Can we reduce the number of medications for the Elderly?

Should anti-peptic ulcer prophylaxis be given ?

Outline Prevalence of inappropriate acid suppression Guidelines on prophylaxis Effectiveness of prophylaxis Besides that extra pill(s), it is harmless, isn’t it? Recommendations

Prevalence of Inappropriate Acid Suppression Therapy Institution dependent Prescribing practice – local setting in19981 “NSAIDs & antacids…. … top 2 drugs”

More recent surveys 2 - 4

1. Yap KB, Chan KM. The prescribing pattern of hospital doctors. Singapore Med J. 1998 Nov;39(11):496–500. 2. Gupta R, Garg P, Kottoor R, Munoz JC, Jamal MM, Lambiase LR, et al. Overuse of acid suppression therapy in hospitalized patients. South Med J. 2010

Mar;103(3):207–11. 3. Naunton M, Peterson GM, Bleasel MD. Overuse of proton pump inhibitors. J Clin Pharm Ther. 2000 Oct;25(5):333–40. 4. Nardino RJ, Vender RJ, Herbert PN. Overuse of acid-suppressive therapy in hospitalized patients. Am J Gastroenterol. 2000 Nov;95(11):3118–22.

What are they using it for ? Started Inappropriately Low risk patients

Inappropriate Indication Percent of Patients

Indeterminate chest pain 30.6%

Nonspecific abdominal pain 22.6%

Co-prescribed with aspirin 14.6%

Co-prescribed with low dose steroids 12.0%

Co-prescribed with warfarin 10.6%

Co-prescribed with antibiotics 5.6%

NPO (nulla per os) 2%

Nausea 2%

1. Rashid S, Rajan D, Iqbal J, Lipka S, Jacob R, Zilberman V, et al. Inappropriate Use of Gastric Acid Suppression Therapy in Hospitalized Patients with Clostridium difficile-Associated Diarrhea: A Ten-Year Retrospective Analysis. ISRN Gastroenterol. 2012;2012:902320.

Going beyond hospitalization Continued Inappropriately1,2

1. Gupta R, Garg P, Kottoor R, Munoz JC, Jamal MM, Lambiase LR, et al. Overuse of acid suppression therapy in hospitalized patients. South Med J. 2010 Mar;103(3):207–11.

2. Manoharan T. Acid suppression in the elderly. Australasian Journal on Ageing. 2006;25(3):164–6.

Guidelines on Prophylaxis 2009 guidelines1 Stratified into 3 groups NSAIDs use, GI bleeding & CV risk CV risk = aspirin use

NSAIDs (except ASA) use has declined

1. Lanza FL, Chan FKL, Quigley EMM, Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009 Mar;104(3):728–38.

Low Risk Moderate Risk High Risk

No risk factors (1 to 2 risk factors) > 2 risk factors

Age > 65 years old

High dose NSAIDs pHx complicated ulcer

pHx uncomplicated ulcer

Concurrent aspirin, corticosteroids, anticoagulation

Guidelines on Prophylaxis (II) 2008 Expert Consensus Document1 High risk of GI toxicity

1. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert

Consensus Documents. J Am Coll Cardiol. 2008 Oct 28;52(18):1502–17.

Presence of :- Or 2 of the following:-

History of Ulcer Disease Age > 60

History of Ulcer Complications Corticosteroids use

GI Bleeding Dyspepsia or GERD

Dual Antiplatelet

Concomitant anticoagulation

Effectiveness of prophylaxis PPI effective in high risk patients1

Age > 60 or Ulcer in last 5 years New ulcers

Misoprostol better than lansoprozole2 But poorly tolerated at recommended dose3

Placebo Esomeprazole 20 Esomeprazole 40 RRR

Venus 20.4% (15.1 - 25.7%) 5.3% (2.4 – 8.2%) 4.7% (2.0 – 7.5%) 0.77

Pluto 12.3% (7.2 – 17.4%) 5.2% (1.9 – 8.5%) 4.4% (1.4 – 7.4%) 0.64

Pooled 17% 5.2% 4.6% 0.73

1. Scheiman JM, Yeomans ND, Talley NJ, et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 2006; 101:701.

2. Graham DY, Agrawal NM, Campbell DR, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162:169.

3. Hooper L, Brown TJ, Elliott R, et al. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ 2004; 329:948.

Isn’t it safer to just cover? Emerging data of longer term side effects

GI Bleed Infections

Malabsorptions

Clostridium Diarrhea Mounting evidence of association with acid suppression1 65% increase in the incidence of CDAD among PPI users

In community setting2 31% without antibiotics had PPI

Culminated to FDA advisory3 “…include information about the increased risk of CDAD with

use of PPIs in the drug labels.”

1. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012 Jul;107(7):1001–10.

