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Original Investigation |

Risk of Upper Gastrointestinal Hemorrhage in Warfarin Users Treated With Nonselective NSAIDs or COX-2 Inhibitors FREE

Marisa Battistella, BScPhm, PharmD; Muhammad M. Mamdami, PharmD, MA, MPH; David N. Juurlink, MD, PhD; Linda Rabeneck, MD, MPH; Andreas Laupacis, MD, MSc
[+] Author Affiliations

Author Affiliations: University Health Network (Dr Battistella); Departments of Pharmacy (Dr Mamdami) and Medicine (Drs Mamdami, Juurlink, and Rabeneck), University of Toronto; Institute for Clinical Evaluative Sciences (Drs Juurlink, Rabeneck, and Laupacis); and Clinical Epidemiology and Healthcare Research Program (Dr Juurlink), Toronto, Ontario.


Arch Intern Med. 2005;165(2):189-192. doi:10.1001/archinte.165.2.189.
Text Size: A A A
Published online

Background  Little is known about the risk of upper gastrointestinal (GI) hemorrhage during the concomitant use of warfarin and selective cyclooxygenase (COX)-2 inhibitors. We examined the association between the concomitant use of warfarin and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) or selective COX-2 inhibitors in older adults hospitalized for upper GI hemorrhage.

Methods  This nested case-control analysis of multiple linked health care databases conducted over 1 year identified a cohort of patients in Ontario, Canada, who were older than 66 years and continuously prescribed warfarin. Case patients were those admitted to the hospital with upper GI hemorrhage while taking warfarin. We compared their prescription records prior to hospitalization with those of age- and sex-matched controls who were also receiving warfarin (the control-case ratio was 4:1). Odds ratios (ORs) for the risk of hospitalization for upper GI hemorrhage while concomitantly using warfarin and celecoxib, rofecoxib, or nonselective NSAIDs were determined.

Results  During the study period, we identified 98 821 elderly patients continuously receiving warfarin. Of those, 361 (0.3%) were admitted to the hospital with upper GI hemorrhage. After adjusting for other potential confounders, case patients were significantly more likely to be also taking nonselective NSAIDs (OR, 1.9; 95% confidence interval [CI], 1.4-3.7), celecoxib (OR, 1.7; 95% CI, 1.2-3.6), or rofecoxib (OR, 2.4; 95% CI, 1.7-3.6) prior to hospitalization relative to controls.

Conclusions  Patients taking warfarin concomitantly with selective COX-2 inhibitors have an increased risk of hospitalization for upper GI hemorrhage. The risk appears similar to that of patients simultaneously taking warfarin and nonselective NSAIDs.

Warfarin is an anticoagulant commonly used for the management of patients with a variety of thromboembolic conditions1 but it is implicated in many drug-drug interactions. Some interactions alter warfarin pharmacokinetics and others involve drugs that directly influence hemostasis or gastrointestinal integrity.2,3 Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coprescribed to patients receiving warfarin, potentially resulting in a significantly increased risk of upper gastrointestinal (GI) hemorrhage.4 This increased risk may be mediated through several pathways. First, many NSAIDs are substrates for the cytochrome P450 2C9 isoenzyme. Their use may interfere with the oxidative metabolism of S-warfarin, the more active enantiomer of commercially available racemic warfarin, thereby increasing the hypoprothrombinemic response to warfarin.5 Second, the nonspecific inhibition of cyclooxygenase (COX) enzymes by nonselective NSAIDs leads to significant inhibition of COX-1–generated thromboxane A 2, impairing platelet aggregation,6,7 which may be further compounded by the concomitant use of warfarin.8 Third, traditional NSAIDs can cause gastric erosion, thereby further increasing the risk of GI bleeding in patients treated with warfarin.9

The introduction of the selective COX-2 inhibitors has been met with wide acceptance10 given their potentially lower risk of adverse GI events relative to nonselective NSAIDs.1113 This perception of greater safety with the selective COX-2 inhibitors may result in a higher rate of coprescription with warfarin among users of selective COX-2 inhibitors relative to users of nonselective NSAIDs.10 While recent pharmacodynamic evidence suggests that at least 1 of the selective COX-2 inhibitors may slightly augment the pharmacodynamic effect of warfarin by increasing prothombin time,14,15 information on the clinical consequences of this combination of drug therapy is limited.16 We conducted a population-based study of older adults to examine the association between the concomitant use of warfarin with these drugs and the risk of hospitalization for upper GI hemorrhage.

