Supplementary Figure 2 Explanation of sensitivity analysis with observation time truncated at the time of the event. Observed IRRs of drug monotherapy for the main analysis in SCCS and sensitivity analysis. A key assumption of the SCCS is that the exposure distribution within the observation period and the observation period itself must be independent of prior event times. This could have been violated for some subjects, because use of an nsNSAID without gastroprotection is relatively contraindicated after UGIB. By truncating follow-up at the time of UGIB, we observed that the IRRs changed in magnitude for some drugs. We used a change of 10% of the initial estimate as an arbitrary cutoff to quantify the magnitude of the change.
The estimates were higher for monotherapy of corticosteroids, SSRIs, GPAs, aldosterone antagonists, antiplatelets, and nitrates and lower for nsNSAIDs and low-dose aspirin in the analysis with truncation of follow-up time at the event. The estimates did not change by more than 10% of the initial estimate only for COX-2 inhibitor monotherapy. These analyses indicate that the exposure of, for instance, nsNSAIDs did not change significantly after the event but show the relative contraindication of nsNSAIDs after UGIB, because the IRR in the initial analysis was higher than that in sensitivity analyses ( Supplementary Figure 1).
However, these analyses show that confounding by contraindication is unlikely. We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects).
Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB.
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We measured relative risk (incidence rate ratio IRR during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction RERI). Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. Upper gastrointestinal bleeding (UGIB) has a major impact on patients’ quality of life and public health care costs.
X 1 Rahme, E., Barkun, A.N., Adam, V. Treatment costs to prevent or treat upper gastrointestinal adverse events associated with NSAIDs. 2004; 27: 1019–1042 Although great improvements in prevention and treatment of UGIB have been achieved in recent decades, UGIB-related morbidity and mortality remain substantial. X 2 Lanas, A., Garcia-Rodriguez, L.A., Polo-Tomas, M. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice.
Am J Gastroenterol. 2009; 104: 1633–1641 Most previous studies have focused on risks associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs), which is one of the most common causes of UGIB. Clinical guidelines therefore recommend preventive strategies for at-risk patients treated with NSAIDs, including coprescription of proton pump inhibitors.
Another preventive strategy is use of cyclooxygenase-2 selective inhibitors (COX-2 inhibitors), developed as a safer alternative to nonselective (ns)NSAIDs, especially among high-risk patients. X 3 Bombardier, C., Laine, L., Reicin, A.
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000; 343: 1520–1528 Use of low-dose aspirin is considered the standard of care for cardiovascular prevention. However, low-dose aspirin is also known to increase the risk of UGIB. X 4 Lanas, A., Garcia-Rodriguez, L.A., Arroyo, M.T. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations.
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2006; 55: 1731–1738 The relative risk of UGIB associated with current use of low-dose aspirin compared with no use ranges from 1.6 to 4.0. X 4 Lanas, A., Garcia-Rodriguez, L.A., Arroyo, M.T. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations.
2006; 55: 1731–1738 , x 5 Garcia Rodriguez, L.A., Lin, K.J., Hernandez-Diaz, S. Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. 2011; 123: 1108–1115 , x 6 Lanas, A., Bajador, E., Serrano, P.
Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med.
2000; 343: 834–839 Thus, coprescription of gastroprotective agents (GPAs) is also recommended for at-risk patients treated with low-dose aspirin as a key strategy to minimize upper gastrointestinal events. X 7 Lanas, A.
And Scheiman, J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment. Curr Med Res Opin. 2007; 23: 163–173 Adherence to preventive strategies in patients treated with low-dose aspirin is especially important given that an estimated 20% of these patients will also use NSAIDs and approximately 35% of the elderly population regularly uses low-dose aspirin.
X 7 Lanas, A. And Scheiman, J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment.
