Impact of Coronary Artery Severity and Revascularization Prior to Transcatheter Aortic Valve Implantation

ARTICLE IN PRESS Impact of Coronary Artery Severity and Revascularization Prior to Transcatheter Aortic Valve Implantation Gabby G. Elbaz, MDa,b,c, Kayley A. Henning, MPHd, Feng Qiu, MScd, Stephen E. Fremes, MDd,e,f, Peter C. Austin, PhDd,f, Ikki Komatsu, MDa, Dennis T. Ko, MDa,d,f, Sam Radhakrishnan, MDa, and Harindra C. Wijeysundera, MDa,d,f,* The prevalence of coexisting coronary artery disease (CAD) is high in patients who underwent transcatheter aortic valve implantation (TAVI). Our objective was to first determine if the severity of CAD before TAVI had an important impact on post-TAVI outcomes and second, if revascularization with percutaneous coronary intervention (PCI) before TAVI modified this relation. In this retrospective population-based study in Ontario, Canada, we identified all patients with obstructive CAD who underwent TAVI from April 1, 2012 to March 31, 2017. Our primary outcomes of interest were allcause mortality within 30-day and 1-year post-TAVI procedure. Secondary outcomes included 30-day and 1-year all-cause readmissions. We developed multivariable Cox proportional hazard models, with a robust sandwich-type variance estimator to account for clustering within TAVI centers. These models included an interaction term between severity of CAD and PCI before TAVI. The study cohort included 888 of whom 444 (50%) patients underwent PCI before TAVI procedure. In the Cox models, we found that severity of CAD before TAVI was not significantly associated with post-TAVI outcomes. The only exception was 1 to 2 vessel/s disease which was a significant predictor of 1-year readmission. Pre-TAVI PCI was not significantly associated with outcomes, nor did it modify the relation between severity of CAD pre-TAVI and outcomes. In conclusion, we did not find a consistent relation between severity of CAD and revascularization with post-TAVI outcomes. © 2019 Elsevier Inc. All rights reserved. (Am J Cardiol 2019;00:1−7)

The prevalence of coexisting coronary artery disease (CAD) is high in patients with aortic stenosis (AS),1 with approximately 40% to 75% of patients who underwent transcatheter aortic valve implantation (TAVI) having important CAD.2−4 There are several competing issues regarding the necessity and timing of coronary revascularization and TAVI.5−8 Some studies have shown that CAD appears to be a Division of Cardiology, Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; bDepartment of Cardiology, Hadassah Medical Center, Jerusalem, Israel; cFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; dICES, Toronto, Ontario, Canada; eDivision of Cardiac Surgery, Department of Surgery, Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; and fInstitute for Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Manuscript received October 22, 2019; revised manuscript received and accepted December 16, 2019. Funding: This study is funded by a grant-in-aid from the Heart and Stroke Foundation of Canada and from an Early Research award from the Ministry of Research and Innovation of Ontario. Dr. H. Wijeysundera is supported by a Phase 2 Award from the Heart and Stroke Foundation of Canada. Dr. Austin is supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation. Dr. Fremes is supported by the Bernard S. Goldman Chair in Cardiovascular Surgery. Dr. Ko is supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation. *Corresponding author: Tel: (416) 480-4527; fax: (416) 480-4657 E-mail address: [email protected] (H.C. Wijeysundera).

0002-9149/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2019.12.021

associated with impaired clinical outcomes.9−16 Other studies have shown a neutral impact,17−22 and some suggesting that revascularization before TAVI may even be associated with an increased risk of adverse clinical outcomes.23 This literature is predominantly based on single-center studies of relatively small sample size, and represent the early experience with TAVI.9,13,18 There is a paucity of multicenter studies in the modern TAVI era.12,17 To address this gap in knowledge: first, we examined the relation between the burden of CAD in patients who underwent TAVI on short- or long-term post-TAVI outcomes and second, if revascularization with PCI before TAVI modified the relation between severity of CAD and outcomes. Methods This retrospective cohort study was approved by the Institutional Research Ethics Board of Sunnybrook Health Sciences Center in Toronto, Ontario. The use of data was authorized under section 45 of Ontario’s Personal Health Information Protection Act, which permits the use of anonymized administrative data without patient consent at ICES. All residents have universal access to health care and hospital services through a publicly funded health care program administered by a single third-party payer, the Ontario Ministry of Health and Long-Term Care (MOHLTC). Our study utilized data collected in the CorHealth Ontario TAVI Registry. The registry contains demographic, www.ajconline.org

