슬라이드 1

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범식 어금
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1 Resolving pain medicationrelated GI trouble 성균관대학교내과이준행

2 What is NSAID? N on S teroidal A nti I nflammatory D rug N umerous S ide effects A nd I ndispensable D rug

3 Number of deaths US mortality data in ,000 15th cause of death in USA 20,000 20,197 16,685 16,500 Hospitalization : 100,000/ year and 15,000 10,000 10, % of them die 5,000 5,338 4,441 1,437 0 Singh et al. J Rheumatol 1999

5 A double-edged sword

6 위장관손상기전 성균관대학교내과이준행

7 PG dependent pathway

8 PG independent pathway Ion trapping hypothesis NSAIDs remains unionized and diffusible in acid gastric juice, but on entering mucosal cell, it ionized and becomes indiffusible. Ion trapping in gastric mucosal cell enhances gastric toxicity

9 Small bowel injury: enteropathy NSAIDs Uncoupling of mitochondrial oxidative phosphorylation Increased intestinal permeability Invasion of luminal aggressive factors such as bile, hydro-/proteolytic enzyme, bacteria Inflammation Ulcer, perforation, strictures, bleeding Matsui, et al. J Clin Biochem Nutr 2011

10 상부위장관손상 성균관대학교내과이준행

11 Dyspepsia is so common Dyspepsia : at least 10% - 20% Within a six-month period of treatment, 5% - 15% of patients with rheumatoid arthritis discontinue NSAID therapy due to dyspepsia.

12 급성복통 아스피린 2 일복용후

13 만성복통 - 강직성척추염 Ankylosing spondylitis on NSAID

14 Endoscopically determined ulcer >= 3 mm - in patients with osteoarthritis placebo ibuprofen week 12 week 24 week Hawkey CJ. Arthritis Rheum 2000;43:370

15 Probability of upper GI complication Cumulative incidence (%) There is no plateau. MUCOSA Trial 1 VIGOR Trial NSAIDs (n=4439) 1.50 Naproxen (n=4029) Month Month 1. Silverstein FE et al. Ann Intern Med. 1995;123: FDA Arthritis Advisory Committee; February 8, 2001; Gaithersburg

16 출혈 (F/72) - on aspirin + clopidogrel

17 Aspirin-induced bleeding (F/72 with melena)

18 PCI 후 aspirin, ticagrelor 3 주후출혈 PPI add. 다시약을씀 2 주후재출혈 PCI 3 주후첫출혈 2 주후재출혈

20 Peptic ulcer with complication occurs in more than 1% for the first 1 year - CLASS study (Celecoxib Long-term Arthritis Safety Study) Ulcer complications All ulcers Ibuprofen celecoxib Silverstein FE. JAMA 2000;284:

1978; 28:527-532 Singh et al.arch Intern Med.

21 Most patients are asymptomatic. N = 141 N = 1,921 Without Symptoms 81% with Symptoms 19% Without Symptoms 58% with Symptoms 42% Armstrong, Blower. Gut. 1978; 28: Singh et al.arch Intern Med. 1996; 156: * Bleeding, perforation, and gastric outlet obstruction

22 NSAID 십이지장궤양 협착 수술 송지현. 대한소화기내시경학회지 2006;32:

23 Multiple joint pain 으로 NSAIDs 를반년이상복용하다가갑작스런복통 (M/58) 수술장 : Stomach LB AW 0.5cm sized ulcer perforation 있으며그주변으로 inflammatory change 로 stomach wall fibrosis, edema 심함.

