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TRANSCATHETER AORTIC VALVE REPLACEMENT (TAVR)

Aortic stenosis is a narrowing of the aortic valve opening that causes an obstruction of the blood flow from the left ventricle into the ascending aorta. There are many conditions that may contribute to aortic stenosis, such as calcification of the aortic valve, rheumatic fever, and congenital anomalies.

When there is an elevated level of calcium traveling through the bloodstream, calcium deposits can occur, hardening the tissue and causing a narrowing, or stenosis, of the valve, which diminishes blood flow through the valve. This is referred to as calcification of a valve. Calcification risk factors include advanced age, male gender, smoking, hypertension (elevated blood pressure), and hyperlipidemia (an elevation of lipids or fats in the blood stream). When left untreated, severe aortic stenosis can result in heart failure and even sudden cardiac arrest.

Transcatheter aortic valve replacement (TAVR), also called transcatheter aortic valve implantation (TAVI), has been developed as an alternative treatment for individuals with severe aortic stenosis who are candidates at risk for open-heart-surgery or not surgery candidates at all. The procedure is performed percutaneously, most often through the transfemoral artery approach. It may also be performed through the subclavian artery approach and transapically using mediastinoscopy.

Currently, several transcatheter aortic valves have Food and Drug Administration (FDA) approval for the treatment of aortic stenosis. The Edwards SAPIEN™  balloon-expandable valve and the self-expanding Medtronic CoreValve™ Transcatheter Aortic Valve Replacement System (Medtronic Inc., Minneapolis, MN), LOTUS Edge™ Valve System (Boston Scientific Corporation, Marlborough, MA), and Portico™ with FlexNav™ (Abbott Medical, Abbott Park, Illinois).

The Edwards SAPIEN™ Transcatheter Heart Valve System (Edwards LifeSciences, Irvine, CA) received original FDA approval in November 2011, via the transfemoral approach, for individuals with severe aortic stenosis who are not eligible for open heart procedures and have calcified aortic annulus (a fibrous ring in the wall of the root of the aorta), who are not candidates for open-heart procedures; who have been determined by a cardiac surgeon to be inoperable for open aortic valve replacement; and in whom comorbidities exist that would not preclude the expected benefit from correction of the aortic stenosis.

Since then, numerous FDA premarket approvals (PMA) have been granted for the Edwards SAPIEN™ (Edwards LifeSciences, Irvine, CA) with expanded indication for use. Approval was granted for both the transfemoral and transapical approaches. In 2012, indications for the transapical approach were expanded to include both inoperable individuals and individuals who are at high risk for open surgery. In June 2014, the next-generation SAPIEN™ XT Transcatheter Heart Valve (Model 9300TFX) was approved by the FDA for use with the NovaFlex+ delivery system. In June 2015, SAPIEN™3 Transcatheter Heart Valve (Model 9600TFX) was approved by the FDA for the treatment of severe aortic stenosis in individuals with symptomatic heart disease who are judged by a Heart Team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., Society of Thoracic Surgeons [STS] operative risk score 8 percent or greater or at a 15 percent or greater risk of mortality at 30 days, and other clinical comorbidities unmeasured by the STS risk calculator). Compared to the previous-generation SAPIEN™ XT, the SAPIEN™3 can be inserted thru smaller iliofemoral arteries, has an improved delivery system that reportedly allows more accurate positioning, and contains a skirt to help prevent paravalvular leak. Additionally, in August 2016, The EDWARDS INTUITY Elite valve system received PMA supplemental approval (P150036) indicated for the replacement of diseased, damaged, or malfunctioning native or prosthetic aortic valves. This approval was based on the TRANSFORM clinical trial, in which participants were treated between September 26, 2012, and December 2, 2015, and included 889 individuals at 29 investigational sites. This device can be used as a treatment for aortic stenosis or stenosis-insufficiency of an aortic valve requiring a planned replacement as indicated in the preoperative evaluation, when a an individual is scheduled to undergo planned aortic valve replacement with or without concomitant coronary bypass surgery.

In August 2016, the FDA through a PMA supplement, approved an expanded indication for the SAPIEN™XT and SAPIEN™3 transcatheter heart valves for individuals with aortic valve stenosis who are at intermediate or greater risk (i.e., STS operative risk score 3 percent or greater at 30 days, and other clinical comorbidities unmeasured by the STS risk calculator) for death or complications associated with open-heart surgery. 

In January 2014, FDA granted approval for the CoreValve™ Transcatheter Aortic Valve Replacement System (Medtronic, Inc., Minneapolis, MN, USA) for individuals with symptomatic heart disease due to severe native calcific aortic stenosis, who are at extreme high risk or who are not suitable for open surgery. In June 2014, the FDA expanded the indication for CoreValve™ to include individuals at high risk for open surgery. FDA labeling indicates that the device can be delivered via femoral, subclavian/axillary or ascending aortic access. In March 2015, the FDA expanded approval of the CoreValve™ system for "valve-in-valve" replacement to treat certain individuals who have previously had a tissue aortic valve replacement and are in need of a second one. The Medtronic Evolut R is the new generation of the CoreValve™ self-expanding family of valves. The valve has been re-engineered to be shorter, to provide a more consistent radial force within the recommended size range, and to allow recapture, repositioning, and redeployment prior to final release. The CoreValve™ Evolut R system was approved by FDA in June 2015 as a supplement to the original CoreValve approval from 2014. The CoreValve™ Evolut PRO system was approved by FDA in June 2015 as a supplement to the original CoreValve approval from 2014. 

In August 2019, the U.S. Food and Drug Administration approved an expanded indication for several transcatheter heart valves to include individuals with severe aortic valve stenosis who are at low risk for death or major complications associated with open-heart surgery to replace the damaged valves.​

Given both the high-risk nature of procedures involving these catheter interventions and the availability of established alternative treatment options using traditional surgical approaches, several considerations are being recommended for institutions and professional providers planning to implement these new technologies, such as TAVR. Recommendations for performing TAVR were developed with the collaboration of cardiologists and cardiothoracic surgeons from the following specialty societies: the American College of Cardiology Foundation (ACCF), the Society for Cardiovascular Angiography and Interventions (SCAI), the American Association for Thoracic Surgery (AATS), and the Society of Thoracic Surgeons (STS). These recommendations were established to guarantee a successful TAVR program that ensures individual safety and demonstrates commitment to excellence by the institution and procedural volume requirements.

PEER-REVIEWED LITERATURE

Transcatheter Aortic Valve Replacement for Individuals with Aortic Stenosis Who Are Not Suitable Candidates for Open Surgery
There have been several case series of TAVR, the majority of which have included individuals who are considered high risk and inoperable for surgery. However, the selection of individuals for TAVR has been largely subjective: expert opinion of cardiac surgeons and/or cardiologists has been the main determining factor of individual suitability for the surgery. Consequently, it is difficult to clearly distinguish individuals who are high-risk operable candidates, and, therefore, some overlap may exist.

In 2010, the Agency for Healthcare Research and Quality (AHRQ) reviewed 84 case studies involving 2,375 individuals. Overall, TAVR was successful in 94 percent of individuals, and the aggregated 30-day survival rate was 89 percent across all studies. Adverse event rates were reported in larger case studies, with an estimated 30-day rate of major cardiovascular adverse events and stroke of eight percent.

The two largest studies included in the AHRQ review reported on 646 individuals treated with the Medtronic CoreValve™ and on 339 individuals treated with the Edwards SAPIEN™ valve. The CoreValve™ study by Piazza et al (2008) used an objective individual selection criteria that included: Logistic EuroScore of greater than or equal to 15 percent, 75 years of age or older, or 65 years of age or older with a condition (condition defined as: liver cirrhosis, pulmonary insufficiency, pulmonary hypertension, previous cardiac surgery, porcelain aorta, recurrent pulmonary emboli, right ventricular insufficiency, previous chest burns or radiation precluding open surgery, or body mass index (BMI) =18kg/m²⁾

Piazza et al (2008) reported a procedural success of 97 percent, a 30-day survival of 92 percent, and a 30-day combined rate of death, myocardial infarction (MI), or stroke of 9.3 percent. A study using Edwards SAPIEN™ valve by Rodes-Cabou et al (2010) included a subjective inclusion criteria (relying on the judgment of participating surgeons to determine eligibility for TAVR), and reported a procedural success rate of 93.3 percent, a 30-day mortality of 10.4 percent, and, at a median follow-up of eight months, a mortality rate of 22.1 percent.

A systematic review by Figulla et al (2011) included studies that enrolled symptomatic individuals with severe aortic stenosis, had a mean age of 75 years or older, reported on 10 or more individuals, and had a follow-up duration of 12 months or longer. A total of 12 studies met these criteria and were compared to a group of 11 studies that treated severe aortic stenosis with nonsurgical therapy. The procedural success in these studies ranged from 86 percent to 100 percent, and the 30-day mortality ranged from 5.3 percent to 23 percent. The combined mean survival rate at one year was 75.9 percent (95 percent confidence interval [CI]:73.3-78.4). This one-year survival rate compared favorably to medical therapy, which was estimated to be 62.4 percent (95 percent CI: 59.3-65.5).

A case series from on 697 individuals treated with the CoreValve™ reported a procedural success of 98.4 percent, and a 30-day mortality of 12.4 percent. Another large case series from Italy that included 663 individuals treated with the CoreValve™ device reported a procedural success of 98 percent and 15 percent mortality at one year. A study published by Gurvitch et al in 2010 reported on durability and longer clinical outcomes for up to three years. Seventy individuals who underwent TAVR and survived for greater than 30 days were included. Survival at one, two, and three years was 81 percent, 74 percent, and 61 percent, respectively. One individual (1.5 percent) required reoperation during this time period. The valve area decreased from 1.7 + 0.4 cm² following the procedure to 1.4 +0.3 cm² at three years. Aortic incompetence was trivial or mild in 84 percent of individuals and did not worsen over time.

The PARTNER (Placement of AoRtic TraNscathetER Valves) trial is a pivotal multicenter RCT of TAVR performed in the US, Canada, and Germany, using the Edwards SAPIEN™ heart-valve system. In 2010, Leon et al reported results of the cohort of individuals who were not candidates for open surgery. Individuals were considered not suitable for open surgery if they had a predicted probability of 50 percent or greater for death or a serious irreversible condition at 30 days post-surgery as determined by two surgeon investigators using clinical judgment and the Society of Thoracic Surgery (STS) risk score. The executive committee of the PARTNER trial reviewed all individual selection decisions and approved the classification of individuals as unsuitable for surgery. Of the total 3,105 individuals screened for aortic-valve surgery, 12 percent were included in the cohort of individuals deemed unsuitable for surgery. The primary outcome was death from any cause over the course of the trial (median follow-up 1.6 years); a co-primary endpoint was the composite of time to death from any cause or time to repeat hospitalization related to aortic stenosis or TAVR. Secondary endpoints were cardiovascular mortality, New York Heart Association (NYHA) functional class, the rate of hospitalization due to aortic stenosis or TAVR, the six-minute walk test, valve performance as measured by echocardiography, and procedural complications (MI, stroke, acute kidney injury, vascular complications, and bleeding).

A total of 358 individuals were randomized to TAVR (performed via the transfemoral approach) or usual care. Standard therapy was determined by the treating clinicians and included balloon valvuloplasty of the aortic valve in most cases (83.8 percent). A small number of individuals (6.7 percent) underwent open surgical valve replacement despite the high risk, and another 2.2 percent of individuals underwent TAVR at a center outside the US that was not participating in the trial. The mean age of enrolled individuals was 83.2 years, and there were some baseline imbalances in the individual population indicating that the standard therapy group may have had a higher severity of illness. Standardized scores of surgical risk were higher in the standard therapy group. The Logistic EuroSCORE in the standard therapy group compared to the TAVR group was (30.4+19.1 vs. 26.4+17.2, p=0.04) and the Society of Thoracic Surgery (STS) score was (12.1+6.1 vs. 11.2+5.8, p=0.14). Significantly more individuals in the standard therapy group had chronic obstructive pulmonary disease (COPD) (52.5 percent vs. 41.2 percent, p=0.04) and atrial fibrillation (48.8 percent vs. 32.9 percent, p=0.04), and there was a nonsignificant trend for more individuals in the standard therapy group having a lower ejection fraction (51.1 percent vs. 53.9 percent) and frailty, as determined by pre-specified criteria (28.0 percent vs. 18.15 percent).

At one-year follow-up, death from any cause was lower for the TAVR group (30.7 percent vs. 49.7 percent, p<0.001). This represents a 19 percent absolute risk reduction, a 38.2 percent relative risk reduction, and a number needed to treat of 5.3 to prevent one death over a one-year follow-up.

Cardiovascular death was lower in the TAVR group (19.6 percent vs. 44.1 percent, p<0.001). The composite of all-cause mortality and repeat hospitalization was reached by 42.5 percent of the individuals in the TAVR group compared with 70.4 percent in the standard therapy group. The percentage of individuals in NYHA Class I or II at one year was higher for the TAVR group (74.8 percent vs. 42.0 percent, p<0.001). The authors also reported a significant improvement in the six-minute walk test for the TAVR group but not the standard group. Subgroup analysis did not report any significant differences in outcomes according to clinical and demographic factors.

