Supplementary Online Content. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and

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1 1 Supplementary Online Content Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on sympton burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA. doi: /jama etable 1. Study Inclusion and Exclusion Criteria etable 2. Changes in Atrial Fibrillation Severity Scores (AFSS) at and 3 Months efigure 1. Complete Anthropometric Data and Use of Antihypertensives and Antiarrhythmic Agents Between the Study Groups efigure 2. Changes in Primary (AFSS Symptom Burden and Symptom Severity Scores) and Secondary Outcomes (AFSS Symptom Frequency, Symptom Duration and Global Episode Severity Scores), Between the 2 Groups etable 3. Sensitivity Analysis for the Primary Outcomes Following the Exclusion of Control Subjects Who Underwent an AF Ablation etable 4. Complete Structural Data for the Control and Intervention Study Subjects efigure 3. Outline of Obstructive Sleep Apnea Management in Each Study Group etable 5. Descriptive Comparisons Between the Retained and Dropout Study Subjects etable 6. Descriptive Comparison of Control and Intervention Subjects Who Dropped Out efigure 4. Propensity Score Analysis: Propensity Score Adjusted Outcomes, I: AFSS Symptom Burden Score and AFSS Symptom Severity Score

2 efigure 5. Propensity Score Analysis: Propensity Score Adjusted Outcomes, II: Secondary (Holter Data) and Post Hoc (AFSS) Analysis etable 7. Adverse Events Documented During the Study efigure 6. Sensitivity Analyses efigure 7. Imputation Analysis (I) for Subjects Undergoing AF Ablation (Return-to- Method) efigure 8. Imputation Analysis (II) for Subjects Undergoing AF Ablation (Last Observation Method) efigure 9. Atrial Fibrillation Severity Score (AFSS) Algorithm efigure 10. Mixed-Effects Models Analysis of Residuals I and II 36

3 37 etable 1. Study Inclusion and Exclusion Criteria Inclusion Criteria Patients years of age Exclusion Criteria Serious underlying medical disorder: e.g. malignancy, chronic uncontrolled autoimmune or inflammatory disorder. Patients with paroxysmal or persistent AF, in sinus rhythm at the time of recruitment Serious underlying psychiatric disorder: e.g. eating disorder, severe psychotic disorder with recent (3 month) hospitalization or psychiatric illness requiring supervised care precluding full independent function. Patients unable to provide informed consent. Recent weight loss program participation: Recent (3 month) participation in a weight loss program, either commercial or medically supervised. Gastrointestinal malabsorption disorder: A previously diagnosed gastrointestinal malabsorption disorder interfering with macro or micronutrient absorption. Unstable INR: Elevated INR (supra-therapeutic INR and concomitant bleeding or elevated INR requiring hospitalization for pharmacological reversal administration). Persistently sub therapeutic INR (<2.0 for 14 consecutive days) in a patient with a CHADS 2 thromboembolic risk score 2. The presence of diabetes mellitus (either autoimmune or adult-onset), necessitating insulin therapy. Moderate or severe cardiac valvular lesion (stenosis or regurgitation) on echocardiography or valvular lesion requiring intervention. Diagnosed endocrinopathy: Including subclinical thyroid disease (isolated abnormal serum thyrotropin levels)

4 etable 1 (Continued) Inclusion Criteria Exclusion Criteria Age >75 years or <18 years or women of childbearing age. Active gout or history of recurrent gout in the absence of prophylactic therapy. Previous or active gallbladder disease etable 1: Study recruitment inclusion and exclusion criteria. CHADS 2 specifies the composite thromboembolic risk in AF where C is cardiac failure (1), H is hypertension (1), A is age >75 (1), D is diabetes (1) and S is stroke or TIA (2). 42

