Procedural Success and 30-Day Clinical Outcomes (see full title below)

From the Ferrarotto Hospital, Catania, Italy The authors report no conflicts of interest regarding the content herein. Manuscript submitted September 16, 2008, provisional acceptance given October 16, 2008, final version accepted October 27, 2008. Address for correspondence: Prof. Corrado Tamburino, MD, FSCAI, FESC, Cardiology Chair and Division, Ferrarotto Hospital, via Citelli 6, 95124 Catania, Italy. E-mail: tambucor@unict.it

_______________________________________
ABSTRACT: Background. Percutaneous aortic valve replacement (PAVR) is an emerging alternative for high-risk patients with severe aortic stenosis. The aim of this study was to report acute and short-term outcomes of PAVR with the 18 Fr CoreValve Revalving System. Methods. From January 2007 to July 2008, 69 high-risk symptomatic patients with severe aortic stenosis were screened to assess their eligibility criteria for PAVR. All candidates were evaluated by a cardiac surgeon and a cardiologist. Thirty patients (13 men, 17 women, ages 82 ± 5 years, range 73–88 years) met all the eligibility criteria and were enrolled in the study. Results. Twenty-nine patients (97%) underwent successful valve implantation by a retrograde approach, with improvement in valve area (0.61 ± 0.18 cm² to 1.49 ± 0.39 cm²; ^p p n = 12) and 2+ (n = 2). Procedural success was achieved in 93% of patients, with 1 case of pericardial tamponade occurred during the first 48 hours after implantation. At 30-day mortality was 7%. The mean NYHA Functional Class declined from 2.72 ± 0.59 to 1.31 ± 0.47 (p Conclusions. Our initial experience of PAVR in a cohort of older and high-risk surgical patients has been positive, with excellent acute and encouraging short-term results in terms of safety and efficacy.

J INVASIVE CARDIOL 2009;21:93–98

_______________________________________
Aortic stenosis is the most common valve disorder in the western countries and its prevalence is increasing with the aging population.^1,2 At present, surgical aortic valve replacement (SAVR) is the primary treatment modality recommended for severe aortic stenosis, offering both symptomatic and prognostic benefits.^3,4 However, it is estimated that 33% of patients who need SAVR do not undergo cardiac surgery due to age and comorbidities that increase surgical risks and periprocedural morbidity.5 Therefore, the search for a less invasive option for high-risk patients has finally culminated in small trials of stent-based aortic valve prostheses.^6–8 The present study reports our initial institutional experience with percutaneous aortic valve replacement (PAVR) using the CE mark-approved 18 Fr CoreValve Revalving™ System (CoreValve, Irvine, California). We review the technique, procedural success rates and clinical outcomes up to 30 days after implantation.

Methods

Study design and patient population. The study was designed as a prospective, single-center, nonrandomized, single-arm study. Enrollment criteria included: native aortic valve stenosis with an aortic valve area 2 (2/m²) determined by echocardiography; aortic valve annulus diameter ≥ 20 mm and ≤ 27 mm; sinotubular junction ≤ 43 mm; diameter of iliac and femoral arteries ≥ 6 mm; contraindication to surgery because of concomitant comorbid conditions assessed and agreed to by both an independent cardiologist and a cardiovascular surgeon. The exclusion criteria were: femoral, iliac or aortic pathologies hampering a catheter’s transit, aortic aneurysm, carotid or vertebral artery obstruction ≥ 70%, coagulopathies, myocardial infarction (MI) or cerebrovascular accident within the previous month, severe tricuspid or mitral valvular regurgitation, left ventricular or atrial thrombus, uncontrolled atrial fibrillation, sepsis or active endocarditis, hypersensitivity or contraindications to any medication used in the study. Preprocedure screening included transthoracic echocardiography, carotid and arteriovenous duplex ultrasonography, computed tomographic angiography (CTA), and invasive cardiac evaluation with right and left cardiac catheterization, coronary arteriography, aortography and peripheral vascular angiography. Complete selection criteria based on imaging characteristics of the aortic valvular complex and left ventricle are described elsewhere.⁹ The baseline risk of the patient population was estimated by the logistic EuroSCORE.¹⁰ Additional risk criteria included cirrhosis of the liver, history of radiotherapy to the mediastinum, severe connective tissue disease and/or porcelain aorta as assessed by CTA. The study was conducted according to the Declaration of Helsinki. The local medical ethics committee approved the protocol and written informed consent was obtained from all patients and their closest relatives. Device description and procedure. The third-generation (18 Fr) CoreValve Revalving System was used in the present study.¹¹ This device consists of:

1) A bioprosthetic aortic porcine pericardial tissue valve with a trileaflet configuration attached to a scalloped skirt and sutured on a self-expanding nitinol frame; 2) An intravascular delivery catheter system comprised of an over-the-wire delivery catheter, which holds the collapsed valve covered by a protective sheath at the deployment end of the 18 Fr catheter; 3) A compression and loading system designed to radially compress the prosthesis before implantation to facilitate its loading on the delivery catheter system.

