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CLINICAL TRIALS: Edited by Neal S. Kleiman

Recent clinical trials in valvular heart diseases

Goel, Sunny; Ro, Richard; Lerakis, Stamatios; Khera, Sahil

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Current Opinion in Cardiology: July 2020 - Volume 35 - Issue 4 - p 313-318
doi: 10.1097/HCO.0000000000000750
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Abstract

INTRODUCTION

In recent years, no other field of cardiology has experienced a greater influx of transformational therapeutic options as valvular heart disease (VHD), with the low-risk transcatheter aortic valve replacement (TAVR) trials and COAPT trial for functional mitral regurgitation leading at the forefront [1▪▪,2▪▪,3▪▪]. Positive results of the early feasibility studies of transcatheter tricuspid and pulmonic valves therapies have also impacted the clinical practice for management of these forgotten valves [4,5]. The present review is aimed at discussing recent key clinical trials in the field of valvular heart disease. 

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AORTIC VALVE

Two landmark randomized clinical trials evaluated the outcomes of TAVR versus surgical aortic valve replacement (SAVR) in patients with low surgical risk. The PARTNER 3 (The Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients with Aortic Stenosis) evaluated TAVR with SAPIEN 3 valve (Edwards Lifesciences) versus SAVR in patients with severe Aortic Stenosis (AS) and low surgical risk [1▪▪]. It was a multicenter RCT that randomized patients to TAVR (n = 503) versus SAVR (n = 497) with 1 year follow-up (mean age 73 years and mean STS 1.9%). The primary endpoint (composite of death, stroke, or rehospitalization) was tested for noninferiority and superiority in the as-treated population. At 1 year, the primary outcome in the TAVR group (8.5%) was lower when compared to the SAVR group (15.1%) with a hazard ratio of 0.54 (95% Confidence Interval (CI), 0.37--0.79; P = 0.001 for superiority), primarily driven by reduced rehospitalizations [1▪▪]. The Kaplan–Meier estimate of mortality rate was 1.0% in the TAVR group versus 2.5% in the surgery group (hazard ratio = 0.41; 95% CI, 0.14--1.17). TAVR was also associated with a lower incidence of stroke and new onset atrial fibrillation at 30 days, shorter length of stay, and greater improvement in quality of life compared to SAVR. Permanent pacemaker rate was 6.5% with TAVR versus 4.0% with SAVR, a difference that was not statistically significant. The percentage of patients with moderate or severe paravalvular regurgitation did not differ significantly between the TAVR and the SAVR groups (0.8% and none, respectively, at 30 days; 0.6 and 0.5% at 1 year). The percentage of patients with mild paravalvular regurgitation at 1 year was higher with TAVR than with SAVR (29.4 vs. 2.1%, P < 0.05) [1▪▪] Similarly, the percentage of patients with moderate or severe aortic regurgitation did not differ significantly between the TAVR and the SAVR groups (0.8 and 0.2%, respectively, at 30 days; 1.1 and 0.5% at 1 year). The percentage of patients with mild aortic regurgitation at 1 year was higher with TAVR than with surgery (30.4 vs. 5.7%, P < 0.05) [1▪▪].

Similarly, Evolut Low Risk Trial (Medtronic Evolut TAVR in Low Risk Patients) randomized patients with severe symptomatic AS to TAVR (n = 725) using a self-expandable CoreValve, Evolut R or Evolut PRO or SAVR (n = 678) [2▪▪]. The cohort's mean age was 74 years and mean STS 1.9%. The 24-month estimated incidence of primary end point (death or disabling stroke) was 5.3% in the TAVR versus 6.7% in the SAVR group, demonstrating noninferiority of TAVR [2▪▪]. At 2 years, estimated all-cause mortality was 4.5% for TAVR versus 4.5% for SAVR (P = NS). Disabling stroke remained lower in TAVR versus SAVR (1.1 vs. 3.5%) [2▪▪]. Permanent pacemaker implantation occurred in 17.4% of the patients in the TAVR group and in 6.1% in the SAVR group (difference, 11.3 percentage points; credible interval for the difference, 8.0–14.7). New-onset atrial fibrillation, acute kidney injury, and life threating or severe bleeding were higher in the SAVR arm [2▪▪]. Valve performance at 2 years was similar between the two strategies, with lower mean gradients and higher effective orifice areas seen with TAVR. However, moderate or severe total aortic regurgitation was present in 3.5% of the patients in the TAVR group and in 0.5% in the SAVR group at 30 days and 5.8% in TAVR group and none in SAVR group at 2 years. One of the major limitations was incomplete 24-month follow-up of the entire cohort. Also, similar to the PARTNER 3 trial, there was unblinded adjudication for all endpoints [2▪▪]. Furthermore, the latest-generation Evolut PRO valve, which has an outer porcine pericardial wrap at the lower 2 rows of the stent frame with the objective to decrease paravalvular leak, was used in only in quarter of the patients with TAVR, which may have contributed to the higher incidence of significant aortic regurgitation observed in TAVR group.