STUDY DESIGN AND DATA SOURCES

We conducted a nested case-control analysis of multiple linked health care databases over 1 year (April 1, 2000, to March 31, 2001) in Ontario, Canada. This research was approved by the ethics review board of Sunnybrook and Women’s College Health Sciences Center.

Prescriptions were identified from the Ontario Drug Benefit Program, which records prescription medications dispensed to Ontario residents who are 65 years and older. Admissions for upper GI hemorrhage were identified from the Canadian Institute for Health Information Discharge Abstract Database (CIHI DAD), which contains a detailed record of all hospital admissions in Ontario. Basic demographic information for each Ontario resident was obtained from the Ontario Registered Persons Database. The databases are linked through encrypted numbers identifying patients.

COHORT DEFINITION

We studied elderly patients whose prescription records allowed us to define a period of uninterrupted warfarin use. This observation period began with the first prescription for warfarin after their 66th birthday and ended with hospital admission for upper GI hemorrhage, the end of the study period, the patient’s death, or discontinuation of warfarin, whichever occurred first. We chose not to study patients during their first year of eligibility for prescription drug coverage, ie, during their 66th year, to avoid incomplete medication records. Patients were deemed to have discontinued warfarin treatment if more than 120 days had elapsed between prescriptions. In these cases, we extended the observation period to 90 days after the last prescription to include admissions for GI hemorrhage that may have led to cessation of therapy. A similar method has previously been used to define periods of continuous drug use.1719

CASE PATIENTS

Within the cohort of continuous warfarin users, we defined as case patients those registered in the CIHI DAD as having been admitted to the hospital with any diagnosis of upper GI hemorrhage between April 17, 2000, and March 31, 2001. The most commonly found International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification diagnostic codes were 531.0, 531.2, 531.4, 531.6, 532.0, 532.2, 532.4, 532.6, 533.0, 533.2, 533.4, 533.6, 534.0 534.2, 534.4, 534.6, 578.0, 578.1, and 578.9),20 and these codes have been shown to have a positive predictive value of 86% for upper GI hemorrhage.21 These specific dates were chosen because both celecoxib and rofecoxib were made available on the provincial formulary on April 17, 2000, and our hospital database, the CIHI DAD, was complete until March 31, 2001, at the time of the study. The date of admission for upper GI hemorrhage served as the index date for all analyses.

CONTROL PATIENTS

From the cohort of continuous warfarin users, we randomly selected 50 controls for each case, matching for age (born within 1 year of the case patient) and sex. When numerous controls existed for each case patient, we randomly selected 4 matched controls for analysis. When fewer than 4 potential controls were available, we analyzed only those controls and did not alter the matching process. A case patient could serve as a control for a different case patient prior to his or her admission date, and each control could be used for multiple case patients.22,23

EXPOSURE TO INTERACTING MEDICATIONS AND COVARIATES

We identified prescriptions for any COX-2 inhibitor and any prescription for an NSAID in the 90 days prior to the index date. As a test of robustness, we also examined any prescriptions for ocular antibiotics in our cohort of warfarin users to test if no association was observed where none was expected.

