass typically with hypothermia and cold crystalloid cardioplegic cardiac arrest. Valve implantation was typically in a supraannular position, using a noneverting suture technique with 2-0 Ethibond (Ethicon Inc, Somerville, NJ). Fig 2. Regent aortic valve prosthesis.

3 Ann Thorac Surg BACH ET AL 2002;74: REGENT AORTIC VALVE 2005 LV Mass IVS LVIDD PW 3 LVIDD 3 0.6, where IVS interventricular septum, LVIDD LV internal diameter in diastole, and PW posterior wall. Left ventricular mass index was calculated as LV mass divided by body surface area. If present, aortic regurgitation was quantified as trivial, mild, moderate, or severe based on measurement of regurgitant jet diameter relative to the diameter of the LV outflow tract [7], assessment of aortic regurgitation deceleration slope on spectral continuous-wave Doppler, and assessment of diastolic flow reversal in the descending thoracic aorta. Aortic regurgitation when present was categorized by location as valvular, paravalvular, or indeterminate, based on jet location and characteristics in all available views. Statistical Analysis All data are presented as mean standard deviation. Kaplan-Meier analyses for bleeding event, embolism, endocarditis, paravalvular leak, valve reoperation, allcause mortality, and valve-related mortality were created using SAS system statistical software (SAS Institute, Inc, Cary, NC). Results Clinical Follow-Up Follow-up for the study group to date is patientyears (average follow-up, years per patient; range, 0.0 to 2.7 years); 253 (70%) of patients have been followed at least 6 months. Of 361 patients who originally underwent aortic valve replacement, 17 (4.7%) died, 6 (1.7%) were lost to follow-up, and 3 (0.8%) underwent subsequent valve explantation, yielding a group of 335 patients available for continuing follow-up. At the time of writing, a total of 348 patients were available for clinical assessment at discharge, 320 at 2 months, 253 at 6 months, 176 at 1 year, and 67 at 2 years after operation. Anticoagulation with warfarin or a warfarin derivative was used in all patients at hospital discharge and at all subsequent postoperative intervals. New York Heart Association functional class before operation and at postoperative intervals is shown in Figure 3. Absolute rates for early adverse events and linearized rates for late adverse events are shown in Table 1. Kaplan-Meier freedom from adverse events is shown in Table 2. In all cases of adverse events, rates fell within objective performance criteria guidelines. Two patients experienced a valve-related death. One patient with cardiomyopathy had an embolic stroke 5 weeks after operation, with the apparent source a new LV thrombus. The other patient had a history of multiple myeloma and experienced an intracranial hemorrhage 8 months after operation, at a time when the international normalized ratio was above target. In neither case was there evidence of valve dysfunction. Reoperation occurred in 3 patients within 2 weeks of operation and in 1 patient 14 months after operation. All Fig 3. New York Heart Association functional class before and after Regent aortic valve replacement. ;; ;; ;;; ;;; class I; ;;; class II; o class III; class IV. (Preop preoperative; R number of patients at risk.) reoperations were to address paravalvular leak; 2 (1 early and 1 late) were sequelae of infective endocarditis. Valves were replaced in 3 patients (2 early and 1 late), and the leak was repaired without valve replacement in the other. Bleeding occurred in 32 patients (27 early and 5 late). Procedure-related bleeding occurred in 25 patients, and anticoagulation-related hemorrhage occurred in 10. (More than one bleeding event occurred in 8 patients, including both procedure-related and anticoagulation- Table 1. Early (Absolute) and Late (Linearized) Rates of Adverse Events Adverse Event Early Events (Absolute Rates) n % n Late Events (Linearized Rates) Pt-Yrs at Risk %/ Pt-Yr Embolism All RIND/CVA/ Peripheral Paravalvular leak Structural deterioration Endocarditis Major bleeding event Hemolysis Thrombosis Reoperation All Repair Explant Death All causes Valve-related Cardiac Other causes CVA cerebrovascular accident; Pt-Yr patient-years; RIND reversible ischemic neurological deficit.

