Therapeutically treated groups |
Childhood Cancer Survivor Study | Mulrooney et al [93] | Heart | Smoking, BMI, diabetes, hypertension, dyslipidaemia, racial/ethnic group, education, chemotherapy | Heart failure incidence CTCAE v4.03 ≥ 3 | NA | 0.022 (-0.093 to 0.138)a | Presented RR of various cardiac endpoints are adjusted for race, BMI, smoking, exercise intensity. Unadjusted analyses not presented. Additional analysis in which cardiotoxic exposures are adjusted for did not appreciably change RR for heart failure, coronary artery disease, valvular disease, pericardial disease, arrhythmia in relation to initial cancer endpoint: change in RR always < 10%. |
Coronary artery disease incidence CTCAE v4.03 ≥ 3 | NA | 0.066 (-0.020 to 0.152)a |
Valvular disease incidence CTCAE v4.03 ≥ 3 | NA | 0.064 (-0.178 to 0.306)a |
Pericardial disease incidence CTCAE v4.03 ≥ 3 | NA | -0.005 (-0.082 to 0.072)a |
Arrhythmia incidence CTCAE v4.03 ≥ 3 | NA | 0.005 (-0.049 to 0.058)a |
French–UK childhood cancer study | Tukenova et al [94] | Heart | Epipodophyllotoxins, anthracyclines, alkylating agents, vinca alkaloids, antimetabolites, antibiotics | All cardiac disease | NA | 0.6 (0.2 to 2.5) | Presented ERR is adjusted for alkylating agents, vinca alkaloids, anthracyclines (including dose), antimetabolites. No unadjusted ERR are presented. Radiation dose did not significantly interact with exposure to anthracyclines (p > 0.3) or any other type of drug. |
French (Institut Gustave Roussy) childhood cancer cardiac study | Haddy et al [95] | Heart | Smoking, BMI, anthracyclines, alkylating agents, vinca alkaloids, epipodophyllotoxins, antimetabolites | Cardiac disease (ICD9 391, 393–397, 410–413, 420, 423–424, 426–428; ICD10 I05–I09, I20–I25, I30–I32, I44–I50) incidence: without anthracyclines | 0.49 (0.26 to 1.3) | NA | ERR are not adjusted for any variable. RR in highest dose group (> 30 Gy) are “similar when the analysis is controlled for smoking status and BMI”. |
Cardiac disease incidence: with anthracyclines | 0.07 (0.03 to 0.13) | NA |
French Childhood Cancer Study case-control study | Mansouri et al [84] | Heart | Smoking, BMI, physical activity, anthracyclines, alkylating agents, vinca alkaloids | Heart failure incidence (CTCAE v4.03 grade ≥ 1) with concomitant anthracyclines | NA | 0.09 (0.02 to 0.22) | ERR were adjusted for splenectomy, type of first malignancy, vinca alkaloids, alkylating agents and other chemotherapy. A modifying effect of anthracycline suggested (but no test of significance). Apart from effect of anthracyclines “no other factors significantly modified the effects of radiation. However, HF risk increased with each category of age, with ERR/Gy values for the MHD of 0.06, 0.33, 0.38 and 0.48 in those aged < 15, 15–25, 25–35, and ≥ 35 years, respectively.” |
Heart failure incidence (CTCAE v4.03 grade ≥ 1) without concomitant anthracyclines | NA | 0.44 (0.18 to 1.12) |
Netherlands Hodgkin lymphoma coronary heart disease case-control study | van Nimwegen et al [86] | Heart EQD2 | Smoking, BMI, diabetes, hypertension, hyper-cholesterolemia, physical activity, alkylating agents, procarbazine, vincristine, anthracyclines, splenectomy | Coronary heart disease incidence (angina pectoris, myocardial infarction requiring intervention) CTCAE v4.0 grades ≥ 2 | NA | 0.074 (0.033 to 0.148) | ERR is adjusted for chemotherapy. There is no unadjusted analysis. There is “no evidence for statistically significant modification of the effect of MHD on CHD risk by chemotherapy, sex, cardiovascular disease risk factors, and recent smoking at HL diagnosis.” |