To adjust for potential confounders we included several comorbidities in the analysis, as outlined in Table 1. We included hospitalizations for upper GI hemorrhage in the 3 years prior to the index date using the CIHI DAD. For procedures such as endoscopy and upper GI radiologic studies, we examined the data of the Ontario Health Insurance Plan, which records all physician claims for diagnostic and therapeutic procedures. We also examined drug use patterns during the 120 days prior to the index date as markers for conditions that may be associated with an increased risk for upper GI hemorrhage or as drugs that could interfere with the metabolism of warfarin (Table 1).24,25 We also identified residence in a long-term care institution, since this may be an indicator of comorbidities.26 Finally, we adjusted for the number of different drugs prescribed in the year prior to the index date as a recently validated measure of comorbidity.27

Table Graphic Jump LocationTable 1. Potential Confounders Accounted for in the Analysis of Elderly Patients Taking Warfarin and Either a COX-2 Inhibitor or NSAIDs
STATISTICAL ANALYSIS

Conditional logistic regression was used to estimate the odds ratios (ORs) for the association between hospital admission for upper GI hemorrhage and receipt of COX-2 inhibitors or nonselective NSAIDs. The 95% confidence intervals (CIs) were constructed using nonparametric bootstrap methods with resampling of controls over 1000 iterations.28 To avoid the extreme OR estimates that may occur with low exposure rates,29 for each interaction we report the point estimate of the median univariate OR from bootstrap analysis. In the multivariate analysis we adjusted for use of COX-2 inhibitors or NSAIDs when they were not the primary exposure of interest, in addition to the covariates outlined in Table 1.

We identified 98 821 elderly patients treated continuously with warfarin for a total of 65 064 patient-years of therapy. Their mean (SD) age at entry was 77 (6.8) years and approximately 50% were women.

During the study period, 361 elderly patients were admitted to the hospital with GI hemorrhage. Their mean (SD) age was 79.8 (6.9) years and 51.5% were women (Table 2). Of these 361 case patients, 24 (6.6%) had received a prescription for a nonselective NSAID within the preceding 90 days, while 23 (6.1%) had received celecoxib and 25 (6.9%) had received rofecoxib. After adjusting for other potential interacting medications and comorbidities, we found that patients receiving warfarin who were admitted with GI hemorrhage were more likely to have been treated with celecoxib (OR, 1.7; 95% CI, 1.2-3.6), nonselective NSAIDs (OR, 1.9; 95% CI, 1.4-3.7), or rofecoxib (OR, 2.4; 95% CI, 1.7-3.6) in the preceding 90 days (Table 3). As expected, no significant association was observed for ocular antibiotics (OR, 0.9; 95% CI, 0.7-1.3).

Table Graphic Jump LocationTable 2. Baseline Characteristics of Elderly Patients Using Nonselective NSAIDs and COX-2 Inhibitors*
Table Graphic Jump LocationTable 3. Association Between Hospitalization for Upper Gastrointestinal Hemorrhage Among Elderly Warfarin Users and Exposure to Potential Interacting Drugs in the Preceding 90 Days

The findings of this study suggest that increases in the risk of upper GI hemorrhage are similar in warfarin users concomitantly taking either nonselective NSAIDs or selective COX-2 inihibitors compared with patients not treated with these drugs. While the concomitant use of warfarin with NSAIDs is a recognized risk factor for GI hemorrhage,4,5 to our knowledge our study is the first to examine the comparative safety of the COX-2 inhibitors celecoxib and rofecoxib in patients receiving warfarin. Previous studies of this potential interaction have been conducted in healthy volunteers and have relied on small samples and surrogate outcome rather than actual bleeding episodes.14,15 Furthermore, in the Celecoxib Long-term Arthritis Safety Study (CLASS), the comparison of patients receiving celecoxib and aspirin with patients receiving standard NSAID therapy demonstrated no difference in ulcer complications. This may suggest that a COX-2 inhibitor taken with an agent that increases the risk of bleeding may not be safer than NSAIDs alone. A small nested case-control study recently observed differences in the results of exposure to nabumetone or meloxicam when compared with nonselective NSAIDs in patients with or without bleeding complications who were concomitantly using coumarine.16 However, this study was questionnaire-based with a significant differential in response rates between case patients (approximately 70%) and controls (approximately 31%) and it lacked sufficient information on celecoxib and rofecoxib. Furthermore, patients in this study received phenprocoumon or acenocoumarol, whereas in our study patients only received warfarin. These differences would preclude direct comparisons between this study and ours.

