GASTROENTEROLOGY 2007;133:790 798

Risk of Peptic Ulcer Hospitalizations in Users of NSAIDs With Gastroprotective Cotherapy Versus Coxibs
CLINICAL ALIMENTARY TRACT

WAYNE A. RAY,*, CECILIA P. CHUNG, C. MICHAEL STEIN,, WALTER E. SMALLEY,, KATHI HALL,* PATRICK G. ARBOGAST,# and MARIE R. GRIFFIN*,,**
*Division of Pharmacoepidemiology, Department of Preventive Medicine, Divisions of Rheumatology, Clinical Pharmacology, Gastroenterology, and **Internal Medicine, Department of Medicine, and #Department of Biostatistics, Vanderbilt University School of Medicine, Nashville; and Veterans Administration Tennessee Valley Health Care System, Geriatric Research, Education and Clinical Center, Nashville, Tennessee

See Maiden L et al on page 1040 in the September 2007 issue of CGH.

Background & Aims: The primary strategies to reduce the risk of serious gastropathy caused by traditional nonsteroidal anti-inammatory drugs (NSAIDs) are use of a coxib or concurrent use of a proton pump inhibitor or double-dose histamine-2 receptor antagonist. However, the relative clinical effectiveness of these therapeutic alternatives is understudied. Methods: We studied peptic ulcer hospitalizations in a cohort of Tennessee Medicaid enrollees between 1996 and 2004. To decrease potential channeling bias, the study included only new episodes of prescribed NSAID or coxib use and controlled for multiple baseline risk factors for upper gastrointestinal disease. There were 234,010 and 48,710 new episodes of NSAID and coxib use, respectively, with 363,037 person-years of follow-up and 1223 peptic ulcer hospitalizations. Results: Current users of NSAIDs with no gastroprotective cotherapy had an adjusted incidence of peptic ulcer hospitalizations of 5.65 per 1000 person-years, 2.76 (95% condence interval, 2.353.23) times greater than that for persons not currently using either NSAIDs or coxibs. This risk was reduced by 39% (16%56%, 95% CI) for current users of NSAIDs with gastroprotective cotherapy and 40% (23% 54%) for current users of coxibs without such cotherapy. Concurrent users of NSAIDs and proton pump inhibitors had a 54% (27%72%) risk reduction, very similar to the 50% (27% 66%) reduction for concurrent users of proton pump inhibitors and coxibs. Conclusions: These ndings suggest that coprescribing a proton pump inhibitor with an NSAID is as effective as use of a coxib for reducing the risk of NSAIDinduced gastropathy. onsteroidal anti-inammatory drugs are among the most commonly prescribed medications in the world.1 However, the traditional drugs in this class (NSAIDs) substantially increase the risk of serious upper

gastrointestinal disease (NSAID-induced gastropathy), including peptic ulcers, perforations, and upper gastrointestinal hemorrhages.1,2 At present, there are 2 primary strategies to reduce this risk: use of a coxib or concurrent use of medications that protect the gut from the adverse effects of NSAIDs (gastroprotective cotherapy).35 Coxibs confer a 40% 60% lower risk of ulcer complications than the NSAIDs6 8 but also can cause serious cardiovascular disease.7,9 11 The synthetic prostaglandin misoprostol reduces ulcer complications in NSAID users by 40%12 but is poorly tolerated and now infrequently used. The histamine-2 receptor antagonists (in doses twice those recommended for ulcer healing) and the proton pump inhibitors are well-tolerated medications that reduce the occurrence of NSAID-associated peptic ulcers identied by endoscopic examination by 60% 80%.13 There are critical unanswered questions regarding the effectiveness of these strategies to prevent NSAID-induced gastropathy. The clinical trials of proton pump inhibitors and double-dose histamine-2 receptor antagonists had endoscopic lesions as an end point,14 16 so it remains uncertain whether or not these agents prevent the clinically relevant ulcer complications. Despite this lack of data, expert bodies have recommended use of gastroprotective cotherapy for high-risk NSAID users.35 However, these guidelines are frequently not followed in practice,17,18 perhaps because of the limited information on which they are based. At present, no adequately powered gastrointestinal outcomes trials have directly compared a coxib with an NSAID with gastroprotective cotherapy. Although the pivotal coxib trials6 8 were powered to study ulcer complications, they compared these agents with NSAID use without gastroprotective cotherapy. Unlike earlier studies, the recently completed trial comparing etoricoxib and diclofenac permitted proton pump inhibitor use; however, there was no reduction in ulcer complications for
Abbreviations used in this paper: CI, condence interval; IRR, incidence rate ratio. 2007 by the AGA Institute 0016-5085/07/$32.00 doi:10.1053/j.gastro.2007.06.058

