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Review

Nonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Bleeding: Risk Factors and Prevention Strategies

by
Marino Venerito
,
Thomas Wex
and
Peter Malfertheiner
*
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, D-39120 Magdeburg, Germany
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2010, 3(7), 2225-2237; https://doi.org/10.3390/ph3072225
Submission received: 9 June 2010 / Revised: 6 July 2010 / Accepted: 14 July 2010 / Published: 14 July 2010
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
Versions Notes

Abstract

:
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed medications in the World. A frequent complication of NSAID use is gastroduodenal bleeding. Risk factors for gastroduodenal bleeding while on NSAID therapy are age, prior peptic ulcer and co-medication with anti-platelet agents, anticoagulants, glucocorticosteroids and selective serotonin-reuptake inhibitors (SSRI). Prevention strategies for at-risk patients include the use of the lowest effective dose of NSAIDs, co-therapy with proton-pump inhibitors and/or the use of a COX-2 selective agent. Treatment of Helicobacter pylori infection is beneficial for primary prophylaxis of NSAID-induced gastroduodenal bleeding in NSAID-naive patients. For patients with cardiovascular risk factors requiring NSAIDs, naproxen should be selected. In very high risk patients for both gastrointestinal and cardiovascular complications NSAID therapy should be avoided altogether.

1. Introduction

NSAIDs are the most widely used medications worldwide [1]. These drugs exert anti-inflammatory, antipyretic and analgesic effects by inhibiting cyclooxygenases (COX-1 and COX-2), the enzymes responsible for the production of prostaglandins, prostacyclins and thromboxanes. The beneficial actions of NSAIDs have been linked to their ability to inhibit inducible COX-2 activity, while side effects (e.g., gastrointestinal damage) are thought to be mediated by inhibition of COX-1 [2,3]. NSAIDs are classified in non-selective NSAIDs (inhibition of both COX-1 and COX-2) and COXibs (selective inhibition of the isoenzyme COX-2). Differently from all other NSAIDs, aspirin has the peculiarity of inhibiting COX enzymes irreversibly. Aspirin effects vary with dose [4]. Particularly at low doses (75–325 mg/day), aspirin preferentially acetylates serine 529 of COX-1 leading to an inhibition of platelet-derived thromboxane A2 [5]. This anti-thrombotic effect is routinely used in the prophylaxis of cardiovascular and cerebrovascular events, and results mostly from the fact that after the irreversible inhibition of COX-1, platelets are unable to newly synthesize COX-1 [6]. Therefore, the inhibition of platelets remains for their life-cycle. Table 1 shows a classification of NSAIDs according to the selectivity for COX enzymes and the type of COX inhibition (reversible/irreversible).
Table
Table 1. Classification of NSAIDs according to the selectivity for COX enzymes and the type of COX inhibition (reversible/irreversible).
Table 1. Classification of NSAIDs according to the selectivity for COX enzymes and the type of COX inhibition (reversible/irreversible).
Selective/non-selective inhibition of COX isoenzymesReversible/irreversible inhibition of COX isoenzymes
NSAIDsnon-selective inhibition of both COX isoenzymesreversible
COXibsSelective inhibition of COX-2reversible
ASAnon-selective inhibition of both COX isoenzymesirreversible
NSAIDs: traditional non-steroidal anti-inflammatory drugs, COXibs: NSAIDs that were specifically “designed” to selectively inhibit COX-2; ASA: aspirin.
NSAID intake increases the risk of developing peptic ulcers and their complications (bleeding, perforation or obstruction). Indeed, the risk of upper gastrointestinal bleeding in NSAID users has been shown to be approximately 4-fold higher than in people not taking NSAIDs [7] with an annual event rate per 1,000 persons of 13.6 (absolute risk frequency per year = 74) [8]. Gastric ulcers are approximately four times more common than duodenal ulcers in patients taking NSAIDs [9]. The risk of upper gastrointestinal complications increases also with the regular intake of aspirin at low-doses. Indeed, in a case-control study the risk of hospitalization for bleeding peptic ulcer with the current prophylactic aspirin regimens was 2.3 with the intake of 75 mg aspirin/day and increased to 3.2 and 3.9 with the intake of 150 mg/day and 300 mg/day, respectively [10]. In a meta-analysis of 14 placebo-controlled trials on vascular protection the absolute rate increase risk of major gastrointestinal bleeding with low-dose aspirin above placebo was 0.12% per year (95% CI: 0.07–0.19%) with a number-needed-to-harm of 833 patients (95% CI: 526–1429) [11].

