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Serious Bleeding Events due to Warfarin and Antibiotic Co-prescription in a Cohort of Veterans

      Abstract

      Background

      Antibiotics may interact with warfarin, increasing the risk for significant bleeding events.

      Methods

      This is a retrospective cohort study of veterans who were prescribed warfarin for 30 days without interruption through the US Department of Veterans Affairs between October 1, 2002 and September 1, 2008. Antibiotics considered to be high risk for interaction with warfarin include: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin. Low-risk antibiotics include clindamycin and cephalexin. Risk of bleeding event within 30 days of antibiotic exposure was measured using Cox proportional hazards regression, adjusted for demographic characteristics, comorbid conditions, and receipt of other medications interacting with warfarin.

      Results

      A total of 22,272 patients met inclusion criteria, with 14,078 and 8194 receiving high- and low-risk antibiotics, respectively. There were 93 and 36 bleeding events in the high- and low-risk groups, respectively. Receipt of a high-risk antibiotic (hazard ratio [HR] 1.48; 95% confidence interval [CI], 1.00-2.19) and azithromycin (HR 1.93; 95% CI, 1.13-3.30) were associated with increased risk of bleeding as a primary diagnosis. TMP/SMX (HR 2.09; 95% CI, 1.45-3.02), ciprofloxacin (HR 1.87; 95% CI, 1.42-2.50), levofloxacin (HR 1.77; 95% CI, 1.22-2.50), azithromycin (HR 1.64; 95% CI, 1.16-2.33), and clarithromycin (HR 2.40; 95% CI, 1.16-4.94) were associated with serious bleeding as a primary or secondary diagnosis. International normalized ratio (INR) alterations were common; 9.7% of patients prescribed fluconazole had INR value >6. Patients who had INR performed within 3-14 days of co-prescription were at a decreased risk of serious bleeding (HR 0.61; 95% CI, 0.42-0.88).

      Conclusions

      Warfarin users who are prescribed high-risk antibiotics are at higher risk for serious bleeding events. Early INR evaluation may mitigate this risk.

      Keywords

      Clinical Significance
      • Patients who receive warfarin and a high-risk antibiotic are at increased risk for significant bleeding events.
      • Alterations in the international normalized ratio (INR) are common among patients who receive antibiotics.
      • INR evaluation within 3-14 days of antibiotic prescription may reduce the risk of serious bleeding events among patients receiving warfarin.
      Warfarin is a widely used anticoagulant with indications for the prevention and treatment of thromboembolic events in patients with atrial fibrillation,
      The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators.
      • Ezekowitz M.D.
      • Bridgers S.L.
      • James K.E.
      • et al.
      Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      mechanical heart valves,
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • et al.
      2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease.
      and venous thromboembolisms.
      • Kearon C.
      • Kahn S.R.
      • Agnelli G.
      • et al.
      Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      Warfarin has a narrow therapeutic index, requiring frequent laboratory monitoring to prevent life-threatening complications due to under- and over-anticoagulation.
      • Schulman S.
      • Beyth R.J.
      • Kearon C.
      • Levine M.N.
      Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      • Fang M.C.
      • Chang Y.
      • Hylek E.M.
      • et al.
      Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation.
      Warfarin produces its anticoagulant effect by inhibiting the vitamin K-dependent activation of clotting factors II, VII, IX, and X.
      • Hirsh J.
      • Dalen J.
      • Anderson D.R.
      • et al.
      Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.
      A wide variety of factors including genetic factors,
      • Gage B.F.
      • Lesko L.J.
      Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues.
      • Gage B.F.
      • Eby C.
      • Johnson J.A.
      • et al.
      Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.
      dietary factors,
      • Schulman S.
      Clinical practice. Care of patients receiving long-term anticoagulant therapy.
      drug interactions,
      • Holbrook A.M.
      • Pereira J.A.
      • Labiris R.
      • et al.
      Systematic overview of warfarin and its drug and food interactions.
      and comorbidities
      • Schulman S.
      • Beyth R.J.
      • Kearon C.
      • Levine M.N.
      Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      can produce significant variability in an individual's dose-response to warfarin. Co-prescribed medications may alter the metabolism of warfarin by inducing or inhibiting cytochrome P450-2C9, resulting in a decrease or increase in anticoagulant effect.
      • Jacobs L.G.
      Warfarin pharmacology, clinical management, and evaluation of hemorrhagic risk for the elderly.
      Interactions between warfarin and antibiotics including trimethoprim/sulfamethoxazole (TMP/SMX),
      • Glasheen J.J.
      • Fugit R.V.
      • Prochazka A.V.
      The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens.
      • Visser L.E.
      • Penning-van Bees F.J.
      • Kasbergen A.A.
      • et al.
      Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants.
      metronidazole,
      • O'Reilly R.A.
      The stereoselective interaction of warfarin and metronidazole in man.
      fluconazole,
      • Kunze K.L.
      • Wienkers L.C.
      • Thummel K.E.
      • Trager W.F.
      Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.
      • Black D.J.
      • Kunze K.L.
      • Wienkers L.C.
      • et al.
      Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies.
      ciprofloxacin,
      • Israel D.S.
      • Stotka J.
      • Rock W.
      • et al.
      Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin.
      levofloxacin,
      • Glasheen J.J.
      • Fugit R.V.
      • Prochazka A.V.
      The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens.
      azithromycin,
      • Lane G.
      Increased hypoprothrombinemic effect of warfarin possibly induced by azithromycin.
      • Woldtvedt B.R.
      • Cahoon C.L.
      • Bradley L.A.
      • Miller S.J.
      Possible increased anticoagulation effect of warfarin induced by azithromycin.
      and clarithromycin
      • Recker M.W.
      • Kier K.L.
      Potential interaction between clarithromycin and warfarin.
      have been described. In addition to interacting with warfarin via cytochrome P450-2C9, these antibiotics also may eliminate vitamin K-producing bacteria in the intestines to further alter international normalized ratio (INR).
      • Udall J.A.
      Human sources and absorption of vitamin K in relation to anticoagulation stability.
      • Hochman R.
      • Clark J.
      • Rolla A.
      • et al.
      Bleeding in patients with infections. Are antibiotics helping or hurting?.
      Conversely, cephalexin and clindamycin are believed to have only minimal interactions with warfarin. Prior studies have demonstrated that warfarin users are commonly prescribed antibiotics with known interactions.
      • Lane M.A.
      • Devine S.T.
      • McDonald J.R.
      High-risk antimicrobial prescriptions among ambulatory patients on warfarin.
      In this study, we used the Department of Veterans Affairs (VA) national databases to characterize the risk of serious bleeding events that require hospitalization among warfarin users who receive antibiotics. We have utilized VA pharmacy, administrative, and laboratory databases to identify risk factors for serious bleeding events.

