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Valvular heart disease
Original article
Systemic inflammatory response syndrome after transcatheter or surgical aortic valve replacement
  1. Brian R Lindman1,
  2. Jacob S Goldstein2,
  3. Michael E Nassif1,
  4. Alan Zajarias1,
  5. Eric Novak1,
  6. Anjan Tibrewala2,
  7. Anna M Vatterott1,
  8. Cassandra Lawler1,
  9. Ralph J Damiano3,
  10. Marc R Moon3,
  11. Jennifer S Lawton3,
  12. John M Lasala1,
  13. Hersh S Maniar3
  1. 1Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA
  2. 2Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
  3. 3Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
  1. Correspondence to Dr Brian R Lindman, Cardiovascular Division, Washington University School of Medicine, Campus Box 8086, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; blindman{at}dom.wustl.edu

Abstract

Objective An inflammatory response after cardiac surgery is associated with worse clinical outcomes, but recent trials to attenuate it have been neutral. We evaluated the association between systemic inflammatory response syndrome (SIRS) and mortality after transcatheter (TAVR) and surgical aortic valve replacement (SAVR) for aortic stenosis (AS) and evaluated whether diabetes influenced this relationship.

Methods Patients (n=747) with severe AS treated with TAVR (n=264) or SAVR (n=483) between January 2008 and December 2013 were included and 37% had diabetes mellitus. SIRS was defined by four criteria 12–48 h after aortic valve replacement (AVR): (1) white blood cell count <4 or >12; (2) heart rate >90; (3) temperature <36 or >38°C; or (4) respiratory rate >20. Severe SIRS was defined as meeting all four criteria. The primary endpoint was 6-month all-cause mortality (60 deaths occurred by 6 months). Inverse probability weighting (IPW) was performed on 44 baseline and procedural variables to minimise confounding.

Results Severe SIRS developed in 6% of TAVR patients and 11% of SAVR patients (p=0.02). Six-month mortality tended to be higher in those with severe SIRS (15.5%) versus those without (7.4%) (p=0.07). After adjustment, severe SIRS was associated with higher 6-month mortality (IPW adjusted HR 2.77, 95% CI 2.04 to 3.76, p<0.001). Moreover, severe SIRS was more strongly associated with increased mortality in diabetic (IPW adjusted HR 4.12, 95% CI 2.69 to 6.31, p<0.001) than non-diabetic patients (IPW adjusted HR 1.74, 95% CI 1.10 to 2.73, p=0.02) (interaction p=0.007). The adverse effect of severe SIRS on mortality was similar after TAVR and SAVR.

Conclusions Severe SIRS was associated with a higher mortality after SAVR or TAVR. It occurred more commonly after SAVR and had a greater effect on mortality in diabetic patients. These findings may have implications for treatment decisions in patients with AS, may help explain differences in outcomes between different AVR approaches and identify diabetic patients as a high-risk subgroup to target in clinical trials with therapies to attenuate SIRS.

https://doi.org/10.1136/heartjnl-2014-307057

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    Introduction

    Cardiac surgery can stimulate a systemic inflammatory response that has deleterious consequences.1–3 This is the rationale for clinical trials to attenuate the inflammatory response.4 ,5 The Dexamethasone for Cardiac Surgery trial failed to meet its primary endpoint, but steroids improved some secondary endpoints.4 In the recent Steroids in Cardiac Surgery (systemic inflammatory response syndrome (SIRS)) trial, approximately 7500 patients were administered intravenous methylprednisolone or placebo during any surgery that required cardiopulmonary bypass.5 A clinical benefit was not observed in the SIRS trial in terms of reduced mortality and morbidity; instead, there was evidence for an increased risk of myocardial infarction in patients receiving intravenous steroids.6 Whether this is due to the wrong anti-inflammatory strategy or the failure to identify a subgroup of patients who may benefit is unclear.

    The incidence and effect of SIRS on mortality after surgical aortic valve replacement (SAVR) for aortic stenosis (AS) have not been studied. One recent report demonstrated that the development of SIRS after transcatheter aortic valve replacement (TAVR) adversely affects short-term and long-term survival.7 Related to this, diabetes mellitus is a pro-inflammatory state that may influence the development, severity or effect of SIRS after aortic valve replacement (AVR).8 Diabetes is known to adversely affect outcomes after TAVR and SAVR.9 ,10 A recent post hoc analysis of the PARTNER trial, however, suggested that high-risk patients with AS and diabetes may do better when treated with TAVR compared with SAVR.11 We hypothesised that these findings may be explained, in part, by: (1) a higher incidence of SIRS after SAVR than TAVR and (2) the combination of SIRS and diabetes leads to worse clinical outcomes. Accordingly, we examined the incidence of SIRS after SAVR and TAVR in patients with AS and evaluated whether its effect on mortality was influenced by the presence of diabetes.

