The first of the TAVR randomized clinical trials, the Edwards sponsored multi-center PARTNER trial tested TAVR for the treatment of severe symptomatic aortic valve stenosis and included a prohibitive surgical risk cohort (STS score >15% or not surgical candidates; cohort B) and a high risk (STS score >10%; cohort A) cohort. Cohort B was published first and randomized 358 patients to TAVR with the Sapien balloon expandable device vs. medical therapy (including balloon angioplasty). The results were striking. The treatment group had an all-cause death rate at 1-year of 30.7% vs. 50.7% in the control arm (p<0.001), a number-needed-to-treat to save one life of 5. The rate of the composite of major stroke or death from any cause at 1-year was 33% vs. 51.3% (p<0.001). TAVR was later approved by the FDA for treatment of high and prohibitive risk severe aortic stenosis patients, ushering in a new era of transcatheter valve disease management.
The PARTNER trial Cohort A was a multi-center, randomized controlled trial comparing balloon expandable TAVR with the Edwards Sapien transcatheter device to surgical aortic valve replacement in high-surgical risk (STS score >10%) patients. The trial was conducted at 25 centers and randomized 699 patients. The primary end-point of death from any cause at 1-year was reached in 24.2% of the TAVR arm and 26.8% (p=0.44) in the surgical arm, meeting criteria for noninferiority of TAVR (p=0.001). The stroke rate was higher in the TAVR group 5.1% vs 2.4% at 1-year (p=0.07), as were vascular complications 11% vs. 3.2% (p<0.001), whereas major bleeding 9.3% vs. 19.5% (p<0.001), and new-onset atrial fibrillation 8.6% vs. 16.0% (p=0.006) where higher in the surgical arm.
The PARTNER 2 trial was a multi-center, randomized controlled trial comparing the balloon expandable Edwards Sapien XT TAVR device vs. surgical aortic valve replacement in symptomatic severe aortic stenosis patients at intermediate surgical risk (STS risk >4%). PARTNER 2 included 57 centers in the US and Canada and enrolled 2032 patients. There was no significant difference between the primary end-point of death from any cause or disabling stroke at 2-years in the intention-to-treat or as-treated analysis (p=0.25 and p=0.18 respectively), meeting criteria for noninferiority of TAVR in both analyses. In the transfemoral access only cohort, TAVR had a significantly lower rate of death from any cause or disabling stroke in both the intention-to-treat and as-treated analyses (HR 0.79 p=0.05 and HR 0.78, p=0.04). The absolute rate of any stroke did not differ between the TAVR and SAVR groups, 5.5% vs. 6.1% (p=0.57) at 30-days. The rate of new permanent pacemaker in 30-days after treatment was similar between TAVR and SAVR (8.5% and 6.9%, p=0.17).
Published in tandem with the low-risk Evolut trial, PARTNER 3 was a multi-center, randomized controlled trial comparing the balloon expandable Edwards Sapien 3 TAVR device vs. surgical aortic valve replacement in symptomatic severe aortic stenosis patients at low surgical risk. PARTNER 3 included 71 centers and 1000 patients were enrolled. The mean STS risk score was 1.9%. The primary end point was a composite of death, stroke, or rehospitalization at 1-year with pre-specified noninferiority and superiority testing in the as-treated cohort. The primary end point was met in 8.5% of the TAVR group vs. 15.1% of the surgical group p<0.001 for noninferiority and p=0.001 for superiority of TAVR over SAVR. TAVR was also superior to SAVR for key secondary end points including 30-day stroke rate (0.6% vs. 2.4%, p=0.02), and 30-day rate of death or stroke (1.0% vs. 3.3%, p=0.01). The rate of new permanent pacemaker at 30-days was 6.5% for TAVR vs. 4.0% for SAVR (HR 1.66, 95% CI 0.93-2.96). These results lead to FDA approval for the use of TAVR in symptomatic severe aortic stenosis of all surgical risk levels.