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1 Supplementary Online Content Leibowitz M, Karpati T, Cohen-Stavi CJ, et al. Association between achieved low-density lipoprotein levels and major adverse cardiac events in patients with stable ischemic heart disease taking statin treatment. JAMA Intern Med. Published online June 20, doi: /jamainternmed etable 1. Statin potency classification based on US Food and Drug Administration s classification etable 2. ICD-9 codes for outcomes of MACE etable 3. Number of events by LDL-C group for each individual component of MACE etable 4. Variables included in PS and Cox models efigure 1a. Kaplan-Meier survival analysis for low versus moderate LDL-C groups efigure 1b. Kaplan-Meier survival analysis for moderate versus high LDL-C groups efigure 2a. Distribution of the PS before and after matching: Low versus Moderate LDL-C groups efigure 2b. Distribution of the PS before and after matching: Moderate versus High LDL-C group efigure 3. Calculation of the standardized difference for each kind of variable etable 5a. Standardized difference before and after matching Low versus Moderate LDL- C groups etable 5b. Standardized difference before and after matching Moderate versus High LDL- C groups etable 6a. After propensity-matching Low versus Moderate LDL-C groups etable 6b. After propensity-matching Moderate versus High LDL-C groups This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Statin potency classification based on US Food and Drug Administration s classification Potency Category Atorva a Fluva b Pitava c Lova d Prava e Rosuva f Simva g % LDL-C h Low 40 mg 1 mg mg 10 mg 30% mg 10 mg 80 mg 2 mg mg 20 mg 38% mg Moderate 20 mg 4 mg mg 5 mg 40 mg 41% mg High 40 mg 10 mg 80 mg 47% 80 mg 20 mg 55% 40 mg 63% Preparations equivalent to Simvastatin 20mgm (38% LDL-C lowering) are classified as low intensity, preparations equivalent to Simvastatin 40mgm (41% LDL-C lowering) are moderate intensity, and all preparations with higher lipid lowering effects are classified as high intensity, equivalent to Simvastatin 80mgm. a. Atorva Atorvastatin; b. Fluva Fluvastatin; c. Pitava Pitavastatin; d. Lova Lovastatin; e. Prava Pravastatin; f. Rosuva Rosuvastatin; g. Simva Simvastatin; h. LDL- C Low-density lipoprotein cholesterol

3 etable 2. ICD-9 a codes for outcomes of MACE b Outcome ICD-9 codes Myocardial infarction 410 and related sub-classifications Unstable angina 411.1, 411.8, , 413.0, Stroke , , , , , Percutaneous coronary intervention procedural code 36 Coronary artery bypass grafting procedural code 36.1 a. ICD-9 International Classification of Diseases, Ninth Revision; b. MACE Major adverse cardiac events

4 etable 3. Number of events by LDL-C a group for each individual component of MACE b LDL-C group Low ( 70mg/dl) Moderate ( mg/dl) High ( mg/dl) Population N 9,086 16,782 5,751 All-cause mortality 693 1, Acute MI c CABG d PTCA e 794 1, CVA f Angina Total MACE 2,681 4,595 1,759 a. LDL-C Low-density lipoprotein; b. MACE Major adverse cardiac events; c. MI Myocardial infarction; d. CABG Coronary artery bypass grafting; e. PTCA Percutaneous transluminal coronary angioplasty; f. CVA Cerebrovascular accident