    Methods

    Patient population

    We retrospectively included all patients ≥40 years of age with severe AS (indexed aortic valve area ≤0.6 cm2/m2 or transvalvular mean gradient >40 mm Hg or peak velocity >4 m/s) treated with isolated SAVR or TAVR between January 2008 and December 2013 at Barnes-Jewish Hospital in St. Louis, Missouri, USA. All TAVR procedures were performed with a balloon expandable Edwards SAPIEN valve under general anaesthesia. We excluded patients who had a concomitant surgical procedure (eg, coronary bypass, mitral valve repair), endocarditis or a valve-in-valve TAVR and also excluded patients who died during their procedure as our objective was to evaluate the association between SIRS (that developed after the procedure) and mortality. The study complied with the Declaration of Helsinki and was approved by the local institutional review board from which a waiver of written informed consent was obtained given the retrospective design of the study.

    Clinical data

    Clinical variables were obtained by chart abstraction. The publicly available Society of Thoracic Surgeons (STS) website (http://www.riskcalc.sts.org) provided definitions for the clinical variables and allowed for the calculation of the STS risk score for each patient. The STS defines diabetes according to criteria from the American Diabetes Association.12 The clinical characteristics, medication usage, laboratory values, and procedural and postprocedural data and events are routinely obtained and entered at or near the time of the procedure into our institution's database and submitted to the national STS database. The SIRS criteria were defined according to existing guidelines: (1) white blood cell (WBC) count <4 or >12 (109/L); (2) heart rate (HR) >90 bpm; (3) temperature <36 or >38°C; or (4) respiratory rate >20 per minute.13 ,14 To minimise spurious findings, we did not evaluate for the occurrence of these criteria during the first 12 postoperative hours given the numerous medication and ventilation changes made in the immediate postoperative setting; we evaluated between 12 and 48 h after the patient left the operating room. Also, to avoid the influence of a potentially misleading, isolated vital sign, we considered the HR and respiratory rate criteria met only if there were two or more recordings above the designated threshold. While the standard definition of SIRS is the occurrence of two or more of these criteria,13 given the frequency of an inflammatory response after cardiac surgery, we hypothesised that a more severe SIRS phenotype (characterised by more criteria being met and indicative of a more marked systemic inflammatory response) might identify a higher risk group of patients in this clinical scenario.

    Statistical analysis

    The incidence of individual SIRS criteria (WBC, HR, temperature and respiratory rate) and definitions based on number of criteria met (≥2, ≥3 or 4) were compared between AVR treatment groups using Fisher's exact test. Those who met four SIRS criteria were considered to have ‘severe SIRS’. Comparisons of baseline clinical, procedural and postprocedural characteristics between those with and without severe SIRS were conducted with Student's two sample t test or Fisher's exact test for continuous and categorical data, respectively. For non-normal and ordinal data, median (1st, 3rd quartiles) was provided as the summary statistic and the between-group comparison was conducted using the Kruskal–Wallis test.

    Outcomes were evaluated using inverse probability weighting (IPW) methods to achieve balance between groups in order to adjust for factors known or hypothesised to be associated with mortality in this patient population. This method allows for adjustment of many more variables than are commonly included in multivariable models to more adequately adjust for potential confounders without developing adjusted models that are overfit.15 ,16 Using logistic regression, propensity for having severe SIRS was determined using 44 baseline and procedural variables (see online supplement). Propensity for having the individual SIRS criteria was evaluated similarly. Standardised differences were calculated to determine covariate balance before and after IPW. Difference in mortality between those with versus without severe SIRS (or meeting vs not meeting the individual criteria) was evaluated by the HR produced from a Cox proportional hazards model and using robust SEs as appropriate for IPW analysis. Surgery date was used as the start time and follow-up was completed through 7 February 2014. Our primary endpoint was 180-day mortality. This time point was chosen as relatively few deaths occur by 30 days and the effect of SIRS on 1-year mortality is likely to be diluted by other comorbidities. A separate model was built to examine the association between SIRS and mortality according to AVR type (TAVR vs SAVR). The difference between AVR treatment groups was evaluated by the interaction between SIRS and AVR type. A similar model was built to evaluate patients with and without diabetes.