      Methods

      This study was approved by the institutional review boards of the participating institutions.

      Data Sources

      Inpatient and outpatient International Classification of Diseases, Version 9, Clinical Modification (ICD-9-CM) diagnosis codes, encounter data, and patient demographic data were obtained from the VA's Austin Information Technology Center, a repository for VA administrative data. Pharmacy data for all study subjects, including both inpatient and outpatient medications, were obtained from the VA's Pharmacy Benefits Management program.

      Study Population

      The study included all veterans who were prescribed warfarin for ≥30 days without interruption from a VA between October 1, 2002 and September 1, 2008. Subjects were required to have had ≥2 INR laboratory results while receiving warfarin to demonstrate utilization of the VA for ongoing health care.

      Subject-time in Cohort

      Subject-time began 30 days after the date of the first warfarin prescription, in order to establish a stable warfarin regimen and exclude the initial dose-finding period during which bleeding risk may be elevated. Because prescription length for warfarin is 30 days, subject-time continued while warfarin prescriptions continued, allowing lapses of up to 30 days between subscriptions. Subject-time ended 30 days after the last projected warfarin pill (last prescription date plus duration of prescription). Subjects contributed more than one continuous treatment course of warfarin if they were treated with warfarin on multiple occasions with a >30-day lapse during the study period.

      Antibiotic Exposure

      Subjects were considered to be receiving an antibiotic from the date of prescription plus the number of days prescribed. Antibiotic prescriptions lasting <3 days were excluded. Antibiotics were grouped based upon what is known about their degree of interaction with warfarin. Antibiotics known to interact in a way that may increase bleeding risk were considered “high-risk.” High-risk antibiotics included trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin. Low-risk antibiotics included clindamycin and cephalexin. For patients receiving 2 high-risk antibiotics, outcomes were attributed to each medication equally. Outcomes that occurred among patients receiving high- and low-risk antibiotics were attributed to the high-risk antibiotic.

      Primary Outcome

      The primary outcome was hospitalization for serious bleeding event. A hospitalization was considered to be caused by a serious bleeding event if an ICD-9-CM code found in the Appendix (online) occurred in the field designating primary reason for hospitalization. ICD-9-CM codes for serious bleeding event are a modification of a previously described group of codes.
      • Arnason T.
      • Wells P.S.
      • van Walraven C.
      • Forster A.J.
      Accuracy of coding for possible warfarin complications in hospital discharge abstracts.
      A bleeding event that occurred during subject-time was attributed to an antibiotic if it occurred within 30 days of the last prescribed dose of the antibiotic.

