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A New Frontier for TAVR
Evidence mounting for use in patients with aortic stenosis at intermediate or low risk for surgery.
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Adoption of transcatheter aortic valve replacement for intermediate- and low-risk patients is accelerating after a recent spate of regulatory approvals and positive research findings.
Until recently, both TAVR systems approved in the United States — one using balloon-expandable valves (Sapien family, Edwards Lifesciences) and one using self-expanding valves (CoreValve family, Medtronic) — were indicated for patients at high risk or extreme risk for surgery, or who were considered inoperable.
In August, however, the FDA granted an indication for two balloon-expandable systems (Sapien 3 and Sapien XT, Edwards Lifesciences) for use in intermediate-risk patients. Recently, the Sapien 3 system and a self-expanding system (CoreValve Evolut R, Medtronic) received a CE mark for use in intermediate-risk patients in Europe (see Sidebar).
A number of recent studies have shown TAVR has similar efficacy compared with surgical AVR in intermediate-risk patients.
Cover illustration © Lisa Clark
“The expansion of TAVR toward lower-risk patient populations, although dramatic, is natural, given its superb clinical outcomes,” Danny Dvir, MD, interventional cardiologist at St. Paul’s Hospital Vancouver, and the University of Washington Medical Center, Seattle, told Cardiology Today’s Intervention. “The vast majority of clinicians know that this is a highly beneficial technology, which is both effective and reasonably safe. With technological improvements and by targeting lower-risk patient populations, we see a decrease in procedural complication. It is clear that TAVR has become a relatively safe procedure.”
With lower-risk patients no longer off-limits for TAVR, these developments have prompted experts to further refine who should receive it instead of surgery.
Data Support Expanded Use
Findings of several recent trials have borne out the hypothesis that TAVR is as safe and effective in intermediate- and low-risk populations as surgical AVR.
The largest trial of TAVR in intermediate-risk patients was the PARTNER 2 study, which evaluated use of the Sapien XT device compared with surgical AVR in more than 2,000 patients. At 2 years, rates of death or disabling stroke were similar between those who underwent TAVR and those who had surgical AVR, and were more favorable for TAVR in those who had transfemoral access (see Table).
“In general, patients at lower risk for surgery do well with TAVR,” Susheel Kodali, MD, director of the Structural Heart and Valve Center at NewYork-Presbyterian/Columbia University Medical Center and physician contributor to the Cardiovascular Research Foundation, told Cardiology Today’s Intervention.
The PARTNER 2 S3i trial evaluated the use of the Sapien 3 device in more than 1,000 intermediate-risk patients. Results showed 30-day mortality rates (1.1%) and stroke rates (1%) that represented some of the lowest levels of complications seen in TAVR studies, experts said.
“Based on the PARTNER 2 trial, I believe all patients deemed to be at intermediate risk for surgery would benefit from TAVR, especially those that can be treated via a transfemoral route,” Kodali said.
The randomized NOTION trial demonstrated that the self-expanding system had similar efficacy to surgical AVR in lower-risk patients. In an intention-to-treat population of 280 patients, more than 80% of whom were considered low risk (Society of Thoracic Surgeons predicted risk of mortality score < 4%), the primary endpoint of all-cause death, stroke or MI at 1 year occurred in 13.1% of those assigned TAVR and 16.3% of those assigned surgery (absolute difference, –3.2%; P = .43).
However, the TAVR group had lower risk for life-threatening bleeding (P = .03), cardiogenic shock (P = .05), acute kidney injury (P = .01) and new-onset or worsening atrial fibrillation (P < .001), but high risk for permanent pacemaker implantation (P < .001). The study was underpowered, Kodali said.
“The safety of TAVR in the intermediate- and low-risk [populations] appears very good from existing data,” Michael J. Reardon, MD, professor of cardiothoracic surgery, Allison Family Distinguished Chair of Cardiovascular Research, Houston Methodist DeBakey Heart & Vascular Center, told Cardiology Today’s Intervention. “We expect to be presenting the SURTAVI trial intermediate-risk result in 2017, and I would expect continued safety outcomes to be excellent. The issue in low risk is: Will the efficacy seen early persist and will these valves have a durability similar to that of surgical valves?”
Philippe Généreux, MD, interventional cardiologist and director of the structural program at Hôpital du Sacré-Coeur, Montreal, and director of the angiographic core laboratory at the Cardiovascular Research Foundation/Columbia University Medical Center, told Cardiology Today’s Intervention that TAVR is no longer considered only an option for the frailest of patients, and if trends continue, the suitable patient population should expand even further.
