SUPPLEMENTARY MATERIAL

Adherence to lipid-lowering treatment by single-pill combination of statin and ezetimibe

Federico REA ^1,2, Laura SAVARÉ ^1,3,4, Giovanni CORRAO ^1,2, Giuseppe MANCIA ^5,6

1 National Centre for Healthcare Research & Pharmacoepidemiology, at the University of Milano-Bicocca Milan, Italy

2 Laboratory of Healthcare Research & Pharmacoepidemiology, Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy

3 MOX - Laboratory for Modeling and Scientific Computing, Department of Mathematics, Politecnico di Milano, Milan, Italy

4 CADS - Center for Analysis Decisions and Society, Human Technopole, Milan, Italy

5 University of Milano-Bicocca (Emeritus Professor), Milan, Italy

6 Policlinico di Monza, Monza, Italy

SUPPLEMENTARY MATERIAL

Supplementary Table S1. Distribution of the statin drug classes prescribed at index date

Class Two-pill

combination (N=2,881)

Fixed combination (N=5,351)

Simvastatin 154 (5.3%) 5,005 (93.5%)

Rosuvastatin 918 (31.9%) 346 (6.5%)

Atorvastatin 1,639 (56.9%) -

Others 170 (5.9%) -

Supplementary Table S2. Characteristics of cohort members according to the categories of adherence and drug treatment strategy

Two-pill combination Single-pill combination

Low adherence

(n=271)

Intermediate adherence

(n=1,102)

High adherence

(n=756)

P value

Low adherence

(n=57)

Intermediate adherence

(n=621)

High adherence

(n=1,451)

P value

Male gender 133 (49.1%) 675 (61.3%) 503 (66.5%) <0.001 32 (56.1%) 360 (58.0%) 942 (64.9%) 0.007 Age (year)

40-54 64 (23.6%) 328 (29.8%) 216 (28.6%) 0.021 19 (33.3%) 186 (30.0%) 373 (25.7%) 0.243

55-64 96 (35.4%) 394 (35.8%) 305 (40.3%) 17 (29.8%) 218 (35.1%) 535 (36.9%)

65-80 111 (41.0%) 380 (34.5%) 235 (31.1%) 21 (36.8%) 217 (34.9%) 543 (37.4%)

Therapy based on statin

Duration of therapy

(years): mean (SD) 4.3 (1.5) 4.3 (1.5) 4.3 (1.5) 0.939 4.2 (1.5) 4.1 (1.5) 4.3 (1.5) 0.057

Adherence with therapy (PDC):

mean (SD)

0.49 (0.3) 0.62 (0.25) 0.80 (0.2) <0.001 0.54 (0.3) 0.59 (0.3) 0.69 (0.3) <0.001

High potency of

statins at baseline 118 (43.5%) 644 (58.4%) 564 (74.6%) <0.001 30 (52.6%) 382 (61.5%) 914 (63.0%) 0.256 Baseline

Co-treatments Antihypertensive

drugs 223 (82.3%) 939 (85.2%) 690 (91.3%) <0.001 51 (89.5%) 522 (84.1%) 1,283 (88.4%) 0.021 Antithrombotic

drugs 167 (61.6%) 750 (68.1%) 638 (84.4%) <0.001 37 (64.9%) 425 (68.4%) 1,119 (77.1%) <0.001 Antiarrhythmic

drugs 17 (6.3%) 66 (6.0%) 49 (6.5%) 0.910 2 (3.5%) 35 (5.6%) 93 (6.4%) 0.565

NSAIDs 146 (53.9%) 541 (49.1%) 341 (45.1%) 0.034 32 (56.1%) 330 (53.1%) 657 (45.3%) 0.002

Antigout drugs 25 (9.2%) 146 (13.3%) 82 (10.9%) 0.102 6 (10.5%) 86 (13.9%) 159 (11.0%) 0.166

Antidiabetics

drugs 91 (33.6%) 368 (33.4%) 227 (30.0%) 0.274 24 (42.1%) 190 (30.6%) 451 (31.1%) 0.195

Respiratory

medicine 59 (21.8%) 255 (23.1%) 179 (23.7%) 0.816 12 (21.1%) 156 (25.1%) 310 (21.4%) 0.166

Antidepressant

drugs 60 (22.1%) 205 (18.6%) 102 (13.5%) 0.001 9 (15.8%) 113 (18.2%) 226 (15.6%) 0.333

Number of co- treatments

0-4 98 (36.2%) 367 (33.3%) 223 (29.5%) 0.111 16 (28.1%) 228 (36.7%) 455 (31.4%) 0.020

5-9 112 (41.3%) 515 (46.7%) 379 (50.1%) 23 (40.4%) 262 (42.2%) 702 (48.4%)

