Supplementary tables:
Supplementary table 1: Tyrosine kinase- targeting and anti-CD20 drugs registered in Israel in 2003-2012
Supplementary table 2: Cancer sites diagnosed among cases with heart failure and matched controls
Supplementary table 3: Number of cases and matched controls, mean ages, and main malignant diseases in each tyrosine-kinase targeting and anti-CD20 drugs users group
Supplementary table 4: Risk for new-onset heart failure associated with tyrosine-kinase targeting drugs and the anti CD-20 drug. Multivariable model results
Supplementary table 5: Ages and frequencies of comorbid conditions among anthracycline-treated patients and non anthracycline-treated patients
Supplementary table 1: Tyrosine kinase-targeting drugs registered in Israel in 2003-2012:
2003 / CML, GIST, ALL / BCR-ABL, c-KIT, PDGFR / Imatinib (Gleevec) / Small molecule
2003 / NSCLC / EGFR / Gefitinib (Iressa)
2005 / NSCLC / EGFR / Erlotinib (Tarceva)
2006 / RCC, HCC / multiple / Sorafenib (Nexavar)
2006 / GIST, RCC, pNET / PDGFR, VEGFR, KIT / Sunitinib (Sutent)
2010 / CML / BCR-ABL / Nilotinib (Tasigna)
2010 / RCC, STS / VEGFR, PDGFR, c-KIT / Pazopanib (Votrient)
2010 / CML, ALL / BCR-ABL, SRC, PDGFR / Dasatinib (Sprycel)
2011 / Melanoma / BRAF / Vemurafenib (Zelboraf)
2011 / NSCLC / ALK / Crizotinib (Xalkori)
2012 / Breast cancer / EGFR, HER-2 / Lapatinib (Tykerb)
2012 / Medullary thyroid cancer / EGFR, VEGFR / Vandetanib (Caprelsa)
2012 / RCC / VEGFR / Axitinib (Inlyta)
2012 / MPD / JAK / Ruxolitinib (Jakavi)
1998 / NHL / CD20 / Rituximab (Mabthera) / Antibody
1999 / Breast cancer, gastric cancer / HER2 / Trastuzumab (Herceptin)
*withdrawn 2012 / CLL, T-cell lymphoma / CD52 / Alemtuzumab (Mabcampath)
**withdrawn 2010 / AML / CD33 / Gemtuzumab (Mylotarg)
2004 / CRC, NSCLC, RCC, breast, glioblastoma, ovarian, fallopian, primary peritoneal cancer / VEGFR / Bevacizumab (Avastin)
2008 / CRC, SCCHN / EGFR / Cetuximab (Erbitux)
2009 / CRC / EGFR / Panitumumab (Vectibix)
2011 / melanoma / CTLA-4 / Ipilimumab (Yervoy)
2012 / breast cancer / HER-2 / Pertuzumab (Perjeta)
CML: chronic myeloid leukemia, GIST: gastrointestinal stromal tumor; ALL: acute lymphoblastic leukemia; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; HCC: hepatocellular carcinoma; pNET: pancreatic neuroendocrine tumors; STS: Soft Tissue Sarcoma; MPD: myeloproliferative disease; NHL: non-Hodgkin's lymphoma; CLL: chronic lymphocytic leukemia; AML: acute myelogenous leukemia; CRC: colorectal cancer; SCCHN: squamous cell cancer of the head and neck; *There is no information about application date (Israel). Withdrawn from the market in 2012 at the request of the marketing-authorization holder **withdrawn from the market in 2010 due to adverse effects (not HF)
Supplementary table 2: Cancer sites diagnosed among cases with heart failure and matched controls without heart failure
Breast Cancer / 168 (18.1) / 4585 (18.1)
Malignancy of Colon or Rectum / 147 (15.8) / 6038 (23.8)
Non Hodgkin Lymphoma / 111(11.9) / 2715 (10.7)
Malignancy of Lung / 108 (11.6) / 2488 (9.8)
Multiple Myeloma / 67 (7.2) / 1197 (4.7)
Acute Leukemia / 36 (3.9) / 686 (2.7)
