Placement of Aortic Transcatheter Valves (Cohort B): Transfemoral TAVR vs. Medical Management | Clinical Trial - PARTNER Cohort B: Transfemoral TAVR vs. Medical Management

Oct 24, 2017
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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:
09/13/2014
Date Published:
09/27/2017
Date Updated:
10/24/2017
Original Posted Date:
09/13/2014
References

Contribution To Literature:

The PARTNER Cohort B trial showed that TAVR is superior to routine management for clinical outcomes up to 5 years for the management of patients with prohibitive surgical risk.

Description:

As many as one-third of patients with severe aortic stenosis (AS) are high-risk surgical candidates and are conservatively managed. However, nonsurgical management of symptomatic AS is associated with a median survival of about 2 years. The PARTNER trial sought to compare outcomes between standard therapy and transcatheter aortic valve replacement (TAVR) in patients with inoperable AS. TAVR is a procedure in which a bioprosthetic aortic valve is inserted through a catheter and implanted within the diseased native aortic valve.

Study Design

  • Parallel
  • Randomized

Patient Populations:

  • Severe senile degenerative native valve AS (aortic valve area <0.8 cm2, mean aortic valve gradient ≥40 mm Hg, or peak aortic jet velocity ≥4 m/sec on Doppler echocardiography)
  • NYHA class II, III, or IV symptoms
  • High-risk surgical candidates (either an STS score of ≥10%, presence of coexisting conditions that would be associated with a predicted risk of death 30 days after surgery of ≥15%, presence of coexisting conditions that would be associated with a predicted risk of death or serious comorbidity of ≥50% within 30 days of surgery)
  • Agreement between at least two cardiac surgeons that patient was not a suitable candidate for surgery
  • Number of screened applicants: 3,105
  • Number of enrollees: 358
  • Duration of follow-up: 2 years
  • Mean patient age: 83.2 years
  • Percentage female: 54%
  • Ejection fraction: 52%
  • NYHA class: II (7%), III or IV (93%)

Exclusions:

  • Unicuspid, bicuspid, or noncalcified aortic valve
  • Aortic or mitral valve regurgitation >3+
  • Substantial coronary artery disease requiring revascularization
  • LVEF <20%
  • Aortic annulus diameter <18 mm or >25 mm
  • Transient ischemic attack/stroke within the preceding 6 months
  • Acute myocardial infarction within the preceding 6 months
  • Severe renal insufficiency (serum creatinine >3.0 mg/dl, or needing chronic dialysis)
  • Any invasive therapeutic coronary procedure within 30 days (or 6 months if drug-eluting stent implantation)
  • Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe mitral annular calcification
  • White blood cell count <3000/mm3, hemoglobin <9 mg%, or platelet count <50,000/mm3
  • Bleeding diathesis or coagulopathy
  • Hemodynamic instability needing inotropic therapy or mechanical support devices
  • Need for emergent surgery for any reason
  • Hypertrophic obstructive cardiomyopathy
  • Active peptic ulcer disease or gastrointestinal bleeding within 3 months
  • Life-expectancy <12 months due to noncardiac causes
  • Significant abdominal or thoracic aortic disease
  • Iliofemoral vessel characteristics that would preclude safe placement of 22- or 24-French sheaths, such as severe calcification, severe tortuosity, or vessel diameter <7 mm (for 23 mm valve/22-French system) ,and <8 mm (for 26 mm valve/24-French system)
  • Bulky calcified aortic valve leaflets in close proximity to coronary ostia
  • Active bacterial endocarditis or other infections

Primary Endpoints:

  • All-cause mortality at 1 year
  • Hierarchical composite of all-cause mortality or time to the first occurrence of repeat hospitalization after the index procedure due to valve-related or procedure-related clinical deterioration

Secondary Endpoints:

  • Cardiovascular mortality at 1 year
  • Repeat hospitalization after the index procedure due to valve-related or procedure-related clinical deterioration
  • NYHA class at 1 year
  • Six-minute walk distance at 1 year
  • Valve performance based on echocardiographic parameters at 1 year
  • Complications at 1 year

