Clinical Studies Assessing Transcatheter Aortic Valve Replacement

Introduction

Degenerative aortic stenosis is the most common acquired valvular heart disease in the developed countries, affecting more than 300,000 people in the United States alone.1 Symptoms of aortic stenosis are latent until there is critical narrowing of the aortic valve that results in left ventricular hypertrophy, increased left ventricular diastolic pressure and left ventricle mass, and increased myocardial oxygen demand causing subendocardial ischemia.2 Once symptoms develop, the prognosis changes dramatically unless the aortic stenosis is corrected.2

Surgical aortic valve replacement (sAVR) is the recommended therapy for patients with symptomatic aortic stenosis. The most recent American College of Cardiology and American Heart Association (ACC/AHA) guidelines for sAVR are found in Table 1.3 It is important to note that none of these recommendations are based on evidence from large-scale, randomized clinical trials but instead rely on the expert opinion of experienced clinicians. The Society for Thoracic Surgery Predicted Risk of Mortality (STS-PROM) has been used to estimate 30-day mortality operative risk. Other surgical risk scores, such as the logistic EuroSCORE, while correlated with overall prediction of risk, are poorly calibrated to estimate precise sAVR mortality rates.4

Table 1.

ACC-AHA recommendations for surgical aortic valve replacement.3

Class	LOE	Recommendation
I	B	AVR is indicated for symptomatic patients with severe AS.
I	C	AVR is indicated for patients with severe AS undergoing coronary artery bypass graft surgery (CABG).
I	C	AVR is indicated for patients with severe AS undergoing surgery on the aorta or other heart valves.
I	C	AVR is recommended for patients with severe AS and LV systolic dysfunction (ejection fraction less than 0.50).
IIa	B	AVR is reasonable for patients with moderate AS undergoing CABG or surgery on the aorta or other heart valves.
IIb	C	AVR may be considered for asymptomatic patients with severe AS and abnormal response to exercise (e.g., development of symptoms or asymptomatic hypotension).
IIb	C	AVR may be considered for adults with severe asymptomatic AS if there is a high likelihood of rapid progression (age, calcification, and CAD) or if surgery might be delayed at the time of symptom onset.
IIb	C	AVR may be considered in patients undergoing CABG who have mild AS when there is evidence, such as moderate to severe valve calcification, that progression may be rapid.
IIb	C	AVR may be considered for asymptomatic patients with extremely severe AS (aortic valve area less than 0.6 cm2, mean gradient greater than 60 mmHg, and jet velocity greater than 5.0 m per second) when the patient’s expected operative mortality is 1.0% or less.
III	B	AVR is not useful for the prevention of sudden death in asymptomatic patients with AS who have none of the findings listed under the class IIa/IIb recommendations.

AS: aortic stenosis; AVR: aortic valve replacement; CABG: coronary artery bypass graft surgery; CAD: coronary artery disease; LOE: level of evidence; LV: left ventricular.

Many patients cannot undergo sAVR due to excessive surgical risk, including porcelain aorta,5, 6 hostile mediastinum, severe lung or liver disease, frailty, renal failure,7-9 advanced age, and prior CABG,10 among other factors,11, 12 many of which are not included in current surgical risk assessment algorithms. In patients who are deemed unsuitable for sAVR due to comorbidities, transcatheter aortic valve replacement (TAVR) has been used as an alternative to relieve symptoms and extend life. Almost 50,000 patients have been treated worldwide with one of the two commercially approved TAVR devices, including the balloon-expandable Edwards SAPIEN Transcatheter Heart Valve (Edwards LifeSciences, Irvine, California) and the self-expanding CoreValve Revalving System (Medtronic, Minneapolis, Minnesota). A number of additional transfemoral and transapical devices are under evaluation.

The purpose of this report is to review the clinical trials used to evaluate TAVR in patients who are at higher risk for sAVR. The clinical evidence base includes both prospective registries and randomized clinical trials. Future trial designs evaluating TAVR in intermediate populations will also be discussed.

Extreme-Risk or Inoperable Patients for sAVR

Early clinical evaluation of TAVR included patients deemed unsuitable for sAVR. The logistic Euroscore was the primary risk algorithm used for reporting these series, but a number of specific clinical factors, including advanced age, prior CABG, cirrhosis, pulmonary disease and pulmonary artery hypertension, right ventricular failure, or mediastinal radiation were used for inclusion of patients in TAVR studies.

Balloon-Expandable TAVR Registries and Randomized Clinical Trials

The Edwards SAPIEN Transcatheter Heart Valve consists of a trileaflet bovine pericardial valve and a balloon-expandable, stainless-steel support frame. The SAPIEN valve has undergone clinical study in the United States in 23-mm and 26-mm sizes. It is placed by means of a 22-French (Fr) or 24-Fr sheath from the femoral artery or via the transapical approach using a modified frame and larger delivery sheath. A second-generation 18-Fr RetroFlex II delivery system and a 29-mm SAPIEN XT valve are both available outside the United States and are currently undergoing US-based clinical trials through the PARTNER II study.