24 Risk factors for ulcer complications induced by NSAIDs Prior complicated ulcer Use of multiple NSAIDs (including aspirin) High-dose of NSAIDs Anticoagulant therapy Prior uncomplicated ulcer Age > 70 years H. pylori infection Glucocorticoid therapy

25 There is no safe NSAID. Individual NSAID RR (95% CI) Non-use Reference Celecoxib 1.0 (0.4 to 2.1) Aceclofenac 2.6 (1.5 to 4.6) Diclofenac 3.1 (2.3 to 4.2) Ibuprofen 4.1 (3.1 to 5.3) Naproxen 7.3 (4.7 to 11.4) Ketoprofen 8.6 (2.5 to 29.2) Indomethacin 9.0 (3.9 to 20.7) Meloxicam 9.8 (4.0 to 23.8) Ketorolac 14.4 (5.2 to 39.9) Low High Lanas. Am J Med Sci 2009;338:96 106

26 Risk of complications in the elderly Age Case N=1,457 Control N=10,000 RR * Aging is one of the most important risk factors for everything in medicine. Rodriguez LAG. Lancet 1994;343:769

27 High dose is more dangerous. However, lower dose is not safe. Lanas. Gut 2006:55:

28 Concomitant use of other medications - With tnsaids, warfarin is the worst. Relative risk compared with those of nonusers of both types of drugs tnsaid + aspirin: 4.9 tnsaid + steroid: 4.3 tnsaid + warfarin: 12.5 Luis. Gastroenterology 2007:132:

29 H. pylori - an important factor Huang. Lancet 2002;359:14-22

30 Naïve NSAID user or long-term user? Patients initiating chronic treatment with NSAID should be tested for H. pylori infection. Those who test positive should be offered eradication therapy The benefit of testing and treating H. pylori in a patient already taking an NSAID remains unclear ACG Guideline 2017

31 H. pylori in patients who are already receiving NSAID Eradication of H. pylori is not recommended for prevention of ulcers in patients who are already being treated with NSAIDs. PPI therapy provides a more effective ulcer risk reduction strategy than H. pylori eradication in patients on chronic NSAIDs JSGE guideline 2016 ACG Clinical Guideline 2017

32 There is a cumulative effect. % No Risk Factor 1-2 Factors 3 Factors 4 Factors Silverstein FE. Ann Intern Med 1995;123:241-9

33 GI risk factors in Korean OA patients J Korean Med Sci 2011;26:

34 NSAIDs 관련상부위장관손상예방 - 위험도에따른접근 성균관대학교내과이준행

35 위험도에따른접근 GI risk NSAID CV risk H.pylori Ulcer

36 Esomeprazole vs famotidine - Prevention of UGI bleeding in ACS of AMI The study was terminated, and the patients were prescribed open-label PPI for their safety Am J Gastroenterol 2012;107:

37 Cumulative rate of ulcer development - Venous study Placebo: 20.4% Esomeprazole 20 mg: 5.3% Esomeprazole 40 mg: 4.7% Scheiman et al. Am J Gastroenterol 2006;101:

38 PPI + COX-2 the best method for upper GI tract complication prevention Chan. Lancet 2007;369:

39 We used the Manitoba Population Health Research Data Repository to perform a population-based matched case-control analysis Targownik. Gastroenterology 2008;134:

40 Utilization of protective strategies by presence of GI risk factors 1 Risk Factor More Risk Factors 2.5% 10.8% 0.1% 4.0% 14.7% 0.2% 86.6% 81.2% Coxib alone Protective strategy (PS) PS + Coxib No gastroprotection Sturkenboom. Rheumatology 2003;42(S3):22-31

41 Dyspepsia: change of the medication, dose reduction, empirical treatment with H 2 RA or PPI H. pylori infection: eradication treatment in patients with risk factor(s) Active ulcer (NSAID discontinued): H 2 RA or PPI Active ulcer (NSAID continued): PPI Prophylactic therapy: misoprostol, PPI, COX-2 selective agent Lee JH. Korean J Gastroenterol 2009;54:

