Abstract: Background. Transcatheter aortic valve replacement (TAVR) is a viable alternative to surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (SAS) who are at high risk for surgery. We sought to evaluate the outcomes of TAVR vs SAVR in low-intermediate risk patients with SAS. Methods and Results. We performed random-effects meta-analysis of randomized controlled trials (RCTs) and propensity-matched observational studies comparing TAVR vs SAVR for low-intermediate risk patients. Five RCTs and 5 observational studies with a total of 6891 patients (3489 TAVR patients; 3402 SAVR patients) were included. Pooled data from RCTs showed no significant differences in all-cause mortality between TAVR and SAVR at 30 days (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.73-1.47) and intermediate-term follow-up (RR, 0.86; 95% CI, 0.67-1.10). A trend toward decreased mortality was found with TAVR using the self-expandable vs balloon-expandable valves (RR, 0.77; 95% CI, 0.52-1.15 and RR, 1.91; 95% CI, 0.25-14.53, respectively) and transfemoral vs transthoracic approach [RR, 0.74; 95% CI, 0.55-1.01 and RR, 2.09; 95% CI, 0.40-11.03, respectively). Compared to SAVR, TAVR was associated with similar risks of stroke (RR, 0.91; 95% CI, 0.74-1.11) and myocardial infarction [RR, 1.00; 95% CI, 0.71-1.41). Furthermore, risks of major vascular complications, moderate-severe paravalvular regurgitation, and new permanent pacemaker implantation were higher with TAVR, whereas SAVR was associated with higher rates of acute kidney injury, atrial fibrillation, and major or life-threatening bleed. Finally, the above results from RCTs were consistent with pooled analyses of observational studies. Conclusion. TAVR appears to be a suitable alternative for patients with SAS who are at low-intermediate risk for SAVR.
J INVASIVE CARDIOL 2017;29(6):209-216.
Key words: severe aortic stenosis, transcatheter aortic valve replacement, surgical valve replacement, low risk, intermediate risk
Aortic stenosis (AS) is a degenerative valvular disease, mainly of the elderly population, that significantly impacts morbidity and survival, particularly after onset of symptoms.1 Continuous evolutions in valve systems and implantation techniques have made transcatheter aortic valve replacement (TAVR) a viable alternative to surgical aortic valve replacement (SAVR) for treatment of severe symptomatic AS.2-4 Similar outcomes with TAVR compared to SAVR in high-risk severe AS patients from the large multicenter, randomized clinical trials (RCTs) led to guideline approval of TAVR in this patient population.3-5
More recently, several observational studies and small RCTs have suggested a clinical equipoise between TAVR and SAVR in patients at low-intermediate surgical risk.6-13 These findings have been recently validated in the large SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) and PARTNER 2 (Placement of Aortic Transcatheter Valves) randomized trials, each of which reported that TAVR was non-inferior to SAVR (primary composite outcome of all-cause mortality or disabling stoke at 2 years) in intermediate-risk patients.14,15 Although the results are encouraging, individual trials have been either underpowered or limited by their non-inferiority design.12-15 Furthermore, the two modalities differ in terms of risks of various procedure-related complications and paravalvular regurgitation.15 Therefore, we conducted the present updated meta-analysis to study cumulative evidence for efficacy and safety of TAVR vs SAVR in patients at low-intermediate risk.
Study design. The review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-analysis of Observational studies in Epidemiology) guidelines.16,17
We carried out a literature search using MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science, and Cochrane databases for all studies published between January 1, 2000, and March 17, 2017, reporting on comparison between TAVR and SAVR for severe AS in low-intermediate risk patients. No language restrictions were applied. We used the following MeSH search headings in different combinations: aortic stenosis; aortic valve replacement; transcatheter aortic valve replacement; TAVR; SAVR; surgical valve replacement; intermediate risk; and low risk.
The following criteria were applied for study inclusion: (1) RCTs and prospective observational studies with propensity-matched samples comparing TAVR and SAVR in severe AS patients at low surgical risk (Society of Thoracic Surgeons [STS] score <4% or logistic European System for Cardiac Operative Risk Evaluation [EuroScore] <10%) or intermediate surgical risk (STS 4%-8% or logistic EuroScore 10%-20%); (2) published in peer-reviewed journals; (3) mean follow-up of at least 1 month; and (4) reporting at least one clinical endpoint based on valve replacement approach. Exclusion criteria were: (1) observational studies reporting non-propensity matched populations; (2) high-risk (STS >8% or logistic EuroScore >20%) or inoperable patients with severe AS; and (3) non-published studies.