Complication rates were higher in TAVR group: stroke or transient ischemic attack (TIA) at one year was more than twice as frequent for the TAVR group (10.6 percent vs. 5 percent, p=0.04). Major bleeding and vascular complications occurred in a substantial percent of individuals undergoing TAVR and were significantly higher than the standard therapy group (22.3 percent vs. 11.2 percent, p=0.007; and 32.4 percent vs. 7.3 percent, p=0.001, respectively).

In 2012, Quality of Life (QOL) outcomes were reported by Reynolds et al for the PARTNER trial. QOL were evaluated using the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score, the Medical Outcomes study short-form 12 (SF-12), and the EuroQol (EQ-5D). The exact number of participants who completed the QOL measurement was not clearly reported; however, estimates from the graphical representation show that 149-170 individuals in the TAVR group and 138-157 individuals in the medical therapy group completed baseline QOL measurements. At the follow-up time points of 30 days, 6 months, and 12 months, the change in the QOL score was greater for the TAVR group. At 30 days, the mean difference in the KCCQ was 13.3 points (95 percent CI: 7.6-19.0 p<0.001). This mean difference increased at six months to 20.8 points (95 percent CI: 14.7-27.0, p<0.001) and 26.0 points (95 percent CI: 18.7-33.3, p<0.001) at 12 months. Similar patterns were also seen in SF-12 and EQ-5D measurements.

The two-year outcomes of the PARTNER trial reported mortality at 43.3 percent in TAVR group compared to 68.0 percent in the medical therapy group (Hazard ratio 0.58, 95 percent CI: 0.36-0.92, p=0.02). Cardiovascular mortality and rate of hospitalization were also lower in the TAVR group compared to standard therapy (31.0 percent vs. 62.4 percent, p<0.001) and (35.0 percent vs. 72.5 percent, p<0.001), respectively. Detailed mortality outcomes comparing both arms of the PARTNER trial were published by Svensson et al in 2014. The PARTNER B RCT compared open surgical repair with TAVR in prohibitive open surgical risk individuals, and the PARTNER A RCT compared open surgical repair with TAVR in high surgical risk individuals. For the 258 individuals who were considered inoperable and enrolled in the PARTNER B RCT, 237 had died at last follow-up. Those randomized to standard therapy exhibited an early peak in mortality that was higher than those randomized to TAVR and prolonged beyond six months. Compared with standard therapy, the lifetime benefit added by transfemoral TAVR was 0.50 years [90 percent CI, 0.30,0.67].

The PARTNER B trial reported a large decrease in all-cause mortality and cardiovascular mortality at one year for TAVR compared to standard therapy. The large decrease in mortality and improved QOL was also reported for the TAVR group at two-year follow-up. Baseline group differences between the TAVR group and the standard therapy group were present, indicating that the TAVR group may have been healthier. While these differences are unlikely to account for the degree of mortality benefit reported, they may have resulted in an overestimation of the mortality benefit. The TAVR group also reported increased stroke risk, as well as substantial increase in vascular complication and major bleeding. Overall generalizability of this study is also uncertain because individual selection was primarily determined by the judgment of the cardiovascular surgeons and/or cardiologists.

Transcatheter Aortic Valve Replacement for Individuals with Aortic Stenosis Who Are High-Risk Candidates for Open Surgery
The PARTNER trial reported results on individuals who were high-risk for open surgery, but still suitable candidates in June 2011. The inclusion and exclusion criteria were generally the same as for the prior cohort, except that these candidates were classified as high-risk for surgery rather than unsuitable for surgery. A predicted perioperative mortality of 15 percent or greater as determined by a cardiac surgeon and cardiologist was determined to be a high-risk individual. An STS score of 10 or greater was included as a guide for high-risk status, but an STS score threshold was not a required criterion for enrollment. Of the total 3,105 individuals screened for aortic valve surgery, 22.5 percent of these were included in the cohort of individuals deemed high-risk for surgery.

The primary hypothesis was that TAVR was non-inferior to open aortic valve replacement (AVR), using a one-sided non-inferiority boundary of 7.5 percent absolute difference in mortality at one year. A total of 699 individuals were randomized to TAVR or usual care. TAVR was performed under general anesthesia using the transfemoral approach, if possible (n=492), and through transapical approach (n=207) if the transfemoral approach was not possible. The comparison groups underwent open AVR. The primary outcome was death from any cause at one-year follow-up and the secondary powered endpoint was non-inferiority at one-year for the individuals undergoing TAVR by the transfemoral approach. Secondary endpoints were cardiovascular mortality, NYHA function class, re-hospitalizations, the six-minute walk test, valve performance as measured by echocardiography, and procedural complications (MI, stroke, acute kidney injury, vascular complications, and bleeding). The mean age of enrolled individuals was 83.6 years in the TAVR group and 84.5 years in the open AVR group. Other baseline demographics and clinical characteristics were generally well-balanced, except for a trend toward an increased percentage of individuals in the TAVR group with a creatinine level >2.0 (11.1 percent vs. 7.0 percent, p=0.06).

At one-year follow-up, death from any cause was 24.2 percent for the TAVR group compared to 26.8 percent for the open AVR group (p=0.44 for difference between groups). The upper limit of the 95 percent confidence interval (CI) for the difference between groups was a 3.0 percent excess mortality in the TAVR group, which was well within the non-inferiority boundary of 7.5 percent. Thus, the criterion of non-inferiority was met, with a p value of 0.001. Results were similar for the subgroup of individuals who underwent TAVR by the transfemoral approach with 22.2 percent mortality in the TAVR group compared with 26.4 percent mortality in the open AVR group (p=0.002 for non-inferiority). The secondary outcomes of cardiovascular mortality (14.3 percent vs. 13.0 percent, p=0.63) and rehospitalization (18.2 percent vs. 15.5 percent, p=0.38) were not significantly different for the TAVR versus open AVR groups. The percent of individuals in NYHA Class I or II was similar between groups at one year, as was the improvement in the six-minute walk test. On subgroup analysis, there was a significant effect of gender with women deriving greater benefit than men (p=0.045), and a significant effect for prior coronary artery bypass graft (CABG) with individuals who had not had prior CABG deriving greater benefit in the TAVR group.

Significant differences were observed between groups for certain complications. Stroke or TIA at one year was higher for the TAVR group compared to the open AVR group (8.3 percent vs. 4.3 percent, respectively, p=0.04). Vascular complications were higher in TAVR group than open AVR group (18 percent vs. 4.8 percent respectively, p=0.01), as were major vascular complications (11.3 percent vs. 3.5 percent, p=0.01). Major bleeding, however, was more common in the open AVR group than the TAVR group (25.7 percent vs. 14.7 percent, respectively, p=0.01).

Of the 699 individuals in the trial, 628 completed baseline QOL measures. Overall, individuals in both the TAVR and the open AVR groups demonstrated significant improvements in all QOL measures over the 12 months following treatment. Although the TAVR group reported superior improvement at one month on the KCCQ (mean difference 9.9, 95 percent CI: 4.9-14.9, p<0.001), this difference was no longer present at six months or 12 months. A similar pattern of results was also reported for the SF-12 and EQ-5D measures. Overall, for high-risk individuals who were eligible for open surgical AVR, there were no differences observed between TAVR and open AVR in terms of mortality at one year and most major secondary outcomes. The non-inferiority boundaries for this trial included an upper limit of 7.5 percent absolute increase in mortality, but in actuality the reported mortality for the TAVR group was lower than for the open AVR group. QOL was also similar at one year between the TAVR and AVR groups. Stroke or TIA were more common in the TAVR group. Other secondary outcomes were similar between groups, except for higher rates of vascular complications in the TAVR group and higher rates of major bleeding in the open surgery group. Generalizability of results is a concern because participant selection relied largely on the judgment of participating surgeons and cardiologists.

In 2012, the FDA broadened indications for TAVR to include individuals who are at high risk for surgery, as defined by an STS risk score of 8 percent or greater or judged by a Heart Team to have an operative mortality of 15 percent or greater for open surgery. The US CoreValve™ High Risk Study by Adams et al (2014) was a RCT comparing open surgical aortic valve replacement with TAVR using a self-expanding transcatheter valve prosthesis (CoreValve™ device) in individuals who had severe aortic stenosis and were considered at risk of death during surgery. A total of 795 individuals were randomized in a 1:1 ratio to TAVR with self-expanding transcatheter valve (TAVR group) to open surgical aortic-valve replacement (surgical group). For the study's primary end point, the rate of death from any cause at one year, was lower in TAVR group than in open surgical group (14.2 percent vs 19.1 percent; absolute risk reduction, 4.9; upper boundary of the 95 percent confidence interval, −0.4; P<0.001 for noninferiority; P=0.04 for superiority). At 30 days, major vascular complications occurred in 5.9 percent of the TAVR group compared with 1.7 percent of the open surgical group (p=0.003). Permanent pacemaker implantation was also significantly higher in the TAVR group as compared to the open surgical group (19.8 percent to 7.1 percent (p<0.001) respectively).

The Portico Re-sheathable Transcatheter Aortic Valve System US Investigational Device Exemption (PORTICO IDE) trial enrolled persons with severe aortic stenosis at high or extreme surgical risk. Individuals  were randomized to a Portico valve (n=381) or another FDA-approved valve (n=369). The primary efficacy endpoint was a composite of all-cause mortality and stroke at 1 year, and the primary safety endpoint was a composite of all-cause mortality, disabling stroke, life-threatening bleeding, AKI, or major vascular complications. Overall, the mean age was 83 years with females comprising 52.7% of participants. Additional demographic characteristics were not reported. The primary efficacy endpoint at 1 year was similar between groups (14.8% in the Portico group vs. 13.4% with other valves; absolute difference 1.5%; 95% CI, -3.6 to 6.5). For the composite safety endpoint at 30 days, the event rate was higher with the Portico valve (13.8% vs. 9.6%; absolute difference 4.2%; 95% CI, -0.4 to 8.8). At 2 years, the rates of death or disabling stroke were similar between groups.

Transcatheter Aortic Valve Replacement for Individuals with Aortic Stenosis Who Are Intermediate or Low Risk Risk Candidates for Open Surgery
Advancements in transcatheter valve systems and improved operator experience have led to increased use of TAVR in intermediate risk individuals. Since, the approval of transcatheter valve replacement systems for individuals who are immediate risk candidates for open surgery in August 2016, there has been an increase in clinical trials for individuals who are low risk candidates. Currently, there are two manufactures (Medtronic CoreValve (Minneapolis, MN) and Edwards LifeSciences SAPIEN 3 (Irvine, CA)) with approvals based on clinical trials to demonstrating safety and effectiveness of transcatheter aortic valve replacement in low-risk individuals. 

PARTNER 2 is an umbrella trial for several arms and comparators. In the PARTNER 2A trial, Leon et al (2016) evaluated TAVR and open surgical AVR in a multicenter, RCT involving 2032 individuals with intermediate risk (i.e., predicted risk of surgical mortality three percent or greater at 30 days, based on the STS risk score and other clinical comorbidities unmeasured by the STS risk calculator) for open surgery and severe aortic stenosis, with the mean age of 82 years. Individuals were assessed for TAVR access before randomization, with 76.3 percent suitable for transfemoral placement and 23.7 percent required transthoracic placement (transapical or transaortic access). Individuals were then randomized to TAVR using the SAPIEN™ XT valve system versus open surgical AVR, and were followed for two years. The primary end point was death from any cause or disabling stroke at two years. The hypothesis was that TAVR would not be inferior to open surgical AVR. The rate of death from any cause or disabling stroke was similar in the TAVR group and the open surgical AVR group (P=0.001 for noninferiority). At two years, the Kaplan–Meier event rates were 19.3 percent in the TAVR group and 21.1 percent in the open surgical AVR group (hazard ratio in the TAVR group, 0.89; 95 percent confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoral access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95 percent CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic access cohort, outcomes were similar in the two groups. The authors report that TAVR resulted in larger aortic-valve areas than did open surgical AVR and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation. This trial proposes to support previous findings that major clinical outcomes with TAVR appear similar to open surgical AVR, and may turn out to actually reduce mortality and morbidity in individuals in whom transfemoral approach can be used or in individuals with high risk of major bleeding.

In a second study, Thourani et al (2016) conclude that TAVR with SAPIEN™ 3 was both noninferior and superior to surgical valve replacement at one year in a propensity score analysis of 1,077 intermediate-risk individuals for the primary composite endpoint of mortality, strokes, and moderate or severe aortic regurgitation (pooled weighted proportion difference: 9.2 percent; P< 0.0001 for both). The propensity score analysis compared one-year results of this study with those from the surgical arm of PARTNER 2A. The propensity score analysis included 963 individuals treated with SAPIEN™ 3 TAVR and 747 with surgical valve replacement. Furthermore, the 30-day mortality was 80 percent lower than the STS predicted risk. The authors conclude that TAVR with SAPIEN™ 3 in intermediate-risk individuals with severe aortic stenosis is associated with low mortality, strokes, and regurgitation at one year. The propensity score analysis indicates a significant superiority for the composite outcome with TAVR compared with surgery, suggesting that TAVR may be the preferred treatment alternative in intermediate-risk individuals.