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the etoricoxib arm and no randomized comparison of this agent with diclofenac plus a proton pump inhibitor.19 The trials that have directly compared these 2 therapeutic modalities20,21 were not powered to study ulcer complications. However, it is increasingly unlikely that large clinical trials of gastroprotective cotherapy in NSAID users will be conducted. Proton pump inhibitors are available generically, which limits the incentives for pharmaceutical manufacturers to fund such studies. Furthermore, because NSAID-induced gastropathy is frequent and potentially life-threatening,1 the ethics of randomizing patients to NSAID use without gastroprotective cotherapy are questionable. For example, all patients in the in-progress PRECISION trial comparing celecoxib, naproxen, and ibuprofen in patients at high risk of cardiovascular disease will receive a proton pump inhibitor (www.clinicaltrials.gov, NCT00346216), and thus this trial will not provide information on the relative efcacy of a coxib alone versus an NSAID with gastroprotective cotherapy. Thus, observational studies may provide the best current alternative to obtaining data that are essential to guide clinical practice. We conducted a large cohort study to directly compare the effect of an NSAID with gastroprotective cotherapy with that of a coxib on the incidence of peptic ulcer hospitalizations.

The cohort excluded persons with serious illnesses in the past 730 days (cancer other than nonmelanoma skin cancer, human immunodeciency virus infection, renal failure, liver disease, respiratory failure, or transplantation), because these were considered likely to have shortened follow-up or to have disease-related upper gastrointestinal complications. Patients also were excluded if they had serious upper gastrointestinal diseases that cause bleeding unrelated to NSAID use (liver cirrhosis, esophageal varices, chronic alcoholism, bariatric/other surgery resulting in gastrojejunal anastomosis) or who were in the hospital in the preceding 30 days. Follow-up began on t0 and extended through the rst of the end of the study, death, occurrence of a study end point, loss of TennCare enrollment, or diagnosis of an exclusion illness. Follow-up also ceased 365 days following last NSAID/coxib use or when the patient switched to a drug in the other category. Patients who left the cohort could subsequently reenter if they met the study criteria. Person-time in the hospital and within 30 days of discharge was excluded because in-hospital events were not considered study end points and because we did not have information on in-hospital medications (eg, heparin) and up to 30 days could be required to detect medication changes made in the hospital.

Medication Exposure Materials and Methods Cohort and Follow-up

Study data were obtained from computerized les of TennCare, Tennessees expanded Medicaid program.22,23 Study les (enrollment, hospital, outpatient, nursing home, linked death certicate) allowed identication of the study cohort, classication of baseline upper gastrointestinal disease risk and other medical comorbidity, tracking of current use of NSAIDs/coxibs and gastroprotective cotherapy, and ascertainment of end points.22,24 The cohort consisted of persons with a new episode of prescribed NSAID or coxib use, which should reduce several types of potential bias.25 It included those who lled a prescription for an NSAID (excluding low-dose aspirin) or coxib between January 1, 1996, and December 31, 2004, and who had no prior use of these drugs in the 365 days preceding the date the prescription was lled (t0). As of t0, cohort members were 40 years of age or older (younger persons were not included because of lower incidence of peptic ulcer disease) and had enrollment for at least 730 days preceding t0 (lapses 7 days allowed) in a category with full drug benets, providing a 2-year period to characterize patients baseline risk of upper gastrointestinal disease. To assure that cohort members had active medical surveillance, we also required lling of at least 1 prescription in each of the rst and second years preceding t0. TennCare pharmacy records were used to classify each person-day of follow-up according to probable use of NSAIDs, coxibs, gastroprotective cotherapy, and other medications. These included the date prescription was dispensed, drug, quantity, dose, and days of supply (usually limited to 30 days), edited to resolve infrequent discrepancies with drug quantity. Computerized pharmacy records are an excellent source of medication data because they are not subject to information bias22 and have high concordance with patient self-report of medication use.26 28 Although many study medications are available over the counter, the low-income Medicaid patients had an economic incentive to obtain these via prescription, and, during the study period, the TennCare program had a relatively generous drug benet with no deductible or co-payment. Although there will be some misclassication due to nonprescription drugs, our past experience suggests that this is limited29 31 and is most likely to bias toward the null. Current use was dened as the period between the lling of the prescription and the end of the days of supply (for aspirin, this period extended an additional 7 days, the typical platelet half-life), indeterminate use as that from the end of the days of supply through 90 days following the lling of the prescription, and former use as the remainder of the 365 days following the ll date. The most frequently prescribed study drugs were naproxen (38% of current NSAID use), ibuprofen (28%), celecoxib (47% of current coxib use), and rofecoxib (40%),

