Sekundär- und Primärprophylaxe der ASS-/NSAR-Gastropathie: Eine Übersicht anhand vier klinischer Szenarien

Zusammenfassung

In vier klinischen Szenarien werden anhand der aktuellen Literatur die Möglichkeiten der Sekundär- und Primärprophylaxe eines Ulkus oder einer Ulkusblutung bei fortgesetzter Therapie mit unselektiven nichtsteroidalen Antirheumatika (NSAR) oder niedrig dosiertem ASS sowohl bei Helicobacter-positiven als auch -negativen Patienten verglichen.

Zur Sekundärprophylaxe eines Rezidivulkus oder Blutung reicht bei fortgesetzter unselektiver NSAR-Medikation für Helicobacter-infizierte Patienten eine alleinige Eradikation nicht aus, sondern nach der Eradikation ist eine begleitende Medikation mit Protonenpumpenblockern (PPI) oder die Umstellung von unselektiven NSAR auf einen selektiven COX-2-Inhibitor erforderlich. Auch für primär H.p.-negative Patienten ist zur Sekundärprophylaxe eine begleitende Medikation mit PPI oder die Umstellung auf einen selektiven COX-2-Inhibitor erforderlich. Welche der beiden Alternativen effektiver und kostengünstiger ist, muss durch weitere direkt vergleichende Studien geklärt werden. Zur Sekundärprophylaxe eines Rezidivulkus oder Blutung unter fortgesetzter Low-Dose-ASS-Therapie reicht bei H.p.-positiven eine alleinige Eradikation aus. Eine Fortsetzung der PPI-Therapie nach Eradikation ist nicht erforderlich, kann jedoch bei erhöhtem Risiko für gastrointestinale Komplikationen (Ulkusanamnese, begleitende Medikation mit Kortikosteroiden, Antikoagulanzien oder NSAR mit höherem relativen Risiko für gastrointestinale Komplikationen, Alter > 65 Jahre, schwere kardiovaskuläre Begleiterkrankungen) in Erwägung gezogen werden. Ein Umstellen von ASS auf das teurere Clopidogrel ist nicht gerechtfertigt.

Die Primärprophylaxe eines Ulkus oder einer Ulkusblutung ist vor Beginn einer Dauertherapie mit NSAR für Patienten mit erhöhtem Risiko für gastrointestinale Komplikationen (s. o.) sinnvoll. Sowohl die Gabe von COX-2-Inhibitoren als auch von unselektiven NSAR unter PPI-Schutz ist möglich, bei letzterer ist eine H.p.-Diagnostik und Eradikation bei H.p.-positivem Befund zu empfehlen. Es gibt keine validen Daten, die eine zwingende Überprüfung des Helicobacter-Status und ggf. anschließende Eradikation zur Primärprophylaxe vor Einleitung einer Low-Dose-ASS-Therapie fordern. Ob dies für Patienten mit erhöhtem Risiko für gastrointestinale Komplikationen zu empfehlen ist, müsste durch Studien validiert werden.

Abstract

Based on current references four clinical scenarios were discussed and different management strategies were compared for secondary and primary prophylaxis of ulcer or peptic ulcer bleeding under continuous therapy with non-steroidal antiinflammatory drugs (NSAID) or low-dose-aspirin, for H.pylori-positive and H.pylori-negative patients.

Used as secondary prophylaxis eradication alone is insufficient in preventing recurrent peptic ulcer or recurrent ulcer bleeding for H.pylori-positive patients who continue to take unselective NSAIDs. Maintenance therapy with PPIs or switching from nonselective NSAID to COX-2-inhibitors is required after eradication of H.pylori or primary H.pylori-negative patients. Further evaluation is needed of what kind of secondary prophylaxis - maintenance therapy with PPI or switching to COX-2-inhibitor - is more (cost-)effective. It is sufficient to use eradication of H.pylori alone as secondary prophylaxis in preventing recurrent peptic ulcer or recurrent ulcer bleeding for H.pylori-positive patients, who continue to take low-dose-aspirin. Maintenance therapy with PPI is not generally required. However it can be considered for patients with increased risk for gastrointestinal complications (previous history of peptic ulcer, age over 65 years, concomitant use of corticosteroids, anticoagulants or individual NSAID with higher risk for gastrointestinal complications, serious cardiovascular disease). Switching from low-dose-aspirin to clopidogrel is not required.

