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1 Beatrice Nardone MD PhD, 1 Ashley S. Kim, 1 Sara Majewski BS,

Melanoma and non-melanoma skin cancer associated with antihypertensive drugs: A report from the RADAR (Research on Adverse Drug events And Reports) project. 1 Beatrice Nardone MD PhD, 1 Ashley S. Kim, 1 Sara Majewski BS,

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1 Beatrice Nardone MD PhD, 1 Ashley S. Kim, 1 Sara Majewski BS,

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  1. Melanoma and non-melanoma skin cancer associated with antihypertensive drugs: A report from the RADAR (Research on Adverse Drug events And Reports) project 1Beatrice Nardone MD PhD, 1Ashley S. Kim,1Sara Majewski BS, 1Anne E Laumann MBChB, MRCP (UK ), 2-3A. Rademaker PhD, 1,3Dennis P. West PhD 1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL; 2Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL; 3Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL Northwestern Medicine Enterprise Data Warehouse (NMEDW) is supported by NUCATS grant UL1RR025741.

  2. New Zealand Dermatological Society Conference 26th-29th August 2015, Auckland, New Zealand Beatrice Nardone, MD PhD Melanoma and non-melanoma skin cancer associated with antihypertensive drugs: A report from the RADAR (Research on Adverse Drug events And Reports) project I do not have any relevant conflict of interest to disclosure

  3. INTRODUCTION • As anti-hypertensive agents, angiotensin-receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and thiazides (TZ) are among the most widely used in the US. • An overall increased risk of cancer with the use of these medications, particularly ARBs, has been previously reported1. • In 2011, the U.S. Food and Drug Administration (FDA) issued a safety announcement after a review of the potential risk for cancer associated with ARBs, based on 31 clinical trials, and concluded that treatment with an ARB medication does not increase the risk of cancer. Sipahi I, et al. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010;11:627-36.

  4. INTRODUCTION • Randomized controlled trials of ARBs and ACEIs have focused on assessment of their effects on cardiovascular and renal endpointsand may have under-reported cancer. • Particularly for malignant melanoma (MM), and non-melanoma skin cancer (NMSC), reporting biases includes lack of long term follow-up and lack of skin cancer definition (MM vs BCC vs SCC). • In addition, these classes of drugs may possess ultraviolet light action spectra as part of their physico-chemical characteristics and some are reported to have photosensitizing potential that may function as co-carcinogenic with chronic UV radiation exposure.

  5. INTRODUCTION • On the contrary, some studies showed an overall chemopreventive effect for cancer1. • However, a study specifically for MM did not find a chemopreventive effect2. • A recent case-control study showed an increased risk of skin cancer, including melanoma, associated with the use of an antihypertensive agent.3 • Consequently, an association for MM and NMSC with ARBs, ACEIs and TZs remains somewhat unclear. Lindberg H, et al. Angiotensinconvertingenzymeinhibitors for cancer treatment? Acta Oncol 2004;43:142-52. Koomen ER, et al. Melanoma incidence and exposure to angiotensin-convertingenzymeinhibitors and angiotensinreceptorblockers. Cancer Epidemiol 2009;33:391-5. Schmidt SA, et al. Use of antihypertensive drugs and risk of skin cancer. J EurAcadDermatolVenereol. 2015;29:1545-54.

  6. OBJECTIVE • To examine whether exposure to ARBs or ACEIs or TZ is associated with malignant melanoma (MM), basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), within a large, urban, academic center electronic medical record (EMR) repository.

  7. RADAR The Research on Adverse Drug events And Reports project: • An academic- based, proactive, post-marketing pharmacovigilance long-standing program to detect and define previously unrecognized adverse drug and device reactions Aims • Data mining of available databases to detect and define previously undetected and/or undefined safety signals. • Assess completeness and accuracy of the mined data

  8. METHODS • Using RADAR methodology1, we searched a large urban academic center EMR patient repository (>2.5 million individuals) that includes an NCI-designated Comprehensive Cancer Center as well as an NCI-designated Chemoprevention Center • Search period: January 2010 through February 2015 • Included all individuals who had a clinic encounter within the search time frame McKoy JM, et al. Results from the first decade of Research Conducted by the Research on Adverse Drug Events and Reports (RADAR) project. Drug Saf. 2013; 36(5): 335-47.