“TAVR used to be reserved for the sickest of the sickest,” he said. “We are now trying to make the procedure available for mainstream patients. ... In the future, TAVR may even be [used] to treat asymptomatic patients.”
Kodali noted, however, that there are some caveats to the recent data.
“Patients with a bicuspid valve were not systematically included in the trials,” he said. “Currently, we don’t have any rigorous trial data in low-risk patients. The PARTNER 3 and CoreValve low-risk studies are ongoing, which are randomizing low-risk patients between TAVR and surgery.”
Factors Favoring TAVR, Surgery
The strongest case for TAVR in lower-risk patients appears to be in the elderly and in those who are at risk for bleeding, atrial fibrillation and kidney injury, experts said.
“Although [PARTNER 2] was conducted in an intermediate-risk population, it was still an elderly population with a mean age over 80 years,” Kodali said. “Older patients in general don’t tolerate complications due to frailty. Therefore, avoiding the morbidity of surgery in these patients leads to better outcomes. The PARTNER 2 trial and others have demonstrated that TAVR, when compared with surgery, is associated with lower rates of postoperative bleeding, AF and acute kidney injury. All three of these complications lead to worse outcomes, especially in octogenarians and above.”
Dvir agreed, noting that “although these were relatively old patients, with a majority older than 80 years, mortality within 1 month was below 4%,” he said.
However, TAVR is not without risks, and some populations may be better off with surgery, according to Dvir.
Although factors such as length of hospital stay and time to functional recovery help favor TAVR in many patients, “there are several patient populations that may do better with conventional surgery,” Dvir said. “These may include those with symptomatic coronary disease not amenable to safe percutaneous treatment, those with multivalvular disease and those with a severely dilated ascending aorta. In addition, patients with bicuspid aortic valves are more challenging for TAVR, and although recent data suggest that utilizing novel [transcatheter heart valve] devices may be associated with reasonable clinical outcomes, this population should be further studied.”
Risk Scores Beneficial
Other data published recently have offered further ways to refine who is and is not an appropriate candidate for TAVR.
One group of researchers developed a simple scoring system for TAVR using novel predictors of outcome that effectively categorized early and late mortality risks in extreme- and high-risk patients and may assist in identifying other candidates for the procedure. Results were published in the Journal of the American College of Cardiology.
James B. Hermiller, MD, from St. Vincent Heart Center of Indiana, Indianapolis, and colleagues analyzed data from 3,687 patients from the CoreValve U.S. Pivotal Trial program, who were stratified into a derivation cohort (n = 2,482) and a validation cohort (n = 1,205). Within the cohort, the overall mortality rate was 5.8% at 30 days and 22.8% at 1 year. Independent predictors of death at 30 days included home oxygen use (HR = 1.74; 95% CI, 1.16-2.61), assisted living (HR = 1.68; 95% CI, 1.05-2.69), albumin level less than 3.3 g/dL (HR = 1.6; 95% CI, 1.04-2.47) and age older than 85 years (HR = 1.46; 95% CI, 0.99-2.15). Predictors of mortality at 1 year included falls in the last 6 months (HR = 1.36; 95% CI, 1.03-1.81), an STS predicted risk of mortality score greater than 7% (HR = 1.36; 95% CI, 1.05-1.77) and severe ( 5) Charlson comorbidity score (HR = 1.27; 95% CI, 0.98-1.65), as well as home oxygen use (HR = 1.9; 95% CI, 1.47-2.44) and albumin level less than 3.3 g/dL (HR = 1.4; 95% CI, 1.04-1.91).
From this cohort and variables, the researchers crafted a scoring system to assess mortality risk at 30 days and 1 year by stratifying patients into three categories: low risk, moderate risk and high risk. The system demonstrated a threefold difference in mortality risk at 30 days for the low-risk (3.6%) and high-risk (10.9%) groups, as well as 1-year mortality for low-risk patients (12.3%) and high-risk patients (36.6%), Hermiller and colleagues wrote.
“What is unique about this risk-prediction algorithm is that, in addition to the usual variables predictive of death, assessments of frailty and disability were also used,” Michael J. Mack, MD, and Elizabeth M. Holper, MD, MPH, both from the Heart Hospital Baylor Plano in Texas, wrote in an editorial accompanying publication of the findings in JACC. “The decreasing 30-day and 1-year mortality rates in patients undergoing TAVR present an opportunity to focus on mitigating risk in the higher-risk groups and optimizing outcomes in the lower-risk groups.”
Key to determining who is appropriate for TAVR are anatomical characteristics such as vascular access and annulus anatomy that can determine acute complication risk, and patient comorbidities, which indicate if a patient is likely to tolerate the procedure and complications, Kodali told Cardiology Today’s Intervention.