Netherlands Hodgkin lymphoma heart failure case-control study | van Nimwegen et al [87] | Heart EQD2 | Smoking, BMI, diabetes, hypertension, hyper-cholesterolemia, physical activity, anthracyclines, splenectomy | Heart failure incidence CTCAE v3.0, v4.0 grades ≥ 2 | 0.038 (-0.001 to 0.146)b | NA | Although many adjusting variables are available, only RR for unadjusted analysis are presented. RR in high dose group (≥ 26 Gy) “did not differ significantly according to use of anthracycline chemotherapy (p = 0.45 for MHD, 0.09 for MLVD) or with splenectomy (p = 0.71 for MHD, 0.62 for MLVD).” No additional significant interactions by sex (p = 0.72), age at HL diagnosis (p = 0.43), or time since HL diagnosis (p = 0.92) |
Nordic breast cancer case–control study | Darby et al [41] | Heart | Smoking, BMI, diabetes, hypertension, analgesic medication, thyroid medication, surgery, HRT, chemotherapy, ovarian ablation, history of IHD or COPD | IHD incidence (ICD10 I20-I25) | NA | 0.074 (0.029 to 0.145) | ERR was estimated adjusting for cardiac risk factor (history of IHD or other circulatory disease, smoking, BMI, history of COPD, diabetes, analgesic medication). The risk was very “similar for women with and those without cardiac risk factors” (ERR/Gy = 0.074 (95% CI 0.018, 0.178) for those with no cardiac risk factors vs 0.074 (95% CI 0.011, 0.195) for those with at least one cardiac risk factor, p = 0.99 heterogeneity). Unadjusted analysis not presented. |
Netherlands-Groningen breast cancer study | Roos et al [96] | Heart | Smoking, BMI, diabetes, hypertension, hyper-cholesterolemia, COPD, pulmonary embolism, chemotherapy, endocrine therapy, history of IHD, CAC | Acute coronary event incidence (myocardial infarction (ICD10 I21-I24), coronary revascularization, death from ischemic heart disease (ICD10 I20-I25)) | 0.17 (0.00 to 0.37) | 0.18 (0.00 to 0.39) | ERR adjusted for history of IHD, diabetes, BMI, hypercholesterolaemia, hypertension, CAC. A number of simpler models also presented, e.g., as shown here adjusted for history of IHD, diabetes, CAC. |
Netherlands-Groningen breast cancer study | van den Bogaard et al[97] | Heart | Smoking, BMI, diabetes, hypertension, hyper-cholesterolemia, chemotherapy, hormonal therapy, trastuzumab, other heart disease | Incidence of myocardial infarction (ICD10 I21-24), coronary revascularisation or death from IHD (CD10 I20-I25) among patients with atherosclerotic plaque in LAD | 0.116 (-0.079 to 0.353) | 0.117 (-0.098 to 0.383) | ERR adjusted for history of IHD, hypertension, hypercholesterolaemia, diabetes. Unadjusted ERR are also presented. |
Incidence of myocardial infarction (ICD10 I21-24), coronary revascularisation or death from IHD (CD10 I20-I25) among patients without atherosclerotic plaque in LAD | 0.153 (-0.017 to 0.353) | 0.161 (-0.034 to 0.395) |
Netherlands-NKI-Rotterdam breast cancer case-control study | Jacobse et al [85] | Heart | Smoking, BMI, hypertension, diabetes, surgery, chemotherapy, endocrine therapy, prior CVD | Myocardial infarction incidence | 0.064 (0.013 to 0.160) | NA | Although many adjusting variables are available, only ERR for unadjusted analysis is presented. The “dose response relationship for women with and without cardiovascular risk factors at BC diagnosis was similar (p > 0.5)”. There are modifications in risk by age at exposure (ERR/Gy age < 45 = 0.242 (95% CI 0.044, 0. 823), age 50–70 = 0.025, 95% CI -0.014, 0.119, heterogeneity p = 0.054), and also increased with longer follow-up (heterogeneity p = 0.053 for < 10 vs > 15 years) |
Netherlands-NKI-Rotterdam breast cancer case-control study | Boekel et al [88] | Heart | Smoking, BMI, diabetes, hypertension, hyper-cholesterolemia, menopausal status, chemotherapy, endocrine therapy, surgery | Heart failure (CTCAE v3.0, v4.0 grade ≥ 2) incidence – no treatment with anthracyclines | 0.00 (-0.03 to 0.08) | NA | Although many adjusting variables are available, only ERR for unadjusted analysis is presented. A modifying effect of anthracycline is suggested (but there is no test of significance). |
