Expanding TAVI to Low and Intermediate Risk Patients

TAVI has become the standard treatment in patients at increased surgical risk and is increasingly being performed in patients at intermediate to low surgical risk. While non-inferiority has been demonstrated in intermediate risk patients, several challenges—particularly with regard to valve durability—need to be addressed before expansion to lower risk and younger patients can be recommended on a broad basis. Current trends, trials results, and remaining challenges are summarized and discussed in the light of updated treatment guidelines.


INTRODUCTION
Severe aortic valve stenosis (AS) represents the most common valvular heart disease in developed countries. Since its prevalence is associated with increasing age, a growing disease burden is expected in the future considering an aging patient population (1). Surgical aortic valve replacement (SAVR)-the traditional standard of care for patients with severe symptomatic AS-is increasingly complemented by transcatheter aortic valve implantation (TAVI). After the first TAVI procedure in 2002 (4), the number of procedures has increased exponentially in the past years and has recently outperformed the number of isolated SAVR per year in Germany (5). Several prospective randomized trials demonstrated non-inferiority for TAVI compared to SAVR in patients at high surgical risk (6,7). More recently, three additional trials reported non-inferiority of TAVI in intermediate-risk patients (Figure 1, Table 1) (8)(9)(10). Current debates focus on the expansion of TAVI as the standard of care for the treatment of patients with AS and low to intermediate operative risk. However, important additional factors, e.g. active malignancy, frailty, porcelain aorta, chest wall radiation, liver cirrhosis, or neurological impairment, were not comprehensively integrated in these risk models. In addition, treatment decisions may differ in elderly patients without comorbidities (low operative risk despite advanced age) and young patients with significant comorbidities (increased operative risk despite young age). The 2017 ESC/EACTS guidelines for the management of valvular heart disease incorporate these difficulties and opt for a more differentiated approach to operative risk and choice of treatment modality (13).

TREATMENT SELECTION ACCORDING TO CURRENT GUIDELINES
To help navigate the choice of treatment modality in patients with low to intermediate surgical risk, European (13) and American (14) guidelines were recently updated. In general, the indication for TAVI was expanded to intermediate risk patients in both versions on the basis of three major trials (8)(9)(10). American guidelines in its current version consider TAVI a reasonable alternative to SAVR in patients at intermediate operative risk (STS-PROM ≥4%), depending on patientspecific procedural risks, values, and preferences (14). European guidelines emphasize, that the treatment selection (TAVI or SAVR) in patients at increased surgical risk (STS-PROM ≥4%, logistic EuroSCORE ≥10% or risk factors not considered in these algorithms) should be made by the Heart Team on an individualized basis (13). According to the guideline's authors, factors in favor of a catheter-based approach include patient age ≥75 years, prior cardiac surgery, frailty, restricted mobility or anticipated prolonged rehabilitation, favorable transfemoral access, prior chest radiation, porcelain aorta, severe chest deformation, or expected prosthesis-patient mismatch. Other aspects, e.g. patient age <75 years, suspicion of endocarditis, unfavorable anatomy for TAVI (access, low coronary take-off, unfavorable aortic root, valvular, or annular anatomy), and concomitant cardiac conditions that require additional surgical treatment favor SAVR. Overall, SAVR remains the standard therapy for patients <75 years of age with low surgical risk at current as long-term durability data for THV remain insufficient. In the absence of a perfect risk assessment, both guidelines emphasize the integral role of the interdisciplinary heart team in patient evaluation, assessment of technical suitability, and identification of the appropriate treatment modality (13,14).

EVIDENCE FROM INTERMEDIATE-RISK TRIALS OR REGISTRIES
Essential evidence for the expansion of TAVI for the treatment of intermediate risk patients stems from three prospective randomized trials and reports from major contemporary registries.