42 Risk assessment in NSAID user Lanza. AJG 2009

43 Algorithm for NSAID gastropathy NSAID 자료제공 : 이혁 Chronic NSAID user HP(-/+) Naive NSAID user ulcer(-) Ulcer (-) Ulcer (+) HP (-) HP (+) Low risk High risk Low risk High risk CV(-/+) CV(-/+) Low risk Moderate risk High risk No prevention Coxib+PPI HP eradication (?) NSAID 중단 PPI No prevention Coxib+PPI HP eradication HP eradication +/- PPI

44 자료제공 : 이혁 Moderate risk Moderate risk Ulcer history (-) Ulcer history (+) Ulcer history (-) Ulcer history (+) NSAID + PPI or Coxib Coxib + PPI HP eradication (?) NSAID + PPI or Coxib Coxib + PPI CV(+) NSAID (Naproxen) + PPI CV(+) NSAID (Naproxen) + PPI

45 CASE 1 76YO Male No cardiovascular disease Starting of ibuprofen d/t RA Recent EGD: HP positive Next management? HP eradication NSAID +/- PPI

46 자료제공 : 이혁 Algorithm for NSAID gastropathy NSAID Chronic NSAID user HP(-/+) Naive NSAID user ulcer(-) Ulcer (-) Ulcer (+) HP (-) HP (+) Low risk High risk Low risk High risk CV(-/+) CV(-/+) Low risk Moderate risk High risk No prevention Coxib+PPI HP eradication (?) NSAID 중단 PPI No prevention Coxib+PPI HP eradication HP eradication +/- PPI

47 CASE 2 52YO Female History of gastric ulcer Recent stroke with aspirin Long-term use of aceclofenac d/t OA Recent EGD: HP negative Next management? NSAID (Naproxen) + PPI

48 자료제공 : 이혁 Algorithm for NSAID gastropathy NSAID Chronic NSAID user HP(-/+) Naive NSAID user ulcer(-) Ulcer (-) Ulcer (+) HP (-) HP (+) Low risk High risk Low risk High risk CV(-/+) CV(-/+) Low risk Moderate risk High risk No prevention Coxib+PPI HP eradication (?) NSAID 중단 PPI No prevention Coxib+PPI HP eradication HP eradication +/- PPI

49 자료제공 : 이혁 Moderate risk Moderate risk Ulcer history (-) Ulcer history (+) Ulcer history (-) Ulcer history (+) NSAID + PPI or Coxib Coxib + PPI HP eradication (?) NSAID + PPI or Coxib Coxib + PPI CV(+) NSAID (Naproxen) + PPI CV(+) NSAID (Naproxen) + PPI

50 CASE 3 48YO Female No cardiovascular disease Long-term use of coxib d/t OA Recent EGD: ulcer scar with HP positive Next management? Coxib + PPI HP eradication

51 자료제공 : 이혁 Algorithm for NSAID gastropathy NSAID Chronic NSAID user HP(-/+) Naive NSAID user ulcer(-) Ulcer (-) Ulcer (+) HP (-) HP (+) Low risk High risk Low risk High risk CV(-/+) CV(-/+) Low risk Moderate risk High risk No prevention Coxib+PPI HP eradication (?) NSAID 중단 PPI No prevention Coxib+PPI HP eradication HP eradication +/- PPI

52 자료제공 : 이혁 Moderate risk Moderate risk Ulcer history (-) Ulcer history (+) Ulcer history (-) Ulcer history (+) NSAID + PPI or Coxib Coxib + PPI HP eradication (?) NSAID + PPI or Coxib Coxib + PPI CV(+) NSAID (Naproxen) + PPI CV(+) NSAID (Naproxen) + PPI

53 Celecoxib alone 만으로는부족할수있다. - 궤양출혈병력이있는환자에서 celecoxib 사용하고 melena

54 요약 : 위험도에따른접근 NSAIDs 처음사용자에서 H. pylori 감염여부를확인하여제균치료를한다. 저위험환자에서도치료할수있다. NSAIDs 장기사용자에서는 Hp 제균치료보다 PPI 사용이효과적이다. 그러나제균치료는해볼수있다. nsnsaid + PPI 전략은 celecoxib로바꾸는것과유사하다. 더강한예방은 celecoxib + PPI 이다. CV 위험인자가있으면 naproxen을우선적으로사용한다.