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co-morbidity, and procedural variables from the 10 tertiary centers across the province; entry of data into the registry is a mandatory perquisite for provincial TAVI funding. These data elements have been validated through selected chart abstractions and core laboratory analyses.24 Data from the CorHealth registry were linked using unique encoded identifiers to the following administrative datasets held at ICES. We used the Canadian Institute for Health Information Discharge Abstract Database (CIHIDAD) for data on acute hospitalizations, as well as to supplement baseline co-morbidity and procedural data. Dementia diagnoses were determined through linkage with any of the following 3 administrative databases: Ontario Health Insurance Program (OHIP) physician claims database, Ontario Drug Benefit (ODB) database or CIHI-DAD.25 Validated ICES-derived databases were used to identify diabetes26 heart failure (HF), hypertension (HTN),27 and chronic obstructive pulmonary disease (COPD).28 Medical frailty was determined using the John Hopkins Adjusted Clinical Group (ACG) Case-Mix adjustment system (The Johns Hopkins ACG System, version 10).29 Mortality was ascertained via the Registered Persons Database (RPDB) as were additional demographic variables such as neighborhood income quintile and rural residence. We included all patients ≥18 years old who underwent TAVI in Ontario from April 1, 2012 to March 31, 2017 who had an index angiogram in 1 year before the TAVI procedure showing obstructive CAD. Over the time period of

the study, TAVI was indicated for inoperable and high-risk patients in Ontario, based on mandatory evaluation by a local heart team consisting of at least 1 interventional cardiologist and 1 cardiac surgeon. CAD was defined as having >70% obstruction in any of the left anterior descending artery, circumflex artery, or right coronary artery, or >50% obstruction in the left main coronary artery. We excluded patients with data quality issues (ie, patients who died before the procedure date) or with an invalid procedure date. For patients with more than 1 TAVI, we considered the first procedure as the index event for study inclusion. We excluded patients with previous coronary artery bypass graft (CABG), in order to ensure that our classification of burden of CAD was accurate—the presence of grafts would increase the complexity of the anatomy and thereby have potential for misclassification. In order to limit the patient heterogeneity, we excluded TAVI valvein-valve procedures. Patients were categorized into PCI versus non-PCI subgroups based on whether they underwent PCI after the index angiogram but before TAVI. They were further subcategorized by the degree of CAD present at the time of TAVI. Severity of CAD was defined as the number of the diseased vessels after PCI in the PCI group and total number of diseased vessels in the non-PCI group. For the purpose of modeling, we categorized CAD severity into 1 to 2 vessel/s, 3 vessels/left main, with 0 vessels as the reference. As such, the PCI group could categorize as 0, 1, 2, 3

Figure 1. Cohort selection.

ARTICLE IN PRESS Valvular Heart Disease/PCI, Coronary Artery Disease, and TAVI

vessels disease or LM disease, whereas the non-PCI group could be 1, 2, 3 vessels disease or LM disease. Patients were followed from the date of TAVI procedure for up to 1 year. Our primary clinical outcomes of interest were all-cause mortality within 30-day and 1-year post-TAVI procedure. Secondary outcomes included 30-day and 1-year all-cause readmissions. Postprocedural complications, as documented in either the CIHI-DAD or CorHealth registry were noted, specifically pacemaker implantation, vascular complication, stroke, bleeding and acute renal injury events that occurred during the index hospitalization, all defined based on the Valve Academic Research Consortium (VARC)-2 statement. We also examined TAVI wait-times from referral to procedure, as well as length of hospital stay (LOS). Descriptive statistics were provided for baseline demographic and clinical characteristics, total wait time, length of stay, and postprocedural complications. We modeled the effect of the severity of CAD before TAVI on the hazard of 30-day and 1-year mortality using Cox proportional hazard models, with a robust (sandwich-type) variance estimator to account for the clustering of patients within each of the 10 TAVI centers across the province. Multivariable Cox models were adjusted for all baseline and procedural variables, whose inclusion was based on clinical relevance. Multivariable cause-specific Cox models were developed to model the

