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Percutaneous Aortic Valve Replacement: New Hope for
Inoperable and High-Risk Patients
Aortic stenosis is the most common valvular heart disease in the Western world and its prevalence is increasing with an aging population. Critical aortic stenosis affects an estimated 3% of individuals over 75 years of age.1 Without intervention, progressive disability due to symptoms of angina, syncope or heart failure ensues, and survival rarely exceeds 2 to 3 years. Currently, surgical aortic valve replacement is the only treatment that offers both symptomatic and prognostic benefit. In patients who are declined cardiac surgery, physicians have little to offer. The search for an alternative therapy for these patients has been underway for a number of years and has finally culminated in multicenter trials of aortic valve prostheses designed to be implanted percutaneously. This review describes the devices, techniques and their development, as well as the initial results in more than 160 patients. The current limitations of the procedures are explained alongside the ongoing work necessary in order that such therapy may eventually be made widely available.
Who Would Benefit?
A consensus of opinion and unambiguous guidelines state that aortic valve surgery should be offered to patients with symptomatic severe valvular stenosis. The age and comorbidities of those most commonly affected, however, mean that in reality, cardiologists, surgeons and patients themselves are often faced with a far more difficult decision. Analysis of data from the EuroHeart Survey2 revealed that one-third of elderly patients with severe symptomatic aortic stenosis are denied valve surgery, and a similar study found this figure to be as high as 41%.3 Predictive factors of the decision not to operate were older age and lower left ventricular (LV) ejection fraction. Although both are strong predictors of operative risk, there is also evidence that it is those patients with LV dysfunction who derive the greatest benefit from intervention.4 Surgical decisions are also based on associated pathologies such as neurological dysfunction, previous cardiac surgery or associated coronary artery disease, renal impairment and chronic lung disease with predicted operative mortality being calculated using systems such as the Euroscore algorithm. While the accuracy and value of such scoring systems remain the subject of some debate, the risk of perioperative mortality in some patients with multiple comorbidities is clearly unacceptable to one or all of those involved in the decision-making process. In the absence of any effective medical therapy, both symptomatic deterioration and death are inevitable outcomes in those who are denied or decline cardiac surgery.
Development of Percutaneous Aortic Valve Therapies
Recent progress in the search for a solution to offer this ever-increasing cohort of elderly patients with multiple comorbidities began in 1985 when Alain Cribier performed the first percutaneous balloon aortic valvuloplasties (BAV), reporting encouraging results in 3 patients.5 The technique effectively decreased the transvalvular systolic pressure gradient while avoiding median sternotomy and cardiopulmonary bypass. By 1991, BAV had been successfully performed in thousands of inoperable patients and the outcomes followed closely in a number of registries. While undoubtedly providing short-term symptomatic relief, and in some cases providing a bridge to subsequent surgical valve replacement, event-free survival at 24 months was as low as 18%, and it soon became apparent that this was the result of valvular restenosis.6,7
Consequently, BAV (Figure 1) is now performed infrequently, either as a short-term palliative measure, or to provide temporary hemodynamic improvement, allowing noncardiac surgical interventions to be performed. The first nonsurgical implantation of a bioprosthetic heart valve in a human was performed by Cribier in 2002 on a patient in cardiogenic shock in whom the results of BAV had not been sustained. The valve, more than 10 years in development in animals and designed to be delivered percutaneously, comprised 3 bovine pericardial leaflets mounted within a stainless-steel balloon expandable stent.8 Since this initial pioneering procedure in which immediate hemodynamic and symptomatic improvement was achieved, the same device has been further developed and deployed in a single-center pilot study, the results of which were published in 2006.9 The Cribier-Edwards Prosthetic Valve System and Procedure The Cribier-Edwards valve (2nd generation) is currently constructed from a tubular, slotted, stainless steel stent with an attached trileaflet valve (Figure 2A), the lower third (LV portion) of which is covered with a fabric cuff. Prior to insertion, this structure is crimped onto a valvuloplasty balloon catheter (Figures 2B and C). Two stent sizes are currently in use: 23 mm diameter x 14.5 mm height and 26 x 16 mm (fully expanded), chosen according to the diameter of the aortic annulus. Delivery of this device to the aortic root has been achieved by three methods: antegrade, retrograde and transapical (Table 1).
Procedure. The procedure is performed under local (anterograde approach) or general anesthesia (retrograde or transapical) without cardiopulmonary bypass. Premedication comprises aspirin, clopidogrel and antibiotics, with unfractionated heparin added during the procedure. Measurement of baseline hemodynamics and insertion of a right ventricular pacing lead precede catheterization of the aortic valve. Predilatation of the valve with a valvuloplasty balloon is required before carefully positioning the bioprosthesis using X-ray visualization of the calcified aortic valves, contrast aortography and, in some cases, using echocardiographic guidance (Figure 3). Deployment by balloon inflation is completed during rapid right ventricular pacing to lower LV stroke volume (Figure 4), thus decreasing the risk of device migration.