    Secondary outcomes were also evaluated and included initial intensive care unit (ICU) hours, ICU readmission and length of hospital stay. Initial ICU hours and length of hospital stay were log-transformed and evaluated through linear regression. β-Coefficients represent the difference between SIRS groups of the log-transformed variable. Exponentiation of the β-coefficient yields the difference in the geometric mean of ICU hours or length of stay between groups. Difference in ICU readmission (yes vs no) was determined by the OR produced from a logistic regression model. Linear and logistic regression models were developed using generalised estimating equations to obtain robust SE estimates. Comparisons for TAVR versus SAVR and diabetic versus non-diabetic were conducted for all secondary outcomes by developing models containing the corresponding SIRS interaction. A two-sided p value <0.05 was considered significant. All statistical analyses were conducted using SAS V.9.4 (SAS Institute, Cary, North Carolina, USA).

    Results

    There were 747 patients included in the analysis, including 483 treated with SAVR and 264 treated with TAVR (transfemoral (n=117), transapical (n=102) and transaortic (n=45)). The mean age was 75 years, 46% were female patients and 37% were diabetic (38% of diabetic patients were treated with insulin). The STS score for patients undergoing TAVR (10.5±5.6) was higher than for those undergoing SAVR (4.1±4.0) (p<0.001). Two or more SIRS criteria were met in 84% of the population and this was not associated with 6-month mortality (HR 1.22, 95% CI 0.58 to 2.56, p=0.61). Likewise, three or more SIRS criteria were met in 45% of the population and this was not associated with 6-month mortality (HR 1.06, 95% CI 0.64 to 1.77, p=0.81). In contrast, severe SIRS (four SIRS criteria met) occurred in 9.5% of the population and was associated with a higher mortality at 6 months (HR 2.25, 95% CI 1.17 to 4.32, p=0.015).

    Characteristics of patients with severe SIRS

    Compared with those without severe SIRS, those who developed severe SIRS after valve replacement were younger and had a lower prevalence of cerebrovascular disease, higher baseline haemoglobin and WBC count, and more frequently were on dialysis (table 1). There were no differences in sex, BMI (body mass index), EF or glomerular filtration rate, and no differences in the prevalence of coronary disease, diabetes, atrial arrhythmia, immunocompromised state, chronic corticosteroid use, smoking or lung disease. Those with severe SIRS were more likely to have been treated with SAVR than TAVR, had longer cardiopulmonary bypass times, and more often had an intra-aortic balloon pump inserted preoperatively or intraoperatively (table 2). There was no difference in the use of intraoperative blood products.

    View this table:
    Table 1

    Baseline clinical characteristics

    View this table:
    Table 2

    Procedural and postprocedural characteristics

    Incidence of SIRS according to AVR procedure

    The incidence of each SIRS criteria and increasing combinations of them are shown according to type and route of AVR (table 3). SIRS criteria were more frequently met in those who underwent SAVR compared with TAVR (p<0.05 for all comparisons except temperature). In unadjusted analyses, SAVR was associated with a higher odds of developing severe SIRS (OR 1.99, 95% CI 1.12 to 3.55, p=0.02). After balancing the SAVR and TAVR groups on 29 baseline characteristics using inverse probability weighting (see online supplementary methods), this relationship was attenuated (IPW adjusted OR 1.89, 95% CI 0.91 to 3.94, p=0.09). Transfemoral TAVR generally had the lowest incidence of SIRS criteria met in comparison with non-transfemoral TAVR and SAVR. Non-transfemoral TAVR procedures tended to have a somewhat lower incidence of most, but not all, SIRS criteria compared with SAVR. The SIRS criteria for respiratory rate were met in almost all patients regardless of procedural approach.