4 2006 BACH ET AL Ann Thorac Surg REGENT AORTIC VALVE 2002;74: Table 2. Kaplan-Meier Freedom From Adverse Events Adverse Event n 1-year Freedom (%) 2-year Freedom (%) Embolism All RIND/CVA/Peripheral Paravalvular leak Structural deterioration Endocarditis Major bleeding event Hemolytic anemia Thrombosis Reoperation All Repair Explant Death All causes Valve-related Cardiac Other causes RIND reversible ischemic neuro- CVA cerebrovascular accident; logical deficit. related bleeding in 4.) Anticoagulation-related hemorrhage was gastrointestinal in 8, and intraocular, intracranial, and after ileostomy in 1 each. Anticoagulation was above target in four of eight cases of gastrointestinal bleeding, therapeutic in three, and unknown in one. Hemodynamics Echocardiograms were successfully performed in 318 (91.4%) of 348 eligible patients at discharge, 269 (84.2%) of 320 eligible patients at 2 months, 197 (77.9%) of 253 at 6 months, 120 (68.2%) of 176 at 1 year, and 39 (58.2%) of 67 at 2 years after operation. Values for mean pressure gradient, peak pressure gradient, and effective orifice area by valve size at 6 months are shown in Table 3. Graphic depiction of gradients and effective orifice area at hospital discharge and through 1 year of follow-up are shown in Figure 4. For the group as a whole, mean pressure gradient decreased significantly between discharge ( mm Hg) and 6 months of follow-up ( mm Hg; mm Hg; p 0.001). Similarly, a statistically significant decrease in peak pressure gradient was observed between discharge ( mm Hg) and 6 months ( mm Hg; mm Hg; p ). No further significant decrease in gradients was observed. Effective orifice area increased significantly between discharge ( cm 2 ) and 6 months of follow-up ( cm 2 ; cm 2 ; p 0.002). Cardiac output remained stable between early postoperative ( L/min), 6 months after operation ( L/min; p 0.51), and 1 year after operation ( L/min; p 0.34 versus early postoperative). Left Ventricular Mass Regression Left ventricular mass index was greater than normal on early postoperative echocardiograms, consistent with significant LV hypertrophy. Left ventricular mass index as a function of time is shown in Figure 5. There was a statistically significant decrease in LV mass index between early postoperative ( g/m 2 ) and 6 months ( g/m 2 ; ; p ), with a large proportion of the decrease observed in the first 2 months. Between discharge and 6 months, LV mass decreased significantly for valve sizes 19 mm ( to g/m 2 ; p 0.03), 21 mm ( to g/m 2 ; p 0.006), 23 mm ( to g/m 2 ; p ), and 25 mm ( to g/m 2 ; p 0.003); LV mass regression was of similar magnitude but failed to reach statistical significance among patients with a 27-mm valve ( to g/m 2 ; p 0.26). Left ventricular mass regression from discharge to 6 months was similar (p 0.7 among groups) for patients with preoperative aortic stenosis ( 28.8 g/m 2 ; p ), aortic regurgitation ( 26.7 g/m 2 ; p 0.005), and mixed stenosis and regurgitation ( 20.9 g/m 2 ; p 0.001). At 6 months, LV mass had returned to normal in 88 of 187 (47.1%) patients, including 46 of 94 (51.1%) with preoperative aortic stenosis, 20 of 44 (45.5%) with preoperative aortic regurgitation, and 22 of 49 (44.9%) with mixed disease. Aortic Regurgitation The presence and severity of aortic regurgitation on hospital discharge and subsequent follow-up intervals is shown in Figure 6. There was no to mild aortic regurgitation in 99.3%, 98.4%, 99.4%, 98.2%, and 96.9% of patients at discharge, 2 months, 6 months, 1 year, and 2 years, respectively. At 1 year after operation, more than mild aortic regurgitation was found in 2 patients: 1 with severe paravalvular regurgitation resulting from endocarditis, and 1 with moderate regurgitation of indeterminate origin. At 2 years, more than mild regurgitation Table 3. Hemodynamic Variables by Valve Size at 6 Months Postoperatively Variable 19 mm (n 12) 21 mm (n 52) 23 mm (n 65) 25 mm (n 39) 27 mm (n 13) 29 mm (n 2) Mean gradient (mm Hg) Peak gradient (mm Hg) Effective orifice area (cm 2 ) EOA-I (cm 2 /m 2 ) EOA-I indexed effective orifice area.

5 Ann Thorac Surg BACH ET AL 2002;74: REGENT AORTIC VALVE 2007 Fig 5. Temporal change in left ventricular (LV) mass index after Regent aortic valve replacement. Data with a sample size fewer than 5 are excluded. (Data not displayed for 17-mm or 29-mm valves, and for 19-mm valve at 1 year, owing to small sample sizes.) 19 mm; 21 mm; 23 mm; 25 mm; 27 mm; all sizes. (R number of patients at risk.) Comment The Standard and HP Series St. Jude Medical bileaflet mechanical prostheses have very good associated hemodynamics [1] and excellent records for durability and for freedom from adverse events [2]. The St. Jude Medical Regent mechanical aortic valve prosthesis represents a design modification of the existing St. Jude Medical bileaflet valves, with a modified external profile that results in a larger geometric orifice area without changing the existing design of the pivot mechanism or bloodcontact surface areas. As such, it is anticipated that the valve should have even better hemodynamics than the Standard and HP St. Jude Medical valves, and an equivalent profile for freedom from adverse events. The present report is a description of the hemodynamic and early clinical performance characteristics of the Regent valve. It provides characterization of the gradients and effective orifice area that can be anticipated; and with Fig 4. Temporal change in hemodynamics after Regent aortic valve replacement. (A) Mean pressure gradient. (B) Peak pressure gradient. (C) Effective orifice area (EOA). (Data not displayed for 17-mm and 29-mm valves owing to small sample sizes.) 19 mm; 21 mm; 23 mm; 25 mm; 27 mm; all sizes. (R number of patients at risk.) occurred in a single patient, who had severe central valvular regurgitation. This patient remains in New York Heart Association functional class I, and no other tests have been performed to evaluate the valve. Fig 6. Presence and severity of aortic regurgitation after Regent aortic valve replacement. ;; ;; ;;; ;;; none/trivial; ;;; mild; o moderate; severe. (R number of patients at risk.)

