Risk of non-melanoma skin cancer among hypertensive adults in the United Kingdom treated with angiotensin converting enzyme inhibitors: a population based, active comparator, new user, retrospective cohort study

Date of ISAC Approval: 
29/03/2019
Lay Summary: 
Recently the European Medicines Agency issued advice to doctors that hydrochlorothiazide (a medicine taken every day over long periods of time to treat heart failure and high blood pressure) may increase the risk of non-melanoma skin cancer. This is one of the commonest cancers, mainly caused by excessive exposure to sunlight. Hydrochlorothiazide is known to make skin more sensitive to sunlight, and this may be how it increases the risk of this type of skin cancer. Angiotensin-converting enzyme inhibitors are a type of medicine commonly prescribed to treat heart failure, and high blood pressure. Some of these medicines also make the skin more sensitive to sunlight. Some studies have investigated whether angiotensin converting enzyme inhibitors increase the risk of skin cancer among individuals in North American and Scandinavian countries, but the results are conflicting. None of the studies have been conducted in the United Kingdom to date. The purpose of this study is to investigate whether angiotensin converting enzyme inhibitors increase the risk of non-melanoma skin cancer among adults in the UK.
Technical Summary: 
In 2018, the European regulator issued warnings to prescribers that hydrochlorothiazide (HCTZ), a photosensitiser used to treat hypertension and heart failure, may increase the risk of non-melanoma skin cancer (NMSC). An important risk factor for NMSC is ultraviolet light, and although its incidence demonstrates geographic variation, it is particularly common among Caucasians. Angiotensin converting enzyme inhibitors (ACEi) are recommended in the UK as first line therapy for hypertension in Caucasian subjects under the age of 55. Photosensitivity is an adverse reaction to ACEi, for example estimated to occur in more than 1 in 1000 but less than 1 in 100 with perindopril. Studies to date on the association between ACEi and NMSC are conflicting, and none have been conducted in the UK. In most, the reference group has been non-exposure, with potential for confounding by indication. Most have not adjusted for use of HCTZ. HCTZ is frequently prescribed with ACEi, but studies to date have not investigated the potential for effect modification by HCTZ. We propose a population-based, historical cohort study to determine the risk of NMSC among new users of ACE-I as compared to new users of calcium channel blockers (CCB) for the treatment of hypertension in adults in the UK. Primary objective is to determine whether the risk of first cSCC and of first BCC is greater among adults with hypertension exposed to an ACEi compared to those exposed to a CCB. As secondary objectives, the study will evaluate whether there is effect modification by exposure to HCTZ and by ethnicity. Strength of association will be measured using hazards ratios, after multivariable adjustment with Cox proportional hazards regression.
Health Outcomes to be Measured: 
First diagnosis of cutaneous squamous cell cancer (cSCC), first diagnosis of basal cell cancer (BCC)
Collaborators: 

Dr Laurie Tomlinson - Chief Investigator - London School of Hygiene & Tropical Medicine (LSHTM)
Ian Douglas - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Professor Liam Smeeth - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Rhea Fitzgerald - Corresponding Applicant - Trinity College Dublin
Sarah-Jo Sinnott - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Sinead Langan - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Yun "Angel" Wong - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)

Linkages: 
HES Admitted;Patient IMD