Registries
Several large-scale nationwide registries evaluated outcomes and trends in the treatment of aortic valve stenosis. Long before first results from prospective randomized intermediate-risk trials were available, large registries had already reported a paradigm shift of TAVI towards lower risk patients: According to the  (17).
A shift in patients' disease severity and advancements in procedural and technical aspects over the past years have most likely contributed to these consistent improvements of outcomes after TAVI. However, a comparison of treatment modalities from these registries' results is impeded by very different risk profiles in the treatment groups, calling for appropriate randomized trials.

Randomized Trials
In addition to several real-world registries, few comprehensivebut highly selective-industry-sponsored trials evaluated outcomes after TAVI in different risk categories (see Table 1 for selected results, Figure for risk profile). Results of intermediate risk trials are discussed in the following.
The first randomized trial to evaluate TAVI in low to intermediate risk patients was the Nordic STACCATO trial. It started patient recruitment as early as 2008 and aimed to compare transapical TAVI to SAVR in operable patients ≥75 years of age (18). Due to an excess of serious adverse events in the transapical TAVI arm, the study was prematurely terminated after inclusion of 70 patients. The trial was heavily criticized for its design, including only a transapical TAVI arm.
One year later, the NOTION (Nordic Aortic Valve Intervention) trial (9) 11.3%, p < 0.001) were reported after SAVR while patients after TAVI had a higher risk for major vascular complications (8.6 vs. 5.5%, p = 0.006). Interestingly, rates of permanent pacemaker implantations were not significantly different in both groups in this trial. An overall faster recovery and shorter hospitalization (in-hospital: median 6 vs. 9 days, ICU: median 2 vs. 4 days, p < 0.001 for both) were observed after TAVI. While lower transprosthetic gradients were reported in the TAVI arm, the rate of moderate/severe PVL was significantly higher compared to SAVR (8.0 vs. 0.6%, p < 0.001) and a trend towards more aortic valve re-interventions was observed after TAVI at 2 years (1.4 vs. 0.6%, p = 0.09). This observation has to be followed closely as the TAVI indication is expanded to younger patients. Of note, 14.5% of patients in the SAVR arm underwent concomitant coronary artery bypass graft surgery for significant coronary artery disease.
After a recruitment period of almost 4 years, the SURTAVI trial (8) 12.5%) were observed after SAVR. While hemodynamic measures were in favor of TAVI (transprosthetic gradients, effective orifice area), the incidence of PVL (moderate/severe at 1 year: 5.3 vs. 0.6%) and the need for pacemaker implantation (25.9 vs. 6.6%) were lower after SAVR. Quality of life at 2 years was similar in both groups. Aortic valve reintervention was reported more often after TAVI (2.7 vs. 0.7% at 2 years), although no structural valve deterioration was found in either group.