5 43 44 etable 2. Changes in Atrial Fibrillation Severity Scores (AFSS) at and 3 Months Variable Stage Control Treatment P-value ( ) ( ) AFSS Symptom burden months ( ) ( ) AFSS Frequency 7.33 ( ) 7.09 ( ) months 7.06 ( ) 6.66 ( ) 7.37 ( ) 7.08 ( ) AFSS Duration months 7.27 ( ) 6.38 ( ) 6.90 ( ) 6.84 ( ) AFSS Global episode severity months 6.69 ( ) 6.59 ( ) ( ) ( ) AFSS Symptom severity months ( ) ( ) etable 2: Data presented as mean and 95% confidence interval. The P value represents the significance of the group-time interaction derived from the mixed effects model. AFSS Atrial fibrillation Severity Score. 47

6 efigure 1. Complete Anthropometric Data and Use of Antihypertensives and Antiarrhythmic Agents Between the Study Groups (cm ) efigure 1: Shown is the decrease in waist circumference (cm), body weight (kg) and body mass index (kgm -2 ) from baseline (enrolment), to 15 months follow-up, at each 3 month time point. Also shown is the number of antihypertensive and antiarrhythmic agents used over the study duration in each group. Shown below each graph is the number of subjects in each group at each time point. Data presented as mean and 95% confidence interval (CI).

7 efigure 2. Changes in Primary (AFSS Symptom Burden and Symptom Severity Scores) and Secondary Outcomes (AFSS Symptom Frequency, Symptom Duration and Global Episode Severity Scores), Between the 2 Groups efigure 2: Changes in Atrial Fibrillation Severity Score (AFSS) components between the 2 study groups, over the study followup duration. The primary outcomes of AF symptom burden and AF symptom severity score are shown (mean and 95% CI). Secondary analysis shows the 3 burden components of symptom frequency, symptom duration and episode global severity scores. Data shown as mean and 95% CI.

8 68 69 etable 3. Sensitivity Analysis for the Primary Outcomes Following the Exclusion of Control Subjects Who Underwent an AF Ablation Outcome Control (n=61) Treatment (n=75) P-value for betweengroup comparison P-value for group-time interaction AFSS Symptom burden Follow-up 21.8 ( ) 18.6 ( ) 20.5 ( ) 8.8 ( ) 0.4 AFSS Symptom severity Follow-up 16.3 ( ) 13.6 ( ) 15.5 ( ) 6.7 ( ) 0.3 AFSS Symptom frequency Follow-up 7.4 ( ) 6.5 ( ) 6.9 ( ) 3.3 ( ) 0.4 AFSS Symptom duration Follow-up 7.4 ( ) 6.3 ( ) 6.9 ( ) 2.4 ( ) 0.4 AFSS Episode severity Follow-up 7.0 ( ) 5.8 ( ) 6.7 ( ) 3.1 ( ) 0.7 Any AF on rhythm monitor Follow-up 31 (62%) 26 (57%) 46 (66%) 16 (23%) AF episodes on rhythm monitor Follow-up AF duration on rhythm monitor (min.) Follow-up 2.84 ( ) 2.04 ( ) 1394 ( ) 1546 ( ) 3.11 ( ) 0.60 ( ) 1176 ( ) 491 ( ) 0.2 etable 3: Sensitivity analysis. It is conceivable that subjects with a greater AF symptom burden and/or a greater arrhythmia recording burden may have undergone an ablation procedure preferentially. Their censorship may therefore potentially confound the observed group differences in the study results. This sensitivity analysis shown provides a conservative estimate of the treatment effect, by exclusion of control subjects who have undergone an ablation procedure. Re-analysis of the remaining subjects does not alter the observed study results with respect to the primary and secondary outcomes. Data shown as mean and 95% CI. AFSS, Atrial Fibrillation Severity Score.