6 2008 BACH ET AL Ann Thorac Surg REGENT AORTIC VALVE 2002;74: more than 300 patient-years of follow-up, provides assessment of the early clinical performance of the prosthesis. Clinical Outcomes Ultimately, assessment of clinical outcomes relies on long-term assessment for years and decades. However, within the available follow-up of just more than 300 patient-years, there were excellent clinical outcomes among patients after implantation with the Regent mechanical aortic valve. Functional status assessed by New York Heart Association classification was excellent, and there were very low rates of adverse events. Postoperative bleeding events predominantly comprised early procedure-related events that were not directly related to the prosthesis. In all cases of adverse events, rates fell within objective performance criteria guidelines. Hemodynamics in Context The present study reveals excellent hemodynamic variables associated with the Regent aortic valve prosthesis, with low mean and peak transvalvular gradients and large effective orifice area and indexed effective orifice area. Left ventricular mass regression was noted with smaller as well as with larger valve sizes, confirming that good transvalvular hemodynamics are associated with the entire range of available valve sizes. Although previously reported with stentless bioprostheses [8], this finding has not been described with mechanical prostheses. Transvalvular gradients decreased and effective orifice area increased in the first 6 months after operation, which has not been previously reported with a mechanical prosthesis. Stable cardiac output and an increase in orifice area suggest that the decrease in gradients was not areflection of altered flow across the valve. Incomplete valve opening early after operation is unlikely in light of normal cardiac output. The most likely explanation for improved hemodynamics in the months after valve replacement may be related to regression of LV outflow tract hypertrophy after aortic valve replacement, suggesting that early postoperative gradients were contributed to by subvalvular narrowing. Further research to test this hypothesis would be of interest. The problem of prosthesis-patient mismatch is well documented and clinically evident among a subset of patients after aortic valve replacement [9, 10]. Prosthesispatient mismatch results in less symptomatic improvement and suboptimal LV mass regression after aortic valve replacement [10]. Because prosthesis-patient mismatch of the aortic valve usually can be avoided if the indexed effective orifice area is more than 0.85 cm 2 /m 2 [10], excellent hemodynamics in general, and the finding in the present report of indexed effective orifice area of at least 1.0 cm 2 /m 2 for all Regent valve sizes, suggests that patient-prosthesis mismatch should be uncommon with the use of this prosthesis. In the present report, there was a low prevalence of hemodynamically significant aortic regurgitation. Although trivial or mild aortic regurgitation was not uncommon, this is an anticipated finding with all bileaflet mechanical valves. There was a very low prevalence of significant periprosthetic regurgitation. Study Limitations The present study reports clinical outcomes with follow-up of just more than 300 patient-years. The data are sufficient to conclude that there are excellent hemodynamics associated with the Regent valve. However, longterm follow-up is desirable to continue to assess clinical outcomes and objective performance criteria. No direct comparison is made between the Regent valve and other mechanical or biologic prostheses, although such comparisons may be the subject of future investigations. Conclusion The present report demonstrates excellent hemodynamic performance of the Regent bileaflet aortic valve prosthesis, with rapid and significant LV mass regression. Patient functional class and freedom from adverse events were very good. Long-term clinical assessment of the valve is ongoing. References 1. Otto CM. Echocardiographic evaluation of prosthetic valve dysfunction. In: Otto CM, ed. Textbook of clinical echocardiography. 2nd ed. Philadelphia, PA: WB Saunders, 2000: Baudet EM, Puel V, McBride JT. Long-term results of valve replacement with the St. Jude Medical prosthesis. J Thorac Cardiovasc Surg 1995;109: U.S. Food and Drug Administration, Division of Cardiovascular, Respiratory, and Neurological Devices, October 14, Draft Replacement Heart Valve Guidance Document. 4. Edmunds LH Jr, Clarke RE, Cohn LH, Miller DC, Weisel RD. Guidelines for reporting morbidity and mortality after cardiovascular operations. J Thorac Cardiovasc Surg 1996;112: Feigenbaum H. Hemodynamic information derived from echocardiography. In: Feigenbaum H, ed. Echocardiography. 5th ed. Philadelphia, PA: Lea & Febiger, 1994: Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57: Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol 1987;9: Bach DS, David T, Yacoub M, et al. Hemodynamics and left ventricular mass regression following implantation of the Toronto SPV valve. Am J Cardiol 1998;82: Rahimtoola SH. The problem of valve prosthesis-patient mismatch. Circulation 1978;58: Pibarot P, Dumesnil JG. Hemodynamic and clinical impact of prosthesis-patient mismatch in the aortic valve position and its prevention. J Am Coll Cardiol 2000;36:

