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Supplemental Data

Supplemental tables :

Table e-1. Patient Characteristics According to Vaccination Status, Before and After Propensity Score Matching: The PERFORM trial

Before Propensity Score Matching / After Propensity Score Matching
No. (%) of patients / No. (%) of patients

Factor

/ NV
(n = 13 872) / V
(n = 5174) / P / NV
(n = 4539) / V
(n = 4539) / P
Age, mean (SD), yr / 65.8 (7.5) / 71.0 (7.6) / <0.001 / 69.9 (7.5) / 70.0 (7.2) / 0.48
Men / 8841 (63.7) / 3073 (59.4) / <0.001 / 2761 (60.8) / 2757 (60.7) / 0.93
Body mass index, mean (SD), kg/m² / 27.1 (4.3) / 27.0 (4.2) / 0.23 / 27.1 (4.4) / 27.0 (4.2) / 0.36
Systolic blood pressure, mean (SD), mmHg / 137 (15) / 138 (16) / 0.009 / 137 (16) / 137 (16) / 0.62
Diastolic blood pressure, mean (SD), mmHg / 80 (8) / 78 (9) / <0.001 / 78 (9) / 78 (9) / 0.95

Qualifying event

/ 0.002
Stroke / 12533 (90.4) / 4595 (88.8) / 4057 (89.4) / 4052 (89.3) / 0.86
Transient ischemic attack / 1339 (9.7) / 579 (11.2) / 482 (10.6) / 487 (10.7)

Region

/ <0.001
Western Europe / 4523 (32.6) / 3053 (59.0) / 2651 (58.4) / 2669 (58.8) / 0.90
Eastern Europe / 5583 (40.3) / 488 (9.4) / 510 (11.2) / 487 (10.7)
North America / 214 (1.5) / 268 (5.2) / 185 (4.1) / 187 (4.1)
South America / 1091 (7.9) / 677 (13.1) / 604 (13.3) / 609 (13.4)
Asia / 1828 (13.2) / 348 (6.7) / 351 (7.7) / 347 (7.6)
Oceania / 266 (1.9) / 309 (6.0) / 206 (4.5) / 209 (4.6)
Africa / 367 (2.6) / 31 (0.6) / 32 (0.7) / 31 (0.7)

Medical history

Hypertension / 11647 (84.0) / 4279 (82.7) / 0.037 / 3754 (82.7) / 3735 (82.3) / 0.60
Diabetes / 3786 (27.3) / 1500 (29.0) / 0.02 / 1334 (29.4) / 1316 (29.0) / 0.68
Dyslipidemia / 6424 (46.3) / 2735 (52.9) / <0.001 / 2366 (52.1) / 2346 (51.7) / 0.67
Current smoking / 4114 (29.7) / 946 (18.3) / <0.001 / 916 (20.2) / 909 (20.0) / 0.85
Cardiovascular disease / 2914 (21.0) / 1124 (21.7) / 0.28 / 922 (20.3) / 972 (21.4) / 0.19
Coronary artery disease / 3122 (22.5) / 987 (19.1) / <0.001 / 793 (17.5) / 829 (18.3) / 0.32
Peripheral artery disease / 519 (3.7) / 216 (4.2) / 0.17 / 181 (4.0) / 174 (3.8) / 0.70

Medications

Aspirin / 6508 (46.9) / 3023 (58.4) / <0.001 / 2624 (57.8) / 2609 (57.5) / 0.75
Other antiplatelet agent / 7902 (57.0) / 2686 (51.9) / <0.001 / 2275 (50.1) / 2318 (51.1) / 0.37
Oral anticoagulant / 994 (7.2) / 554 (10.7) / <0.001 / 470 (10.4) / 482 (10.6) / 0.68
ACE inhibitor / 7442 (53.7) / 2453 (47.4) / <0.001 / 2189 (48.2) / 2155 (47.5) / 0.47
Calcium channel blocker / 3396 (24.5) / 1305 (25.2) / 0.29 / 1113 (24.5) / 1115 (24.6) / 0.96
Diuretic / 4248 (30.6) / 1873 (36.2) / <0.001 / 1572 (34.6) / 1590 (35.0) / 0.69
Beta-blocker / 3308 (23.9) / 1383 (26.7) / <0.001 / 1150 (25.3) / 1160 (25.6) / 0.81
Angiotensin II receptor blocker / 1625 (11.7) / 961 (18.6) / <0.001 / 808 (17.8) / 807 (17.8) / 0.98
Statin / 7784 (56.1) / 3635 (70.3) / <0.001 / 3149 (69.4) / 3109 (68.5) / 0.36

Abbreviations: ACE, angiotensin-converting enzyme;NV, patients not vaccinated against influenza; SD, standard deviation; V, patients vaccinated against influenza.