Leon et al (2016) reported on results of a multicenter noninferiority RCT (PARTNER 2A) comparing TAVI with the Edwards SAPIEN XT valve system in participants with severe aortic stenosis who were at intermediate risk for open surgery, stratified by access route (transfemoral or transthoracic).71, Eligible participants had degenerative aortic valve stenosis, with NYHA functional class II or higher, and had a STS PROM score of 4 or greater (or <4 if determined by a heart team to have an “intermediate-risk patient profile with important comorbidities not represented in the STS Risk Calculator algorithm.") The trial used a noninferiority design, with a primary composite endpoint of death from any cause or disabling stroke (score of ≥2 on the modified Rankin Scale) at 2 years and a noninferiority margin of 1.2 (ie, noninferiority was considered met if upper bound of 2-sided CI for the RR for the primary outcome was <1.2). A total of 2032 individuals were randomized to TAVI (n=1011) or surgical repair (n=1021), with 1550 considered suitable for transfemoral placement (76.3%) and 482 (23.7%) requiring transthoracic access. At baseline, the mean STS Risk Score was 5.8%; 81.3% had a score between 4% and 8%. The primary outcome results and select additional results of the trial are summarized in Table 6. Also, similar to other TAVI trials, the frequency and severity of paravalvular regurgitation was higher after TAVI than in surgical repair. The presence of paravalvular regurgitation was associated with all-cause mortality during follow-up (HR for moderate or severe paravalvular regurgitation vs. none or trace, 2.85; 95% CI, 1.57 to 5.21; p<.001). The 5 year outcomes from the PARTNER 2A study revealed no significant difference in the incidence of death from any cause or disabling stroke between the TAVI and surgical repair groups (47.9% vs. 43.4%; HR, 1.09; 95% CI, 0.95 to 1.25; p=.21).86, Overall, more participants in the TAVI group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%), experienced repeat hospitalizations (33.3% vs. 25.2%), and underwent aortic valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar between the groups.

Reardon et al (2017) published 2-year results from an RCT (SURTAVI trial) that compared clinical outcomes for 1746 participants at intermediate surgical risk randomized to TAVI or SAVR.79, For the primary outcome (composite death at 2 years), an improvement was observed in the TAVI-treated group, compared with surgery (12.6% of TAVI arm vs. 14.0% of SAVR participants [95% credible interval, -5.2% to 2.3%]; posterior probability, >.999). Rates of death, MI, and disabling stroke were comparable between groups, as were secondary outcomes that included echocardiographic measurement of aortic valve gradient and paravalvular regurgitation (data reported in the supplemental material). More individuals were assigned to the CoreValve bioprosthesis (n=724) than received Evolut R bioprosthesis (n=137), which might have affected the results; also, a considerable number of participants withdrew consent before surgery, resulting in an as-treated population of 1660. Finally, the authors acknowledged a gap in knowledge of how baseline characteristics of participants who received surgery differed from those who did not. The authors noted the low 30-day surgical mortality ratio (0.38; observed-to-expected) and the similarity of this rate between groups (2.2% of the TAVI treatment arm vs. 1.7% of surgical treatment arm).

The Nordic Aortic Valve Intervention Trial (NOTION) was the first to include all risk population (high, immediate, low surgical risk individuals) (n=280) and compared individuals with either transcatheter (TAVR) or surgical aortic valve replacement (SAVR) implants in a 1:1 ratio. All participants had severe aortic stenosis. The trials primarily evaluated death from any cause, stroke, or myocardial infraction (MI) at one year. The composite rate of death from any cause, stroke, and MI were not significantly different amongst the two groups (13.1% versus 16.3%, in TAVR and SAVR, respectively; p=0.43 for superiority). Post-procedure, the TAVR group had lower rates of major or life- threatening bleeds compared to the surgical arm (11.3% versus 20.9%, p= 0.03). NOTION was the first randomized trial to include low or immediate risk individuals; the trial failed to distinguish the variance of severity of risk amongst the participants.

Results after 5 years of follow-up were reported by Thyregod et al (2019). There were no significant differences between TAVI and SAVR in the incidence of the composite primary outcome (38.0% vs. 36.3%, p=.86) or any of the components of the composite. The incidence of moderate/severe total aortic regurgitation (8.2% vs. 0.0%, p<.001) and a new pacemaker (43.7% vs. 8.7%, p<.001) were both higher in the TAVI group. Four individuals had prosthetic re-intervention. Søndergaard et al (2019) compared the durability of TAVI versus SAVR after 6 years of follow-up from NOTION. At 6 years, the rates of all-cause mortality were similar for TAVI (42.5%) and SAVR (37.7%) individuals. The rate of moderate to severe structural valve deterioration was higher for SAVR than TAVI (24.0% vs. 4.8%; p<.001) and there were no differences in nonstructural valve deterioration (57.8% vs. 54.0%), bioprosthetic valve failure (6.7% vs. 7.5%), or endocarditis (5.9% vs. 5.8%).  At 8 years of follow-up, Jørgensen et al (2021) found no significant difference between TAVI and SAVR in the composite outcome of mortality, stroke, or MI.

Popma et al (2019) reported results of prespecified, interim analyses of the multinational Evolut Low Risk Trial, a noninferiority trial conducted from 2016 to 2018 comparing TAVI (n=734) to SAVR (n=734) in participants who had severe aortic stenosis and were at low surgical risk (STS-PROM ≤3%).  Participants with bicuspid aortic valves were excluded from the study enrollment. Participants assigned to TAVI were treated with 1 of the 3 Medtronic self-expanding, supra-annular bioprostheses (CoreValve, Evolut R, or Evolut PRO). Preliminary analyses were performed when 850 participants had reached 12-month follow-up. Long-term follow-up is scheduled to continue for 10 years. The primary outcome was a composite of death or disabling stroke at 24 months. At the time of the preliminary analysis, 149 participants had reached the 24 months visit. The 24-month estimated incidence of the primary outcome was 5.3% in the TAVI group and 6.7% in the SAVR group (RD=−1.4%; 95% Bayesian credible interval, −4.9 to 2.1; posterior probability of noninferiority >.999). Several 30-day outcomes were also reported. The incidence at 30 days of disabling stroke (0.5% vs. 1.7%), bleeding complications (2.4% vs. 7.5%), AKI (0.9% vs. 2.8%), and atrial fibrillation (7.7% vs. 35.4%) were lower in TAVI compared to SAVR. The incidence at 30 days of moderate or severe aortic regurgitation (3.5% vs. 0.5%) and pacemaker implantation (17.4% vs. 6.1%) was higher in TAVI compared to SAVR. There was not a statistically significant difference in the KCCQ overall summary score at 30 days (88.7±14.2 in the TAVI group vs. 78.6±18.9 in the SAVR group). In 2022, Forrest et al published 2-year outcomes. Follow-up data was available for 97.7% in the TAVI group and 92.3% in the SAVR group. The Kaplan-Meier estimate of all-cause mortality or disabling stroke at 2 years was 4.3% and 6.3% in the TAVI and SAVR groups, respectively (p=.084). The number of participants requiring new permanent pacemaker implantation was significantly higher with TAVI (23.8% vs. 7.0%).

Mack et al (2019) reported results of the multinational PARTNER 3 trial, randomizing participants with severe aortic stenosis and low surgical risk to either TAVI with the SAPIEN (n=503) or SAVR (n=497) in 2016 to 2017. Individuals with bicuspid aortic valves were excluded. The primary outcome was a composite of death, stroke, or rehospitalization at 1 year. Follow-up is designed to continue for at least 10 years. Primary analyses were performed and reported in the as-treated population (n=496 in the TAVI; n=454 in SAVR) but sensitivity analyses of the primary outcome performed in the intention-to-treat population with multiple imputations for missing data were reportedly consistent with the primary analysis. The number of participants that did not receive the assigned treatment was higher in the SAVR group (7 vs. 43). The most common reported reason was refusal to undergo surgery or choosing to undergo surgery at a non-trial site. The estimated incidence of the primary outcome at 1 year was significantly lower in TAVI versus SAVR (8.5% vs. 15.1%; RD, -6.6%; 95% CI, -10.8 to -2.5; p<.001 for noninferiority). All components of the composite (death, stroke, and hospitalization) individually favored TAVI at 30 days and 1 year. At 30 days, the rate of stroke (0.6% vs. 2.4%; HR, 0.25; 95% CI, 0.07 to 0.88; p =.02) and new-onset atrial fibrillation (5.0% vs. 39.5%; HR, 0.10; 95% CI, 0.06 to 0.16; p<.001) was lower in TAVI than SAVR and index hospitalization time was shorter (3 days vs. 7 days, p<.001). There were no significant differences at 30 days in major vascular complications, new permanent pacemaker insertions, or moderate or severe paravalvular regurgitation. The incidence of mild paravalvular regurgitation at 1 year was higher with TAVI (29.4% vs. 2.1%). In an analysis specific to the echocardiographic findings of the PARTNER 3 trial, Pibarot et al (2020) reported that the percentage of moderate or severe aortic regurgitation was low and not statistically different between the TAVI and SAVR groups at 30 days (0.8% vs. 0.2%; p=.38); mild aortic regurgitation occurred more frequently after TAVI than SAVR (28.8% vs. 4.2%; p<.001).87, Mean transvalvular gradient (13.7±5.6 vs. 11.6±5.0 mmHg; p=.12) and aortic valve area (1.72±0.37 vs. 1.76±0.42 cm2; p=.12) were similar between groups at 1 year. In another analysis specific to atrial fibrillation (N=781), Shahim et al (2021) found lower early postoperative atrial fibrillation in participants following TAVI compared with SAVR (19.5% vs. 36.6%; p<.0001).88,At 2-year follow-up, Leon et al (2021) reported continued improvement of the composite primary endpoint with TAVI versus SAVR (11.5% vs. 17.4%; HR, 0.63; 95% CI, 0.45 to 0.88; p=.007); however, there was no significant difference in death or stroke between TAVI and SAVR.

Toff et al (2022) published 1-year results from an investigator-initiated, publicly funded, pragmatic RCT in the United Kingdom (UK TAVI) that compared clinical outcomes for 913 participants aged ≥80 years, or aged ≥70 years with low-to-intermediate surgical risk, with severe, symptomatic aortic stenosis randomized to TAVI or SAVR. For the primary outcome (all-cause mortality at 1 year), TAVI was noninferior to SAVR (4.6% vs. 6.6%; adjusted absolute risk difference, -2.0% [1-sided 97.5% CI, -∞ to 1.2%]; p<.001) based on a prespecified margin of 5%. The adjusted hazard ratio for death from any cause was 0.69 (95% CI, 0.38 to 1.26; p=.23). No significant differences in cardiovascular deaths or strokes (fatal or nonfatal) were found between groups. While TAVI was associated with significantly shorter hospital stay and fewer major bleeding events, it was also associated with more vascular complications (p<.001), conduction disturbances requiring pacemaker implantation (p=.01), and mild or moderate aortic regurgitation (p<.001). Trial follow-up out to 5 years is planned and on-going.

Transcatheter Aortic Valve Replacement (TAVR) for Individuals with Degenerated Bio-prosthetic Valves ("Valve-In-Valve") Who Are at a High or Greater Risk Candidates for Open Surgery
Bioprosthetic valves have limited durability; the best current valves can be expected to degenerate within 10 to 20 years, resulting in stenosis or regurgitation.

TAVR is also used for the treatment of failed surgical bioprosthetic valves in the aortic position. Indications include bioprosthetic valve stenosis, regurgitation, or a combination of the two, in individuals who are at a high or greater risk for open surgical valve replacement. In March 2015 and October 2015 respectively, FDA expanded the indication for the Core™Valve system and SAPIEN™ XT transcatheter heart valve to include treatment of a failed surgical bioprosthesis (transcatheter aortic valve-in-surgical aortic valve [TAV-in-SAV] or "valve-in-valve").

The evidence comprises case series, the largest includes 459 individuals, and systematic reviews of the available case series. Relevant outcomes are overall survival, symptoms, morbid events, and treatment related mortality and morbidity. These series have reported high rates of technical success of valve implantation, but also have reported high rates of short-term complications. Reported one-year postprocedural mortality rates are often high, but high proportions of individuals have improvement in heart failure related symptoms.

Aedma et al (2022) conducted an umbrella or meta-meta-analysis evaluating the efficacy and safety of valve-in-valve (ViV) TAVI compared to redo-surgical aortic valve replacement (rSAVR).89, Nine analyses were included for review. ViV TAVI was associated with a significantly lower risk of 30-day mortality (OR, 0.60; 95% CI, 0.53 to 0.68; p<.00001) and procedural mortality (OR, 0.52; 95% CI, 0.27 to 0.98; p=.04). No significant differences in long-term mortality (1 year follow-up) or hospital readmissions were identified. ViV TAVI was also associated with a lower risk several complications, including stroke (OR, 0.71; 95% CI, 0.59 to 0.84; p<.001), major bleeding (OR, 0.44; 95% CI, 0.35 to 0.57; p<.000001), acute kidney injury (OR, 0.57; 95% CI, 0.43 to 0.75; p<.0001), and pacemaker implantation (OR, 0.67; 95% CI, 0.52 to 0.86; p<.002). No association of acute myocardial infarction with ViV TAVI and redo-SAVR was found (OR, 1.15; 95% CI, 0.84 to 1.59; p=.38); however, ViV TAVI was associated with a higher risk of vascular complications (OR, 2.70; 95% CI, 1.58 to 4.62; p<.0003).