A number of single-center series have evaluated the outcomes of TAVR using the Edwards SAPIEN system.13 The largest of these is the SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry, which assessed the initial clinical results of TAVR in consecutive patients in Europe using the SAPIEN valve after commercialization; patients undergoing the transapical approach had a higher logistic EuroSCORE that those undergoing the transfemoral approach (29.1% versus 25.7%, respectively).14 Short-term procedural success was observed in 93.8% of patients, with reported complications including stroke (2.5%), valve embolization (0.3%), and coronary obstruction (0.6%). Thirty-day mortality was 6.3% in transfemoral patients and 10.3% in transapical patients.14 The SOURCE registry reported a total Kaplan Meier 1-year survival of 76.1% overall, with 72.1% for transapical patients and 81.1% for transfemoral patients.14 At 1 year, 73.5% of surviving patients were in New York Heart Association (NYHA) class I or II.14 The cause of late mortality was cardiac in 25.1%, noncardiac in 49.2%, and unknown in 25.7%.14 The most frequent noncardiac causes of death were due to pulmonary complications (23.9%), renal failure (12.5%), cancer (11.4%), and stroke (10.2%).14 Multivariable analysis identified logistic EuroSCORE, renal disease, liver disease, and smoking as variables with the highest hazard ratios for 1-year mortality.14

Two randomized clinical trials demonstrated the value of balloon-expandable TAVR in patients poorly suited for sAVR (Table 2). The PARTNER I-B study included 358 patients who were deemed inorperable and randomly assigned to standard therapy (including balloon aortic valvuloplasty) or transfemoral TAVR.15 The primary endpoint, 1-year all-cause mortality (Kaplan-Meier analysis), was 30.7% with TAVR and 50.7% with standard therapy (hazard ratio with TAVI: 0.55; P <0.001).15 The frequency of severe cardiac symptoms (New York Heart Association class III or IV) in 1-year survivors was lower in patients who had undergone TAVR than in those who had received standard therapy (25.2% versus 58.0%, P <0.001).15 Major strokes were higher at 30 days in patients treated with TAVR (5.0% versus 1.1% in medically-treated patients, P=0.06), and major vascular complications were also higher in patients undergoing TAVR (16.2% versus 1.1% in medically-treated patients, P <0.001).15 There was no deterioration in bioprosthetic valve functioning at 1 year, as assessed by evidence of stenosis or regurgitation on an echocardiogram.15

Table 2.

Trial design for ongoing and completed studies for TAVR.

	Definition	Trial Design	Control	Number Pts	Primary Endpoint
Extreme-Risk or “Inoperable” Patients
PARTNER I-B	>50% risk of death or irreversible morbidity at 30 days	Prospective, randomized 1:1	Medical Therapy including BAV	358	Rate of death from any cause over the duration of the trial Coprimary end point was the rate of a hierarchical composite of the time to death from any cause or the time to the first occurrence of repeat hospitalization
PARTNER II-B	>50% risk of death or irreversible morbidity at 30 days	Prospective, randomized 1:1	Medical Therapy including BAV	NR	1-year time to death, major stroke, and repeat hospitalization
US CoreValve	>50% risk of death or irreversible morbidity at 30 days	Prospective Registry	Performance Goal	487	1-year all-cause mortality and major stroke (versus performance goal)
High-Risk Surgical Patients
PARTNER I A	>15% risk of 30-day death (with STS >8)	Prospective, randomized 1:1	SAVR	699	1-year all-cause mortality
US CoreValve	>15% risk of 30-day death	Prospective, randomized 1:1	SAVR	790	1-year all-cause mortality
Intermediate-Risk Patients
PARTNER II A	STS PROM 4-8	Prospective, randomized 1:1	SAVR or SAVR-CABG	2000	2-year all-cause mortality and major stroke
SURTAVI	STS PROM >3 for OUS and >4 for US patients	Prospective, randomized 1:1	SAVR or SAVR-CABG	1200	2-year all-cause mortality and major stroke

Cohort A of the PARTNER Trial randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either transcatheter aortic valve replacement with a balloon-expandable bovine pericardial valve (using a transfemoral or transapical approach) or surgical replacement (Table 2).16 The rates of death from any cause were 3.4% in the TAVR group and 6.5% in the sAVR group at 30 days (P=0.07) and 24.2% and 26.8%, respectively, at 1 year (P=0.44), a reduction of 2.6 percentage points in the TAVR group (P=0.001 for noninferiority).16 The rates of major stroke were 3.8% in the TAVR group and 2.1% in the sAVR group at 30 days (P=0.20) and 5.1% and 2.4%, respectively, at 1 year (P=0.07). At 30 days, major vascular complications were significantly more frequent with TAVR (11.0% versus 3.2%, P <0.001); adverse events that were more frequent after sAVR included major bleeding (9.3% versus 19.5%, P <0.001) and new-onset atrial fibrillation (8.6% versus 16.0%, P=0.006).16 More patients undergoing TAVR had an improvement in symptoms at 30 days, but by 1 year there was not a significant difference between groups.16