Curr Med Res Opin. 2007; 23: 163–173 Clinical guidelines suggest avoiding use of certain drugs in combination with nsNSAIDs as well as COX-2 inhibitors; these drugs include corticosteroids, anticoagulants, selective serotonin reuptake inhibitors (SSRIs), and antiplatelets. X 8 Lanza, F.L., Chan, F.K., and Quigley, E.M. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009; 104: 728–738 However, the concurrent use of NSAIDs and these other drugs has not been widely studied, and it remains unknown if, and to what extent, combinations of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with specific other drug groups exert synergistic effects on the risk of UGIB.
Understanding drug synergism is important in developing strategies to minimize the risk of UGIB, particularly in elderly patients who are at high risk for UGIB and are likely to use multiple drugs. X 9 Vogiagis, D., Glare, E.M., Misajon, A. Cyclooxygenase-1 and an alternatively spliced mRNA in the rat stomach: effects of aging and ulcers. Am J Physiol Gastrointest Liver Physiol. 2000; 278: G820–G827 , x 10 Cryer, G., Lee, E., and Feldman, M.
Factors influencing gastroduodenal mucosal prostaglandin concentrations: roles of smoking and aging. Ann Intern Med. 1992; 116: 636–640 Therefore, we aimed to estimate the magnitude of interaction between nsNSAIDs, COX-2 inhibitors, or low-dose aspirin and specific drug groups reported to affect the risk of diagnosed UGIB.
Data were obtained from a network of 7 electronic health record (EHR) databases from 3 countries. The EU-ADR Project (Exploring and Understanding Adverse Drug Reactions by integrative mining of clinical records and biomedical knowledge) has successfully established a platform that integrates data from various repositories of European EHRs for evaluation of drug safety. X 11 Coloma, P.M., Schuemie, M.J., Trifiro, G. Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project. Pharmacoepidemiol Drug Saf.
2011; 20: 1–11 We analyzed data from 3 primary care databases (Integrated Primary Care Information IPCI, The Netherlands; Health Search/CSD Longitudinal Patient Database HSD, Italy; and Pedianet Italy) and 4 administrative/claims databases (Aarhus University Hospital Database Aarhus, Denmark, PHARMO Institute PHARMO, The Netherlands, and the regional databases of Lombardy UNIMIB, Italy and Tuscany ARS, Italy). The characteristics and study periods of the databases are shown in Table 1.
All of these databases have been extensively used in epidemiological studies. X 11 Coloma, P.M., Schuemie, M.J., Trifiro, G. Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project. Pharmacoepidemiol Drug Saf. 2011; 20: 1–11 , x 12 Herings, R. And Klungel, O. An epidemiological approach to assess the economic burden of NSAID-induced Gastrointestinal Events in the Netherlands.
2001; 19: 655–665 , x 13 Verhamme, K., Mosis, G., Dieleman, J. Spironolactone and risk of upper gastrointestinal events: population based case-control study. 2006; 333: 330 , x 14 Sorensen, H.T., Mellemkjaer, L., Blot, W.J. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol.
2000; 95: 2218–2224 Subjects can enter and may also leave the database at any time for several reasons (eg, death, moving out of the region, leave of practice). The primary care databases capture all prescriptions from general practitioners and some from secondary care (eg, repeat prescriptions). The study protocol was approved by the review board for all databases. Table 1 Database Characteristics and Number of Cases of UGIB per Database Database (country) No. The study population included all people registered in the database network with at least 1 year of valid and continuous data. A self-controlled case series (SCCS) analysis was performed on all identified cases of UGIB. The SCCS is a case-only study (ie, control subjects are not included) in which the relative incidence of UGIB is estimated for exposed and nonexposed time in each case.
X 15 Whitaker, H.J., Farrington, C.P., Spiessens, B. Tutorial in biostatistics: the self-controlled case series method. 2006; 25: 1768–1797 , x 16 Whitaker, H.J., Hocine, M.N., and Farrington, C.P. The methodology of self-controlled case series studies. Stat Methods Med Res. 2009; 18: 7–26 Each case serves as its own control.