Raschpichler et al (2022) published a systematic review and meta-analysis of nonrandomized studies comparing ViV TAVI with redo-SAVR.90, A total of 15 studies including 8881 participants were identified for analysis, which included 4458 participants (50.2%) treated with ViV TAVI and 4423 participants (49.8%) treated with redo-SAVR. Short-term mortality (<30 days) was 2.8% in participants undergoing ViV TAVI compared with 5.0% in individuals undergoing redo-SAVR (RR, 0.55; 95% CI, 0.34 to 0.91). Midterm mortality (up to 5 years) was not significantly different between groups (HR, 1.27; 95% CI, 0.72 to 2.25). The rate of acute kidney failure was lower following ViV (RR, 0.54; 95% CI, 0.33 to 0.88); however, prosthetic aortic valve regurgitation (RR, 4.18; 95% CI, 1.88 to 9.3; p=.003) and severe participant-prosthesis mismatch (RR, 3.12; 95% CI, 2.35 to 4.1; p<.001) were significantly more frequent. Additionally, the transvalvular gradient was significantly higher following ViV procedures (standard mean difference, 0.44; 95% CI, 0.15 to 0.72; p=.008). There were no significant differences between groups with respect to stroke (p=.26), myocardial infarction (p=.93), or pacemaker implantation (p=.21). The authors concluded that the early safety advantages of ViV should be weighed against a potential midterm benefit of redo-SAVR. The authors also noted that given the likely selection bias in individual studies, an adequately powered multicenter randomized trial with sufficiently long follow-up in individuals with low-to-intermediate surgical risk is warranted.

Hahn et al (2022) published 5-year follow-up outcomes from the PARTNER 2 registry. The Kaplan-Meier rates of all-cause mortality, any stroke, and all neurological events (all strokes and transient ischemic attacks) in participants with high surgical risk were 50.6%, 10.5%, and 13.8%, respectively. The incidence of structural valve deterioration, related hemodynamic valve deterioration, or bioprosthetic valve failure was 6.6%. Aortic valve re-replacement was performed in 14 participants (6.3%). Reasons for reintervention included stenosis (n=6) and combined aortic insufficiency/paravalvular regurgitation (n=3). Improvements in NYHA functional class and KCCQ overall score were maintained at 5 years. Individuals receiving a 23-mm SAPIEN XT valve were found to have a significantly increased risk of mortality compared to individuals who received a 26-mm SAPIEN XT valve (HR, 1.55; 95% CI, 1.09 to 2.20; p=.01).

In 2022, van Steenbergen et al published outcomes of ViV TAVI and redo-SAVR via a propensity score-matched analysis of data from the Netherlands Heart Registry collected between 2014 and 2018 from 16 cardiac centers. Participants with concomitant coronary procedures such as percutaneous coronary interventions or coronary artery bypass grafting were eligible for inclusion. A total of 653 high-risk participants were identified, including 374 treated with ViV TAVI and 279 with redo-SAVR; following propensity score-matching, 165 pairs were included for analysis. EuroSCORE I surgical risk was significantly higher for the ViV TAVI group compared to redo-SAVR (19.4 [IQR, 13.3 to 27.9] vs. 13.8 [IQR, 8.3 to 21.9]; p<.01). The primary endpoint of composite 30-day all-cause mortality and in-hospital postoperative stroke was not significantly different for ViV TAVI and redo-SAVR (OR, 1.30; 95% CI, 0.57 to 3.02). Additionally, no significant differences in procedural, 30-day, and 1-year all-cause mortality rates or incidence of in-hospital post-operative stroke, pacemaker implantation, and redo procedures within 1 year were identified. Study interpretation is limited by its retrospective nature, small sample size, and possible selection bias.

A subsequent time-to-event analysis of all-cause mortality in ViV TAVI versus redo-SAVR in 10 studies conducted by Sá et al (2023) similarly found a short-term protective effect with ViV TAVI in the first 44 days (HR, 0.67; 95% CI, 0.49 to 0.93; p=.017). A HR reversal was observed after 197 days favoring redo-SAVR (HR, 1.53; 95% CI, 1.22 to 1.93; p<.001). Additionally, a statistically significant association of participant-prosthesis mismatch with all-cause mortality during follow-up for ViV TAVI was identified via Cox regression modeling (p<.001).

Webb et al reported 3-year results from the PARTNER 2 valve-in-valve registry. The registry included 365 individuals who had valve-in-valve 94,95, procedures with a mean age of 79 (±10) years and mean STS-PROM score of 9.1% (±4.7). The estimated incidence of all-cause mortality at 3 years was 32.7%. Aortic valve re-replacement was performed in 1.9% by 3 years. From baseline to year 3, NYHA functional class improved; 90.4% of participants were in class III or IV at baseline and 14.1% were in class III or IV at 3 years (p<.0001). Quality of life as measured by the KCCQ overall score also increased from baseline to 3 years (43.1 to 73.1; p<.0001).

Percutaneous Closure of Paravalvular Leak of Aortic Valve

Paravalvular leak, also called paravalvular regurgitation, refers to a leak caused by a space left between natural heart tissue and the valve replacement from a previous transcatheter aortic or mitral valve replacement. This condition most often affects the mitral valve, rather than the aortic valve. Paravalvular leaks have been reported to occur in up to 25 percent of individuals following transcatheter aortic valve replacement (TAVR) compared to five percent of individuals following surgical valve replacement.

There are many studies supporting the use of percutaneous closure of a paravalvular leak of the aortic valve of varying study designs, including retrospective cohorts, prospective cohorts, case series, and registries. The body of evidence dates at least as far back as 2006, with Pate and colleagues (2006) case series of percutaneous paravalvular leak closures of both mitral and aortic valves.

Recently, Flores-Umanzor and colleagues (2023) summarized multicenter registry data from 14 hospitals in Europe and North America. Forty-five individuals were enrolled with a median age of 80 years old. There was successful percutaneous closure of a paravalvular leak of the aortic valve in 94% of participants, reducing aortic regurgitation to mild or better in 91% of participants.

Cerebral Embolic Protection During Transcatheter Aortic Valve Implantation

Cerebral embolic protection seeks to reduce the risk of stroke due to an embolization of debris from the valve or vasculature during transcatheter aortic valve implantation. There are a variety of devices (e.g., Sentinel, TriGUARD 3, ProtEmbo CPS) that either deflect or capture the emboli. The devices are removed at the end of the procedure.

The Claret Embolic Protection and TAVI (CLEAN-TAVI) trial was s single-center, blinded, RCT performed at the Heart Center at the University of Leipzig, Germany. Participants with symptomatic severe aortic stenosis were eligible for enrollment if they were considered at increased risk for open surgery. Individuals were randomized to transfemoral TAVI with the Medtronic CoreValve with (n=50) or without (n=50) CEP using the Claret Montage Dual Filter System, a precursor to the Sentinel system. The study primary endpoint was the numerical reduction in positive postprocedure diffusion-weighted MRI lesions relative to baseline at 2 days following TAVI in potentially protected territories, with a 50% reduction in the number of positive brain lesions considered clinically significant. Secondary endpoints included serial volumetric and numerical reductions in brain lesions at 2 and 7 days, in addition to serial neurological and neurocognitive assessments. The procedural success rate was 90%, defined as successful positioning and deployment of both filters in correct anatomical position, correct positioning of both filters during TAVI, and successful retrieval of both filters after TAVI. A significant reduction in both lesion number and volume was seen in potentially protected regions and in the entire brain in the CEP group at both 2 and 7 days. However, stroke incidence did not significantly differ between groups, with 5 (10%), 5 (10%), and 4 (8%) non-disabling strokes reported at 2, 7, and 30 days in both control and CEP groups. Outcomes were not stratified by baseline STS risk score. At 30 days, a lower proportion of those treated with CEP exhibited an overall worsening of National Institute of Health Stroke Scale and modified Rankin Scale scores compared to TAVI alone, whereas a higher proportion exhibited an overall worsening on the Montreal Cognitive Assessment. It is unclear whether these differences were statistically significant. Authors additionally noted that the CEP device used in the study failed to protect the left vertebral circulation and that results may not be generalizable to broader populations.

The MRI Investigation in TAVI with Claret (MISTRAl-C) multicenter, double-blind trial randomized individuals with aortic stenosis to transfemoral TAVI with (n=32) and without (n=33) CEP with the Sentinel device at 4 study sites in the Netherlands. The primary end point was the number of new cerebral lesions by diffusion-weighted MRI at 5 to 7 days after TAVI. Twenty-eight participants did not undergo a follow-up MRI for various reasons, including: implantation of a non-MRI compatible pacemaker (n=10), participant refusal (n=6), unstable clinical condition/deceased (n=5), logistical challenges (n=4), and delirium (n=3). Of the 57% of participants with a follow-up MRI available, 78% had new brain lesions. Lesions were numerically fewer with a smaller total lesion volume in CEP versus control groups (95 mm³ vs. 197 mm³, respectively). In protected brain regions, no lesions were detected in 55% and 20% in the CEP and control groups, respectively (p=.04). While changes in neurocognitive performance were not significantly different at 5 days, neurocognitive deterioration was present in 1 (4%) participant in the CEP groups compared to 6 (27%) in the control group (p=.017). Two participants had a disabling stroke in the control group compared to none in the CEP group. 

The Cerebral Protection in Transcatheter Aortic Valve Replacement SENTINEL Study was a randomized, double-blind trial comparing TAVI with and without transcatheter CEP with the Sentinel device across 19 centers in the U.S. and Germany. Individuals with severe symptomatic aortic stenosis and high surgical risk were randomized 1:1:1 into a safety arm (n=123; CEP only), a control imaging arm (n=119), and a CEP device imaging arm (n=121). Blinded diffusion-weighted MRI and neurocognitive function assessments were performed in the device and control arms, in addition to histopathologic evaluation of particulate debris from extracted CEP filters in the device arm. Post-procedure neurological evaluations were conducted at 30 and 90 days. MRI studies were conducted at baseline and 2 to 7 days to identify the formation of any new lesions. The primary safety endpoint was occurrence of MACCE at 30 days compared with a historical performance goal of 18.3% based on prior studies. MACCE was defined as all deaths, all strokes (disabling and non-disabling), and acute kidney injury (stage 3). The primary efficacy endpoint was reduction in median total new lesion volume in protected territories between the device and control arms as assessed by MRI at 2 to 7 days post-TAVI, with a pre-specified success criterion of 30% reduction. The correlation of lesion volume with neurocognitive function changes and histopathological evaluations was a prespecified secondary endpoint. While the CEP device safety cohort met the noninferiority margin for 30-day MACCE rates (p<.001), the trial failed to meet the primary effectiveness superiority endpoint. No significant differences were noted between device and control cohorts in the efficacy population for any MACCE (p=.405), all cause death (p=.65), stroke (p=.25) or acute kidney injury (p=1.00). While the CEP device efficacy cohort met the 30% prespecified treatment effect success criterion with a reduction in median total new lesion volume of 42% in protected territories, this outcome was not significantly different in device versus control arms (p =.33). Additionally, no significant differences were noted between groups for median number of new lesions in protected or all territories, (p=.90 or.81, respectively) or median total new lesion volume in all territories (p=.77). Neurocognitive testing showed no difference in overall composite scores at baseline, 30 days, or 90 days between study arms. A post hoc analysis adjusting for valve type, baseline T2/FLAIR lesion volume, and their interaction found significant reductions in new lesion volume in both protected and all territories in the device versus control arms (p=.025 and.050, respectively). Particulate debris, including acute thrombus, was found in filters from 99% of participants. The study investigators noted that the SAPIEN 3 TAVI device derived little to no benefit from CEP compared to other TAVI device types used in the trial, for reasons that are not clear. 

The SENTINEL trial formed the basis for de novo regulatory approval in the United States. The FDA Circulatory System Devices Panel of the Medical Devices Advisory Committee concluded that the device demonstrated reasonable assurance of safety, but only possible benefit for reducing peri-procedural ischemic injury to the brain. The panel agreed that while MRI evaluations of new lesion volume had limitations as a surrogate endpoint for clinical stroke, consistent capture of embolic debris is a meaningful outcome.

The Stroke PROTECTion with Sentinel During Transcatheter Aortic Valve Replacement study (PROTECTED TAVR) was an open label, randomized trial of TAVI with (n=1501) and without CEP (n=1499) with the Sentinel device conducted across 51 sites in the United States, Australia, and Europe. The primary end point was incidence of stroke within 72 hours after TAVI or before discharge. CEP device deployment was considered successful in 94.4% of participants. The incidence of the primary outcome was not significantly different between CEP and control groups (p=.30). Disabling stroke occurred in 0.5% of the participants in the CEP group and 1.3% of those in the control group, with a NNT of 125. No significant differences between CEP and control groups were observed for total deaths (0.5% vs. 0.3%), stroke, transient ischemic attack, or delirium (3.1% vs. 3.7%), or acute kidney injury (0.5% vs. 0.5%). One individual (0.1%) had a vascular complication at the CEP access site. 

