Placement of Aortic Transcatheter Valves 2A - PARTNER 2A

Oct 13, 2020
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Edwards Lifesciences
Date Presented:
09/28/2019
Date Published:
10/12/2020
Date Updated:
10/13/2020
Original Posted Date:
04/02/2016
References

Contribution To Literature:

The PARTNER 2A trial showed that TAVR is noninferior to SAVR for the primary endpoint at 2 years for the treatment of severe aortic stenosis in intermediate-risk patients (STS-PROM 4-8%; median 5.8%).

Description:

The goal of the trial was to assess the safety and efficacy of balloon-expandable transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR) in intermediate-risk patients.

Study Design

Patients were stratified in cohorts according to access route (transfemoral [76.3%] or transthoracic) and were then randomly assigned (in a 1:1 ratio) to undergo either TAVR (n = 1,011) or SAVR (n = 1,021). TAVR was performed with the balloon-expandable TAVR XT valve system.

  • Total number of enrollees: 2,032
  • Duration of follow-up: 2 years
  • Mean patient age: 81.6 years
  • Percentage female: 46%

Other salient features/characteristics:

  • Median Society of Thoracic Surgeons (STS)-PROM score: 5.8% (>5% had an STS-PROM of >10%)
  • Coronary artery disease: 68%, cardiovascular disease: 32%, peripheral artery disease: 30%
  • Oxygen-dependent chronic obstructive pulmonary disease: 3.3%
  • 5 m walk distance >7 seconds (measure of frailty): 45%
  • Left ventricular ejection fraction: 56%

Inclusion criteria:

  • Severe symptomatic aortic stenosis
  • STS PROM ≥4%. Patients with an STS risk score of <4.0% could also be enrolled if there were coexisting conditions that were not represented in the risk model
  • Heart team (including examining cardiac surgeon) agrees on eligibility including assessment that TAVR or SAVR is appropriate
  • Study patient agrees to undergo SAVR – if randomized to control treatment

Exclusion criteria:

  • Evidence of an acute myocardial infarction ≤1 month (30 days) before the intended treatment
  • Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is noncalcified
  • Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+)
  • Pre-existing mechanical or bioprosthetic valve in any position
  • Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 30 days of the index procedure (unless part of planned strategy for treatment of concomitant coronary artery disease)
  • Any patient with a balloon valvuloplasty (BAV) within 30 days of the procedure (unless BAV is a bridge to procedure after a qualifying echocardiogram)
  • Patient with planned concomitant surgical or transcatheter ablation for atrial fibrillation
  • Leukopenia (white blood cell count <3000 cell/ml), acute anemia (hemoglobin <9 g/dl), thrombocytopenia (Pit. <50,000 cell/ml)
  • Hypertrophic cardiomyopathy with or without obstruction (HOCM)
  • Severe ventricular dysfunction with left ventricular ejection fraction <20%
  • Echocardiographic evidence of intracardiac mass, thrombus, or vegetation
  • Active upper gastrointestinal bleeding within 3 months prior to procedure
  • Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic attack within 6 months of the procedure
  • Renal insufficiency (creatinine >3.0 mg/dl) and/or renal replacement therapy at the time of screening
  • Estimated life expectancy <24 months
  • Heart team assessment of inoperability
  • Complex coronary artery disease, including unprotected left main coronary artery, or SYNTAX score >32 (in the absence of prior revascularization)
  • Native aortic annulus size <18 mm or >27 mm, as measured by echocardiogram

Principal Findings:

Primary endpoint: All-cause mortality or disabling stroke for TAVR vs. SAVR at 2 years: 19.3% vs. 21.1%, p = 0.001 for noninferiority, p = 0.33 for superiority

Also at 2 years (TAVR vs. SAVR):

  • All-cause mortality: 16.7% vs. 18.0%, p = 0.45
  • Cardiovascular mortality: 10.1% vs. 11.3%, p = 0.38
  • Disabling stroke: 6.2% vs. 6.4%, p = 0.83

Secondary outcomes for TAVR vs. SAVR:

