Transcatheter aortic valve replacement (TAVR), first performed in 2002, “has transformed the care of more than 300,000 patients with severe aortic stenosis (AS) worldwide, allowing them to receive mechanical treatment for their mechanical problem,” said David R. Holmes, Jr., MD, MACC, past ACC president and interventional cardiologists who has played key roles in TAVR research and discussions to date. “It has facilitated their return to a more active lifestyle and improved survival at least in the groups of patients who had no other effective treatment modality.”

First reserved for patients at high surgical risk or inoperable, TAVR has been expanded to patients with symptomatic intermediate-risk and looks to continue to move down the scale to patients at lower risk.

"(TAVR) has transformed the care of more than 300,000 patients with severe aortic stenosis (AS) worldwide, allowing them to receive mechanical treatment for their mechanical problem." — David R. Holmes, Jr., MD, MACC

“The evolution of TAVR over the past 15 years has been unprecedented. It has gone from a crazy idea to the standard of care for many patients suffering from aortic stenosis. Once the durability of TAVR is confirmed, it will replace SAVR for the vast majority of patients with aortic stenosis,” said William F. Fearon, MD, FACC.

Some reassurance about the durability of percutaneous valves, at least through five years, recently came from the international, prospective, non-randomized, ADVANCE study of patients with symptomatic, severe AS at high surgical risk receiving a self-expanding bioprosthesis.¹ In the 465 (of 996) patients who completed the 5-year follow-up, all-cause mortality was 50.7 percent and major stroke was 5.4 percent. Aortic regurgitation (AR) decreased over time, with a reduction in moderate AR from 12.8 percent to 8.0 percent. Hemodynamics remained consistent for paired patients. Twenty-two (2.6 percent) of the 860 patients with echocardiographic data or a re-intervention after 30 days met the Valve Academic Research Consortium-2 (VARC-2) criteria for valve dysfunction.

"The evolution of TAVR over the past 15 years has been unprecedented. It has gone from a crazy idea to the standard of care for many patients suffering from aortic stenosis." — William F. Fearon, MD, FACC

Prohibitive and High-Risk Patients

The recently published American Heart Association (AHA)/ACC Focused Update on valvular heart disease gave a Class I recommendation (with a Level of Evidence upgrade to A) for TAVR for patients with symptomatic severe AS who are at prohibitive or high surgical risk.²

“There is no question that TAVR is the treatment of choice in the extreme-risk patient who cannot have surgery,” said Martin B. Leon, MD, FACC, during an ACC.17 session on TAVR. “Their median life expectancy will be increased from 11 months to almost 30 months with TAVR.”

He added that the transcatheter option is “in most cases, the preferred alternative” to surgery for high-risk patients too, assuming the patient is a good candidate for TAVR.

"There is no question that TAVR is the treatment of choice in the extreme-risk patient who cannot have surgery. Their median life expectancy will be increased from 11 months to almost 30 months with TAVR." — Martin B. Leon, MD, FACC

Intermediate-Risk Patients

The bulk of patients with severe AS undergoing SAVR today are younger and at lower risk. For those at moderate or intermediate surgical risk – classified as having a Society of Thoracic Surgeons (STS) score ≥4-8 percent in the focused update – TAVR is a reasonable alternative to SAVR, with a Class IIa recommendation (Figure). Based on the PARTNER 2A findings presented at ACC.16, this recommendation was further supported by the results from the SURTAVI trial presented at ACC.17.

“I’m beginning to believe that with the [SURTAVI trial] that it’s likely that this will also move up to a Class I indication as an alternative to surgery in intermediate risk,” said Leon.

SURTAVI – which lowered the risk bar a bit farther from PARTNER 2A and considered patients with an STS score ≥3 percent as “intermediate” risk – showed clear non-inferiority for TAVR using the self-expanding CoreValve or second-generation Evolut R, as compared with SAVR. The trial included 1,746 patients from 87 centers. The mean STS Predicted Risk of Mortality (PROM) score was 4.4 percent (vs. 5.8 percent for PARTNER 2A) and mean age was 79 years (vs. 81.6 years for PARTNER 2A).

The primary composite endpoint of all-cause mortality or disabling stroke was similar between TAVR and SAVR (p < 0.005 for non-inferiority), as were both components of the primary endpoint and 30-day mortality.