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for which individual analyses were performed. Valdecoxib accounted for 12% of coxib current use, and other NSAIDs/coxibs each accounted for 5% or less of current use. NSAID and coxib current use was classied as low or usual dose, with the latter dened as doses at or above those studied in key clinical trials for osteoarthritis or rheumatoid arthritis (eg, 1000 mg for naproxen, 2400 mg for ibuprofen, 200 mg for celecoxib, 25 mg for rofecoxib). Usual doses accounted for 66% of NSAID and 87% of coxib current use. Gastroprotective cotherapy13 included misoprostol, the proton pump inhibitors (omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole), in any dose, and the histamine-2 receptor antagonists in twice the doses recommended for ulcer healing (cimetidine 1600 mg, ranitidine 600 mg, famotidine 80 mg, nizatidine 600 mg). The study cohort included 234,010 new episodes of NSAID use and 48,710 new episodes of coxib use, with 363,037 person-years of follow-up. There were 67,657 (22% of total follow-up) and 20,987 (41%) person-years for current use of NSAIDs or coxibs, respectively. NSAID and coxib users had gastroprotective cotherapy for 16% and 34% of current use, respectively. Proton pump inhibitors accounted for 71% of gastroprotective cotherapy, double-dose histamine-2 receptor antagonists for 22%, misoprostol for 1%, and use of multiple agents for 6%. Gastroprotective cotherapy use was present before t0 for 68% of proton pump inhibitor use during follow-up and 86% of double-dose histamine-2 receptor antagonist use.

for persons 40 44 years of age to 18.2 per 1000 for those 90 years of age or older. Persons with a prior peptic ulcer hospital admission subsequently had a 5.6-fold increase in the age-adjusted rate of ulcer hospitalizations (P .001).

CLINICAL ALIMENTARY TRACT

Potential Confounders
To control for channeling of high-risk patients to either coxibs or gastroprotective cotherapy, we identied an extensive set of baseline characteristics of the cohort members as well as changes in some of these during follow-up. Baseline characteristics included demographic factors (age, gender, TennCare uninsured enrollment, race, urban residence, calendar year, living in nursing home) as well as factors indicating increased risk for upper gastrointestinal disease. The latter included history of peptic ulcer, gastritis or duodenitis, other upper gastrointestinal symptoms, use of drugs to treat peptic ulcer disease (proton pump inhibitor, histamine-2 receptor antagonist, other antiulcer drug, prior Helicobacter pylori eradication therapy33), and other medications that can cause gastrointestinal bleeding (prescribed low-dose aspirin, other antiplatelet drugs [dipyridamole, ticlopidine, clopidogrel], anticoagulants, or systemic corticosteroids). To control for the effect of general medical frailty1 on the risk of peptic ulcer hospitalizations, we constructed a baseline summary medical comorbidity score from prior prescriptions and medical care encounters for lower gastrointestinal, cardiovascular, metabolic, musculoskeletal, neurologic, mental, respiratory, and infectious diseases as well as indicators of general frailty (any other nongastrointestinal hospital admission or emergency department visit, fall-related injuries, prescription of wheelchair or other mobility aid, prescription for home oxygen). To calculate the score, we performed a Poisson regression analysis among former users of NSAIDs/coxibs with no gastroprotective cotherapy using a model that included demographic factors and the medical comorbidity indicators listed previously. The score was then dened for the entire cohort as the deciles of the sum 1*M1 2*M2 . . . k*Mk, where the M values are the individual variables indicating medical comorbidity and the values are the regression coefcients estimated from the Poisson model. After controlling for demographic factors, there was a greater than 5-fold difference in end point incidence between the lowest (0) and highest (9) value of the comorbidity score. This technique to summarize the effect of multiple risk factors34 yields estimates similar to those obtained by including the individual score components in regression models.35 Potential time-dependent confounders were use of low-dose aspirin, other antiplatelet drugs, anticoagulants or systemic corticosteroids, new residence in a nursing home, and new nongastrointestinal hospital admission. The analysis did not control for gastrointestinal disease diagnosed after cohort entry because this was potentially