  • Intraprocedural valve embolization: 0.1% vs. 0%
  • Intensive care unit length of stay: 2 vs. 4 days, p < 0.001
  • Index length of stay: 6 vs. 9 days, p < 0.001
  • All-cause mortality at 30 days: 3.9% vs. 4.1%, p = 0.78
  • Any neurological event at 30 days: 6.4% vs. 6.5%, p = 0.94; all strokes at 30 days: 5.5% vs. 6.1%, p = 0.57
  • Major vascular complication at 30 days: 7.9% vs. 5.0%, p = 0.008
  • Life-threatening or disabling bleeding at 30 days: 10.4% vs. 43.4%, p < 0.0001
  • New atrial fibrillation at 30 days: 9.1% vs. 26.4%, p < 0.001
  • New permanent pacemaker at 30 days: 8.5% vs. 6.9%, p = 0.17
  • Rehospitalization at 2 years: 19.6% vs. 17.3%, p = 0.22
  • Aortic valve area at 2 years: 1.54 cm2 vs. 1.4 cm2, p < 0.001
  • Moderate to severe paravalvular aortic regurgitation (leak) (PVL) at 2 years:  8.0% vs. 0.6%, p < 0.001

Transfemoral access cohort: All-cause mortality or disabling stroke at 2 years for TAVR vs. SAVR: 16.8% vs. 20.4%, hazard ratio 0.79, 95% confidence interval 0.62-1.00, p = 0.05

Quality-of-life assessments: The Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score was higher for TAVR vs. SAVR at 1 month (difference = 11.4; p < 0.001), but there was no difference at 12 and 24 months. Significant interaction with access site was highest for transfemoral at 1 month (difference = 14.1, p < 0.001). Moderate or substantial improvement in KCCQ at 1 month in the transfemoral subgroup for TAVR vs. SAVR was 64.0% vs. 41.2%, p < 0.001; there was no difference at 12 months (71.1% vs. 68.9%, p > 0.05) or 24 months (67.2% vs. 66.2%, p > 0.05).

Cost-effectiveness analysis: Analysis was done using PARTNER 2A (randomized controlled trial) and PARTNER S3i (registry) data. PARTNER 2A (n = 1,938): Index hospital costs for SAVR with Sapien-XT valve vs. SAVR: $61,433 vs. 58,545, p = 0.014. Follow-up costs were lower for TAVR compared with SAVR up to 12 months, but not between 12 and 24 months; total 2-year costs were similar between the two arms ($107,716 vs. 114,132, p = 0.014). On incremental cost-effectiveness ratio (ICER) analysis, a TAVR strategy was highly cost-effective (<$50,000/QALY) 100% of the time, and cost-dominant 84% of the time.

For PARTNER S3i registry cost-effectiveness data: Index hospital costs for SAVR with Sapien-S3 valve vs. SAVR: $54,256 vs. 58,410, p < 0.001. Follow-up costs were lower for TAVR compared with SAVR up to 12 months. Total 1-year costs were lower with TAVR ($80,977 vs. $96,489, p < 0.001). On ICER analysis, a TAVR strategy was highly cost-effective (<$50,000/QALY) 100% of the time, and cost-dominant 97% of the time.

Patients with prior cardiac surgery (n = 509): Primary outcome for TAVR vs. SAVR: 15.8% vs. 17.8%, p = 0.47 (p for interaction = 0.85). All-cause mortality: 13.3% vs. 14.4%, p = 0.7; stroke: 10.2% vs. 9.0%, p = 0.71. At 30 days, major vascular complications: 2.9% vs. 9.5%, p = 0.002, life-threatening or disabling bleeding: 7.8% vs. 52.8%, p < 0.0001. For both of these outcomes, p for interaction was significant, with higher rates with TAVR compared with SAVR among patients who did not undergo prior cardiac surgery and lower rates with TAVR among those who had prior cardiac surgery.

Five-year results: The primary endpoint for TAVR vs. SAVR was 47.9% vs. 43.4% (p = 0.21). In the transfemoral subset: 44.5% vs. 42.0% (p = 0.80); in the transthoracic cohort: 59.3% vs. 48.3% (p = 0.03). Freedom from valve intervention was 96.8% vs. 99.4% (p = 0.003). Mean gradient on echocardiogram: 11.4 vs. 10.8 mm Hg (p = NS). Mild paravalvular leak (PVL): 17% vs. 3.5%, moderate to severe PVL: 4.1% vs. 0.42% (p < 0.05). Patients with moderate to severe PVL had higher long-term mortality. Quality-of-life indices were similar.

Structural valve degeneration (SVD) at 5 years: SVD was defined based on Valve Academic Research Consortium 3 (VARC 3); bioprosthetic valve failure was defined based on European and VARC 3 definitions. SVD for Sapien-XT vs. SAVR was 9.5% vs. 3.5% (HR 2.61, 95% CI 1.45-4.69; p < 0.001). SVD-related bioprosthetic valve failure (BVF) was 3.7% vs. 0.8% (HR 4.73, 95% CI 1.38-16.2, p = 0.006). All-cause BVF was 4.7% vs. 1.3% (HR 3.00, 95% CI 1.35-6.66, p = 0.004). The most common reason for re-intervention at 5 years was SVD in the TAVR arm and endocarditis in the SAVR arm.