These two landmark trials suggest that low surgical risk patients do as well and perhaps even better with TAVR compared with SAVR in short-term follow-up and that surgical risk score is less so a deciding factor, especially in elderly patients. However, long-term follow-up is essential to understand long-term durability and structural valve degeneration. Also, young patients with bicuspid aortic valves and patients with high-risk anatomy were excluded from both these trials, thereby making the conclusions not generalizable to the overall AS population.

Despite the less thrombogenic profile of transcatheter heart valves, recent studies have reported the occurrence of subclinical leaflet thrombosis seen on multidetector computed tomography (MDCT) as a hypo-attenuating defect, termed as hypo-attenuating leaflet thickening (HALT) [6]. HALT is identified in more than 15% of patients undergoing TAVR and although its long-term effects are still unknown, observational studies have documented its resolution with oral anticoagulants [7,8]. To test these findings, GALILEO trial (Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy to an Antiplatelet-based Strategy after Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes) compared use of rivaroxaban versus clopidogrel among TAVR patients [9▪]. It was a randomized, open label trial that randomized patients after TAVR to rivaroxaban 10 mg plus aspirin 75–100 mg daily (n = 826) versus clopidogrel 75 mg plus aspirin 75–100 mg daily (n = 818). At 90 days, rivaroxaban alone was continued in the experimental group, whereas aspirin alone was continued in the control group. Total duration of follow up was 18 months with mean patient age of 80 years. Patients with atrial fibrillation, other indications for anticoagulation or contraindications to anticoagulants were excluded. SAPIEN 3 valve was used in 47% of patients and Evolut R in 25%. The trial was terminated early because of safety concerns. After a median of 17 months, the primary safety outcome (major, disabling, or life-threatening bleeding) occurred in 4.3 per 100 person-years in the rivaroxaban group versus 2.8 per 100 person-years in the clopidogrel group (P = 0.08). The primary efficacy outcome [composite of death or thromboembolic events] occurred in 9.8 per 100 person-years in the rivaroxaban group versus 7.2 per 100 person-years in the clopidogrel group (P = 0.04). All-cause mortality was 7.7% in rivaroxaban group versus 4.6% in the clopidogrel group (P = 0.009). Of note, most of the deaths in the rivaroxaban group were sudden or because of noncardiovascular causes, and a minority of the patients who died had had a bleeding event [9▪]. In addition, 37% of the patients discontinued rivaroxaban during the trial, and most deaths occurred long after drug discontinuation, which raises concerns regarding the overall trial outcome.

The imaging substudy of the main GALILEO trial, GALILEO-4D was reported simultaneously, evaluating subclinical leaflet thickening and reduced leaflet motion of bioprosthetic aortic valves [10]. GALILEO-4D enrolled a total of 231 patients at 12 sites that were involved in the main trial and were able to perform four-dimensional CT after TAVR. Patients underwent CT after a mean duration of 90 days after randomization. The primary endpoint was the percentage of patients with at least one prosthetic valve leaflet with grade 3 or higher motion reduction (i.e. involving >50% of the leaflet) – 2.1% in the rivaroxaban group versus 10.9% in the clopidogrel group. Leaflet thickening was also assessed, and the proportion of patients with at least one prosthetic leaflet with reduced leaflet motion was significantly lower with rivaroxaban. The mechanism for these unexpected findings is unknown; if a higher or lower dose of rivaroxaban would have resulted in a more favorable risk to benefit profile is also up for debate. However, it seems that the use of direct oral anticoagulants after TAVR should be refrained until more evidence is obtained and perhaps not to screen asymptomatic patients for subclinical leaflet thrombosis.