  9. METHODS • Inclusion Criteria: • Time frame: January 2010-February 2015 • Age range: 18-89 years • Documented data for race, gender and age • Documented exposure (at least 2 consecutive drug orders for an ARB or ACEI or TZ) • One clinic encounter and a follow-up time of 1 month or more • Only patients with a single agent antihypertensive medication prescription were included

  10. METHODS • Exclusion Criteria: • One or more prescription for any other antihypertensive medication • One or more prescriptions for a combination of antihypertensive medications • Diagnoses of previous cancer and/or previous solid organ transplantation

  11. METHODS • Patients with a first time diagnosis of MM, SCC or BCC were included only if the diagnosis was documented at least 2 months after the antihypertensive prescription. • ICD-9 codes were used to detect patients with MM diagnosis (172.0-172.9); SCC (173.02-179.92); BCC (173.01-173.91) • For patients with more than one type of skin cancer, only the first type was considered.

  12. METHODS • Control population consisted of all patients within the same time frame, with no documented prescription for ARBs, ACEIs or TZs. • The same exclusion criteria as the exposed population were applied. • Logistic regression analyses were used to determine if an association existed between incident cutaneous melanoma, basal cell carcinoma and squamous cell carcinoma and the use of ACEI, ARB or TZ, adjusting for age, gender and race.

  13. RESULTS • A total of 823 (0.13%) MM, 2,051 (0.33%) BCC and 490 (0.08%) SCC were detected out of 635,687 individual patients, between January 2010 and February 2015. • 13,617 patients were exposed to an ACEI, of which 28 developed (0.21%) MM, 94 (0.69%) BCC and 35 (0.26%) SCC. • 5,772 patients were exposed to an ARB of which 23 (0.40 %) MM, 45 (0.78%) BCC and 18 (0.31%) SCC • 3,400 patients were exposed to a TZ: 9 (0.26%) MM, 18 (0.53%) BCC and 13 (0.38%) SCC were detected

  14. RESULTS * Significant association

  15. RESULTS • MM • ARBs (OR: 2.21; 1.45-3.36; p=0.0002), • TZs (OR: 2.03; 1.04-3.92; p=0.036); • BCC • ARBs (OR: 1.36; 95% C.I. 1-1.83; p=0.044), • ACEIs (OR: 1.31; 95% C.I. 1.06-1.62; p=0.01); • SCC • ARBs (OR: 1.75; 95% C.I. 1.08-2.8; p=0.021), • ACEIs (OR: 1.59;95% C.I. 1.12-2.25; p=0.008), • TZs (OR: 3.47; 95% C.I. 1.99-6.04; p<0.0001).

  16. RESULTS • Time to event (median, IQR): • MM • ARBs: 27 (range:11-45) • TZs: 29 (range: 12-31) • BCC • ARBs: 32 (range: 19-46.5) • ACEIs: 39 (range: 16-49) • SCC • ARBs: 31.5 (range: 9.5-41) • ACEIs: 28 (range: 11-47) • TZs: 25 (range: 11-36.5)

  17. CONCLUSIONS Limitations: • Verification for diagnostic coding and documentation of drug exposure beyond original EMR data entry is not practically achievable. • Otherpotential MM and NMSC risk factor data such as chronic inflammatory diseases, immunosuppression, as well as co-morbidities and concurrent drugs were not evaluated in this population.

  18. CONCLUSIONS • We identified a significant association between exposure to ARBs and TZ and malignant melanoma, exposure to ARB and ACE and basal cell carcinoma, as well as exposure to ARB, ACEI and TZ and squamous cell carcinoma. • Our findings are, in part, consistent with a recent study focusing on skin cancer that showed an increased risk of melanoma associated with long-term use of ARBs1. • Contrary to this recent paper we found a significant association between ACEIs or ARBs and BCC and SCC, and between TZs and MM and SCC1. Schmidt SA, et al. Use of antihypertensive drugs and risk of skin cancer. J EurAcadDermatolVenereol. 2015;29:1545-54.

  19. CONCLUSIONS • Our findings add to the existing evidence suggesting an association between exposure to some antihypertensive agents and an increased risk for melanoma and non-melanoma skin cancer. • Although the exact mechanism underlying this association remains still unclear, increased education and pharmacovigilance is warranted for patients and health practitioners. • Further investigation in large, prospective studies examining the risk of melanoma and non-melanoma skin cancer with anti-hypertensive agents is needed to establish the true magnitude of this association

  20. Acknowledgments • New Zealand Dermatological Society, International Dermatology Scholarship • Sue Peck, SP Conference Management • Northwestern Medicine Enterprise Data Warehouse (NMEDW) • Department of Dermatology, Northwestern University

  21. THANK YOU!

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