9 etable 4. Complete Structural Data for the Control and Intervention Study Subjects BASELINE FOLLOW-UP Echo parameter CONTROL (75) INTERVENTION (75) CONTROL (52) INTERVENTION (57) P LA area indexed (cm 2 m -1 ) 14.0 ( ) 13.5 ( ) 12.9 ( ) 11.5 ( ) 0.02 LA volume indexed (mlm -1 ) 41.5 ( ) 39.4 ( ) 37.7 ( ) 34.3 ( ) 0.20 Posterior wall thickness (mm) 10.1 ( ) 10.3 ( ) 9.8 ( ) 9.2 ( ) Septal wall thickness (mm) 11.5 ( ) 11.3 ( ) 10.8 ( ) 10.2 ( ) 0.01 LVEDD (mm) 48 (47-49) 48 (47-49) 48 (46-49) 46 (45-47) 0.04 Myocardial mass indexed (gm -1 ) 1.2 ( ) 1.1 ( ) 1.1 ( ) 0.9 ( ) <0.01 A wave (ms.) 52.5 ( ) 54.9 ( ) 51.5 ( ) 57.1 ( ) 0.20 E wave (ms.) 73.2 ( ) 72.5 ( ) 79.1 ( ) 72.3 ( ) 0.10 E/A ratio 1.5 ( ) 1.4 ( ) 1.6 ( ) 1.4 ( ) 0.62 E deceleration time (ms.) ( ) ( ) ( ) ( ) 0.65 E (ms.) 6.4 ( ) 6.6 ( ) 7.1 ( ) 7.1 ( ) 0.32 E/E ( ) ( ) ( ) ( ) etable 4: Group-time interaction. LA area, LA volume and myocardial mass are indexed to body height. LA left atrium, LVEDD left ventricular end-diastolic diameter. Data presented as mean and 95% confidence interval (CI). 0.55

10 85 efigure 3. Outline of Obstructive Sleep Apnea Management in Each Study Group efigure 3: Conservative therapy includes either oral appliances or positional therapy. Patients not receiving either CPAP or conservative therapy (other than weight loss) were considered untreated. OSA obstructive sleep apnea, CPAP continuous positive airways pressure.

11 etable 5. Descriptive Comparisons Between the Retained and Dropout Study Subjects Characteristic Retained Drop-outs (n=109) (n=41) P-value Age (years) ( ) ( ) 0.2 Female, n (%) 38 (35) 11 (27) 0.35 Waist circumference (cm) ( ) ( ) 0.6 Weight (kg) ( ) ( ) 0.2 BMI (kg/m ) ( ) ( ) 0.4 BSA (m ) ( ) ( ) 0.2 Blood glucose (mg/dl) ( ) ( ) 0.8 Triglyceride (mg/dl) ( ) ( ) 0.09 Total cholesterol (mg/dl) ( ) ( ) 0.7 HDL (mg/dl) ( ) ( ) 0.3 LDL (mg/dl) ( ) ( ) 0.6 C-reactive protein (mg/l) ( ) ( ) 0.02 Duration of AF (months) ( ) ( ) 0.4 Longest episode of AF (hours) ( ) ( ) 0.8 Paroxysmal AF, n (%) 109 (73) 41 (27) 0.9 AFSS - Episode frequency ( ) ( ) 0.2 AFSS - Episode duration ( ) ( ) 0.8 AFSS - Episode severity ( ) ( ) 0.6 AFSS - Burden ( ) ( ) 0.4 AFSS - symptom severity subscale ( ) ( ) 0.7 No. antiarrhythmic drugs, n (%) (62.5) 3 (37.5) 1 60 (73) 22 (27) 2 44 (73) 16 (27) No. antihypertensive drugs, n (%) (72) 8 (28) 1 46 (72) 18 (28) 2 24 (71) 10 (29) 3 13 (81) 3 (19) 4 5 (71) 2 (29) Tobacco use, n (%) 0.8 Never 62 (70) 26 (30) Current 5 (71) 2 (29) Reformed 42 (76) 13 (24)