Used as primary prophylaxis in preventing peptic ulcer or ulcer bleeding before starting long-term therapy with NSAIDs, COX-2-inhibitors or unselective NSAIDs concomitant with PPIs are recommended for patients with increased risk for gastrointestinal complications. Patients starting long-term therapy with unselective NSAIDs should be screened for H.pylori and eradicated. There are no valid data supporting screening for H.pylori and eradication for patients starting long-term therapy with low-dose-aspirin. Further studies are needed to evaluate a possible benefit for patients with increased risk for gastrointestinal complications.

Schlüsselwörter

Helicobacter pylori - ASS - nichtsteroidale Antirheumatika - Ulkus - gastrointestinale Blutung - Protonenpumpenblocker - COX-2-Inhibitoren - Clopidogrel - Prophylaxe

Key words

H. pylori - low-dose-aspirin - non-steroidal antiinflammatory drugs - ulcer - gastrointestinal bleeding - PPI - cox-2-inhibitors - clopidogrel - prophylaxis

Literatur

• 1 Halter F, Tarnawski A S, Schmassmann A. et al . Cyclooxygenase 2-implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives.  Gut. 2001;  49 (3) 443-453
• 2 Lazzaroni M, Bianchi G Porro. Nonsteroidal anti-inflammatory drug gastropathy and Helicobacter pylori: The search for an improbable consensus.  Am J Med. 2001;  110 (1A) 50S-54S
• 3 Labenz J, Meining A, Tillenburg B. et al . Helicobacteriose: Update 1999.  Leber Magen Darm. 1999;  (29/2) 80-82
• 4 Chan F KL, Chung S C, Suen B Y. et al . Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen.  N Engl J Med. 2001;  344 967-973
• 5 Langman M J, Jensen D M, Watson D J. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDŽs.  JAMA. 1999;  282 1929-1933
• 6 Schnitzer T J. Cyclooxygenase-2-specific inhibitors: Are they safe?.  Am J Med. 2001;  110 (1A) 46S-49S
• 7 Hawkey C, Laine L, Simon T. et al . Comparison of the effect of rofecoxib (a cyclooxygenase-2-inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis.  Arthritis Rheum. 2000;  43 370-377
• 8 Silverstein F E, Faich G, Goldstein J L. et al . Gastrointestinal toxicity with celecoxib vs non-steroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The Class study: a randomized controlled trial.  JAMA. 2000;  282 1247-1255
• 9 Laine L, Harper S, Simon T. et al . A randomized trial comparing the effect of rofecoxib, a cyclooxy-genase-2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.  Gastroenterology. 1999;  117 776-783
• 10 Simon L S, Weaver A, Graham D Y. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial.  JAMA. 1999;  282 1921-1928
• 11 Emery P, Zeidler H, Kvien T K. et al . Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomized double-blind comparison.  Lancet. 1999;  354 2106-2111
• 12 Bombardier C, Laine L, Reicin A. et al . Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.  N Engl J Med. 2000;  343 1520-1528
• 13 Goldstein J L, Correa P, Zhao W W. et al . Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2-inhibitor, compared to naproxen in patients with arthritis.  Am J Gastroenterol. 2001;  96 (4) 1019-1027
• 14 Simon L S, Lanza F L, Lipsky P E. et al . Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase-2-inhibitor.  Arthritis Rheum. 1998;  1 1591-1592
• 15 Cannon G W, Breedveld F C. Efficacy of cyclooxygenase-2-specific inhibitors.  Am J Med. 2001;  110 (3A) 6S-12S
• 16 Bensen W G, Fiechtner J J, Millen JI Mc. et al . Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2-inhibitor: a randomized controlled trial.  Mayo Clin Proc. 1999;  74 1095-1105
• 17 Hawkey C J, Karrasch J A, Szczepanski L. et al . Omeprazole compared with misoprostol for ulcers associated with non-steroidal anti-inflammatory drugs.  N Engl J Med. 1998;  338 727-734
• 18 Graham D Y, Agrawal N M, Campbell D R. Ulcer prevention in long-term users of nonsteroidal antiinflammatory drugs.  Arch Intern Med. 2002;  162 169-175
• 19 Yeomans N D, Tulassay Z, Juhasz L. et al . A comparison of omeprazole with ranitidine for ulcers associated with non-steroidal anti-inflammatory drugs.  N Engl J Med. 1998;  338 719-726