2. Risk Factors for NSAID-Induced Gastroduodenal Bleeding

Risk factors for gastroduodenal bleeding in patients on NSAID therapy are age, prior peptic ulcer and co-medication with anti-platelet agents, anticoagulants, glucocorticosteroids and selective serotonin-reuptake inhibitors (SSRI) (Table 2).
Table
Table 2. Risk Factors for NSAID-associated gastroduodenal bleeding.
Table 2. Risk Factors for NSAID-associated gastroduodenal bleeding.
Risk factorsOR (95% CI)
Prior ulcer or ulcer complication [12]4.76 (4.05–5.59)
Advanced age (60 years or older) [12]5.52 (4.63–6.60)
Co-medication with
- anti-platelet agents (ASA, Clopidogrel™l) [25]7.4 (3.5–15)
- anticoagulants [19]9.7 (4.6–20.2)
- glucocorticosteroids [12]1.83 (1.20–2.78)
- SSRI [20]12.2 (7.1–19.5)
H. pylori infection [57]6.13 (9.98–373)
ASA: aspirin, SSRI: selective serotonin-reuptake inhibitors
The risk for NSAID associated gastroduodenal bleeding may further increase in the presence of more than one risk factor.
A history of peptic ulcer or ulcer complications have consistently emerged as important risk factors for NSAID-associated gastroduodenal bleeding. In a meta-analysis of 10 case-control or cohort studies the odds ratio (OR) for a first gastroduodenal bleeding with NSAID treatment was 2.39 (95% confidence interval CI, 2.16–2.65), whereas the risk in patients with a prior (or unspecified) history of a GI event increased to 4.76 (95% CI, 4.05–5.59) [12]. In a nested case-control study including 2,105 cases and 11,500 controls, patients on NSAIDs with a previous ulcer complication (bleeding or perforation) presented the greatest absolute risk of upper gastrointestinal bleeding with an incidence rate between 20 and 30 per 1000 person-years [13].
In the same study, the risk of developing upper gastrointestinal bleeding was found to depend also on dosage of NSAIDs (medium daily dose: RR = 2.4, 95% CI = 1.9–3.1; high daily dose: RR 4.9, 95% CI = 4.1–5.8) as well as on the pharmacokinetic of the NSAID used (plasma half-life less than 12 hours: RR = 3.1, 95% CI = 2.5–3.8; plasma half-life greater than 12 hours: RR = 4.5, 95% CI = 3.5–5.9) [13].
Advanced age is also a substantial risk factor. Although there does not appear to be a threshold age at which risk dramatically increases, the relative risk for developing a gastroduodenal bleeding increases linearly at the rate of approximately 4% per year of advanced age [14]. A systematic review of 18 case-control and cohort studies on serious gastrointestinal tract complications, showed an increased absolute risk of upper gastrointestinal bleeding among patients older than 75 years taking NSAIDs, with an absolute incidence rate around 20 per 1,000 person-years [15].
The risk of NSAID-induced gastroduodenal bleeding increases further with the intake of more than one NSAID or the combined medication with anti-platelet agents, anticoagulants, glucocorticoids and selective serotonin-reuptake inhibitors. Different studies have shown that a co-therapy with low-dose aspirin further increases the risk of developing a gastroduodenal bleeding of 2- to 6-fold in patients on NSAIDs [16,17,18,19]. Also the co-medication with anticoagulants has been shown to further increase the risk of gastroduodenal complications. In a case-control study conducted in Spain the OR for the development of a gastroduodenal bleeding was as high as 9.7 (95% CI 4.6–20.2) in patients receiving NSAIDs and vitamin K antagonists [20].
In a population-based study conducted in Denmark on 26,005 patients on SSRI (selective serotonin reuptake inhibitors) over four years, the risk of gastroduodenal bleeding was found to be 3.6-fold higher than expected and the concomitant use of SSRI and either NSAID or low-dose aspirin further increased the risk to 12.2 (95% CI, 7.1–19.5) and 5.2 (95% CI, 3.2–8.0), respectively [21]. The mechanisms by which SSRI aggravate NSAID-induced gastroduodenal injury have been poorly investigated. In an animal model the SSRI Paroxetine™ increased the severity of indomethacin-induced antral ulcers by impairing anti-oxidative systems (decrease in gastric mucosal superoxide dismutase and glutathione content) [22].
Mono-therapy with glucocorticosteroids does not increase the risk of a gastroduodenal bleeding [23]. However a meta-analysis of 16 studies demonstrated that the combined use of NSAIDs and glucocorticosteroids is associated with an increased risk of gastroduodenal bleeding (OR 1.83 95 % CI: 1.20 to 2.78) [12]. Studies on animal models suggest that glucocorticosteroids aggravate NSAID-induced gastroduodenal injury by inhibiting mucosal prostaglandin synthetase, thus further decreasing the biosynthesis of gastro-protective prostaglandins [24]. Furthermore 24-h pre-treatment with dexamethasone inhibited the peroxidase activity of COX enzymes by 83% in Wistar rats leading to an increase of reactive hydroxyl radicals that subsequently damage gastroduodenal mucosa [25].
Low-dose aspirin represents the standard therapy for the secondary prophylaxis of cardiovascular events. Current guidelines recommend the use of a double-antiplatelet therapy with aspirin and clopidogrel in patients with acute coronary syndrome or receiving a coronary artery stent. However in a population-based case-control study (1,443 cases of serious upper gastrointestinal bleeding during 2000–2004, 57,720 age and sex matched controls), patients receiving a combined therapy with low-dose aspirin and clopidogrel had an OR for developing a gastroduodenal bleeding as high as 7.4 (95% CI, 3.5–15) [26].
Thus, current data suggest that patients on NSAIDs with previous peptic ulcer or ulcer complications, age (>60 years) or combined therapy with anti-platelet agents, anticoagulants, glucocorticosteroids and SSRI should be considered as patients at increased risk for the development of a gastroduodenal bleeding.