Consistent with other trials, TAVR was associated with higher rates of residual AR and early pacemaker implantation (25.9 vs. 6.6 percent; p < 0.05), while SAVR was associated with more bleeding, acute kidney injury, atrial fibrillation and transfusion.

The higher rate of pacemaker implantation is a concern, said Michael J. Mack, MD, FACC, former president of the Society of Thoracic Surgeons and current member of the ACC’s Board of Trustees. A cardiothoracic surgeon, Mack is also PARTNER 3 principal investigator.

“I think that you can’t assume that a pacemaker is a benign event when patients are younger and lower risk and have longer to live with their pacemakers since the risk of the pacemaker is increased,” said Mack. “On the other hand, it may be that the need for a new pacemaker is less in the lower risk population because they have less underlying conduction system disease.”

The rate of stroke in SURTAVI was significantly lower with TAVR than with SAVR. Data presented by A. Pieter Kappetein, MD, PhD, at EuroPCR 2017 showed the 30-day rate was 3.3 percent vs. 5.4 percent (log-rank p = 0.031) and at 2 years was 6.3 vs. 8.0 percent (log-rank p = 0.143). An independent committee adjudicated the neurological events using the VARC-2 definition of stroke.

In what the authors say is the first demonstration of a lower risk of stroke with TAVR, the baseline characteristics were similar in the patients who did and did not have a stroke. Quality of life, as measured by the SF-36 physical summary, was higher at 30 days in patients in both groups who did not have a stroke. In patients who had a stroke, quality of life improved faster in TAVR patients and was significantly better than for SAVR patients at 30 days (mean change from baseline 4.3 vs. –2.6). Overall, quality of life was similar at six months.

Reassuring new data come from the PARTNER 2A trial showing that despite higher rates of paravalvular AR and pacemaker implantation, patient-reported health status was similar at one and two years with TAVR via transfemoral access and SAVR.³ With the transthoracic approach, no difference was seen in health status at any time. While the data may not yet be overwhelmingly in favor of TAVR for the intermediate-risk cohort as a whole, especially given concerns over long-term durability, there seems to be some room to consider TAVR for elderly patients with severe AS at intermediate risk.

“I believe like the Europeans, if they’re over 80, give them a TAVR. That’s what they’ve been doing for years and they’re not even that concerned about the STS score,” said Deepak L. Bhatt, MD, MPH, FACC, in the inaugural ACC Cardiology Hour with JACC Editor-in-Chief Valentin Fuster, MD, PhD, MACC.

Bhatt called the pacemaker issue “a little bit of a concern, but not something new.”

“For younger patients who seem to be good surgical candidates, we don’t have very long term follow-up and I think surgery in these low risk patients – and some of these intermediate-risk are kind of low-risk patients – performs very well,” said Bhatt.

“We don’t have 10-year follow-up on any of these valves yet, so for a younger patient, I think the jury is still out,” concurred ACC.org Editor-in-Chief Kim A. Eagle, MD, MACC, during the Cardiology Hour discussion.

"I believe like the Europeans, if they’re over 80, give them a TAVR. That’s what they’ve been doing for years and they’re not even that concerned about the STS score." — Deepak L. Bhatt, MD, MPH, FACC

The CoreValve Evolut PRO received U.S. Food and Drug Administration (FDA) approval in March for symptomatic severe AS in patients at high or extreme risk for SAVR. Medtronic announced July 10 the FDA has expanded the indication to intermediate-risk patients for the CoreValve series.

What About Durability?

As patient age and risk drops, durability obviously increases as a post-TAVR concern. In SURTAVI, structural valve deterioration at 24 months was not seen in either group. Leon was unmoved by the durability issues raised at EuroPCR 2016, calling it “relatively sketchy echo data looking at parameters that were non-standardized.” A second report on the topic, presented at TCT 2016, was far more robust and reported virtually no issues with durability, he said.

With five- to 10-year data still lacking, Leon takes a pragmatic approach to the unanswered durability issue: “For the lower risk patients, it boils down to simply this: does the known value of TAVR versus open surgery outweigh the unknown long-term durability considerations of TAVR?”

Mack also wasn’t impressed with the durability issues highlighted in data presented at EuroPCR 2016.⁴ But the valve thrombosis data presented at ACC.17 does give him pause.

“Even though there hasn’t been a significant signal on durability, we really don’t know the answer for sure yet because there are very few at-risk patients that are out over five years,” said Mack. “There have been plenty of surgical valves that looked good at five years. And then by eight to ten years, we saw structural valve deterioration and those valves are not on the market anymore. So, I don’t think we have any clue as to what the real answer is on durability.”

