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- Amelia Scholtz, PhD∗ ()
- ↵∗Address for correspondence:
Amelia Scholtz, PhD, American College of Cardiology, 2400 N Street NW, Washington, DC 20037.
In a wide-ranging discussion, Prof. Dr. Eberhard Grube spoke with Amelia Scholtz about new directions for transcatheter aortic valve replacement (TAVR) being pursued around the world.
The chief of cardiac interventions and innovations at the University of Bonn, a consulting professor at Stanford University, and a staff physician at Instituto de Cardiologia Dante Pazzanese in São Paulo, Brazil, Prof. Dr. Eberhard Grube has been closely involved in the technical development and geographical diffusion of TAVR. In addition to these globe-spanning appointments, his work as a proctor for the TAVR industry has taken him to numerous countries in Europe and East Asia. In this transnational context, Grube reflected on aspects of the procedure ranging from risk stratification to facilities and personnel.
The current spectrum of risk stratification practices vis-à-vis TAVR and surgical aortic valve repair (SAVR) bears the marks of TAVR’s origins. “The STS score and the EuroSCORE were surgical scores and never TAVR scores,” Grube explained, “but since we didn’t have TAVR scores, we had to use STS score.” Although international consensus favored the use of these scores, interpretation and utilization varied greatly between countries. The publication of findings from the U.S. PARTNER (Placement of Aortic Transcatheter Valves) and CoreValve trials in high–surgical-risk patients helped to bring consistency to the interpretation of these scores and to ease tensions between interventionalists and surgeons (1,2). More recently, trial and registry data have allowed “cardiologists and surgeons to agree upon outcomes. The cardiologists needed some proof that we were not attacking the surgeons but rather, in a joint conference, could decide what is best for the patient,” Grube opined.
However, the relationship between reimbursement and Society of Thoracic Surgeons score has turned out to be more complex. In parts of Europe, such as Germany, France, Italy, and Spain—and even in Japan—risk scores are the key criterion for reimbursement. “In Germany, for example,” Grube explained, “we have to stick to the risk score. If you include a patient who is 65 years old with low risk, for example, now, you will not be reimbursed.” Across the English Channel, score-based reimbursement is maintained more rigidly; “they have fewer centers, and it’s absolutely clear: the risk score is mandatory for reimbursement.” The United States lies at the far end of the spectrum in this regard, adhering to what Grube termed “by far the most rigid reimbursement policy.”
A lack of reimbursement makes for less central control in China and Latin America. In the latter, clinicians will certainly consider risk scores for orientation, “but if a certain cardiologist agrees to do a TAVR, if the patient pays, he gets a TAVR regardless of the risk score,” Grube explained, adding, “the state doesn’t appear because it doesn’t reimburse.” Similarly, clinicians in China may “assess different things such as financial and family situations. They don’t look so rigidly at the risk scores, at least in clinical practice. In publications and in conventions, yes, but in clinical practice, they don’t really care as much.”
This bifurcation between expert consensus and real-world clinical practice also shapes considerations of futility. On the one hand, international consensus has formed around a definition of futility as a life expectancy of <1 year even after TAVR—a position espoused in ACC clinical policy (3). On the other hand, reimbursement—or the lack thereof—determines the degree of importance ascribed to a judgment of futility and whether other factors may also be considered. “If state reimbursement is applied to TAVR, clinicians have to stick to the rules” and apply this definition to decision making, but “if that is not the case, then it is based on individual decisions between patient and physician,” Grube explained.
Although the larger European economies may be defined by their strict reimbursement protocols, they also have been at the forefront of extending the procedure to intermediate-risk populations. CE mark approval for the use of the CoreValve in intermediate-risk patients came in 2016. The U.S. Food and Drug Administration followed suit in 2017 in response to the release of the SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial, which demonstrated an incidence of the trial’s primary endpoint—a composite of all-cause mortality or disabling stroke at 24 months—of 12.6% in the TAVR arm and 14.0% in the SAVR arm (4).
Some feel that we are on the precipice of performing TAVR in lower-risk patients. Asked about the prospect of such a move, Grube asserted that “there’s absolutely no doubt and no question about that. The jury is out with the low-risk trials, but there’s no indication that we’ll see anything different.” Although the trials in low-risk patients are still ongoing, 5-year outcomes for the smaller NOTION (Nordic Aortic Valve Intervention) trial were presented in March 2018 at the ACC’s annual meeting (5). A total of 139 patients underwent TAVR, while 135 underwent SAVR, with a primary composite outcome of all-cause mortality, stroke, or myocardial infarction. At 5 years, that outcome had occurred in 39.2% of TAVR patients and 35.8% of SAVR patients. “As soon as the randomized data are confirmed or released for the larger trials, the lower-risk patients will be included,” Grube speculated, adding, “that’s going to be happening very, very fast, and that’s the majority of patients.”