5 etable 4. Variables included in PS a and Cox models Variables Low vs Moderate Moderate vs High Cox PS Cox PS Age X X X X Sex X X X X Ethnicity (Jews / Arabs) X X X X SES b (Low / Medium-High) X X X X Residence (Urban / Rural) X X BMI c (<18.5 / / / 30+ / No X X measure) Smoking status (Non-smoker / Actual smoker) X X X X Glucose level (Low / Normal / Borderline / High / X X Very high / No measure) Diabetic (No / Yes) X X X X Insulin use (No / Yes) X X X Statin potency (Low / Medium / High) X X Time on statin (Categorical: 12-23m / 24-71m / X X 72m+) Time on statin (Continuous in months) X X Other non-statin lipid lowering meds (No / Yes) X X HDL X Total Cholesterol Triglycerides Visits above 24 (No / Yes) X X X X Lipid profiles above 9 (No / Yes) X X Chronic meds count (0-4 / 5-7 / 8+) X X CKD d stage (1 / 2 / 3A / 3B / 4 / 5 / Unclassified) X X X Number of angioplasties (PTCA) X X X Charlson risk score (0-1 / 2 / 3-4 / 5+) X X X X a. PS Propensity score; b. SES Socioeconomic status; c. BMI Body mass index; d. CKD Chronic Kidney Disease. For the Cox regression, variables that were thought to be clinical predictors of the appearance of a MACE event were included into the model. For the PS secondary analysis, variables that were considered to be predictors of being in a specific LDL-C group were included in the PS model. The effect of each variable on the multivariable model was assessed for instability and collinearity. Forward stepwise analysis was used to select the variables that were included in the final model. Age and sex were forced into the model if the stepwise analysis excluded them.

6 efigure 1a. Kaplan-Meier survival analysis for low versus moderate LDL-C a groups a. LDL-C Low-density lipoprotein

7 efigure 1b. Kaplan-Meier survival analysis for moderate versus high LDL-C a groups a. LDL-C. Low-density lipoprotein

8 efigure 2a. Distribution of the PS a before and after matching: Low versus Moderate LDL- C b groups a. PS Propensity score; b. LDL-C Low-density lipoprotein

9 efigure 2b. Distribution of the PS a before and after matching: Moderate versus High LDL- C b group a. PS Propensity score; b. LDL-C Low-density lipoprotein

10 efigure 3. Calculation of the standardized difference for each kind of variable For continuous variables the formula is based on the means and standard deviation: 2 Where denote the sample mean and denote the variance of the variables in the treatment and control groups. For binary categorical variables, the standard difference is calculated as follows: Where denotes the proportion of the binary variable in the treatment and control groups. For multi-categorical variables, the standard difference is calculated as in the case of binary categories, but for each category in the variable separately.

11 etable 5a. Standardized difference before and after matching Low versus Moderate LDL-C a groups Variable Difference Before Difference After 30-49y Age 65-74y y Sex Female Smoking Smoker Missing Diabetes Yes A CKD 3B Unknown Time on statins Visits > Lipid Profiles > Low HDL High Missing Low Borderline Glucose High Very high Not measured Medium Statin Potency High missing Chronic meds Charlson score Unknown Non-statins meds Yes a. LDL-C Low-density lipoprotein; b. SES Socioeconomic status; c. CKD Chronic kidney disease; d. PTCA - Percutaneous transluminal coronary angioplasty The groups were matched 1:1 using a greedy algorithm technique, and the best fit model was chosen by the Akaike information criterion measure. After matching, the standardized difference for each of the variables in the PS model was calculated using different formulas depending on whether the variables were continuous, binary categorical or multi-categorical, and then

12 compared to the differences before matching. A difference greater than the absolute value of 10 is considered unbalanced.[8]

13 etable 5b. Standardized difference before and after matching Moderate versus High LDL-C a groups Variable Difference Before Difference After Age Sex Residence Rural Unknown Smoker Smoker Missing Diabetes Diabetes CKD A B Unknown Time on Statin Visits > Lipid Profiles > PTCA HDL Low High Missing Total Cholesterol Low High Missing Triglycerides High Missing Glucose Low Borderline Hyperglycemia Diabetic Unknown Statin potency Medium High missing Chronic Meds Charlson score