Table e-2. Patient Characteristics According to Vaccination Status, Before and After Propensity Score Matching: The OPTIC Registry

Before Propensity Score Matching / After Propensity Score Matching
No. (%) of patients / No. (%) of patients

Factor

/ NV
(n = 3068) / V
(n = 416) / P / NV
(n = 381) / V
(n = 381) / P
Age, mean (SD), yr / 64.6 (10.9) / 70.0 (9) / <0.001 / 70.3 (10.9) / 69.9 (9.4) / 0.62
Men / 1755 (57.2) / 221 (53.1) / 0.12 / 192 (50.4) / 200 (52.5) / 0.57
Body mass index, mean (SD), kg/m² / 27.5 (4.9) / 27.1 (4.7) / 0.11 / 27.1 (4.6) / 27.1 (4.7) / 0.98
Systolic blood pressure, mean (SD), mmHg / 144 (24) / 144 (25) / 0.70 / 146 (25) / 144 (25) / 0.38
Diastolic blood pressure, mean (SD), mmHg / 85 (13) / 84 (13) / 0.07 / 84 (14) / 84 (13) / 0.76

Qualifying event

Stroke / 2261 (73.7) / 328 (78.8) / <0.001 / 304 (79.8) / 303 (79.5) / 0.93
Transient ischemic attack / 807 (26.3) / 88 (21.2) / 77 (20.2) / 78 (20.5)

Region

South America / 1176 (38.3) / 332 (79.8) / <0.001 / 301 (79.0) / 304 (79.8) / 0.85
Middle East / 987 (32.2) / 26 (6.3) / 24 (6.3) / 22 (5.8)
Africa / 905 (29.5) / 58 (13.9) / 56 (14.7) / 55 (14.4)

Medical history

Hypertension / 2523 (82.2) / 354 (85.1) / 0.15 / 322 (84.5) / 325 (85.3) / 0.77
Diabetes / 1110 (36.2) / 156 (37.5) / 0.60 / 148 (38.9) / 145 (38.1) / 0.83
Dyslipidemia / 1050 (34.8) / 194 (47.2) / <0.001 / 174 (45.7) / 182 (47.8) / 0.53
Current smoking / 673 (22.7) / 47 (11.5) / <0.001 / 49 (12.9) / 40 (10.5) / 0.30
Cardiovascular disease / 692 (23.1) / 91 (22.9) / 0.67 / 69 (18.1) / 79 (20.7) / 0.36
Coronary artery disease / 376 (12.4) / 67 (16.1) / 0.03 / 57 (15.0) / 57 (15.0) / 1.00
Peripheral artery disease / 225 (7.7) / 37 (9.2) / 0.28 / 38 (10.0) / 35 (9.2) / 0.72

Medications

Aspirin / 2360 (76.9) / 348 (86.7) / 0.002 / 332 (87.1) / 321 (84.3) / 0.23
Other antiplatelet agent / 1547 (50.4) / 135 (32.5) / <0.001 / 113 (29.7) / 120 (31.5) / 0.57
Oral anticoagulant / 226 (7.4) / 20 (4.8) / 0.056 / 17 (4.5) / 16 (4.2) / 0.86
ACE inhibitor / 1285 (41.9) / 169 (40.6) / 0.63 / 160 (42.0) / 156 (40.9) / 0.76
Calcium channel blocker / 839 (27.4) / 126 (30.3) / 0.21 / 110 (28.9) / 116 (30.5) / 0.64
Diuretic / 786 (25.6) / 111 (26.7) / 0.64 / 101 (26.5) / 103 (27.0) / 0.87
Beta-blocker / 612 (20.0) / 93 (22.4) / 0.25 / 84 (22.1) / 85 (22.3) / 0.93
Angiotensin II receptor blocker / 474 (15.5) / 72 (17.3) / 0.33 / 59 (15.5) / 65 (17.1) / 0.56
Statin / 2118 (69.0) / 311 (74.8) / 0.02 / 306 (80.3) / 287 (75.3) / 0.08

Abbreviations: ACE, angiotensin-converting enzyme;NV, patients not vaccinated against influenza; SD, standard deviation; V, patients vaccinated against influenza.