End Points
The study end point was hospitalization with peptic ulcer disease, identied from a primary discharge diagnosis code for peptic ulcer (International Classication of Diseases, Ninth Revision, Clinical Modication codes of 531, 532, 533), gastritis with hemorrhage (535.01, 535.41, 535.51), or gastrointestinal hemorrhage (578). The latter code, which could indicate bleeding from either the upper or lower gastrointestinal tract, was accepted only if a secondary diagnosis indicated a peptic ulcer or there were no diagnoses for lower gastrointestinal disease. The date of end point occurrence was considered the day of the hospital admission or the prior day if there was an emergency department visit on that day. We assessed the accuracy of the end point denition in a random sample of 135 cases. Blinded adjudication using the case denition from the TARGET study8,32 classied 90% as either denite/probable (lesion identied by diagnostic procedure) or possible (signs and symptoms consistent with upper gastrointestinal disease and no evidence from diagnostic procedures of lower gastrointestinal hemorrhage) cases. We thus identied 1223 peptic ulcer hospitalizations during cohort follow-up, or 3.4 per 1000 person-years. Incidence increased with age, from 1.6 per 1000 per year

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Table 1. Baseline Cohort Characteristics, According to NSAID/Coxib Status

NSAID Gastroprotective cotherapya 27,927 55.9 11.0 20.5 69.9 39.0 77.6 47.8 58.6 5.1 48.6 4.1 14.8 21.4 32.5 4.5 100.0 70.4 67.1 4.3 3.5 57.1 21.6 10.0 5.3 38.2 5.8

All Characteristics at baseline New episodes of use, N Age, mean SD (y) 65 years of age or older (%) Female (%) TennCare enrollment uninsured (%) White race (%) Residence in Standard Metropolitan Statistical Area (%) Year cohort entry 2002 or later (%) In nursing home (%) Medical care in the 2 years before baseline Diagnosed upper gastrointestinal disease (%) Peptic ulcer hospitalization (%) Peptic ulcer, outpatient (%) Gastritis (%) Other upper gastrointestinal symptoms (%) Helicobacter pylori eradication treatment (%) Drugs for upper gastrointestinal disease (%) Proton pump inhibitor (%) Histamine-2 receptor antagonist (%) Other drug for ulcer treatment (%) Antacid (%) Any medication that can cause gastrointestinal bleeding (%) Low-dose aspirin (%) Other antiplatelet drug (%)b Anticoagulant (%) Systemic corticosteroid (%) Medical comorbidity score, meanc
aDened

Coxib 48,710 61.2 12.8 38.6 70.7 43.0 75.2 50.7 61.0 5.5 30.7 2.2 8.5 11.0 20.7 2.6 58.0 34.1 40.2 2.2 2.2 51.3 18.3 8.2 6.5 32.5 5.2

234,010 55.8 12.0 21.9 71.1 39.5 69.7 52.7 30.9 5.3 27.8 1.8 7.3 9.2 19.3 1.6 46.0 15.8 37.9 2.0 1.7 42.5 14.5 5.4 3.9 27.7 4.6

NOTE. Data (except for number of episodes and age) adjusted for age by the method of Brenner et al.43 as use of a proton pump inhibitor, histamine-2 receptor antagonist (double dose), or misoprostol within 30 days of the beginning of follow-up. bDipyridamole, ticlopidine, or clopidogrel. cSummary score calculated from medical care for nongastrointestinal illness that ranges from 0 (least comorbidity) to 9 (most comorbidity).

on the causal pathway for NSAID-induced gastropathy. Because low-dose aspirin may be obtained over the counter and thus not be recorded in the TennCare data, some analyses controlled for eligibility for low-dose aspirin use (history of cardiovascular disease for which the Food and Drug Administration recommends long-term aspirin prophylaxis7); these had identical ndings as the primary analysis.