14 Unknown Non-statin meds Yes a. LDL-C Low-density lipoprotein; b. SES Socioeconomic status; c. BMI Body mass index

15 etable 6a. After propensity-matching Low versus Moderate LDL-C a groups Characteristics Moderate LDL- Low LDL-C, p value C, mg/dl* (n=7,879) 70 mg/dl** (n=7,879) Age Mean (SD b ) 67.8 (9.6) 67.7 (9.6) Median (IQR c ) 69.0 ( ) 68.0 ( ) (3.5%) 307 (3.5%) ,966 (33.6%) 3,003 (34.0%) ,037 (34.4%) 3,081 (34.9%) ,518 (28.5%) 2,442 (27.6%) Sex Male 6,711 (76.0%) 6,741 (76.3%) Female 2,122 (24.0%) 2,092 (23.7%) Ethnicity Jewish 7,998 (90.5%) 7,863 (89.0%) Non-Jewish 835 (9.5%) 970 (11.0%) SES d Mid-High 6,026 (68.2%) 5,881 (66.6%) Low 2,807 (31.8%) 2,952 (33.4%) Index LDL-C Mean (SD) 58.5 (9.7) 83.7 (8.3) Median (IQR) 60.9 ( ) 83.0 ( ) HDL e Mean (SD) 45.2 (11.9) 45.9 (11.5) Median (IQR) 43.0 ( ) 44.0 ( ) BMI f Mean (SD) 29.1 (5.1) 29.3 (5.2) Median (IQR) 28.4 ( ) 28.4 ( ) < (0.2%) 20 (0.2%) ,647 (18.6%) 1,553 (17.6%) ,941 (44.6%) 3,908 (44.2%) 30+ 3,115 (35.3%) 3,242 (36.7%) Unknown 116 (1.3%) 110 (1.2%) Chronic diseases Diabetics 5,446 (61.7%) 5,425 (61.4%) Use Insulin 688 (7.8%) 629 (7.1%) Hypertension 3,975 (45.0%) 4,002 (45.3%) CHF g 1,611 (18.2%) 1,582 (17.9%) AF h 1,185 (13.4%) 1,090 (12.3%) CVA i 61 (0.7%) 62 (0.7%) Charlson score (3.8%) 333 (3.8%) (8.4%) 744 (8.4%) 3-4 2,495 (28.2%) 2,545 (28.8%) 5+ 5,197 (58.8%) 5,149 (58.3%) Unknown 68 (0.8%) 62 (0.7%) CKD j stage (2.2%) 192 (2.2%) 2 1,789 (20.3%) 1,782 (20.2%) 3A 4,349 (49.2%) 4,377 (49.6%)

16 3B 1,383 (15.7%) 1,379 (15.6%) (8.4%) 739 (8.4%) (3.1%) 270 (3.1%) Unknown 98 (1.1%) 94 (1.1%) PTCA k 0 7,593 (86.0%) 7,603 (86.1%) 1-2 1,186 (13.4%) 1,187 (13.4%) (0.6%) 43 (0.5%) Number of visits >24 5,414 (61.3%) 5,441 (61.6%) Numper of lipid profiles >9 4,396 (49.8%) 4,463 (50.5%) Time on statins (years) Mean (SD) 6.7 (3.4) 6.9 (3.4) Median (IQR) 7.0 ( ) 7.0 ( ) Statin potency Low 439 (5.0%) 435 (4.9%) Medium 4,599 (52.1%) 4,575 (51.8%) High 3,766 (42.6%) 3,790 (42.9%) missing 29 (0.3%) 33 (0.4%) Simvastatin 4,706 (53.3%) 4,557 (51.6%) Atorvastatin 2,414 (27.3%) 2,886 (32.7%) Rosuvastatin 1,578 (17.9%) 1,165 (13.2%) Pravastatin 135 (1.5%) 224 (2.5%) MACE l (outcome) 2,583 (29.2%) 2,625 (29.7%) a. LDL-C Low-density lipoprotein; b. SD Standard deviation; c. IQR Interquartile range;; d. SES Socioeconomic status; e. HDL High-density lipoprotein; f. BMI Body mass index; g. CHF Congestive heart failure; h. AF Atrial fibrillation; i. CVA Cerebrovascular accident; j. CKD Chronic kidney disease; k. PTCA Percutaneous transluminal coronary angioplasty; l. MACE Major adverse cardiac events; * mg/dl 1.8mmol/l-2.6mmol/l; ** mg/dl mmol/l;