Drug/Procedures Used:

TAVR was performed under general anesthesia, and under transesophageal echocardiographic guidance. A standard balloon aortic valvuloplasty (BAV) was initially performed, followed by transfemoral insertion of either a 22- or 24-French sheath (for a 23 or 26 mm valve, respectively). The valve itself was part of the Edwards SAPIEN heart-valve system, which consists of a trileaflet bovine pericardial valve mounted on a balloon-expandable, stainless steel support frame. This system was advanced across the native aortic valve. The valve and support frame were then balloon expanded across the native valve during rapid ventricular pacing. Standard therapy consisted of medical management and BAV alone if deemed necessary.

Concomitant Medications:

All patients undergoing TAVR received heparin during the procedure, and dual antiplatelet therapy consisting of aspirin and clopidogrel for 6 months after the procedure.

Principal Findings:

Of the more than 3,000 patients with severe AS who were screened, a total of 358 patients (12%) were randomized across 21 sites, 179 to TAVR, and 179 to standard therapy. Baseline characteristics were fairly similar between the two arms. The mean Society of Thoracic Surgeons (STS) score was 11.6%, with a corresponding mean logistic EuroSCORE of 28.4. Other conditions contributing to a high-risk designation included heavily calcified (“porcelain”) aorta in 15.1%, chest wall deformity or irradiation (13.1%), oxygen-dependent respiratory insufficiency (23.5%), and frailty based on prespecified criteria (23.1%).

About 93% of the patients had New York Heart Association (NYHA) class III or IV symptoms, with a mean aortic valve area of 0.6 cm2, and a mean aortic valve gradient of 44 mm Hg. The mean left ventricular ejection fraction (LVEF) was 52%, with moderate to severe mitral regurgitation present in about 23% of the patients. Pulmonary hypertension was present in about 43% of the patients. Coexisting coronary artery disease was noted in about 71% of the patients, with 41% having undergone prior coronary artery bypass grafting, and 27% prior percutaneous coronary intervention. About 20% of patients had undergone BAV at some point prior to randomization.

30-day and 1-year outcomes: There was no difference in 30-day mortality between the TAVR and standard therapy arms (5.0% vs. 2.8%, p = 0.41). However, at 1 year, the primary endpoint of all-cause mortality was significantly lower in the TAVR arm (30.7% vs. 50.7%, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.40-0.74, p < 0.001). Other outcomes such as cardiovascular death at 1 year (20.5% vs. 44.6%, HR 0.39, 95% CI 0.27-0.56, p < 0.001) and death or rehospitalization at 1 year (42.5% vs. 71.6%, HR 0.46, 95% CI 0.35-0.59, p < 0.001) were also lower in the TAVR arm. Major strokes at 30 days (5.0% vs. 1.1%, p = 0.06) and at 1 year (7.8% vs. 3.9%, p = 0.18) were numerically higher in the TAVR arm. Major vascular complications were significantly higher in the TAVR arm, both at 30 days (16.2% vs. 1.1, p < 0.001) and at 1 year (16.8% vs. 2.2%, p < 0.001). Similarly, major bleeding was higher in the TAVR arm at 30 days (16.8% vs. 3.9%, p < 0.001) and at 1 year (22.3% vs. 11.2%, p = 0.007).

Other complications such as acute kidney injury, endocarditis, and new pacemaker requirement were similar between the two arms. BAV was necessary in 36.9% of the patients in the standard therapy arm over 1 year of follow-up, whereas repeat TAVR was necessary in three (1.7%) patients in that time frame.

Echocardiographic parameters such aortic valve area (0.6-1.5 cm2) and mean aortic valve gradient (44.5-11.1 mm Hg) showed significant improvement in the TAVR arm at 30 days (p < 0.001 for both). Moderate or severe paravalvular and valvular aortic regurgitation were noted in 11.8% and 1.3% of the patients at 30 days, respectively, in the TAVR arm. NYHA class demonstrated significant improvements in the TAVR arm at 30 days and at 1 year, as compared with the standard therapy arm (p < 0.001).

