Accepted Manuscript Surgery is Not Associated with Improved Survival Compared to Medical Therapy in Isolated Severe Tricuspid Regurgitation Andrea L. Axtell, MD, Vijeta Bhambhani, MS, MPH, Philicia Moonsamy, MD, Emma W. Healy, BS, Michael H. Picard, MD, Thoralf M. Sundt, MD, Jason H. Wasfy, MD PII: S0735-1097(19)34996-4 DOI: https://doi.org/10.1016/j.jacc.2019.04.028 Reference: JAC 26233 To appear in: Journal of the American College of Cardiology Received Date: 8 January 2019 Revised Date: 10 April 2019 Accepted Date: 25 April 2019 Please cite this article as: Axtell AL, Bhambhani V, Moonsamy P, Healy EW, Picard MH, Sundt TM, Wasfy JH, Surgery is Not Associated with Improved Survival Compared to Medical Therapy in Isolated Severe Tricuspid Regurgitation, Journal of the American College of Cardiology (2019), doi: https:// doi.org/10.1016/j.jacc.2019.04.028. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Accepted Manuscript
Surgery is Not Associated with Improved Survival Compared to Medical Therapy inIsolated Severe Tricuspid Regurgitation
Andrea L. Axtell, MD, Vijeta Bhambhani, MS, MPH, Philicia Moonsamy, MD, EmmaW. Healy, BS, Michael H. Picard, MD, Thoralf M. Sundt, MD, Jason H. Wasfy, MD
PII: S0735-1097(19)34996-4
DOI: https://doi.org/10.1016/j.jacc.2019.04.028
Reference: JAC 26233
To appear in: Journal of the American College of Cardiology
Received Date: 8 January 2019
Revised Date: 10 April 2019
Accepted Date: 25 April 2019
Please cite this article as: Axtell AL, Bhambhani V, Moonsamy P, Healy EW, Picard MH, Sundt TM,Wasfy JH, Surgery is Not Associated with Improved Survival Compared to Medical Therapy in IsolatedSevere Tricuspid Regurgitation, Journal of the American College of Cardiology (2019), doi: https://doi.org/10.1016/j.jacc.2019.04.028.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.
Surgery is Not Associated with Improved Survival Compared to Medical Therapy in Isolated Severe Tricuspid Regurgitation Andrea L. Axtell, MDa,c, Vijeta Bhambhani, MS, MPHb, Philicia Moonsamy, MDa,d, Emma W. Healy, BSb, Michael H. Picard, MDb, Thoralf M. Sundt, MDa, and Jason H. Wasfy, MDb a Corrigan Minehan Heart Center and Division of Cardiac Surgery; Massachusetts General Hospital b Division of Cardiology, Department of Medicine, Massachusetts General Hospital c Minehan Outcomes Fellow, Corrigan Minehan Heart Center d Martignetti Outcomes Fellow, Division of Cardiac Surgery Brief Title: Surgery for Severe TR Funding: This work was funded in part from grants from the American Heart Association (18 CDA 34110215), the National Institutes of Health and Harvard Catalyst (KL2 TR001100), and the Massachusetts General Hospital Corrigan Minehan Heart Center SPARK grant, all awarded to Dr. Wasfy. Disclosures: None of the authors have a relevant conflict of interest to disclose. Meeting Presentation: Presented at the AATS Annual Meeting, Toronto, Canada, May 2019 Tweet: “In patients with isolated severe tricuspid regurgitation, surgery is not associated with improved survival compared to medical therapy alone.” Corresponding Author: Jason H. Wasfy, MD, MPhil Massachusetts General Hospital 55 Fruit Street Boston, MA 02114 Telephone: 617-726-2000 Fax: 617-726-5804 Email: [email protected] Twitter: @jasonwasfy
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Abstract Background: Patients with isolated tricuspid regurgitation (TR) in the absence of left-sided valvular dysfunction are historically managed nonoperatively. Objectives: To assess the impact of surgery for isolated TR, we compared survival for isolated severe TR patients who underwent surgery to those who did not. Methods: A longitudinal echocardiography database was used to perform a retrospective analysis on 3,276 adult patients with isolated severe TR from November 2001-March 2016. All-cause mortality for patients who underwent surgery versus those who did not was analyzed in the entire cohort and a propensity-matched sample. To assess the possibility of immortal time bias, the analysis was performed considering time from diagnosis to surgery as a time-dependent covariate. Results: Of 