3. Strategies for Preventing Gastroduodenal Bleeding in Patients on NSAIDs

The first option for reducing GI toxicity of NSAIDs is to avoid medications that increase the risk of NSAID-induced gastroduodenal bleeding. Therefore, wherever possible the intake of drugs like anticoagulants, glucocorticosteroids and SSRI should be avoided. Moreover, a single NSAID should be prescribed using the lowest effective dose. The use of proton pump inhibitors (PPI) has been shown to significantly reduce endoscopic (RR 0.37, 95% CI 0.3–0.5) and symptomatic ulcers (RR 0.09, 95% CI 0.02–0.47) in patients on NSAIDs [27], and is therefore likely to be effective for primary prevention of NSAID-induced ulcer bleeding in patients with risk factors. There is no evidence for the superiority of one PPI over another or for high-dose of PPI over low-dose for preventing NSAID-induced gastroduodenal bleeding [28]. Therefore, a standard once-daily dosage of the cheapest PPI should be prescribed.
Switching to a COXib represents another option for reducing the risk of a gastroduodenal bleeding in patients on NSAIDs. Indeed the use of COXibs including the newest Lumiracoxib™ and Etoricoxib™ decreased the risk for serious gastrointestinal complications when compared with non-selective NSAIDs by 8 cases for every 1,000 patients treated with COXibs [8,17,27,29].
However, the 6-month rate of relapse for patients with previous gastroduodenal bleeding is still high, even if the patients take non-selective NSAIDs plus PPI or a COXib [30,31]. In a randomized controlled trial the combination of both strategies (COXib plus PPI) was evaluated [32]. Patients, taking NSAIDs for arthritis and admitted to the hospital due to acute gastroduodenal bleeding, were randomized to receive either Celecoxib™ 200 mg twice/day with Esomeprazole™ 20 mg twice/day or Celecoxib™ 200 mg twice/day with placebo. The combination treatment was found to be more effective than Celecoxib™ alone for prevention of ulcer bleeding in patients at high risk (13-month cumulative incidence of recurrent gastroduodenal bleeding was 0% in the combined-treatment group and 8.9% in the controls (95% CI: 4.1 to 13.7; p = 0.0004). Therefore, the combination of a COXib plus a PPI appears to be the safest option in patients at highest risk for developing a gastroduodenal bleeding. However, in very high-risk patients, if possible NSAIDs should be avoided altogether.

4. NSAIDs Therapy: Balancing Gastrointestinal and Cardiovascular Risk

The use of COXibs or traditional NSAIDs, with the possible exception of naproxen, has been associated with an increased risk of serious cardiovascular events [33,34,35,36,37,38]. As a consequence, in April 2005, the US Food and Drug Administration (FDA) mandated that all NSAIDs should include a “black box” warning to highlight the potential increase in the risk of serious cardiovascular thrombotic events, along with the warning about potentially life-threatening gastrointestinal bleedings [available at http://www.fda.gov/cder/drug/ infopage/cox2/default.htm]. This means that before prescribing a NSAID, a multitude of gastrointestinal and cardiovascular factors needs to be considered. In a recent international workshop on gastrointestinal and cardiovascular effects of NSAIDs, clinical recommendations were generated by a panel of 19 experts for safer NSAID-treatment of patients with different levels of gastrointestinal and cardiovascular risks [39]. High gastrointestinal risk was defined as age ≥70 year, a positive history of a former upper gastrointestinal event (e.g. bleeding, ulcer) and/or the concomitant use of low-dose aspirin, glucocorticosteroids or anticoagulants. High cardiovascular risk was defined as established coronary artery disease, any cardiovascular disease that required prophylactic low-dose aspirin, or an estimated 10-year cardiovascular risk greater than 20%. The panel of experts recommended that patients with high cardiovascular risk requiring NSAIDs should be prescribed naproxen, whereas in high risk patients for both gastrointestinal and cardiovascular complications, NSAIDs should be avoided (Table 3).
Table
Table 3. Algorithm for NSAID prescription based on gastrointestinal and cardiovascular risk factors.
Table 3. Algorithm for NSAID prescription based on gastrointestinal and cardiovascular risk factors.
Low-risk for GI complicationsHigh-risk for GI complications
Low-risk for CV eventsnon-selective NSAIDsnon-selective NSAIDs + PPI or COXibs + PPI
High-risk for CV events/ ASA medicationnaproxen + PPIavoid NSAIDs
naproxen + PPI
GI: gastrointestinal, CV: cardiovascular, ASA: low-dose aspirin