Age Versus Risk
Talk of extending TAVR to lower-risk populations often focuses on patients age <75 years, but Grube cautioned that “it’s extremely important that we don’t confuse low risk with younger age.” Indeed, with younger age comes a host of considerations that may not weigh as heavily in decisions about older patients—matters such as valve durability, bicuspid valves, and the prospect of pacemaker implantation. The last of these “might not be a severe complication in older age,” Grube reflected, “but if you are 60 or 65 … that’s something different.” Similarly, a patient who receives a prosthetic valve at age 60 years “most likely needs another valve in 15 years at the latest,” whereas an older patient is less likely to ever require repeat valve replacement. Post-TAVR cognitive impairment may also be more problematic in a patient of 60 years, who may still be working, than in a person age 80 years.
Given the greater prevalence of bicuspid anatomy among these younger TAVR candidates, is there a need for prosthetic valves to be developed specifically for patients with bicuspid valves? Grube disagreed with calls for such specialized valves. “We are already treating bicuspid valves quite successfully” with existing designs, he opined, citing the example of China, where “60% of patients have bicuspid anatomies and they’re using classical valves.” Rather than radical changes in prosthesis design, Grube envisages more subtle refinements to lower valve profile, allow coronary access, and reduce paravalvular leakage and conduction disturbances. “Lower sheath sizes—below 10 French” are in development, he noted, but “that’s in animals and on the spreadsheet.”
The solidification of market position for leading developers Medtronic and Edwards represents another respect in which the prosthetic aortic valve market has reached equilibrium. “The rest of the world, except for China, is basically following the internationally accepted market leaders for valves that are generally approved in the United States,” Grube explained. This preference for a small number of valves is a result not only of regulatory decisions, but also of clinicians’ preference for devices supported by a surfeit of clinical data. “Physicians really care about data and safety; the larger the dataset is, the more comfortable the physician is using that valve.” Thus, in European countries in which a relatively wide range of valves has been approved, “the market leaders remain the market leaders.”
Intriguingly, the situation is rather different in China. Rather than using valves favored in other parts of the world, Chinese clinicians are using Chinese-made prostheses. “Basically, all the valves being used are copycats of the ones that we are using except with a Chinese brand,” Grube noted. Whereas Edwards successfully protected its patent early in the history of TAVR, Medtronic did not safeguard its intellectual property vis-à-vis CoreValve. As a result, the vast majority of these “replica” valves in use in China are self-expanding (similar to CoreValve). Moreover, trade protectionism makes it unlikely that industry will make inroads into the Chinese market in the near future, according to Grube. Western-made valves “probably won’t be approved in the next 3 or 4 years,” he surmised. Intellectual property, geopolitical, and regulatory factors will therefore shape valve use along with clinical data.
For Grube, the question of optimal alternative points of access for TAVR is not of great urgency. In his estimation, consensus is neither likely nor necessary in this area. The development of valves with increasingly small sheath sizes has made transfemoral access feasible in patients in whom this was previously problematic. “I don’t even know when I last used an alternative access point,” Grube reflected, “it’s been years, because we are so good now in transfemoral access.” Moreover, choice of access “depends on individual preference, surgical preference, and local adherence and experience,” noted Grube. In his estimation, then, the factors driving each choice of alternative access are so heterogeneous as to stymie the development of consensus in this area.
Facilities and personnel constitute another area of procedural variation. U.S. TAVR centers employ “by far the largest infrastructure, the most people, the most hardware,” Grube observed. Unlike facilities in other parts of the world, U.S. centers “still prime the heart-lung machine,” he noted, speculating that this “maximalist” approach to TAVR has its roots in “regulation, infrastructure, education, and culture.” In Grube’s estimation, European facilities utilize fewer personnel and instruments due in part to their slightly less strict regulatory environments. Similarly, Japanese institutions are subject to strict regulation “by the ethics committee and the hospital administration but not legally.” Chinese centers appear to be subject to fewer requirements than those in Japan, Europe, and the United States. TAVR may be performed “with surgeons, without surgeons, with machines, without machines,” Grube observed, concluding that the situation “is completely different in individual centers across China.”
The number of TAVR centers has likely peaked in Europe and the United States. In Latin America, a lack of governmental reimbursement currently hampers dissemination of the procedure. Expansion is still underway in other parts of the world, however, particularly in Japan and China. The latter country “will blow us away in the coming years,” opined Grube. “Millions of people need that procedure, and it will expand very, very rapidly. In no time, the numbers will be higher than even the United States.” With China becoming the world’s largest market for TAVR, clinicians and patients around the world may benefit from transnational opportunities in innovation, research, and training.
- 2019 American College of Cardiology Foundation
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