Table e-3. Patient Characteristics According to Vaccination Status, Before and After Propensity Score Matching: The AMISTAD Study

Before Propensity Score Matching / After Propensity Score Matching
No. (%) of patients / No. (%) of patients

Factor

/ NV
(n = 423) / V
(n = 157) / P / NV
(n = 134) / V
(n = 134) / P
Age, mean (SD), yr / 59.6 (12.6) / 71.7 (10.6) / <0.001 / 69.3 (10.8) / 70.0 (10.3) / 0.32
Men / 306 (72.3) / 105 (66.9) / 0.20 / 81 (60.5) / 92 (68.7) / 0.16
Body mass index, mean (SD), kg/m² / 25.8 (4.3) / 26.2 (4.5) / 0.31 / 26.2 (4.6) / 26.4 (4.5) / 0.79
Systolic blood pressure, mean (SD), mmHg / 138 (18) / 142 (19.6) / 0.057 / 140 (17) / 142 (19) / 0.48
Diastolic blood pressure, mean (SD), mmHg / 80 (12) / 77 (11) / 0.002 / 76 (10) / 77 (11) / 0.33

Qualifying event

Stroke / 288 (68.1) / 96 (61.2) / 0.12 / 84 (62.7) / 81 (60.5) / 0.71
Transient ischemic attack / 135 (31.9) / 61 (38.9) / 50 (37.3) / 53 (39.5)

Medical history

Hypertension / 309 (73.1) / 140 (89.2) / <0.001 / 116 (86.6) / 119 (88.8) / 0.53
Diabetes / 75 (17.7) / 36 (22.9) / 0.157 / 30 (22.4) / 31 (23.1) / 0.88
Dyslipidemia / 166 (39.2) / 89 (56.7) / <0.001 / 70 (52.2) / 72 (53.7) / 0.80
Current smoking / 173 (41.0) / 26 (16.6) / <0.001 / 20 (14.9) / 25 (18.7) / 0.38
Cardiovascular disease / 60 (14.2) / 35 (22.3) / 0.02 / 26 (19.4) / 24 (17.9) / 0.76
Coronary artery disease / 53 (12.5) / 32 (20.4) / 0.02 / 23 (17.2) / 25 (18.7) / 0.75
Peripheral artery disease / 38 (9.0) / 14 (8.9) / 0.97 / 12 (9.0) / 12 (9.0) / 1.00

Medications

Aspirin / 321 (75.9) / 109 (69.4) / 0.11 / 94 (70.2) / 95 (70.9) / 0.90
Other antiplatelet agent / 133 (31.4) / 50 (31.9) / 0.93 / 38 (28.4) / 44 (32.8) / 0.40
Oral anticoagulant / 84 (19.9) / 40 (25.5) / 0.14 / 36 (26.9) / 34 (25.4) / 0.78
ACE inhibitor / 75 (17.7) / 46 (29.3) / 0.002 / 34 (25.4) / 38 (28.4) / 0.54
Calcium channel blocker / 193 (45.6) / 81 (51.6) / 0.20 / 69 (51.5) / 71 (53.0) / 0.80
Diuretic / 115 (27.2) / 49 (31.2) / 0.34 / 38 (28.4) / 41 (30.6) / 0.68
Beta-blocker / 120 (28.4) / 65 (41.4) / 0.003 / 50 (37.3) / 54 (40.3) / 0.59
Angiotensin II receptor blocker / 121 (28.6) / 43 (27.4) / 0.77 / 37 (27.6) / 39 (29.1) / 0.78
Statin / 377 (89.1) / 139 (88.5) / 0.84 / 115 (85.8) / 121 (90.3) / 0.26

Abbreviations: ACE, angiotensin-converting enzyme;NV, patients not vaccinated against influenza; SD, standard deviation; V, patients vaccinated against influenza.