      Secondary Outcomes

      Secondary outcomes included elevations in INR >4, and serious bleeding events coded in secondary diagnosis fields of a hospitalization.

      Data Analysis

      For descriptive and bivariate analysis, chi-squared test was used for dichotomous variables. Continuous variables were analyzed using Student's t test. A 2-sided P-value of ≤.05 was considered statistically significant. Risk of outcomes was described using hazard ratios and 95% confidence intervals. Cox proportional hazards regression was performed for time-to-event analysis. Regression models were adjusted for age, sex, race, comorbid diagnosis, indication for anticoagulation, and co-prescription of other medications known to interact with warfarin. Each drug was modeled separately and adjusted as described. Because patients living further from a VA hospital are more likely to seek care at a non-VA facility in case of emergency, the model was adjusted for proximity to the nearest VA hospital based upon zip code data. Patients residing in zip codes where the mean distance was >20 miles from the nearest VA hospital were considered to be distant to a VA hospital. Maximum INR values within 30 days of antibiotic exposure were analyzed by antibiotic. During data analysis, INR values from 2 VA hospitals were found to have a disproportionate number of values >12. After closer evaluation, these values likely represented a systematic error (entry of prothrombin times instead of INR into the INR field), and reported INR values from these facilities were excluded from analysis. All analyses were performed using SAS software version 6.12 (SAS Institute, Cary, NC).

      Validation

      Fifty patients who were hospitalized for a bleeding event and 50 patients not hospitalized for a bleeding event at a single center during the study period were randomly identified by ICD-9-CM codes. All medical records, including admission histories, discharge summaries, and daily notes were reviewed by 2 physicians (MAL and JRM). Hospitalization was classified as “for a bleeding event” or “not for a bleeding event” by each reviewer, based on their interpretations of primary reason for hospitalization. Consensus was achieved between the 2 reviewers in all cases. Adjusted sensitivity and specificity were calculated by extrapolating the validation results over the entire study population.

