title: Antihypertensive drugs and risk of cancer: a systematic review and meta-analysis of randomised controlled trials
Creators: name: Che Roos, Nur Aishah
Publisher: name: University of Glasgow
Year: 2019
Subjects: subject: Antihypertensive, angiotensin-converting enzyme inhibitor, ACEI, angiotensin receptor blocker, ARB, calcium channel blocker, calcium antagonist, CCB, beta-blocker, BB, thiazide, diuretics, cancer.

description: Pharmacovigilance plays an important role in monitoring adverse drug reactions (ADRs) resulting from an intervention related to medicinal products. Due to the frequencies and potentially serious consequences, ADRs pose a considerable economic and clinical burden. Patients with an underlying risk factor or established cardiovascular disease (CVD) are usually on long-term treatment, thus it is important to monitor the efficacy and safety of drugs prescribed. Modern antihypertensive drugs have been showed to effectively reduce high blood pressure (BP) hence prevents the development or complications of CVD in high-risk patients. However, there is evidence from clinical trials and observational studies suggesting the association between antihypertensive drugs and risk of cancer. Furthermore, these observations are inconsistent and the majority of clinical trials were directed towards cardiovascular outcomes. The thesis is divided into five main result chapters (4 to 8) based on the antihypertensive drug classes evaluated for risk of cancer in the systematic review and meta-analyses. Altogether, 90 randomised controlled trials (RCTs) enrolling 390,750 participants with an average follow-up of 3.5 years were included for qualitative and quantitative analysis. Angiotensin-converting enzyme inhibitor (ACEI) and risk of cancer: ACEI lowers BP through preventing the conversion of angiotensin 1 to angiotensin II by ACE in the renin-angiotensin system (RAS) pathway. In the present study, no significant association between ACEI and risk of cancer incidence or cancer-related death is reported. Factors such as tissue binding capacity, comparator used, clinical settings, age, and study duration do not affect the risk of cancer overall. Angiotensin receptor blockers (ARB) and risk of cancer: In the RAS pathway, ARB acts directly on the angiotensin type 1 (AT1) receptor to inhibit downstream signalling which results in downregulation of sympathetic activity and lowering of BP. The present meta-analysis has reported no association between ARB use and risk of cancer incidents or cancer-related mortality. Subgroup assessment indicates that valsartan has a cancer-protective effect, particularly against lung cancer. Patients’ clinical settings, age, and study duration do not influence the risk of cancer in relation to ARB overall. Calcium channel blockers (CCB) and risk of cancer: As a class, CCBs are potent vasodilators and are recommended for use as first or second-line drugs in treating hypertension. This study has reported a marginally increased risk of cancer incidents (P=0.06) but not cancer-related death overall in relation to CCB use. DHP-CCB is associated with a 9% increased risk for cancer compared to controls (P=0.05). A positive relationship is also observed with older patients and in patients with longer exposure to CCB. Therefore, a properly designed further research into the risk of a specific type of cancer with use of DHP CCB is warranted to detect a safety signal. Beta-blockers (BB) and risk of cancer: Inhibition of stress mediators from activating beta-adrenoceptors has been proposed to be the underlying mechanism by which BB lower the risk of cancer. This study has found no evidence of an association between BB and the risk of cancer or cancer-related death. Factors such as cardioselectivity, treatment indication, age and study duration do not have an impact on cancer risk altogether. Thiazide diuretics (TZ) and risk of cancer: TZ induces diuresis at the distal convoluted tubule and a great number of studies had attempted to link TZ and risk of renal cancer. No evidence of an association between TZ and the risk of cancer or cancer mortality is reported in the present study. Chemical structure differences, clinical settings, age, and study duration does not significantly influence the risk of cancer in relation to TZ use. Strengths and limitation: The strengths of the systematic review and meta-analyses conducted in this thesis include; only RCTs were included, a comprehensive search strategy spanning over 60 years with no language restrictions, and a sufficiently large sample size of over 390,000 trial participants from various clinical settings with an average 3.5 years follow-up duration. Lack of individual-level data and non-standard reporting of cancer in RCTs are the main limitations. Future recommendations: All RCT evaluating drug intervention should pre-identify cancer as one of the study outcomes as part of drug safety monitoring.