Risk of upper gastrointestinal ulcer bleeding associated with selective COX-2 inhibitors, traditional non-aspirin NSAIDs, aspirin, and combinations

Hospital Universitario Ramón y Cajal, Madrid, Madrid, Spain
Gut (Impact Factor: 14.66). 01/2007; 55(12):1731-8. DOI: 10.1136/gut.2005.080754
Source: PubMed


The risks and benefits of coxibs, non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin treatment are under intense debate.
To determine the risk of peptic ulcer upper gastrointestinal bleeding (UGIB) associated with the use of coxibs, traditional NSAIDs, aspirin or combinations of these drugs in clinical practice.
A hospital-based, case-control study in the general community of patients from the National Health System in Spain. The study included 2777 consecutive patients with endoscopy-proved major UGIB because of the peptic lesions and 5532 controls matched by age, hospital and month of admission. Adjusted relative risk (adj RR) of UGIB determined by conditional logistic regression analysis is provided.
Use of non-aspirin-NSAIDs increased the risk of UGIB (adj RR 5.3; 95% confidence interval (CI) 4.5 to 6.2). Among non-aspirin-NSAIDs, aceclofenac (adj RR 3.1; 95% CI 2.3 to 4.2) had the lowest RR, whereas ketorolac (adj RR 14.4; 95% CI 5.2 to 39.9) had the highest. Rofecoxib treatment increased the risk of UGIB (adj RR 2.1; 95% CI 1.1 to 4.0), whereas celecoxib, paracetamol or concomitant use of a proton pump inhibitor with an NSAID presented no increased risk. Non-aspirin antiplatelet treatment (clopidogrel/ticlopidine) had a similar risk of UGIB (adj RR 2.8; 95% CI 1.9 to 4.2) to cardioprotective aspirin at a dose of 100 mg/day (adj RR 2.7; 95% CI 2.0 to 3.6) or anticoagulants (adj RR 2.8; 95% CI 2.1 to 3.7). An apparent interaction was found between low-dose aspirin and use of non-aspirin-NSAIDs, coxibs or thienopyridines, which increased further the risk of UGIB in a similar way.
Coxib use presents a lower RR of UGIB than non-selective NSAIDs. However, when combined with low-dose aspirin, the differences between non-selective NSAIDs and coxibs tend to disappear. Treatment with either non-aspirin antiplatelet or cardioprotective aspirin has a similar risk of UGIB.

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    • "The clinical use of NSAIDs is associated with the occurrence of adverse effects in the upper digestive tract, such as gastric erosions, ulceration, bleeding, and perforation (Lanas et al., 2006; Scarpignato and Hunt, 2010). It is widely recognized that the detrimental effects exerted by NSAIDs on gastroduodenal mucosa depend on the blockade of cyclooxygenase (COX) isoenzymes (COX-1 and COX-2) and subsequent decrease in mucosal prostaglandin production (Musumba et al., 2009). "
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    ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAID-activated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase-3 expression; 2) ulcer area; and 3) prostaglandin E(2) (PGE(2)) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE(2) levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing.
    Full-text · Article · Apr 2012 · Journal of Pharmacology and Experimental Therapeutics
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    • "Observational studies have reported the relative risks of upper GI bleeding associated with ASA above 500 mg/day to be similar to those of other NSAIDs, but information on dose, duration of treatment, type of use, and indication is often limited or absent. Observational studies often do not differentiate between chronic and acute OTC ASA use or they do not capture OTC use at all, severely limiting the interpretation of the data.[7–9] Moreover, data regarding more frequent GI side effects associated with NSAID use such as dyspepsia are rarely reported in the literature.[10] "
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    ABSTRACT: Acetylsalicylic acid (ASA [aspirin]) is a commonly used over-the-counter drug for the treatment of pain, fever, or colds, but data on the safety of this use are very limited. The aim of this study was to provide data on the safety of this treatment pattern, which is of interest to clinicians, regulators, and the public. A meta-analysis of individual patient data from 67 studies sponsored by Bayer HealthCare was completed. The primary endpoints were patient-reported gastrointestinal (GI) adverse events (AEs); the secondary endpoints were the incidence of patient-reported non-GI AEs. Event incidence and odds ratios (ORs) based on Cochran-Mantel-Haenszel estimates are reported. In total, 6181 patients were treated with ASA, 3515 with placebo, 1145 with acetaminophen (paracetamol), and 754 with ibuprofen. Exposure to ASA was short term (82.5% of patients had a single dose). GI AEs were more frequent with ASA (9.9%) than with placebo (9.0%).[OR 1.3; 95% CI 1.1, 1.5]. Dyspeptic symptoms were infrequent (4.6% in placebo subjects). The ORs for ASA were 1.3 (95% CI 1.1, 1.6) versus placebo; 1.55 (95% CI 0.7, 3.3) versus ibuprofen; and 1.04 (95% CI 0.8, 1.4) versus acetaminophen. There were very few serious GI AEs (one ASA case; three placebo cases). No differences were found for non-GI AEs and no cases of cerebral hemorrhage were reported. Short-term, mostly single-dose exposure to ASA for the treatment of pain, fever, or colds was associated with a small but significant increase in the risk of dyspepsia relative to placebo. No serious GI complications were reported.
    Full-text · Article · Sep 2011
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    • "Patients receiving low-dose ASA who develop upper GI bleeding are often advised to discontinue ASA until ulcers have healed (Bhatt et al., 2008). There is no evidence that non-ASA antiplatelet drugs such as clopidogrel will reduce this bleeding risk in the presence of active ulcers (Lanas et al., 2006). "
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    ABSTRACT: The aim of this review is to provide evidence-based recommendations on the secondary prevention of atherothrombotic ischemic stroke. Antiplatelets are the major therapy for the secondary stroke prevention. The most commonly used antiplatelets agents are aspirin, clopidogrel, and extended-release dipyridamole. A lot of progress had been made in last years regarding aspirin resistance and genotyping of clopidogrel metabolism. According to the results of the accomplished studies it is difficult to broadly recommend one antithrombotic agent in favor of the other. Instead, a review of the currently published data suggests the importance of focusing on the individualizing approach in antiplatelet therapy.
    Full-text · Article · Jul 2011 · Frontiers in Neurology
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