3,276 patients with isolated severe TR, 171 (5%) underwent tricuspid valve surgery, including 143 (84%) repairs and 28 (16%) replacements. The remaining 3,105 (95%) patients were medically managed. When considering surgery as a time-dependent covariate in a propensity matched sample, there was no difference in overall survival between patients who received medical versus surgical therapy (HR 1.34 [0.78-2.30], p=0.288). In the subgroup that underwent surgery, there was no difference in survival between tricuspid repair versus replacement (HR 1.53 [0.74-3.17], p=0.254). Conclusion: In patients with isolated severe TR, surgery is not associated with improved long-term survival compared to medical management alone after accounting for immortal time bias. Condensed Abstract: To assess the effect of surgery for isolated severe TR on mortality, we compared survival for patients who underwent surgery to those who did not. In a propensity-matched sample considering surgery as a time-dependent covariate, there was no difference in overall survival between patients who received medical versus surgical management (HR 1.34 [0.78-2.30], p=0.288).These results underscore the importance of accounting for immortal time bias in observational comparative-effectiveness research and suggest that in patients with isolated severe TR, surgery is not associated with improved long-term survival. Key Words: Isolated severe tricuspid regurgitation, immortal time bias, survival analysis Abbreviations: CABG – Coronary Artery Bypass Graft NIS – Nationwide Inpatient Sample RPDR - Partners Research Data Repository TR - Tricuspid Regurgitation VSD - Ventricular Septal Defect
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Introduction
Moderate to severe tricuspid valve regurgitation (TR) affects >1.6 million people in the
United States and is generally associated with a poor prognosis (1). Most patients with
significant TR have concomitant left-sided heart disease and heart failure. Historically, these
patients were treated with medical therapy targeting the underlying disease processes and
diuretics to address volume overload (2). It is generally unclear if these therapies alter prognosis
or improve symptoms, especially in patients with primary valve disease(3). Current American
College of Cardiology/American Heart Association guidelines now recommend tricuspid valve
surgery for patients with severe, symptomatic TR, especially those with annular dilation and
right heart failure. However, this is associated with a weak (Class C) level of evidence and is
only recommended in patients undergoing concomitant left-sided valve surgery (4). As a result,
only about 500 patients in the U.S. undergo surgery for isolated tricuspid regurgitation each year
(4).
While the clinical significance of TR is well established in patients with left-sided
valvular heart disease, the impact of isolated TR was only recently described in 2004 when it
was shown to be a significant predictor of mortality independent of the underlying degree of
pulmonary hypertension or ventricular function(5). Recent studies have reported a growing
population of adult patients without left-sided heart disease, pulmonary hypertension, or
congenital abnormalities who are developing isolated severe TR (1). However, the role of
surgery in these patients is unclear. Single center studies have reported variable perioperative
outcomes and long-term mortality rates following isolated tricuspid valve surgery (6) and there is
a distinct lack of comparative outcomes for medically versus surgically treated patients.
Furthermore, percutaneous techniques to repair or replace the tricuspid valve are in development
RVSP, mmHg 54.4 ± 19.9 52.6 ± 22.7 0.47 52.3 ± 22.2 44.8 ± 21.2 0.37 * COPD – Chronic Obstructive Pulmonary Disease; LVEF – left ventricular ejection fraction; RVSP – right ventricular systolic pressure; RV – right ventricle ╪ Standardized bias assesses the balance of a measured covariate between comparison groups in a propensity matched analysis. A covariate is considered well-balanced if the standardized bias is <0.10.