Heart failure (CTCAE v3.0, v4.0 grade ≥ 2) incidence – treatment with anthracyclines | 0.08 (-0.03 to 0.43) | NA |
Heart failure (CTCAE v3.0, v4.0 grade ≥ 2) incidence | 0.01 (-0.02 to 0.10) | NA |
Case-control study nested within ESCaRa breast cancer cohort study | Baaken et al[98] | Heart | BMI, chemotherapy, endocrine therapy, previous CVD | Incidence of myocardial infarction, angina pectoris, congestive heart failure, dysrhythmia, valvular heart disease, or mortality from cardiac infarction (ICD10 I21-I23), chronic IHD (ICD10 I25.0-I25.9), acute IHD (ICD10 I21.0-I24.9), congestive heart failure (ICD10 I50.0-I50.9), angina pectoris (ICD10 I20.0-I20.9), cardiac arrest (ICD10 I46), dysrhythmia/conduction disorder (ICD10 I44.0-I49.9), vitium cordis (ICD10 I34.0-I37.9) | -0.01 (-0.06 to 0.05) | -0.01 (-0.06 to 0.05) | Analysis adjusted for chemotherapy, endocrine therapy and BMI. Unadjusted ERR also presented. |
Severance Hospital breast cancer study | Chung et al[99] | Heart | Smoking, BMI, diabetes, hypertension, exercise, surgery, chemotherapy, endocrine treatment | Stable angina pectoris, unstable angina, myocardial infarction, IHD, heart failure, atrial fibrillation, coronary revascularisation, death from IHD | 0.22 (0.13 to 0.30) | 0.23 (0.15 to 0.32) | Analysis adjusted for exercise status, BMI, hypertension, diabetes, previous heart disease, anthracycline, anti-HER2 treatment, aromatase inhibitors. Unadjusted analysis also presented. |
Severance Hospital breast cancer substudy | Kim et al[100] | Heart | Smoking, BMI, diabetes, hypertension, exercise, anthracycline and other chemotherapy, anti-HER2 treatment, surgery, previous CVD | Acute coronary events (ST-elevation/non-ST-elevation myocardial infarction and unstable angina pectoris) | 0.03 (0.00 to 0.05)c ** | 0.22 (0.01 to 0.46)c ** | Analysis adjusted for BMI, laterality, diabetes, smoking, anthracyclines, history of heart disease. Unadjusted analysis also presented. |
Heart disease other than acute coronary events | 0.20 (0.11, 0.29) * | 0.13 (0.03 to 0.24) * | Analysis adjusted for BMI, laterality, diabetes, smoking, type of surgery, anthracyclines, anti-HER2 treatment, CAC score. Unadjusted analysis also presented. |
University of Michigan non-small cell lung cancer study | Dess et al[101] | Heart EQD2 | Smoking, diabetes, systolic blood pressure, cholesterol, previous CVD, KPS | CTCAE v4.03 grade ≥ 3 cardiac event incidence | 0.08 (0.03 to 0.13) | 0.07 (0.02 to 0.13) | Analysis adjusted for sex, diabetes, smoking, systolic blood pressure, previous cardiac disease, Framingham risk score. Unadjusted analysis also presented. |
University of Michigan non-small cell lung cancer study | Xue et al [102] | Pericardium | Smoking, hypertension, COPD, chemotherapy, previous CVD, KPS | Pericardial effusion incidence | 0.066 (0.028, 0.105) | 0.050 (0.009 to 0.093) | Analysis adjusted for sex, smoking, hypertension, COPD, chemotherapy, previous CVD, KPS. Unadjusted analysis also presented. |
Dana Farber/Brigham Women’s Hospital non-small cell lung cancer study | Atkins et al [103, 104] | Heart | Smoking, BMI, diabetes, hypertension, cholesterol, hyperlipidaemia, previous CVD, chemotherapy, statins | Major adverse cardiac events (cardiac death, unstable angina, myocardial infarction, heart failure hospitalization or urgent visit, coronary revascularization) | 0.02 (0.00 to 0.06) | 0.03 (0.00 to 0.06) | Adjusted for hypertension, hyperlipidaemia, diabetes, previous CVD (stroke, peripheral vascular disease, coronary artery disease, myocardial infarction, congestive heart failure, arrhythmia, valvulopathy, Framingham score, statins. Unadjusted analysis also presented. |