Analysis
Estimates of incidence rate ratios (IRRs) adjusted for potential differences between study groups were calculated from Poisson regression models that included NSAID or coxib exposure, gastroprotective cotherapy, and baseline as well as time-dependent potential confounders. In some analyses, adjusted incidence was calculated by multiplying the unadjusted rate for the reference category by the adjusted IRR. Planned subgroup analyses were performed for patients who met current guidelines for use of gastroprotective cotherapy,35 lowdose aspirin users, and the most frequently prescribed

individual NSAIDs/coxibs. Because the study began before the availability of the coxibs, we conducted an analysis restricted to 1999 through 2004; ndings did not differ materially from those of the primary analysis (data not shown). All analyses were performed with SAS version 9.0 (SAS Institute Inc, Cary, NC). All P values are 2 sided. The study was approved by the Vanderbilt Committee for the Protection of Human Subjects as well as the State of Tennessee Bureau of TennCare and Department of Health and Environment. The study was funded by a grant from the Agency for Healthcare Quality and Research. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results
Coxib users had a mean age 5 years greater than that of NSAID users (61 vs 56 years; Table 1) but otherwise had comparable demographic characteristics. After

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Figure 1. Adjusted incidence of peptic ulcerrelated hospitalizations for NSAID and coxib users, according to gastroprotective cotherapy. The left y-axis shows the adjusted rate of hospitalizations per 1000 person-years (PY) of follow-up; the right y-axis shows the IRR. Vertical bars are 95% CIs. The reference group is former users of either NSAIDs or coxibs with no gastroprotective cotherapy. All rates and IRRs are adjusted for baseline demographic factors, baseline history of upper gastrointestinal disease, baseline medical comorbidity, use of medications that cause upper gastrointestinal bleeding (baseline and during follow-up), and hospital or nursing home admission during follow-up. The person-years of follow-up were as follows: 57,032 (NSAID, no gastroprotective cotherapy), 10,625 (NSAID, gastroprotective cotherapy), 13,962 (coxib, no gastroprotective cotherapy), 7,025 (coxib, gastroprotective cotherapy), and 135,758 (former). Data shown in the gure exclude 120,640 person-years for indeterminate users and 17,995 for former users with concurrent gastroprotective cotherapy.

adjusting for age, coxib users had more frequent use of medications for ulcer treatment or upper gastrointestinal symptoms (58% vs 46%). Coxib users also had more frequently received other drugs that cause gastrointestinal bleeding (51% vs 42%) and had a slightly higher medical comorbidity score (5.2 vs 4.6). However, NSAID users with baseline gastroprotective cotherapy had an

even greater baseline prevalence of upper gastrointestinal disease, use of medications that cause gastrointestinal bleeding, and other medical comorbidity than the coxib users (Table 1). Current users of NSAIDs with no gastroprotective cotherapy had an adjusted incidence of peptic ulcer hospitalizations of 5.65 per 1000 person-years, nearly 3 times greater than that of 2.04 per 1000 for comparable persons who had stopped using either NSAIDs or coxibs (Figure 1; IRR, 2.76; 95% condence interval [CI], 2.35 3.23; P .0001). In this group, peptic ulcer hospitalization incidence increased with NSAID dose (IRRs for usual and low doses: 3.27 [2.74 3.90] and 2.10 [1.69 2.62], respectively). Gastroprotective cotherapy or use of a coxib reduced, but did not eliminate, this increased risk (Figure 1). Among current users of NSAIDs with gastroprotective cotherapy and current users of coxibs without or with such cotherapy, the respective IRRs were 1.68 (1.20 2.34), 1.65 (1.28 2.14), and 1.37 (0.94 1.98). When compared with NSAID use alone, use of either an NSAID with gastroprotective cotherapy or a coxib was associated with a similar reduction in the incidence of peptic ulcer hospitalizations (Table 2). For current users of either NSAIDs with gastroprotective cotherapy or coxibs without or with such cotherapy, the respective risk reductions were 39% (16%56%), 40% (23%54%), and 50% (28% 66%). Among current users of NSAIDs, concurrent users of proton pump inhibitors had the greatest risk reduction (54% [27%72%]), which was very similar to that for concurrent users of proton pump inhibitors and coxibs (50% [27% 66%]). We performed a dose-adjusted analysis for naproxen, ibuprofen, rofecoxib, and celecoxib, the most frequently used individual drugs in the study cohort (Table 3). There were 2 primary comparisons. In the rst, current use of naproxen (the most frequently used NSAID) with