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hazard of readmission within 30 days and 1 year of TAVI, treating mortality as a competing risk. Whether patients underwent PCI was included in the models, along with an interaction term between PCI status and residual CAD. We included this interaction term to determine if PCI status was an effect modifier. We first tested if the interaction term was statistically significant. If it was not, we reported results from the models that did not include the interaction term. If the interaction term was statistically significant, we reported results from the appropriate contrasts within stratified subgroups (eg, in patients with 1 vessel disease, the impact of PCI vs no PCI). All data analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Statistical significance was considered to be 2-sided p values of ≤0.05. Results A total of 2,999 TAVI procedures were performed between April 1, 2012 and March 31, 2017 (Figure 1). Of these patients, 1,967 underwent a coronary angiogram during the year before their TAVI procedure. A further 1,070 patients were excluded due to normal or nonsignificant CAD in the angiogram. This left us with 888 TAVI patients with obstructive CAD in the final cohort. Of those, 50% (444) TAVI patients underwent PCI before TAVI procedure. There

Figure 2. Proportion of 0, 1, 2, 3, and LM in the total cohort and in the subgroups; with and without pre-TAVI PCI.

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Table 1 Baseline characteristics by number vessels pre-TAVI Number of coronary arteries narrowed Variable Age (Mean § SD) Women Men Income quintile 1 2 3 4 5 (Highest) rural Comorbidities Charlson score Mean § SD Frailty mean § SD Congestive heart failure Chronic obstructive lung disease Dementia Malignancy Liver disease Renal disease Dialysis Cardiac arrhythmia/atrial fibrillation Cerebrovascular disease Interstitial lung disease Cerebrovascular disease Peripheral vascular disease Coronary risk factors Diabetes mellitus Hypertension Hyperlipidemia Cardiac surgery *Previous valve surgery TAVI procedure Nontransfemoral Transfemoral TAVI procedure status Elective Urgent/emergent TAVI valve type Edwards Medtronic Missing Other TAVI waiting location Home Acute hospitalization Other

0 (n = 227)

1-2 (n = 552)

3 or LM (n = 109)

Total (n = 888)

p Value

83.88 § 6.11 122 (53.7%) 105 (46.3%)

84.16 § 6.54 227 (41.1%) 325 (58.9%)

82.01 § 7.67 27 (24.8%) 82 (75.2%)

83.82 § 6.61 376 (42.3%) 512 (57.7%)

0.008 <.001

32 (14.1%) 55 (24.2%) 40 (17.6%) 47 (20.7%) 53 (23.3%) 27 (11.9%)

69 (12.5%) 110 (19.9%) 117 (21.2%) 127 (23.0%) 126 (22.8%) 49 (8.9%)

17 (15.6%) 20 (18.3%) 18 (16.5%) 25 (22.9%) 28 (25.7%) 14 (12.8%)

118 (13.3%) 185 (20.8%) 175 (19.7%) 199 (22.4%) 207 (23.3%) 90 (10.1%)

0.53

1.99 § 1.95

1.81 § 1.77

1.90 § 1.96

1.87 § 1.84

0.47

3.90 § 5.58 169 (74.4%) 70 (30.8%) 25 (11.0%) 18 (7.9%) 0 (0.0%) 25 (11.0%) 5 (2.2%) 59 (26.0%) 19 (8.4%) 2 (0.9%) 8 (3.5%) 9 (4.0%)

2.98 § 4.37 417 (75.5%) 198 (35.9%) 44 (8.0%) 29 (5.3%) 7 (1.3%) 54 (9.8%) 14 (2.5%) 139 (25.2%) 31 (5.6%) 6 (1.1%) 17 (3.1%) 42 (7.6%)

2.25 § 3.35 77 (70.6%) 34 (31.2%) 9 (8.3%) 8 (7.3%) 0 (0.0%) 5 (4.6%) 4 (3.7%) 17 (15.6%) 6 (5.5%) 0 (0.0%) 3 (2.8%) 3 (2.8%)