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Table 2: Multivariable Predictors of Mortality in Propensity Matched Sample Adjusting for Time from Diagnosis to Surgery as a Time Dependent Covariate
Table 3: Multivariable Predictors of Mortality in Surgical Subgroup Risk Factors HR 95% CI p-value TV Intervention Replacement Ref Repair 1.53 0.74-3.17 0.254 Age, years 1.04 1.02-1.06 <0.001 Sex, female 0.77 0.47-1.26 0.298 Year of Operation 2001-2006 Ref 2007-2011 0.49 0.24-1.00 0.06 2012-2016 0.46 0.18-1.14 0.09 Hypertension 0.72 0.44-1.17 0.182 Coronary Artery Disease 0.80 0.44-1.46 0.472 Heart Failure 2.86 1.46-5.62 0.002 Chronic Kidney Disease 1.32 0.76-2.28 0.329 COPD 1.42 0.80-2.51 0.234 LVEF, % 1.00 0.98-1.01 0.521 * Model also includes adjustment for patient race. HR – Hazard Ratio; CI – Confidence Interval; COPD – Chronic Obstructive Pulmonary Disease; LVEF – Left Ventricular Ejection Fraction
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Supplemental Material Sensitivity Analysis #1: RVSP Included in Propensity Model Supplemental Table S1: Baseline Characteristics of Entire Cohort and Propensity Matched Sample Including RVSP in Model
† Standardized bias assesses the balance of a measured covariate between comparison groups in a propensity matched analysis. A covariate is considered well-balanced if the standardized bias is less than 0.10.
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Supplemental Table S2: Multivariable Predictors of Mortality in Propensity Matched Sample Including PAP in Model
Risk Factors HR 95% CI p-value
Management Medical Ref
Surgical 0.71 0.38-1.30 0.270 Age, years 1.01 0.99-1.03 0.334 Sex, female 0.60 0.32-1.11 0.106 Hypertension 1.14 0.56-2.31 0.722 Coronary Artery Disease 1.10 0.40-3.02 0.722 Heart Failure 2.93 1.25-6.87 0.013 Chronic Kidney Disease 1.86 1.00-3.47 0.050 COPD 0.76 0.36-1.62 0.480 RVSP, mmHg 0.99 0.98-1.01 0.668 * Model accounts for time from diagnosis to surgery as a time-dependent covariate. HR – Hazard Ratio; CI – Confidence Interval; COPD – Chronic Obstructive Pulmonary Disease; RVSP – right ventricular systolic pressure
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Sensitivity Analysis #2: Loyalty Cohort
Supplemental Table S3: Baseline Characteristics of Loyalty Cohort and Propensity Matched Loyalty Sample
* COPD – Chronic Obstructive Pulmonary Disease; LVEF – left ventricular ejection fraction; RVSP – right ventricular systolic pressure
† Standardized bias assesses the balance of a measured covariate between comparison groups in a propensity matched analysis. A covariate is considered well-balanced if the standardized bias is less than 0.10.
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Online Figure 1: Loyalty Cohort
(A) Unadjusted comparison in entire loyalty cohort accounting for time from diagnosis of severe
TR to surgery as a time-dependent covariate. (B) Propensity matched loyalty sample accounting
for time from diagnosis to surgery as a time dependent covariate.
* Hazard ratio (HR) is for surgery relative to medical management. Curves generated using an
extended Kaplan-Meier estimator which allows the cohorts to vary with time depending on the
covariate pattern (surgery vs no surgery.) The time of origin is the first echocardiographic
diagnosis of severe TR for all patients, however, each curve does not correspond to a fixed
cohort of patients, as surgical patients are allowed to contribute risk to the medical group prior to
the time of surgery.
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Sensitivity Analysis #3: Considering Covariate Pattern at Time of Surgery
* The following analyses (S4&S5) consider the covariate pattern in the surgical group AT THE TIME OF SUGERY (as opposed to the time of diagnosis as reported in the primary analysis.)
Supplemental Table S4: Baseline Characteristics of Entire Cohort and Propensity Matched Sample Considering Covariate Pattern at Time of Surgery
* COPD – Chronic Obstructive Pulmonary Disease; LVEF – left ventricular ejection fraction; RVSP – right ventricular systolic pressure
† Standardized bias assesses the balance of a measured covariate between comparison groups in a propensity matched analysis. A covariate is considered well-balanced if the standardized bias is less than 0.10.
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Supplemental Table S5: Multivariable Predictors of Mortality in Propensity Matched Sample Including PAP in Model
* Model accounts for time from diagnosis to surgery as a time-dependent covariate. HR – Hazard Ratio; CI – Confidence Interval; COPD – Chronic Obstructive Pulmonary Disease