The SCCS method assumes that all cases in the analysis should (1) have exposed and unexposed person-time, (2) experience an UGIB, and (3) contribute follow-up time before and after the UGIB. The primary advantage of the SCCS is that it automatically adjusts for confounding factors that are fixed within subjects (ie, genetic factors, sex, chronic disease, or other comorbidity). From the study population, we identified all subjects who experienced an UGIB during follow-up by using pertinent disease codes from the different coding systems in each database. X 11 Coloma, P.M., Schuemie, M.J., Trifiro, G. Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: the EU-ADR Project.
Pharmacoepidemiol Drug Saf. 2011; 20: 1–11 UGIB was assessed by using hospital discharge codes (in claims databases) or general practitioner diagnosis/recordings (in primary care databases). We included all codes indicating gastroduodenal ulcers and hemorrhages, melena, and hematemesis.
Codes for variceal bleeding specifically were not included. We only included codes corresponding to an acute UGIB, because for the SCCS the outcome should be an acute event with a clear disease onset. Supplementary Table 1 shows the corresponding codes for each coding system. A free-text search of clinical narratives was performed in IPCI and HSD. A validation study was conducted in 4 of the databases used in the current study x 17 Valkhoff, V.E., Coloma, P.M., Masclee, G.M.
Validation study in four health-care databases: upper gastrointestinal bleeding misclassification affects precision but not magnitude of drug-related upper gastrointestinal bleeding risk. J Clin Epidemiol. 2014; 67: 921–931 and showed a high concordance for International Classification of Diseases (ICD)-9 (positive predictive value PPV of 78% and 72%) and ICD-10 codes (PPV of 77%) that was not seen with the International Classification for Primary Care coding system (PPV of 21% for codes and free text only). To estimate the relative incidence of UGIB, incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were obtained using conditional Poisson regression by comparing the incidence rate of UGIB during periods of drug exposure with the incidence rate during all other observed time periods. Age-adjusted IRRs were calculated within each database and by pooling all data together (IRRp). To account for heterogeneity between the databases, pooling of data was also performed by a random effects meta-analytic model on the database-specific risk estimates resulting in an overall IRR. To estimate the magnitude of drug interaction (excess risk), the following measures were calculated: the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S).
X 32 Rothman, K.J. Interactions between causes. Mod Epidemiol. 1986;: 311–326 Interaction on an additive scale meant that the observed effect of the drug combination was larger than the sum of the effects of the drugs separately but less than multiplicative.
If the IRR of the combination was more than the sum of the 2 drugs separately, interaction (at least on an additive scale) was present. Corresponding 95% CIs were also calculated for the RERI using the Hosmer–Lemeshow delta method. X 33 Hosmer, D.W. And Lemeshow, S. Confidence interval estimation of interaction. 1992; 3: 452–456 The estimated measure of the RERI, AP, or S itself does not provide any information on risk and cannot be interpreted in isolation. However, based on the relative risk, it can be concluded that an excess risk is present when the RERI is larger than 0 and the CIs around it do not cross 0.
Additionally, it may be concluded that there is more excess risk with a RERI of 1 than with a RERI of 2 (see Supplementary Table 3 for more details). Population attributable risk (PAR) was calculated to estimate the proportion of UGIB in the general population that is attributable to concomitant use of drugs using the following formula: x 12 Herings, R. And Klungel, O. An epidemiological approach to assess the economic burden of NSAID-induced Gastrointestinal Events in the Netherlands. 2001; 19: 655–665 For this calculation, drug utilization data from the participating databases (data not shown) were used to derive the prevalence of exposure (p) to which the IRR pertained.