All patients received acetylsalicylic acid 100 mg, which was started before the procedure and continued indefinitely. A 300 mg loading dose of clopidogrel was administered the day before the procedure, followed by 75 mg daily for 3 months. Standard antibiotic prophylaxis was started before the procedure and continued for 5 days. During the intervention, 100 IU/kg of unfractionated heparin was administered to achieve an activated clotting time of 250–300 seconds. The procedure was performed with surgical backup and general anesthesia was employed only when intraprocedural transesophageal echocardiography (TEE) guidance was used. Otherwise, the patient received conscious sedation in addition to local anesthesia. The best femoral artery was cannulated with a 9 Fr introducer into which a 0.035 inch standard wire was inserted. The 9 Fr introducer was replaced by a Prostar™ XL 10 Fr system (Abbott Vascular, Abbott Park, Illinois) in order to position two sutures wires. The Prostar system was then removed through the standard wire and a 9 Fr introducer was reinserted in the artery. A 5 Fr Pigtail catheter was placed in the ascending aorta through the contralateral femoral artery. The left femoral vein was cannulated with a 6 Fr introducer and a temporary pacemaker (PM) electrode was placed in the right ventricle. Once past the valve with an Amplatz Left 7 Fr catheter, an Amplatz Super Stiff exchange wire was placed in the left ventricle. Subsequently, the 9 Fr introducer was replaced with an 18 Fr introducer and balloon valvuloplasty was performed using a Nucleus balloon catheter (NuMed, Inc,. Canada). With the purpose of obtaining stable positioning of the balloon during the inflation, rapid right ventricular pacing was executed with a burst of 180 bpm for 5 seconds (Figure 1). Then, the DCS with the loaded valve was positioned and released in the native aortic valve under fluoroscopic guidance (Figure 2). After valve deployment, the final transvalvular gradient was measured with an end-hole catheter and aortography was performed to assess the presence of valvular or paravalvular leaks (Figure 3). The 18 Fr introducer was retrieved and arterial hemostasis was obtained using the two sutures previously positioned through the Prostar system. Contralateral femoral artery hemostasis was achieved with the Perclose™ device (Abbott Vascular, Abbott Park, Illinois) and temporary pacing was maintained for 48 hours. Data collection and definitions. All clinically relevant baseline and follow-up variables were recorded on case report forms and prospectively entered into a dedicated database. Clinical events were adjudicated by an independent clinical events committee. Device success was defined as stable device placement and function as assessed by angiography and echocardiography. Acute procedural success was defined as device success without any periprocedural major adverse cardiovascular and cerebrovascular events (MACCE) within 48 hours from prosthesis implantation. MACCE were defined as the composite of death from any cause, MI, cardiac tamponade, stroke, urgent or emergent conversion to surgery or balloon valvuloplasty, emergent PCI, cardiogenic shock, endocarditis or aortic dissection. MI was defined as a creatine kinase-MB enzyme elevation ≥ 3 times the upper limit of normal. Major bleeding was defined as bleeding associated with a hemoglobin decrease of > 5 g/dL (or a hematocrit decrease of 15%). Statistical analysis. Baseline characteristics of patients were summarized in terms of frequencies and percentages for categorical variables and by means with standard deviations for continuous variables. Comparison of continuous variables was performed using the Student’s t-test. Differences were considered statistically significant for p (SPSS, Inc., Chicago, Illinois). The authors had full access to the data and take full responsibility for their integrity.