    View this table:
    Table 3

    Incidence of systemic inflammatory response syndrome (SIRS) criteria in treatment subgroups

    Severe SIRS and mortality

    For our primary endpoint of 6-month all-cause mortality, there were 60 deaths in the whole population. There were 18 deaths at 30 days and 88 deaths at 365 days. Six-month mortality tended to be higher in those with severe SIRS (15.5%) versus those without (7.4%) (p=0.07). After inverse probability weighting to adjust for confounders, the association between severe SIRS and increased 6-month mortality was strengthened (IPW adjusted HR 2.77, 95% CI 2.04 to 3.76, p<0.001) (table 4) (figure 1). This association was similar whether patients were treated with TAVR or SAVR (interaction p>0.05). In contrast, severe SIRS had a greater effect on mortality in diabetic (IPW adjusted HR 4.12, 95% CI 2.69 to 6.31, p<0.001) than non-diabetic patients (IPW adjusted HR 1.74, 95% CI 1.10 to 2.73, p=0.02) (interaction p=0.007). Similarly, severe SIRS was associated with increased 30-day (IPW adjusted HR 3.86, 95% CI 2.31 to 6.45, p<0.001) and 1-year mortality (IPW adjusted HR 1.79, 95% CI 1.38 to 2.33, p<0.001) and more adversely affected diabetic patients at each time point (table 4). Time-to-event curves are shown for the first year after AVR (figure 2). Although most of the 44 baseline and procedural variables were well balanced between the groups, some were borderline (figure 1). After further adjusting for AVR type, cerebrovascular disease, NYHA class, prior myocardial infarction and chronic corticosteroid use in the statistical models, the association between severe SIRS and increased 6-month mortality was strengthened further (adjusted HR 3.90, 95% CI 2.74 to 5.57, p<0.001) (see online supplementary table S1). As a sensitivity analysis, we evaluated the association between severe SIRS and 6-month mortality in more traditional multivariable models without inverse probability weighting and our results were similar (see online supplementary table S2).

    View this table:
    Table 4

    Impact of systemic inflammatory response syndrome (SIRS) criteria on mortality in propensity adjusted analyses

    Figure 1
    Figure 1

    Covariate balancing between those with and without severe systemic inflammatory response syndrome (SIRS). Covariate balancing is shown between those with versus without severe SIRS (four criteria met) before and after inverse propensity weighting.

    Individual SIRS criteria and mortality

    To better understand which SIRS criteria were associated with mortality we analysed the relationship between individual SIRS criteria and mortality. After adjustment, meeting the SIRS WBC criteria alone was associated with a higher 6-month mortality (IPW adjusted HR 2.12, 95% CI 1.50 to 3.00, p<0.001) (table 4) (see online supplementary figure S1). In a sensitivity analysis in which we excluded patients with a preprocedure WBC <4 or >12, the results were unchanged. Similarly, meeting the SIRS HR criteria alone was associated with a higher 6-month mortality (IPW adjusted HR 2.43, 95% CI 1.59 to 3.70, p<0.001) (table 4) (see online supplementary figure S2). For both WBC and HR alone, there were no significant interactions observed between the SIRS criteria met and AVR type or diabetes. There was no significant relationship between meeting the SIRS temperature criteria and 6-month mortality (table 4) (see online supplementary figure S3). We did not evaluate the relationship between the SIRS respiratory rate criteria and mortality because it was met in almost all patients.

    Figure 2
    Figure 2

    Systemic inflammatory response syndrome (SIRS) and mortality after aortic valve replacement. Time-to-event curves are shown based on inverse probability weighting Kaplan–Meier estimates. HRs are shown for Cox proportional hazards models using inverse propensity weighting. Comparison between those with and without severe SIRS is shown (A) as well as for those with and without severe SIRS and diabetes (B).

    SIRS and secondary clinical outcomes

    Secondary clinical outcomes were also evaluated, including ICU time, ICU readmission and total hospital length of stay (table 5). Severe SIRS was associated with more frequent ICU readmissions (adjusted OR 5.93, 95% CI 1.84 to 19.09, p=0.003) and meeting the WBC or HR criteria alone was associated with longer ICU and hospital stays (table 5).

    View this table:
    Table 5

    Impact of systemic inflammatory response syndrome (SIRS) criteria on other clinical outcomes in propensity adjusted analyses

    Discussion

    We found that a severe SIRS phenotype was associated with higher 30-day, 6-month and 1-year all-cause mortality in patients with severe AS treated with SAVR or TAVR. SIRS occurred more commonly after SAVR than TAVR and had a greater effect on mortality in diabetic patients. Meeting the WBC or HR criteria individually was also associated with increased mortality. In addition, SIRS was associated with increased resource utilisation in terms of a longer ICU stay, more frequent readmission to the ICU and a longer hospital stay. Importantly, these relationships were observed after extensive adjustment for potential confounders. These findings may have implications for treatment decisions in patients with AS and may help explain differences in outcomes between different AVR approaches. Further, these findings identify diabetic patients as a high-risk subgroup to target in clinical trials with therapies to attenuate SIRS. This is particularly relevant in light of recent neutral trials using corticosteroids to mitigate inflammation after cardiac surgery as a means to improve clinical outcomes.