      Results

      There were a total of 22,272 veterans on warfarin for ≥30 days who also were prescribed an included antibiotic during the study period (Table 1). There were 8194 patients who received a low-risk antibiotic and 14,078 patients who received a high-risk antibiotic. Patients receiving a high-risk antibiotic were slightly older and were more likely to have a malignancy or chronic lung disease. Diabetes mellitus, hypertension, and alcohol dependence were slightly less common among those receiving a high-risk antibiotic. Those receiving a high-risk antibiotic were less likely to be receiving anticoagulation for heart valve replacement compared with warfarin users who received low-risk antibiotics. Patients prescribed a high-risk antibiotic also were more frequently receiving other medications known to interact with warfarin when compared with those receiving a low-risk antibiotic. More patients receiving a high-risk antibiotic lived >20 miles from the nearest VA when compared with those receiving low-risk antibiotics. Additionally, more patients receiving a high-risk antibiotic had an INR test within 3-14 days of antibiotic prescription when compared with those who were prescribed a low-risk antibiotic.
      Table 1Demographic and Clinical Characteristics
      TotalLow-risk Antibiotic
      Low-risk antibiotics: clindamycin, cephalexin.
      High-risk Antibiotic
      High-risk antibiotics: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin and clarithromycin.
      P-Value
      n22,722819414,078
      Mean age, years (SD)69.5 (10.8)68.8 (11.1)69.8 (10.7)<.0001
      Sex (% male)21,702 (97.4)8031 (98.0)13,167 (97.1)<.0001
      Race (%)
       White19,631 (88.1)7323 (89.4)12,308 (87.4)<.0001
       Black1803 (8.1)568 (6.9)1235 (8.8)<.0001
       Other838 (3.8)303 (3.7)535 (3.8).7
      Comorbidities (%)
       Diabetes mellitus9930 (44.6)3739 (45.6)6191 (44.0).02
       Hypertension19,592 (88.0)7268 (88.7)12,324 (87.5).01
       Heart failure9701 (43.6)3518 (42.9)6183 (43.9).2
       Malignancy6676 (30.0)2369 (28.9)4307 (30.6).008
       Chronic lung disease11,170 (50.2)3610 (44.1)7560 (53.7)<.0001
       Renal failure3501 (15.7)1301 (15.9)2200 (15.6).6
       Liver disease930 (4.2)335 (4.1)595 (4.2).6
       Ischemic heart disease14,745 (66.2)5395 (65.8)9350 (66.4).4
       Valvular heart disease5663 (25.4)2135 (26.1)3528 (25.1).1
       Alcohol dependence1624 (7.3)643 (7.9)981 (7.0).02
       None of the above423 (1.9)170 (2.1)253 (1.8).1
      Indication for anticoagulation (%)
       Heart valve replacement4325 (19.4)1672 (20.4)2653 (18.9).005
       Other19,113 (85.8)7028 (85.8)12,085 (85.8).9
      Interacting medications (%)19,555 (87.8)6872 (83.9)12,085 (85.8)<.0001
      Distance >20 miles (%)12,288 (55.2)4415 (53.9)7873 (55.9).003
      Early INR check
      Low-risk antibiotics: clindamycin, cephalexin.
      (%)
      9770 (43.8)3504 (42.8)6266 (44.5).01
      INR = international normalized ratio.
      Low-risk antibiotics: clindamycin, cephalexin.
      High-risk antibiotics: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin and clarithromycin.
      There were 36 and 93 bleeding events among patients receiving a low- and high-risk antibiotic, respectively (Table 2). The demographic characteristics between those who had a serious bleeding event and those that did not were largely similar. Malignancy (hazard ratio [HR] 1.89; 95% confidence interval [CI], 1.33-2.70) and renal failure (HR 2.53; 95% CI, 1.74-3.68) were associated with an increased risk of serious bleeding events. Co-prescription of other interacting medications increased the risk of serious bleeding events (HR 2.29; 95% CI, 1.01-5.19). Early INR evaluation, occurring within 3-14 days of antibiotic co-prescription, reduced the risk of serious bleeding events (HR 0.61; 95% CI, 0.42-0.88). Receipt of a high-risk antibiotic also increased the risk of serious bleeding when compared with receipt of a low-risk antibiotic (HR 1.48; 95% CI, 1.00-2.19). Of the individual high-risk antibiotics, azithromycin was associated with an increased risk of serious bleeding event when compared with the low-risk antibiotics (HR 1.93; 95% CI, 1.13-3.30). When ICD-9-CM codes for serious bleeding events in either the primary or secondary diagnosis position were considered, diabetes mellitus (HR 1.25; 95% CI, 1.01-1.56), malignancy (HR 1.56; 95% CI, 1.27-1.97), and renal failure (HR 2.07; 95% CI, 1.64-2.60) were associated with an increased risk for serious bleeding events. Early INR evaluation was associated with a similar reduction in risk of bleeding as seen in the primary outcome measure. Gastrointestinal bleeding events accounted for 57% of all serious bleeding events among patients receiving high-risk antibiotics, followed by bleeding in the genitourinary system (24.7%).
      Table 2Multivariate Predictors of Bleeding Event as Primary Diagnosis
      (+) Bleeding Event(−) Bleeding EventHR (95% CI)