The PARTNER II (Cohort B) Trial is designed to determine the safety and effectiveness of the Edwards 18-Fr SAPIEN XT™ device and NovaFlex delivery system in inoperable patients with symptomatic critical aortic stenosis.17 Patients will be randomized in a 2:1 fashion to the SAPIEN XT device or the SAPIEN RetroFlex III device.17 The primary noninferiority endpoints are all-cause mortality, major stroke, and repeat hospitalization at 1 year.17

Self-Expanding TAVR Registries and Randomized Clinical Trials

The Medtronic CoreValve ReValving System (Medtronic, Inc., Minneapolis, MN) consists of a trileaflet porcine pericardial valve and a self-expanding nitinol support frame. The CoreValve is available for clinical study in the United States in 23-mm, 26-mm, 29-mm, and 31-mm sizes. It is placed by means of an 18-Fr sheath from the femoral artery or subclavian (axillary) arteries or via direct aortic access.

The 18-Fr Safety and Efficacy Study included 126 patients (logistic EuroSCORE=23.4%) with severe aortic valve stenosis.18 The overall technical success rate was 83.1%, and the 30-day all-cause mortality was 15.2%.18 All-cause mortality was 38.1% at 2 years. There was a significant difference in 2-year mortality between moderate-risk and high-risk groups (27.8% versus 45.8%, respectively; P=0.04), mainly attributable to an increased risk of noncardiac mortality among patients in the high-risk groups.18 Hemodynamic results remained unchanged during follow-up (mean gradient: 8.5±2.5 mmHg at 30 days and 9.0±3.4 mmHg at 2 years).18 Functional class improved in 80% of patients and remained stable over time. There was no incidence of structural valve deterioration.

A number of national registries have been developed to evaluate the safety and efficacy of the CoreValve TAVR (Table 3).19-25 These registries have included 2,156 patients, and a preliminary meta-analysis of these registries has been reported.19-25 Although there were no consistent definitions, procedure success rates ranged from 92.6 to 98%, and 30-day mortality rates ranged from 84.9 to 92.1%.19-25

Table 3.

National registries with self-expanding CoreValve TAVR.

Registry	Age	Males, %	Logistic EuroSCORE	NYHA Class III-IV, %	Mean Gradient, mmHg	Vascular Complic, %	Stroke, %	PPM, %
Italian19	81±7.3	44	23±13.7	71.5	51.8±17	2.0	1.2	16.6
Belgian20	82±6	44	25±15	78	49±16	—	4	22.0
French21	82.5±5.9	48.5	24.7±11.2	74.6	46±15	7.5	4.5	25.7
Spanish23	78.6±6.7	45.4	16±13.9	58.4	55±14.3	5.6	0	35.2
UK22	83	52	20.3	74	—	4.0	4.3	26.0
German24	81.4±6.3	44.2	20.5±13.2	88.2	48.7±17	4.0	2.8	39.3
Australia-NZ25	82.7±7.7	59.3	18±12	84	51±16	6.5	1.9	40.0

Complic: complications; NYHA: New York Heart Association; PPM: permanent pacemaker placement; TAVR: transcatheter aortic valve replacement

The United States CoreValve Extreme Risk Pivotal Registry has completed enrollment of 487 patients deemed to have a predicted 30-day surgical mortality risk or irreversible serious morbidity risk that exceeds 50%. The primary endpoint, the combination of 1-year all-cause mortality or major stroke, will be compared with a performance goal determined from the PARTNER B study and contemporary balloon valvuloplasty registries. In addition, up to 200 patients diagnosed as extreme risk but whose iliofemoral anatomy precludes placement of an 18-Fr sheath will undergo either an axillary or direct aortic approach described below.

The CoreValve US Pivotal Trial includes 790 high-risk patients deemed to have an estimated 30-day mortality of between 10% and 15% due to the presence of comorbidities. Patients are assigned in 1:1 fashion to either TAVR or to sAVR. The primary endpoint, 1-year all-cause mortality, will assess the noninferiority of TAVR with sAVR. Up to 20% of patients can be treated using a noniliofemoral approach. Patients with significant residual coronary artery disease are excluded as coronary artery bypass surgery is allowed at the time of sAVR.