5. Prevention of Gastroduodenal Bleeding in Patients on Double Antiplatelet Therapy

Current guidelines recommend a double antiplatelet therapy with low-dose aspirin plus Clopidogrel™ for ≥1 month after implantation of a bare metal coronary artery stent, ≥1 year after a drug-eluting stent, ≥1 month and 1 year after unstable angina or non-ST-elevation myocardial infarction managed without intervention, and 1 year after ST-elevation myocardial infarction [40,41,42]. In particular, the double antiplatelet therapy after implantation of a coronary artery stent has a crucial role in preventing a stent-thrombosis, an event associated with mortality rates of 20–45% [43]. The combined intake of low-dose aspirin and Clopidogrel™ is associated with an increased risk of gastroduodenal bleeding, with a number-needed-to-harm of 124 patients [26]. Therefore, the prescription of PPI in these patients has been recommended by the ACCF/ACG/AHA Expert Consensus Document [44]. Indeed, a gastroduodenal bleeding in these patients would have the clinical consequence of discontinuing at least the Clopidogrel™ therapy which in turn would increase the risk of a stent thrombosis. However, observational studies have shown that the use of PPI in patients taking Clopidogrel™ is associated with a small but statistically significant increased risk of re-admission or death for acute coronary syndrome (highest OR 1.40, CI 95% 1.10–1.77) [45,46,47]. As both Clopidogrel and PPIs are converted to their active metabolites by cytochrome P450 (CYP2C19) it has been hypothesized that the intake of PPIs might interfere with the activation of Clopidogrel™. As a consequence, the regulatory authorities FDA and EMEA have issued recommendations, discouraging concomitant use of PPI and Clopidogrel™-containing medicines (available online: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190784.htm and http://www.emea.europa.eu/humandocs/PDFs/EPAR/Plavix/32895609en.pdf]. However, two prospective randomized controlled studies did not confirm a negative influence of PPI use on the clinical efficacy of Clopidogrel™ [48,49]. Thus, the current clinical evidence does not support the conclusion that PPIs increase the risk of cardiovascular events in all patients on Clopidogrel™. Moreover, ex-vivo pharmacodynamic studies using the platelet reactivity index (PRI) or the ADP-induced platelet aggregation as surrogate markers for the levels of platelet aggregation reported a reduced effect of Clopidogrel™ in patients on Omeprazole™, but not in patients taking other PPIs [50,51,52].
According to the current evidence and international expert recommendations, PPIs (i.e., Omeprazole™) with the highest potential of interaction with Clopidogrel™ should be avoided in patients on Clopidogrel™ therapy. Furthermore, as both medications have very short half-lives, it may be appropriate to give one drug in the morning and the other in the evening to prevent possible interactions [53,54,55].

6. The Role of H. pylori Infection in NSAID-Induced Gastroduodenal Bleeding

H. pylori and NSAIDs are the most important risk factors in the pathogenesis of peptic ulcers and ulcer bleeding [56]. A meta-analysis of observational studies showed that the risk of developing gastroduodenal ulcer bleeding in H. pylori-infected patients on NSAIDs was 6.13, which was almost the sum of the two individual ORs estimated for H. pylori infection and NSAID use alone [57]. In a meta-analysis on the efficacy of H. pylori eradication in NSAID users has been shown that eradication therapy is beneficial for primary prevention of gastroduodenal ulcers (OR 0.26, 95% CI: 0.14–0.49), but does not reduce the risk of a gastroduodenal ulcer/ulcer bleeding relapse (OR 0.95, 95% CI: 0.53–1.72) in patients on NSAIDs [58]. A possible explanation for this phenomenon comes from the HELP NSAIDs study, in which the type of lesions having affected the patients over the previous 5 years was the most important determinant of the site of ulcer recurrence, irrespective of whether H. pylori was eradicated or not. This suggests that once a substantial mucosal injury has occurred, local mucosal factors are determinants for relapse, and the H. pylori status becomes less relevant [59].
However this may not be true when low-dose aspirin intake is considered. In a study by Chan et al.,250 H. pylori-positive subjects on low-dose aspirin with upper gastrointestinal bleeding were randomly assigned to administration of 20 mg Omeprazole™ daily for six months or one week of eradication therapy [60]. No significant differences were found between eradication therapy for H. pylori infection and maintenance treatment with Omeprazole™ for preventing recurrent bleeding in patients on low-dose aspirin. Indeed, only three patients had recurrent bleeding: two had been assigned to eradication therapy, and one to Omeprazole™. Noteworthy, one of the two patients who had recurrent bleeding after the eradication of H. pylori, took a concomitant NSAID for musculoskeletal pain. Thus, although the study was grossly underpowered for any definitive conclusion, both strategies appear to be effective for secondary prevention of low-dose aspirin induced ulcer bleeding, provided that other risk factors like concomitant NSAID intake are excluded. One likely explanation for the different effect of H. pylori eradication on ulcer relapse in NSAID users and low-dose aspirin users is that low-dose aspirin may not be as ulcerogenic as NSAIDs and induces bleeding mostly in pre-existing H. pylori-related ulcers. Thus, healing peptic ulcers by H. pylori eradication might be a potential option to reduce the risk of bleeding relapse in patients on long-term low-dose aspirin intake. However, currently available data are insufficient to answer this question. Therefore, a trial with a similar study design and a placebo arm is needed for definitive conclusions on this issue. No studies evaluating H. pylori eradication for primary prevention of low-dose aspirin-induced gastroduodenal ulcer bleeding are available. Taking in consideration the high mortality carried by a coronary artery stent thrombosis and the beneficial effect of H. pylori eradication on recurrent ulcer bleeding in patients on low-dose aspirin we suggest to test and treat for H. pylori infection all patients receiving combined therapy with low-dose aspirin and Clopidogrel™ after implantation of a coronary artery stent. Whether this option may represent a good alternative to PPI co-medication for preventing gastroduodenal bleeding in patients on double antiplatelet therapy still needs to be analyzed in a prospective randomized controlled trial.