12 etable 5: Descriptive comparisons between the retained and drop-out study subjects (continued) CPAP use, n (%) Yes 10 (83) 2 (17) Characteristic Retained Drop-outs (n=109) (n=41) No 98 (73) 37 (27) 0.5 P-value OSA, n (%) 0.4 Absent 15 (88) 2 (12) Mild 34 (76) 11 (24) Moderate 22 (67) 11 (33) Severe 24 (77) 7 (23) Hypertension, n (%) 0.8 Absent 13 (68) 6 (32) Present 96 (73) 35 (27) SBP (mmhg) ( ) ( ) 0.9 DBP (mmhg) (81-85) (82-87) 0.3 Diabetes mellitus, n (%) 0.5 Absent 75 (71) 31 (29) Present 34 (77) 10 (23) Metformin use, n (%) 1.0 Absent 107 (73) 40 (27) Present 2 (67) 1 (33) Oral hypoglycemic use, n (%) 1.0 Absent 107 (73) 40 (27) Present 2 (67) 1 (33) Alcohol consumption, n (%) Absent 65 (67) 32 (33) Present 44 (83) 9 (17) Lipid-lowering therapy use, n (%) Absent 79 (71) 32 (29) Present 30 (77) 9 (23) etable 5: Shown is descriptive data comparing the baseline characteristics of patients who completed the study and patients who did not. P values were derived from Fisher s exact test or analysis of variance. The groups were well matched with respect to all variables, except; serum C-reactive protein (greater in the retained population as compared to the drop-outs) and the consumption of 30g alcohol per week (greater in the retained population as compared to the drop-outs). BMI body mass index, BSA body surface area, HDL high density lipoprotein, LDL low density lipoprotein, AFSS Atrial Fibrillation Severity Score, CPAP continuous positive airways pressure, OSA obstructive sleep apnea, SBP systolic blood pressure, DBP diastolic blood pressure. Continuous data is shown as mean and 95% CI. Proportional data is shown as number (No.) and %

13 etable 6. Descriptive Comparison of Control and Intervention Subjects Who Dropped Out Characteristic Control Treatment (n=23) (n=18) P-value Age (years) ( ) ( ) 0.2 Female, n (%) 16 (53) 14 (47) 0.7 Waist circumference (cm) ( ) ( ) 0.5 Weight (kg) ( ) ( ) 0.5 BMI (kg/m ) ( ) ( ) 0.9 BSA (m ) ( ) ( ) 0.5 Blood glucose (mg/dl) ( ) ( ) 0.3 Triglyceride (mg/dl) ( ) ( ) 0.5 Total cholesterol (mg/dl) ( ) ( ) 0.05 HDL (mg/dl) ( ) ( ) 0.4 LDL (mg/dl) ( ) ( ) 0.1 C-reactive protein (mg/l) ( ) ( ) 0.4 Duration of AF (months) ( ) ( ) 0.4 Longest episode of AF (hours) ( ) ( ) 0.3 Paroxysmal AF, n (%) 23 (56) 18 (44) 0.7 AFSS - Episode frequency ( ) ( ) 0.4 AFSS - Episode duration ( ) ( ) 0.5 AFSS - Episode severity ( ) ( ) 0.3 AFSS - Burden ( ) ( ) 0.7 AFSS - symptom severity subscale ( ) ( ) 0.6 No. antiarrhythmic drugs, n (%) (33) 2 (67) 1 12 (55) 10 (45) 2 10 (62.5) 6 (37.5) No. antihypertensive drugs, n (%) (37.5) 5 (62.5) 1 10 (56) 8 (44) 2 5 (50) 5 (50) 3 3 (100) 0 (0) 4 2 (100) 0 (0) Tobacco use, n (%) 1.0 Never 15 (58) 11 (42) Current 1 (50) 1 (50) Reformed 7 (54) 6 (46)

