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- ↵∗Address for correspondence:
Dr. Michael J. Mack, Baylor Scott & White Health, 1100 Allied Drive, Plano, Texas 75075.
Transcatheter aortic valve replacement (TAVR) has been demonstrated in randomized controlled trials (RCTs) to be superior to medical therapy in inoperable patients with severe symptomatic aortic stenosis and to be noninferior to surgical aortic valve replacement (SAVR) in high and intermediate surgical risk patients (1–6). TAVR has thus become widely accepted as the standard of care in these patient cohorts due in large part to the robust body of evidence generated by 6 RCTs. We also have some outcome data in low-risk patients from a single randomized trial, NOTION (Nordic Aortic Valve Intervention Trial; NCT01057173) (7). The outcomes of these 7 trials as well as current clinical outcomes in the United States from the STS/ACC TVT Registry (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry) are summarized in Table 1. There are 2 more RCTs comparing TAVR with SAVR in low surgical risk patients with 2 different devices that have now completed enrollment of approximately 2,000 patients, and the outcomes of these trials are expected to become available in early 2019 (PARTNER 3 [Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis (P3), NCT02675114]; Medtronic Evolut [Medtronic Evolut Transcatheter Aortic Valve Replacement in Low Risk Patients, NCT02701283]).
With this background in mind, we now consider the study by Waksman et al. (8) reported in this issue of the Journal. It is an observational, nonrandomized study of 200 low surgical risk patients with severe symptomatic aortic stenosis who underwent TAVR. The primary endpoint of the study is all-cause mortality at 30 days. Important exclusions included bicuspid aortic valves and unsuitability for transfemoral access. The mean age was 73.6 years, and the STS PROM (Society of Thoracic Surgeons Predicted Risk of Mortality) was 1.8. A balloon-expandable valve, Sapien 3 (Edwards Lifesciences, Irvine, California), was used in 88.2% of the patients and a self-expanding valve, CoreValve Evolut R (Medtronic, Dublin, Ireland), in 11.8%. Notable procedural findings are that 75% of the procedures were performed without general anesthesia, all by transfemoral access, and there was 1 conversion to surgery due to coronary artery obstruction (0.5%).
The 30-day results are excellent in that there was no mortality and a 0.5% stroke rate. Also of note is that there was a low incidence of the need for new permanent pacemaker implantation (5%) and a low rate of new-onset atrial fibrillation (3%), and there were 2 patients (1.0%) with a moderate-severe paravalvular leak at discharge. The study also included a surveillance multidetector row computerized tomographic scan at 30 days that demonstrated evidence of leaflet thrombosis in 14.5% (27 of 186) of the evaluable scans. This included hypoattenuated leaflet thickening, reduction in leaflet motion, and hypoattenuation affecting motion, which was defined as hypoattenuated leaflet thickening with at least a moderate reduction in leaflet motion. The findings were found less frequently, but not significantly so, in patients on anticoagulation versus antiplatelet therapy and were not associated with clinical events.
The authors then proceeded to compare the outcomes of this prospectively enrolled and adjudicated study of 200 TAVR patients with a historical control of SAVR patients undergoing surgery in the same institutions. From a total cohort of 2,959 SAVR patients at these institutions, they selected 686 patients deemed to be low risk by STS PROM and compared the observed outcomes. There are some problems, however, with this comparison. The SAVR procedures were performed in an earlier time period, 2013 to 2017, compared with 2016 to 2018 for TAVR and included patients undergoing concomitant coronary artery bypass grafting and not just isolated SAVR. Because the patients were selected post hoc from a clinical database on the basis of STS score alone without the selection rigor or event adjudication of the TAVR cohort, questions can be raised regarding the validity of the comparison. They attempted to correct for any confounders by propensity matching using inverse probability weighting. Although inverse probability weighting is a good approach to adjust for possible confounders, the key is to include the right confounders in the propensity matching. The main concerns with this study is that they did not account for site variation, and more importantly, many of the variables they used in the propensity score are already included in the STS PROM, which is a variable that was included in the propensity. This is not acceptable, because it introduces issues with multicollinearity by “double counting” some of the variables. Furthermore, they tested multiple outcomes independently, but they did not account for this in the analysis, that is, they did not account for multiple comparisons. This is important because after accounting for multiple comparisons, none of the outcome differences highlighted in the paper would be significant given the relatively low number of events.
Nonetheless, despite the concerns of the comparison to a historical SAVR cohort, the excellent early outcomes of TAVR do stand on their own without the need to be compared in a retrospective manner. The results should not be totally unexpected or surprising in view of the progressively better outcomes achieved in the RCTs because the risk profiles have become lower, the third-generation device and delivery systems have improved, and with greater experience in patient selection and procedure performance. The results are significantly better than the TAVR outcomes at 30 days in the low-risk NOTION trial, but it should be noted that those patients were treated with first-generation devices in an earlier timeframe from 2011 through 2013. The study should also be considered in the context of current “real-world” outcomes of “all comers” from the STS/ACC TVT Registry, which now demonstrate a 30-day mortality of 3.0%, stroke rate of 1.8%, and 1-year mortality of 15.2% for TAVR.
So, what new do we learn from this TAVR study? With only 200 nonrandomized patients with 30-day follow-up, the incremental information gained is relatively limited, but reassuring, while we await the outcomes of the 2 low-risk randomized trials. What we can state confidently is that TAVR is safe in low-risk patients with no 30-day mortality and a low stroke rate. It is hoped that the investigators will expand their experience and provide longer-term follow-up so we can begin to understand efficacy and durability because these will be the key issues in low-risk patients. Information in this study is further limited in that most of the experience is with 1 device, a balloon-expandable valve (88%), and one cannot assume a class effect. The finding of valve thrombosis also deserves particular attention and does need detailed follow-up. Although there were no clinical events at 30 days from this subclinical imaging finding, we should not be reassured. The impact of thrombus and leaflet immobility on valve durability and early structural valve deterioration is still an unanswered question. Valve thrombosis was less common with anticoagulation, but the study was underpowered to determine significance. There are approximately 800 patients who underwent TAVR and SAVR in the 2 low-risk randomized trials who underwent surveillance multidetector row computerized tomography that will shed further light on the many issues regarding valve thrombosis including incidence, clinical significance, predisposing factors, and treatment.
In conclusion, this study gives us an early peek into what we may expect regarding the early safety of TAVR in low-risk patients. The forthcoming randomized trials, which have a 1-year endpoint with all patients being followed for 10 years, will give us insight into efficacy and durability as well as comparative effectiveness to SAVR. Until we have these results from these trials, this study gives us some degree of reassurance regarding the safety of TAVR in low-risk patients.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Mack has been a trial principal investigator for Edwards Lifesciences.
- 2018 American College of Cardiology Foundation
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