Cost-effectiveness analyses: The total procedural cost of TAVR, excluding MD fees, was $42,806 (all values in 2010 USD), while the total index admission cost was $78,540. On 12-month follow-up, total costs were significantly lower with TAVR compared with medical therapy: $29,352 vs. $52,724 (p < 0.001). Increased life expectancy of about 1.9 years was noted with TAVR. Cost-effectiveness analyses demonstrated an incremental cost-effectiveness ratio of $50,212 per life-year gained, which is close to the $50,000 life-year gained that is commonly used for evaluation of newer technologies.

Two-year results: On intent-to-treat analysis, the primary endpoint of all-cause mortality was significantly lower in the TAVR arm as compared with the standard treatment arm (43.3% vs. 67.6%, HR 0.57, 95% CI 0.44-0.75, p < 0.0001). The number needed to treat at 2 years was five patients. This was also true on landmark analysis: mortality between 1 and 2 years was lower in the TAVR arm (18.2% vs. 35.1%, p = 0.019). Similarly, cardiovascular mortality (31.0% vs. 62.4%, HR 0.44, 95% CI 0.32-0.60, p < 0.0001) and repeat hospitalizations (35.0% vs. 72.5%, p < 0.0001) were significantly lower in the TAVR arm at 2 years. All strokes were higher in the TAVR arm (13.8% vs. 5.5%, HR 2.79, 95% CI 1.25-6.22, p = 0.009). Other clinical outcomes such as major bleeding (28.9% vs. 20.1%, p = 0.093), endocarditis (2.3% vs. 0.8%, p = 0.32), and new pacemaker were similar between the two arms (6.4% vs. 8.6%, p = 0.47).

About 85% of patients in the standard therapy arm underwent repeat BAV over this period, as compared to 2.8% in the TAVR arm (p < 0.001); re-TAVR was required in 1.7% of patients. At 2 years, NYHA class III/IV symptoms were significantly lower in the TAVR arm (16.9% vs. 57.5%, p < 0.0001). On echocardiography, the mean gradient in the TAVR arm remained about 10.2-10.6 mm Hg between 30 days and 3 years, while the aortic valve area remained between 1.55 and 1.68 cm2 over this time period. As far as paravalvular leaks were concerned, only 16.4% progressed; the majority either stayed the same (41%) or improved (42.6%).

On stratifying by STS score (<5, 5-14.9, ≥15), there was a significant risk-response relationship in the TAVR arm, such that the lowest STS score tertile had the lowest 2-year mortality (p = 0.012).

Three-year results: On intent-to-treat analysis, the primary endpoint of all-cause mortality was significantly lower in the TAVR arm as compared with the standard treatment arm (54.1% vs. 80.9%, HR 0.53, 95% CI 0.41-0.68, p < 0.0001). The number needed to treat at 3 years was four patients. This was also true on landmark analysis: mortality between 2 and 3 years was lower in the TAVR arm (19.3% vs. 40.3%, p = 0.03). Similarly, cardiovascular mortality (41.4% vs. 74.5%, HR 0.41, 95% CI 0.30-0.56, p < 0.0001) and repeat hospitalizations (42.3% vs. 75.7%, p < 0.0001) were significantly lower in the TAVR arm at 3 years. The number of days alive out of hospital was 944 vs. 368 days (p < 0.0001). There were two additional strokes between years 2 and 3 (overall stroke rate at 3 years: 15.7% vs. 5.5%, p = 0.0094).

On echocardiography at 3 years, the mean gradient in the TAVR arm remained approximately 10.2-11.3 mm Hg between 30 days and 3 years, while the aortic valve area remained at about 1.5 cm2 over this time period. No major worsening of paravalvular leaks was noted between years 2 and 3. Interestingly, mortality was not different in the TAVR arm when stratified by severity of paravalvular leak.