14 etable 6: Descriptive comparison of control and intervention subjects who dropped out. (Continued) CPAP use, n (%) Yes 1 (50) 1 (50) Characteristic Retained Drop-outs (n=109) (n=41) No 22 (59) 15 (41) 1.0 P-value OSA, n (%) 0.4 Absent 2 (100) 0 (0) Mild 5 (45) 6 (55) Moderate 8 (73) 3 (27) Severe 3 (43) 4 (57) Hypertension, n (%) 1.0 Absent 3 (50) 3 (50) Present 20 (57) 15 (43) SBP (mmhg) ( ) ( ) 1.0 DBP (mmhg) (83-89) (79-86) 0.07 Diabetes, n (%) 0.08 Absent 20 (65) 11 (35) Present 3 (30) 7 (70) Metformin use, n (%) 1.0 Absent 22 (55) 18 (45) Present 1 (100) 0 (0) Oral hypoglycemic use, n (%) 1.0 Absent 22 (55) 18 (45) Present 1 (100) 0 (0) Alcohol consumption, n (%) Absent 17 (53) 15 (47) Present 6 (67) 3 (33) Lipid-lowering therapy use, n (%) Absent 18 (56) 14 (44) Present 5 (56) 4 (44) etable 6: Shown is descriptive data comparing the control and treatment arms in the drop-outs. P values were derived from Fisher s exact test or analysis of variance. The groups were well matched with respect to all variables; however there was a trend towards significance for; diastolic blood pressure (greater in the control group arm as compared to the intervention arm) and the presence of diabetes mellitus (greater in the control population as compared to the intervention population). BMI body mass index, BSA body surface area, HDL high density lipoprotein, LDL low density lipoprotein, AFSS Atrial Fibrillation Severity Score, CPAP continuous positive airways pressure, OSA obstructive sleep apnea, SBP systolic blood pressure, DBP diastolic blood pressure. Continuous data is shown as mean and 95% CI. Proportional data is shown as number (No.) and %

15 Propensity score analysis In order to account for baseline imbalances, a propensity score for treatment allocation group was generated based on the following covariates: age, gender, baseline body-mass index, baseline alcohol and tobacco use, hypertension, diabetes, hypercholesterolemia, obstructive sleep apnea, number of antiarrhythmic and antihypertensive agents used, left atrial area, the occurrence of any AF on baseline Holter monitoring and the cumulative duration of AF on baseline Holter monitoring. Mixed effects models were then repeated with adjustment for this propensity score. We generated a propensity score for each participant based on the following variables: age, gender, baseline body-mass index, baseline alcohol and tobacco use, hypertension, diabetes, hypercholesterolemia, obstructive sleep apnea, number of antiarrhythmic and antihypertensive agents used, left atrial area, the occurrence of any AF on baseline Holter monitoring and the cumulative duration of AF on baseline Holter monitoring. We then repeated all analyses adjusting for this propensity score. The adjustment did not alter the significance of our findings favoring the treatment group. All group-time interaction term p-values remained (efigure 4 and efigure 5 below).

16 efigure 4. Propensity Score Analysis: Propensity Score Adjusted Outcomes, I: AFSS Symptom Burden Score and AFSS Symptom Severity Score efigure 4: Propensity score adjusted outcomes I: AFSS symptom burden score and AFSS symptom severity score. The following variables were adjusted for; age, gender, baseline body-mass index, baseline alcohol and tobacco use, hypertension, diabetes, hypercholesterolemia, obstructive sleep apnea, number of antiarrhythmic and antihypertensive agents used, left atrial area, the occurrence of any AF on baseline Holter monitoring and the cumulative duration of AF on baseline Holter monitoring. AFSS Atrial fibrillation severity score.

17 efigure 5. Propensity Score Analysis: Propensity Score Adjusted Outcomes, II: Secondary (Holter Data) and Post Hoc (AFSS) Analysis efigure 5: Propensity score adjusted outcomes II: propensity score adjusted analysis for the secondary outcome of cumulative AF duration (on 7-day Holter recordings) and the secondary AFSS analyses of AF symptom frequency (AFSS1), AF symptom duration (AFSS2) and AF global episode symptom severity (AFSS3). The following variables were adjusted for; age, gender, baseline body-mass index, baseline alcohol and tobacco use, hypertension, diabetes, hypercholesterolemia, obstructive sleep apnea, number of antiarrhythmic and antihypertensive agents used, left atrial area, the occurrence of any AF on baseline Holter monitoring and the cumulative duration of AF on baseline Holter monitoring. AFSS Atrial fibrillation severity score.

