GASTROPROTECTIVE DRUGS Dr Elia SAMAHA Pr Christophe Cellier Hôpital Européen Georges Pompidou, Paris

Gastroprotector: a drug that protects the gastric mucosa to prevent ulcers and bleeding

Drugs available Anti-H2 IPP Anti-acides, Protecteurs Cytotec Anti-acides, Protecteurs Drug discovery vol2 fevrier 2003

Pedagogic goals Situation of the issue: prescription of PPIs in France What risk factors have been identified? Does treatment with PPIs reduce the risk of bleeding? Does eradication of Hélicobacter pylori reduce the risk of bleeding?

Prescription of ulcer drugs in France Prevalence: 12% (PPI= 85%) Prescribers: General Practitioners = 80% Main reasons: GERD 58% Gastroprotection 50% Dyspepsia 24.7% Ulcer disease 9.5% Ile de France 2002. Urcamif - assurance-maladie

Non-compliance rate in PPI treatment GPs in Grenoble region in 2004: 46% Patients admitted to an internal medicine unit in Rouen: 67% Main differences from references: Upper GI endoscopy Respect for indications Marie I. et al. Rev Med Int 2007 Levy-Neumand O et al. Gastroenterol Clin Biol 2007

Non-compliance rate in PPI treatment €150 Million Reports to the Social Security accounting committee – October 2009

Growth of use by volume from 2004 to 2008 (number of UCD / inhabitant) Cost > €1 billion in 2006 (3rd ranked) National Health Insurance – 19 October 2007

Pedagogic goals Situation of the issue: prescription of PPIs in France What risk factors have been identified? Does treatment with PPIs reduce the risk of bleeding? Does eradication of Hélicobacter pylori reduce the risk of bleeding?

Upper digestive tract lesions with low-dose aspirin EROSIONS: 50% ULCERS: 10% Incidence (%) in patients receiving low-dose aspirin (75-325 mg/d)

The risk of bleeding ulcer with aspirin is dose-dependent Weil et al. BMJ 1995

Complications of GD bleeding in relation to aspirin dose Number of patients to treat to observe an additional severe bleeding episode / year as compared to the group without aspirin ASPIRIN 75-325 mg > 325 mg 833 247 Laine Aliment Pharmacol Ther 2006; 24: 897-908

Demonstrated risk factors for gastroduodenal bleeding with low-dose aspirin (≤ 325 mg/d) Relative Risk History of bleeding ulcer 6.5 History of ulcer 2 Co-prescription AVK 2 NSAIDs 2-4 Steroids 3-7 Coxib 2 Clopidogrel 7

Is age a risk factor? AGE: The risk of lesions in the digestive tract increases, especially ulcers. SUBJECT > 65 years: Subject at risk for GI complications with NSAIDs

Pedagogic goals Situation of the issue: prescription of PPIs in France What risk factors have been identified? Does treatment with PPIs reduce the risk of bleeding? Does eradication of Hélicobacter pylori reduce the risk of bleeding?

Survival without recurrence of a major GI event in high-risk patients with aspirin vs. clopidogrel ± PPIs 14,627 patients Aspirin + PPI > Aspirin Clopidogrel = Clopidogrel + PPI Taiwan. Pas de bénéfice à rajouter IPP sur clopidogrel. Asp + IPP > clopidogrel NS Asp + PPI > clopidogrel Hsiao et al. Clinical Therapeutics/Volume 31, Number 9, 2009

Risk of recurring GDU P = 0.001 P = 0.002 Chan et al. N Engl J Med. 2005;352: 238–244. Lai et al. Clin Gastroenterol Hepatol. 2006; 4:860–865.

Cumulative incidence of GD ulcers after 26 weeks of treatment with low-dose aspirin 991 patients > age 60 Risk of ulcer reduced by 70% with PPI Yeomans ND et al. Am J Gastroenterology 2008

Should Helicobacter pylori be taken into account?

Prevalence of GDU with NSAIDs or aspririn in relation to H Prevalence of GDU with NSAIDs or aspririn in relation to H. pylori status Meta-analysis 16 controlled studies RR: 2.12 (95% CI: 1.68-2.67) Huang et al. Lancet 2002

Rate of recurrent bleeding after 6 months with low-dose aspirin or NSAIDs (PPI vs Eradication) Randomized prospective study 400 patients Hp+: -250 Aspirin -150 Naproxen P=0.005 Le risque hémorragique de l’aspirine à faible dose pourrait être lié à son pouvoir anti thrombotique favorisant le saignement de lésions induites par Hp. Alors que AINS effet ulcérogène indépendant NS Chan et al. NEJM 2001

Recommendations for the use of PPIs - Approval GERD and its complications Gastric and duodenal ulcers and their complications Eradication of Hélicobacter pylori Zollinger-Ellison Syndrome Prevention of GI ulcer with NSAIDs in presence of risk factors Prevention of GI stress ulcers in resuscitation HAS – December 2009 AFSSAPS – November 2007

PREVENTION OF GI LESIONS INDUCED BY NSAIDs Risk situations: Age > 65 years History of gastroduodenal ulcer (look for and treat Helicobacter pylori infection) Association with platelet antiaggregant (low-dose aspirin or clopidogrel), an anticoagulant or steroids Half-dose PPI (except omeprazole) (Grade A) Stop PPI at same time as NSAIDs HAS – December 2009

PREVENTION OF GI LESIONS INDUCED BY LOW-DOSE ASPIRIN (≤ 325 MG/DAY) No systematic gastroprotection (little evidence) In patients with GI bleeding on low-dose aspirin. If continued, it is advisable to associate a PPI (Grade A) systematically. Always look for and treat Helicobacter pylori infection in cases of ulcer history. AFSSAPS – November 2007

PREVENTION OF ACUTE STRESS LESIONS (RESUSCITATION) Two main risk factors: Intubation with mechanical ventilation > 48h Coagulation disorders No drug not approved PPI or anti-H2 (Grade A) No justification for prescribing an antisecretory agent if no RF (Grade A) “traitement préventif des lésions gastroduodénales dans les situations de stress”. Cook et al. N Engl J Med. 1994 Am J Health-Syst Pharm. 1999

PRESCRIPTION OF PPI WITHOUT ENDOSCOPY IN 2 SITUATIONS Typical GERD, in a patient < age 55 with no warning signs Prevention of NSAID-induced lesions in patients > age 65 or with risk factors In other circumstances, endoscopy is necessary before ANY treatment. AFSSAPS – November 2007

Valid indications for PPIs as protection: TAKE-HOME MESSAGE Key role of general practitioners Valid indications for PPIs as protection: Prevention with NSAIDs in presence of RF Age > 65 years History of GI ulcer Co-prescription (antiaggregants, AVK, steroids) Secondary prevention with low-dose aspirin Prevention of stress ulcer in resuscitation

TAKE-HOME MESSAGE Dyspepsia = NO Low-dose aspirin = NO Efficacy = PPIs 28

Questions? ~ Answers! Thank you for your attention International Congress of Medicine for Everyday Practice Thank you for your attention Questions? ~ Answers! 29