CLINICAL ALIMENTARY TRACT

Table 2. Incidence of Peptic Ulcer Hospitalizations for Current Users of NSAIDs or Coxibs, According to Use of Gastroprotective Cotherapy
Person-years NSAID No gastroprotective cotherapy Any gastroprotective cotherapya Proton pump inhibitor Histamine-2 receptor antagonist, double dose Misoprostol Coxib No gastroprotective cotherapy Any gastroprotective cotherapya Proton pump inhibitor 57,032 10,625 6227 3077 405 13,962 7025 6027 Rate/1000, Adjusted 5.65 3.44 2.57 4.72 3.94 3.38 2.80 2.80 IRR 1 0.608 0.456 0.835 0.697 0.598 0.495 0.496 95% CI Reference 0.440.84 0.280.73 0.501.40 0.172.80 0.460.77 0.340.72 0.340.73 P value

.003 .0011 .4959 .6106 .0001 .0002 .0004

NOTE. Double dose represents twice the dose recommended for ulcer healing. All rates and IRRs are adjusted for baseline demographic factors, baseline history of upper gastrointestinal disease, baseline medical comorbidity, use of medications that cause upper gastrointestinal bleeding (baseline and during follow-up), and hospital or nursing home admission during follow-up. aThe total for any gastroprotective cotherapy includes person-time with concurrent use of more than a single type of therapy, which is excluded from the specic gastroprotective cotherapy therapy analyses. For the coxibs, sample size was insufcient to assess concurrent use of double-dose histamine-2 receptor antagonists or misoprostol.

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Table 3. Incidence of Peptic Ulcer Hospitalizations for Current Users of Frequently Prescribed Individual NSAIDs or Coxibs, Adjusted for Dose and According to Concurrent Use of Proton Pump Inhibitors
Comparison with naproxen, no gastroprotective cotherapy Person-years Naproxen No gastroprotective cotherapy Concurrent proton pump inhibitor Ibuprofen No gastroprotective cotherapy Concurrent proton pump inhibitor Rofecoxib No gastroprotective cotherapy Concurrent proton pump inhibitor Celecoxib No gastroprotective cotherapy Concurrent proton pump inhibitor 22,559 1925 16,900 1387 5700 2321 6690 2760 Rate/1000, adjusted 7.80 4.09 4.57 2.03 4.13 3.77 2.66 1.40 IRR 1 0.524 0.585 0.261 0.530 0.483 0.341 0.179 95% CI Reference 0.271.03 0.440.77 0.080.82 0.370.76 0.280.83 0.240.49 0.090.37 P value Comparison with naproxen, concurrent proton pump inhibitor P value

.0616 .0002 .0216 .0006 .0086 .0001 .0001

Reference .7575 .2958 .9759 .8481 .2565 .0275

NOTE. All rates and IRRs are adjusted for baseline demographic factors, baseline history of upper gastrointestinal disease, baseline medical comorbidity, use of medications that cause upper gastrointestinal bleeding (baseline and during follow-up), and hospital or nursing home admission during follow-up. Adjustment for dose performed by adding a term for dose of current use (low versus usual) to the Poisson regression model

no gastroprotective cotherapy was the reference category. Relative to this group, concurrent users of naproxen and a proton pump inhibitor had a 48% (3% to 73%; P .0616) reduction in the incidence of peptic ulcer hospitalizations and there were reductions of 47% (24% 63%; P .0006) for rofecoxib and 66% (51%76%) for celecoxib, each with no gastroprotective cotherapy. In the second comparison, concurrent use of naproxen with a proton pump inhibitor was the reference category, which tested whether or not the other drugs, with or without a proton pump inhibitor, conferred an additional protective effect. None of these had a statistically signicant further reduction in risk, with the exception of concurrent users of celecoxib and a proton pump inhibitor (P .0275). The gastroprotective effect of concurrent proton pump inhibitor or coxib use was present in subgroups of patients with factors that increase risk of NSAID-induced gastropathy (Figure 2). These included increased NSAID dose, age 65 years or older, past history of peptic ulcer disease, medical frailty, use of low-dose aspirin, and use of other antiplatelet drugs or oral anticoagulants. Within each subgroup, the gastroprotective strategies were associated with reduced incidence of peptic ulcer hospitalizations, relative to that for current NSAID use with no gastroprotective cotherapy, although in some of the smaller subgroups the differences were not statistically signicant. For patients with prescribed aspirin, the only gastroprotective strategy associated with a statistically signicant risk reduction was concurrent coxib and proton pump inhibitor use.