However, more worrisome is registry data presented by Raj R. Makkar, MD, FACC, at ACC.17, showing subclinical leaflet thrombosis of bioprosthetic aortic valves in 12 percent of patients post TAVR and 4 percent post SAVR.⁵ Fortunately, the issue resolved in all patients started on anticoagulation.

“I don’t think that it’s a deal breaker, but it’s going to mean that these patients are going to need more aggressive or more frequent anticoagulation with TAVR than with surgery if these findings hold true. Because I think that it’s likely that early valve thrombosis does lead to eventual structural valve deterioration,” said Mack.

Supporting the idea that subclinical leaflet thrombosis might hasten valve deterioration, Makkar and colleagues found that aortic valve gradients of >20 mm Hg and increases in aortic valve gradients of >10 mm Hg were seen in 14 percent of patients with subclinical leaflet thrombosis compared with only 1 percent of those with normal leaflet motion (p < 0.0001). Stroke rates did not differ between those who did and did not have leaflet thrombosis on CT imaging.

" …these patients are going to need more aggressive or more frequent anticoagulation with TAVR than with surgery if these findings hold true. Because I think that it’s likely that early valve thrombosis does lead to eventual structural valve deterioration." — Raj R. Makkar, MD, FACC

The ongoing trials of patients at low risk are enrolling significant numbers into CT imaging substudies to better understand this phenomenon, reported Leon.

Low-Risk Patients

All of TAVR’s success thus far is laudable and life-saving for the target populations. But, roughly 80 percent of all SAVR procedures in the U.S. are performed in low-surgical risk patients. In NOTION, the only randomized trial to date in this patient group, which enrolled less than 300 lower-risk patients with a mean STS score about 3 percent, TAVR offered non-inferior rates of all-cause death, stroke or myocardial infarction at 1 year.

Again, Leon’s approach is somewhat circumspect: “Considering the favorable and improving outcomes with TAVR in extreme-, high- and intermediate-risk AS patients, is it plausible to suggest that TAVR will be less safe and effective compared with surgery in appropriately selected low-risk patients?” he asked.

To answer his question, the PARTNER 3 trial (of which Leon is a principal investigator along with Mack) will enroll about 1,300 severe AS patients aged 65 years or older, with an STS risk score <4 percent, and randomize them to either TAVR using the Sapien 3 valve or SAVR.

Patients will be followed for 10 years, but the primary study endpoint, evaluated as a non-inferiority analysis, is 12-month all-cause mortality, stroke and rehospitalization. PARTNER 3 findings will not be available before fall of 2019, said Mack.

In the meantime, there are new registry data from France showing that as technology, technique and access have improved, just as in the U.S., TAVR is moving to lower risk patients, and with good results.⁶ In-hospital and 30-day mortality was nearly halved at 4.4 percent and 5.4 percent in the more recent FRANCE TAVI registry (January 2013 to December 2015) compared with 8.2 percent and 10.1 percent in the FRANCE 2 registry (January 2010 to January 2013). Moderate-to-severe AR was reduced by 35 percent to 10.2 percent vs. 15.7 percent (p < 0.001). Overall, the median age of patients was 84.6 years, half were men, and the EuroScore 15 percent; the transfemoral approach was used in 80 percent. Pacemaker implantation was higher in the later cohort at 17.5 percent, vs. 12.6 percent in the earlier cohort (p < 0.001), but the authors note more patients received the SapienValve in the later cohort.

Asymptomatic Severe AS Patients

Will TAVR ever be recommended for the AS patient who is yet to develop symptoms, the one who may not even realize they have the disease? There are those who think this possibility should be tested based on what’s been seen with several cardiac conditions, where early intervention appears to offer better long-term outcomes than watchful waiting.

Forty to 50 percent of all severe AS detected in major echocardiography studies is asymptomatic, reported Philippe Genereaux, MD, in an ACC.17 talk.

Indeed, about half a million patients over 65 years in the U.S. are estimated to have asymptomatic severe AS. Yet, the natural history of the disease is unpredictable and variable, making the decision to intervene invasively not a simple one.

“If you have a positive stress test [in an asymptomatic patient], it’s a Class I indication to do aortic valve replacement,” said Genereaux during an ACC.17 session dedicated to asymptomatic AS. The problem with this recommendation is that only 5-6 percent of doctors give these patients stress tests because they are “scared to put them on the treadmill,” he said.