Interestingly, up to one half of patients with severe AS are asymptomatic at the time of diagnosis. Also, symptoms related to AS can be challenging to ascertain in sedentary, deconditioned, and/or elderly patients [11]. The Randomized Comparison of Early Surgery versus Conventional Treatment in Very Severe Aortic Stenosis (RECOVERY) trial evaluated long-term clinical outcomes of early SAVR (n = 73) with those of a conservative strategy (n = 72) based on current guidelines in asymptomatic patients with very severe AS (aortic-valve area of ≤0.75 cm2 with either an aortic jet velocity of ≥4.5 m per second or a mean trans-aortic gradient of ≥50 mm Hg) and a median follow up of 6.2 years [12]. The primary endpoint of death during or within 30 days after surgery (operative mortality) or death from cardiovascular causes during the entire follow-up period occurred in one patient in the early-surgery group (1%) and in 11 of 72 patients in the conservative-care group (15%) [12]. Although encouraging, these results need to be interpreted with caution and should be considered as hypothesis generating only. We will have to await the results of large, randomized studies of early TAVR for asymptomatic severe AS for further guidance, which include AVATAR (NCT02436655), EVOLVED (NCT03094143), ESTIMATE (NCT02627391), and EARLY TAVR (NCT03042104) [13–15].

MITRAL VALVE

Mitral regurgitation is the second most common valvular disorder after AS, affecting more than 2 million people in the United States annually [16]. In patients with degenerative mitral regurgitation and high or prohibitive surgical risk, percutaneous repair using MitraClip has established itself as a well tolerated alternative to surgery [17]. However, the role of MitraClip for secondary or functional MR has been questionable, considering that the cause of functional mitral regurgitation is left ventricular dysfunction and not the mitral valve itself [17]. Recently, two landmark studies evaluated the role of MitraClip in functional mitral regurgitation.

The MITRA-FR trial (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) evaluated the clinical efficacy and safety of MitraClip with medical treatment in patients with heart failure and severe functional mitral regurgitation [18▪]. It was a multicenter, randomized, open-label, controlled phase III trial that was conducted in France, which included 307 patients from 37 centers (mean age 70, 79% males) [18▪]. Patients were randomized to either MitraClip repair plus medical therapy or medical therapy alone. Patients inclusion criteria included LVEF of 15–40%, effective regurgitant orifice area (EROA) of more than 20 mm2 or regurgitant volume more than 30 cc/beat, NYHA functional class II or greater, and at least one hospitalization within the last 12 months because of heart failure [18▪]. Patients were excluded if they were considered to be candidates for surgery. Patients were followed for 12 months for primary (composite of death from any cause or unplanned hospitalization for heart failure) and secondary (individual components of the primary outcome, death from cardiovascular causes, and survival free from major adverse cardiovascular events) endpoints, as per the protocol. At 1-year follow-up, MitraClip patients showed marked improvement in MR with more than 90% of patients having a reduction to 2+ or less at 12 months, and a reduction in NYHA class relative to the baseline prior to intervention [18▪]. However, no significant difference in the primary or secondary endpoints were noted between the two groups. In the intention-to-treat analysis, the composite primary outcome occurred in 83 patients (54.6%) in the intervention group and in 78 patients (51.3%) in the control group [odds ratio (OR) = 1.16; 95% CI, 0.73–1.84; P = 0.53]. At 12 months, a total of 37 deaths (24.3%) had occurred in the intervention group and 34 (22.4%) in the control group (hazard ratio = 1.11; 95% CI, 0.69–1.77) [18▪]. The authors concluded that MitraClip was well tolerated and effective in reducing secondary mitral regurgitation, but does not improve prognosis. Recently, 2-year follow-up results of MITRA-FR were reported with similar outcomes [18▪].