    While the occurrence of an inflammatory response after cardiac surgery is widely recognised,1 ,2 the commonly employed SIRS criteria have not been applied to patients undergoing AVR; therefore, the incidence and severity of this inflammatory response in such patients are unknown. It is important to note that in applying these criteria to this clinical setting in which an inflammatory response is common, we have allowed for the possibility that a stricter definition of SIRS (ie, more criteria met than the traditional two) may be required to identify an association between the severity of an inflammatory response and clinical outcomes.13 Given the numerous factors that could confound the relationship between SIRS and mortality, we adjusted for variables including diabetes, insulin treatment, use of cardiopulmonary bypass and crossclamp time, severity of comorbidities, and intraoperative blood products administered (44 baseline and procedural variables in total) to minimise confounding.

    Sinning et al7 recently reported the occurrence of SIRS after TAVR and found that it was associated with increased short-term and long-term mortality. They defined SIRS as the presence of two or more criteria.13 The incidence of SIRS in their study was 40%, whereas 73% of our TAVR population met two or more criteria. The WBC and HR criteria were met in 41% and 21% in their population, respectively, compared with 38% and 48% in our TAVR population. There were several important procedural differences between our TAVR populations that could have influenced the development of SIRS. Those in the study described by Sinning et al were all treated percutaneously via a transfemoral approach using the self-expanding CoreValve without general anaesthesia. In contrast, our TAVR population was treated with an alternative access approach in 56% of cases, transfemoral cases were generally performed with a surgical cut-down and all procedures were performed with a balloon expandable Edwards SAPIEN valve under general anaesthesia. Importantly, they linked the development of SIRS (≥2 criteria) with increased circulating levels of the inflammatory cytokines interleukin 6, interleukin 8 and C reactive protein. The prevalence of diabetes in their study was not reported, the patient population and number of events smaller, and their multivariable adjustment more limited.

    Clinical implications

    Our observation that the SIRS criteria (individually and collectively) occur more commonly after SAVR than TAVR may underlie differences observed in outcomes after these procedures. While the PARTNER trial showed no difference in mortality between TAVR and SAVR,17 the recently reported CoreValve trial demonstrated decreased 1-year mortality after TAVR compared with SAVR in high-risk patients with AS.18 Interestingly, in a post hoc analysis of the PARTNER trial, diabetic patients were noted to have decreased 1-year mortality when treated with TAVR compared with SAVR.11 Our finding that severe SIRS is more strongly associated with mortality in diabetic patients may help explain this result. Taken together, these observations may tend to favour a transcatheter approach when either approach would be a reasonable option, particularly in those with diabetes. However, our findings are too preliminary to make definitive recommendations regarding procedural approach based on the incidence and hazard of severe SIRS. Certainly, despite our findings, there are scenarios when for a diabetic patient SAVR would be preferable to TAVR such as for the diabetic patient with left ventricular dysfunction, multivessel coronary disease and severe AS. More studies are needed to better understand the mechanisms of inflammation in the peri-operative setting and how procedural approach and diabetes intersect with these processes to affect clinical outcomes.

    Insofar as an inflammatory response after AVR is associated with a worse outcome, it is important to consider what steps might be taken to limit or blunt this response. For patients undergoing TAVR, Sinning et al7 found that the number of pacing runs and major vascular complications were associated with the development of SIRS. Incorporating a comparison of our two studies, one might also hypothesise that alternative access approaches, a surgical cutdown for transfemoral cases and the use of general anaesthesia may also increase the incidence of SIRS after TAVR. Fortuitously, the movement toward smaller profile devices and a more ‘minimalist’ procedural approach (conscious sedation, no mechanical ventilation, etc) will allow for more transfemoral procedures (which tended to have the lowest incidence of severe SIRS) with fewer of the factors that may induce an inflammatory response.19