Results

Patient population. From January 2007 to July 2008, 69 high-risk symptomatic patients with severe aortic stenosis were screened to assess their eligibility criteria for PAVR. All candidates were evaluated by a cardiac surgeon and a cardiologist on the basis of their findings from clinical history, physical examination, cardiac surgery risk calculated by the logistic EuroSCORE, additional risk factors and aortic valve anatomy. Vascular access represented a contraindication to PAVR in 5 patients (7.2%) because of extensive tortuosity or calcification. Finally, 30 patients (13 men, 17 women, aged 82 ± 5 years, range 73–88 years) met all the eligibility criteria and were enrolled in the present study. Their baseline characteristics are summarized in Table 1. Echocardiographic peak and mean transvalvular aortic pressure gradients were 85.6 ± 22.0 mmHg and 58.1 ± 17.6 mmHg, respectively. The preprocedural mean calculated aortic valve area was 0.61 ± 0.18 cm², and 29 patients (99.7%) also had aortic regurgitation (n = 15 with grade 1+, n = 13 with grade 2+, n = 1 with grade 3+, respectively). The peak-to-peak aortic transvalvular gradient, as assessed in the catheterization laboratory before the procedure, was 63.6 ± 24.0 mmHg. The left ventricular ejection fraction was 52.6 ± 8.4% (range 31–67%), the mean logistic EuroSCORE was 25.3 ± 8.1%, and 67% of the patients were in New York Heart Association Functional Class III or IV. Acute device, procedural success and in-hospital MACCE. Acute device success was achieved in 29 patients (97%). In one patient, a too high placement of the prosthesis in a patient with an angulated aorta resulted in 3+ aortic regurgitation and needed to be corrected by implantation of a second CoreValve prosthesis (valve-in-valve). Peak-to-peak aortic transvalvular gradient, as assessed in cath lab post the procedure, was 1.8 ± 4.0 mmHg. MACCE within 48 hours after implantation were observed in 1 patient (3%) who experienced nonfatal pericardial tamponade and remained event-free during the 30-day follow-up period. Thus, acute procedural success was achieved in 28/30 patients (93%). Other periprocedural events not included in the definition of MACCE were vascular access complications (16.6%) consisting of 4 cases of femoral artery pseudoaneurysm successfully managed with ultrasound-guided compression repair (3) or surgical repair (1), and 1 case of total occlusion of the femoral artery treated with thrombo-endarterectomy. The incidence of new onset complete heart block requiring for permanent pacemaker implantation was 20% (5/25 patients without a previously implanted pacemaker). Major bleeding occurred in 1 patient (3%). Follow-up clinical results. Overall mortality at 30 days was 6.7%. One patient died as a consequence of hemorrhagic stroke probably due to the double antiplatelet therapy. Another patient died as a consequence of an ischemic stroke that did not appear to be related to the device or the procedure. At 30 days, no other events occurred. Of note, the mean NYHA functional class declined from 2.72 ± 0.59 preprocedure to 1.31 ± 0.47 postprocedure (p Acute and follow-up echocardiographic results. The baseline echocardiographic measurements are summarized in Table 1. Mean pressure gradients were clearly reduced immediately after CoreValve implantation, as seen in Figure 4. These findings were sustained at 30-day follow up. The estimated aortic valve area increased after PAVR from 0.61 ± 0.18 cm² to 1.49 ± 0.39 cm² (p Discussion PAVR was initially reported in humans by Cribier et al in 2002.¹² The device used was a balloon-expandable prosthesis featuring a stainless steel stent sutured with a bovine pericardial trileaflet valve with a dedicated catheter and a crimping system.¹³ Since the first report of CoreValve implantation in a human,14 the device has been improved in terms of feasibility, efficacy and safety. The reduction in diameter of the delivery catheter system from 25 Fr to 18 Fr has made the retrograde approach easier, overcoming all the technical challenges encountered with vascular access and passage from the aortic arch to the ascending aorta. The procedure has been simplified, thus avoiding the need for cardiopulmonary bypass, which was routinely used in patients treated with 25 Fr and 21 Fr devices and in the early procedures using the third-generation 18 Fr delivery catheter system. In our experience, PAVR was performed with a mortality rate that favorably compares with that of open-heart surgery in selected high-risk patients. Intraprocedural and 30-day mortality rates were 0% and 6.7%, respectively, whereas the population enrolled in our series presented with a median logistic EuroSCORE of 25%. Although the accuracy of the EuroSCORE for outcome stratification in high-risk surgical candidates is controversial, these results are encouraging and better than those reported by Grube at al8 in the largest series currently available (n = 86) using the second and third generations of the CoreValve Revalving System (Table 4). This is not surprising, since patients in our series had 97% and 90% acute device and procedural success rates, respectively. A possible explanation for this might be the availability of the third-generation CoreValve system featuring a reduced sheath size of 18 Fr, which allows nearly all procedures to be performed with local anesthesia only at the groin site and requires no surgical cutdown at the access site, providing obvious advantages in terms of hemodynamic stability. Nevertheless, even in the subgroup of 36 patients treated with a smaller 18 Fr sheath who had a 6-point lower mean EuroSCORE than that of our patients, Grube reported lower rates of procedural success (69%) and 30-day mortality (14%). Of note, although one theoretical advantage of the antegrade approach is a lower risk of atheroma embolis during delivery catheter advancement through an atheromatous aorta, no periprocedural strokes were observed in our series using the retrograde approach. The 2 cases of stroke noted after 48 hours up to 30 days did not appear to be related to the procedure itself. However, one cause of fatal intracranial hemorrhage could be related to the antithrombotic therapy. Thus, our results corroborate the procedure’s previously reported feasibility and safety findings when a rigorous selection of candidates strictly excludes those with a clinical indication of high surgical risk or inoperability, and the anatomy of the valve and the vascular access are carefully assessed for satisfaction of all the inclusion criteria. The hemodynamic results of this study clearly show the efficacy of the percutaneous approach in reducing the mean aortic valve pressure gradient. The prosthetic valve area of 1.7 cm² compares favorably with currently available surgical valves. Paravalvular leakages were common but mild in most cases and were very stable, with no hemodynamic consequences. Further improvements in the skirt of the prosthesis will likely mitigate the incidence of paravalvular aortic regurgitation, which will encourage wider usage of the device. Since the first devices were implanted nearly 1 year ago, follow up continues. At a mean follow-up period of 4.9 ± 4.0 months, no other events occurred, suggesting a sustained mid-term benefit of PAVR, though more data are required to strengthen these findings. Study limitations. This was a single-center study describing only the short-term results after CoreValve implantation. Rigorous longer-term follow up is ongoing. Another caveat is the absence of a control group. Additional studies are required to assess the appropriateness of this procedure for patients with lower EuroSCOREs who are good candidates for surgery.