Early SAVR is “rarely performed” in asymptomatic patients because the risk of sudden death is 1-2 percent per year, while the perioperative mortality after SAVR is 1-5 percent.

“So, we clearly don’t have the equipoise with surgery… but TAVR might allow us to believe and dream that early intervention might be a good option for these patients,” he said, especially given, as seen in PARTNER 2A, that TAVR significantly reduces perioperative acute kidney injury, life-threatening or disabling bleeding and new atrial fibrillation, not unimportant secondary outcomes.

"…we clearly don’t have the equipoise with surgery… but TAVR might allow us to believe and dream that early intervention might be a good option for these patients." — Philippe Genereaux, MD

The first patient was consented in mid-March 2017 for the EARLY TAVR trial, which will enroll 1,109 asymptomatic patients (with negative stress test or confirmation via medical history). Patients with bicuspid valves, a class I indication for AVR, or who are not suitable for transfemoral access will be excluded.

What’s Ahead?

There are many details yet to clarify with TAVR, beyond those of long-term valve durability, clinical indications and post-procedural pacemaker need. Among these are risk assessment, conscious sedation or general anesthesia, transesophageal or transthoracic echocardiography guidance, transfemoral or alternative access sites, pre-operative imaging, cognitive outcomes after TAVR and cerebro-embolic protection, optimal adjunct pharmacology, valve-in-valve TAVR, bicuspid valve TAVR and failing surgical valve TAVR.

The ACC’s 2017 Expert Consensus Decision Pathway for TAVR offers clear guidance for clinical centers performing TAVR and those considering starting a TAVR program. The document provides a framework for managing a potential TAVR candidate by outlining key steps in patient selection and evaluation, imaging assessment, issues in performing the TAVR procedure and recommendations for post-TAVR management. For each section, an algorithm is provided along with checklists that can be readily integrated into electronic health records.

" It has been both uplifting and humbling to see the transformation of the treatment of a disease change in the past two decades. To have played a small role in this disruptive therapy has been one of the highlights of my career." — Michael J. Mack, MD, FACC

While the document tries to reflect the most recent evidence, it does not attempt to replace or update the AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease. The authors of the decision pathway do attempt to provide a clear framework for the expanded use of TAVR in populations at lower risk.

TAVR has been considered as an option for those who do poorly with surgery, said Leon in his ACC.17 talk. “In the future, at least I predict, the conversation will be, ‘Who does well with TAVR?’ and those patients who don’t do well because of anatomic or clinical factors will become surgical candidates. But we need more data to demonstrate that,” said Leon.

“It has been both uplifting and humbling to see the transformation of the treatment of a disease change in the past two decades,” said Mack. “To have played a small role in this disruptive therapy has been one of the highlights of my career.”

“The success of TAVR has emboldened the cardiovascular community to develop transcatheter approaches for many other types of valvular heart disease, which should further broaden the reach of transcatheter valve therapy,” said Fearon. Indeed, it’s now being explored for transcathether mitral valve disease.

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References

1. Gerckens U, Tamburino C, Bleiziffer S, et al. Eur Heart J 2017;June 13:[Epub ahead of print].
2. Nishimura RA, Otto CM, Bonow RO, et al. J Am Coll Cardiol 2017;March 10:[Epub ahead of print].
3. Baron SJ, Arnold SV, Wang K, et al. JAMA Cardiol 2017;June 28:[Epub ahead of print].
4. Dvir D. First look at long-term durability of transcatheter heart valves: assessment of valve function up to 10 years after implantation. Presented at EuroPCR 2016, Paris, France. May 17, 2016.
5. Chakravarty T, Sondergaard L, Friedman J, et al. Lancet 2017; March 19;[Epub ahead of print].
6. Auffret V, Lefevre T, Van Belle E, et al. J Am Coll Cardiol 2017;70:41-55.

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Keywords: ACC Publications, Cardiology Magazine, Bioprosthesis, Aortic Valve, Aortic Valve Insufficiency, Prospective Studies, Atrial Fibrillation, Life Expectancy, Transcatheter Aortic Valve Replacement, Quality of Life, Standard of Care, Aortic Valve Stenosis, Heart Valve Prosthesis, Heart Valve Diseases, Stroke, Acute Kidney Injury, Hemodynamics

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