An important aspect of these studies is the inclusion of patients who are treated with an alternative noniliofemoral access route. In patients with a minimal lumen iliofemoral diameter of <6.0 mm in a noncalcified vessel and <7.0 mm in a calcified vessel, those with aneurysmal dilatation of the abdominal aorta or with prior surgical or percutaneous aneurysm repair will be treated using either the subclavian (axillary) or direct aortic approaches.26-30

The ADVANCE Registry was a prospective, multicenter, observational study in 1,015 patients undergoing TAVR with CoreValve in Europe. CoreValve implantation was performed in 996 patients. In a preliminary report of this registry, the primary endpoint, a composite of major adverse cardiac and cerebrovascular events at 30 days, occurred in 8.3% of patients, with a 30-day all-cause mortality rate of 4.3%.31

Intermediate-Risk Patients

With the noninferiority of TAVR demonstrated in patients at high-risk for sAVR, there is general interest in expanding the clinical trial portfolio to include lower-risk patients (Figure 1). An STS-PROM >4 comprises the highest 25% risk of patients currently undergoing sAVR, and an STS-PROM >3 identifies the highest 33% risk.17 Two studies have been designed to address this population of intermediate-risk patients.

Figure 1.

Spectrum of surgical risk in patients with aortic stenosis.

The PARTNER II Cohort A Trial is a noninferiority study of up to 2,000 patients with severe, symptomatic aortic valve stenosis who have an elevated risk for traditional open-heart surgery (STS-PROM ≥4).17 Patients without coronary artery disease will be randomly assigned to TAVR (SAPIEN XT) or sAVR.17 Patients with coronary artery disease will be randomly assigned to TAVR (SAPIEN XT), percutaneous coronary intervention or sAVR, and coronary artery bypass graft surgery. Those undergoing TAVR will be treated with either a transfemoral or transapical approach. The primary endpoint to be evaluated is a composite of death and major stroke at 2 years, with secondary endpoints that include valve performance and quality-of-life indicators.17

The SURgery and Transcatheter Aortic Valve Implantation (SURTAVI) trial is an international, multicenter, randomized clinical study that plans to enroll up to 2,000 patients in Europe and the United States to evaluate safety and efficacy of TAVR versus surgical AVR. The study will evaluate a broader range of patients including those with intermediate risk for undergoing sAVR. Patients outside the United States will have an STS-PROM >3, and patients enrolled in the United States will have an STS-PROM >4. Clinical centers with previous experience in TAVR will be eligible to participate in the study. SURTAVI will use a heart team approach that includes an interventional cardiologist and cardiac surgeon. The study’s primary endpoint is 2-year all-cause mortality and major stroke. Secondary endpoints include valve failure, endocarditis, and regression of the left ventricle and need for PPMI.

Continuing Evidence Development

The STS and American College of Cardiology have recommended that additional clinical study be performed to determine the value of TAVR in patients who are not included in the randomized trials and registries (Table 4).32 For the majority of patients who are poor candidates for sAVR, there is little question of the profound clinical benefit from undergoing TAVR. Implementation of a multidisciplinary team is essential for appropriate patient selection. Several complications with TAVR require careful procedural attention during the periprocedural period, including stroke,33 vascular complications, perivalvular regurgitation,34, 35 and the need for permanent pacemaker placement.36 New TAVR designs will be available to potentially lower these complication rates (Table 4). In addition, multidetector CT imaging has been very valuable in predicting the appropriate valve size and guiding vascular access.

Table 4.

STS-ACC recommendations for continued evidence development.31 STS: Society of Thoracic Surgeons; ACC: American College of Cardiology; LVEF: left ventricular ejection fraction

Clinical Condition

• Aortic valve is a congenital unicuspid or bicuspid valve; or is non-calcified.

• Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) mitral insufficiency.

• Severe ventricular dysfunction with LVEF <20.

• Renal insufficiency (Creatinine >3.0) and/or end-stage renal disease requiring chronic dialysis.

• Low-gradient low-output aortic stenosis.

• Patients who have significant associated valvular lesions that cannot be treated surgically.

Recommended Endpoints

• Mortality

• Functional improvement per NYHA functional class

• Stroke

• Other major adverse cardiovascular events

• Length of hospital stay

Based on growing evidence, TAVR is now recognized as superior to medical therapy in patients who are not suitable candidates for sAVR and equivalent for 1-year mortality in patients who are deemed high-risk for sAVR, albeit with an improved quality of life within the first 6 months. Randomized clinical trials are assessing the value of TAVR in intermediate-risk patients. Registry studies will provide increasing insight into patients with bioprosthetic valve failure (valve-in-valve), bicuspid disease, low-gradient/low-output aortic stenosis, and in other clinical subsets not currently included in randomized clinical trials.

Conflict of Interest Disclosures: All authors have completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported.

Funding/Support: Dr. Popma acknowledges receiving institutional research grants from Medtronic, Inc.