3.12 § 4.63 663 (74.7%) 302 (34.0%) 78 (8.8%) 55 (6.2%) 7 (0.8%) 84 (9.5%) 23 (2.6%) 215 (24.2%) 56 (6.3%) 8 (0.9%) 28 (3.2%) 54 (6.1%)

0.004 0.56 0.32 0.39 0.32 0.12 0.16 0.72 0.08 0.33 0.55 0.92 0.05

108 (47.6%) 217 (95.6%) 142 (62.6%)

232 (42.0%) 525 (95.1%) 384 (69.6%)

53 (48.6%) 100 (91.7%) 75 (68.8%)

393 (44.3%) 842 (94.8%) 601 (67.7%)

0.23 0.29 0.16

0 (0.0%)

6 (1.1%)

1 (0.9%)

7 (0.8%)

0.29

26 (11.5%) 201 (88.5%)

86 (15.6%) 465 (84.2%)

22 (20.2%) 87 (79.8%)

134 (15.1%) 753 (84.8%)

0.26

183 (80.6%) 44 (19.4%)

443 (80.3%) 109 (19.7%)

88 (80.7%) 21 (19.3%)

714 (80.4%) 174 (19.6%)

0.99

82 (36.1%) 80 (35.2%) 54 (23.8%) 11 (4.8%)

238 (43.1%) 170 (30.8%) 110 (19.9%) 34 (6.2%)

42 (38.5%) 31 (28.4%) 24 (22.0%) 12 (11.0%)

362 (40.8%) 281 (31.6%) 188 (21.2%) 57 (6.4%)

0.16

166 (73.1%) 37 (16.3%) 24 (10.6%)

408 (73.9%) 84 (15.2%) 60 (10.9%)

81 (74.3%) 20 (18.3%) 8 (7.3%)

655 (73.8%) 141 (15.9%) 92 (10.4%)

0.79

0.76

TAVI = transcatheter aortic valve implantation. * Previous valve surgery (including mitral/tricuspid and/or pulmonary).

was impressive interhospital variation in the proportion of TAVI cases that had preprocedural PCI, ranging from 17.6% to 73.5%. The proportions of number vessels disease (0, 1, 2, 3, and LM) and the baseline characteristics stratified by number of diseased vessels are presented in Figure 2 and in Table 1, respectively. In our cohort, before TAVI, 25.6% had no residual coronary disease, 46.8% had 1 vessel disease, 15.4% had 2 vessels disease, 5.7% had 3 vessels

disease, and 6.6% had untreated LM disease. In Appendix Table 1, we present the baseline characteristics based on PCI group versus non-PCI group before the TAVI. Crude outcomes stratified by the number of diseased vessels are found in Table 2; we found no significant differences. In Appendix Table 2, we present outcomes based on the whether there was a PCI before the TAVI. There were no crude differences between PCI versus non-PCI groups in 30-day mortality or 30-day readmission. In terms of

ARTICLE IN PRESS Valvular Heart Disease/PCI, Coronary Artery Disease, and TAVI

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Table 2 Crude Outcomes by vessel number pre-TAVI Number of coronary arteries narrowed

Mortality Within 30 days Within 1 year All-cause hospital readmission Within 30 days Within 1 year Other complications In-hospital cerebrovascular accident/transient ischemic attack In-hospital any bleeding In-hospital major bleeding In-hospital minor bleeding In-hospital no bleeding In-hospital acute kidney injury In hospital dialysis In-hospital acute kidney injury requiring dialysis Pacemaker insertion at the time of the TAVI procedure Length of stay (days) TAVI procedure to discharge (mean §SD) TAVI admission to discharge (mean §SD)

0 (n = 227)

1-2 (n = 552)

3 or LM (n = 109)

Total (n = 888)

p Value

16 (7.0%) 39 (17.2%)

34 (6.2%) 91 (16.5%)

11 (10.1%) 24 (22.0%)

61 (6.9%) 154 (17.3%)

0.33 0.38

28 (12.3%) 87 (38.3%)

95 (17.2%) 253 (45.8%)

18 (16.5%) 47 (43.1%)

141 (15.9%) 387 (43.6%)