Conclusions

Our initial experience of PAVR in a cohort of older and high-risk surgical patients has been positive, with excellent acute and encouraging short-term results in terms of safety and efficacy as assessed by hemodynamic and NYHA functional class improvement. The rigorous selection of the candidates played an important role in the success of the procedures. Longer-term results of the published percutaneous aortic valve series are awaited to confirm the device’s durability and long-term efficacy, and randomized trials are needed before the indications can be expanded.

References

1. Rajamannan NM, Bonow RO, Rahimtoola SH. Calcific aortic stenosis: An update. Nat Clin Pract Cardiovasc Med. 2007;4:254–262. 2. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: A population-based study. Lancet 2006;368:1005–1011. 3. Vahanian A, Baumgartner H, Bax J, et al; Task Force on the Management of Valvular Hearth Disease of the European Society of Cardiology; ESC Committee for Practice Guidelines. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28:230–268. 4. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons, Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Society of Cardiovascular Anesthesiologists: Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84–e231. 5. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe aortic stenosis: Why are so many denied surgery? Eur Heart J 2005;26:2714–2720. 6. Cribier A, Eltchaninoff H, Tron C, et al. Treatment of calcific aortic stenosis with the percutaneous heart valve: Mid-term follow-up from the initial feasibility studies: The French experience. J Am Coll Cardiol 2006;47:1214–1223. 7. Grube E, Laborde JC, Gerckens U, et al. Percutaneous implantation of the CoreValve self-expanding valve prosthesis in high-risk patients with aortic valve disease: The Siegburg first-in-man study. Circulation 2006;114:1616–1624. 8. Grube E, Schuler G, Buellesfeld L, et al. Percutaneous aortic valve replacement for severe aortic stenosis in high-risk patients using the second- and current third-generation self-expanding CoreValve prosthesis: Device success and 30-day clinical outcome. J Am Coll Cardiol 2007;50:69–76. 9. Piazza N, Grube E, Gerckens U, et al. Procedural and 30-day outcomes following transcatheter aortic valve implantation using the third generation (18 Fr) CoreValve ReValving System: Results from the multicentre, expanded evaluation registry 1-year following CE mark approval. EuroInterv 2008;4:242–249. 10. Roques F, Nashef SA, Michel P, et al. Risk factors and outcome in European cardiac surgery: Analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg 1999;15:816–822. 11. Laborde JC, Borenstein N, Behr L, et al. Percutaneous implantation of the CoreValve aortic valve prosthesis for patients presenting high risk for surgical valve replacement. Eurointerv 2006;1:472–474. 12. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: First human case description. Circulation 2002;106:3006–3008. 13. Cribier A, Eltchaninoff H, Tron C, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004;43:698–703. 14. Grube E, Laborde JC, Zickmann B, et al. First report on a human percutaneous transluminal implantation of a self-expanding valve prosthesis for interventional treatment of aortic valve stenosis. Catheter Cardiovasc Interv 2005;66:465–469. 15. Webb JG, Pasupati S, Humphries K, et al. Percutaneous transarterial aortic valve replacement in selected high-risk patients with aortic stenosis. Circulation 2007;116:755–763. 16. Marcheix B, Lamarche Y, Berry C, et al. Surgical aspects of endovascular retrograde implantation of the aortic CoreValve bioprosthesis in high-risk older patients with severe symptomatic aortic stenosis. J Thorac Cardiovasc Surg 2007;134:1150–1156.