New TAVR data, valve approval provide hope for patients with severe aortic stenosis

Late 2011 marked the first US commercial approval of a transcatheter device that enables aortic valve replacement without the need for CABG. In the wake of the FDA approval, positive data on transcatheter aortic valve replacement from the PARTNER cohort B trial at 2 years and quality of life and cost-effectiveness from the PARTNER cohort A trial were announced at the 23rd annual Transcatheter Cardiovascular Therapeutics scientific symposium.

“The current playing field for transcatheter aortic valve replacement (TAVR) is rapidly evolving. We are getting more information every day from registries and randomized trials, both in the United States and Europe,” David J. Cohen, MD, MSc, professor of medicine at the University of Missouri-Kansas City and PARTNER trial investigator, said in an interview. “This information is helpful in understanding the benefits and risks of the procedure and in determining the optimal patients to treat.”

Peter C. Block, MD, Cardiology Today Section Editor, discussed the future of TAVR in the United States. Photo credit: Jack Kearse, Emory University

Approval of the Sapien transcatheter heart valve was announced by the FDA on Nov. 2. The device 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 valvereplacement and in whom existing comorbidities would not preclude the expected benefit from correction of the aortic stenosis.

“The good news is that there is a commercially available, off-the-shelf valve that can be used in highly selected, inoperable patients with aortic stenosis. The bad news is that there are very specific limits on which patients you can use this valve,” Peter C. Block, MD, professor of medicine and cardiology at Emory University and co-author of PARTNER, said in an interview. Block is also the Intervention section editor at Cardiology Today.

The valve (Edwards Lifesciences) is made of cow tissue and polyester supported with a stainless steel mesh frame. To replace the diseased valve, the Sapien valve is compressed onto the end of a delivery catheter, which is inserted into the femoral artery through a small cut in the leg and threaded to the site of the diseased valve. The heart valve is then released from the delivery catheter and expanded with a balloon and is immediately functional.

PARTNER B: Increase in survival at 2 years

Two-year data from the PARTNER cohort B trial further support the role of TAVR as the standard of care for inoperable, symptomatic patients with severe aortic stenosis. The results, presented at TCT 2011, demonstrate a widening survival benefit at 2 years for patients who received TAVR.

“The new data confirm an increase in survival with TAVR beyond 1 year,” Raj R. Makkar, MD, director of interventional cardiology and the Cardiac Catheterization Laboratory at Cedars-Sinai Medical Center, told Cardiology Today.

At 2 years, the all-cause mortality rate was 43.3% for patients who underwent TAVR compared with 67.6% for patients who received standard therapy (HR=0.57; 95% CI, 0.44-0.75). When Makkar and the PARTNER investigators conducted a landmark analysis to examine all-cause mortality from 1 to 2 years, they found a rate of 18.2% for patients who underwent implantation and a rate of 35.1% for patients who received standard therapy (HR=0.58; 95% CI, 0.37-0.92). At 1 year, all-cause mortality was 30.7% for TAVR and 50.7% for standard therapy, as published in 2010 in The New England Journal of Medicine. A similar trend was observed for CV mortality at 2 years; the rate was 31% with TAVR vs. 62.4% with standard therapy in the intent-to-treat analysis (HR=0.44; 95% CI, 0.32-0.60) and 13.2% vs. 32.1% in the landmark analysis from 1 to 2 years (HR=0.48; 95% CI, 0.29-0.81).

The PARTNER cohort B trial was designed to compare TAVR vs. standard therapy in patients with severe aortic stenosis who are not candidates for CABG. Researchers randomly assigned 358 patients to transfemoral TAVR with the early-generation valve (Sapien) or standard therapy, including balloon valvuloplasty.

“A common question related to TAVR is: Are we just prolonging life in people who are older and will probably experience no or little improvement in quality of life?” Makkar said. To counter that, he discussed results showing that TAVR also improved NYHA Class and decreased NYHA Class III/IV symptoms when compared with standard therapy. At 2 years, Class III/IV HF was present in approximately 17% of the TAVR group vs. 58% of the standard therapy group.

Raj R. Makkar

Results also showed that TAVR was associated with a 35% rate of repeat hospitalization compared with a 72.5% rate with standard therapy (HR=0.41; 95% CI, 0.30-0.58). The median calculated number of days alive outside of the hospital was 699 for TAVR patients and 355 for standard therapy patients, “a difference of nearly 1 year.”

“Whatever data you look at, it is clear that not only is there improvement in survival but also in quality of life,” Makkar said.

Stroke rate at 2 years, however, was higher with TAVR: 13.8% vs. 5.5% (HR=2.79; 95% CI, 1.25-6.22). After 30 days, between-group differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR patients. There were also more neurologic events with TAVR compared with standard therapy (16.2% vs. 5.5%; P=.003).

“We have to continue to improve the stroke rate with TAVR,” Makkar said.