Discussion
The ndings from this large cohort study show that use of an NSAID in conjunction with a proton

pump inhibitor has a gastrointestinal safety advantage over NSAID use alone comparable to that of a coxib, with respective reductions in the risk of peptic ulcer hospitalizations of 54% and 40%. This is similar to the 40% 60% reduction in ulcer complications reported from the pivotal coxib trials.6 8 Because the present study included substantial numbers of high-risk patients generally excluded from the coxib trials, such as those with recent peptic ulcers or other upper gastrointestinal disease or use of medications that cause gastrointestinal bleeding, our ndings further suggest that the benets of these strategies for preventing NSAID-induced gastropathy will be present in the patients for whom they would be most important but who have not been well studied. Because the currently available guidelines for prevention of NSAID-induced gastropathy did not distinguish between the individual agents recommended for cotherapy,35,13 our initial analysis grouped proton pump inhibitors and double-dose histamine-2 receptor antagonists. However, proton pump inhibitors provide more complete suppression of gastric acid and greater efcacy for healing of NSAID-related peptic ulcers36 and presently are the most commonly used gastroprotective cotherapy. Thus, we conducted a planned analysis of the different types of gastroprotective cotherapy, which showed greater efcacy for the proton pump inhibitors. Our ndings are consistent with those from other recently published epidemiologic studies. Her et al found that concomitant prescribing of a proton pump inhibitor with diclofenac reduced the odds ratio of an ulcer hospitalization from 2.4 to 1.3.37 Garca-Rodrguez et al reported that coxibs conferred a lower risk of serious upper gastrointestinal complications than did NSAIDs

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Figure 2. Subgroup analyses. Adjusted incidence of peptic ulcerrelated hospitalizations in users of NSAIDs with concurrent proton pump inhibitor (PPI) use or users of coxibs without or with concurrent PPI use. The chart depicts the IRR and 95% CIs, with the reference category that of NSAID users with no gastroprotective cotherapy. All rates and IRRs are adjusted for baseline demographic factors, baseline history of upper gastrointestinal disease, baseline medical comorbidity, use of medications that cause upper gastrointestinal bleeding (baseline and during follow-up), and hospital or nursing home admission during follow-up. The rate in parentheses after the subgroup description is the adjusted rate in that subgroup of peptic ulcerrelated hospitalizations per 1000 person-years (PY) among NSAID users with no gastroprotective cotherapy. Past ulcer is dened as diagnosis of peptic ulcer disease or gastritis in the 2 years preceding start of follow-up, medical comorbidity is dened as the upper quintile of summary medical comorbidity score, and low dose aspirin is dened as current use of low-dose aspirin; antiplatelet drugs are dipyridamole, ticlopidine, or clopidogrel.

but that addition of gastroprotective cotherapy reduced the risk associated with NSAIDs by nearly 40%.38 Lanas et al noted that among current users of NSAIDs, concurrent use of histamine-2 receptor antagonists or proton pump inhibitors was associated with a 35% and 67% reduction in the risk of hospitalization for upper gastrointestinal bleeding.39 Our analysis of individual drugs and high-risk patient subgroups included several interesting ndings. Naproxen without gastroprotective cotherapy was associated with the greatest risk of peptic ulcer hospitalizations. This was reduced by approximately half with concurrent use of a proton pump inhibitor or with use of rofecoxib alone, although the former nding did not reach conventional levels of statistical signicance. Among patients with no gastroprotective cotherapy, the incidence of peptic ulcer hospitalizations was lower for use of ibuprofen than for naproxen and was comparable to that for rofecoxib. This is consistent with the ndings of numerous epidemiologic studies that ibuprofen is less likely than other NSAIDs to cause peptic ulcers.40 The

best gastroprotection was associated with concurrent use of celecoxib and a proton pump inhibitor, which was signicantly better than either naproxen alone or naproxen with a proton pump inhibitor. This nding is consistent with the recently reported clinical trial of Chan et al,41 in which patients not taking low-dose aspirin randomized to celecoxib with esomeprazole had lower risk of recurrent peptic ulcer bleeding than did patients treated with celecoxib alone. We conducted an analysis according to current use of prescribed low-dose aspirin. Although the numbers of such patients in the cohort were small, neither a concurrent proton pump inhibitor nor a coxib alone provided statistically signicant gastroprotection. The latter nding is consistent with ndings from the randomized controlled trials.6,8 However, we did nd a marked and statistically signicant protective effect in patients treated with aspirin who received a coxib with a proton pump inhibitor. Further study of how to best provide gastroprotection to patients who take both an NSAID and low-dose aspirin is needed.