7. Conclusions

A multitude of gastrointestinal and cardiovascular risk factors should be considered before prescribing NSAIDs including low-dose aspirin. H. pylori test and treat strategy should be performed before starting a long-term NSAID-therapy. Whether this strategy is cost-effective, depends on the prevalence of H. pylori infection in the different countries, the efficacy of treatment available regimens and demographics. Prevention strategies for patients at high risk for gastrointestinal complications include the use of the lowest effective dose of NSAIDs, co-therapy with PPIs and/or the singular use of a COXib. For patients with cardiovascular risk factors requiring NSAIDs, naproxen should be selected. In patients on combined therapy with low-dose aspirin and Clopidogrel™ at increased risk for gastroduodenal bleeding, PPIs such as Omeprazole™ with the highest potential of interaction with Clopidogrel™ should be avoided and medications should be given with a separation of 12–15 hours (i.e., PPI before breakfast and Clopidogrel™ at bedtime) to reduce possible interactions. H. pylori test and treat strategy may be beneficial for preventing gastroduodenal bleeding and its dangerous consequences in patients on double antiplatelet therapy after implantation of a coronary artery stent.

References

  1. Kaufman, D.W.; Kelly, J.P.; Rosenberg, L.; Anderson, T.E.; Mitchell, A.A. Recent patterns of medication use in the ambulatory adult population of the United States, the Slone survey. JAMA 2002, 287, 337–344. [Google Scholar]
  2. Halter, F.; Tarnawski, A.S.; Schmassmann, A.; Peskar, B.M. Cyclooxygenase 2-implications on maintenance of gastric mucosal integrity and ulcer healing, controversial issues and perspectives. Gut 2001, 49, 443–453. [Google Scholar]
  3. Warner, T.D.; Mitchell, J.A. Cyclooxygenases, new forms, new inhibitors, and lessons from the clinic. FASEB J. 2004, 18, 790–804. [Google Scholar] [CrossRef] [PubMed]
  4. Weissmann, G. Aspirin. Sci. Am. 1991, 264, 84–90. [Google Scholar]
  5. Funk, C.D.; Funk, L.B.; Kennedy, M.E.; Pong, A.S.; Fitzgerald, G.A. Human platelet/erythroleukemia cell prostaglandin G/H synthase, cDNA cloning, expression, and gene chromosomal assignment. FASEB J. 1991, 5, 2304–2312. [Google Scholar] [PubMed]
  6. Hunt, R.H.; Bazzoli, F. Review article, should NSAID/low-dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing. Aliment. Pharmacol. Ther. 2004, 19, 9–16. [Google Scholar] [CrossRef] [PubMed]
  7. Hernandez-Diaz, S.; Rodriguez, L.A. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation, an overview of epidemiologic studies published in the 1990s. Arch. Int. Med. 2000, 160, 2093–2099. [Google Scholar]
  8. Moore, R.A.; Derry, S.; McQuay, H.J. Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk. BMC. Musculoskelet. Disord. 2007, 8, 73. [Google Scholar]
  9. Laine, L.; Harper, S.; Simon, T.; Bath, R.; Johanson, J.; Schwartz, H.; Stern, S.; Quan, H.; Bolognese, J. A randomized trial comparing the effect of rofecoxib, a COX-2 specific inhibitor, to ibuprofen on the gastroduodenal mucosa of osteoarthritis patients. Gastroenterology 1999, 117, 776–783. [Google Scholar] [CrossRef] [PubMed]
  10. Weil, J.; Colin-Jones, D.; Langman, M.; Lawson, D.; Logan, R.; Murphy, M.; Rawlins, M.; Vessey, M.; Wainwright, P. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 1995, 310, 827–830. [Google Scholar]
  11. McQuaid, K.R.; Laine, L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am. J. Med. 2006, 119, 624–638. [Google Scholar]
  12. Gabriel, S.E.; Jaakkimainen, L.; Bombardier, C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann. Intern. Med. 1991, 115, 787–796. [Google Scholar] [PubMed]
  13. García Rodríguez, L.A.; Hernández-Díaz, S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 2001, 12, 570–576. [Google Scholar]
  14. Singh, G.; Triadafilopoulos, G. Epidemiology of NSAID induced gastrointestinal complications. J. Rheumatol. 1999, 26, 18–24. [Google Scholar]
  15. Hernández-Díaz, S.; Rodríguez, L.A. Association between nonsteroidal anti-inflammatory drugs and uppergastrointestinal tract bleeding/perforation: an overview of epidemiologic studiespublished in the 1990s. Arch. Intern. Med. 2000, 160, 2093–2099. [Google Scholar]