Currently Active Intermediate to Low Risk Trials
Building on the results of intermediate-risk trials and registries named above, several prospective randomized trials are currently active, either recruiting patients or in follow-up, to evaluate outcomes after TAVI in patients at low to intermediate operative risk. The results of these trials will determine future guideline recommendations on the treatment of aortic stenosis in low to intermediate risk patients (see Table 2 for major characteristics of these trials).
The PARTNER 3 trial (clinicaltrials.gov NCT02675114) randomly assigns 1,328 patients with low surgical risk (STS-PROM<4%) to TAVI with the Sapien 3 device or SAVR. Patients will be followed for 10 years and the primary endpoint is a composite of all-cause mortality, stroke and rehospitalization at 1 year. Results of the primary endpoint are expected to be presented in 2019.
The Medtronic TAVR low risk trial (clinicaltrials.gov NCT02701283) includes 1,200 patients with an STS-PROM<3%. Patients are randomized to TAVI with the CoreValve or CoreValve Evolut R self-expandable THV or SAVR. Patients will be followed for 10 years and the primary endpoint is a composite of all-cause mortality or disabling stroke at 2 years.
While both studies are industry-sponsored and limited to one THV, two additional investigator-initiated trials have been initiated: The Nordic NOTION-2 trial (clinicaltrials.gov NCT02825134) aims to randomize 992 low risk patients (STS<4%, ≤75 years) to TAVI with any CE-marked device or SAVR. Due to the exclusion of elderly patients, this trial will particularly gain important insights into outcomes of TAVI in younger patients at low risk. Interestingly, combined procedures (SAVR and concomitant CABG or TAVI and PCI) are also included in the trial. The primary endpoint is a composite of all-cause mortality, stroke or myocardial infarction at 1 year. The trial is investigator-initiated but industry-funded.
The DEDICATE trial (DEDICATE-DZHK6, clinicaltrials.gov NCT03112980) is multicenter investigator-initiated and industry-independent study. It is funded by the DZHK (German Center for Cardiovascular Research), the Deutsche Herzstiftung e.V., and supported by German health insurance providers. Overall 1,600 patients at low to intermediate surgical risk (STS-PROM 2-6%) will be included. As opposed to previous trial designs, DEDICATE aims to investigate a true all-comers patient population and evaluate real-world outcomes. After 1:1 randomization to either TAVI or SAVR, the remaining treatment decisions (e.g. access route, THV type, periprocedural treatment, etc.) are left to the interdisciplinary heart team. All CE-marked devices can be utilized to avoid any potential device-based bias. To account for the increasing importance of long-term data in low risk patients, the primary endpoint was chosen as overall survival after 5 years. Low to intermediate risk patients undergoing aortic valve treatment at the study sites who are not included in the randomized trial will be captured in a nested registry to evaluate an all-comers population.
All of these active trials will add significantly to the current evidence for TAVI in intermediate to low risk patients and allow first insights into long-term results on a broad basis.

REMAINING CHALLENGES
Within the last decade, TAVI has become the standard of care for high-risk patients with severe and symptomatic AS. It has increasingly been performed in intermediate and also low-risk patients more recently. Particularly for younger and low-risk patients, additional challenges need to be addressed:

Valve Durability and Function
The unresolved issue of long-term valve durability is probably the key challenge in expanding TAVI to lower risk and younger age patients. Longitudinal echocardiographic evaluation of the PARTNER trials (PARTNER 1A, 1B, and continued access) demonstrated stable hemodynamic results after TAVI over 5 years of follow-up (19). Similar results were reported in other series and for self-expanding transcatheter heart valves (20). Recently results from the Nordic NOTION trial confirmed not only robust hemodynamic data over 5 years of follow-up but also favorable hemodynamics after TAVI compared to SAVR (2). Particularly in patients with smaller aortic annuli, TAVI may yield a lower incidence of patient-prosthesis mismatch, compared to SAVR. However, increased rates of PVL were consistently observed after TAVI compared to SAVR. Due to an adverse effect of significant paravalvular leakage on survival (10), reduction of residual regurgitation will be essential to improve long-term outcomes. Although progress has been made to reduce residual AR after TAVI in recent studies with next-generation devices (21), further improvements will be required to match data from SAVR cohorts.
Additionally, subclinical leaflet thrombosis, its effects on hemodynamic and clinical results need to be evaluated due to a significantly higher incidence after TAVI compared to SAVR (22). Overall, the incidence of structural valve degeneration and aortic valve re-intervention were low but will naturally become an issue as follow-up length and patient numbers increase. Recently published definitions of prosthesis degeneration may aid comprehensive analysis of this important topic (23,24). To eliminate durability concerns after TAVI, very solid durability data available for surgical bioprostheses over the course of more than a decade will need to be matched (25). Nevertheless, degeneration of THV will occur at some point in patient life, leading to either surgical valve replacement or valve-in-valve procedures. Valve-in-valve procedures have demonstrated encouraging results in patients with degenerated surgical aortic bioprostheses (26). Whether these results can be systematically achieved for valve-in-valve procedures in degenerated THV needs to be demonstrated. Different design features of THV may yield variable results after valve-in-valve implantation, for example with regard to coronary access in degenerated supra-annular THV.
While moving towards younger patients, the prevalence of biscuspid aortic valve disease will inevitably increase. Data from retrospective registries demonstrated lower procedural success and higher residual PVL after TAVI in patients with bicuspid compared to tricuspid aortic valve disease (27)(28)(29)(30). Implantation of new-generation devices yielded improved outcomes, giving rise to hope that TAVI may become a valid treatment option in bicuspid aortic valve disease in the future (30). Due to the paucity of data, guidelines favor SAVR in these patients at current (13).