55 하부위장관손상 성균관대학교내과이준행

56 NSAID enteropathy may be subtle Sub-clinical damage Increased in mucosal permeablility Mucosal inflammation Fecal occult blood loss Ileal dysfunction Malabsorption Clinical damage Anemia Bleeding/ Perforation Exacerbation of underlying disease Diverticultitis Strictures Ulcerations Colitis Chronic inflammatory bowel disease Angiodysplsatic lesions

Estimated rates of hospitalizations per 100,000 people per year 100,00

57 Upper GI Complications are decreasing Lower GI complications are increasing. Estimated rates of hospitalizations per 100,000 people per year 100,00 90,00 80,00 70,00 60,00 50,00 40,00 30,00 20,00 10,00 0,00 Upper GI Lower GI Undefined GI

58 Aspirin-related jejunal ulcer bleeding

59 NSAIDs-induced enteropathy

60 NSAID-induced colopathy

61 Spectrum of NSAID-related large bowel diseases Ulcers: usually, right-sided. bleeding, perforation Strictures: diaphragm-like and broad-based Colitis: diarrhea with/without bleeding eosinophilic, collagenous, pseudomembraneous, nonspecific especially, mefenamic acid and flufenamic acid Anorectal inflammation, ulceration, stricture NSAIDs may exacerbate preexisting lesions, including diverticulitis, reactivation of inflammatory bowel diseases, and intestinal bleeding from angiodysplastic lesions. Lanas. Am J Med Sci 2009;338:96 106

62 Prevention of lower NSAID enteropathy - No therapies specifically designed or approved for the prevention of NSAID-induced enteropathy Selective NSAID (?) Co-therapy Misoprostol Mucoprotective drugs (Rebamipide) Antimicrobials Probiotics Phosphatidylcholine-associated NSAID Nitric oxide-releasing NSAID Hydrogen sulphide-releasing NSAID

63 Subject with small bowel injury (%) Subject with small bowel injury (%) PPI may increase small bowel injury 50 P = P = P = COX-2 SI COX-2 + PPI 0 Jejum Ileum Washio, et al. Clin Gastroenterol Hepatol 2016

64 임상에서주의해야할점 Jun Haeng Lee, M.D. Samsung Medical Center, Seoul

65 Aspirin-associated ulcer 로 PPI 장기복용권하였으나 PPI 끊고 aspirin 쓰면서재출혈

66 끊지않고계속사용하는것이중요

67 NSAID ulcer 환자에게드리는말씀

68 Management of rheumatoid arthritis - a multidisciplinary approach Rheumatologist Surgeon Endoscopist

69 집으로가져가는메세지 NSAIDs 처음사용자에서 H. pylori 감염여부를확인하여제균치료를한다. 저위험환자에서도치료할수있다. NSAIDs 장기사용자에서는 Hp 제균치료보다 PPI 사용이효과적이다. 그러나제균치료는해볼수있다. nsnsaid + PPI 전략은 celecoxib로바꾸는것과유사하다. 더강한예방은 celecoxib + PPI 이다. CV 위험인자가있으면 naproxen을우선적으로사용한다.

(Microsoft PowerPoint - PGYVEDMWALGD [\310\243\310\257 \270\360\265\345])

$(Microsoft PowerPoint - PGYVEDMWALGD [\310\243\310\257 \270\360\265\345])$ NSAID Induced Gastropathy & Enteropathy 서울의대내과학교실 분당서울대학교병원 내과이동호 Table of contents Mechanism Gastropathy NSAIDs, Coxibs & H. pylori NSAIDs and Lower GI Safety Diagnosis/ Management for GI Complications