The evidence related to the use of CEP devices during TAVI consists of 4 RCTs with follow-up ranging from 72 hours to 30 days. Three RCTs largely focused on the number and/or volume of new brain lesions detected on MRI. Only the CLEAN-TAVI trial found a statistically significant reduction in the number of new brain lesions with CEP; however, the relevance of this trial is limited as it used a precursor to the currently marketed Sentinel device. The largest and most recent RCT, PROTECTED TAVR, enrolled 3000 participants. In this RCT, the primary outcome, the incidence of stroke within 72 hours post-TAVI or before hospital discharge, was not significantly different between CEP and control groups. Prior trials have also generally failed to show a significant reduction in major cardiac and cerebrovascular events or neurocognitive protection. While trials enrolled participants across all surgical risk levels, outcome reporting was not stratified by risk level. The pivotal SENTINEL trial also noted that TAVI procedures performed with the SAPIEN 3 valve derived little to no benefit from CEP compared to other TAVI valves used in the trial for reasons that are unclear.

Several recent meta-analyses and systematic reviews (Caminiti et al., 2025, Mansouri et al., 2025, Shahid et al., 2025, Ismayl et al., 2025) have all concluded that CEP provides no added benefit when used in conjunction with TAVR in reducing important clinical endpoints, particularly when analyzing randomized controlled trials.

TRANSCATHETER PULMONARY VALVE (TPV) IMPLANTATION

Congenital heart disease, including tetralogy of Fallot, pulmonary atresia, and transposition of the great arteries, is generally treated by surgical repair at an early age. This involves reconstruction of the right ventricular outflow tract (RVOT) and pulmonary valve by means of a surgical homograft or a bovine derived valved conduit. These repairs are prone to development of pulmonary stenosis or regurgitation over long periods of follow-up. Because individuals with surgically corrected congenital heart disease repair are living longer into adulthood, RVOT dysfunction following initial repair has become more common. Calcification of the RVOT conduit can lead to pulmonary stenosis, while aneurysmal dilatation can result in pulmonary regurgitation.

Right ventricular outflow tract (RVOT) dysfunction can lead to decreased exercise tolerance, potentially fatal arrhythmias, and/or irreversible right ventricular dysfunction. Interventions for RVOT dysfunction often require repeat open heart surgery, resulting in numerous open heart procedures for individuals who live into adulthood. Treatment options for pulmonary stenosis are open surgery with valve replacement, balloon dilatation, or percutaneous stenting. Interventions for pulmonary regurgitation are primarily surgical, either reconstruction of the RVOT conduit or replacement of the pulmonary valve through open surgery.

Transcatheter pulmonary valve (TPV) implantation offers a potentially less invasive treatment option for individuals with prior surgery for congenital heart disease and RVOT dysfunction. It is possible that the use of less invasive valve replacement techniques can spare individuals from multiple repeat open heart procedures over long periods of follow-up.

The TPV and the valve delivery system are used together for percutaneous replacement of a dysfunctional pulmonary valve. For example, the Melody® valve consists of a section of bovine jugular vein with an intact native venous valve. The valve and surrounding tissue is sutured within a platinum-iridium stent scaffolding. The transcatheter delivery system consists of a balloon-in-balloon catheter with a retractable sheath and distal cup into which the valve is placed. The procedure is performed on the beating heart without use of cardiopulmonary bypass. The valve is first crimped to fit into the delivery system. It is introduced through the femoral vein and advanced into the right side of the heart and put into place at the site of the pulmonary valve. The inner balloon is inflated to open the artificial valve, and then the outer balloon is inflated to position the valve into place.

PEER-REVIEWED LITERATURE

In January 2010, the Melody® Transcatheter Pulmonary Valve (TPV) and the Ensemble® Transcatheter Valve Delivery System (Medtronic, Minneapolis, MN) were approved by the FDA under the Humanitarian Device Exemption (HDE) Program. Approval was for use as an adjunct to surgery in the management of pediatric and adult individuals with the following clinical conditions:

• Existence of a full (circumferential) right ventricular outflow tract (RVOT) conduit that was 16 mm or greater in diameter when originally implanted
• Dysfunctional RVOT conduits with clinical indication for intervention
• Moderate-to-severe regurgitation or stenosis (mean RVOT gradient 35 mm Hg or greater )

In January 2015, approval of the Melody® Transcatheter Pulmonary Valve (TPV) and the Ensemble® Transcatheter Valve Delivery System was amended to a premarket approval (PMA) because FDA determined that the device represents a breakthrough technology. The PMA was based, in part, on two prospective clinical studies, the Melody® TPV Long-term Follow-up Post Approval Study (PAS) and the Melody® TPV New Enrollment PAS.

The US Melody® TPV trial was a multicenter, prospective uncontrolled trial designed to assess the safety, procedural success, and short-term effectiveness of the Melody® TPV. It was the pivotal trial on which FDA approval of the Melody® valve was based. The investigators planned to follow 150 individuals over a five-year period. Eligibility criteria included a dysfunctional RVOT conduit or a dysfunctional bioprosthetic pulmonary valve, plus evidence of heart failure. For individuals with New York Heart Association (NYHA) class I heart failure, a Doppler mean gradient of 40 mm Hg or greater or severe pulmonary regurgitation was required, and for individuals with NYHA class II to IV heart failure, a mean gradient of 35 mm Hg or greater or moderate pulmonary regurgitation was required. These inclusion criteria generally were indications for pulmonary valve replacement. The primary outcomes were defined as procedural success, adverse events (AEs) from the procedure, and effectiveness, as measured by the proportion of individuals with acceptable valve function at six months.

Armstrong et al (2014) published one-year follow-up results of the Melody® TPV Long-term Follow-up PAS, a prospective study designed to evaluate the short-term hemodynamic changes following device implantation. PAS enrolled 120 individuals, 101 of whom underwent attempted TPV implantation. Subject selection was based on the criteria used in an IDE cohort trial, but did not include the age and weight (30 kg or greater) limitations. Procedure related significant AEs occurred in 16 individuals (13.3 percent of total cohort; 15.8 percent of those who had an attempted TPV implantation), the most common of which was a confined conduit tear. Procedural success occurred in 99 subjects (98 percent of those with an attempted TPV implantation). At one-year follow-up, the proportion of individuals in NYHA class I heart failure increased from 35 percent at baseline to 89 percent. Of the 99 individuals implanted for at least 24 hours, 87 had acceptable TPV hemodynamic function confirmed at six months (96.7 percent of those with evaluable echocardiographic data, 87.9 percent of entire cohort) and 82 had acceptable TPV hemodynamic function at one year (94.3 percent of those with evaluable echocardiographic data, 82.8 percent of the entire cohort). Following the procedural period, serious device related AEs occurred in eight percent, most commonly endocarditis.

Trial results have been published in other reports including Cheatham et al (2015) reported on outcomes up to seven years following TPV implantation for the 148 individuals who received and were discharged with a TPV in the US Melody® TPV trial (of 171 individuals enrolled). Of the 171 individuals enrolled, 167 underwent catheterization, 150 had a Melody® valve implanted, and 148 of those survived to discharge with the Melody® valve in place. On echocardiogram at discharge, pulmonary regurgitation was absent/trivial or mild in 140 individuals and five individuals, respectively, which represented a significant improvement from baseline. Over a median follow-up of 4.5 years (range, 0.4-7.0 years), four deaths occurred. During the follow-up period, 32 individuals required a reintervention on RVOT, 25 of which were TPV reinterventions. A total of 11 individuals required Melody® valve explantation. Among the 113 individuals who were alive and free from reintervention at a median of 4.5 years post-implantation, the most recent RVOT gradient was unchanged from early after valve implantation. Functional outcomes generally improved during the study: before TPV implantation, 14 percent of individuals were in NYHA class I and 17 percent were in class III or IV. At every post-implantation annual evaluation, at least 74 percent of individuals were in class I and no more than one-two percent were in class III or IV.

In 2015, Gillespie et al evaluated results of TPV implantation after a Ross procedure (i.e., the individual's diseased aortic valve is replaced with his or her own pulmonary valve) in a retrospective review of pooled findings from the US. Melody® TPV trial and PAS and an additional European registry, the manufacturer sponsored Melody® TPV Post-Market Surveillance Study conducted in Canada and Europe (NCT00688571). In the pooled sample (total N=358 individuals), 67 (19 percent) had a prior Ross procedure. A Melody® valve was successfully implanted in 56 (84 percent) of 67 Ross individuals who underwent catheterization with intent for TPV implantation. Six (nine percent) individuals had symptomatic coronary artery compression after TPV implantation or did not undergo implantation due to the risk of compression. Right ventricular hemodynamics generally improved after TPV implantation, but RVOT reinterventions were required in 12 of 55 individuals discharged from the implant hospitalization with the Melody® valve in place.

Jones et al (2021) reported on 10-year outcomes of the Melody IDE trial. There were 171 participants enrolled in the Melody IDE trial, and 58 of those participants completed the 10-year follow-up assessment. The primary outcome assessed was freedom from TPV dysfunction; additional outcomes were time-dependent (i.e., time to catheter reintervention, surgical RVOT reoperation, stent fracture, and death). The estimated freedom at 10 years from TPV dysfunction was 53% (95% CI, 40% to 65%) and was significantly shorter in children than in adults. The estimated freedom from mortality at 10 years was 90% (95% CI, 79% to 96%) and did not differ significantly between age groups. The estimated freedom from any TPV reintervention and freedom from RVOT reoperation were 60% (95% CI, 47% to 71%) and 79% (95% CI, 67% to 87%), respectively.

In February 2016, the SAPIEN™ XT Transcatheter Heart Valve (THV) (Pulmonic) (Edwards LifeSciences, Irvine, CA), composed of a stainless steel frame with bovine pericardial tissue leaflets, available in 23, 26, and 29 mm sizes, was approved by FDA through the PMA process for use in individuals with a dysfunctional, non-compliant RVOT conduit with a clinical indication for intervention and pulmonary regurgitation, moderate or greater and/or mean RVOT gradient 35mmHg or greater. The COMPASSION (COngenital Multicenter trial of Pulmonic vAlve regurgitation Studying the SAPIEN InterventIONal THV) trial was conducted using the SAPIEN THV, Edwards' first generation THV, which is no longer available for distribution. There were no clinical data collected on SAPIEN XT, Edwards' second generation THV, in the COMPASSION trial. However, there is extensive clinical evidence on Edwards SAPIEN XT THVs in the aortic position from the PARTNER 1 and 2 trials.

Georgieve et al (2020) investigated a database of all participants who had undergone TPVI (n=241) with the Melody valve or SPVR (n=211) between 2006 and 2018 at a European heart center. If technically possible, TPVI was preferred. Individuals with inappropriate anatomy of the coronary arteries or with large RVOTs were treated with SPVR. The median follow-up time was 5.4 years (3 months to 12.5 years). Estimated survival after 10 years was 94% in the Melody group and 92% in the SPVR group. Infective endocarditis tended to be higher with the percutaneous approach, but there was no difference in survival of the implanted pulmonary valve (TPVI: 80% vs. SPVR: 73%, p=.46). There were a number of significant differences in participant characteristics and follow-up, limiting interpretation of these results.​

Ribeiro et al (2020) performed a systematic review and meta-analysis of 18 nonrandomized comparative studies of surgical pulmonary valve replacement (SPVR) and transcutaneous pulmonary valve replacement (TPVR). No RCTs were identified. There were no significant differences in age or gender between the groups, but there were significant differences in anatomic and functional characteristics. Participants undergoing TPVR were more likely to have pulmonary stenosis (29% vs. 12%), while those undergoing SPVR were more likely to have pulmonary regurgitation (57% vs. 22%). There were large numerical differences in the presence of a native ventricle outflow tract/transannular patch (TPVR: 16%, SPVR: 60%; odds ratio [OR]: 0.20; 95% confidence interval [CI]: 0.03 to 1.31), but this difference did not achieve statistical significance. Meta-analysis suggested a reduction in peri-procedural complications (16.5% vs. 41.3%, p=.01) and length of hospital stay (-4.32 days) with the percutaneous approach, with an increased risk of infective endocarditis (5.8% vs. 2.7%, p<.001). There were no significant differences in early mortality, late mortality and need for reintervention. Interpretation is limited by the differences in baseline characteristics between the 2 groups and the possibility of selection bias. The authors noted that a number of participants underwent SPVR because they were not candidates for TPVR due to RVOT anatomy and/or other cardiac defects.

In 2021, The Harmony™ Transcatheter Pulmonary Valve (Medtronic) received breakthrough technology status. The Harmony TPV is composed of self-expanding Nitinol wire struts, a knitted polyester fabric graft, and a porcine pericardial tissue valve. This device is indicated for use in pediatric and adult individuals with severe pulmonary regurgitation (determined by echocardiography and/or pulmonary regurgitant fraction ≥ 30% by cardiac magnetic resonance imaging) who have a native or surgically-repaired right ventricular outflow tract and are clinically indicated for surgical pulmonary valve replacement.

There were 70 participants in the implanted cohort, 20 were from the feasibility phase (NCT01762124), 31 individuals were in the pivotal phase (NCT02979587) with the current TPV 22 and TPV 25 devices, and 19 were in the pivotal cohort with an earlier version (cTPV 25). Technical success was achieved in 95.7% of implantations, and the clinical endpoint of acceptable hemodynamic function without reintervention at 6 months was met in 89.2% of participants. The proportion of individuals with severe pulmonary regurgitation decreased from 84.4% at baseline to 1.7% at 6 months. Four out of 70 (5.7%), required explant of the TPV; 2 were in the feasibility phase and 2 were with a prior version of the device. There were no explants with the current devices in the pivotal study and no mortalities up to the 6 month follow-up. Quality of life, measured by the 36-item short form survey, was improved most in the areas of physical functioning and role limitations due to physical health. Five-year outcomes from the early feasibility study were published in 2021 in the form of a research letter, demonstrating sustained valve function and freedom from moderate-to-severe valve or perivalvular leak.17, There were no additional explanations beyond the 2 previously reported and no reports of endocarditis. One sudden cardiac death of unknown relatedness to the device occurred 3.5 years post-implantation.