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The primary limitation of this nonrandomized study is possible confounding due to channeling of patients at high risk of peptic ulcer disease to use of either a coxib or gastroprotective cotherapy. The study design thus included several measures to reduce this potential bias. We required cohort members to have a new episode of prescribed NSAID or coxib use, preceded by a drug-free period, and stopped follow-up if a patient switched to a drug in the other class. This effectively excluded patients who had switched from an NSAID to a coxib because of gastrointestinal symptoms, a type of channeling that is particularly difcult to address with traditional designs. We also controlled for an extensive set of baseline risk factors for upper gastrointestinal disease in the statistical analysis, which should further reduce channeling bias. Because we measured these factors before NSAID therapy began, they would not be markers for NSAID-induced gastropathy and controlling for them would not introduce the bias ordinarily caused by controlling for variables on the causal pathway between exposure and end point.42 At baseline, coxib users were 5 years older than NSAID users, and, after adjusting for age, were slightly more likely to have a history of upper gastrointestinal or other medical comorbidity. This raises the possibility that residual confounding could cause the gastrointestinal benet of coxibs to be underestimated. However, baseline NSAID users with gastroprotective cotherapy had an even greater prevalence of upper gastrointestinal and other medical comorbidity. Thus, any residual confounding should understate the gastrointestinal benets of both coxibs and proton pump inhibitors, and, in the comparison of these 2 strategies for preventing NSAIDinduced gastropathy, favor the coxibs. Another study limitation was the use of a computerized database of medical care encounters to dene exposure to study medications. Although automated pharmacy dispensing records are an excellent unbiased source of information on drug use,22,26 28 some NSAIDs, omeprazole, and several histamine-2 receptor antagonists were available over the counter, use that would not have been recorded in the prescription database. However, Medicaid paid for over-the-counter drugs when prescribed, and thus patients had strong economic incentive to obtain these drugs by prescription. Our previous studies suggest that in this circumstance, over-the-counter use is minimal.29 31 However, some exposure misclassication is inevitable and should bias toward the null. Similarly, aspirin could be obtained both via prescription and over the counter. However, the results of an analysis that excluded patients for whom low-dose aspirin prophylaxis is recommended, the group in which misclassication would be of greatest concern, did not differ from those of the primary analysis. In conclusion, our ndings strongly support concurrent use of a proton pump inhibitor for NSAID-treated

References
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patients with high risk of upper gastrointestinal disease, because this strategy conferred gastroprotection equivalent to that of a coxib. They thus underscore the need for future clinical trials of coxibs to directly compare these agents to an NSAID with a proton pump inhibitor. Finally, further investigation is urgently needed of the benets of adding a proton pump inhibitor to celecoxib and other coxibs, because our ndings suggest this strategy provided the best gastroprotection and was effective for patients taking low-dose aspirin.

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Received April 16, 2007. Accepted June 11, 2007. Address requests for reprints to: Wayne A. Ray, PhD, Department of Preventive Medicine, 1500 21st Avenue South, Suite 2600, Nashville, Tennessee 37212. e-mail: wayne.ray@vanderbilt.edu; fax: (615) 3430962. Supported by the Agency for Healthcare Research and Quality, Centers for Education and Research on Therapeutics cooperative agreement (grant HS1-0384). The sponsor had no role in the design or conduct of the study. No support from any pharmaceutical company was provided for this study. W.A.R. has received research support from Pzer and is a consultant for plaintiffs attorneys in rofecoxib litigation. W.E.S. is a consultant for Novartis. M.R.G. is a consultant for Merck and has received research support from Pzer. All other authors report no conict of interest. The authors thank the Tennessee Bureau of TennCare and Department of Health, which provided study data.