Use of Antihypertensive Medications and Survival Rates for Breast, Colorectal, Lung, or Stomach Cancer

Yong Cui; Wanqing Wen; Tao Zheng; Honglan Li; Yu-Tang Gao; Hui Cai; Mingrong You; Jing Gao; Gong Yang; Wei Zheng; Yong-Bing Xiang; Xiao-Ou Shu

Disclosures

Am J Epidemiol. 2019;188(8):1512-1528. 

In This Article

Abstract and Introduction

Abstract

Using time-dependent Cox regression models, we examined associations of common antihypertensive medications with overall cancer survival (OS) and disease-specific survival (DSS), with comprehensive adjustment for potential confounding factors. Participants were from the Shanghai Women's Health Study (1996–2000) and Shanghai Men's Health Study (2002–2006) in Shanghai, China. Included were 2,891 incident breast, colorectal, lung, and stomach cancer cases. Medication use was extracted from electronic medical records. With a median 3.4-year follow-up after diagnosis (interquartile range, 1.0–6.3), we found better outcomes among users of angiotensin II receptor blockers with colorectal cancer (OS: adjusted hazard ratio (HR) = 0.62, 95% confidence interval (CI): 0.44, 0.86; DSS: adjusted HR = 0.61, 95% CI: 0.43, 0.87) and stomach cancer (OS: adjusted HR = 0.62, 95% CI: 0.41, 0.94; DSS: adjusted HR = 0.63, 95% CI: 0.41, 0.98) and among users of β-adrenergic receptor blockers with colorectal cancer (OS: adjusted HR = 0.50, 95% CI: 0.35, 0.72; DSS: adjusted HR = 0.50, 95% CI: 0.34, 0.73). Better survival was also found for calcium channel blockers (DSS: adjusted HR = 0.67, 95% CI: 0.47, 0.97) and diuretics (OS: adjusted HR = 0.66, 95% CI: 0.45, 0.96; DSS: adjusted HR = 0.57, 95% CI: 0.38, 0.85) with stomach cancer. Our findings suggest angiotensin II receptor blockers, β-adrenergic receptor blockers, and calcium channel blockers might be associated with improved survival outcomes of gastrointestinal cancers.

Introduction

Hypertension is one of the most common comorbidities among cancer patients due to their shared risk factors and the cardiotoxic effects of certain anticancer treatments.[1–3] Widely used antihypertensive medications include angiotensin I-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, and β-adrenergic receptor blockers (β-blockers).[4] Recently, potential impacts of antihypertensive medications on cancer prognostic outcomes have drawn great attention, particularly with respect to medications that target the renin-angiotensin system (RAS), including ARBs and ACEIs, and those that target the sympathetic nervous system, such as β-blockers.

Angiotensin II is the major bioactive product of the RAS, playing an important role in the regulation of arterial blood pressure and cell proliferation.[5] Studies have shown that tumor cells with activated RAS respond to angiotensin II stimulation by expression and/or secretion of various molecules, including interleukin-8, granulocyte-macrophage colony-stimulating factor, vascular endothelial growth factor, monocyte chemotactic protein 1, tissue inhibitor of metalloproteinase 1, and hypoxia-inducible factors HIF1α and HIF2α.[6] Inflammatory cells in tumor microenvironments have also been shown to express RAS components and respond to angiotensin II stimulation by increasing secretion of interleukin-1α, interleukin-6, interleukin-8, monocyte chemotactic protein 1, and macrophage colony-stimulating factor.[6]

The β-adrenergic signaling pathway mediates sympathetic nervous system–induced stress responses and modulates multiple cellular processes.[7,8] Three subtypes of the β-adrenergic receptor (β1, β2, and β3), have been identified at several tumor sites, including the breast, colon, lung, and stomach in humans.[9,10] Recent studies have shown that β-adrenergic signaling regulates multiple cellular processes, including inflammation, angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial-mesenchymal transition.[7,8]

Although several lines of evidence have shown certain classes of antihypertensive medications possessing potential antitumor properties, suggesting a rationale for use of antihypertensive medications in clinical oncology, large population-based studies examining the association between antihypertensive medication use and survival outcomes are limited, and results have been mixed.[11–19] The inconsistencies might be attributable to multiple factors, such as a difference in study populations, study design, sample size, and cancer types/sites, and the influence of potential confounding factors, including concurrent use of other medications.[20] Additionally, the potential influence of immortal time bias (referring to a period of cohort follow-up or observation time during which death cannot occur) has been a major concern for many early studies.[21]

In this study, we comprehensively examined associations of commonly used classes of antihypertensive medications (ARBs, ACEIs, CCBs, diuretics, and β-blockers) with survival from breast, colorectal, lung, and stomach cancers, using data from 2 large, prospective cohort studies in Shanghai, China: the Shanghai Women's Health Study (SWHS) and the Shanghai Men's Health Study (SMHS).

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