Cardiac glycosides use and the risk of lung cancer: a nested case–control study

Sbastien Couraud 0 1 Laurent Azoulay 1 Sophie Dell'Aniello 1 Samy Suissa 0 1 0 Department of Epidemiology , Biostatistics and Occupational Health , McGill University , Montreal, Quebec , Canada 1 Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital , Montreal H3T 1E2, Quebec , Canada Background: Two studies have reported statistically significant associations between the use of cardiac glycosides (CGs) and an increased risk of lung cancer. However, these studies had a number of methodological limitations. Thus, the objective of this study was to assess this association in a large population-based cohort of patients. Methods: We used the United Kingdom Clinical Practice Research Datalink (CPRD) to identify a cohort of patients, at least 40 years of age, newly-diagnosed with heart failure, or supra-ventricular arrhythmia. A nested case-control analysis was conducted where each incident case of lung cancer identified during follow-up was randomly matched with up to 10 controls. Exposure to CGs was assessed in terms of ever use, cumulative duration of use and cumulative dose. Rate ratios (RRs) with 95% confidence intervals (CIs) were estimated using conditional logistic regression after adjusting for potential confounders. Results: A total of 129,002 patients were included, and followed for a mean (SD) of 4.7 (3.8) years. During follow-up, 1237 patients were newly-diagnosed with lung cancer. Overall, ever use of CGs was not associated with an increased risk of lung cancer when compared to never use (RR = 1.09, 95% CI: 0.94-1.26). In addition, no dose-response relationship was observed in terms of cumulative duration of use and cumulative dose with all RRs around the null value across quartile categories. Conclusion: The results of this large population-based study indicate that the use of CGs is not associated with an increased risk of lung cancer. - Background Cardiac glycosides (CGs) are natural steroids, derived from digitalis, that share a chemical structure with estrogens and are therefore considered phytoestrogens. The CG family includes digoxin, digitoxin and lanatoside C which remain important drugs in the treatment of atrial fibrillation (AF), some types of heart failure (HF), atrial flutter (AFl) and other supra-ventricular tachycardia (SVT) [1,2]. Due to their ability to bind to estrogen receptors, [3] there has been interest in assessing whether the use of CGs is associated with the incidence of breast cancer. [4-9] Namely, two casecontrol studies found that the use of digoxin was associated with an increased risk of breast cancer (RR: 1.30, 95% CI: 1.14-1.48 and RR: 1.39, 95% CI: 1.32-1.46), respectively. [4,5] There has also been interest on the effects of CGs on the incidence of lung cancer. Indeed, there are data supporting a role of female sexual hormones on lung cancer carcinogenesis, [10] which raises the hypothesis that the use of CGs may be associated with an increased risk of lung cancer. The main epidemiologic argument is the dramatic increase of non-small cell lung cancer in women over the last decades. [11] In addition, some observational studies found an association between lung cancer and some reproductive factors. [12-14] This biological rational is supported by the finding that estrogen receptors are frequently expressed in lung cancer tumors [15-17]. To date, only two only observational studies have investigated the link between the use of CGs and lung cancer incidence. [11,12] In one study, the use of digitalis-related compounds was associated with a 65% increased risk of death from lung cancer. [11] In the other study, digitoxin users were found to have a significantly higher incidence of lung cancer compared to a matched control population (standardized incidence ratio: 1.35, 95% confidence interval [CI]: 1.04-1.74). [12] However, lung cancer was a secondary outcome in these studies, and the models were not adjusted for important potential confounders, such as smoking. Given the limited data assessing the association between the use of CGs and the risk of lung cancer, we conducted a large population-based study to investigate whether the use of these drugs are associated with an increased risk of lung cancer in patients newly-diagnosed with HF, AF, AFl and/or SVT. Methods Data source This study was conducted using the United Kingdom (UK) Clinical Practice Research Datalink (CPRD), formerly known as the General Practice Research Database. The CPRD is the world largest databank on primary care. Since its inception in 1987, it systematically records medical diagnoses and procedures, drug prescriptions issued by general practitioners, patient characteristics (such as body mass index [BMI]), and lifestyle factors (such as smoking and alcohol use). [13] Currently, the CPRD contains data on over 12 million patients registered with more than 650 participating general practices across the UK. Medical diagnoses and procedures are coded using the Read classification, and drugs are coded based on the UK Prescription Pricing Authority Dictionary. Cancer diagnoses, including lung cancer, in the CPRD have been shown to have a high validity [14]. The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD and the Research Ethics Board of the Jewish General Hospital, Montreal, Quebec, Canada. Study population Within the CPRD population, we identified all patients diagnosed for the first time with HF, AF, AFl and/or SVT, between January 1, 1988 and December 31, 2010, and followed until December 31, 2012. Cohort entry was defined as the date of any of the previously considered diagnoses, whichever appeared first in the patients medical record. The cohort was then restricted to patients at least 40 years of age at cohort entry, and those with at least two years of up-to-standard medical history in the general practice prior to cohort entry. In order to identify new users of CGs during follow-up, we excluded all patients who previously received these drugs at any time prior to cohort entry. Finally, we excluded all patients previously diagnosed with any cancer (excluding non-melanoma skin cancer) at any time prior to cohort entry to ensure the identification of incident cases of lung cancer during follow-up, and to avoid the inclusion of patients with metastatic disease to the lung from other cancer sites. Patients meeting the study inclusion criteria were then followed until a first-ever diagnosis of lung cancer, death from any cause, end of registration with the general practice, or end of the study period (December 31, 2012), whichever came first. Casecontrol selection Within the cohort defined above, we conducted a nested casecontrol analysis, which produces odds ratios that are unbiased estimators of rate ratios (RRs) (i.e. no need for the rare disease assumption) [15]. Cases consisted of all those newly-diagnosed with lung cancer during follow-up. Up to 10 control (...truncated)