Late in 2011, the Edwards Lifesciences SAPIEN valve for transcatheter aortic valve replacement (TAVR) was approved by the FDA for use in patients with symptomatic aortic stenosis (AS). The FDA’s approval was based on the results of the PARTNER I(B) Trial in 365 patients who were not eligible for open-heart surgery. Half of the patients received the SAPIEN valve and the other study patients received “standard medical” treatment that included balloon aortic valvuloplasty in most. PARTNER I(B) showed that TAVR patients had a higher complication rate (two and a half times more strokes and eight times as many vascular/ bleeding complications) than patients who did not receive the implant, but mortality at one year was markedly improved in the TAVR group. At one year, about 70% of the TAVR patients were alive compared with 50% of “controls”. Since FDA approval, selected hospital sites in the US (in addition to those involved with the PARTNER Trial) have had training by Edwards Lifesciences to perform TAVR. Training of physicians within the sites has been a careful, proctored process to ensure patient safety and maximize outcomes, and is ongoing. The final number of “approved” sites in the U.S. has not been determined, and will depend on a number of factors which include patient volumes, ability to work within the “Heart Team” concept, experience/ability/interest of operators, and of course, reimbursement. With FDA approval and commercial availability of a TAVR device, expansion of TAVR use is occurring, but is limited.

Indications for “Commercial Use” of the Edwards SAPIEN Device

Restrictions on patient selection is limited by an interplay of the FDA approved “Instructions for Use” and the National Coverage Decision (NCD) for TAVR. Readers are urged to review both of these detailed documents. Below is an abbreviated summary of these documents:

1. Instructions for Use of the Edwards SAPIEN Transcatheter Heart Valve states: “is indicated for transfemoral delivery in patients with severe symptomatic native aortic valve stenosis who have been determined by a cardiac surgeon to be inoperable for open aortic valve replacement and in whom co-existing co-morbidities would not preclude the expected benefit from correction of the aortic stenosis. The RetroFlex delivery system is indicated for the transfemoral delivery of the Edwards SAPIEN heart valve”.
2. The Centers for Medicare & Medicaid Services (CMS) covers transcatheter aortic valve replacement for patients with symptomatic AS. Two cardiac surgeons must have independently examined the patient and determined the patient’s suitability for open aortic valve replacement surgery, and have deemed the patient as non-operative or at extremely high operative risk.

Thus, for commercial use of TAVR, only the highest risk patients are suitable, and must be non-operative candidates. The indications for “commercial” TAVR are thus clear, but one must remember that PARTNER I(B) recruited only patients that had adequate ileofemoral vasculature to allow access for the SAPIEN device, Thus for patients requiring a 26 mm SAPIEN TAVR, ileofemoral artery diameter has to be minimally 8.0 mm if the arteries are free of calcium on CT, 8.5 mm if mild calcification is present, and 9.0 if there is significant calcification (especially circumferential calcium). For those requiring a 23 mm SAPIEN TAVR ileofemoral arterial sizes are 7.5, 8.0 and 8.5 mm respectively.

Whether alternate access routes are “allowed”, and will be reimbursed, is not clear, but obviously it makes a lot of difference to individual patients. Multiple alternate access routes have been successfully used for TAVR (e.g. iliac conduit, transapical, trans-subclavian, trans-aortic, and trans-carotid). Specifically the iliac conduit approach was “allowed” within PARTNER I(B) if femoral or external iliac artery size was inadequate at the time of the TAVR attempt. The transapical approach was studied in the PARTNER I(A) Trial which randomized such patients against standard cardiac surgery in high-risk (STS >10 Score) patients and found the results to be non-inferior. But other access for TAVR has not been studied in the U.S. in a systematic manner. It has been argued that FDA approval hinges on “indications” rather than access route, and all forms of TAVR in inoperable patients with AS are covered. However, most U.S. sites are cautious about using access routes alternate to the transfemoral route and are attempting to understand exactly what the inclusion criteria for the FDA and CMS wording imply. Thus most U.S. sites using “commercial” TAVR are making individual decisions concerning patients who have inadequate ileofemoral access but are otherwise excellent TAVR candidates.