Data collection. Two reviewers (AG and SA) independently screened study reports for eligibility, assessed risk of bias, and collected data from each eligible study using predetermined forms. Any disparities between the two investigators were discussed with a third investigator (AS) until consensus was reached.
We collected information on study characteristics (study design, year of publication, inclusion and exclusion criteria, population size, length of follow-up, funding source, and primary and secondary endpoint definitions), baseline patient characteristics, transcatheter valve systems (balloon expandable or self expandable), approach of transcatheter intervention (transfemoral [TF] or transthoracic [TT]), mean STS score and logistic EuroScore, and event rate of primary and secondary outcomes from the studies that met inclusion criteria. We compared the two interventions for the following outcomes: 30-day and intermediate-term (1-2 year) all-cause mortality, and myocardial infarction and stroke at intermediate-term (1-2 year) follow-up. Secondary outcomes of interest were new-onset or worsening atrial fibrillation (AF), new permanent pacemaker (PPM) implantation, acute kidney injury (AKI), major vascular complications, major or life-threatening bleeding, and moderate-severe paravalvular regurgitation (PVR). Periprocedural complications were defined according to the Valve Academic Research Consortium (VARC) definitions.18
Statistical analysis. We conducted this meta-analysis according to recommendations from the Cochrane Collaboration using Review Manager, version 5.3.19 We undertook independent pooling of data from RCTs and observational studies to minimize the risk of bias. For each clinical endpoint, pooled risk ratio (RR) and 95% confidence interval (CI) were calculated using the random-effects model with the Mantel-Haenszel method. A P-value of <.05 was assigned as the measure of statistical significance. Heterogeneity between studies was calculated using the I2 statistic. Heterogeneity was considered significant if I2 was >50%. Furthermore, forest plots were generated to show the relative effect size of TAVR vs SAVR for each clinical outcome. Sensitivity analyses were performed by excluding each study at a time to test the influence of individual studies on pooled estimates.
We also performed meta-analysis for the endpoint of all-cause mortality stratified by valve system (balloon expandable vs self expandable) and access route (TF vs TT) by pooling subgroup data from the eligible RCTs where available.
Publication bias for the studies included in the analysis was assessed using Egger’s regression tests.20
Study characteristics. As reported in Figure 1, the initial search identified 814 publications that were screened at abstract level. Thirteen reports were eligible for full-text review after exclusion of duplicate and irrelevant studies. Three observational studies were excluded either due to unavailability of propensity-matched data6,21 or non-prospective design.7 After full-text review, 10 studies (5 RCTs and 5 observational studies) were included in the final analysis.8-12,14,15,21-23 These studies included a total of 6891 patients (3489 treated with TAVR and 3402 treated with SAVR). The mean duration of follow-up was 18.3 months (range, 1-36 months).
Characteristics of individual studies, including definitions of primary endpoints, are described in Table 1. Patients in the two arms were well matched for baseline characteristics. Mean patient age was 79.8 years, and 48% were males. Mean STS score and logistic EuroScore were 4.36 and 11.1, respectively. Two studies exclusively utilized the balloon-expandable valve system for TAVR (Edwards Lifesciences).12,15 Iterations of the self-expandable TAVR bioprosthesis (Core- Valve; Medtronic, Inc) were exclusively used in 6 studies,8,9,14,22-24 whereas 2 studies utilized both types.10,11 Seven studies reported data on access site; TF and TT approaches were used in 87% and 13% of patients, respectively.
Primary outcomes. All-cause mortality occurred in 978 patients (14.3%) (Figure 2) at the conclusion of the longest reported follow-up, with no significant differences in TAVR vs SAVR in meta-analyses of RCTs at either 30 days or intermediate-term follow-up (RR, 1.04; 95% CI, 0.73-1.47 and RR, 0.86; 95% CI, 0.67-1.10, respectively). Similar findings were found in the pooled analyses of observational studies at both short-term and intermediate-term follow-ups (RR, 0.89; 95% CI, 0.61-1.30 and RR, 1.10; 95% CI, 0.90-1.33, respectively). There was mild heterogeneity (I2 = 54%) among RCTs for all-cause mortality at intermediate-term follow-up, but none was detected for observational studies. Visual inspection of the funnel plot for all-cause mortality did not reveal significant asymmetry (Supplementary Figure 1).