  16. Sørensen, H.T.; Mellemkjaer, L.; Blot, W.J.; Nielsen, G.L.; Steffensen, F.H.; McLaughlin, J.K.; Olsen, J.H. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am. J. Gastroenterol. 2000, 95, 2218–2224. [Google Scholar]
  17. Schnitzer, T.J.; Burmester, G.R.; Mysler, E.; Hochberg, M.C.; Doherty, M.; Ehrsam, E.; Gitton, X.; Krammer, G.; Mellein, B.; Matchaba, P.; Gimona, A.; Hawkey, C.J. TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004, 364, 665–674. [Google Scholar] [PubMed]
  18. Weideman, R.; Kelly, K.C.; Kazi, S.; Cung, A.; Roberts, K.W.; Smith, H.J.; Sarosi, G.A.; Little, B.B.; Cryer, B. Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis. Gastroenterology 2004, 127, 1322–1328. [Google Scholar]
  19. Laine, L.; Maller, E.S.; Yu, C.; Quan, H.; Simon, T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology 2004, 127, 395–402. [Google Scholar]
  20. Lanas, A.; García-Rodríguez, L.A.; Arroyo, M.T.; Gomollón, F.; Feu, F.; González-Pérez, A.; Zapata, E.; Bástida, G.; Rodrigo, L.; Santolaria, S.; Güell, M.; de Argila, C.M.; Quintero, E.; Borda, F.; Piqué, J.M. Asociación Española de Gastroenterología. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut 2006, 55, 1731–1738. [Google Scholar] [PubMed]
  21. Dalton, S.O.; Johansen, C.; Mellemkjaer, L.; Nørgård, B.; Sørensen, H.T.; Olsen, J.H. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch. Intern. Med. 2003, 163, 59–64. [Google Scholar]
  22. Kojo, A.; Nukui, K.; Tanaka, A.; Amagase, K.; Takeuchi, K. Aggravation by Selective Serotonin Re-Uptake Inhibitor of Antral Ulcers Induced by Indomethacin in Rats: Pathogenic Importance of Impaired Anti-Oxidative System. DDW 2010. Abstract, T1142. [Google Scholar]
  23. Piper, J.M.; Ray, W.A.; Daugherty, J.R.; Griffin, M.R. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann. Intern. Med. 1991, 114, 735–740. [Google Scholar]
  24. Yokota, A.; Taniguchi, M.; Takahira, Y.; Tanaka, A.; Takeuchi, K. Dexamethasone damages the rat stomach but not small intestine during inhibition of COX-1. Dig. Dis. Sci. 2007, 52, 1452–1461. [Google Scholar] [PubMed]
  25. Bandyopadhyay, U.; Biswas, K.; Bandyopadhyay, D.; Ganguly, C.K.; Banerjee, R.K. Dexamethasone makes the gastric mucosa susceptible to ulceration by inhibiting prostaglandin synthetase and peroxidase--two important gastroprotective enzymes. Mol. Cell. Biochem. 1999, 202, 31–36. [Google Scholar]
  26. Hallas, J.; Dall, M.; Andries, A.; Andersen, B.S.; Aalykke, C.; Hansen, J.M.; Andersen, M.; Lassen, A.T. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006, 333, 726–730. [Google Scholar]
  27. Hooper, L.; Brown, T.J.; Elliott, R.; Payne, K.; Roberts, C.; Symmons, D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs, systematic review. BMJ 2004, 329, 948–957. [Google Scholar]
  28. Barkun, A.N.; Bardou, M.; Kuipers, E.J.; Sung, J.; Hunt, R.H.; Martel, M.; Sinclair, P. International Consensus Upper Gastrointestinal Bleeding Conference Group. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann. Intern. Med. 2010, 19, 101–113. [Google Scholar]
  29. Hunt, R.H.; Harper, S.; Callegari, P.; Yu, C.; Quan, H.; Evans, J.; James, C.; Bowen, B.; Rashid, F. Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib. Aliment. Pharmacol. Ther. 2003, 17, 201–210. [Google Scholar]
  30. Chan, F.K.; Hung, L.C.; Suen, B.Y.; Wu, J.C.; Lee, K.C.; Leung, V.K.; Hui, A.J.; To, K.F.; Leung, W.K.; Wong, V.W.; Chung, S.C.; Sung, J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding inpatients with arthritis. N. Engl. J. Med. 2002, 347, 2104–2110. [Google Scholar] [PubMed]
  31. Lai, K.C.; Chu, K.M.; Hui, W.M.; Wong, B.C.; Hu, W.H.; Wong, W.M.; Chan, A.O.; Wong, J.; Lam, S.K. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am. J. Med. 2005, 118, 1271–1278. [Google Scholar]
  32. Chan, F.K.; Wong, V.W.; Suen, B.Y.; Wu, J.C.; Ching, J.Y.; Hung, L.C.; Hui, A.J.; Leung, V.K.; Lee, V.W.; Lai, L.H.; Wong, G.L.; Chow, D.K.; To, K.F.; Leung, W.K.; Chiu, P.W.; Lee, Y.T.; Lau, J.Y.; Chan, H.L.; Ng, E.K.; Sung, J.J. 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, 1621–1626. [Google Scholar] [PubMed]