The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial was a multicenter, randomized, controlled, parallel-group, open-label trial mainly based in USA and Canada, and included 614 patients from 78 centers [3▪▪]. Inclusion criteria included baseline Ejection Fraction of 20–50%, LV end-systolic dimension (LVESD) ≤70 mm, moderate-severe mitral regurgitation (3+) to severe mitral regurgitation (4+), NYHA class II–IV despite maximally tolerated medical therapy, cardiac resynchronization therapy (if appropriate) and at least one hospitalization in the past 12 months [3▪▪]. Patients were excluded if they were considered to be candidates for surgery, had hemodynamic instability, severe COPD, severe pulmonary hypertension, other valvular problems, mitral valve orifice area less than 4.0 cm2 and life expectancy less than 12 months. Enrolled patients were randomly assigned, in a 1 : 1 ratio, to undergo MitraClip to be performed within 14 days after randomization, and receive guideline directed medical therapy (device group) or to receive guideline directed medical therapy alone (control group). Crossover was not to be permitted before 2 years of follow-up [3▪▪]. Rate of hospital admissions because of heart failure through 24 months and device-related complications at 12 months were selected as the primary efficacy and safety endpoints, respectively. The mean age was 72 years and 36.0% were women. The cause of cardiomyopathy was ischemic in 60.7% of the patients and nonischemic in 39.3%. At 2-year follow-up, the device group had a significantly lower primary endpoint of heart failure hospitalizations as compared to the control group (35.8% in MitraClip group vs. 67.9% in control group (hazard ratio = 0.53; 95% CI, 0.40–0.70; P < 0.001). The number needed to treat to prevent one hospitalization for heart failure within 24 months was 3.1 (95% CI, 1.9–7.9). All-cause mortality within 24 months was significantly lower with MitraClip than with medical therapy alone (29.1 vs. 46.1%; hazard ratio = 0.62; 95% CI, 0.46–0.82; P < 0.001). The number needed to treat to save one life within 24 months was 5.9 (95% CI, 3.9–11.7). The study also showed a significant difference in all the secondary endpoints in favor of MitraClip with medical therapy, which included death or heart failure hospitalizations, cardiovascular death, need for LV assist device or heart transplant, mitral regurgitation severity at least 2% at 24 months, mean change in LV end-diastolic volume at 1 year compared with baseline, and KCCQ-OS [3▪▪]. Finally, this study demonstrated that MitraClip is a relatively well tolerated procedure, having a risk of complications of less than 4% [3▪▪]. The results remained consistent at 3-year follow up even though there was crossover of 18.6% patients from control group to device group, suggesting that benefit noted for the original MitraClip arm could be replicated in the control arm with MitraClip implantation.

The contrasting results from these two major randomized trials (MITRA-FR and COAPT) might be explained by some important observations. Patients in the COAPT trial had more severe MR relative to the severity of LV remodeling, whereas the patients enrolled in MITRA-FR had more severe LV remodeling relative to the severity of mitral regurgitation, a concept now known as disproportionate mitral regurgitation [19▪]. In COAPT trial, a very strict and thorough screening criterion was adopted, and patients who were selected for the trial were already on maximally tolerated doses of medicine and received treatment with cardiac resynchronization therapy, defibrillators, and revascularization, if appropriate [3▪▪]. Only a few major adjustments in treatment occurred during follow-up. On the other hand, in the MITRA-FR trial, patients at baseline were not medically optimized and multiple adjustments in medical treatment were allowed during follow-up, making it reflective of real world practice. The success rate of MitraClip placement and acute reduction of 2+ mitral regurgitation was higher in the COAPT trial compared to the MITRA-FR trial (95 vs. 91.9%). Also, the reduction of mitral regurgitation to a grade of 2+ or less sustained at 12 months was higher in the COAPT trial as compared to the MITRA-FR group, which may have contributed to the persistent clinical and mortality benefit.

PULMONIC VALVE

The Melody (Medtronic) valve has established its role in patients undergoing transcatheter pulmonary valve replacement with its low complication rates and good durability [20,21]. However, it is associated with relatively high rates of frame fractures, endocarditis, and has size limitations [22,23]. Based on extensive clinical experience with the SAPIEN XT valve in TAVR, its use has been expanded to treat patients with pulmonary VHD as well [24]. The COMPASSION (Congenital Multicenter Trial of Pulmonic Valve Regurgitation Studying the SAPIEN Interventional THV) study was designed to assess the safety and efficacy of the SAPIEN XT valve for the treatment of moderate to severe Pulmonary Regurgitation and/or obstruction [5]. The overall device success rate was 95.2%. At 3 years, no stent fractures were reported. Freedom from all-cause mortality was 100% at 1 year and 98.4% at 2 years of follow-up. Freedom from re-intervention was 97.1% at both 1 and 2 years and 93.7% at 3 years [5]. Freedom from major cardiovascular events at 3 years was 87.5%. Through 3 years of follow-up, no patient was classified in NYHA functional class IV, and 80.4% of patients were classified as class I. Freedom from endocarditis was 97.1% at 3 years [5].