0.24 0.16

6 (2.6%) 31 (13.7%) 20 (8.8%) 11 (4.8%) 196 (86.3%) 9 (4.0%) 5 (2.2%) 1 (0.4%) 28 (12.3%)

21 (3.8%) 56 (10.1%) 34 (6.2%) 22 (4.0%) 496 (89.9%) 12 (2.2%) 14 (2.5%) 1 (0.2%) 85 (15.4%)

2 (1.8%) 8 (7.3%) 4 (3.7%) 4 (3.7%) 101 (92.7%) 4 (3.7%) 1 (0.9%) 0 (0.0%) 16 (14.7%)

29 (3.3%) 95 (10.7%) 58 (6.5%) 37 (4.2%) 793 (89.3%) 25 (2.8%) 20 (2.3%) 2 (0.2%) 129 (14.5%)

0.47 0.17 0.40

7.48 § 8.14 10.57 §11.64

8.41 § 16.82 11.48 § 19.18

10.45 § 21.73 13.00 § 22.48

8.42 §15.84 11.43 §18.03

0.28 0.51

0.33 0.58 0.68 0.54

TAVI = transcatheter aortic valve implantation.

complications, the only difference was seen in bleeding, where a higher proportion of post-PCI patients had a major bleed (7.7% vs 5.4%, respectively, p value ≤0.01). In all models, we found that the interaction term between severity of CAD and pre-TAVI PCI was not statistically significant. Therefore, the results of the Cox models without the interaction term are reported in Table 3. We found that neither the number of disease vessels nor PCI before TAVI were significantly associated with either 30-day or 1-year mortality. In regard to readmission, we found mixed results. There was no association between 3-vessel disease or PCI; however, presence of 1 to 2 vessel/s disease was a significant predictor of 1 year but not of 30-day readmission. The full models are found in Appendix Tables 3a to b. Discussion In this study of all contemporary TAVI patients with CAD in Ontario, we found no consistent relation between

severity of CAD, or pre-TAVI PCI with post-TAVI outcomes. Our findings have reinforced the uncertainty regarding the optimal management of severe AS with concomitant CAD. Based on contemporary guidelines, CABG is recommended in patients with a primary indication for SAVR and concomitant CAD (Class I). However, performing PCI in patients who underwent TAVI is a Class IIa recommendation, highlighting the paucity of evidence.30 The literature shows conflicting outcomes associated with performing PCI before TAVI, with some studies demonstrating favorable outcomes whereas others showing no benefit.16,18,19 The majority of the data are from the early TAVI era between the years 2005 and 2014, and were collected from single centers with small sample size.9,13,18 As experience with TAVI has grown and the indications expanded, understanding the impact of CAD on post-TAVI outcomes in a contemporary era is important.

Table 3 Cox model—Number of coronary arteries narrowed pre-TAVI Mortality Within 30 days 0 1-2 HR (95% CI) 0.76 (0.38-1.50) p Value 0.42 3 or LM HR (95% CI) 1.50 (0.54-4.2) p Value 0.44 Percutaneous coronary intervention prior TAVI HR (95% CI) 0.92 (0.50-1.67) p Value 0.77

Readmission Within 1 year

Within 30 days

Within 1 year

1.01 (0.81-1.26) 0.93

1.28 (0.85-1.93) 0.24

1.34 (1.05-1.71) 0.02

1.49 (0.86-2.57) 0.15

1.22 (0.74-2.01) 0.44

1.30 (0.95-1.77) 0.10

1.21(0.79-1.86) 0.39

0.95 (0.71-1.25) 0.70

1.09 (0.92-1.29) 0.33

Reference

CI = confidence interval; HR = hazard ratio; TAVI = transcatheter aortic valve implantation.