Besides clinical advantages, the new data demonstrate that improvements in hemodynamic performance were sustained at 2 years. TAVR hemodynamics by echocardiography showed durable improvements in aortic valve area and mean gradients up to 3 years after implantation. Moderate or severe paravalvular aortic regurgitation in TAVR patients did not influence 2-year survival, and there was a trend toward reduced paravalvular aortic regurgitation between 1 and 2 years, according to the results.

A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is in patients without extreme clinical comorbidities.

“We have to be somewhat humble because what is clear is that, at 2 years, 46% of these patients are dying, even in the TAVR group. This is because of the nature of the population, not related to the device,” Makkar said. “The ultimate value of TAVR in inoperable patients will depend on careful selection of patients who are not surgical candidates and do not have extreme comorbidities that overwhelm the benefits of TAVR and render the intervention futile.”

PARTNER A: TAVR improved quality of life

Attendees at the TCT 2011 meeting were also presented with data on the quality-of-life effect and cost-effectiveness of TAVR. The data were based on the clinical outcomes of the PARTNER cohort A trial, a noninferiority study designed to compare TAVR (Sapien) and surgical AVR in patients with severe aortic stenosis who were at high risk for morbidity and mortality. The quality-of-life and economic analyses were performed as both a combined and access site-specific analysis for each of the two transcatheter valve delivery approaches. There were 699 patients enrolled in cohort A: 348 were randomly assigned to TAVR and 351 to surgical AVR. TAVR patients were then separated into groups based on those who were eligible for transfemoral valve implantation (n=491) and transapical implantation (n=207).

Patients were assessed with a variety of validated methods in the PARTNER trial upon enrollment and at 1-, 6- and 12-month intervals, on a broad range of factors, such as their symptoms and physical and social limitations. Researchers measured quality of life using the Kansas City Cardiomyopathy Questionnaire, the SF-12 health status survey and the EuroQOL.

David J. Cohen

In comparing transfemoral TAVR with surgery, transfemoral patients reported feeling better at 1 month and had results at 1 year that were comparable to surgical AVR. With transapical TAVR, patients did not demonstrate a quality-of-life benefit at 1 month; however, the transapical and surgical groups showed comparable results at 1 year.

“Combined with previous data, these findings demonstrate that for patients suitable for a transfemoral approach, TAVR provides meaningful clinical benefits compared with surgical AVR from the patient’s perspective,” said Cohen, who is also director of CV research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

“This lack of benefit and suggestion of worse outcomes among patients ineligible for the transfemoral approach suggest that the transapical approach may not be preferable to surgical AVR in such patients. Whether further experience and refinements in the transapical approach can overcome these limitations should be the subject of future investigation,” Cohen said.

Cost-effectiveness data

An economic analysis of the PARTNER cohort A was performed to determine the relative value of TAVR vs. surgery at 1 year in high-risk patients. On average, the transfemoral TAVR procedure was 87 minutes faster and the length of hospital stay was more than 6 days shorter than surgery. Index admission costs were also $2,500 lower in TAVR patients. In comparing transapical TAVR with surgery, the transapical procedure was 130 minutes shorter and the length of hospital stay was 1.5 days shorter than with surgery. However, index admission costs were $11,000 higher in transapical TAVR patients.

“Results of this trial indicate that for patients with severe aortic stenosis and high surgical risk, TAVR is an economically attractive and possibly dominant strategy compared with surgical AVR, provided that patients are suitable for the transfemoral approach,” Matthew R. Reynolds, MD, director of the Economics and Quality of Life Research Center at Harvard Clinical Research Institute, said in a press release.

“Current results for TAVR via the transapical approach, compared with surgical AVR, are unattractive from a health economic perspective. Whether the transapical approach can be refined to provide faster recovery and better results from a cost perspective should be the subject of further study,” Reynolds said.

Looking ahead

Michael J. Mack

The first commercial valves have already been implanted in the United States. As of press time, at least 15 US centers reported TAVR training. Each site trained had to present with five potential candidates for TAVR so that they could put their training to use, said Michael J. Mack, MD, FACC, president of The Society of Thoracic Surgeons.

“Very soon we will see a significant number of patients receive these valves in new centers,” Mack told Cardiology Today.

The PARTNER cohort A data are expected to go before the FDA in 2012. Commercial transapical valve implantation will not be permitted in the United States until approved by the FDA.

TAVR and the preferred route of access will continue to be studied in the PARTNER II trial. Designed to evaluate the Edwards Lifesciences next-generation Sapien XT transcather heart valve, PARTNER II will follow a design similar to PARTNER, with A and B cohorts. The Sapien XT valve is commercially available in Europe, where it received a CE mark in March 2010. It is not yet available commercially in the United States.