It is important to note that the Agency for Healthcare Research and Quality supports clinical research studies that CMS determines meet the above-listed standards and addresses research questions. Thus, TAVR is covered for uses that are not expressly listed as an FDA approved indication when performed within a clinical study. It is highly likely that ongoing research registries will be formed that will study outcomes in alternate access TAVR patients, making “off-label” use not only more available to patients with AS, but also making outcomes in such patients part of our understanding of appropriate TAVR use.

Other Options for TAVR Available for Patients With Symptomatic AS

1. Small Vessel Registry

The latest iteration of the Edwards Lifesciences TAVR device being used in research sites in the U.S. is the SAPIEN XT device which has a smaller (18 Fr) external diameter. Thus, patients can be enrolled in this non-randomized registry if they are deemed inoperable and have ileofemoral vessels between 6 and 7 mm diameter. This registry has numerical limits for each TAVR site, and many sites within the U.S. have already filled their quota of patients. When all sites in the U.S. have filled their quota, this registry will be closed and outcomes data assessed for this group of patients with AS. Whether there will be a “continued access” to TAVR for such patients is not presently known.

2. Randomized U.S. Trials

• The PARTNER II trial is currently enrolling patients with symptomatic AS who are operative candidates. In contrast to PARTNER I(A), patients enrolling in PARTNER II are lower risk surgical patients (STS scores >4). In the trial, patients are identified for either a transapical or transfemoral approach, using the newer, smaller diameter SAPIEN XT device, and are randomized against standard surgical aortic valve replacement. The results of this non-inferiority trial will allow understanding of whether lower risk surgical patients with symptomatic AS should be offered TAVR with the SAPIEN XT device as an option.
• The Medtronic CoreValve U.S. Trial includes two studies in different patient populations. The first is a study of patients diagnosed as high risk for aortic valve surgery. Patients in the high risk group will be randomized one-to-one to either transcatheter aortic valve implantation (TAVI) with CoreValve or to surgical aortic valve replacement (SAVR). Importantly, the modified trial will now include the assessment of alternative implantation routes, including the subclavian approach. The second study is of patients diagnosed as extreme risk. Patients deemed at extreme risk will not be randomized to “medical management” (outcomes for such patients have already been shown to be significantly worse in PARTNER I(B) than those treated with TAVR). Rather, this patient group will be evaluated against a performance goal derived from contemporary studies.

Both of these U.S. trials offer patients with aortic stenosis the possibility of having TAVR using devices smaller than those available “commercially”. Both the Edwards SAPIEN XT and the CoreValve can be delivered in sheaths roughly 18Fr in diameter, making patients with ileofemoral vessels larger than 6 or 6.5 mm in diameter candidates. However, in the high risk group, patients face possible randomization to standard open aortic valve replacement, which the patient must accept.

3. Options Outside the U.S.

In Europe and Canada both the SAPIEN XT and the CoreValve devices have achieved CE Mark status, making them available for implantation outside of clinical trials. Other newer generation TAVR devices such as JenaValve, DirectFlow, Sadra, Portico, etc. have also achieved CE Mark status or are in Phase I clinical trials. Experience with these devices is still relatively small compared to the thousands of implants of CoreValve and SAPIEN devices. Nonetheless, some patients who are good candidates for TAVR but do not meet the criteria for the “commercial” Edwards SAPIEN valve or who do not wish to be part of a randomized trial which might include a surgical option have chosen to have their TAVR outside of the U.S., which is an ongoing option.

Keywords: Transcatheter Aortic Valve Replacement, Aortic Valve Stenosis, Cardiac Surgical Procedures, Hemorrhage, Transcatheter Aortic Valve Replacement

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