Antegrade approach. The device is inserted via a 22 or 24 Fr sheath in the femoral vein (23 or 26 mm valve). Transseptal puncture is performed and a guidewire directedd first across the mitral, then, the aortic valve is snared and externalized via a 7 Fr sheath in the opposite femoral artery. A guide catheter facilitates dilatation of the intra-atrial septum and positioning of the device. At present, this technique has been abandoned in favor of the less complicated retrograde approach.
Retrograde approach (Figure 5). This requires the 22 or 24 Fr introducer sheath to be inserted into the femoral artery, which must be closed by conventional vascular surgery at the end of the procedure. This remains an important limitation necessitating the exclusion of patients with significant calcification or tortuosity of the iliac arteries and those with smallcaliber femoral arteries (< 6–7 mm) Procedure time for this approach is 70–110 minutes.
Transapical approach (Figure 6). The transapical approach is performed with the patient under general anesthesia by ateam comprised of cardiac surgeons and interventional cardiologists. A left-anterolateral intercostal incision is used to expose the LV apex through which a hemostatic sheath is inserted directly with subsequent sequential dilatations up to 22 or 24 Fr. The balloon catheter and device are positioned and the device is deployed during rapid pacing using epicardial leads. The myocardium is closed using sutures placed at the outset. It is hoped that such an approach (being studied in Europe as part of the REVIVE protocol) will allow treatment of patients currently excluded on the basis of ileo-femoral disease.
Postprocedure standard procedure calls for monitoring patients on an intensive care unit until they are hemodynamically stable. Antibiotics are given for 48 hours and lowmolecular weight heparin is administered until hospital discharge. Discharge medications include lifelong aspirin and 6 months of clopidogrel.
Evidence to Date
The feasibility of the percutaneous procedure and the efficacy of the bioprosthesis implanted in the aortic position has to date been confirmed by published reports concerning successful implantation of the Cribier-Edwards device in over 80 patients. In the I-REVIVE trial, continued as the RECAST registry9 involving 33 patients with debilitating native valve stenosis, the percutaneous device was successfully deployed in 27 (82%). In each of these patients, previously turned down for standard aortic valve replacement by two cardiac surgeons, a decrease in mean transvalvular gradient to 10 mmHg and an increase in aortic valve area by transthoracic echocardiography were consistently achieved. Echocardiographic improvement, including recovery of LV function, was associated with amelioration of symptoms as evidenced by an increase in NYHA functional class in all patients. Incidence of aortic insufficiency following valve deployment was mild (Grade 0 or 1) in 10 patients, and moderate (Grade 2) in 12 patients. More severe (Grade 3) regurgitation was observed in 2 patients. In each case, regurgitation was paravalvular, and in 4 cases had improved on follow-up echocardiography.
In the first published reports of Dr. Webb’s Canadian team, procedural success with the Cribier-Edwards system was achieved in 16 of 18 patients enrolled for implantation via the retrograde approach, with similar reports of hemodynamic and symptomatic improvement.10 Aortic valve area was increased from 0.6 ± 0.2 cm2 to 1. 6 ± 0.4 cm2. In another 7 patients with prohibitive ileofemoral or aortic disease, the Cribier- Edwards valve was implanted transapically. Procedural success was achieved in all patients with similar improvements in echocardiographic parameters.11 More recent data presented by the Vancouver team, but as yet published only in abstract form (ACC 2006), have illustrated the major role of the learning phase in this new technique. The mortality rate in the first 23 patients treated approached 17%, but was less than 5% in the second 23 patients who were selected according to the same criteria. Notably, this mortality rate fell well below that which would be predicted for the same patients treated surgically, with a mean logistic Euroscore of 25% for the group.
The predominant reason for procedural failure reported in these early studies is a failure to cross the valve with the device due to extensive calcification. This difficulty is less frequently encountered with the antegrade or transapical approach. Migration of the device during deployment has also led to procedural failure in 2 cases in which the device was then deployed in the descending aorta without consequence.
Safety
In those patients with a successful implantation, 30-day major adverse cardiac or cerebrovascular events (MACCE) as a result of procedural or postprocedural complications in the French series was 26%.9 The complications already known to be associated with balloon valvuloplasty procedures were encountered with a similar frequency during prosthetic heart valve implantation (PHV) procedures. Cardiac tamponade occurred in 2 patients, associated in both cases with the temporary pacing wire, and stroke occurred in 1 patient. A complication specific to the antegrade approach involved disruption of the mitral valve apparatus, which led to hemodynamic collapse in 2 patients. With the retrograde approach, the risk of access site complications causes the greatest concern and seems to be closely related to both patient selection and operator experience. After the first 25 cases, the rate of access site complications had fallen to below 5%. With the transapical approach, the smaller published experience allows few conclusions to be drawn, but 30-day mortality was limited to 1 of the first 7 patients who died of postoperative pneumonia.