Our meta-analysis of RCTs based on stratification by type of valve system showed a trend toward a mortality benefit with TAVR using the self-expandable bioprosthesis (RR, 0.77; 95% CI, 0.52-1.15) but not the balloon-expandable bioprosthesis (RR, 1.91; 95% CI, 0.25-14.53) (Figure 3). Similarly, there was a trend toward improved survival in patients undergoing TF-TAVR (RR, 0.74; 95% CI, 0.55-1.01) vs TT-TAVR (RR, 2.09; 95% CI, 0.40-11.03) compared to SAVR (Figure 3).
Stroke occurred in 423 patients (6.6%) at end of reported follow-up (Figure 4). TAVR and SAVR were associated with similar risks of stroke at intermediate-term follow-up (RR, 0.91; 95% CI, 0.74-1.11) in the pooled analysis of RCTs. Similarly, pooled estimates showed similar risk of myocardial infarction in patients undergoing TAVR compared to SAVR (RR, 1.00; 95% CI, 0.71-1.41) (Figure 4). The results for each endpoint based on pooling of observational studies were consistent with those from RCTs. No significant heterogeneity was detected between studies for either stroke or myocardial infarction.
Secondary outcomes. TAVR was associated with significant increases in risks of major vascular complications (RR, 3.09; 95% CI, 1.51-6.35) and moderate-to-severe PVR (RR, 10.82; 95% CI, 5.60-20.91)compared with SAVR in RCTs (Figure 5).
Similarly, risk of new PPM implantation (RR, 3.10; 95% CI, 1.44-6.66) was higher with TAVR but with significant heterogeneity (I2 = 92%) noted among studies (Figure 6). On subgroup analyses, the results for PPM reached significance for only self-expandable valves (RR, 4.28; 95% CI, 2.52-7.26; I2 = 69%). Risk of PPM implantation was similar, however, between TAVR using a balloon-expandable valve system and SAVR (RR, 1.21; 95% CI, 0.93-1.56) (Figure 6).
Pooled estimates of RCTs showed significantly decreased risks of AKI (RR, 0.38; 95% CI, 0.26-0.54)and AF (RR, 0.41; 95% CI, 0.30-0.56; I2 = 84%) in patients undergoing TAVR compared with SAVR (Figure 7). Furthermore, there was a trend toward lower risk of major or life-threatening bleeding (RR, 0.64; 95% CI ,0.34-1.20; I2 = 94%) with TAVR compared with SAVR (Figure 7). Results were consistent between RCTs and observational studies for each secondary endpoint.
Finally, confirming the robustness of our findings, exclusion sensitivity analyses did not reveal disproportionate effects of any single study on the composite pooled results for each individual endpoint.
The main finding of this large analysis of over 6000 low-intermediate risk patients with severe symptomatic AS is a similar 1-month and 1-2 year risk of mortality and stroke with TAVR compared to SAVR in both RCTs as well as propensity-matched observational studies. The two modalities differed in risks of various periprocedural complications. These data have important implications for the expansion of TAVR to patient populations that currently tend to undergo SAVR.
Current practice guidelines recommend TAVR for treatment of severe AS in patients who are inoperable or at high risk for surgery.3 However, there has been increasing adoption of TAVR in patients at lower risk. In fact, TAVR has shown better outcomes in patients with low-intermediate risk when compared to high-risk patients in a prospective registry.25 A previous meta-analysis attempted to compare the outcomes of intermediate-risk patients undergoing TAVR vs SAVR, but the results were limited due to lack of substantial data from RCTs as well as combined pooling of observational and randomized studies.26 Apart from separate pooling of RCTs and comparing the results with real-world patients, we studied the primary endpoints (mortality, stroke, and myocardial infarction) separately since composite endpoints have limitations on the basis of assumption that each component is of similar importance.