In summary, the evidence for the use of TPV implantation consists of a systematic review, a prospective, interventional, noncomparative pivotal studies, a prospective, non-randomized study on which the device's FDA approval was based, along with a postapproval registry study and a number of additional case series. Overall, the evidence suggests that TPV implantation is associated with high rates of short-term technical success and improvements in heart failure related symptoms and hemodynamic parameters. Studies with follow-up extending to a maximum of 10 years postprocedure have suggested that the functional and hemodynamic improvements are durable, with 30 percent to 40 percent requiring reintervention on the pulmonary valve.

MITRAL VALVE TRANSCATHETER EDGE-TO-EDGE REPAIR (TEER)

Mitral regurgitation (MR) is the second most common valvular heart disease which can result from a heterogeneous set of disease processes that may affect one or more parts of the mitral valve complex. Mitral regurgitation is a common valvular heart disease that can result from either a primary structural abnormality of the mitral valve complex or a dilated left ventricle due to ischemic or dilated cardiomyopathy, which leads to secondary dilation of an anatomically normal mitral valve.

Mitral regurgitation is classified into degenerative and functional mitral valve disease. In degenerative mitral valve regurgitation, disease results from primary structural abnormality of the mitral valve complex. Common cause of degenerative mitral regurgitation (DMR) include MV prolapse syndrome with subsequent myxomatous degeneration, rheumatic heart disease, coronary artery disease, infective endocarditis and collagen vascular disease.

In functional mitral regurgitation, the primary abnormality is a dilated ventricle due to ischemic or dilated cardiomyopathy, which leads to secondary dilation of an anatomically normal mitral valve. The severity of MR is classified into mild, moderate, and severe disease on the basis of echocardiographic and/or angiographic findings (1+, 2+ and 3-4+ angiographic grade respectively).

In individuals with multiple comorbidities, surgical therapy may be underutilized. To address the unmet need for less invasive mitral valve repair, transcatheter approaches have been presented as a potential alternative to surgical therapy for MR, particularly among individuals who face prohibitively high surgical risks due to their age and comorbidities. 

 
The MitraClip® Clip Delivery System (Abbott Vascular Menolo Park, CA), which has the largest body of evidence for mitral repair, consists of implant catheters and the MitraClip device. The device, which is percutaneously deployed via a transfemoral approach, with transseptal puncture used to access the left side of the heart and the MV, is a permanent implant that attaches to the mitral valve leaflets as a treatment for reducing MR with the intended outcomes to improve recovery of the heart from overwork, improve function and potentially halt the progression of heart failure. The procedure is performed under general anesthesia via echocardiographic and fluoroscopic guidance. The heart beats normally during the procedure, and heart-lung bypass support is generally not required. The MitralClip Delivery System received FDA approval through the premarket approval process in October 24, 2013. The device received approval for treatment of significant symptomatic mitral regurgitation (MR >3+) due to primary abnormality of the mitral apparatus (DMR) in individuals who have been determined to be at prohibitive risk for mitral valve surgery by a Heart Team.

Common approaches to MV repair include direct leaflet repair (also referred to as transcatheter edge-to-edge repair),  repair of the mitral annulus via direct annuloplasty, or indirect repair based on the annulus's proximity to the coronary sinus. There are also devices in development to counteract ventricular remodeling, and systems designed for complete MV replacement via catheter. The purpose of surgical and transcatheter mitral annuloplasty is to reduce the annular circumference and obtain better coaptation of the mitral leaflets. Techniques to repair the mitral annulus include those that target the annulus itself (direct annuloplasty) and those that tighten the mitral annulus via manipulation of the adjacent coronary sinus (indirect annuloplasty). 

Devices for transcatheter mitral valve repair that use different approaches are under development for indirect annuloplasty and include the Carillon Mitral Contour System (Cardiac Dimension) and the Monarc device (Edwards Lifesciences). The CE-marked Carillon Mitral Contour System is comprised of self-expanding proximal and distal anchors connected with a nitinol bridge, with the proximal end coronary sinus ostium and the distal anchor in the great cardiac vein. The size of the connection is controlled by a manual pull back on the catheter. The Carillon system was evaluated in the Carillon Mitral Annuloplasty Device European Union Study and the follow-up Tighten the Annulus Now study (TITAN), with further studies planned. The Monarc system also involves 2 self-expanding stents connected by a nitinol bridge, with one end implanted in the coronary sinus via the internal jugular vein and the other in the great cardiac vein.  Several weeks after implantation, the biologically degradable coating over the nitinol bridge degrades, allowing the bridge to shrink and the system to shorten. It has been evaluated in the Clinical Evaluation of the Edwards Lifesciences Percutaneous Mitral Annuloplasty System for the Treatment of Mitral Regurgitation trial.

Direct annuloplasty devices include the Mitralign Percutaneous Annuloplasty System (Mitralign) and the AccuCinch® System (Guided Delivery Systems), both of which involve transcatheter placement of anchors in the MV; they are cinched or connected to narrow the mitral annulus. Other transcutaneous direct annuloplasty devices under investigation include the enCorTC™ device (MiCardia), which involves a percutaneously insertable annuloplasty ring that is adjustable using radiofrequency energy, a variation on its CE-marked enCorsq Mitral Valve Repair System, and the Cardioband Annuloplasty System (Valtech Cardio), an implantable annuloplasty band with a transfemoral venous delivery system.

Depending on individual anatomy, possible access routes to the mitral valve include transfemoral, transseptal, transapical or transthoracic approaches. The Intrepid mitral valve (Medtronic) was first studied with transapical delivery. Transthoratic exposure is a new approach with no FDA approved devices utilizing a transthoratic exposure approach. The evidence for transthoratic has consisted of case-series with small sample sizes, additional well-designed studies to evaluate the safety and effectiveness of a thansthoratic exposure are warranted before considering this approach during a transcatheter valve repair. 

PEER-REVIEWED LITERATURE

The evidence for the use of MitralClip® in individuals with severe symptomatic DMR who are considered at prohibitive risk for open surgery includes single-arm cohort studies. No RCTs have been published evaluating MitraClip in prohibitive surgical risk populations. The reported results from Endovascular Valve Edge-to-Edge Repair Study (EVEREST) II high risk registry (HRR) and Real World Expanded Multicenter Study of the MitraClip® System (REALISM) registry subset of prohibitive risk DMR individuals served as a basis for the FDA premarket approval. The EVEREST II studies included individuals from the EVEREST I feasibility study, EVEREST II RCT, the EVEREST II single arm HRR, and the REALISM Continued Access Protocol (CAP) registry that included high risk and non-high-risk enrollment. From 2003-2012, 544 individuals with ≥ 3+ DMR were prospectively enrolled in EVEREST I, EVEREST II RCT, EVEREST II HRR registry and the REALISM CAP registry. Of these 544 individuals, 141 were chosen. The charts for these 141 individuals were retrospectively reviewed by a multidisciplinary team that included two experienced mitral valve surgeons and one experienced mitral valve cardiologist for what the authors defined as prohibitive risk. The team also included echocardiographers to assess MR severity. From this group of 141 individuals, 127 met the definition of prohibitive risk and had at least one-year follow-up.

This cohort included 25 individuals from EVEREST II HRR, 98 from the REALISM CAP registry and four other individuals. This cohort of individuals had a mean age of 82 years, 87 percent New York Heart Association (NYHA) functional class III/IV, with STS score of 13.2 ± 7.3 percent. Comorbidities included congestive heart failure (125/127), coronary artery disease (95/125), cerebrovascular disease history (24/127), chronic obstructive pulmonary disease (40/127), and diabetes (38/127). Adverse events were adjudicated by an independent Clinical Events Committee.

In individuals who received the device, either one (44.1 percent) or two (51.2 percent) clips were implanted. Six individuals did not receive a device, with four of these failures due to technical reasons and the remaining two having complications during the procedure that included tamponade and hemodynamic instability. Despite being determined to be at prohibitive risk for surgery three individuals did have open surgery, with two of the three alive at one year. Adverse events at one year included 30 deaths (23.6 percent) as well as stroke (2.4 percent), renal failure (3.9 percent), bleeding complication (15.7 percent), vascular complication (7.1 percent), and gastrointestinal complication requiring surgery (2.4 percent). Most surviving individuals (82.9 percent) at one year had MR ≤ 2+ and were in NYHA functional class I or II. One-year survival appeared to be better for individuals who had 1+ or 2+ MR at discharge versus those who had 3+ or 4+. Short Form-36 health survey scores improved, and the authors reported that hospitalizations were reduced in individuals whose MR was reduced.

The authors stated that the data were limited in that it was not completely from a randomized trial, due to not having a control arm to randomize to (as medical therapy lacks a treatment role in DMR, and surgical options are not standard in prohibitive surgical risk individuals). Because the cohort was retrospectively identified, all analyses were post-hoc.

The authors concluded that MitraClip therapy is safe in individuals with severe, primary DMR for whom a Heart Team has determined that mitral valve surgery is associated with a prohibitive risk/benefit ratio. Transcatheter reduction of DMR in these individuals provides significant benefits including improvements in symptoms and functional status, a decrease in hospitalizations, and favorable left ventricular remodeling at one year.

In September 2022, the FDA approved the PASCAL Precision Transcatheter Valve Repair System through the premarket approval process for treatment of significant, symptomatic mitral regurgitation (MR ≥3+) due to primary abnormality of the mitral apparatus (degenerative MR) in individuals who have been determined to be at prohibitive risk for mitral valve surgery by a heart team . The PASCAL (PAddles Spacer Clasps ALfieri) Mitral Repair System (Edwards Lifesciences) is also a direct coaptation device and works in a similar manner to the MitraClip system. The delivery system consists of a 10-mm central spacer that attaches to the MV leaflets by 2 paddles and clasps.

An open-label head-to-head trial by Gercek et al (2021) evaluated the efficacy of the PASCAL system versus the MitraClip system in individuals with severe primary MR. During the study time frame, 38 individuals with primary MR underwent percutaneous edge-to-edge MV repair; 22 received the PASCAL device and 16 received MitraClip intervention. The decision of the device used was made at the discretion of the interventionalist. All participants were in NYHA functional class III or IV and had MR severity scores of 3+ or 4+. Procedural success was achieved in 95.5% of participants who had PASCAL implantation versus 87.5% of participants with MitraClip implantation.  86.4% of the PASCAL device group reported a residual MR severity grade <1+ was achieved, whereas, reduction to MR severity grade <1+ with MitraClip was achieved in 62.5% of individuals (p=.039). No participants in either group had any periprocedural major adverse events.

The second cohort  enrolled into the single-arm PASCAL IID registry cohort included: individuals with primary MR enrolled in the CLASP IID/IIF trial comparing PASCAL and MitraClip who were eligible for use of PASCAL but ineligible to undergo randomization due to complex mitral valve anatomy precluding use of MitraClip. Among 92 participants who underwent successful PASCAL implantation (6 individuals did not receive the device due to inability to grasp leaflets, increased transmitral valve gradient, or insufficient MR reduction), mean age was 81 years; most were male (62%) and White (73%; 3.3% were Asian and 4.3% were Black or African American). At 30-day follow-up, 8.7% of the registry cohort had experienced a major adverse event, the most common of which was severe bleeding (4.3%); at 6-month follow-up, 12% had experienced a major adverse event and all-cause mortality was 6.5%. Severity of MR was ≤2+ in 91% of participants at 6 months.

Transcatheter Mitral Valve Replacement (TMVR) for Individuals with Heart Failure and Secondary Mitral Valve Regurgitation 

The evidence for the use of MitraClip in participants with SMR consists of 2 RCTs, the COAPT and the MITRA-FR,  Both trials compared MitraClip plus medical therapy to medical therapy alone in individuals with SMR and heart failure, but they differed in their eligibility criteria and primary outcome measures. COAPT enrolled 614 participants at 78 centers in the U.S. and Canada. MITRA-FR enrolled 304 participants at 37 centers in France.

COAPT found a significant benefit for Mitraclip on the primary efficacy outcome (all HF hospitalizations within 24 months) and the primary safety outcome (freedom from device-related complications at 12 months). Improvements in MR severity, quality-of-life measures, and functional capacity persisted to 36 months in participants who received TMVR. In the final analysis of COAPT through 5-year follow-up, rates of all-cause death (hazard ratio [HR] 0.72, 95% CI 0.58 to 0.89) and cardiovascular death (HR 0.71, 95% CI 0.56 to 0.90), hospitalization for any reason (HR 0.75, 95% CI 0.63 to 0.89) and for cardiovascular reason (HR 0.64, 95% CI 0.53 to 0.77), death or hospitalization for heart failure (HR 0.53, 95% CI 0.44 to 0.64), and unplanned mitral valve intervention or surgery (HR 0.09, 95% CI 0.05 to 0.17) were significantly lower in the MitraClip arm. The 5-year rate of freedom from device-related complications was 89.2%; severe mitral stenosis was reported in 7.6% of those treated with the MitraClip, none of whom underwent surgery for severe mitral stenosis. No participants in the control group developed mitral stenosis. Crossover TMVR had been performed in 21.5%  in the control group at median 26 months after randomization; in a post hoc analysis, crossover TMVR was independently associated with lower risk of subsequent death or hospitalization for heart failure (HR 0.53, 95% CI 0.36 to 0.78).