Several limitations of our study deserve mention. First, although we controlled for many important confounders, we were unable to account for some potentially important factors such as smoking, alcohol consumption, and the use of nonprescription analgesics. In our study, case patients presented with a higher prevalence of GI comorbidity. Previous research also suggests that COX-2 inhibitor users also typically present with greater GI comorbidity relative to control populations or nonselective NSAID users.13 The implications of these discrepancies in comorbidity profiles between groups could result in an overestimation of true risk. Second, the low absolute number of events in the study groups precluded reliable subgroup analyses such as comparisons among users of specific NSAIDs. Third, the generalizability of our findings to younger patients or settings with different drug policies over longer durations of follow-up is uncertain. Fourth, we were not able to examine international normalized ratios in any patients, making it difficult to determine whether patients with GI hemorrhage had supratherapeutic international normalized ratios. Furthermore, the incidence of GI hemorrhage in patients taking warfarin in our study was surprisingly low (0.3%) compared with a prediction model based on different risk factors (high, middle, and low) in which the proportion of bleeding events was 7%, 4%, and 1%, respectively, after 3 months of therapy.30 Our lower incidence of GI hemorrhage may be secondary to intermittent dosing of anti-inflammatory agents or other patient-level factors. Finally, we did not examine the interaction between COX-2 inhibitors and aspirin use.

Our findings suggest that the risk of upper GI hemorrhage is similarly heightened in warfarin users treated with either selective COX-2 inhibitors or nonselective NSAIDs. Given the observational nature of this study, our findings should be viewed as preliminary and require confirmation through well-designed clinical trials. Regardless, physicians and pharmacists who care for elderly patients taking warfarin should be aware of the potential risks of concomitant therapy with NSAIDs or COX-2 inhibitors, particularly because the latter are among the fastest-growing class of prescription medications and have rapidly gained acceptance in clinical practice.

Correspondence: Marisa Battistella, BScPhm, PharmD, University Health Network–Toronto General Hospital, 200 Elizabeth St, ENG Room 260, Pharmacy Department, Toronto, Ontario, Canada M4G2C4 (Marisa.battistella@uhn.on.ca).

Accepted for Publication: July 19, 2004.

Financial Disclosure: Dr Rabeneck has received speaking honoraria from Pfizer Inc.

Funding/Support: Dr Mamdani is supported by a New Investigator Award from the New Emerging Teams of the Canadian Institutes of Health Research (CIHR). Dr Juurlink is supported by a New Investigator Award from the CIHR and the University of Toronto Drug Safety Research Group. Dr Laupacis is a senior scientist of the CIHR.