Malignancy of Bladder / 32 (3.4) / 896 (3.5)
Malignancy of Prostate / 28 (3.0) / 542 (2.1)
Malignancy of Pancreas / 28 (3.0) / 656 (2.6)
Hodgkins Lymphoma / 24 (2.6) / 570 (2.2)
Polycytemia Vera / 21(2.3) / 531 (2.1)
Malignancy of Ovary / 20 (2.2) / 835 (3.3)
Chronic Leukemia / 19 (2.0) / 316 (1.2)
Stomach Cancer / 16 (1.7) / 602 (2.4)
Malignancy of Kidney / 16 (1.7) / 324 (1.3)
Malignancy of Uterus / 14 (1.5) / 345 (1.4)
Malignancy of Other Sites / 14 (1.5) / 362 (1.4)
Malignancy of Larynx / 9 (1.0) / 191(0.8)
Malignancy of Pharynx / 9 (1.0) / 247 (1.0)
Malignancy of Liver / Bile Ducts / 8 (0.9) / 217 (0.9)
Malignancy of Brain / CNS / 8 (0.9) / 302 (1.2)
Myelodysplastic Syndrome / 6 (0.6) / 103 (0.4)
Myelo/Lymphoproliferative Syndrome / 4 (0.4) / 74 (0.3)
Melanoma / 4 (0.4) / 163 (0.6)
Malignancy of Bone / 3 (0.3) / 35 (0.1)
Malignancy of Connective Tissue / Sarcoma / 3 (0.3) / 127 (0.5)
Malignancy of Esophagus / 3 (0.3) / 87 (0.3)
Malignancy of Other Male/Female Genital Organs / 2 (0.2) / 32 (0.1)
Malignancy of Cervix Uteri / 1(0.1) / 61 (0.2)
Malignancy of Thyroid / 1(0.1) / 45 (0.2)
Neurofibromatosis / 0 (0) / 10 (0.0004)
A nested case-control analysis within a cohort of27,992 patients treated systemically for malignant diseases. Controls matched to heart failure cases by calendar year of cohort entry, age +/- 2 years, gender, and duration of follow up.
Supplementary table 3: Number of cases and matched controls, mean ages, and main malignant diseases in each tyrosine-kinase targeting and anti-CD20 drugs users groups:
25382) / Total, No. (%) (n=
26312) / Mean Age at Cohort Entry (SD) (Total Cohort) / Main Malignant Diseases Diagnosed in Patients Treated with the Drug
Rituximab / 156 (16.77) / 3815 (15.03) / 3971 (15.09) / 70.4(10.1) / Acute Leukemia, breast, chronic leukemia, Hodgkins Lymphoma, colon/rectum, lung, prostate, multiple myeloma, NHL, stomach
Trastuzumab / 87 (9.35) / 1669 (6.58) / 1756 (6.67) / 63.7(11.9) / Breast
Cetuximab / 23 (2.47) / 497 (1.96) / 520 (1.98) / 71.1(9.9) / Colon/Rectum, larynx, pharynx
Bevacizumab / 41 (4.41) / 1859 (7.32) / 1900 (7.22) / 69.4(9.7) / Breast, brain/ CNS, colon/rectum, lung
Panitumumab / 4 (0.43) / 53 (0.21) / 57 (0.22) / 72.9(9.5) / Colon/rectum
Imatinib / 11 (1.18) / 399 (1.57) / 410 (1.56) / 68.5(10.7) / Acute leukemia, chronic leukemia, stomach
Gefitinib / 9 (0.97) / 155 (0.61) / 164 (0.62) / 74.6(9.1) / Lung
Erlotinib / 22 (2.37) / 400 (1.58) / 422 (1.60) / 71.2(9.2) / Lung
Sunitinib / 15 (1.61) / 175 (0.69) / 190 (0.72) / 68.8(9.0) / Kidney
Sorafenib / 4 (0.43) / 127 (0.50) / 131 (0.50) / 71.4(9.3) / Kidney, liver/bile ducts
Dasatinib / 2 (0.22) / 25 (0.10) / 27 (0.10) / 70.5(8.2) / Acute Leukemia
Lapatinib / 3 (0.32) / 25 (0.10) / 28 (0.11) / 63.1(13.6) / Breast Cancer
Nilotinib / 3 (0.32) / 53 (0.21) / 56 (0.21) / 69.4(10.6) / Acute leukemia
Pazopanib / 4 (0.43) / 33 (0.13) / 37 (0.14) / 75.4(6.4) / Kidney
A nested case-control analysis within a cohort of 27,992 patients treated systemically for malignant diseases. Controls matched to heart failure cases by calendar year of cohort entry, age +/- 2 years, gender, and duration of follow up.