Table e-4. Risk of Cardiovascular Events in Patients With and Without Influenza Vaccination In each Study

Propensity ScoreMatched Analysis / Propensity ScoreAdjusted Analysis
No. of events (KM) / HR(95%CI)a / P / No. of events (KM) / HR (95%CI)b / P
Study / Outcome / NV / V / NV / V
PERFORM trial / (n=4539) / (n=4539) / (n=13 801) / (n=5137)
MCE / 417 (9.5) / 443 (10.0) / 1.02 (0.88-1.17) / 0.83 / 1199 (8.9) / 512 (10.2) / 1.04 (0.92-1.16) / 0.56
MI (fatal/nonfatal) / 62 (1.4) / 54 (1.2) / 0.91 (0.62-1.33) / 0.63 / 164 (1.2) / 72 (1.5) / 0.83 (0.61-1.13) / 0.24
Stroke (fatal/nonfatal) / 352 (8.0) / 384 (8.7) / 1.05 (0.90-1.22) / 0.52 / 1030 (7.7) / 436 (8.7) / 1.07 (0.94-1.22) / 0.29
OPTIC registry / (n=381) / (n=381) / (n=2696) / (n=381)
MCE / 64 (17.5) / 47 (13.0) / 0.71 (0.47-1.05) / 0.09 / 407 (15.9) / 47 (13.0) / 0.76 (0.55-1.06) / 0.10
MI (fatal/nonfatal) / 15 (4.2) / 9 (2.6) / 0.53 (0.23-1.26) / 0.15 / 88 (3.5) / 9 (2.6) / 0.68 (0.33-1.42) / 0.30
Stroke (fatal/nonfatal) / 42 (11.7) / 28 (7.8) / 0.67 (0.41-1.10) / 0.11 / 274 (10.8) / 28 (7.8) / 0.68 (0.45-1.03) / 0.07
AMISTAD study / (n=134) / (n=134) / (n=404) / (n=154)
MCE / 10 (7.5) / 7 (5.3) / 0.78 (0.29-2.09) / 0.62 / 14 (3.5) / 9 (6.0) / 1.23 (0.47-3.23) / 0.68
MI (fatal/nonfatal) / 1 (0.8) / 1 (0.8) / - / - / 1 (0.2) / 2 (1.4) / - / -
Stroke (fatal/nonfatal) / 6 (4.6) / 5 (3.8) / 1.00 (0.29-3.45) / 1.00 / 10 (2.5) / 6 (3.9) / 1.32 (0.41-4.24) / 0.64

Abbreviations: CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier estimates; MCE, major cardiovascular event; MI, myocardial infarction; NV, patients not vaccinated against influenza; V, patients vaccinated against influenza vaccination.aCox-regression model stratified on the matched pairs; b Cox-regression model stratified on study and adjusted on propensity score (introduced as continuous variable)

Supplemental Figures :

Figure e-1. Study flow chart

Abbreviations: NV, patients not vaccinated against influenza; TIA, transient ischemic attack; V, patients vaccinated against influenza.

A) PERFORM trial

B) Optic registry

C) AMISTAD study

Figure e-2. Absolute Standardized Differences Between Vaccinated and Unvaccinated Patients, Before and After Propensity Score Matching: The PERFORM Trial

Abbreviations: ACE, angiotensin-converting enzyme;BP, blood pressure; CAD, coronary artery disease;CVD, cerebrovascular disease; NV, patients not vaccinated against influenza; PAD, peripheral artery disease; V, patients vaccinated against influenza.

Figure e-3. Absolute Standardized Differences Between Vaccinated and Unvaccinated Patients, Before and After Propensity Score Matching: The OPTIC Registry

Figure e-4. Absolute Standardized Differences Between Vaccinated and Unvaccinated Patients, Before and After Propensity Score Matching: The AMISTAD Study

Figure e-5. Cumulative Incidence of Cardiovascular Death, Myocardial Infarction, and Stroke by Influenza Vaccination Status, After Propensity Score-Matching: The OPTIC Registry

Propensity score-matched hazard ratio (HR) for use of influenza vaccination at baseline is reported with the 95% confidence interval (CI).

Figure e-6. Cumulative Incidence for Cardiovascular Death, Myocardial Infarction, and Stroke by Influenza Vaccination Status, After Propensity Score-Matching: The PERFORM Trial

Propensity score-matched hazard ratio (HR) for use of influenza vaccination at baseline is reported with the 95% confidence interval (CI).

Figure e-7. Cumulative Incidence Curve for Cardiovascular Death, Myocardial Infarction, and Stroke by Influenza Vaccination Status, After Propensity Score-Matching: The AMISTAD Study

Propensity score-matched hazard ratio (HR) for use of influenza vaccination at baseline is reported with the 95% confidence interval (CI).