Five-year results: On intent-to-treat analysis, the primary endpoint of all-cause mortality was significantly lower in the TAVR arm as compared with the standard treatment arm (71.8% vs. 93.6%, HR 0.50, 95% CI 0.39-0.65, p < 0.0001). This was also true on landmark analysis: mortality between 3 and 5 years was lower in the TAVR arm (38.9% vs. 66.7%, p = 0.028). The median survival was 29.7 months in the TAVR arm and 11.1 in the standard therapy arm. Similarly, cardiovascular mortality (57.5% vs. 85.9%, HR 0.41, 95% CI 0.31-0.55, p < 0.0001) and repeat hospitalizations (47.6% vs. 87.3%, p < 0.0001) were significantly lower in the TAVR arm at 5 years. Interestingly, noncardiovascular death was higher than cardiovascular death in the TAVR arm (34% vs. 17%). Results were similar irrespective of underlying STS score or in patients >85 years of age. Overall stroke rate at 5 years was 16.0% vs. 18.2% (p < 0.05).

On echocardiography at 5 years, the mean gradient in the TAVR arm remained approximately 10.6-11.3 mm Hg between 3 and 5 years, whereas the aortic valve area remained at approximately 1.5 cm2 over the 5-year time period. No major worsening of paravalvular leaks was noted between years 3 and 5. Interestingly, mortality was not different in the TAVR arm when stratified by severity of paravalvular leak, although cardiovascular mortality was higher in patients with moderate to severe paravalvular leak.

Quality-of-life assessment: A composite analysis of the patients undergoing TAVR in the pooled PARTNER cohorts (cohorts A and B from the clinical trial, 2,068 from the registry) was performed. Poor outcome at 6 months (death, Kansas City Cardiomyopathy Questionnaire [KCCQ] score <45 or decrease ≥10 points in the KCCQ-Overall Summary Scale [KCCQ-OS] score) was observed in 33% of the total cohort. Independent risk predictors were oxygen-dependent chronic obstructive pulmonary disease, poor renal function, major arrhythmia, lower baseline mean aortic valve gradient, lower baseline mini-mental status exam (MMSE) score, and lower 6-minute walk distance. Results were similar at 1 year.

Long-term hemodynamic evaluation: Data from the PARTNER 1 trial (cohorts A and B) as well the continued access registry were analyzed (n = 2,795; 2,482 TAVR, 313 surgical AVR). Complete 5-year echocardiographic data were available in 424 patients who received TAVR, while serial paired echocardiographic data were available in 399 patients. LV mass was significantly lower at 5 years (76.3 vs. 63.7 g post-implant vs. 5 years, p < 0.001). The average mean gradient was 6.4 mm Hg, and the average AVA was 1.57 cm2.

Among patients with ≥1 follow-up echocardiogram, at a medium follow-up of 3.1 years, moderate/severe transvalvular regurgitation was noted in 3.7% after TAVR and increased over time. Patients with surgical AVR showed no significant changes. Reintervention occurred in 20 patients (0.8%) after TAVR and in one (0.3%) after surgical AVR and became less frequent over time. However, reintervention was caused by structural deterioration of transcatheter heart valves in only five patients. Overall mortality was very high: 63.1%.

Interpretation:

PARTNER is a landmark trial in the field of structural heart disease and in the management of patients with severe AS. Patients in this trial were very high risk to begin with, as evidenced by >50% mortality at 1 year in the standard therapy arm. The results of the inoperable group of patients (cohort B) are reported here.

TAVR resulted in 45% reduction in all-cause mortality and 61% reduction in cardiovascular mortality at 1 year in these high-risk AS patients compared with standard therapy. Echocardiographic criteria such as aortic valve area and mean aortic valve gradients, and symptom criteria such as NYHA class, also demonstrated a significant improvement. Preliminary cost-effectiveness analyses indicate significantly increased life expectancy at an incremental cost per life-year gained, which is commonly accepted.

