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SUPPLEMENTAL DATA
Supplemental Table 1: Baseline characteristics of patients with missing data that were excluded from the final analytic cohort versus those included
Supplemental Table 2: Adjusted mortality hazard ratios with 95% CI for female gender in the analytic cohort (patients with no missing data) and imputed dataset
Supplemental Table 3: Mediation analysis results reported as total effect and indirect effect of female gender on mortality
Supplemental data: E-value for association of female gender with early mortality
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Supplemental Table 1 Baseline characteristics of patients with missing data that were excluded from the final analytic cohort versus those included
Patients with missing data
(n=5,933)
Analytic cohort (n=9,565)
P-value
Age at implant, years 55.58 (13.14) 56.23 (13.15) 0.003
Female gender 1,159 (19.5%) 2,066 (21.6%) 0.002
Body Surface Area, m2 2.03 (0.30) 2.06 (0.32) <0.001
Centrifugal Pump 2,589 (43.6%) 2,972 (31.1%) <0.001
Ischemic heart failure etiology 1,931 (42.1%) 3,765 (39.4%) 0.002 Cardiogenic Shock at implant
(INTERMACS 1 and 2 vs. profiles 3-7)
1,094 (18.7%) 1,282 (13.4%) <0.001
Serum Sodium, meq/L 135.69 (5.43) 134.97 (4.63) <0.001
BUN, mg/dL 35.07 (28.81) 29.24 (19.28) <0.001
Hemoglobin, gm/dL 11.60 (6.29) 11.38 (2.32) 0.002
INR 1.40 (0.55) 1.31 (0.40) <0.002
Total Bilirubin, mg/dL 1.53 (2.47) 1.31 (1.40) <0.001
Stages of CKD
• 1-2
• 3A
• 3B
• 4-5
2,907 (51.3%) 1,279 (22.6%) 1,043 (18.4%) 434 (7.7%)
4,901 (51.2%) 2,311 (24.2%) 1,754 (18.3%) 599 (6.2%)
<0.001
MELD score 11.99 (6.55) 11.39 (5.72) <0.001
3 Heart Mate 2 Risk Score category
• Low Risk
• Medium Risk
• High Risk
1,926 (49.8%) 1,279 (33.1%) 659 (17.1%)
5,236 (54.7%) 3,109 (32.5%) 1,220 (12.8%)
<0.001
PA Diastolic Pressure, mm Hg 25.08 (9.54) 25.03 (8.92) 0.79
Cardiac Index, L/min/m2 2.05 (0.68) 2.04 (0.67) 0.46
BUN: Blood Urea Nitrogen; CKD stage: Chronic Kidney Disease Stage; INR: International Normalized Ratio; INTERMACS Profile: Interagency Registry for
Mechanical Circulatory Support Profile; MELD score: Model for End Stage Liver Disease score;
PA Diastolic Pressure: Pulmonary Artery Diastolic Pressure
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Supplemental Table 2 Adjusted mortality hazard ratios with 95% CI for female gender in the analytic cohort (patients with no missing data) and imputed dataset
Analytic cohort (n=9,565) Imputed dataset* (n=15,498)
HR [95% CI] P-value HR [95% CI] P-value
Over entire follow-up duration 1.36 [1.21 - 1.53] <0.0001 1.39 [1.27 - 1.53] <0.0001
Gender*follow-up time interaction NA 0.02 NA 0.006
In the first 4 months after implant 1.74 [1.47 - 2.06] <0.0001 1.73 [1.51 - 1.97] <0.0001 Landmark analysis after 4 months 1.12 [0.96 - 1.31] 0.16 1.18 [1.05 - 1.34] 0.007
*Results from five imputed data sets were aggregated following Rubin’s rules.
Adjusted mortality hazard ratios with 95% CI for female gender in the analytic cohort (patients with no missing data) and imputed dataset, adjusted for age, BSA, etiology of HF, pump type, presence of cardiogenic shock at implant (INTERMACS profiles 1 and 2 vs. profiles 3-7), serum sodium, BUN, total bilirubin, INR, Hemoglobin, CKD stage, MELD score, HMRS, PADP and CI.