In contrast, the MITRA-FR investigators found no significant differences between Mitra-Clip plus medical therapy and medical therapy alone on the composite primary outcome (death from any cause or unplanned HF hospitalization at 12 months) or any secondary outcome, including all-cause mortality at 12 and 24 months and cardiovascular death at 12 and 24 months.

Although the reasons for these discrepant results are not entirely clear, differences in the studies' design and conduct have been proposed as possible explanations. The severity of MR and HF among the participants in the trials differed. COAPT participants had more severe MR at baseline (effective regurgitant orifice area, 41 vs. 31 mm²) and remained symptomatic despite the use of maximal doses of guideline-directed medical therapy. In both trials, eligible participants had to be symptomatic despite the use of optimal medical therapy. In COAPT, however, a central eligibility committee confirmed that the enrollee was using maximal doses of guideline-directed medical therapy prior to enrollment, and participants who improved with medical therapy were excluded. MITRA-FR had less stringent eligibility criteria and participants had more changes in medical therapy during the trial, indicating their treatment might not have been optimized. Additionally, participants in MITRA-FR had further progressed HF as indicated by LV dilation and may have been less likely to benefit from MR treatment.

The Intrepid valve has been used to treat more than 350 enrollees as part of clinical trials. Currently, the Medtronic APOLLO Trial is evaluating the Intrepid TMVR system in individuals with severe MR with one cohort evaluating individuals with primary or secondary MR who are unsuitable for conventional mitral valve surgery or transcatheter edge-to-edge repair (TEER). A second cohort is evaluating individuals with severe symptomatic MR who are deemed ineligible for conventional mitral valve surgery with mitral annular calcification (MAC). To date, individuals enrolled in the study have received the Intrepid TMVR system using the transapical access route where the valve is compressed inside a hollow catheter and inserted between the ribs into the heart. With IDE approval, APOLLO study investigators will now have the additional option to insert the valve via an incision in the groin into the femoral vein, which has historically been the preferred approach for most transcatheter procedures.

The Intrepid TMVR system, which received Breakthrough Device Designation from FDA (for individuals unsuitable for transcatheter edge-to-edge repair or mitral valve surgery), integrates self-expanding, dual-stent technology with a replacement tissue heart valve to facilitate a catheter-based implantation. Using a delivery catheter to insert the valve into the heart, the new replacement valve is expanded directly into the malfunctioning mitral valve. The outer stent frame is designed to attach and conform to the native valve without the need for additional sutures, tethers, or anchors to secure the prosthesis. The inner stent houses the valve, which is made from bovine tissue and is intended to maintain blood flow. The Intrepid TMVR system is available for investigational use only and it is not approved for use outside of clinical studies.

Transcatheter Mitral Valve Replacement (TMVR) for Individuals with Degenerated Bio-prosthetic Valves ("Valve-In-Valve") Who Are at a High or Greater Risk Candidates for Open Surgery
Bioprosthetic, or tissue, valves can expect to last 10-20 years. For a young person with a tissue valve replacement, the need for additional surgery or another valve replacement later in life is highly likely. As the clinical utility of transcatheter mitral valve replacement procedure increases it can be expected that the need to replace degenerative valves will also increase in the future. Until recently, there was no approved device for mitral valve replacement for individuals with degenerative bio-prosthetic valves in the mitral position.

The Sapien 3 THV was approved for individuals whose own native aortic valves become narrowed by aortic stenosis. The FDA stated the Sapien 3 THV should only be used in persons who are at high or greater risk of death or serious complications from traditional open-heart surgery to replace the failed surgical tissue valve, as determined by their heart team composed of a cardiologist and surgeon. As part of the approval, the manufacturer will participate in the STS/ACC Transcatheter Valve Therapy Registry to ensure FDA surveillance for the device over the next five years.

The registry results were limited by the timing of introduction of new devices. The registry reported on data available for the SAPIEN 3 between June 23, 2015 through June 15, 2016, which created few participants utilizing this newly approved device. Follow-up data is was sparse, as 25 percent of the SAPIEN 3 cohort failed to complete the 30-day follow-up visit; limiting analysis to 48/70 individuals.

In June 2017, the FDA approved an expanded indication for the Sapien 3 Transcatheter Heart Valve (THV) for individuals with symptomatic heart disease due to failure of a previously placed bioprosthetic aortic or mitral valve whose risk of death or severe complications from repeat surgery is high or greater. An analysis of the real-world off-label use data captured in the Society of Thoracic Surgeons (STS) /American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry was performed to support the approval. The registry reported on mortality rates on date of discharge, and 30-day follow-up. 314 cases of individuals who had undergone aortic valve-in-valve procedures and 311 cases who had undergone mitral valve-in-valve procedures, of which only 70 individuals utilized the SAPIEN 3 device. Registry data showed that more than 93 percent of individuals (n=40) who underwent and had 30-day follow-up information in the mitral valve-in-valve procedures with SAPIEN 3 experienced clinically meaningful improvement in their heart failure symptoms 30-days post procedure, demonstrated by their New York Heart Association (NYHA) Classifications. The individuals in the SAPIEN 3 cohort also acknowledged an increase in quality of life according to the Kansas City Cardiomyopathy Questionnaire (KCCQ) (scale 0-100), more than doubling from the date of discharge to the 30-day follow-up. In either of the valve-in-valve procedures, the recipients observed mortality rates were substantially lower than the expected mortality rate for revision surgery.

Whisenant et al. (2020) reported on registry-based prospective cohort study of SAPIEN 3 MViV, participants enrolled in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from June 2015 to July 2019 with objective to assess contemporary outcomes of transcatheter mitral valve-in-valve (MViV) SAPIEN 3 MViV replacement. 

At present, the evidence comprises of several case studies and a few case series exist focusing on the use of mitral valve replacement with degenerated bio-prosthetic valve. 

Transcatheter Mitral Valve Implantation/Replacement

The mitral valves implantation devices under investigation are Tiara (Neovasc Inc., Richmond, Canada), Intrepid, (Medtronic, MN, United States) and Tendyne™ (Abbott, MN, United States). The Tendyne system is in ongoing clinical trials for individuals who have severe mitral annular calcification and need valve replacement but who are not candidates to have open-heart surgery. The results for the 100 first individuals included in the early feasibility study (EFS) at 1 and 2 years are promising. Initially feasible for MR, but further investigations show promising results also for implant in mitral annular calcification. To date, no dedicated TMVI systems are currently approved by the FDA; however, manufacturers of several implants have secured conditional investigational device exemption approval to allow for feasibility studies, including but not limited to:

• Tiara TMVI System (Neovasc Inc.)
• Intrepid TMVI System (Medtronic Inc.)
• Tendyne TMVI System (Abbott)

Additional feasibility studies and FDA approved devices for treatment in of transcatheter mitral valve implantation are warranted. 

Percutaneous Closure of Paravalvular Leak of Mitral Valve

Paravalvular leak, also called paravalvular regurgitation, refers to a leak caused by a space left between natural heart tissue and the valve replacement from a previous transcatheter aortic or mitral valve replacement. This condition most often affects the mitral valve, rather than the aortic valve.

Millan, et al. (2015) reported on a systematic evidence review and meta-analysis of transcatheter closure of paravalvular leaks. The investigators identified 12 clinical studies that compared successful and failed transcatheter PVL reductions in a total of 362 individuals. A Bayesian hierarchical meta-analysis was performed using cardiac mortality as a primary end point. The combined occurrence of improvement in New York Heart Association functional class or hemolytic anemia and the need for repeat surgery, were used as secondary end points. The investigators reported that a successful transcatheter PVL reduction was associated with a lower cardiac mortality rate (odds ratio [OR], 0.08; 95% credible interval [CrI], 0.01-0.90) and with a superior improvement in functional class or hemolytic anemia, compared with a failed intervention (OR, 9.95; 95% CrI, 2.10-66.73). Fewer repeat surgeries were observed after successful procedures (OR, 0.08; 95% CrI, 0.01-0.40). The investigators concluded that a successful transcatheter PVL reduction is associated with reduced all-cause mortality and improved functional class in individuals deemed unsuitable for surgical correction.

Guidelines from the American College of Cardiology (2020) state "Bioprosthetic valve dysfunction may occur because of either degeneration of the valve leaflets or valve thrombosis. Catheter-based treatment for prosthetic valve dysfunction is reasonable in selected individuals for bioprosthetic leaflet degeneration or paravalvular leak in the absence of active infection."

Guidelines from the European Association of Cardiology (Vahanian, et al., 2021) state that "Transcatheter closure of a paravalvular leak is feasible, but experience is limited and there is presently no conclusive evidence to show consistent efficacy. Transcatheter closure of paravalvular leaks should be considered for anatomically suitable paravalvular leaks in candidates selected by the Heart Team."

TRICUSPID VALVE TRANSCATHETER EDGE-TO-EDGE REPAIR (TEER) AND TRANSCATHETER TRICUSPID VALVE REPLACEMENT

TRICUSPID VALVE TRANSCATHETER EDGE-TO-EDGE REPAIR

Few individuals undergo isolated tricuspid valve surgery, which remains associated with high in-hospital mortality rates. Individuals with severe tricuspid regurgitation are often managed medically for years before tricuspid valve repair or replacement. Studies are in progress on the possibility of treating tricuspid valves with transcatheter approaches similar to those used for mitral valve disease with either a clip on the valve leaflets or an annular remodeling device.  

Tricuspid valve TEER could be proposed as an effective treatment for high surgical risk individuals who are non-responsive to optimal medical therapy.  

Bocchino et al. (2021) performed a meta-analysis to assess the pooled clinical and echocardiographic outcomes of different isolated transcatheter tricuspid valve repair strategies for moderate or greater TR in participants who were ineligible for surgery. Fourteen observational studies (n = 771) were included. At a mean follow-up of 212 days, 209 individuals (35%) were in NYHA functional class III or IV compared with 586 participants (84%) at baseline. Six-minute walking distance significantly improved by a mean 50 meters. One hundred forty-seven participants (24%) showed severe or greater TR after isolated transcatheter tricuspid valve repair compared with 616 (96%) at baseline. The included studies are at a high risk of bias due to several factors: small sample size, single-center focus, retrospective design, and/or lack of controls, randomization and blinding. Further results from prospective, randomized controlled trials are needed to confirm these findings. 

von Bardeleben et al. 2023 reported on the 2-year follow-up results and outcomes of the prospective, multicenter, international European and US, single-arm TRILUMINATE trial evaluating the safety and performance of the T-TEER using the TriClip implant. A reduction in heart failure hospitalization and general hospitalization was more pronounced at 2 years than reported previously, with 84% and 49%, respectively. TR reduction at 30 days was unchanged up to 2 years in 50% of subjects, improved in 25%. Although TR grade worsened in 25% of subjects, the majority remained at moderate or less. There was favorable remodeling of RV size and function in the setting of sustained reductions in TR, despite more variable dilatation of the tricuspid annulus and right atrium in the disease process. In this setting, all-cause (and cardiovascular) mortality was low at 30 days, 1 year, and 2 years, respectively, with 0%, 7.3%, and 18.7% (15.3%), respectively. Quality-of-life improvements and 6-minute-walk-test improvements of 60 m were sustained over 24 months. Limitations of this study include its unblinded, nonrandomized, and lack sham device design. Additionally, this arm of the TRILUMINATE trial had a limited number of participants and the investigators indicate that most of the enrolled individuals had preserved left ventricular function, limiting the generalizability of the results, which may vary among different heart failure cohorts. The authors note that further r andomized GDMT-controlled trials to establish the application of this new transcatheter repair in clinical practice are warranted and are ongoing. 

The TriClip G4 System received FDA approval through the premarket approval process on April 1, 2024. This device is indicated for improving quality of life and functional status in individuals with symptomatic severe tricuspid regurgitation despite optimal medical therapy, who are at intermediate or greater risk for surgery and in whom transcatheter edge-to-edge valve repair is clinically appropriate and is expected to reduce tricuspid regurgitation severity to moderate or less, as determined by a multidisciplinary heart team. 

TRILUMINATE,  a multicenter prospective randomized trial of percutaneous tricuspid transcatheter edge-to-edge repair (TEER) for severe tricuspid regurgitation  that was conducted in the US, Canada, and across various European countries using the TriClip device. 

In 2023, Sorajja et al reported results of the pivotal trial. Individuals with symptomatic severe regurgitation were randomly assigned in a 1:1 ratio to receive either TEER or medical therapy (control). The primary endpoint was a hierarchical composite that included death from any cause or tricuspid-valve surgery; hospitalization for heart failure; and an improvement in quality of life as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), with an improvement defined as an increase of at least 15 points in the KCCQ score (range, 0 to 100, with higher scores indicating better quality of life) at the 1-year follow-up. The severity of tricuspid regurgitation and safety were also assessed. 

