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
Prof. Dr. med. H. Wietholtz
Direktor der Medizinischen Klinik II, Klinikum Darmstadt
Grafenstraße 9
64283 Darmstadt