New Jersey non-small cell lung cancer study | Yegya-Raman et al [105] | Heart | Smoking, blood pressure, diabetes, chemotherapy, pre-treatment CAD | First symptomatic cardiac event (myocardial infarction, unstable angina, significant arrhythmia, symptomatic pericardial effusion, pericarditis, congestive heart failure) incidence | 0.058 (0.034 to 0.082) | 0.065 (0.038 to 0.093)d 0.059 (0.032 to 0.086)e | Two different adjusted models, adjusted for (a) CAD or (b) WHO/ISH stratum, also unadjusted |
Chenyang thymoma study | Liao et al [106] | Heart | Smoking, BMI, diabetes, hypertension, hyperlipidemia, chemotherapy, myasthenia gravis, family history of CVD | CTCAE v4.0 grade ≥ 2 cardiovascular disease incidence | 0.074 (0.012 to 0.136)f | 0.084 (0.026 to 0.143)g | Adjusted for chemotherapy status, hypertension, hyperlipidemia, diabetes, BMI, family history of CVD. Unadjusted case and control numbers also given. |
Israeli tinea capitis prevalence study | Sadetzki et al[107] | Breast | Smoking, BMI, diabetes, hypertension, SES | IHD incident prevalence | NA | 7 (1 to 14)h | Adjusted for sex, smoking, SES, hypertension, diabetes. Unadjusted analysis not presented for dose response, although analysis of exposure to radiation (yes vs no) suggests that adjustment for these variables made difference of < 2% (all CVD RR = 1.21 unadjusted vs 1.19 adjusted). |
Brain | CeVD incident prevalence | NA | 0.20 (0.12 to 0.29)h |
Salivary | Carotid artery stenosis incident prevalence | NA | 0.33 (0.04 to 0.71)h |
Rochester thymus enlargement study | Adams et al[80] | Heart | Smoking, dyslipidemia, diabetes, hypertension, family history of myocardial infarction | Coronary heart disease incidence (ICD10 I21-I25, I46) | 0.08 (-0.01 to 0.20) *** | -0.03 (-0.07 to 0.10) *** | Adjusted for sex, diabetes, dyslipidemia, smoking, hypertension. Unadjusted analysis (adjusted for sex) also presented. |
Myocardial infarction incidence (ICD10 I21-I24) | -0.05 (-0.13 to 0.08) | -0.06 (-0.16 to 0.06) |
Diagnostically exposed groups |
Canadian and Massachusetts tuberculosis fluoroscopy cohorts | Tran et al [108] | Lung | Smoking, diabetes, alcohol consumption, antibiotic use, tuberculosis stage | All CVD ICD9 390–459 | -0.024 (-0.042 to -0.005)i | NA | Main analyses adjust for cohort, sex, smoking, tuberculosis status. Additional analysis for some endpoints adjusts for alcohol consumption, diabetes, antibiotic use in Massachusetts cohort |
All CVD ICD9 390–459: <0.5 Gy | 0.246 (0.036 to 0.469)i | 0.262 (0.042 to 0.476)i,j |
Ischemic heart disease ICD9 410–414 | -0.037 (-0.060 to -0.013)i | NA |
Ischemic heart disease ICD9 410–414: < 0.5 Gy | 0.268 (0.003 to 0.552) | 0.286 (0.020 to 0.572)i,j |
Cerebrovascular disease ICD9 430–438 | -0.014 (-0.067 to 0.044)i | NA |
Cerebrovascular disease ICD9 430–438: < 0.5 Gy | 0.441 (-0.119 to 1.090)i | 0.435 (-0.125 to 1.083)i,j |
Hypertensive heart disease ICD9 401–405 | -0.035 (-0.152 to 0.153)i | NA |
Hypertensive heart disease ICD9 401–405: < 0.5 Gy | 1.121 (-0.351 to 3.228)i | 1.147 (-0.333 to 3.266)i,j |
Heart disease apart from hypertensive and IHD ICD9 390–400, 406–410 | -0.010 (-0.064 to 0.043)i | NA |
Heart disease apart from hypertensive and IHD ICD9 390–400, 406–410: < 0.5 Gy | -0.226 (-0.679 to 0.307)i | -0.240 (-0.691 to 0.291)i,j |
All CVD apart from heart and cerebrovascular ICD9 439–459 | 0.055 (-0.028 to 0.164)i | NA |
All CVD apart from heart and cerebrovascular ICD9 439–459: < 0.5 Gy | 0.507 (-0.322 to 1.541)i | 0.511 (-0.320 to 1.547)i,j |