Interpretation:

The results of this trial indicate that TAVR with the second-generation Sapien XT valve is noninferior to SAVR for the primary endpoint of mortality/disabling stroke at 2 years for the treatment of severe symptomatic aortic stenosis in intermediate-risk patients (STS PROM score 4-8%; median 5.8%). Transfemoral TAVR was possible in about 75% of the patients, and in these patients, TAVR appeared to be superior to SAVR. Vascular complications were higher in TAVR patients at 30 days, while new-onset atrial fibrillation, acute kidney injury, and bleeding were higher in the SAVR arm. Valve performance at 2 years was similar between the two strategies, although moderate to severe PVL was significantly higher in the TAVR arm at 2 years. From the patient’s perspective, transfemoral TAVR provided earlier symptomatic benefit; this was comparable to surgery at 2 years of follow-up.

Although upfront costs were higher with TAVR with both Sapien XT and S3 valves (driven by THV valve cost of ~$32,500 compared with ~$5,000 for surgical valves), a TAVR strategy saved $9-10K per patient over 1 year of follow-up, being highly cost-effective and perhaps even cost-dominant. Results between TAVR and SAVR were sustained out to 5 years, including for valve gradients; moderate to severe PVL continued to be higher with TAVR (using second-generation Sapien XT valve). SVD rates at 5 years were higher in the Sapien XT arm.

This is a landmark trial in this field and resulted in approval for intermediate-risk patients. The higher PVL rate with TAVR is an important limitation, although the Sapien device currently commercially available is the third-generation S3 valve (as compared with the second-generation XT valve studied in this trial), which has a skirt around the valve frame specifically to reduce the incidence of this complication. Further long-term data from the S3 cohort of the PARTNER 2 trial also are awaited.

References:

Pibarot P, Ternacle J, Jaber WA, et al. Structural Deterioration of Transcatheter Versus Surgical Aortic Valve Bioprostheses in the PARTNER-2 Trial. J Am Coll Cardiol 2020;76:1830-43.

Editorial Comment: Van Belle E, Delhaye C, Vincent F. Structural Valve Deterioration at 5 Years of TAVR Versus SAVR: Half Full or Half Empty? J Am Coll Cardiol 2020;76:1844-7.

Makkar RR, Thourani VH, Mack MJ, et al., on behalf of the PARTNER 2 Investigators. Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement. N Engl J Med 2020;382:799-809.

Editorial: Van Belle E. TAVR at 5 Years — Rematch or Swan Song for Surgery? N Engl J Med 2020;382:867-8.

Presented by Dr. Vinod H. Thourani at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2019), San Francisco, CA, September 28, 2019.

Chen S, Redfors B, Ben-Yehuda O, et al. Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Prior Cardiac Surgery in the Randomized PARTNER 2A Trial. JACC Cardiovasc Interv 2018;Aug 28:[Epub ahead of print].

Editorial Comment: Gössl M, Ahmed A. TAVR v SAVR – A Prior Sternotomy Is Not the Problem. JACC Cardiovasc Interv 2018;Aug 28:[Epub ahead of print].

Presented by Dr. David J. Cohen at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2017), Denver, CO, October 31, 2017.

Presented by Dr. David J. Cohen at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2016), Washington, DC, November 1, 2016.

Leon MB, Smith CR, Mack MJ, et al., on behalf of the PARTNER 2 Investigators. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374:1609-20.

Editorial: Moat NE. Will TAVR Become the Predominant Method for Treating Severe Aortic Stenosis? N Engl J Med 2016;374:1682-3.

Presented by Dr. Martin B. Leon at the American College of Cardiology Scientific Session, Chicago, IL, April 2, 2016.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and VHD, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Echocardiography/Ultrasound

Keywords: ESC18, ESC Congress, ACC Annual Scientific Session, Acute Kidney Injury, Aortic Valve Stenosis, Atrial Fibrillation, Cardiac Surgical Procedures, Coronary Artery Disease, Diabetes Mellitus, Echocardiography, Heart Valve Diseases, Peripheral Vascular Diseases, Quality of Life, Risk Assessment, Stroke, Transcatheter Aortic Valve Replacement, Transcatheter Cardiovascular Therapeutics, TCT17, TCT19


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