2. Chitnis AS, Holzbauer SM, Belflower RM, et al. Epidemiology of community-associated clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013 Jul 22;173(14):1359–67.

3. FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs) [Internet]. [cited 2013 Aug 3].

Pneumonia Meta-analysis1 of 3 cohort, 5 case control, 23 RCT PPI odds ratio = 1.27 H2RA odds ratio = 1.22

Association with Dose of PPI Within 7 days Duration of exposure (reduce)

Mechanisms Elderly & the risk of aspirations

1. Eom C-S, Jeon CY, Lim J-W, Cho E-G, Park SM, Lee K-S. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ.

2011 Feb 22;183(3):310–9.

Fractures Early epidemiological links PPI to fractures 2 meta-analysis1,2 Case control, Cohort, No RCTs

H2RA no increase risk

Smoking & Consistent use3 FDA Update4

Short term use safe (14 days x 3 / year)

1. Eom C-S, Park SM, Myung S-K, Yun JM, Ahn J-S. Use of Acid-Suppressive Drugs and Risk of Fracture: A Meta-analysis of Observational Studies. Ann Fam Med. 2011 May 1;9(3):257–67.

2. Yu EW, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011 Jun;124(6):519–26. 3. Khalili H, Huang ES, Jacobson BC, Camargo CA, Feskanich D, Chan AT. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a

prospective cohort study. BMJ [Internet]. 2012 Jan 31 [cited 2013 Aug 3];344. Available from: http://www.bmj.com/content/344/bmj.e372.abstract 4. Postmarket Drug Safety Information for Patients and Providers > FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the

use of proton pump inhibitors [Internet]. [cited 2013 Aug 8]. Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm

Hip # risk Spine # Risk

1.30 – 1.31 1.56

Calcium Deficiency Acid frees calcium from food matrix Conflicting results1 RCT on omeprazole & calcium absorption2 Radioisotope studies 12 Healthy adults 18 to 45 years old No difference in absorption

? Mechanism of increased fractures

1. Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep. 2010 Dec;12(6):448–57.

2. Wright MJ, Sullivan RR, Gaffney-Stomberg E, Caseria DM, O’Brien KO, Proctor DD, et al. Inhibiting Gastric Acid Production Does Not Affect Intestinal Calcium Absorption in Young, Healthy Individuals: A Randomized, Crossover, Controlled Clinical Trial. J Bone Miner Res. 2010 Oct;25(10):2205–11.

Gastric Acid

Stein, J. et al. (2010) Diagnosis and management of iron deficiency anemia

in patients with IBD Nat. Rev. Gastroenterol. Hepatol.

doi:10.1038/nrgastro.2010.151

Hoenderop JGJ, Nilius B, Bindels RJM. Calcium Absorption Across Epithelia. Physiol Rev. 2005 Jan 1;85(1):373–422.

Vitamin B12 Deficiency in the Elderly | Medical Progress | MIMS.com [Internet]. [cited 2013 Aug 11].

Vitamin B12 Deficiency Acid liberates B12 from food

Significance unclear; Trend towards lower B12 levels2 With PPI but not H2RA

Relevant in elderly with poor vitamin B12 intake & stores 1. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994 Feb

1;120(3):211–5. 2. Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and

magnesium. Curr Gastroenterol Rep. 2010 Dec;12(6):448–57.

Baseline With Omeprazole

P value

Omeprazole 20 mg 3.2% 0.9% 0.031

Omeprazole 40 mg 3.4% 0.4% <0.05

1

Iron Deficiency Acid facilitates non-haem iron1 (66% - 80% of diet) hypo/ achlorhydria states associated with iron deficiency

anaemia2

Not all studies demonstrates association with PPI3 Case report fulfilling “possible” Naranjo ADR scale4 2 patients

Low iron diet with PPI5 At risk elderly

1. Bezwoda W, Charlton RW, Bothwell T, Torrance J, Mayet F. The importance of hydrochloridric acid in the absorption of nonheme food iron. J Lab Clin Med 978;92:108–16.

2. Annibale B, Capurso G, Delle Fave G. The stomach and iron deficiency anaemia: a forgotten link. Dig Liver Dis. 2003 Apr;35(4):288–95. 3. Stewart CA, Termanini B, Sutliff VE, et al. Assessment of the risk of iron malabsorption in patients with Zollinger-Ellison syndrome treated with long-term

gastric acid antisecretory therapy. Aliment Pharmacol Ther 1998;12:83–98 4. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J. 2004

Sep;97(9):887–9. 5. Miret S, Simpson RJ, McKie AT. Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr 2003;23:283–301

Clopidogrel for Aspirin Substitute aspirin to lower GI risk

Efficacy & Risk of Bleeding with lower dose aspirin3,4

Clopidogrel & GI Bleed1 Aspirin & GI Bleed2 Plavix Aspirin Aspirin Plavix Warfarin Aspirin -

Plavix Aspirin -Warfarin

Plavix - Warfarin

GI Bleed 1.99% 2.66% 1.5% 1.9% 0.9% 3.1% 2.1% 3.8%

Severe GI Bleed 0.49% 0.71%

(Large multicentre RCT - ischemic events) (Retrospective Danish AF population)

Excludes prior GI bleeds Bleeding but not GIB as covariate

Aspirin 325mg Dose not mentioned

1. Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events. Drug Saf. 1999 Oct;21(4):325–35.

2. Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010 Sep 13;170(16):1433–41.

3. Mehta SR, Tanguay J-F, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010 Oct 9;376(9748):1233–43.

4. Peters RJG, Mehta SR, Fox KAA, Zhao F, Lewis BS, Kopecky SL, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003 Oct 7;108(14):1682–7.

Clopidogrel for Aspirin – 2o Prevention Inferiority of Plavix vs Aspirin + PPI

Plavix + PPI? Only retrospective data = no reduction of GI bleed3 COGENT trial4 has aspirin included – premature termination

Aspirin + PPI

Clopidogrel p value Remarks

Chan et al1 0.7 % 8.6% 0.001 n = 320; 12 months follow-up

Lai et al2 0% 13.6% 0.019 n = 170; 52 weeks follow-up

1. Chan FKL, Ching JYL, Hung LCT, Wong VWS, Leung VKS, Kung NNS, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005 Jan 20;352(3):238–44.

2. Lai K-C, Chu K-M, Hui W-M, Wong BC-Y, Hung W-K, Loo C-K, et al. Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications. Clin Gastroenterol Hepatol. 2006 Jul;4(7):860–5.

3. Hsiao F-Y, Tsai Y-W, Huang W-F, Wen Y-W, Chen P-F, Chang P-Y, et al. A comparison of aspirin and clopidogrel with or without proton pump inhibitors for the secondary prevention of cardiovascular events in patients at high risk for gastrointestinal bleeding. Clin Ther. 2009 Sep;31(9):2038–47.

4. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010 Nov 11;363(20):1909–17.

COX-2 inhibitors for NSAIDs + PPI COX-2 inhibitors safer than NSAIDs1 CONCOR2

COX-2 inhibitors +PPI3 Celecoxib + Omeprazole reduces recurrent GI in v. high risk

1. Rostom A, Muir K, Dubé C, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol 2007; 5:818.

2. Chan FKL, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet. 2010 Jul 17;376(9736):173–9.

3. Chan FK, Wong VW, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet 2007; 369:1621.

Celecoxib Diclofenac + Omeprazole

Upper & Lower GI Bleed 0.9% 3.8%

Hazard Ratio 4.3 (2.6-7.0); p<0.0001

Recommendations Need antiplatelet/ NSAIDs/ COX-2 ⊖ Risk Stratify need for prophylaxis Eradicate H. pylori Review medications regularly Monitoring in selected groups1

Iron & Vit B12

Education2 Medication reconciliation (pharmacy)2 Audits 1. Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci. 2011 Apr;56(4):931–50.

2. Gupta R, Marshall J, Munoz JC, Kottoor R, Jamal MM, Vega KJ. Decreased acid suppression therapy overuse after education and medication reconciliation. Int J Clin Pract. 2013 Jan;67(1):60–5.

Risk Stratify Presence of :- Or 2 of the following:-

History of Ulcer Disease Age > 60

History of Ulcer Complications

Corticosteroids use

GI Bleeding Dyspepsia or GERD

Dual Antiplatelet

Concomitant anticoagulation

Screen and Rx H. Pylori

H. Pylori NSAIDs Both

OR = 1.79 OR = 4.85 OR = 6.13

Add PPI

Low Risk Moderate Risk High Risk

No risk factors (1 to 2 risk factors) > 2 risk factors

Age > 65 years old

High dose NSAIDs pHx complicated ulcer pHx uncomplicated ulcer

Concurrent aspirin, corticosteroids, anticoagulation

NSAIDs (Shortest

duration & least ulcerogenic)

Naproxen + PPI/misoprotol

Alternative or COX-2 inhibitor +

PPI/misoprotol

Naproxen + PPI/misoprotol

Naproxen + PPI/misoprotol

Avoid NSAIDs or COX-2 inhibitor

1. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008 Oct 28;52(18):1502–17.

2. Lanza FL, Chan FKL, Quigley EMM, Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009 Mar;104(3):728–38.

Conclusion Inappropriate acid suppression is prevalent Not all patients require gastro-prophylaxis Anemia ≠ Gastro-prophylaxis paradoxical

Gastro-prophylaxis is effective in reducing GI complications PPI benefits high risk patients Risk stratify patients Plavix not better than Aspirin + PPI for 2o prevention

Infection & Malabsorption