In total, 114,835 patients with UGIB (cases) with corresponding follow-up of 930,888 person-years were included in the analysis ( Table 1). For all drugs of interest, monotherapy showed a significantly increased relative risk compared with no use of any of the drugs of interest. Monotherapy with nsNSAIDs was associated with an IRRp of 4.3 (95% CI, 4.1–4.4), which is higher than monotherapy with either COX-2 inhibitors (IRRp, 2.9; 95% CI, 2.7–3.2) or low-dose aspirin (IRRp, 3.1; 95% CI, 2.9–3.2) ( Table 2). The risk of diagnosed UGIB for all other drugs ranged from 1.6 for calcium channel blockers to 4.1 for corticosteroids ( Table 2). IRRs were also estimated for 3 individual SSRIs and yielded an IRRp of 2.0 (95% CI, 1.6–2.5) for fluoxetine, 2.3 (95% CI, 2.1–2.5) for citalopram, and 1.9 (95% CI, 1.7–2.2) for paroxetine, all similar to the IRRp for the overall SSRI class of 2.1 (95% CI, 1.9–2.2). Generally, concomitant use of nsNSAIDs with other drugs showed a higher risk of diagnosed UGIB compared with a combination with low-dose aspirin or COX-2 inhibitors ( Table 2).
To estimate the risk of diagnosed UGIB for drug combinations with nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, estimates of the separate drugs of interest were pooled. Combinations of any of the drugs of interest with nsNSAIDs yielded the highest IRR (6.9; 95% CI, 5.3–9.1), followed by combinations with low-dose aspirin (4.6; 95% CI, 3.6–6.0) and with COX-2 inhibitors (4.2; 95% CI, 3.0–5.9).
Looking at separate drug classes, the highest risk of diagnosed UGIB was observed for the combination of nsNSAIDs and corticosteroids (IRRp, 12.8; 95% CI, 11.2–14.7), which was higher than the risk with use of low-dose aspirin and corticosteroids (IRRp, 8.4; 95% CI, 7.1–9.8) or COX-2 inhibitors and corticosteroids (IRRp, 6.0; 95% CI, 4.3–8.3). Use of aldosterone antagonists with nsNSAIDs resulted in an IRRp of 11.0 (95% CI, 8.6–14.0), which was also higher than the combined use of aldosterone antagonists and low-dose aspirin (IRRp, 5.0; 95% CI, 4.1–6.1) or that with COX-2 inhibitors (IRRp, 4.0; 95% CI, 2.1–7.8). The combination of anticoagulants with nsNSAIDs showed an IRRp of 8.7 (95% CI, 7.3–10.4), which was higher than the combination of anticoagulants with low-dose aspirin (IRRp, 6.9; 95% CI, 5.9–8.2) or that with COX-2 inhibitors (IRRp, 5.0; 95% CI, 3.2–7.8). Combinations with SSRIs were associated with a 5-fold, 6-fold, and 7-fold increased risk for low-dose aspirin, COX-2 inhibitors, and nsNSAIDs, respectively. When using a meta-analytic approach by applying a random effects model, substantial heterogeneity across databases was observed for some drug combinations but generally resulted in minor attenuations of the effects ( Supplementary Table 6). Excess risk due to concomitant drug use, measured by additive interaction of nsNSAIDs/COX-2 inhibitors/low-dose aspirin use with other drugs, is shown in Figure 1 and Supplementary Table 3.
The highest excess risk was observed for the combination of nsNSAIDs and corticosteroids (RERI, 5.5; 95% CI, 3.7–7.3). Corticosteroids had significant interaction with low-dose aspirin as well, but not with COX-2 inhibitors. Aldosterone antagonists showed significant interaction with nsNSAIDs (RERI, 4.5; 95% CI, 1.8–7.1) but not with low-dose aspirin or COX-2 inhibitors. Anticoagulants showed significant interaction with nsNSAIDs and with low-dose aspirin but not with COX-2 inhibitors. Combinations of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with GPAs or nitrates did not show excess NSAID-associated risk of UGIB. Based on an estimated 0.04% prevalence of nsNSAID use, the proportion of cases of UGIB in the general population attributable to nsNSAID monotherapy was 11.8%.