Similarly, the Harmony Feasibility Trial reported 6-month data on the harmony pulmonic valve (Medtronic) [25]. It was a nonrandomized, prospective, multicenter study which enrolled 66 subjects with 6-month follow-up (20 patients were implanted). Median age was 25 years and patients were predominantly diagnosed with tetralogy of Fallot (95%), had severe pulmonary regurgitation (95%), and had trivial or mild stenosis [25]. Proximal migration occurred in one patient during delivery system removal. Two devices were surgically explanted. Based on the data collected during the 6-month visit, overall device integrity and functionality appeared to be well maintained in all patients [25]. Following promising results of the feasibility trial, Medtronic has begun a pivotal study to further examine the safety and efficacy of the Harmony TPV (NCT02979587).

TRICUSPID VALVE

Tricuspid regurgitation is a common VHD, affecting 5% of the elderly population and is an independent predictor of mortality when its severity reaches moderate to severe [26].

TRILUMINATE (Transcatheter edge-to-edge repair for reduction of tricuspid regurgitation) is a prospective, multicenter, single-arm study of the transcatheter TriClip using a clip-based edge-to-edge repair technique [27] being conducted at 21 sites in Europe and the USA. Patients with moderate to severe tricuspid regurgitation, NYHA class II or higher, and who were adequately treated per applicable standards were eligible for enrollment [27]. Patients were excluded if they had systolic pulmonary artery pressure of more than 60 mm Hg, a previous tricuspid valve procedure, or a cardiovascular implantable electronic device that would inhibit TriClip placement. The primary efficacy endpoint was reduction in tricuspid regurgitation severity by at least one grade at 30 days with a performance goal of 35%. The primary safety endpoint was a composite of major adverse events at 6 months, including cardiovascular mortality, myocardial infarction, stroke, new onset renal failure, endocarditis requiring surgery, and nonelective cardiovascular surgery for tricuspid valve repair system-related adverse events post procedure with a performance goal of 39%. The trial has completed enrolment and follow-up is ongoing. A total of 117 patients were screened, of which 85 were enrolled and underwent successful TriClip placement (mean age 78 years) [27]. Tricuspid regurgitation severity was reduced by at least one grade at 30 days in 71 (86%) of 83 patients who had available echocardiogram data and imaging at follow-up, greater than the prespecified performance goal (P < 0.0001). At 6 months, all-cause mortality had occurred in four (5%) of 84 patients with no periprocedural deaths, conversions to surgery, device embolization, myocardial infarctions, or stroke. This study concluded that the TriClip system was safe and effective at reducing tricuspid regurgitation [27].

TRI-REPAIR [TrIcuspid Regurgitation RePAIr with CaRdioband Transcatheter System] was a single-arm, international, multicenter, prospective trial assessing safety, and performance of the Cardioband transcatheter tricuspid valve reconstruction system for the treatment of functional tricuspid regurgitation [28]. Thirty patients were enrolled in eight European centers (mean age 75 years). Inclusion criteria was symptomatic, chronic, and moderate to severe functional tricuspid regurgitation with annular diameter at least 40 mm. Patients were excluded if they had systolic pulmonary artery pressure of more than 60 mm Hg, aortic, mitral, and/or pulmonic valve stenosis and/or regurgitation moderate or severe, a previous tricuspid valve procedure, or a cardiovascular implantable electronic device [28]. Between 6 months and baseline, echocardiography showed reductions of all tricuspid regurgitation parameters and clinical assessment demonstrated 76% of patients improved by at least 1 NYHA functional class with 88% in NYHA functional class I or II. Six-minute walk distance improved by 60 m (P < 0.01), and KCCQ score improved by 24 points (P < 0.01). The authors concluded that Cardioband appears to be well tolerated and effective in treating patients with symptomatic and moderate to severe functional tricuspid regurgitation [28].

CONCLUSION

The emergence of transcatheter therapies have changed the way we treat VHD, especially in high-risk surgical patients. New techniques are evolving and old ones are being refined further to decrease adverse events. In this review, we have summarized the important studies published on management of VHD in past 2 years, which has influenced the clinical practice.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

S.K. is a consultant for Abbott, Medtronic, and Boston Scientific, and has received speakers’ honoraria from Medtronic. All others report no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

REFERENCES

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Keywords:

MitraClip; transcatheter aortic valve replacement; trials; valvular heart diseases

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