Angiotensin-Converting Enzyme Inhibitors (ACEi), but not Angiotensin Receptor Blockers (ARBs) are associated with Ischaemic Colitis

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1 Angiotensin-Converting Enzyme Inhibitors (ACEi), but not Angiotensin Receptor Blockers (ARBs) are associated with Ischaemic Colitis AS Ewing, K Brown, SA Goodbrand, S Glancy, P Fineron, RJ McGregor, I Chakarabarty, H Simmers, N Ventham and MG Dunlop Edinburgh Colorectal Surgery, University of Edinburgh Western General Hospital, Edinburgh UK

2 Ischaemic Colitis (IC) Multifactorial aetiology (Incidence 4-45/100,000 pop n ) Impaired perfusion of colonic mucosa, mucosal inflammatory cell infiltrate Debilitating symptoms, frequently prolonged hospitalisation, appreciable mortality

3 Study Rationale Clinical impression of an excess of IC patients prescribed ACEi ACE2 is a gut mucosal protectant Hashimoto, Nature 2012 ACE2 knockout mouse exhibits colitis phenotype Liu, Transgenic Res % of subjects in Ph 2 trial of Captopril developed IC O Neill, Br J Clin Pharm 1992 Small study (n=161) supports ACEi association with IC Fernández, W J Gastroenterol 2010 Scottish NHS data , patients on ACEi = 475,156. Total prescriptions = 19,780,566

4 Hypothesis ACEi therapy is causally associated with an increased risk of IC

5 Aims Establish/refute putative link between ACEi therapy and IC Investigate whether any association also holds for ARB therapy and IC

6 Methods Case-control study design Systematic case ascertainment NHS Lothian pathology database (APEX) Radiology database for all diagnoses of IC Prescription history, past medical history, smoking status, BMI Lothian databases (TRAK, LSA) and hardcopy note review Exclusions positive stool culture during same hospital admission Statistical analysis: OR and strength of association by X 2 or Fisher tests Meta analysis by Mantel-Haenszel method (weighted OR random effects model)

7 Methods Discovery study ( ) Inclusion criteria - biopsy-proven IC Controls - unrelated cancer patients attending WGH - unmatched local GP controls >50 years (MMGP) Replication study ( ) Inclusion criteria - biopsy-proven IC and/or CT diagnoses Controls - frequency matched (age/gender) GP controls (BMC)

8 Annual IC Caseload by Mode of Ascertainment 80 Number of cases Biopsy All cases CT

9 Discovery Study - Summary Demographics Number Gender Age Males Females Ischaemic colitis (28.2%) 102* (71.8%) Range Mean Median Unmatched Community Controls (MMGP) (47.7%) 1466 (52.3%) All patients >50 year registered on MMGP database *p<0.0001

10 Discovery Study Histological ascertainment , CRC and community controls IC cases (N=142) Hospital Controls (N=138) Community Controls- MMGP (N=2801) All ACEi 43 (30.3%) 21 (15.2%) 576 (20.6%) Lisinopril Ramipril Enalapril Perindopril All ARB 6 (4.2%) 5 (3.6%) 81 (2.9%) Losartan Irbesartan Valsartan Candesartan Telmisartan All Statin 34 (23.9%) 24 (17.4%) 899 (32.1%) Mean bed usage 10 d (range 1-230) In-hospital mortality - 9% Hospital controls OR = 2.42 p = OR = 1.17 p = 0.80 OR = 1.50 p = 0.18 Community controls OR= 1.68 p = OR=1.48 p = 0.36 OR=0.67 p = 0.043

11 Replication Study Histological ascertainment, frequency-matched community controls IC cases N = 191 BMC controls N = 2534 Odds Ratio (95% CI) p-value (X 2 Yates corrected) ACEi ACEi None ARB ARB None Statins Statin None OR = % CI p = < OR = % CI p = OR = % CI p = <0.0001

12 Concordance of CT with Histology as Mode of Ascertainment 40 patients underwent both CT and colonoscopy + biopsy < 1mth of admission 35 (88%) confirmed on biopsy 5 patients with normal histology - comments made about patchy mucosal ulceration CT considered a valid mode of ascertainment

13 Replication Study ACEi Effect by Gender Ascertainment - Histology + CT ( ), frequency-matched community controls IC cases N = 448 BMC controls N = 1453 Odds Ratio (95% CI) p-value (X 2 Yates corrected) Persons ACEi None OR = % CI p = < Females N=329 (73.4%) Males N=119 (26.6%) ACEi None ACEi None OR = % CI p = < OR = % CI p =

14 Replication Study Effect by Agent Histology and CT ascertainment ( ), Frequency-matched community controls IC cases N = 448 BMC controls N = 1453 Odds Ratio (95% CI) p-value (X 2 Yates corrected) ACEi ACEi None ARB ARB None Statins Statin None OR = % CI p = < OR = % CI p = OR = % CI p = <0.0001

15 Risk of IC Associated with ACEi/ARB Therapy in Subjects on Statin Therapy IC Cases (n=248) Matched Community Controls (n=744) Statin + ACEi Statin + ARB ACEi OR = 2.13 (95% CI ) p = < ARB OR = 0.28 (95% CI ) p = <0.0001

16 Meta Analysis Case (%) Control (%) P value OR 95% CI Discovery 43/ / Replication 192/ /1453 < Fernandez et al 44/161 (27%) 59/322 (18%) Random effect meta (p het = , I 2 = 89.37%) 279/ /

17 Conclusions ACEi therapy is associated with ischaemic colitis No association with ARBs suggestive of a protective effect Analysis of subjects on statins argues strongly against confounding due to CVD A causal link is supported by the prior biological evidence and the natural experiment of (largely) random assignment to treatment with ACEi or ARBs Patients admitted with IC should be switched from ACEi therapy to ARB

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