Medium-Term Outcomes
In addition to the 30-day MACCE, 6-month MACCE in the I-REVIVE/RECAST registry was high (37%).9 Mortality occurring between 30 days and 6 months was clearly documented in each case and was not related to valve dysfunction. Instead, the causes of death in these somewhat frail patients were arrhythmia (1 patient), pneumonia (1 patient), stroke (1 patient), progressive renal failure (3 patients), postoperative from noncardiac surgery (3 patients), malignancy (1 patient) and pulmonary embolism (1 patient).
These data must be interpreted in context, as the restriction of PHV therapy, so far, to end-stage inoperable patients,by definition, makes comparison with the published results of surgical intervention biased towards failure. While aortic valve surgery can be performed at low risk in otherwise fit elderly patients, predicted 30-day mortality for the I-REVIVE patients following surgery was > 20%. In the Canadian series, the 30-day mortality rate of 11% compared favorably with the predicted surgical mortality rate of 26%.11 Shorter hospital stays and earlier ambulation by avoidance of median sternotomy would also be expected to decrease short- and mediumterm morbidity in a group of patients with a limited longterm prognosis.
Regarding the durability of the PHV, initial in vitro studies have confirmed sustained function of the PHV after > 200 million cardiac cycles, corresponding to > 5 years of life. So far, clinical follow up is reported in a small number of I-REVIVE patients up to 2 years, with no prosthetic valve dysfunction or recurrence of stenosis to date.
Ongoing Work
Throughout the development of this technique, increased operator experience, in combination with a number of modifications to the device and delivery system, have gradually improved success rates and shortened procedure times. One important modification to the Cribier-Edwards system, a deflectable delivery catheter (Figure 7), has improved the deliverability of the device to the site of implantation. Further modifications are currently focused on two main aspects. Reduction of the incidence of significant paravalvular aortic regurgitation is hoped to be achieved by the use of larger diameter devices (26 mm valve). At the same time, efforts are targeted toward the development of lower-profile delivery systems so that the retrograde approach can be used safely in more patients. Eventually, improved operator experience with larger vascular closure devices may negate the need for surgical closure of the femoral artery.
Alternative Devices — The CoreValve System
A large number of alternative devices for percutaneous treatment of aortic stenosis have been designed and work continues on their development. Those reaching clinical trials are fewer in number, and to date, only the CoreValve (CoreValve SA, Paris, France), a porcine biop rosthesis mounted in a self-expanding nitinol frame, has reported results.12 Of the first 25 patients, 84% underwent successful retrograde implantation, with a marked reduction in transvalvular gradient and no increase in aortic regurgitation. Procedures were carried out under general anesthesia with extracorporeal support, and the survival-free rate of complications or MACCE at 30 days was 68%.
Significant progress has already been made in the development of the CoreValve device since these first results were published. With the third-generation device, the sheath size has been reduced to 18 Fr and the results of a multicenter safety and performance study using the second- and third-generation devices have just been published. 13 In 86 patients enrolled between 2005 and February 2007, device success was achieved in 88%, and procedural success (defined as success with the absence of adjudicated MACE at 48 hours) in 74%. Procedural failures with this device seem to be largely attributable to misplacement of the device, which led to conversion to surgery in 6 patients and a suboptimal result corrected with a second device in 2 more. In addition, stroke occurred in 9 patients and tamponade due to guidewire perforation in 6 patients. Following a successful procedure, symptomatic improvement at 30 days was impressive, however, the total mortality rate at this point was 12%. Again this 30-day mortality rate must be interpreted alongside the risk profile of the cohort who had a mean calculated logistic Euroscore of 21.7, and the majority (83%) of whom had NYHA Class III or IV symptoms. Longer-term results of this largest published percutaneous aortic valve series are awaited, while the device itself continues to undergo modifications, including a staged deployment design allowing repositioning during the procedure.
Further Study
Rigorous longer-term follow up of the initial patient cohorts described is ongoing to confirm the durability and long-term efficacy of the percutaneous devices and to discover whether unforeseen later complications occur. Meanwhile, additional trials are beginning in Europe to determine the feasibility of PHV implantation in a larger number of patients and to compare the approaches. Trials in the United States are now under way to compare outcomes with medical therapy. To date, percutaneous aortic valve implantation is permitted only as part of such trials and, as such, only in severe symptomatic aortic stenosis patients with an absolute contraindication for surgery or a predicted in-hospital mortality from surgery > 20%. Conclusion It remains unlikely that, at least in the medium term, percutaneous aortic valve replacement will provide an acceptable alternative to conventional treatment in patients at low risk for cardiac surgery. However, we now have the beginnings of an effective intervention to offer symptomatic relief to those debilitated patients in whom surgery is not an option. The feasibility and immediate efficacy of both the Cribier-Edwards and the CoreValve device have been demonstrated, while its long-term durability remains to be proven. The rates of serious periprocedural complications are high, and although these are expected to decrease to some extent with technical modifications and operator experience, any improvement in medium-term outcome will remain limited by the restriction of studies to such a high-risk population. While this emerging intervention cannot yet claim to influence prognosis, improvements in functional status can now be achieved in certain patients for whom, until now, medicine had little to offer.
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