≥10 61 (22.5%) 220 (20.0%) 154 (20.4%) 18 (31.6%) 131 (21.1%) 294 (20.3%)

Comorbidities Cardiovascular

disease 102 (37.6%) 549 (49.8%) 515 (68.1%) <0.001 25 (43.9%) 307 (49.4%) 802 (55.3%) 0.018 Ischemic heart

disease 71 (26.2%) 429 (38.9%) 443 (58.6%) <0.001 20 (35.1%) 219 (35.3%) 653 (45.0%) <0.001

Diabetes 59 (21.8%) 258 (23.4%) 183 (24.2%) 0.717 12 (21.1%) 160 (25.8%) 314 (21.6%) 0.116

Kidney disease 3 (1.1%) 35 (3.2%) 23 (3.0%) 0.175 2 (3.5%) 19 (3.1%) 42 (2.9%) 0.950

Respiratory

disease 95 (35.1%) 397 (36.1%) 259 (34.3%) 0.734 25 (43.9%) 211 (34.0%) 503 (34.7%) 0.324

Cancer 20 (7.4%) 75 (6.8%) 46 (6.1%) 0.717 3 (5.3%) 43 (6.9%) 80 (5.5%) 0.449

Clinical profile ^a

Good 163 (60.2%) 574 (52.1%) 369 (48.8%) 0.006 27 (47.4%) 346 (55.7%) 750 (51.7%) 0.192

Intermediate 92 (34.0%) 456 (41.4%) 350 (46.3%) 27 (47.4%) 233 (37.5%) 620 (42.7%)

Poor 16 (5.9%) 72 (6.5%) 37 (4.9%) 3 (5.3%) 42 (6.8%) 81 (5.6%) During follow-up ^b

Comorbidities Cardiovascular

disease 109 (40.2%) 580 (52.6%) 527 (69.7%) <0.001 27 (47.4%) 321 (51.7%) 823 (56.7%) 0.054 Ischemic heart

disease 73 (26.9%) 453 (41.1%) 451 (59.7%) <0.001 21 (36.8%) 230 (37.0%) 666 (45.9%) <0.001

Diabetes 62 (22.9%) 279 (25.3%) 197 (26.1%) 0.585 12 (21.1%) 168 (27.1%) 335 (23.1%) 0.132

Kidney disease 4 (1.5%) 41 (3.7%) 26 (3.4%) 0.179 4 (7.0%) 30 (4.8%) 49 (3.4%) 0.137

Respiratory

disease 115 (42.4%) 443 (40.2%) 285 (37.7%) 0.330 28 (49.1%) 245 (39.5%) 559 (38.5%) 0.267

Cancer 22 (8.1%) 91 (8.3%) 59 (7.8%) 0.940 3 (5.3%) 52 (8.4%) 100 (6.9%) 0.413

PDC: Proportion of days covered; SD: Standard deviation

a The clinical profile was assessed by the Multisource Comorbidity Score according to the hospital admission and the drugs prescribed in the five-year period before the index date. Three categories of clinical profile were considered: good (0≤score≤4), intermediate (5≤score≤14) and poor (score≥15).

b The comorbidities were assessed in the first year after the index combination prescription date.

Figure S1. Representation of the procedure used to identify patients who added ezetimibe to statin therapy

Patients were followed from the first statin dispensation during 2011-2013 (the date of this prescription was defined as index statin prescription

date) until death, emigration or December 31, 2018. All lipid-lowering drugs dispensed during follow-up were identified. The date of the first

dispensation of ezetimibe was identified and was defined as index combination prescription date. For example, patient #1 added ezetimibe

separately, and the date of the first ezetimibe prescription was the index combination prescription date. Patients #2 and #4 switched from the statin

therapy to the single-pill combination, and the date of the first statin/ezetimibe combination was the index combination prescription date. Patient #3

did not add ezetimibe, and thus he/she was not included in the final cohort.

Figure S2. Risk ratios (RR), and 95% confidence intervals (CI), estimating the association between

high adherence to treatment (PDC >75%) and treatment strategy by varying the ratio of daily dose

dispensed between patients under single pill and two-pill administration of a statin and ezetimibe

Figure S3. Simulated influence of a possible unmeasured confounder on the relationship between

the employed pharmacological strategy (exposure) and drug adherence (outcome). The graphs indicate the RR

–OR

combinations (i.e., the confounder–outcome and the confounder–exposure associations) that would be required to move the observed effect of single-pill combination on adherence to treatment towards the null, separately for achievement of high adherence and prevention of low adherence to treatment.

The possible unmeasured confounder was set (i) to have a 30% prevalence in the study population, (ii) to increase the propensity of high adherence up to 10-fold, and (iii) to reduce the risk of low adherence up to 50-fold more in patients exposed than in those unexposed to the confounder.