In other words, of 100 people experiencing UGIB while exposed to nsNSAID monotherapy, 11.8% of these cases were attributable to nsNSAID monotherapy. The corresponding proportion attributable to corticosteroid monotherapy was 10.4% (estimated prevalence of corticosteroid use of 0.04%), while the PAR for concurrent NSAID and corticosteroid use was 6.4%. The PAR for other drugs is shown in Supplementary Table 7.
Age stratification showed that subjects who were 60 years of age or older had higher IRRs of diagnosed UGIB than younger subjects (younger than 60 years) except for the combination of nsNSAIDs and anticoagulants and of COX-2 inhibitors and corticosteroids. No significant difference in risk between male and female subjects was observed.
Sensitivity analyses with truncation of follow-up at the time of UGIB (to avoid confounding by contraindication) showed that the exposure pattern of the drugs (and in particular the nsNSAIDs) did not change after UGIB ( Supplementary Figure 2). When adjusting for acute myocardial infarction and anaphylactic shock, the results were similar ( Supplementary Figure 3). When excluding IPCI from the main analysis, the results were also similar ( Supplementary Figure 4). SSRIs showed statistically significant interaction with nsNSAIDs and COX-2 inhibitors but not with low-dose aspirin. From a biological point of view, this interaction seems plausible because SSRIs decrease the serotonin level, resulting in impaired thrombocyte aggregation and an increased risk of bleeding in general, including UGIB. Based on this mechanism, NSAIDs, and low-dose aspirin to a lesser extent, x 36 Dalton, S.O., Johansen, C., Mellemkjaer, L. 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 , x 37 de Abajo, F.J., Rodriguez, L.A., and Montero, D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. 1999; 319: 1106–1109 are suspected to produce synergism with SSRIs. Although previous studies report an increased risk between 2.6-fold and 16-fold for UGIB with use of SSRIs and NSAIDs when compared with drug monotherapy, x 36 Dalton, S.O., Johansen, C., Mellemkjaer, L. 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 , x 37 de Abajo, F.J., Rodriguez, L.A., and Montero, D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study.
1999; 319: 1106–1109 , x 38 Tata, L.J., Fortun, P.J., Hubbard, R.B. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther. 2005; 22: 175–181 others could not show interaction. X 25 Targownik, L.E., Bolton, J.M., Metge, C.J. Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol.
2009; 104: 1475–1482 , x 38 Tata, L.J., Fortun, P.J., Hubbard, R.B. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther. 2005; 22: 175–181 However, these were not performed primarily on NSAID users, x 37 de Abajo, F.J., Rodriguez, L.A., and Montero, D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. 1999; 319: 1106–1109 did not control for important confounders, x 36 Dalton, S.O., Johansen, C., Mellemkjaer, L.
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 , x 37 de Abajo, F.J., Rodriguez, L.A., and Montero, D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. 1999; 319: 1106–1109 and did not create mutually exclusive drug exposure groups.
X 36 Dalton, S.O., Johansen, C., Mellemkjaer, L. 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. The risk of aldosterone antagonists concurrently used with nsNSAIDs was higher than when used with low-dose aspirin or COX-2 inhibitors. Earlier, case reports indicated a possible association between aldosterone antagonists and UGIB or UGI ulcers.
X 39 Kremer, D., Brown, J.J., Davies, D.L. Amiloride in primary hyperaldosteronism with chronic peptic ulceration. 1973; 2: 216–217 More recently, case-control studies confirmed this association.
X 13 Verhamme, K., Mosis, G., Dieleman, J. Spironolactone and risk of upper gastrointestinal events: population based case-control study.
2006; 333: 330 , x 27 Gulmez, S.E., Lassen, A.T., Aalykke, C. Spironolactone use and the risk of upper gastrointestinal bleeding: a population-based case-control study.