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Our study found no significant differences in the majority of clinical outcomes regardless of whether patients who underwent or did not undergo a pre-TAVI PCI. We were limited by the absence of data on angina severity before and after TAVI which may have been impacted by revascularization. However, our study also found that pre-TAVI PCI may be associated with an increase in the VARC-2 major bleeding rate. This finding may be explained need for dual antiplatelet therapy if TAVI is performed shortly after PCI. It is important to interpret these bleeding results in the context that subsequent device iterations have resulted in smaller sheath sizes used today compared with the period of this study. We did not find a consistent relation between severity of CAD and post-TAVI outcomes. Indeed, we found a relation with hospitalizations with 2-vessel disease but not more severe, which may be related to chance, as the pathophysiologic rationale is unclear. Again, this reinforces the notion that revascularization may not be necessary and suggests that CAD therapy can be deferred until after the valve disease is addressed. The findings of this study should be considered in the context of several limitations that merit discussion. First, our study may have been underpowered for some of the outcomes. Indeed, we did find numerically higher rates of 30day and 1-year mortality in patients with left main and 3-vessel disease. Second, we did not have elements such as the specific segment of coronary artery that was diseased as these are not available in the dataset, or additional details of the lesion, such as complexity or calcification. As such, we were not able to calculate a Syntax score or make conclusions regarding the relation between the complexity of CAD and outcomes. Instead, we used a very basic classification based on number of diseased vessels. In addition, we defined severity of CAD based on visual anatomically severity, as opposed to functional severity based on FFR/IFR. There is substantial body of literature that has elucidated the limitations of visual anatomical estimation of coronary luminal stenosis. We did not include functional severity as this data is not available in the CorHealth registry and it is unclear if it is applicable to patients with concomitant severe aortic stenosis. We also lacked data on some important covariates, such as left ventricular ejection fraction. Finally, our study’s observational design is susceptible to selection bias and we could not account for potential unmeasured confounders. In conclusion, we found that neither the number of narrowed coronary vessels nor PCI before TAVI were consistently associated with outcomes. Given the potential harm associated with PCI before TAVI, we recommend a randomized trial in this area to help guide practice. Conflict of Interest Dr. Wijeysundera receives research funding from Medtronic Inc. and Edwards Life Sciences. Dr. Radhakrishnan is a proctor for Medtronic Inc. The other authors have no declarations of conflicts. Author Contribution Gabby G. Elbaz: data curation, writing—original draft preparation

Kayley A. Henning: conceptualization and methodology Feng Qiu: conceptualization and methodology Stephen E. Fremes: reviewing and editing Peter C. Austin: conceptualization, reviewing, and editing Ikki Komatsu: reviewing and editing Dennis T. Ko: conceptualization, reviewing, and editing Sam Radhakrishnan: reviewing and editing Harindra C. Wijeysundera: conceptualization, methodology, reviewing and editing, supervision Acknowledgment The authors acknowledge that the clinical registry data used in this publication is from participating hospitals through CorHealth Ontario which serves as an advisory body to the Ontario Ministry of Health and Long-Term Care (MOHLTC), is funded by the MOHLTC, and is dedicated to improving the quality, efficiency, access, and equity in the delivery of the continuum of adult cardiac, vascular, and stroke services in Ontario, Canada. The authors thank IMS Brogan Inc for use of their Drug Information Database. This study was supported by the Institute for Clinical Evaluative Science (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions, and statements expressed in the material are those of the authors, and not necessarily those of CIHI. The authors had access to all the study data, take responsibility for the accuracy of the analysis, and had authority over manuscript preparation and the decision to submit the manuscript for publication. Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. amjcard.2019.12.021. 1. Alcalai R, Viola N, Mosseri M, Beeri R, Leibowitz D, Lotan C, Gilon D. The value of percutaneous coronary intervention in aortic valve stenosis with coronary artery disease. Am J Med 2007;120:185 e7-e13. 2. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S, Investigators PT. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–1607. 3. Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, Thourani VH, Tuzcu EM, Miller DC, Herrmann HC, Doshi D, Cohen DJ, Pichard AD, Kapadia S, Dewey T, Babaliaros V, Szeto WY, Williams MR, Kereiakes D, Zajarias A, Greason KL, Whisenant BK, Hodson RW, Moses JW, Trento A, Brown DL, Fearon WF, Pibarot P, Hahn RT, Jaber WA, Anderson WN, Alu MC, Webb JG, Investigators P. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–1620. 4. Danson E, Hansen P, Sen S, Davies J, Meredith I, Bhindi R. Assessment, treatment, and prognostic implications of CAD in patients undergoing TAVI. Nat Rev Cardiol 2016;13:276–285.

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