A total of 350 individuals were enrolled; 175 were assigned to each group. The mean age was 78 years, and 54.9% were women. The results for the primary end point favored the TEER group (win ratio, 1.48; 95% confidence interval, 1.06 to 2.13; P=0.02). The incidence of death or tricuspid-valve surgery and the rate of hospitalization for heart failure did not appear to differ between the groups. The KCCQ quality-of-life score changed by a mean (±SD) of 12.3±1.8 points in the TEER group, as compared with 0.6±1.8 points in the control group (P<0.001). At 30 days, 87.0% of the individuals in the TEER group and 4.8% of those in the control group had tricuspid regurgitation of no greater than moderate severity (P<0.001). TEER was found to be safe; 98.3% of the individuals who underwent the procedure were free from major adverse events at 30 days. The authors concluded that tricuspid TEER was safe for individuals with severe tricuspid regurgitation, reduced the severity of tricuspid regurgitation, and was associated with an improvement in quality of life, however, the components of the primary end point showed no significant differences in all-cause mortality, need for tricuspid valve surgery, or hospitalizations for heart failure between the device and control groups. The end point was driven entirely by change in KCCQ score between the two groups.

In 2025, Kar et al. reported the 2-year outcomes of the TRILUMINATE trial. The prespecified 2-year outcomes were (1) recurrent heart failure hospitalization and (2) freedom from all-cause mortality, tricuspid valve surgery, and tricuspid valve intervention. Individuals were allowed to switch from the control arm to the intervention arm at 1 year. This crossover severely limits interpretation of the results and introduces selection bias. Nevertheless, annualized recurrent heart failure hospitalization was significantly decreased among those who were randomly assigned to the intervention arm compared to those who were randomly assigned to the control arm at 2 years. Additionally, those who were randomly assigned to the intervention arm had greater freedom from the composite all-cause mortality, tricuspid valve surgery, and tricuspid valve intervention compared to those who were randomly assigned to the control arm at 2 years. However, this result is driven primarily through tricuspid valve intervention (i.e., crossover), while all-cause mortality and tricuspid valve surgery were similar between the groups at 2 years.

Also in 2025, Donal et al. published an investigator-initiated randomized trial of TriClip in Belgium and France. The trial enrolled 300 individuals (152 randomly assigned to T-TEER and OMT, 148 randomly assigned to OMT), with very similar inclusion/exclusion criteria as the TRILUMINATE trial. The primary outcome was a composite endpoint comprised NYHA class, patient global assessment (PGA), and occurrence of major cardiovascular events (i.e., cardiovascular heart failure or death) at 1 year. Individuals were considered improved, unchanged, or worse. "Improved" required no major cardiovascular events and a favorable change in NYHA and/or PGA improved to less than 4. "Unchanged" required no major cardiovascular events and no change in NYHA and PGA. "Worse" required a major cardiovascular event, a worsened NYHA, or PGA greater than 4. Rates of improvement were statistically significantly greater among the intervention arm compared to optimal medical therapy (74.1% vs. 40.6%, respectively), primarily driven by NYHA and PGA. There were no differences in hospitalizations or cardiovascular death. Overall, the conclusions of this trial confirm the results found in the TRILUMINATE pivotal trial.

TRANSCATHETER TRICUSPID VALVE REPLACEMENT

Tricuspid valve repair/replacement surgery is associated with high mortality rates, particularly among those with comorbidities. A transcatheter approach is minimally-invasive technique that may be a potential treatment option for those with tricuspid regurgitation.

Bugan et al. (2022) performed a systematic review and meta-analysis to assess the feasibility of orthotopic transcatheter tricuspid valve replacement (TTVR) devices, echocardiographic, functional improvements, and mortality rates following replacement in individuals with significant tricuspid valve regurgitation. The efficacy and safety outcomes for transcatheter tricuspid valve replacement for significant tricuspid valve reguitation  were the improvements in New York Heart Association (NYHA) functional class, 6-minute walking distance, all-cause death, and periprocedural and long-term complications. In addition, a random-effect meta-analysis was performed comparing outcomes before and after transcatheter tricuspid valve replacement. Nine studies with 321 individuals were included in this study. The mean age was 75.8 years, and the mean European System for Cardiac Operative Risk Evaluation II score was 8.2% (95% CI: 6.1 to 10.3). Severe, massive, and torrential tricuspid valve regurgitation was diagnosed in 95% of individuals (95% CI: 89% to 98%), and 83% (95% CI: 73% to 90%) of individuals were in NYHA functional class III or IV.  At a weighted mean follow-up of 122 days, NYHA functional class (risk ratio = 0.20; 95% CI: 0.11 to 0.35; P < 0.001) and 6-minute walking distance (mean difference = 91.1 m; 95% CI: 37.3 to 144.9 m; P < 0.001) improved. The prevalence of severe or greater tricuspid valve regurgitation was reduced after transcatheter tricuspid valve replacement (baseline risk ratio= 0.19; 95% CI: 0.10 to 0.36; P < .001). In total, 28 individuals in the trial (10%; 95% CI: 6% to 17%) died. 

Pooled analyses demonstrated non-significant differences in hospital and 30-day mortality and > 30-day mortality than predicted operative mortality (risk ratio = 1.03; 95% CI: 0.41 to 2.59; P = 0.95, risk ratio = 1.39; 95% CI: 0.69 to 2.81; P = 0.35, respectively). The authors concluded that transcatheter tricuspid valve replacement could be an emerging treatment option for people with severe tricuspid regurgitation who are not eligible for transcatheter repair or surgical replacement because of high surgical risk. Limitations include a potential for bias as the analysis only included single-arm interventional studies case series, and no randomized controlled trials (RCTs). Moderate heterogeneity was found in the consistency of results. In addition, there are no specific guideline recommendations for inclusion criteria for TTVR, therefore, this meta-analysis is limited by the lack of uniformity in the definition of procedural success. Further research including randomized controlled trials with a consistent definition of procedural success are needed to determine the effectiveness of TTVR in individuals with significant tricuspid valve regurgitation.  

The Edwards EVOQUE Tricuspid Valve Replacement System received FDA approval through the premarket approval process on February 1, 2024. This device is indicated for the improvement of health status in individuals with symptomatic severe tricuspid regurgitation despite optimal medical therapy, for whom tricuspid valve replacement is deemed appropriate by a heart team. 

TRISCEND Study, which was a single-arm prospective study, underwent an interim analysis of 176 individuals who received the Edwards EVOQUE Tricuspid Valve Replacement system, discussed by Kudali et al. (2023). The inclusion criteria were individuals with greater than or equal-to moderate tricuspid regurgitation (TR) despite receiving medical therapy and who were deemed appropriate to receive a transcatheter tricuspid valve replacement by a heart team. The results of the study observed significant improvements in clinical (TR reduction, increased stroke volume and cardiac output), functional (NYHA Class improvement), and quality-of-life outcomes (Kansas City Cardiomyopathy Questionnaire [KCCQ]). The improvements were sustained for one year post replacement.

The key limitation of the study is the lack of comparison to a control, which is being completed in the TRISCEND II Pivotal Trial. Investigators also describe the need for a larger more generalizable cohort as their participant population was highly selected. The investigators also report that there was incomplete echocardiographic data, highlighting the challenges of tricuspid valve imaging. Lastly, this is an interim analysis and the not all participants had reached one-year follow-up and were not included.

Triscend II (NCT04482062)  is an ongoing prospective, multi-center, randomized controlled pivotal clinical trial to evaluate the safety and effectiveness of the EVOQUE SYstem with optimal medical therapy (OMT) compared to OMT alone in the treatment of individuals with at least severe tricuspid regurgitation. Subjects will be followed at discharge, 30 days, 3 months, 6 months and annually through 5 years.  The estimated primary completion is June 2024. An interim analysis was performed to assess safety outcomes using EVOQUE, which was included in the FDA approval. Many of the outstanding questions as result of the limitations from TRISCEND I are being investigated in TRISCEND II Pivotal Trial.

Hahn et al. (2025) published the 1-year results of the open-label TRISCEND II trial. A total of 400 individuals were randomly assigned (267 treatment; 133 control). The primary outcome was a hierarchical composite of death from any cause, implantation of a right ventricular assist device or heart transplantation, post index tricuspid-valve intervention, hospitalization for heart failure, an improvement of at least 10 points in the score on the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS), an improvement of at least one NYHA functional class, and an improvement of at least 30 minutes on the 6-minute walk distance. This outcome was analyzed by a win ratio. At 1 year, the win ratio (WR) statistically favored the treatment group (WR: 2.02, P<0.001). The authors concluded that the statistical significance was primarily driven by improvements in symptoms and quality of life, although annualized rate of hospitalization, severe bleeding, and new pacemakers were all greater in the treatment group.

In 2025, Arnold et al. analyzed the quality of life metrics of the TRISCEND II beyond that of Hahn et al. KCCQ-OS scores as a whole, and each individual domain, were significantly greater among individuals receiving the treatment compared to controls at 30 days, 6 months, and 1 year. A similar result is reiterated several times with differing statistical tests throughout the analysis. An exploratory analysis of various subgroups revealed that baseline TR severity, 6-minute walk distance, and right ventricular fractional area change had significant interaction with the treatment.

LIMITATIONS OF THE RELIABLE EVIDENCE

There are several limitations that are worth highlighting, that are consistent across both interventions.

First, the largest threat to individuals suffering from tricuspid regurgitation is mortality – of which the authors of the trials agree – which is why in the hierarchical endpoint, mortality is listed first. Mortality, obviously, is the most clinically important outcome, followed by heart failure hospitalization, and then quality of life indicators. Not only are mortality and heart failure hospitalization the most clinically relevant outcomes, but they are also far less likely to be biased. However, for both interventions, there is no objective evidence that concludes either of these endpoints are significantly reduced compared to optimal medical therapy. In fact, it is only the prone-to-biases primary endpoints that are driving the positive findings of the win-ratios. While it is encouraging to see the decrease in tricuspid regurgitation severity, which may be causing the albeit prone-to-bias quality of life indicator improvements, there is expectation (again as reinforced in the design of the study) that “hard" outcomes are of chief clinical relevance and usefulness in establishing clinical effectiveness. The Kar et al. (2025) paper tries to establish that “hard" outcomes are met at two years within the TRILUMINATE study, but this analysis is wrought with problems.

Second, while primarily a concern for tricuspid valve replacement, there is concern regarding the inducement of bradycardia following intervention. Among those in the TRISCEND study who did not require a pacemaker at baseline, and were randomized to tricuspid valve replacement, 27.8% required a pacemaker by one-year. Given the novelty of this device, there is no routine management when individuals require a tricuspid valve intervention and a pacemaker. Whether the pacemaker is pre-existing, or placed after tricuspid valve intervention, the permanent lead, or surgical passing through the valve for a leadless pacemaker, there is inherently great risk (O'Gara et al., 2025; Hain et al., 2025).

Last, it is important to consider the Centers for Medicare & Medicaid Services (CMS) coverage positions of these interventions. In 2025, CMS decided to provide coverage exclusively when an individual is enrolled in a clinical trial, which is a technique used by CMS when there is promising evidence, but insufficient evidence to provide outright coverage. This is important considering the population most likely to receive transcatheter tricuspid interventions are those in the Medicare population, as the pivotal trials themselves had mean ages of 78 and above. Some limitations of the evidence provided by CMS include (CAG-00467N, CAG-00468N):

• A lack of subgroup analysis based on tricuspid regurgitation etiology
• The lacking demonstration of an improvement in mortality and hospitalizations
• A lack of durability
• Rigorous inclusion/exclusion criteria that limits the generalizability of the results
• A lack of understanding of implant sizing based on an individual's needs

Summary

All in all, these limitations in the evidence preclude the establishment of the safety and effectiveness of transcatheter tricuspid edge-to-edge repair and transcatheter tricuspid valve replacement. Additional studies are needed that display an improvement in clinical outcomes most pertinent to the treatment of the disease, rather than quality of life indicators. While reduction in tricuspid regurgitation and improvement in quality of life scores displays potential improvementdisease state, it is expected that endpoints would consistently move in the same direction. Further publications of high-quality reliable evidence are eagerly awaited.

TRANSCATHETER CAVAL VALVE IMPLANTATION FOR TRICUSPID REGURGITATION

Transcatheter caval valve implantation involves the placement of a valve in the inferior vena cava and another valve in the superior vena cava. Though the valves are not implanted at the tricuspid valve, the hope is that these valves reduce congestion in various organs, helping the right ventricle and tricuspid valve function properly. Several devices have been used for this procedure (e.g., TricValve, Tricento, Trillium, Sapien).

The TRICUS STUDY EURO (Safety and efficacy of the TricValve® transcatheter bicaval valves system in the superior and inferior vena cava in individuals with severe tricuspid regurgitation), investigates the safety and performance in a single-arm, experimental first-in-man trial and is currently on-going.  Currently, case studies were the only available publications for evaluation. Additional publications are needed to consider transcatheter bicaval valve systems in the superior and inferior vena cava in the treatment of tricuspid regurgitation.

TRANSCATHETER TRICUSPID VALVE ANNULOPLASTY

Tricuspid annuloplasty repair has been proposed as a treatment of TR but the technology has limited safety, efficacy, and durability evidence.  The use of these technologies has been met with several challenges, including proximity to right coronary artery, larger annular size of tricuspid valve, procedural imaging limitations, lack of reproducibility, and anchor/suture detachment, a fatal flaw.