Serious adverse events reported in the COPE trial

Patients with CKD (n=834) Patients without CKD (n=1996)P value

Beni + ARB Beni + BB Beni + TD P value TotalBeni +

ARBBeni + BB Beni + TD P value Total

Angina pectoris 2(0.7%) 5(1.8%) 3(1.1%) 0.499 10(1.2%

)4(0.6%) 6(0.9%) 7(1.0%) 0.689 17(0.9%) 0.393

Arteriosclerosis obliterans 2(0.7%) 0(0.0%) 2(0.8%) 0.354 4(0.5%) 3(0.5%) 1(0.2%) 1(0.1%) 0.440 5(0.3%) 0.328

Cardiac failure 1(0.3%) 1(0.4%) 4(1.5%) 0.180 6(0.7%) 3(0.5%) 2(0.3%) 2(0.3%) 0.858 7(0.4%) 0.189

Cataract operation 1(0.3%) 0(0.0%) 4(1.5%) 0.057 5(0.6%) 1(0.2%) 4(0.6%) 3(0.4%) 0.407 8(0.4%) 0.482

Cerebral hemorrhage 2(0.7%) 2(0.7%) 0(0.0%) 0.394 4(0.5%) 3(0.5%) 7(1.1%) 2(0.3%) 0.150 12(0.6%) 0.688

Gastric cancer 2(0.7%) 2(0.7%) 1(0.4%) 0.854 5(0.6%) 3(0.5%) 4(0.6%) 1(0.1%) 0.385 8(0.4%) 0.482

Lacunar infarction 4(1.4%) 2(0.7%) 0(0.0%) 0.154 6(0.7%) 4(0.6%) 3(0.5%) 2(0.3%) 0.690 9(0.5%) 0.375

Lung neoplasm malignant 1(0.3%) 1(0.4%) 2(0.8%) 0.731 4(0.5%) 2(0.3%) 0(0.0%) 2(0.3%) 0.379 4(0.2%) 0.205

Myocardial infarction 2(0.7%) 0(0.0%) 3(1.1%) 0.220 5(0.6%) 3(0.5%) 2(0.3%) 1(0.1%) 0.586 6(0.3%) 0.248

Pneumonia 4(1.4%) 3(1.1%) 2(0.8%) 0.770 9(1.1%) 1(0.2%) 2(0.3%) 2(0.3%) 0.823 5(0.3%) 0.004

Prostate cancer 3(1.0%) 1(0.4%) 2(0.8%) 0.618 6(0.7%) 1(0.2%) 2(0.3%) 6(0.9%) 0.113 9(0.5%) 0.375

Thrombotic stroke 1(0.3%) 1(0.4%) 1(0.4%) 0.998 3(0.4%) 2(0.3%) 3(0.5%) 2(0.3%) 0.844 7(0.4%) 0.976

Transient ischemic attack 1(0.3%) 3(1.1%) 1(0.4%) 0.466 5(0.6%) 1(0.2%) 3(0.5%) 3(0.4%) 0.569 7(0.4%) 0.358

Supplemental data

Abbreviations: Beni=benidipine , ARB =angiotensin receptor blocker, BB = β-blocker, TD = thiazide diuretic,Data are shown as number of patients (%).

Supplemental data

Patients with CKD (n=834) Patients without CKD (n=1996)P valueBeni +

ARBBeni + BB Beni + TD P value Total

Beni + ARB

Beni + BB Beni + TD P value Total

Alanine aminotransferase increased

7(2.4%) 8(2.8%) 8(3.0%) 0.911 23(2.8%) 20(3.0%) 7(1.1%) 25(3.7%) 0.009 52(2.6%) 0.834

Aspartate aminotransferase increased

7(2.4%) 8(2.8%) 7(2.7%) 0.959 22(2.6%) 19(2.9%) 10(1.5%) 19(2.8%) 0.212 48(2.4%) 0.731

Back pain 1(0.3%) 2(0.7%) 6(2.3%) 0.070 9(1.1%) 7(1.1%) 5(0.8%) 4(0.6%) 0.615 16(0.8%) 0.479 Blood alkaline phosphatase increased

6(2.1%) 1(0.4%) 2(0.8%) 0.111 9(1.1%) 8(1.2%) 4(0.6%) 11(1.6%) 0.235 23(1.2%) 0.857

