Debra L. Beck 2017-06-07 01:04:15
If transcatheter aortic valve replacement (TAVR) was a horse race being run today, the high-surgical risk or inoperable severe aortic stenosis (AS) patient would be the hands-down favorite. The symptomatic intermediate-risk patient would be the horse on the home stretch, and the asymptomatic, lower-risk patient would be the dark horse. And some might erroneously consider surgical aortic valve replacement (SAVR) an also ran. But, TAVR isn’t a horse race and SAVR is widely regarded as one of the most life-saving cardiac procedures ever developed. As the field changes rapidly, there are no winners or losers, only scientific and technical gains. What is clear is that TAVR is a winner for patients with severe AS, a transformational procedure that has already saved and improved tens of thousands of lives. And the future looks even brighter. To clarify and summarize the state of TAVR in the spring of 2017, its clinical indications, issues and sticking points, Cardiology: Interventions has read, listened and spoken to leading TAVR investigators and providers. Spoiler alert: the TAVR bulls outnumber the bears handily. Prohibitive and High Risk… Check In the American Heart Association (AHA)/ ACC Focused Update on Valvular Heart Disease published online March 10, 2017, TAVR was given a class I recommendation (with the Level of Evidence bumped up from B to A) in patients with symptomatic severe AS who are at prohibitive or high surgical risk.1 “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. This is encouraging, but about 90 percent of patients undergoing SAVR today are younger and lower risk and severe AS has a prognosis worse than most cancers. What about them? Class I for Intermediate Risk? For those at moderate or intermediate surgical risk – which the TAVR focused update authors classified as having a Society of Thoracic Surgeons (STS) score =4-8 percent – TAVR is a “reasonable alternative” to SAVR, with a Class Iia recommendation (Figure1). This recommendation, which was based on the PARTNER 2A findings presented at ACC.16, was given a big boost of support (and might have been made a bit outdated?) Just one week after they were published when the SURTAVI trial was 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 of?3 percent as “intermediate” risk – showed clear non-inferiority for TAVR using the self-expanding CoreValve or secondgeneration 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 aortic regurgitation and early pacemaker implantation (25.9 percent 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 cardiothoracic surgeon and PARTNER 3 principal investigator Michael J. Mack, MD, FACC, in an interview with Cardiology: Interventions. “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.” Now we’re learning that the rate of stroke was significantly lower with TAVR than with SAVR in the SURTAVI trial. According to data presented by A. Pieter Kappetein, MD, PhD, at EuroPCR 2017 in Paris, 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). Neurological events were adjudicated by an independent committee and the Valve Academic Research Consortium-2 definition of stroke was used. 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. As would be expected, 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. Intermediate-Risk and Elderly: Get a TAVR 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 good consensus that TAVR is the way to go 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 Kim A. Eagle, MD, MACC, during the Cardiology Hour discussion. The CoreValve Evolut PRO received U.S. Food and Drug Administration approval just days after the SURTAVI presentation, albeit for the treatment of symptomatic severe AS in patients who are at high or extreme risk for SAVR. 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 last year’s EuroPCR meeting, 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?” For his part, Mack also wasn’t impressed with the durability issues highlighted in the Dvir et al data presented at EuroPCR 2016.2 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 5 years,” said Mack. “There have been plenty of surgical valves that looked good at five years. And then by eight to 10 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 the registry data presented by Raj R. Makkar, MD, FACC, at ACC.17, which showed subclinical leaflet thrombosis of bioprosthetic aortic valves in 12 percent of patients post TAVR and 4 percent post SAVR.3 Fortunately, the issue resolved in 100 percent of 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 those 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. The ongoing trials of patients at low risk are enrolling significant numbers into CT imaging substudies to better understand this phenomenon, reported Leon. What About the Other 80 Percent of AS? 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 of less than 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. What About the Asymptomatic Severe AS Patient? 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. That said, 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. At the end of the day, 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. 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. Getting the Details Straight There are many details yet to clarify with TAVR, beyond those of long-term valve durability, clinical indications, post-procedural pacemaker need and cognitive outcomes. These include but are not limited to: clinical indications, risk assessment, the choice between 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. In early January, the ACC released the 2017 Expert Consensus Decision Pathway for TAVR that offers clear guidance for clinical centers already performing TAVR and for 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. 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, last given a full update in 2014 and given a focused update in March 2017. The authors of the decision pathway do attempt to provide a clear framework for the expanded use of TAVR in populations at lower risk. Leon mentioned in his ACC.17 talk that TAVR has until now been considered as an option for those who do poorly with surgery. But now, 10 years later, “it’s gone much further, much faster than we expected, and the conversation needs to change,” he said. “In the future, at least I predict, that 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.” With more than 60 TAVR-related sessions at ACC.17, it is clear TAVR has made it to prime time. It’s unlikely to take another 10 years to clarify the pros and cons, how’s, why’s and when’s of TAVR. References 1. Nishimura RA, Otto CM, Bonow RO, et al. J Am Coll Cardiol 2017;March 10:[Epub ahead of print]. 2. 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. 3. Chakravarty T, Sondergaard L, Friedman J, et al. Lancet 2017; March 19;[Epub ahead of print].
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