      n12922,143-
      Mean age (SD)71.2 (9.8)69.5 (10.8)1.00 (0.99-1.02)
      Sex (% male)123 (95.4)21,579 (97.5)0.5 (0.22-1.13)
      Race (%)
       White120 (93.0)19,511 (88.1)Referent
       Black6 (4.7)1797 (8.1)0.47 (0.21-1.10)
       Other3 (2.3)835 (3.8)0.61 (0.19-1.94)
      Comorbidities (%)
       Diabetes mellitus67 (51.9)9866 (44.6)1.07 (0.74 -1.55)
       Hypertension124 (96.1)19,470 (87.9)2.15 (0.87-5.31)
       Heart failure78 (60.5)9629 (43.5)1.21 (0.82-1.80)
       Malignancy64 (49.6)6619 (29.9)1.89 (1.33-2.70)
       Chronic lung disease81 (62.8)11,095 (50.1)1.16 (0.80-1.68)
       Renal failure50 (38.8)3458 (15.6)2.53 (1.74-3.68)
       Liver disease12 (9.3)920 (4.2)1.61 (0.86-3.00)
       Ischemic heart disease99 (76.7)14,648 (66.2)0.83 (0.60-1.44)
       Valvular heart disease55 (42.6)5611 (25.3)1.34 (0.90-1.98)
       Alcohol dependence13 (10.1)1611 (7.3)1.47 (0.82-2.63)
       None of the above0 (0.0)423 (1.9)Referent
      Indication for anticoagulation
       Heart valve replacement51 (39.5)4275 (19.3)2.12 (1.43-3.14)
       Other116 (89.9)19,000 (85.8)1.30 (0.71-2.38)
      Interacting medications (%)123 (95.4)19,436 (87.8)2.29 (1.01-5.19)
      Distance > 20 miles (%)74 (57.4)12,216 (55.2)1.15 (0.80-1.64)
      Early INR check
      INR evaluation within 3-14 days of antibiotic co-prescription.
      (%)
      48 (37.2)9714 (43.9)0.61 (0.42-0.88)
      High-risk antibiotic (%)93 (72.1)13,988 (63.2)1.48 (1.00-2.19)
       TMP/SMX14 (10.9)1964 (8.9)1.79 (0.97-3.32)
       Ciprofloxacin30 (23.3)4349 (19.6)1.42 (0.87-2.31)
       Levofloxacin11 (8.5)2521 (11.4)1.30 (0.66-2.55)
       Metronidazole5 (3.9)755 (3.4)1.63 (0.61-4.39)
       Fluconazole3 (2.3)287 (1.3)2.11 (0.60-7.34)
       Azithromycin33 (25.6)5725 (25.9)1.93 (1.13-3.30)
       Clarithromycin2 (1.6)481 (2.3)1.71 (0.45-6.57)
       Co-prescribed high-risk8 (6.2)991 (4.5)1.75 (0.79-3.89)
       Co-prescribed high- and low-risk8 (6.2)1162 (5.2)1.35 (0.61-2.99)
      Low-risk antibiotic (%)36 (27.9)8155 (36.8)Referent
       Clindamycin11 (8.5)1862 (8.4)0.58 (0.31-1.09)
       Cephalexin34 (26.4)6561 (29.6)0.07 (0.48-1.04)
      CI = confidence interval; HR = hazard ratio; INR = international normalized ratio; TMP/SMX = trimethoprim/sulfamethoxazole.
      INR evaluation within 3-14 days of antibiotic co-prescription.
      In the secondary outcomes analysis examining ICD-9-CM codes for serious bleeding seen in either primary or secondary coding position, TMP/SMX (HR 2.09; 95% CI, 1.45-3.02), ciprofloxacin (HR 1.87; 95% CI, 1.42-2.50), levofloxacin (HR 1.77; 95% CI, 1.22-2.55), azithromycin (HR 1.64; 95% CI, 1.16-2.33), and clarithromycin (HR 2.40; 95% CI, 1.16-4.94) were associated with increased risk of serious bleeding when compared with the low-risk antibiotics. Alterations in INR were common among warfarin users receiving antibiotics (Table 3). Among those prescribed a high-risk antibiotic, 7.8% had INR elevations >4-≤6. Among individual antibiotics, metronidazole (10.1%), fluconazole (13.9%), and receipt of 2 or more high-risk antibiotics (11.1%) was associated with elevations of INR >4-≤6. When compared with those prescribed a low-risk antibiotic, significant INR elevations ≥6 were seen in 9.7% (P <.0001) and 4.9% (P <.0001) of patients receiving fluconazole and metronidazole, respectively. There were no substantial differences in types of bleeding events between antibiotic groups (data not shown).
      Table 3Alterations in INR Following Antibiotic Administration
      TotalPeak INR
      ≤4>4-≤6>6
      High-risk antibiotic (%)22,38120,061 (89.6)1748 (7.8)572 (2.6)
       TMP/SMX28282538 (89.7)227 (8.0)63 (2.2)
       Ciprofloxacin68446195 (90.5)514 (7.5)135 (2.0)
       Levofloxacin33432972 (88.9)279 (8.4)92 (2.8)
       Metronidazole1003853 (85.0)101 (10.1)49 (4.9)
       Fluconazole381291 (76.4)53 (13.9)37 (9.7)
       Azithromycin93318526 (91.4)649 (7.0)156 (1.6)
       Clarithromycin584521 (89.2)46 (7.9)17 (2.9)
       Co-prescribed high-risk13571153 (85.0)151 (11.1)53 (4.0)
       Co-prescribed high- and low-risk24012089 (87.0)226 (9.4)86 (3.6)
      Low-risk antibiotic (%)12,97311,799 (91.0)931 (7.2)243 (2.9)
      INR = international normalized ratio; TMP/SMX = trimethoprim/sulfamethoxazole.
      The medical records of 50 patients identified by ICD-9-CM codes as being hospitalized for a bleeding event and 50 patients not hospitalized for a bleeding event were reviewed. Bleeding events were confirmed in 48 patients, resulting in a positive predictive value of the administrative data to identify a hospitalization for bleeding of 96%. There were 5 hospitalizations for bleeding among the 50 patients identified as not having a bleeding event during the study period. The sensitivity and specificity of the ICD-9 codes to identify a bleeding event was 91% and 96%, respectively. The kappa was 0.86, indicating excellent agreement between the code and our gold standard.

