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1 Supplementary Online Content Zusterzeel R, Selzman KA, Sanders WE, et al. Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patientlevel data. Published online June 23, JAMA Intern Med. doi: /jamainternmed emethods. etable 1. CRT-D to ICD Hazard Ratios for Outcomes by Sex in the Total Population etable 2. CRT-D to ICD Hazard Ratios for Heart Failure or Death in LBBB QRS Duration Intervals by Sex etable 3. CRT-D to ICD Hazard Ratios for Outcomes in LBBB and QRS Duration Groups of Main and Multivariable Adjusted Analysis by Sex efigure 1. CRT-D to ICD Hazard Ratios for Outcomes in non-lbbb QRS<150 and 150 ms Groups by Sex efigure 2. Kaplan-Meier Estimates of Heart Failure or Death in LBBB Stratified by Sex in QRS and 150 ms efigure 3. Kaplan-Meier Estimates of Death in LBBB Stratified by Sex in QRS and 150 ms efigure 4. Smoothed Spline Analysis for Women and Men with LBBB using QRS Duration as a Continuous Variable efigure 5. CRT-D to ICD Hazard Ratios for Outcomes in LBBB and QRS Duration Groups of Main and NYHA I/II Analysis by Sex ereferences. This supplementary material has been provided by the authors to give readers additional information about their work American Medical Association. All rights reserved.

2 Supplementary Appendix Cardiac Resynchronization Therapy in Women: FDA Meta-Analysis of Patient-Level Data Table of contents: emethods etable 1: CRT-D to ICD Hazard Ratios for Outcomes by Sex in the Total Population efigure 1: CRT-D to ICD Hazard Ratios for Outcomes in non-lbbb QRS<150 and 150 ms Groups by Sex etable 2: CRT-D to ICD Hazard Ratios for Heart Failure or Death in LBBB QRS Duration Intervals by Sex efigure 2: Kaplan-Meier Estimates of Heart Failure or Death in LBBB Stratified by Sex in QRS and 150 ms efigure 3: Kaplan-Meier Estimates of Death in LBBB Stratified by Sex in QRS and 150 ms efigure 4: Smoothed Spline Analysis for Women and Men with LBBB using QRS Duration as a Continuous Variable etable 3: CRT-D to ICD Hazard Ratios for Outcomes in LBBB and QRS Duration Groups of Main and Multivariable Adjusted Analysis by Sex efigure 5: CRT-D to ICD Hazard Ratios for Outcomes in LBBB and QRS Duration Groups of Main and NYHA I/II Analysis by Sex ereferences 2

3 emethods R Commands for Calculating Random Intercept Models for CRT-D Effect Across Trials The coxme library for R was used to determine random effects. 1,2 The following model codes were used: 1. Determining sex-by-treatment interactions in random intercepts for CRT-D effect across trials by subgroups: library(coxme); coxme(formula = Surv(time-to-event, event) a ~ treatment b + sex c + sex-by-treatment interaction d + (1 trial) e, data = data f ) 2. Determining random intercepts for CRT-D effect across trials in women and men by subgroups: library(coxme); coxme(formula = Surv(time-to-event, event) a ~ treatment b + (1 trial) c, data = data d ) a Time-to-event and event include one of either end points (heart failure event or death and death alone) b Treatment includes the CRT-D vs. ICD variable for all models c Sex includes either female or male d Sex-by-treatment interaction includes the sex variable multiplied by the treatment variable e Indicates the random intercept per trial f Data includes the specific subgroups for women and men separately (total database, LBBB, non-lbbb, QRS <150 ms, QRS 150 ms, ischemic heart failure etiology, non-ischemic heart failure etiology, LBBB , LBBB , LBBB , LBBB , LBBB , LBBB , LBBB 180, LBBB , LBBB 150) 3

4 etable 1. CRT-D to ICD Hazard Ratios for Outcomes by Sex in the Total Population Total population Women 0.40 Men 0.74 Left bundle branch block Women 0.33 Men 0.60 Non-Left bundle branch block Women 1.02 Men 1.12 QRS duration >150 Women 0.37 Men 0.56 QRS duration <150 Women 0.46 Men 1.09 Ischemic heart disease Women 0.55 Men 0.70 Non-ischemic heart disease Women 0.32 Men 0.79 Hazard Ratio (95% CI) P-value Heart Failure Interactio or Death n Hazard Ratio (95% CI) Death ( ) ( ) 0.85 ( ) ( ) 0.68 ( ) ( ) 1.21 ( ) ( ) 0.71 ( ) ( ) 1.03 ( ) ( ) 0.87 ( ) ( ) 0.70 P-value Interactio n ( ) 0.03 ( ) ( ) 0.08 ( ) ( ) 0.58 ( ) ( ) 0.11 ( ) ( ) 0.15 ( ) ( ) 0.22 ( ) ( ) 0.22 ( ) CRT-D to ICD hazard ratios including 95% confidence intervals for heart failure event or death (left) and for death alone (right) in subgroups separately in women and men. P-values represent sex-by-treatment interactions. This is the same information that is displayed in Figure 1. 4