Supplementary table 4: Risk for new-onset heart failure associated with tyrosine-kinase targeting drugs and the anti CD-20 drug. Multivariable model results
Tyrosine Kinase targeting and anti-CD20 drug
1.57 / 0.98 / 1.24 / Rituximab
2.49 / 1.46 / 1.90 / Trastuzumab
2.69 / 1.10 / 1.72 / Cetuximab
1.19 / 0.52 / 0.79 / Bevacizumab
8.85 / 1.02 / 3.01 / Panitumumab
1.43 / 0.32 / 0.68 / Imatinib
3.10 / 0.74 / 1.51 / Gefitinib
1.77 / 0.68 / 1.09 / Erlotinib
6.47 / 1.78 / 3.39 / Sunitinib
2.93 / 0.35 / 1.02 / Sorafenib
11.92 / 0.37 / 2.09 / Dasatinib
3.54 / 0.28 / 0.99 / Lapatinib
5.39 / 0.29 / 1.25 / Nilotinib
7.93 / 0.77 / 2.47 / Pazopanib
Chemotherapy
1.88 / 1.19 / 1.49 / Nitrogen mustard analogues
2.06 / 0.59 / 1.10 / Other alkylating agents
3.28 / 1.62 / 2.31 / Folic acid analogues
2.46 / 1.03 / 1.59 / Purine analogues
1.70 / 1.16 / 1.41 / Pyrimidine analogues
1.06 / 1.00 / 1.03 / Vinca alkaloids and analogues
3.18 / 0.82 / 1.61 / Etoposide
1.05 / 1.01 / 1.03 / Taxanes
1.38 / 0.76 / 1.03 / Anthracyclines and related substances (doxorubicin, daunorubicine, epirubicin, idarubicin, mitoxantrone)
2.98 / 0.73 / 1.48 / Bleomycin, mitomycin
0.79 / 0.46 / 0.60 / Platinum compounds
1.99 / 0.24 / 0.70 / Procarbazine
3.47 / 0.61 / 1.46 / Other chemotherapeutics (estramustine, tretinoin, mitotane, pegaspargase, arsenic trioxide, anagrelide, visemodegib)
4.99 / 0.32 / 1.26 / Everolimus (high dose)
2.50 / 1.19 / 1.73 / Hydroxycarbamide
2.31 / 1.16 / 1.64 / Bortezomib
1.84 / 0.84 / 1.24 / Topotecan, irinotecan
1.06 / 0.72 / 0.87 / Radiotherapy (all fields)
Comorbidity
1.69 / 1.26 / 1.46 / Diabetes mellitus
1.83 / 1.30 / 1.54 / Hypertension
1.23 / 0.75 / 0.96 / PVD, carotid artery disease
1.12 / 0.79 / 0.94 / Hyperlipidemia
1.65 / 1.05 / 1.31 / Chronic renal failure
5.29 / 0.29 / 1.24 / Cirrhosis
1.84 / 1.34 / 1.57 / Ischemic heart disease
1.57 / 1.01 / 1.26 / Valvular heart disease
2.10 / 1.38 / 1.70 / Atrial fibrillation
2.03 / 1.14 / 1.52 / Other arrhythmia
2.21 / 0.63 / 1.18 / Alcohol abuse
5.29 / 0.66 / 1.86 / Drug abuse
1.52 / 1.12 / 1.31 / Smoker (current/past)
1.28 / 0.94 / 1.10 / Obesity
1.00 / 0.99 / 1 / Total hospital admissions days before cohort entry
Medications
2.40 / 0.77 / 1.36 / Antiarrhythmic, class I and III
3.27 / 0.81 / 1.62 / Thiazolidinediones
1.61 / 1.18 / 1.38 / Corticosteroids, systemic
1.27 / 0.96 / 1.10 / Non-steroidal anti-inflammatory drugs
1.87 / 1.00 / 1.36 / Antimycotic imidazole and triazole derivatives
1.62 / 1.09 / 1.33 / Colony stimulating factors
2.16 / 0.83 / 1.34 / Gonadotropin releasing hormone analogues
0.96 / 0.55 / 0.73 / Hormone antagonists
Supplementary table 5: Age and frequencies of comorbid conditions among patients who were treated with anthracyclines and patients not treated with anthracyclines
<0.001 / 65.2 / 69.0 / Age, mean
0.001 / 23.4 / 27.3 / Diabetes Mellitus
0.001 / 54.4 / 58.7 / Hypertension
<0.001 / 4.3 / 6.7 / PVD/carotid artery stenosis
0.2 / 20.4 / 21.8 / Hyperlipidaemia
<0.001 / 3.3 / 7.4 / Chronic renal failure
0.04 / 0.4 / 0.1 / Cirrhosis
<0.001 / 14.0 / 24.9 / Ischaemic heart disease
<0.001 / 3.7 / 7.5 / Valvular disease
<0.001 / 4.5 / 8.0 / Atrial fibrillation
0.004 / 2.5 / 3.9 / Other arrhythmia
0.001 / 0.1 / 1.0 / Alcohol abuse
<0.001 / 23.6 / 37.8 / Smoking
<0.001 / 36.1 / 26.4 / Obesity
A nested case-control study of new cases of heart failure and matched controls, within a cohort of 27,992 malignant disease patients treated systemically
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