      Discussion

      In this large cohort of warfarin users in the VA health care system, we describe the risk of and risk factors for serious bleeding events following prescription of selected antibiotics. We demonstrated excellent validity of our outcome measure using electronic medical records. We have shown that patients receiving high-risk antibiotics are at increased risk for serious bleeding events compared with those receiving low-risk antibiotics. Warfarin users who received azithromycin had nearly twice the risk of hospitalization for serious bleeding compared with low-risk antibiotics. When ICD-9-CM codes for serious bleeding were permitted in the primary or secondary reasons for admission, TMP/SMX (HR 2.09; 95% CI, 1.45-3.02), ciprofloxacin (HR 1.87; 95% CI, 1.42-2.50), levofloxacin (HR 1.77; 95% CI, 1.22-2.55), azithromycin (HR 1.64; 95% CI, 1.16-2.33), and clarithromycin (HR 2.40; 95% CI, 1.16-4.94) all increased the risk for serious bleeding events.
      Bleeding events were the primary reason for admission in 0.6% of all patients included in this study. A study utilizing a 5% national sample of Medicare beneficiaries with Part D benefits, 2.9% of warfarin users met the case definition of a serious bleeding event. However, differences in study methodology may account for the difference in frequency of bleeding events. In the Medicare study, 78.7% of all warfarin users who had a bleeding event were not exposed to antibiotics before the bleeding event. Our study includes only those patients who are prescribed warfarin and an antibiotic concurrently based on VA pharmacy data. Additionally, this Medicare study includes bleeding events occurring >60 days after antibiotic exposure, whereas our study includes those within 30 days of co-prescription.
      • Baillargeon J.
      • Holmes H.M.
      • Lin Y.-L.
      • Raji M.A.
      • Sharma G.
      • Kuo Y.F.
      Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults.
      A study of 19,935 new users of coumarin anticoagulants in the Netherlands found a 4- to 7-fold increased risk of bleeding related to antibiotics.
      • Penning-van Beest F.
      • Erkens J.
      • Petersen K.U.
      • et al.
      Main comedications associated with major bleeding during anticoagulant therapy with coumarins.
      However, the study did not control for potential confounders. Additionally, patients included in the study were incident users of coumarin anticoagulants. Prior studies have shown significantly higher rates of serious bleeding events in the period immediately after initiation of anticoagulation.
      • Linkins L.A.
      • Choi P.T.
      • Douketis J.D.
      Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis.
      • Landefeld C.S.
      • Goldman L.
      Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy.
      • Douketis J.D.
      • Foster G.A.
      • Crowther M.A.
      • et al.
      Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy.
      • Fihn S.D.
      • McDonell M.
      • Martin D.
      • et al.
      Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group.
      We excluded the early period after initiation in order to estimate the rate of complications during stable long-term use.
      We found that exposure to high-risk antibiotics increases the risk of serious bleeding events as primary diagnosis by nearly 50% when compared with low-risk antibiotics. Azithromycin nearly doubled the risk of a serious bleeding event. When primary and secondary diagnosis codes were included, nearly all high-risk antibiotics increased the risk for bleeding. TMP/SMX was associated with a >2-fold increased risk for bleeding. Other studies also have found that TMP/SMX,
      • Baillargeon J.
      • Holmes H.M.
      • Lin Y.-L.
      • Raji M.A.
      • Sharma G.
      • Kuo Y.F.
      Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults.
      • Fischer H.D.
      • Juurlink D.N.
      • Mamdani M.M.
      • et al.
      Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study.
      • Schelleman H.
      • Bilker W.B.
      • Brensinger C.M.
      • et al.
      Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding.
      fluoroquinolones,
      • Baillargeon J.
      • Holmes H.M.
      • Lin Y.-L.
      • Raji M.A.
      • Sharma G.
      • Kuo Y.F.
      Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults.
      and macrolides
      • Baillargeon J.
      • Holmes H.M.
      • Lin Y.-L.
      • Raji M.A.
      • Sharma G.
      • Kuo Y.F.
      Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults.
      significantly increase the risk for serious bleeding. Prior studies have found a significant increased risk of serious bleeding among warfarin users who received fluconazole.
      • Baillargeon J.
      • Holmes H.M.
      • Lin Y.-L.
      • Raji M.A.
      • Sharma G.
      • Kuo Y.F.
      Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults.
      • Schelleman H.
      • Bilker W.B.
      • Brensinger C.M.
      • et al.
      Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding.
      However, only 3 patients who received fluconazole in our study had a bleeding event, and thus we are likely underpowered to show a clinically significant interaction. Likewise, there were only 5 warfarin users who were prescribed metronidazole and had a bleeding event. Infection may cause elevations in INR independent of antibiotic use.