Our results for low-intermediate risk patients are consistent with the mortality outcomes reported in the RCTs comparing TAVR and SAVR in high-risk patients.3,4 The NOTION (The Nordic Aortic Valve Intervention) trial was the first RCT to study low-risk patients and showed no difference in mortality at either 1 or 2 years.13,24 These findings were recently confirmed in the large SURTAVI and PARTNER 2 trials, which demonstrated non-inferiority of TAVR to SAVR in terms of primary endpoint of all-cause mortality or disabling stroke.14,15 Recently, a post hoc analysis of patients with mean STS score <7% from the CoreValve US Pivotal trial reported improved survival in patients undergoing TAVR using the self-expanding valve systems.23 In line with the CoreValve US Pivotal trial, we found a decreased all-cause mortality in the TAVR arm using the self-expandable valve systems.27 Since individual trials were underpowered to study superiority of TAVR for mortality, whether the improved survival with the self-expandable bioprosthesis is specific to this valve or a class effect needs further validation in well-powered RCTs. Furthermore, highlighting continuing advances in technology, TAVR using the third-generation valve (Sapien 3; Edwards Lifesciences) was associated with superior mortality over SAVR in intermediate-risk patients in a recent observational study.28
Other findings from our analyses also deserve comment. The finding that TAVR via TF approach might be associated with more favorable outcomes compared with SAVR is consistent with previous reports.29,30 Subgroup analysis from the PARTNER 2 trial showed superiority of TAVR via TF access over SAVR for the primary endpoint of death or stroke, while there was no significant difference for the TT cohort.15 Since an alternate access (TT, subclavian, etc) might be unavoidable in certain patients due to anatomical reasons, the non-inferiority of TAVR via access site other than TF with SAVR needs to be explored in prospective, well-powered studies. Our finding of similar stroke incidence with both modalities is also consistent with recent evidence of non-inferiority of TAVR for neurological events.14,15,27 The improvement in risk of stroke with TAVR might be due to increased operator experience, low-profile TAVR systems, and/or decreased risk of new-onset AF after TAVR.
Similar mortality with TAVR compared with SAVR in the low-intermediate risk patients in our analysis may be in part explained by the differential risk profile of the two modalities in terms of several secondary outcomes. TAVR was associated with lower incidences of AKI, new-onset AF, and major or life-threatening bleeding, each of which has been associated with increased mortality.31,32 On the contrary, the risks of new PPM implantation, major vascular complications, and moderate-severe PVR were significantly higher in the TAVR arm vs the SAVR arm. A higher risk of conduction disturbances with self-expanding vs balloon-expandable valves might explain the increased risk of PPM with this device.33 Moderate-severe PVR is a well-known complication after TAVR and is associated with increased risk of late mortality in some studies.15,34 It should be noted that earlier-generation TAVR valve systems were used in the studies included in our analysis. Recent reports with use of third-generation bioprostheses (for example, Sapien 3) have shown absolute decrease in frequency of PVR, particularly moderate-severe PVR.29,35 Furthermore, improvements in valve sizing techniques, including utilization of multidetector computerized tomography and evaluation of predictors of PVR with individual valve systems, would help reduce the incidence of PVR.36
Study limitations. Some limitations of our study should be noted. First, due to lack of patient-level data, we could not perform additional subgroup analyses for other baseline characteristics (for example, gender, age, prior bypass surgery, etc.). However, it should be noted that the trials included patients with various clinical presentations and characteristics, and the results from RCTs were consistent with observational studies, thus making it unlikely that these variables would have confounded the results. Second, for some endpoints, the pooled analysis of RCTs was based predominantly on the PARTNER 2 or SURTAVI trials. However, importantly, no significant influence of a single trial on pooled estimates was found in sensitivity analyses, thus increasing the validity of our results. Third, the analysis was based on 5 RCTs, each of which was underpowered to compare the individual end-points, and thus might have introduced reporting bias. Finally, long-term (5-year) data on durability and efficacy of TAVR are lacking.
Our meta-analysis comparing TAVR vs SAVR for low-intermediate surgical risk patients demonstrates similar risks of mortality and stroke at intermediate-term follow-up. These findings likely reflect a net balance between the significant differences in risks of procedure-related adverse events.
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From the 1Department of Medicine, Saint Peter’s University Hospital, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; 2Cardiovascular Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey; 3Duke Clinical Research Institute, Durham, North Carolina; 4Division of Cardiology, Newark Beth Israel Medical Center, Newark, New Jersey; 5Division of Cardiology, St. Luke’s University Hospital, Bethlehem, Pennsylvania; 6Division of Cardiology, State University of New York Downstate, Brooklyn, New York; 7Division of Cardiology, Lehigh Valley Hospital, Allentown, Pennsylvania; and 8Division of Cardiology, Tulane University, New Orleans, Louisiana.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted January 2, 2017, provisional acceptance given March 7, 2017, final version accepted April 3, 2017.
Address for correspondence: Aakash Garg, MD, Rutgers Robert Wood Johnson Medical School 69 Duke Street, New Brunswick, NJ 08901. Email: firstname.lastname@example.org