  33. Bresalier, R.S.; Sandler, R.S.; Quan, H.; Bolognese, J.A.; Oxenius, B.; Horgan, K.; Lines, C.; Riddell, R.; Morton, D.; Lanas, A.; Konstam, M.A.; Baron, J.A. Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 2005, 352, 1092–1102. [Google Scholar] [PubMed]
  34. Solomon, S.D.; McMurray, J.J.; Pfeffer, M.A.; Wittes, J.; Fowler, R.; Finn, P.; Anderson, W.F.; Zauber, A.; Hawk, E.; Bertagnolli, M. Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 2005, 352, 1071–1080. [Google Scholar] [PubMed]
  35. Hippisley-Cox, J.; Coupland, C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs; population based nested case-control analysis. BMJ 2005, 330, 1366–1372. [Google Scholar] [CrossRef] [PubMed]
  36. Ray, W.A.; Stein, C.M.; Hall, K.; Daugherty, J.R.; Griffin, M.R. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease, an observational cohort study. Lancet 2002, 359, 118–123. [Google Scholar]
  37. Chan, A.T.; Manson, J.E.; Albert, C.M.; Chae, C.U.; Rexrode, K.M.; Curhanm, G.C.; Rimm, E.B.; Willett, W.C.; Fuchs, C.S. Nonsteroidal anti-inflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006, 113, 1578–1587. [Google Scholar] [PubMed]
  38. Kearney, P.M.; Baigent, C.; Godwin, J.; Halls, H.; Emberson, J.R.; Patrono, C. Do selective cyclooxygenase- 2 inhibitors and nonselective non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006, 332, 1302–1308. [Google Scholar]
  39. Chan, F.K.; Abraham, N.S.; Scheiman, J.M.; Laine, L. First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. Management of patients on nonsteroidal anti-inflammatory drugs; a clinical practice recommendation from the First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. Am. J. Gastroenterol. 2008, 103, 2908–2918. [Google Scholar] [PubMed]
  40. Anderson, J.L.; Adams, C.D.; Antman, E.M.; Bridges, C.R.; Califf, R.M.; Casey, D.E., Jr.; Chavey, W.E., 2nd; Fesmire, F.M.; Hochman, J.S.; Levin, T.N.; Lincoff, A.M.; Peterson, E.D.; Theroux, P.; Wenger, N.K.; Wright, R.S.; Smith, S.C., Jr.; Jacobs, A.K.; Halperin, J.L.; Hunt, S.A.; Krumholz, H.M.; Kushner, F.G.; Lytle, B.W.; Nishimura, R.; Ornato, J.P.; Page, R.L.; Riegel, B. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. Circulation 2007, 116, e138–304. [Google Scholar]
  41. King, S.B.; Smith, S.C.; Hirshfeld, J.W.; Jacobs, A.K.; Morrison, D.A.; Williams, D.O.; Feldman, T.E.; Kern, M.J.; O'Neill, W.W.; Schaff, H.V.; Whitlow, P.L.; Adams, C.D.; Anderson, J.L.; Buller, C.E.; Creager, M.A.; Ettinger, S.M.; Halperin, J.L.; Hunt, S.A.; Krumholz, H.M.; Kushner, F.G.; Lytle, B.W.; Nishimura, R.; Page, R.L.; Riegel, B.; Tarkington, L.G.; Yancy, C.W. 2005 WRITING COMMITTEE MEMBERS. 2007 focused update of the ACC/ AHA/SCAI 2005 guideline update for percutaneous coronary intervention. Circulation 2008, 117, 261–295. [Google Scholar] [PubMed]
  42. Antman, E.M.; Hand, M.; Armstrong, P.W.; Bates, E.R.; Green, L.A.; Halasyamani, L.K.; Hochman, J.S.; Krumholz, H.M.; Lamas, G.A.; Mullany, C.J.; Pearle, D.L.; Sloan, M.A.; Smith, S.C., Jr.; Anbe, D.T.; Kushner, F.G.; Ornato, J.P.; Jacobs, A.K.; Adams, C.D.; Anderson, J.L.; Buller, C.E.; Creager, M.A.; Ettinger, S.M.; Halperin, J.L.; Hunt, S.A.; Lytle, B.W.; Nishimura, R.; Page, R.L.; Riegel, B.; Tarkington, L.G.; Yancy, C.W. 2004 Writing Committee Members. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction. Circulation 2007, 117, 296–329. [Google Scholar] [PubMed]
  43. Grines, C.L.; Bonow, R.O.; Casey, D.E., Jr.; Gardner, T.J.; Lockhart, P.B.; Moliterno, D.J.; O'Gara, P.; Whitlow, P. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents. Circulation 2007, 115, 813–818. [Google Scholar]
  44. Bhatt, D.L.; Scheiman, J.; Abraham, N.S.; Antman, E.M.; Chan, F.K.; Furberg, C.D.; Johnson, D.A.; Mahaffey, K.W.; Quigley, E.M.; Harrington, R.A.; Bates, E.R.; Bridges, C.R.; Eisenberg, M.J.; Ferrari, V.A.; Hlatky, M.A.; Kaul, S.; Lindner, J.R.; Moliterno, D.J.; Mukherjee, D.; Schofield, R.S.; Rosenson, R.S.; Stein, J.H.; Weitz, H.H.; Wesley, D.J. American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. 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, 52, 1502–1517. [Google Scholar] [PubMed]
  45. Ho, P.M.; Maddox, T.M.; Wang, L.; Fihn, S.D.; Jesse, R.L.; Peterson, E.D.; Rumsfeld, J.S. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009, 301, 937–944. [Google Scholar]