Blood creatinine increased 7(2.4%) 5(1.8%) 13(4.9%) 0.076 25(3.0%) 1(0.2%) 1(0.2%) 5(0.7%) 0.117 7(0.4%) <0.001Blood urea increased 10(3.5%) 6(2.1%) 9(3.4%) 0.566 25(3.0%) 2(0.3%) 5(0.8%) 5(0.7%) 0.478 12(0.6%) <0.001Bradycardia 0(0.0%) 9(3.2%) 0(0.0%) <0.001 9(1.1%) 3(0.5%) 32(4.9%) 1(0.1%) <0.001 36(1.8%) 0.156 Bronchitis 15(5.2%) 5(1.8%) 10(3.8%) 0.084 30(3.6%) 13(2.0%) 16(2.5%) 15(2.2%) 0.832 44(2.2%) 0.036 Diabetes mellitus 6(2.1%) 13(4.6%) 9(3.4%) 0.252 28(3.4%) 15(2.3%) 25(3.9%) 19(2.8%) 0.229 59(3.0%) 0.588 Eczema 4(1.4%) 2(0.7%) 2(0.8%) 0.646 8(1.0%) 4(0.6%) 3(0.5%) 4(0.6%) 0.930 11(0.6%) 0.230 Gamma-glutamyltransferase increased

2(0.7%) 3(1.1%) 1(0.4%) 0.641 6(0.7%) 7(1.1%) 4(0.6%) 10(1.5%) 0.319 21(1.1%) 0.400

Gastroenteritis 2(0.7%) 0(0.0%) 6(2.3%) 0.021 8(1.0%) 4(0.6%) 5(0.8%) 6(0.9%) 0.847 15(0.8%) 0.583 Glycosylated hemoglobin increased

4(1.4%) 1(0.4%) 5(1.9%) 0.237 10(1.2%) 5(0.8%) 6(0.9%) 9(1.3%) 0.574 20(1.0%) 0.650

Hypercholesterolemia 5(1.7%) 7(2.5%) 3(1.1%) 0.499 15(1.8%) 16(2.4%) 15(2.3%) 25(3.7%) 0.256 56(2.8%) 0.114 Hyperglycemia 4(1.4%) 2(0.7%) 3(1.1%) 0.725 9(1.1%) 4(0.6%) 7(1.1%) 9(1.3%) 0.417 20(1.0%) 0.863 Hyperkalemia 8(2.8%) 1(0.4%) 1(0.4%) 0.009 10(1.2%) 3(0.5%) 5(0.8%) 2(0.3%) 0.457 10(0.5%) 0.045 Hyperlipidemia 7(2.4%) 11(3.9%) 9(3.4%) 0.610 27(3.2%) 17(2.6%) 14(2.2%) 17(2.5%) 0.872 48(2.4%) 0.217 Hypertriglyceridemia 7(2.4%) 9(3.2%) 5(1.9%) 0.628 21(2.5%) 15(2.3%) 22(3.4%) 19(2.8%) 0.475 56(2.8%) 0.654 Hyperuricemia 10(3.5%) 4(1.4%) 28(10.6%) <0.001 42(5.0%) 7(1.1%) 12(1.9%) 47(6.9%) <0.001 66(3.3%) 0.031 Hypokalemia 1(0.3%) 1(0.4%) 5(1.9%) 0.076 7(0.8%) 5(0.8%) 0(0.0%) 20(2.9%) <0.001 25(1.3%) 0.337 Hypotension 2(0.7%) 3(1.1%) 0(0.0%) 0.266 5(0.6%) 3(0.5%) 4(0.6%) 5(0.7%) 0.807 12(0.6%) 0.988 Nasopharyngitis 6(2.1%) 8(2.8%) 10(3.8%) 0.491 24(2.9%) 13(2.0%) 17(2.6%) 13(1.9%) 0.614 43(2.2%) 0.257 Osteoarthritis 3(1.0%) 0(0.0%) 0(0.0%) 0.057 3(0.4%) 6(0.9%) 7(1.1%) 6(0.9%) 0.922 19(1.0%) 0.100 Pharyngitis 5(1.7%) 1(0.4%) 5(1.9%) 0.213 11(1.3%) 3(0.5%) 7(1.1%) 17(2.5%) 0.004 27(1.4%) 0.932 Proteinuria 4(1.4%) 5(1.8%) 4(1.5%) 0.935 13(1.6%) 3(0.5%) 5(0.8%) 9(1.3%) 0.221 17(0.9%) 0.097 Upper respiratory tract inflammation

9(3.1%) 6(2.1%) 7(2.7%) 0.751 22(2.6%) 13(2.0%) 15(2.3%) 9(1.3%) 0.390 37(1.9%) 0.189

Vertigo 0(0.0%) 7(2.5%) 4(1.5%) 0.033 11(1.3%) 4(0.6%) 9(1.4%) 12(1.8%) 0.157 25(1.3%) 0.897

Adverse events reported in the COPE trial

Abbreviations: ALT=alanine aminotransferase, Beni=benidipine , ARB =angiotensin receptor blocker, BB = β-blocker, TD = thiazide diuretic,Data are shown as number of patients (%).