• 20 Klinkenberg-Knol E, Nelis F, Dent J. et al . Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa.  Gastroenterology. 2000;  118 661-669
• 21 Heresbach D, Raoul J L, Bretagne J F. et al . Helicobacter pylori: a risk and severity factor of non-steroidal anti-inflammatory drug induced gastropathy.  Gut. 1992;  33 1608-1611
• 22 Li E KM, Sung J JY, Suen R. et al . Helicobacter pylori infection increases the risk of peptic ulcers in chronic users of non-steroidal anti-inflammatory drugs.  Scand J Rheumatol. 1996;  25 42-46
• 23 Aalykke C, Lauritsen J M, Hallas. et al . Helicobacter pylori and risk of ulcer bleeding among users of non-steroidal antiinflammatory drugs: A case-control study.  Gastroenterology. 1999;  116 1305-1309
• 24 Chan F KL, Sung J JY, Chung S C. et al . Randomized trial of eradication of helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers.  Lancet. 1997;  350 975-979
• 25 Bianchi P orro G, Parente F, Imberi V. et al . Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in long-term non-steroidal anti-inflammatory drug users.  Gut. 1996;  39 22-26
• 26 Pilotto A, Franceschi M, Leandro F. et al . The effect of H.p.-Infection on NSAID-related gastroduodenal damage in the elderly.  Eur J Gastroenterol Hepatol. 1997;  9 951-956
• 27 Li E KM, Sung J JY, Suen R. et al . Helicobacter pylori infection increases the risk of peptic ulcers in chronic users of non-steroidal anti-inflammatory drugs.  Scand J Rheumatol. 1996;  25 42-46
• 28 Taha A S, Dahill S, Morran C h. et al . Neutrophils, Helicobacter pylori, and non-steroidal anti-inflammatory drug ulcers.  Gastroenterology. 1999;  116 254-258
• 29 Huang J Q, Sridhar S, Hunt R H. Role of Helicobacter pylori infection and non-steroidal antiinflammatory drugs in peptic-ulcer disease: a meta-analysis.  Lancet. 2002;  359 14-22
• 30 Taha A S, Nakshabendi I, Lee F. et al . Chemical gastritis and Helicobacter pylori related gastritis in patient receiving non-steroidal anti-inflammatory drugs: comparison and correlation with peptic ulceration.  J Clin Pathol. 1992;  45 135-139
• 31 Barkin J :. The relation between Helicobacter pylori and nonsteroidal anti-inflammatory drugs.  Am J Med. 1998;  105 (5A) 22S-27S
• 32 Goggin P M, Collins D A, Jazrawi R P. et al . Prevalence of Helicobacter pylori and its effects on symptoms and non-steroidal anti-inflammatory drug-induced gastrointestinal damage in patients with rheumatoid arthritis.  Gut. 1993;  34 1677-1680
• 33 Loeb D S, Talley N J, Ahlquist D A. et al . Long-term non-steroidal antiinflammatory drug use and gastroduodenal injury: the role of Helicobacter pylori.  Gastroenterology. 1992;  102 1899-1905
• 34 Laine L, Cominelli F, Sloane R. et al . Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production: a controlled double blind trial.  Aliment Pharmacol Ther. 1995;  9 127-135
• 35 Lanza F L, Evans D G, Graham D Y. Effect of Helicobacter pylori infection on the severity of gastroduodenal mucosal injury after the acute administration of naproxen or aspirin to normal volunteers.  Am J Gastroenterol. 1991;  86 735-737
• 36 Thillainayagam A V, Tabaqchali S, Warrington S J. et al . Interrelationships between Helicobacter pylori infection, non-steroidal antiinflammatory drugs and gastroduodenal disease: a prospective study in healthy volunteers.  Dig Dis Sci. 1994;  39 1085-1089
• 37 Lipscomb G R, Wallis N, Armstrong G. et al . Influence of Helicobacter pylori on gastric mucosal adaption to naproxen in man.  Dig Dis Sci. 1996;  41 1538-1588
• 38 Kim J G, Graham D Y. the Misoprostol Study Group . Helicobacter pylori infection and development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy.  Am J Gastroenterol. 1994;  89 203-207
• 39 Chan F KL, Wu K F, Yung M Y. et al . Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal antiinflammatory drugs: a randomised trial.  Lancet. 2002;  359 9-13
• 40 Chan F KL, Sung J JY, Chung S C. et al . Randomized trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers.  Lancet. 1997;  350 975-979