      • Clark N.P.
      • Delate T.
      • Riggs C.S.
      • et al.
      Warfarin interactions with antibiotics in the ambulatory care setting.
      However, our results suggest that infection alone does not alter the bleeding risk among warfarin users. All patients in our cohort received antibiotics for an infection, but only those who received a high-risk antibiotic were at increased risk of serious bleeding events.
      Anticoagulation intensity, as measured by INR, has been associated with increased risk of serious bleeding.
      • Fang M.C.
      • Chang Y.
      • Hylek E.M.
      • et al.
      Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation.
      • Altman R.
      • Rouvier J.
      • Gurfinkel E.
      • et al.
      Comparison of two levels of anticoagulant therapy in patients with substitute heart valves.
      • Hull R.
      • Hirsh J.
      • Jay R.
      • et al.
      Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
      • Saour J.N.
      • Sieck J.O.
      • Mamo L.A.
      • Gallus A.S.
      Trial of different intensities of anticoagulation in patients with prosthetic heart valves.
      • Turpie A.G.
      • Gunstensen J.
      • Hirsh J.
      • et al.
      Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement.
      Risk of intracranial hemorrhage has been shown to increase significantly at INR values >3.5.
      • Fang M.C.
      • Chang Y.
      • Hylek E.M.
      • et al.
      Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation.
      • Singer D.E.
      • Chang Y.
      • Fang M.C.
      • et al.
      Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study.
      Many studies demonstrating INR alterations after antibiotic administration have been relatively small. Among 27 patients on stable warfarin regimens who were co-prescribed levofloxacin, 11% had an elevation of INR ≥5. Among 16 patients prescribed TMP/SMX, 31% had an elevation of INR ≥5.
      • Glasheen J.J.
      • Fugit R.V.
      • Prochazka A.V.
      The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens.
      In our study, elevations in INR were seen among all high-risk antibiotics. Notably, 4.9% of patients receiving metronidazole and 9.7% of those prescribed fluconazole had a peak INR >6, putting these patients at significant risk for harm. Prior studies suggest that infection may independently cause elevations in INR.
      • Clark N.P.
      • Delate T.
      • Riggs C.S.
      • et al.
      Warfarin interactions with antibiotics in the ambulatory care setting.
      It is possible that some of the alterations in INR are due to the underlying infection. In our multivariate analysis, INR evaluation within 3-14 days of antibiotic co-prescription reduced the risk of serious bleeding event by 39%. This finding strongly supports early INR check after co-prescription.
      Our study has several limitations that may influence the results. This study relies on the accuracy of ICD-9-CM codes to identify bleeding events. Evaluations of the ICD-9-CM codes used in this study have demonstrated the ability to accurately identify serious bleeding events.
      • Arnason T.
      • Wells P.S.
      • van Walraven C.
      • Forster A.J.
      Accuracy of coding for possible warfarin complications in hospital discharge abstracts.
      • Cunningham A.
      • Stein C.M.
      • Chung C.P.
      • Daugherty J.R.
      • Smalley W.E.
      • Ray W.A.
      An automated database case definition for serious bleeding related to oral anticoagulant use.
      Additionally, our validation demonstrated excellent agreement between the ICD-9-CM code definition and the electronic medical records (kappa = 0.86). However, it is possible that some serious bleeding events were misclassified. In order for us to identify an outcome, a subject must have utilized a VA health care facility for their health care needs. We attempted to limit the impact of this by including only patients who have ≥2 INR values checked in the VA system before outcome, to indicate utilization of the VA for health care services. Additionally, our multivariate models included distance to the nearest VA hospital to control for the higher likelihood of seeking non-VA care for a bleeding event in subjects residing further from the nearest VA facility. In addition to antibiotics, multiple medications interact with warfarin. We included interacting medications as a dichotomous variable in our models, but did not assess the impact of individual medications. However, given the complex nature of these multiple drug interactions, this approach may approximate real-world clinical practice. Additionally, we were unable to assess patient adherence to antibiotic therapy, which could alter our estimate of the interaction effect.
      Although warfarin is effective in the prevention and treatment of thromboembolic events, its narrow therapeutic index and multiple drug interactions put patients at risk for serious bleeding events. In this study we have used national VA administrative data to demonstrate an increased risk for serious bleeding events among warfarin users who receive high-risk antibiotics. Our findings suggest that when possible, clinicians should choose antibiotics with low potential to interact with warfarin. Our data strongly support INR monitoring after co-prescription as a means to decrease risk of hospitalization for serious bleeding.