The procedure is complex and fraught with numerous complications, however, as evidenced by a significantly higher risk of major vascular complications and major bleeding, and a trend toward a higher risk of major stroke in the TAVR arm. Thus, while the overall results are very encouraging, the high complication rate should temper any tendencies toward the overaggressive use of TAVR in lower-risk patients, and surgical AVR should still be considered the gold standard for treatment of AS in these patients.

On another note, the design and execution of the PARTNER trial highlight the importance of close collaboration between interventional cardiologists and cardiac surgeons in the management of this complex group of patients.

The 2-year results demonstrate continued superiority of TAVR over medical management in inoperable patients with severe AS. The number needed to treat to prevent one death was only five patients. The Edwards’ valve tested in this trial is now FDA approved, and is likely to be very beneficial for patients with inoperable severe AS. Results of the PARTNER 2 trial with a smaller delivery sheath are eagerly awaited, since major vascular complications are one of the biggest Achilles’ heels of the current device. Further understanding of stroke and its prevention in these patients is also key.

Longer-term results continue to demonstrate superior results for TAVR over medical management. It is sobering to note that despite TAVR, overall mortality was high in this subgroup of patients, especially noncardiac mortality, highlighting the importance of appropriate patient selection for TAVR. Valve durability and performance appeared robust over 5 years of follow-up.

Quality-of-life data are important, and help in the identification of patients who may not derive clinical benefit from TAVR despite a good technical result. This should be factored into the decision-making process before TAVR as well.

References:

Douglas PS, Leon MB, Mack MJ, et al., on behalf of the PARTNER Trial Investigators. Longitudinal Hemodynamics of Transcatheter and Surgical Aortic Valves in the PARTNER Trial. JAMA Cardiol 2017;Sep 27:[Epub ahead of print].

Mack M, Leon MB, Smith CR, et al. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;Mar 15:[Epub ahead of print].

Kapadia SR, Leon MB, Makkar RR, et al. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;Mar 15:[Epub ahead of print].

Kapadia SR, Tuzcu EM, Makkar RR, et al. Long-Term Outcomes of Inoperable Patients with Aortic Stenosis Randomized to Transcatheter Aortic Valve Replacement or Standard Therapy. Circulation 2014;Sep 9:[Epub ahead of print].

Arnold SV, Reynolds MR, Lei Y, et al., on behalf of the PARTNER Investigators. Predictors of Poor Outcomes After Transcatheter Aortic Valve Replacement: Results From the PARTNER (Placement of Aortic Transcatheter Valve) Trial. Circulation 2014;129:2682-90.

Leon MB, Smith CR, Mack M, et al., on behalf of the PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-1607.

Presented by Dr. Martin Leon at the Transcatheter Cardiovascular Therapeutics Meeting (TCT 2010), Washington, DC, September 2010.

Presented by Dr. Matthew Reynolds at the ACC.11/i2 Summit, New Orleans, LA, April 3, 2011.

Presented by Dr. Raj Makkar at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2011), San Francisco, CA, November 10, 2011.

Presented by Dr. Samir Kapadia at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2012), Miami, FL, October 24, 2012.

Presented by Dr. Samir Kapadia at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2014), Washington, DC, September 13, 2014.

Keywords: Heart Valve Prosthesis, Risk, Coronary Artery Disease, Follow-Up Studies, Acute Kidney Injury, Thoracic Wall, Respiratory Insufficiency, Comorbidity, Heart Valve Prosthesis Implantation, Registries, Stainless Steel, Endocarditis, Bioprosthesis, Patient Selection, Cardiomyopathies, Hypertension, Pulmonary, Stroke Volume, Confidence Intervals, Surveys and Questionnaires, Echocardiography, Cooperative Behavior, Stroke, Mitral Valve Insufficiency, Life Expectancy, Percutaneous Coronary Intervention, Echocardiography, Doppler, Pulmonary Disease, Chronic Obstructive, Heart Valve Diseases, Oxygen, Coronary Artery Bypass, Transcatheter Cardiovascular Therapeutics, Echocardiography, Heart Valve Diseases, Transcatheter Aortic Valve Replacement


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