“Since intermediate-risk patients have [fewer] comorbidities than high-risk patients, they do better than those at high risk for surgery,” Kodali said. “Therefore, in an intermediate-risk patient with ideal anatomy for TAVR (ie, excellent vascular risk, minimal left ventricular outflow obstruction calcium, no high-risk features for coronary obstruction, etc), the outcome with TAVR is typically excellent in the short term. However, as is the case with surgery, unpredictable complications such as stroke can occur in any patient.”
The STS and the American College of Cardiology have also created a TAVR risk score, developed from the Transcatheter Valve Therapy registry.
However, clinicians must keep in mind “that the field is evolving rapidly and developing a score for TAVR risk is, therefore, challenging,” Kodali said. “There are many things that contribute to TAVR risk, from patient comorbidities to patient anatomy to device selection. Operator experience also plays a role. In my opinion, it is difficult to incorporate all of these into a risk score. In the future, the risk scores may be better at differentiating, but right now there is not one.”
Evolution Continues
As data have accrued showing favorable outcomes for TAVR in intermediate-risk patients — and, to a lesser extent, low-risk patients — clinicians have changed the decision-making process on who should receive TAVR.
“We used to ask who is a poor candidate for [surgical] AVR and would then consider TAVR,” Reardon said. “We are beginning to ask in lower-risk patients who is a poor candidate for TAVR and then consider [surgical] AVR. This is mainly anatomic information obtained from [CT angiography]. Clearly, the higher the risk, the more appropriate TAVR is with our current data.”
Dvir told Cardiology Today’s Intervention that more research is needed in lower-risk patients, especially younger individuals.
“We will surely need to study closely each [transcatheter heart valve] device/platform and its suitability for younger and lower-risk patients,” he said. “In general, in this population we would like a safe platform. We want a device with low risk for advanced conduction defects and a device associated with superb hemodynamics, excellent sealing and good long-term durability.”
Since TAVR is to be used in patients with longer life expectancy than is common in current practice, “assessment of [transcatheter heart valve] durability will be an important research field in upcoming years,” Dvir said.
“TAVR devices and surgical bioprostheses are tissue valves and will have shorter durability than mechanical valves,” he said. “All must continue to study long-term behavior of both TAVR devices and surgical valves and the risk for valve failure. An important thing for clinicians to realize is that a young patient implanted with biological tissue valve ... either by TAVR or by surgery ... may need a valve-in-valve in the future, and physicians should make sure that the valve platform that this patient is implanted with, is compatible with a safe and effective valve-in-valve.”
Kodali agreed that further progression of TAVR usage will depend on long-term outcomes.
“The outcomes discussed to date have only been short- and intermediate-term. We need to collect longer-term data,” he said.
Among those crucial outcomes, it will also be important to analyze how stroke rates and other cerebrovascular complications are affected by using embolic protection devices during TAVR. “If neurologic complications can be further reduced, the benefit of TAVR may be increased,” Kodali said.
If the technology continues to advance, it may one day be used in applications considered only in theory today, Généreux said.
“Eventually, TAVR could be efficient as a single-use [technology] in combination with multiple-intervention surgery, something along the lines of a mitral-valve replacement,” he said. — by James Clark
Click here to read "Novel Determinants of TAVR Success."
- References:
- Hermiller JB, et al. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2016.04.057.
- Leon MB, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1514616.
- Mack MJ, Holper EM. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2016.05.030.
- Thyregod HGH, et al. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2015.03.014.
- For more information:
- Danny Dvir, MD, can be reached at University of Washington, 1959 NE Pacific St., C502-A, Box 356422, Seattle, WA 98195; email: ddvir@uw.edu.
- Philippe Généreux, MD, can be reached at Cardiovascular Research Foundation, 1700 Broadway, New York, NY 10017; email: pgenereux@crf.org.
- Susheel Kodali, MD, can be reached at 177 Fort Washington Ave., 5th Floor, Room 5C-501, New York, NY 10032; email: sk2427@cumc.columbia.edu.
- Michael J. Reardon, MD, can be reached at 6550 Fannin, Houston, TX 77030; email: mreardon@houstonmethodist.org.
Disclosure: Dvir reports consulting for Edwards Lifesciences, Medtronic, St. Jude Medical and W.L. Gore & Associates. Généreux reports receiving research grants from Boston Scientific and consultant, speaking and proctoring fees from Edwards Lifesciences. Kodali reports consulting for Edwards Lifesciences and Medtronic. Reardon reports serving on an advisory panel for Medtronic and being an investigator for trials funded by Boston Scientific and Medtronic, but does not receive direct compensation for any of those duties.