• 41 Lipsky P E, Abramson S, Breedveld F. Analysis of the effect of COX-2 specific inhibitors and recommendations for their use in clinical practice.  J Rheum. 2000;  27 1338-1340
• 42 Rollhauser C, Fleischer D E:. Nonvariceal gastrointestinal bleeding.  Endoscopy. 2002;  34 (2) 111-118
• 43 Hawkey C J, Lanas A I:. Doubt and certainty about nonsteroidal anti-inflammatory drugs in the year 2000: a multidisciplinary expert statement.  Am J Med. 2001;  110 (1A) 79S-100S
• 44 Silverstein F E, Graham D Y, Senior J R. et al . Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving non-steroidal antiinflammatory drugs: a randomized, doubleblind, placebo-controlled trial.  Ann Intern Med. 1995;  123 241-249
• 45 Langman M JS, Weil J, Wainwright P. et al . Risk of bleeding peptic ulcer associated with individual non-steroidal antiinflammatory drugs.  Lancet. 1994;  343 1075-1078
• 46 Piper J M, Ray W A, Daugherty J R. et al . Corticoid use and peptic ulcer disease: role of nonsteroidal antiinflammatory drugs.  Ann Intern Med. 1991;  114 735-740
• 47 Garcia-Rodriguez L, Jick H. Risk of upper gastroduodenal bleeding and perforation associated with individual non-steroidal antiinflammatory drugs.  Lancet. 1994;  33 769-772
• 48 Shorr R I, Wayne A R, Daugherty J R. et al . Concurrent use of non-steroidal antiinflammatory drugs and oral anticoagulants places elderly persons at higher risk for hemorrhagic peptic ulcer disease.  Arch Intern Med. 1993;  153 1665-1670
• 49 Bjorkman D J. Non-steroidal antiinflammatory drug-induced gastrointestinal injury.  Am J Med. 1996;  101: Suppl 1 A 25S-32S
• 50 Longstreth G F. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population based study.  Am J Gastroenterol. 1995;  90 206-210
• 51 Greene J M, Winickoff R N. Cost-conscious prescribing of non-steroidal antiinflammatory drugs for adults with arthritis: a review and suggestions.  Arch Intern Med. 1992;  152 1995-2002
• 52 Hallas J, Lauritsen J, Villadsen H D. et al . Non-steroidal antiinflammatory drugs and upper gastrointestinal bleeding, identifying high risk groups by excess risk estimates.  Scand J Gastroenterol. 1995;  30 438-444
• 53 Hochain P, Berkelmans I, Czernichow P. et al . Which patients taking non-aspirin non-steroidal antiinflammatory drugs bleed? A case control study.  Eur J Gastroenterol Hepatol. 1995;  7 419-426
• 54 Langman M JS, Weil J, Wainwright P. et al . Risk of bleeding peptic ulcer associated with individual non-steroidal antiinflammatory drugs.  Lancet. 1994;  343 1075-1078
• 55 Mellemkjaer L, Blot W, Sorensen H. et al . Upper gastrointestinal bleeding among users of NSAIDs: a population based cohort study in Denmark.  Br J Clin Pharmacol. 2002;  53 173-181
• 56 Henry D, Lynette L, Garcia-Rodriguez L A. et al . Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.  BMJ. 1996;  312 1563-1566
• 57 Weil J, Langman M J, Wainwright P. et al . Peptic ulcer bleeding: Accessory risk factors and interactions with non-steroidal anti-inflammatory drugs.  Gut. 2000;  46 27-31
• 58 Hernandez-Diaz S, Garcia-Rodriguez L A. Epidemiologic assessment of the safety of conventional non-steroidal anti-inflammatory drugs.  Am J Med. 2001;  110 (3A) 20S-27S
• 59 Graham D Y. Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and ulcers: where we stand.  Am J Gastroenterol. 1996;  91 2080-2086
• 60 Fendrick M, Bandekar R R, Chernew M E. Role of initial NSAR choice and patient risk factors in the prevention of NSAID gastropathy: a decision analysis.  Arthritis & Rheum. 2002;  47 36-43
• 61 Stolte M, Meining A, Schmitz J M. et al . Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during 12 months o treatment with omeprazole and lansoprazole in patients with gastroesophageal reflux disease.  Aliment Pharmacol Ther. 1998;  12 247-253
• 62 Lipsky P E. Recommendations for the clinical use of cyclooxygenase-2-specific inhibitors.  Am J Med. 2001;  110 (3A) 3S-5S
• 63 Buttgereit F, Burmester G, Simon L S. Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors.  Am J Med. 2001;  110 (3A) 13S-19S