BUN: Blood Urea Nitrogen; CKD stage: Chronic Kidney Disease Stage; INR: International Normalized Ratio; INTERMACS Profile:
Interagency Registry for Mechanical Circulatory Support Profile; MELD score: Model for End Stage Liver Disease score; PA Diastolic Pressure: Pulmonary Artery Diastolic Pressure
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Supplemental Table 3 Mediation analysis results reported as total effect and indirect effect
Mediator Total Effect Indirect Effect
Estimate P-value* Estimate P-value*
Time since cardiac diagnosis < 2 years -180.00 <0.0001 0.88 0.48 Pre-implant medical/device therapy
ICD -165.00 <0.0001 0.55 0.76
CRT -165.00 <0.0001 1.65 0.14
Aldosterone Antagonist -194.00 <0.0001 -2.69 0.07
Inotropes -148.00 <0.0001 -0.009 0.98
Amiodarone -161.00 <0.0001 -2.13 0.35
Pre-implant Echocardiographic data
Moderate to Severe MR -192.68 <0.0001 4.00 0.05
Moderate to Severe TR -183.00 <0.0001 -8.94 0.002†
LV End Diastolic Diameter, cm -191.83 <0.0001 -32.12 <0.0001†
Qualitative RV Function -161.00 <0.0001 -0.11 0.91
Pre-implant Inflammatory markers
Platelet count, x103/uL -181.00 <0.0001 2.84 0.01
Uric Acid, mg/dL -205.00 <0.0001 1.71 0.58
Lymphocyte count, % -174.29 <0.0001 3.97 0.09
Psychosocial and socioeconomic
Severe Depression -161.00 <0.0001 0.57 0.91
Other Major Psychiatric Disorder -158.00 <0.0001 -0.19 0.90
Marital status -280.76 <0.0001 8.51 0.09
Working for income -206.00 <0.0001 -4.26 0.08
6 Comorbidities
Solid Organ Cancer -173.00 <0.0001 -2.04 0.03
Recent Pulmonary Embolism -163.00 <0.0001 4.14 0.38
Lymphoma or Leukemia -162.00 <0.0001 -0.15 0.90
*A raw P-value <0.0025 meets Bonferroni corrected P-value significance
†Bonferroni corrected P-value significant
Accelerated Failure Time (AFT) mediation analysis results are decomposed into the total effect of female gender on mortality (path ab + c in the figure below), and the indirect effect mediated via the mediator (path ab in the figure below). In the AFT model, negative estimates indicate shorter survival time, ie increased hazard of death.
All models are adjusted for age, BSA, etiology of HF, pump type, presence of cardiogenic shock at implant (INTERMACS profiles 1 and 2 vs. profiles 3-7), serum sodium, BUN, total bilirubin, INR, hemoglobin, CKD stage, MELD score, HMRS, PADP and CI.
BUN: Blood Urea Nitrogen; CKD stage: Chronic Kidney Disease Stage; CRT: Cardiac Resynchronization Therapy; ICD: Implantable Cardioverter-Defibrillator; INR: International Normalized Ratio; INTERMACS Profile: Interagency Registry for
Mechanical Circulatory Support Profile; LVEDD: Left Ventricular End Diastolic Diameter; MELD score: Model for End Stage Liver Disease score; MR: Mitral Regurgitation; PA Diastolic
Pressure: Pulmonary Artery Diastolic Pressure; TR: Tricuspid Regurgitation
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Supplemental data E-value for association of female gender with early mortality
The E-value is defined as the minimum strength of association that an unmeasured confounder would need to have with both the exposure and the outcome to fully explain away the exposure- outcome association, conditional on the measured covariates.1 It is suggested that all
observational studies reporting evidence on causality include an E-value, in order to allow the scientific community to interpret findings in the context of a non-randomized study design.1,2 In the analysis of the association between female gender and early mortality, the observed hazard ratio of 1.74 could be explained away by an unmeasured confounder that was associated with both female gender and early mortality by a risk ratio of 2.29, above and beyond the measured confounders, but weaker confounding could not do so. Similarly, the corresponding confidence intervals could be moved to include the null by an unmeasured confounder that was associated with both female gender and early mortality by a risk ratio of 1.94, above and beyond the measured confounders, but weaker confounding could not do so.
Supplemental Reference
1. VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med. 2017;167:268-274.
2. Haneuse S, VanderWeele TJ, Arterburn D. Using the E-value to assess the potential effect of unmeasured confounding in observational studies. Jama. 2019;321(6):602-3.