Hirsh  JDalen  JAnderson  D  et al.  Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;1198S- 21S
PubMed Link to Article
Buckley  NDawson  A Drug interactions with warfarin. Med J Aust 1992;157479- 483
PubMed
Wells  PSHolbrook  AMCrowther  NRHirsh  J Interactions of warfarin with drug and food. Ann Intern Med 1994;121676- 683
PubMed Link to Article
Shorr  RIRay  WADaugherty  JRGriffin  MR Concurrent use of non-steroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;1531665- 1670
PubMed Link to Article
Diana  FJVeronich  KKapoor  AL Binding of non-steroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin. J Pharm Sci 1989;78195- 199
PubMed Link to Article
Shafer  AI Effects of nonsteroidal anti-inflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995;35209- 219
PubMed Link to Article
Cronberg  SWallmark  ESoderberg  I Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scand J Haematol 1984;33155- 159
Link to Article
Chan  TY Adverse interactions between warfarin and nonsteroidal anti-inflammatory drugs: mechanisms, clinical significance and avoidance. Ann Pharmacother 1995;291274- 1283
PubMed
Langman  MJWeil  JWainwright  P  et al.  Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;3431075- 1078
PubMed Link to Article
Mamdani  MRochon  PLaupacis  AAnderson  G Initial patterns of use of COX-2 inhibitors by elderly patients in Ontario: findings and implications. CMAJ 2002;1671125- 1126
PubMed
Silverstein  FEFaich  GGoldstein  JL  et al.  Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;2841247- 1255
PubMed Link to Article
Bombardier  CLaine  LReicin  A  et al.  Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;3431520- 1528
PubMed Link to Article
Mamdani  MRochon  PAJuurlink  DN  et al.  Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325624- 629
PubMed Link to Article
Karim  ATolbert  DPiergles  A  et al.  Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects. J Clin Pharmacol 2000;40655- 663
PubMed Link to Article
Schwartz  JIBugianesi  KJEbel  DL  et al.  The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin. Clin Pharmacol Ther 2000;68626- 636
PubMed Link to Article
Knijff-Dutmer  EAVan der Palen  JSchut  GVan de Laar  MA The influence of cyclo-oxygenase specificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant coumarine users. QJM 2003;96513- 520
PubMed Link to Article
Mamdani  MMTu  Kvan Walraven  CAustin  PCNaylor  CD Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy. CMAJ 2000;1621421- 1424
PubMed
Mamdani  MMvan Walraven  CBica  AWilliams  JINaylor  CD Is there an association between lipid-lowering drugs and cholecystectomy? Am J Med 2000;108418- 421
PubMed Link to Article
Juurlink  DNMamdani  MKopp  ALaupais  ARedelmeier  DN Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;2891652- 1658
PubMed Link to Article
 International Classification of Diseases, Ninth Revision, Clinical Modification.  Washington, DC Public Health Service, US Dept of Health and Human Services1988;
Raiford  DSGutthann  SPGarcia Rodriguez  LA Positive predictive value of ICD-9 codes in the identification of cases of complicated peptic ulcer disease in the Saskatchewan hospital automated database. Epidemiology 1996;7101- 104
PubMed Link to Article
Lubin  JHGail  MH Biased selection of controls for case-control analyses of cohort studies. Biometrics 1984;4063- 75
PubMed Link to Article
Langholz  B Case-control study, nested. Armitage  pColton  cEncyclopedia of Biostatistics Chichester, England John Wiley & Sons Ltd1998;514- 519
Weil  JLangman  MJWainwright  P  et al.  Peptic ulcer bleeding: accessory risk factors and interactions with nonsteroidal anti-inflammatory drugs. Gut 2000;4627- 31
PubMed Link to Article
Michalets  E Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998;1884- 112
PubMed
Bravo  GDubois  MFHebet  RDe Wals  PMessier  L A prospective evaluation of the Charlson Comorbidity Index for use in long-term care patients. J Am Geriatr Soc 2002;50740- 745
PubMed Link to Article
Schneeweiss  SSeeger  JDMaclure  MWang  PSAvorn  JGlynn  RJ Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data. Am J Epidemiol 2001;154854- 864
PubMed Link to Article
Efron  BTibshirani  RJ An Introduction to the Bootstrap.  New York, NY Chapman & Hall1993;
Greenland  SSchwartzbaum  JAFinkle  WD Problems due to small samples and sparse data in conditional logistic regression analysis. Am J Epidemiol 2000;151531- 539
PubMed Link to Article
Kuijer  PMHutten  BAPrins  MH  et al.  Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999;159457- 460
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Potential Confounders Accounted for in the Analysis of Elderly Patients Taking Warfarin and Either a COX-2 Inhibitor or NSAIDs
Table Graphic Jump LocationTable 2. Baseline Characteristics of Elderly Patients Using Nonselective NSAIDs and COX-2 Inhibitors*
Table Graphic Jump LocationTable 3. Association Between Hospitalization for Upper Gastrointestinal Hemorrhage Among Elderly Warfarin Users and Exposure to Potential Interacting Drugs in the Preceding 90 Days