17 etable 6b. After propensity-matching Moderate versus High LDL-C a groups Characteristics Moderate LDL-C, High LDL-C, p value mg/dl* (n=5,739) mg/dl ** (n=5,739) Age Mean (SD b ) 66.6 (9.9) 66.5 (10.3) Median 67.0 ( ) 67.0 ( ) (IQR c ) (4.5%) 304 (5.3%) ,216 (38.6%) 2,246 (39.1%) ,792 (31.2%) 1,713 (29.8%) 75+ 1,471 (25.6%) 1,476 (25.7%) Sex Male 3,893 (67.8%) 3,884 (67.7%) Female 1,846 (32.2%) 1,855 (32.3%) Ethnicity Jewish 4,959 (86.4%) 4,970 (86.6%) Non Jewish 780 (13.6%) 769 (13.4%) SES d Med-High 3,668 (63.9%) 3,688 (64.3%) Low 2,071 (36.1%) 2,051 (35.7%) Index LDL-C Mean (SD) 84.3 (8.3) (7.9) Median (IQR) 84.0 ( ) ( ) HDL e Mean (SD) 47.6 (11.8) 48.9 (12.5) Median (IQR) 46.0 ( ) 47.0 ( ) BMI f Mean (SD) 29.2 (5.1) 29.3 (5.3) Median (IQR) 28.4 ( ) 28.6 ( ) < (0.1%) 9 (0.2%) ,050 (18.3%) 1,061 (18.5%) ,432 (42.4%) 2,434 (42.4%) 30+ 2,160 (37.6%) 2,148 (37.4%) Unknown 89 (1.6%) 87 (1.5%) Chronic diseases Diabetics 2,894 (50.4%) 2,859 (49.8%) Use Insulin 304 (5.3%) 297 (5.2%) Hypertension 2,439 (42.5%) 2,456 (42.8%) CHF g 882 (15.4%) 897 (15.6%) AF h 604 (10.5%) 645 (11.2%) CVA i 33 (0.6%) 45 (0.8%) Charlson score (6.4%) 369 (6.4%) (11.7%) 660 (11.5%) 3-4 1,804 (31.4%) 1,784 (31.1%) 5+ 2,867 (50.0%) 2,897 (50.5%) Unknown 30 (0.5%) 29 (0.5%) CKD j stage (2.9%) 163 (2.8%) 2 1,402 (24.4%) 1,374 (23.9%) 3A 2,844 (49.6%) 2,780 (48.4%)

18 3B 758 (13.2%) 806 (14.0%) (6.7%) 414 (7.2%) (2.6%) 164 (2.9%) Unknown 37 (0.6%) 38 (0.7%) PTCA k 0 5,078 (88.5%) 5,090 (88.7%) (11.1%) 621 (10.8%) (0.4%) 28 (0.5%) Number of visits >24 3,065 (53.4%) 3,067 (53.4%) Numper of lipid profiles >9 2,438 (42.5%) 2,439 (42.5%) Time on statins (years) Mean (SD) 7.5 (3.1) 7.6 (3.1) Median (IQR) 8.0 ( ) 8.0 ( ) Statin potency High 2,473 (43.1%) 2,459 (42.8%) Low 496 (8.6%) 498 (8.7%) Medium 2,733 (47.6%) 2,748 (47.9%) missing 37 (0.6%) 34 (0.6%) Simvastatin 2,823 (49.2%) 2,736 (47.7%) Atorvastatin 1,806 (31.5%) 1,999 (34.8%) Rosuvastatin 844 (14.7%) 668 (11.6%) Pravastatin 265 (4.6%) 335 (5.8%) MACE l (outcome) 1,614 (28.1%) 1,757 (30.6%) a. LDL-C Low-density lipoprotein; b. SD Standard deviation; c. IQR Interquartile range;; d. SES Socioeconomic status; e. HDL High-density lipoprotein; f. BMI Body mass index; g. CHF Congestive heart failure; h. AF Atrial fibrillation; i. CVA Cerebrovascular accident; j. CKD Chronic kidney disease; k. PTCA Percutaneous transluminal coronary angioplasty; l. MACE Major adverse cardiac events; * mg/dl 1.8mmol/l-2.6mmol/l; ** mg/dl mmol