  46. Juurlink, D.N.; Gomes, T.; Ko, D.T.; Szmitko, P.E.; Austin, P.C.; Tu, J.V.; Henry, D.A.; Kopp, A.; Mamdani, M.M. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009, 180, 713–718. [Google Scholar] [PubMed]
  47. Rassen, J.A.; Choudhry, N.K.; Avorn, J.; Schneeweiss, S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009, 120, 2322–2329. [Google Scholar]
  48. O'Donoghue, M.L.; Braunwald, E.; Antman, E.M.; Murphy, S.A.; Bates, E.R.; Rozenman, Y.; Michelson, A.D.; Hautvast, R.W.; Ver Lee, P.N.; Close, S.L.; Shen, L.; Mega, J.L.; Sabatine, M.S.; Wiviott, S.D. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor, an analysis of two randomised trials. Lancet 2009, 374, 989–997. [Google Scholar]
  49. Bhatt, D.L.; Cryer, B.; Contant, C.F.; Cohen, M.; Lanas, A.; Schnitzer, T.J.; Shook, T.L.; Lapuerta, P.; Goldsmith, M.A.; Scirica, B.M.; Giugliano, R.P.; Cannon, C.P. COGENT Investigators. A prospective, randomized, placebo-controlled trial of omeprazole in patients receiving aspirin and clopidogrel. In Presented at Transcatheter Cardiovascular Therapeutics, San Francisco, CA, 24 September 2009.
  50. Gilard, M.; Arnaud, B.; Cornily, J.C.; Le Gal, G.; Lacut, K.; Le Calvez, G.; Mansourati, J.; Mottier, D.; Abgrall, J.F.; Boschat, J. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin, the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J. Am. Coll. Cardiol. 2008, 51, 256–260. [Google Scholar] [PubMed]
  51. Siller-Matula, J.M.; Spiel, A.O.; Lang, I.M.; Kreiner, G.; Christ, G.; Jilma, B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am. Heart. J. 2009, 157, 148.e1–5. [Google Scholar]
  52. Small, D.S.; Farid, N.A.; Payne, C.D.; Weerakkody, G.J.; Li, Y.G.; Brandt, J.T.; Salazar, D.E.; Winters, K.J. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J.Clin. Pharmacol. 2008, 48, 475–484. [Google Scholar]
  53. Rude, M.K.; Chey, W.D. Proton-pump inhibitors, clopidogrel, and cardiovascular adverse events, fact, fiction, or something in between? Gastroenterology 2009, 137, 1168–1171. [Google Scholar] [PubMed]
  54. Chow, C.K.; Moayyedi, P.; Devereaux, P.J. Is it safe to use a proton pump inhibitor with clopidogrel? Pol. Arch. Med. Wewn. 2009, 119, 564–568. [Google Scholar] [PubMed]
  55. Laine, L.; Hennekens, C. Proton Pump Inhibitor and Clopidogrel Interaction, Fact or Fiction? Am. J. Gastroenterol. 2009, 105, 34–41. [Google Scholar] [PubMed]
  56. Malfertheiner, P.; Chan, F.K.; McColl, K.E. Peptic ulcer disease. Lancet 2009, 374, 1449–1461. [Google Scholar]
  57. Huang, J.Q.; Sridhar, S.; Hunt, R.H. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease, a meta-analysis. Lancet 2002, 359, 14–22. [Google Scholar]
  58. Vergara, M.; Catalán, M.; Gisbert, J.P.; Calvet, X. Meta-analysis, role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users. Aliment. Pharmacol. Ther. 2005, 21, 1411–1418. [Google Scholar]
  59. Hawkey, C.J.; Tulassay, Z.; Szczepanski, L.; van Rensburg, C.J.; Filipowicz-Sosnowska, A.; Lanas, A.; Wason, C.M.; Peacock, R.A.; Gillon, K.R. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Helicobacter Eradication for Lesion Prevention. Lancet 1998, 352, 1016–1021. [Google Scholar] [PubMed]
  60. Chan, F.K.; Chung, S.C.; Suen, B.Y.; Lee, Y.T.; Leung, W.K.; Leung, V.K.; Wu, J.C.; Lau, J.Y.; Hui, Y.; Lai, M.S.; Chan, H.L.; Sung, J.J. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. New Engl. J. Med. 2001, 344, 967–973. [Google Scholar]

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MDPI and ACS Style

Venerito, M.; Wex, T.; Malfertheiner, P. Nonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Bleeding: Risk Factors and Prevention Strategies. Pharmaceuticals 2010, 3, 2225-2237. https://doi.org/10.3390/ph3072225

AMA Style

Venerito M, Wex T, Malfertheiner P. Nonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Bleeding: Risk Factors and Prevention Strategies. Pharmaceuticals. 2010; 3(7):2225-2237. https://doi.org/10.3390/ph3072225

Chicago/Turabian Style

Venerito, Marino, Thomas Wex, and Peter Malfertheiner. 2010. "Nonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Bleeding: Risk Factors and Prevention Strategies" Pharmaceuticals 3, no. 7: 2225-2237. https://doi.org/10.3390/ph3072225

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