5 efigure 1. CRT-D to ICD Hazard Ratios for Outcomes in non-lbbb QRS<150 and 150 ms Groups by Sex Points reflect CRT-D to ICD hazard ratios for heart failure event or death (left) and for death alone (middle) in subgroups separately in women and men for non-lbbb patients. Solid lines indicate 95% confidence intervals. P-values represent sex-by-treatment interactions. Number of events and total subjects are listed for each subgroup. 5

6 etable 2. CRT-D to ICD Hazard Ratios for Heart Failure Event or Death in LBBB QRS Duration Intervals by Sex Hazard Ratio (95% CI) QRS duration Heart Failure or Death intervals (ms) Women Men ( ) 1.49 ( ) ( ) 0.77 ( ) ( ) 0.92 ( ) ( ) 0.56 ( ) ( ) 0.41 ( ) ( ) 0.51 ( ) ( ) 0.44 ( ) CRT-D to ICD hazard ratios including 95% confidence intervals for heart failure event or death in women (left) and men (right) across QRS duration intervals. 6

7 efigure 2: Kaplan-Meier Estimates of Heart Failure or Death in LBBB Stratified by Sex in QRS and 150 ms Curves reflect the probability of heart failure event or death in women (left) and men (right) with CRT-D (solid line) or ICD (dotted line) in QRS duration (top) and 150 ms (bottom). Log rank P-values are listed on each graph. The number of patients remaining (and event rate) is listed at each year of follow-up. 7

8 efigure 3: Kaplan-Meier Estimates of Death in LBBB Stratified by Sex in QRS and 150 ms Curves reflect the probability of death in women (left) and men (right) with CRT-D (solid line) or ICD (dotted line) in QRS duration (top) and 150 ms (bottom). Log rank P-values are listed on each graph. The number of patients remaining (and event rate) is listed at each year of follow-up. 8

9 efigure 4: Smoothed Spline Analysis for Women and Men with LBBB using QRS Duration as a Continuous Variable Curves reflect the CRT-D to ICD hazard ratio (blue) and 95% confidence intervals (red) for heart failure event or death in women (left) and men (right) with left bundle branch block using QRS duration as a continuous variable. The black horizontal line indicates hazard ratio = 1. 9

10 etable 3. CRT-D to ICD Hazard Ratios for Outcomes in LBBB and QRS Duration Groups of Main and Multivariable Adjusted Analysis by Sex QRS Duration Group ms Hazard Ratio (95% CI) Heart Failure or Death P- value Interac tion Hazard Ratio (95% CI) Death P- value Interac tion Main Women 0.64 ( ) ( ) 0.92 Men 1.49 ( ) 0.76 ( ) Women N/A N/A N/A N/A N/A N/A Multivari ( able Men ) N/A N/A ms Main Women 0.24 Multivari able Men 0.85 Women 0.23 Men ms Main Women 0.33 Multivari able Men 0.47 Women 0.33 Men 0.44 ( ) ( ) 0.86 ( ) ( ) 0.90 ( ) ( ) 0.65 ( ) ( ) 0.62 ( ) ( ) ( ) ( ) ( ) 0.20 ( ) ( ) 0.22 ( ) CRT-D to ICD hazard ratios including 95% confidence intervals for heart failure event or death (left) and for death alone (right) in subgroups separately in women and men for the main and multivariable adjusted analysis. P-values represent sex-by-treatment interactions. This is the same information that is displayed in Figure 3. 10

11 efigure 5. CRT-D to ICD Hazard Ratios for Outcomes in LBBB and QRS Duration Groups of Main and NYHA I/II Analysis by Sex Points reflect CRT-D to ICD hazard ratios for heart failure event or death (left) and for death alone (middle) in subgroups separately in women and men for the main analysis and NYHA class I and II patients. Solid lines indicate 95% confidence intervals. P-values represent sex-by-treatment interactions. Number of events and total subjects are listed for each subgroup. 11

12 ereferences 1. R: A Language and Environment for Statistical Computing. 2013; Accessed April 15, Package coxme for R. 2013; Accessed April 15,