• 64 Slattery J, Warlow C P, Shorrock C J. et al . Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin-analysis of gastrointestinal bleeding during UK-TIA trial.  Gut. 1995;  37 509-511
• 65 Weil J, Duncan C J, Langman M. et al . Prophylactic aspirin and risk of peptic ulcer bleeding.  BMJ. 1995;  310 827-830
• 66 Stalnikowicz-Darvasi R. Gastrointestinal bleeding during low-dose aspirin administration for prevention of arterial occlusive events: a critical analysis.  J Clin Gastroenterol. 1995;  21 13-16
• 67 Patrono C. Aspirin: New cardiovascular uses for an old drug.  Am J Med. 2001;  110 (1A) 62S-65S
• 68 Sorensen H T, Mellemkjaer L, Blot W J. et al . Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin.  Am J Gastroenterol. 2000;  95 2218-2224
• 69 Prichard P J, Kitchingman G K, Walt R P. et al . Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin.  BMJ. 1989;  298 493-496
• 70 Feldman M, Cryer B, Mallat D. et al . Role of Helicobacter pylori infection in gastroduodenal injury and gastric prostaglandin synthesis during long term/low dose aspirin therapy: a prospective placebo-controlled, double-blind randomized trial.  Am J Gastroenterol. 2001;  96 (6) 1751-1757
• 71 Cryer B, Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal and rectal prostaglandin levels and on mucosal injury in healthy humans.  Gastroenterology. 1999;  117 17-25
• 72 Silagy C A, Neil JJ Mc, Donnan G A. et al . Adverse effects of low dose Aspirin in healthy elderly population.  Clin. Pharmacol. Ther.. 1993;  54 84-89
• 73 U.S. Preventive Services Task Force . Aspirin for the primary prevention of cardiovascular events: recommendation and rationale.  Ann Intern Med. 2002;  136 157-160
• 74 Roderick P J, Wilkes H C, Meade T W. The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials.  Br. J. Clin. Pharmac. 1993;  35 210-226
• 75 Patrono C, Culler B, Dalen J E. Platelet-active drugs.The Relationship Among Dose Effectiveness, and Side Effects.  Chest. 1998;  114 470-488
• 76 The Medical Research Council’s General Practice Research Framework . Thrombosis prevention trial: Randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk.  Lancet. 1998;  351 233-241
• 77 CAPRIE Steering Committee . A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events.  Lancet. 1996;  348 1329-1339
• 78 Hirschowitz B I, Hawkey C J. Questions regarding future research on aspirin and the gastrointestinal tract.  Am J Med. 2001;  110 (1A) 74-78
• 79 Wolfe M M, Lichtenstein D R, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.  N Engl J Med. 1999;  340 1888-1899
• 80 Sung J J. Management of nonsteroidal anti-inflammatory drug-related peptic ulcer bleeding.  Am J Med. 2001;  110 (1A) 29-32
• 81 Hawkey C J, Tulussay Z, Szepanski L. et al . Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study.  Lancet. 1998;  352 1016-1621
• 82 Konturek J W, Dembinski A, Konturek S J. et al . Infection of Helicobacter pylori in gastric adaption to continued administration of Aspirin in Humans.  Gastroenterology. 1998;  114 245-255
• 83 Levine J S. Misoprostol and Nonsteroidal Anti-inflammatory Drugs: A tale of effects, outcomes, and costs.  Ann Intern Med. 1995;  123 (4) 309-310
• 84 Labenz J, Blum A L, Bolten W W. et al . Primary prevention of diclofenac associated ulcers and dyspepsia by omeprazole or triple therapy in Helicobacter pylori positive patients: a randomised, double blind, placebo controlled, clinical trial.  Gut. 2002;  51 329-335
• 85 Chan F KL, Hung L CT, Suen B Y. et al . Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.  N Engl J Med. 2002;  347 2104-2110
• 86 Leung W K, Graham D Y. Ulcer and gastritis.  Endoscopy. 2001;  33 (1) 8-15
• 87 Wu J CY, Sung J JY. Ulcer and gastritis.  Endoscopy. 2002;  34 (2) 104-110
• 88 Hawkey C J. Nonsteroidal anti-inflammatory drug gastropathy.  Gastroenterology. 2000;  119 521-535
• 89 Graham D Y. Therapy of Helicobacter pylori: current status and issues.  Gastroenterology. 2000;  118 S2-S8