18 149 etable 7. Adverse Events Documented During the Study Stage Event Comments (months) Control Intervention severe anemia (Hemoglobin <90 g/dl) 1 acute coronary syndrome 1 progressive acute decompensated cardiac failure 1 thyrotoxicosis 2 thyrotoxicosis 1 acute coronary syndrome 1 severe depression 1 severe refractory hypertension 1 malignancy 3 gastrointestinal symptoms 2 unstable INR Due to diabetic renal disease Managed invasively Secondary to atrial tachyarrhythmia cardiomyopathy All de-novo biochemical and clinical. Assumed due to amiodarone. Required prolonged corticosteroids and carbimazole Recurrence of ovarian cancer (>5 years prior) 1 bloating, 1 diarrhea and 1 constipation. All failed conservative management 1 elevated INR (>9) required IV vitamin K, 1 unable to achieve therapeutic INR due to dietary interference Managed invasively Known pre-existing stable treated depression Pre-existing hypertension. Persistent readings >190/110 mmhg despite multiple agents. Referred for investigation of secondary causes 1 malignancy Renal cell 1 troponin negative chest pain 1 progressive acute decompensated cardiac failure Stable coronary artery disease. Cardiorespiratory causes excluded Progression of chronic ischemic coronary artery disease. Managed medically.

19 152 efigure 6. Sensitivity Analyses efigure 6: Depicted are the effects of varying the value taken by missing observations on regression coefficients for the relationship between group allocation (treatment versus control) and change in A) AFSS frequency (afss1), B) AFSS duration (afss2), C) AFSS episode severity (afss3), D) AFSS burden (afss_bdn), E) AFSS symptom severity subscale (afss_sympt). Also shown is the effect of varying the informatively missing odds ratios from 0 to 1 on the risk of having any AF on 7-day Holter monitor at final follow-up (F). 161

20 efigure 7. Imputation Analysis (I) for Subjects Undergoing AF Ablation (Return-to- Method) efigure 7: Imputation analysis using the return to baseline symptom score method (moderately conservative approach). Top panel shows primary outcomes (AFSS symptom burden and AFSS symptom severity). Bottom panel shows secondary outcomes (ambulatory rhythm monitoring). The AFSS1, 2 and 3 refer to the secondary analyses; AFSS symptom frequency score, AFSS symptom duration score and AFSS global episode symptom severity score, respectively. AFSS Atrial fibrillation severity score. 171

21 efigure 8. Imputation Analysis (II) for Subjects Undergoing AF Ablation (Last Observation Method) efigure 8: Imputation analysis using the last measured symptom score method (least conservative approach). Above figure shows the last symptom score method for imputation analysis for the primary outcomes and the secondary analyses of AFSS symptom frequency (AFSS1), AFSS symptom duration (AFSS2) and AFSS global episode severity (AFSS3). AFSS Atrial fibrillation severity score.

22 180 efigure 9. Atrial Fibrillation Severity Score (AFSS) Algorithm efigure 9: Atrial Fibrillation Severity Score algorithm reproduced with permission from Professor Paul Dorian of St Michael s Hospital, The University of Toronto. 186

23 187 efigure 10. Mixed-Effects Models Analysis of Residuals I and II efigure 10: Hanging rootograms displaying residuals of the mixed-effects models for the primary outcomes (AFSS symptom burden and AFSS symptoms severity) and secondary outcomes (cumulative arrhythmia on 7-day ambulatory rhythm monitor and AFSS1 [AFSS symptom frequency], AFSS2 [AFSS symptom duration] and AFSS3 [AFSS global symptom severity score]).