Cohort A is a noninferiority study of up to 2,000 patients with severe, symptomatic aortic valve stenosis who have an elevated risk for transitional CABG (The Society of Thoracic Surgeons score >4), which is a lower risk profile than those who were enrolled in the first PARTNER trial. Patients will be evenly randomly assigned to the Sapien XT valve or surgery. Those undergoing TAVR will be treated either transfemorally or transapically. The primary endpoint is a composite of death and major stroke at 2 years, with secondary endpoints that include valve performance and quality-of-life indicators. Data from the cohort B of inoperable patients are intended to support the US approval of the Sapien XT valve. The study will compare the first-generation and second-generation valves.

“PARTNER II will be the landmark trial to tell us about the more sophisticated engineering of the newer valve,” Block said. “The new valve is much more user-friendly for both the patient and the operator.”

The Sapien XT is a smaller, 18 French device compared with 24 French (Sapien). It features a cobalt chromium stent and a nose cone, which makes it lower profile and easier to cross the valve.

However, experts Cardiology Today interviewed expressed concern about the number of devices available in the United States as compared with Europe.

“What is happening slowly, and I think too slowly for many cardiologists and cardiac surgeons in the United States, is the ability to access the latest devices,” Cohen said.

Four valves are approved for commercial use in Europe vs. the one in the United States. The CoreValve (Medtronic) and first-generation Sapien valve were approved there in 2007, and the JeneValve and Symetis recently received CE mark approval in 2011.

“TAVR has changed the face of care in Europe, but it is too early to say in the United States,” Mack said. “At least in inoperable patients, there is a new option that was not available before. From our experience in the high-risk PARTNER cohort A trial, it will become the preferred alternative in high-risk patients.”

Although new data demonstrate the cost-effectiveness of TAVR, reimbursement is another issue. The American College of Cardiology and The Society of Thoracic Surgeons recently filed with CMS for a national coverage determination to get TAVR reimbursed in the United States. “In all likelihood, they will agree to reimburse this procedure, but for very narrow indications,” Mack said, adding that there are European centers with liberal reimbursement policies, such as in Germany, where about 25% of all current aortic valve procedures are TAVR. However, in countries such as Belgium, where TAVR is not currently reimbursed, adoption of this procedure has been limited.

“Reimbursement policies, to a large degree, determine market adoption,” he said.

The American College of Cardiology and The Society of Thoracic Surgeons have launched the joint TVT Registry to monitor real-world outcomes related to the safety and efficacy of transcatheter aortic valve replacement therapy.

The TVT Registry will serve as the main repository for all clinical data related to transcatheter aortic valve replacement (TAVR). It is also positioned to incorporate additional catheter-based procedures that are not marketed in the United States. The registry will also be linked to the Social Security Death Master File and CMS databases to track long-term outcomes.

David R. Holmes Jr.

According to Mack, the registry will not only offer insight into clinical practice patterns and patient outcomes, but will also optimize “patient safety and ensure the appropriate use of TAVR therapy.”

“The registry can provide relatively rapid feedback to individual sites and help identify trends in its usage … [and] will also provide a rich source of data for long-term research,” David R. Holmes Jr., MD, FAAC, ACC president, said in the press release.

To facilitate accurate and reliable data collection, the ACC and The Society of Thoracic Surgeons will sponsor educational opportunities and events for data managers, such as webinars and conference calls. In addition, participating hospitals will receive quarterly reports comparing an institution’s procedure performance with that of the national experience.

TAVR has been approved for a narrow indication of patients, and experts said there are a number of other patients who are particularly good candidates but have not been studied, such as those on dialysis or those who have a previously implanted heart valve.

“TAVR has a bright future. This is first-generation technology in the United States; we haven’t added the accessories that are likely to reduce the risk for early stroke, such as distal protection devices. It is a promising technology, but it is a work in progress, Makkar said.

“In my opinion, TAVR is here to stay,” he said. – by Katie Kalvaitis

For more information:

• Cohen DJ. Plenary session XIII. Late-breaking clinical trials and first report investigations II. Presented at: 2011 Transcatheter Cardiovascular Therapeutics Scientific Symposium; Nov. 7-11, 2011; San Francisco.
• Leon M. N Engl J Med. 2010;363:1597-1607.
• Makkar RJ. Plenary session XIII. Late-breaking clinical trials and first report investigations II. Presented at: 2011 Transcatheter Cardiovascular Therapeutics Scientific Symposium; Nov. 7-11, 2011; San Francisco.
• Reynolds MR. Plenary session XIII. Presented at: 2011 Transcatheter Cardiovascular Therapeutics Scientific Symposium; Nov. 7-11, 2011; San Francisco.

Disclosure: Dr. Block works at a site (Emory University) for the PARTNER trials. Dr. Cohen has received research grant support from Edwards Lifesciences and Medtronic. Dr. Mack reports receiving research grant support from Edwards Lifesciences, Medtronic and St. Jude Medical and consulting services for Medtronic; he is also a member of the PARTNER Trial Executive Committee. Dr. Makkar reports research grants from Edwards Lifesciences, is the national PI for the St. Jude TAVR program and has equity interest in Entourage Medical Technologies.