    For patients undergoing SAVR, attenuating the inflammatory response after cardiac surgery has been a longstanding goal and the rationale for large randomised clinical trials testing the use of intravenous corticosteroids.4 ,5 Steroids may not be the appropriate anti-inflammatory intervention or the patient subgroup(s) with the most potential benefit has not been targeted. Although diabetes is not associated with an increased risk of SIRS, we have identified diabetic patients as a large subgroup that has a higher adverse event rate when severe SIRS develops. As such, diabetic patients are an attractive target population for investigating the clinical effect of therapeutic interventions designed to attenuate SIRS. In this regard, the subgroup analysis of the recent SIRS trial gave some indication that the effect of corticosteroids might differ based on diabetes status (interaction p=0.13), with the HR for death at 30 days among diabetics favouring treatment with steroids (borderline significance).6 It is also possible that more selective anti-inflammatory therapies will be more effective at attenuating SIRS and improving clinical outcomes.3

    Limitations

    This was a retrospective analysis which could have influenced the accuracy of assessing whether SIRS criteria were met in the early postoperative period given that these are determined mostly by vital signs. However, vital signs are recorded in the medical record hourly (or more frequently) while patients are in the ICU and every 2–4 h upon discharge from the ICU to the floor. We made an effort to eliminate the influence of potentially spurious, isolated vital signs on the determination of whether SIRS criteria were met. The respiratory rate criteria were met in almost all patients, potentially limiting the interpretability of our results on the hazard of meeting ≥2 or ≥3 SIRS criteria. Finally, despite extensive multivariable adjustment, unmeasured confounders may have affected our findings.

    Conclusions

    A severe SIRS phenotype is associated with a higher mortality and increased resource utilisation after SAVR and TAVR. It occurs more commonly after SAVR and has a greater effect on mortality in patients with diabetes. These observations may have implications for treatment decisions in patients with AS and may help explain differences in outcomes between different AVR approaches. Further, these findings identify diabetic patients as a high-risk subgroup to target in clinical trials that are investigating therapies to attenuate SIRS.

    Key messages

    • What is already known on this subject?

    • Cardiac surgery can stimulate a systemic inflammatory response that has deleterious consequences. This is the rationale for recent large randomised clinical trials in cardiac surgery to attenuate the inflammatory response with steroids, but these trials have been neutral.

    • What might this study add?

    • Few studies have examined the incidence of a systemic inflammatory immune response (SIRS) after aortic valve replacement (AVR), particularly after transcatheter AVR. We report the incidence of SIRS after surgical and transcatheter AVR, including different transcatheter aortic valve replacement (TAVR) approaches. We found that diabetes modifies the relationship between a severe SIRS phenotype and mortality; specifically, severe SIRS was more strongly associated with mortality in diabetic patients compared with non-diabetic patients.

    • How might this impact on clinical practice?

    • Given the increased hazard of mortality associated with severe SIRS after AVR, which is amplified in patients with diabetes, and the tendency for severe SIRS to develop more frequently after surgical aortic valve replacement (SAVR) than TAVR, these issues should be considered in deciding between SAVR versus TAVR in diabetic patients. Further, diabetic patients may be a high-risk subgroup to target in clinical trials testing therapies to attenuate SIRS after cardiac surgery.

    Acknowledgments

    The authors thank Joel D Schilling, MD, PhD, and Christopher L Holley, MD, PhD, for their feedback on the manuscript.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors BRL had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: BRL, JSG, MEN, EN, AT, HSM; acquisition of data and critical revision of the manuscript for important intellectual content: all authors; statistical analysis: BRL, EN; analysis and interpretation of data: BRL, JSG, MEN, AZ, EN, HSM; drafting of the manuscript: BRL, JSG, EN.

    • Funding This work was supported by NIH K23 HL116660 (BRL), the Barnes-Jewish Hospital Foundation (EN), and the Washington University Mentors in Medicine Program (JSG). This work utilized REDCaps and CIDER which are supported by CTSA NIH Grant #UL1 TR000448 and Siteman Comprehensive Cancer Center and NCI Cancer Center Support Grant P30 CA091842.

    • Competing interests BRL is a site co-investigator for the PARTNER Trial and has consulted for Gerson Lehrman Group Research. AZ has consulted for Edwards Lifesciences and is a member of the PARTNER Trial Steering Committee. RJD has consulted for AtriCure, received grant support from AtriCure and Medtronic, and received grant support and speaking fees from Edwards Lifesciences. JML has consulted for Boston Scientific and Direct Flow Medical, received speaking fees from Boston Scientific and St. Jude, and received stock options from Direct Flow Medical. The other authors report no potential conflicts of interest.

    • Ethics approval Washington University in St. Louis Institutional Review Board.

    • Provenance and peer review Not commissioned; externally peer reviewed.