7 Ann Thorac Surg BACH ET AL 2002;74: REGENT AORTIC VALVE 2009 Appendix St. Jude Medical Regent Investigational Centers and Principal Investigators European Centers Herzzentrum Leipzig GmbH; University of Leipzig, Leipzig, Germany; Prof. Doctor Friedrich Mohr Krankenhaus Wien-Lainz, Wien, Austria; Prof. Doctor Manfred Deutsch Aarhus University Hospital, Aarhus, Denmark; Prof. Doctor Peter Kildeberg Paulsen Canadian Centers London Health Sciences Center, University of Western Ontario, London, Ontario; Martin Goldbach, MD St. Michael s Hospital, University of Toronto, Toronto; Lee Errett, MD Royal Victoria Hospital, McGill University, Montreal, Quebec; Benoit de Varennes, MD Hopital Laval, Saint-Foy, Quebec; Richard Baillot, MD United States Centers William Beaumont Hospital, Royal Oak, MI; Marc P. Sakwa, MD St. Thomas Hospital, Nashville, TN; Michael Petracek, MD Abbott Northwestern/United Hospitals, Minneapolis, MN; Kit Arom, MD Jewish Hospital, Louisville, KY; Laman Gray, Jr, MD University of Pittsburgh, UPMC Presbyterian, Pittsburgh, PA; Ronald V. Pellegrini, MD Kaiser Permanente, Los Angeles, CA; Siavosh Khonsari, MD St. Luke s Hospital, University of Missouri Medical School, Kansas City, MO; Michael Borkon, MD Cleveland Clinic Foundation, Cleveland, OH; Michael Banbury, MD Columbia-Presbyterian Medical Center, New York, NY; Craig Smith, MD Washington Hospital Center, Washington, DC; Ammar Bafi, MD DISCUSSION DR DAVID FULLERTON (Chicago, IL): Do you see this valve as supplanting the other St. Jude devices? DR EMERY: I would suspect so. There are sites that only stock the St. Jude Medical HP valve and do not stock the standard prosthesis. The Regent modification allows placement of a clearly larger valve size. It is very interesting because at times you think it might not fit, yet sizing is reliable. DR JOACHIM LAAS (Bad Bevensen, Germany): I have two questions. We know from experimental and clinical studies that valve orientation, especially in small-size valves, is very important. I would like to know if you can give any advice on valve orientation? The other question: you gain size by using a smaller sewing ring. However, is it really an advantage to implant a large size 27-mm valve and lose the safety of a pliable sewing ring? Furthermore, we know that in large size valves such as 27 mm, regurgitation can be as much as 25% and more in aortic and mitral subsitutes. DR EMERY: First, I do not have the specifics of valve orientation from this study. Personally I orient the leaflets directed toward the left coronary ostium, with a leaflet guard at the left coronary, so they open in line with the artery. The Regent valve is rotatable as are the standard and HP St. Jude valves. As far as the sizing of the valve, the sewing ring has less bulk. For implanting the standard St. Jude valve, which I have been using for a long time, I generally put in 12 or 13 mattress stitches. As the Regent sewing ring is smaller and thinner, I generally put in 2 or 3 more stitches and make the mattress sutures a bit narrower. I agree with you that there is possible risk. This has not turned out to be the case, however, neither in our hands nor in this multicenter study, that there is an increased incidence of paravalvular leak related to the sewing ring. Regarding aortic regurgitation, the incidence is actually low. (Slide) Here are the core laboratory echocardiographic results indicating none, mild, moderate, and trivial area. You can see over time that no significant aortic insufficiency occurs. One patient had an explant for endocarditis because of a paravalvular leak that occurred late. This patient is the one who went from zero to mild to severe insufficiency with a central jet. She is in New York Heart Association class I. Neither the core laboratory nor the investigative site is perfectly clear what this really means. Originally the jet was called unknown on the echocardiogram. Then it was called a paravalvular leak. And at the last echocardiogram it was called central. The patient is fine, and we are just planning on following her along to find out how she does. We have not done anything. So the regurgitation has really not been an issue with this prosthesis, and one can implant in an appropriate size that gives you excellent hemodynamics rather than trying to fit in an ultralarge size because you are concerned about gradients.