References

Hirsh  JDalen  JAnderson  D  et al.  Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;1198S- 21S
PubMed Link to Article
Buckley  NDawson  A Drug interactions with warfarin. Med J Aust 1992;157479- 483
PubMed
Wells  PSHolbrook  AMCrowther  NRHirsh  J Interactions of warfarin with drug and food. Ann Intern Med 1994;121676- 683
PubMed Link to Article
Shorr  RIRay  WADaugherty  JRGriffin  MR Concurrent use of non-steroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;1531665- 1670
PubMed Link to Article
Diana  FJVeronich  KKapoor  AL Binding of non-steroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin. J Pharm Sci 1989;78195- 199
PubMed Link to Article
Shafer  AI Effects of nonsteroidal anti-inflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995;35209- 219
PubMed Link to Article
Cronberg  SWallmark  ESoderberg  I Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scand J Haematol 1984;33155- 159
Link to Article
Chan  TY Adverse interactions between warfarin and nonsteroidal anti-inflammatory drugs: mechanisms, clinical significance and avoidance. Ann Pharmacother 1995;291274- 1283
PubMed
Langman  MJWeil  JWainwright  P  et al.  Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;3431075- 1078
PubMed Link to Article
Mamdani  MRochon  PLaupacis  AAnderson  G Initial patterns of use of COX-2 inhibitors by elderly patients in Ontario: findings and implications. CMAJ 2002;1671125- 1126
PubMed
Silverstein  FEFaich  GGoldstein  JL  et al.  Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;2841247- 1255
PubMed Link to Article
Bombardier  CLaine  LReicin  A  et al.  Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;3431520- 1528
PubMed Link to Article
Mamdani  MRochon  PAJuurlink  DN  et al.  Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002;325624- 629
PubMed Link to Article
Karim  ATolbert  DPiergles  A  et al.  Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects. J Clin Pharmacol 2000;40655- 663
PubMed Link to Article
Schwartz  JIBugianesi  KJEbel  DL  et al.  The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin. Clin Pharmacol Ther 2000;68626- 636
PubMed Link to Article
Knijff-Dutmer  EAVan der Palen  JSchut  GVan de Laar  MA The influence of cyclo-oxygenase specificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant coumarine users. QJM 2003;96513- 520
PubMed Link to Article
Mamdani  MMTu  Kvan Walraven  CAustin  PCNaylor  CD Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy. CMAJ 2000;1621421- 1424
PubMed
Mamdani  MMvan Walraven  CBica  AWilliams  JINaylor  CD Is there an association between lipid-lowering drugs and cholecystectomy? Am J Med 2000;108418- 421
PubMed Link to Article
Juurlink  DNMamdani  MKopp  ALaupais  ARedelmeier  DN Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;2891652- 1658
PubMed Link to Article
 International Classification of Diseases, Ninth Revision, Clinical Modification.  Washington, DC Public Health Service, US Dept of Health and Human Services1988;
Raiford  DSGutthann  SPGarcia Rodriguez  LA Positive predictive value of ICD-9 codes in the identification of cases of complicated peptic ulcer disease in the Saskatchewan hospital automated database. Epidemiology 1996;7101- 104
PubMed Link to Article
Lubin  JHGail  MH Biased selection of controls for case-control analyses of cohort studies. Biometrics 1984;4063- 75
PubMed Link to Article
Langholz  B Case-control study, nested. Armitage  pColton  cEncyclopedia of Biostatistics Chichester, England John Wiley & Sons Ltd1998;514- 519
Weil  JLangman  MJWainwright  P  et al.  Peptic ulcer bleeding: accessory risk factors and interactions with nonsteroidal anti-inflammatory drugs. Gut 2000;4627- 31
PubMed Link to Article
Michalets  E Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998;1884- 112
PubMed
Bravo  GDubois  MFHebet  RDe Wals  PMessier  L A prospective evaluation of the Charlson Comorbidity Index for use in long-term care patients. J Am Geriatr Soc 2002;50740- 745
PubMed Link to Article
Schneeweiss  SSeeger  JDMaclure  MWang  PSAvorn  JGlynn  RJ Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data. Am J Epidemiol 2001;154854- 864
PubMed Link to Article
Efron  BTibshirani  RJ An Introduction to the Bootstrap.  New York, NY Chapman & Hall1993;
Greenland  SSchwartzbaum  JAFinkle  WD Problems due to small samples and sparse data in conditional logistic regression analysis. Am J Epidemiol 2000;151531- 539
PubMed Link to Article
Kuijer  PMHutten  BAPrins  MH  et al.  Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999;159457- 460
PubMed Link to Article

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