Morbidity and Mortality
After early reports of increased stroke rates after TAVI (6), more recent trials have consistently demonstrated similar outcomes for mortality and stroke after TAVI or SAVR. However, distinct complication patterns have repeatedly been reported for both treatment options (see Table 1). These need to be weighed against the individual patient's risk profile when choosing the optimal treatment modality. These include a higher incidences of acute kidney injury, bleeding events, and atrial fibrillation after SAVR. TAVI was associated with faster recovery and shorter index hospitalization but a higher rate of re-interventions or heart failure were documented during follow-up. Long-term results will be essential to gain further insights into these important first observations. While major vascular complications were common after transfemoral TAVI with first-generation devices (31), a significant decrease was observed in recently reported intermediate-risk trials (8)(9)(10). A shift in patients' risk and device refinements with smaller delivery systems and improved vascular closure devices may be responsible for this decline. Permanent pacemaker implantation remains a concern after TAVI, particularly with self-expanding THV. Although data remain ambiguous regarding the association of pacemaker implantation and outcome after TAVI at current (32,33), this issue requires in-depth evaluation, particularly in the treatment of younger patients.
Although a major advantage of TAVI relates to the less invasive procedure compared to SAVR, the risk for rare but life-threatening complications after TAVI (e.g., annular rupture, valve migration, or coronary obstruction) requiring bail-out emergency cardiac surgery must be taken into account. Recently published data from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI) reported an incidence of emergent cardiac surgery of 0.7% in recent years. Most common causes were left ventricular guidewire perforations (28.3%) and annular ruptures (21.2%). Most of these complications occurred during the procedure and mortality remained high despite emergent cardiac surgery (34). While these serious procedure-related complications were more frequent in the early TAVI era and have become very rare events at this stage (35), expansion of TAVI towards younger and low-risk patients requires an even more critical appraisal and all measures need to be taken to prevent these complications.

Cost-Effectiveness
With the rapid growth of TAVI volume, its implications on healthcare systems and its cost-effectiveness will become even more important, particularly while expanding TAVI indications to lower risk patients (36). An early analysis from the Netherlands demonstrated higher 1-years costs of TAVI vs. SAVR in intermediate-risk patients (37). This cost difference was mainly driven by the difference in device prices. A recent cost-effectiveness analysis from the Partner 2A and Sapien 3 trials reported lower costs at 2 years after TAVI (3). Higher procedural costs were compensated for by shorter hospitalization and substantially lower costs during follow-up. Regional and national differences in reimbursement and device costs impede generalization of these results. However, health economic analyses will gain importance as the field expands.

CONCLUSION
TAVI has become the standard treatment in patients at increased surgical risk and is increasingly being performed in patients at intermediate to low risk at current. Non-inferiority has been demonstrated in different intermediate risk cohorts. However, before broad expansion to lower risk and younger patients can be recommended, several challenges-particularly with regard to valve durability-need to be addressed. Several randomized trials are under way to investigate these issues and will determine future guideline recommendations. For now, distinct risks should be weighed into the decision of TAVI vs. SAVR, incorporating each patient's individual risk profile and personal preferences. Shared-decision making will increasingly become a crucial element in this process. Preferences of the informed patient should be discussed, balanced, and weighed into the joint treatment decision of the interdisciplinary heart team to select the appropriate treatment for every individual patient while expanding TAVI to intermediate and low risk operative patients.