Br J Clin Pharmacol. 2008; 66: 294–299 The potential mechanism may be related to impaired healing of gastric and duodenal erosions due to inhibition of fibrous tissue formation. X 13 Verhamme, K., Mosis, G., Dieleman, J. Spironolactone and risk of upper gastrointestinal events: population based case-control study. 2006; 333: 330. Use of anticoagulants is an acknowledged risk factor for UGIB, with previous studies showing risks from 5.3-fold to 6.5-fold for concomitant use of anticoagulants with low-dose aspirin, x 18 Delaney, J.A., Opatrny, L.O., Brophy, J.M. Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding.
2007; 177: 347–351 , x 30 Hallas, J., Dall, M., Andries, A. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study.
2006; 333: 726 4.6-fold with COX-2 inhibitors, x 18 Delaney, J.A., Opatrny, L.O., Brophy, J.M. Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding.
2007; 177: 347–351 and up to 19-fold with nsNSAIDs. X 4 Lanas, A., Garcia-Rodriguez, L.A., Arroyo, M.T.
Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. 2006; 55: 1731–1738 In the current study, anticoagulants showed a higher risk when combined with low-dose aspirin than with nsNSAIDs or COX-2 inhibitors. The difference between these findings and previous studies may rely on less stringent control for confounders in previous studies than in the current study; furthermore, with the SCCS, all within-person confounders that are fixed over time are immediately dealt with.
In line with others, concomitant use of low-dose aspirin eliminates the presumed benefit of COX-2 inhibitors over nsNSAIDs on the risk of upper gastrointestinal adverse events. X 4 Lanas, A., Garcia-Rodriguez, L.A., Arroyo, M.T. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. 2006; 55: 1731–1738 , x 40 Silverstein, F.E., Faich, G., Goldstein, J.L. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial.
Celecoxib Long-term Arthritis Safety Study. 2000; 284: 1247–1255 , x 41 Laine, L., Maller, E.S., Yu, C. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial.
2004; 127: 395–402 , x 42 Goldstein, J.L., Correa, P., Zhao, W.W. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis. Am J Gastroenterol. 2001; 96: 1019–1027. The increased risk of diagnosed UGIB observed with the concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with GPAs seems counterintuitive; however, no interaction was observed for any of these drug combinations. The increased risk is thus more likely explained by the phenomenon of “channeling,” in which high-risk patients receive concurrent prescriptions for GPAs whereas low-risk patients do not.
Another explanation is protopathic bias, because GPAs might be given as treatment for first symptoms of UGIB. X 43 Schuemie, M.J.
Methods for drug safety signal detection in longitudinal observational databases: LGPS and LEOPARD. Pharmacoepidemiol Drug Saf. 2011; 20: 292–299.
As expected, the risk of diagnosed UGIB with use of the drugs of interest (monotherapy), except antiplatelets, was lower for subjects younger than 60 years of age than for subjects older than 60 years of age. Surprisingly, the difference in risk between younger and older subjects was larger for drug combinations with COX-2 inhibitors than for combinations with nsNSAIDs. Application of a cutoff level of 70 years of age did not yield different results.
However, using an age cutoff of 70 years showed excess risk for the combination of COX-2 inhibitors and corticosteroids, whereas this was not present with an age cutoff of 60 years. In elderly subjects, prostaglandin levels decreased due to decreased conversion of arachidonic acid to prostaglandin, resulting in an increased risk of UGIB. This partially accounts for the recommendation to use gastroprotective measures in elderly patients. X 8 Lanza, F.L., Chan, F.K., and Quigley, E.M.
Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009; 104: 728–738 We hypothesize that COX enzyme selectivity with aging might explain the difference in drug interaction between nsNSAIDs and COX-2 inhibitors. In animal studies, older rats expressed different COX enzyme mRNA levels than younger rats and an impaired response of prostaglandin synthesis to irritants with older age was shown. X 9 Vogiagis, D., Glare, E.M., Misajon, A. Cyclooxygenase-1 and an alternatively spliced mRNA in the rat stomach: effects of aging and ulcers.
Am J Physiol Gastrointest Liver Physiol. 2000; 278: G820–G827 In humans, higher basal acid output in the stomach among elderly patients.
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