      Appendix

      Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth Revision (ICD-9) Codes Used
      CPT Codes
      364.30 Transfusion, blood or blood components (nonspecific)
      ICD-9 Codes
      99.03 Transfusion of blood (whole) NOS (nonspecific)
      99.04 Transfusion of packed cells (nonspecific)
      285.1 Acute post-hemorrhage anemia (nonspecific)
      287.9 Hemorrhagic diathesis (nonspecific)
      360.43 Eye hemorrhage (Ocular)
      362.81 Retinal hemorrhage (Ocular)
      363.61 Choroid hemorrhage (Ocular)
      364.41 Iris/ciliary body hemorrhage (Ocular)
      376.32 Orbital hemorrhage (Ocular)
      379.23 Vitreous hemorrhage (Ocular)
      430 Subarachnoid hemorrhage (CNS)
      431 Intracerebral hemorrhage (CNS)
      432x Other and unspecified intracranial hemorrhage (CNS)
      456.0, .20 Esophageal varices with bleeding (GI)
      459.0 Hemorrhage, unspecified/spontaneous hemorrhage (nonspecific)
      530.21 Esophageal ulcer with bleeding (GI)
      530.82 Esophageal hemorrhage (GI)
      531.0x Gastric ulcer – acute with hemorrhage (GI)
      531.2x Gastric ulcer – acute with hemorrhage and perforation (GI)
      531.4x Gastric ulcer – chronic or unspecified with hemorrhage (GI)
      531.6x Gastric ulcer – chronic or unspecified with hemorrhage and perforation (GI)
      532.0x Duodenal ulcer – acute with hemorrhage (GI)
      532.2x Duodenal ulcer – acute with hemorrhage and perforation (GI)
      532.4x Duodenal ulcer – chronic or unspecified with hemorrhage (GI)
      532.6x Duodenal ulcer – chronic or unspecified with hemorrhage and perforation (GI)
      533.0x Peptic ulcer, site unspecified – acute with hemorrhage (GI)
      533.2x Peptic ulcer, site unspecified – acute with hemorrhage and perforation (GI)
      533.4x Peptic ulcer, site unspecified – chronic or unspecified with hemorrhage (GI)
      533.6x Peptic ulcer, site unspecified – chronic or unspecified with hemorrhage and Perforation (GI)
      534.0x Gastrojejeunal ulcer – acute with hemorrhage (GI)
      534.2x Gastrojejeunal ulcer – acute with hemorrhage and perforation (GI)
      534.4x Gastrojejeunal ulcer – chronic or unspecified with hemorrhage (GI)
      534.6x Gastrojejeunal ulcer – chronic or unspecified with hemorrhage and perforation (GI)
      535.01 Acute gastritis with hemorrhage (GI)
      535.11 Atrophic gastritis with hemorrhage (GI)
      535.21 Gastric mucosal hypertrophy with hemorrhage (GI)
      535.31 Alcoholic gastritis with hemorrhage (GI)
      535.41 Other gastritis with hemorrhage (GI)
      535.51 Unspec. gastritis with hemorrhage (GI)
      535.61 Duodenitis with hemorrhage (GI)
      535.71 Eosinophilic gastritis with hemorrhage (GI)
      537.83 Gastric angiodysplasia with hemorrhage (GI)
      537.84 Hemorrhagic Dieulafoy lesion of stomach/duodenum (GI)
      562.02 Small intestine diverticulosis with hemorrhage (GI)
      562.03 Small intestine diverticulitis with hemorrhage (GI)
      562.12 Colonic diverticulosis with hemorrhage (GI)
      562.13 Colonic diverticulitis with hemorrhage (GI)
      568.81 Hemoperitoneum – non-traumatic (GI)
      569.3 Hemorrhage of the rectum and anus (GI)
      569.85-6 Angiodysplasia with hemorrhage, Dieulafoy lesion (hemorrhagic)(GI)
      578 GI hemorrhage (GI)
      578.0 Hematemesis (GI)
      578.1 Blood in the stool (melena) (GI)
      578.9 Hemorrhage GI tract, unspecified (GI)
      595.0 Hemorrhagic cystitis (GU)
      596.7 Hemorrhage into bladder wall (GU)
      599.7 Hematuria (GU)
      626.2 Excessive menstruation (GU)
      626.6 Metrorrhagia (GU)
      719.1x Hemarthrosis (other)
      784.7 Epistaxis (other)
      784.8 Hemorrhage from throat (other)
      786.3 Hemoptysis (pulmonary)
      Bleeding event by system:
      CNS:
      430 Subarachnoid hemorrhage
      431 Intracerebral hemorrhage
      432x Other and unspecified intracranial hemorrhage
      Ocular:
      360.43 Eye hemorrhage (Ocular)
      362.81 Retinal hemorrhage (Ocular)
      363.61 Choroid hemorrhage (Ocular)
      364.41 Iris/ciliary body hemorrhage (Ocular)
      376.32 Orbital hemorrhage (Ocular)
      379.23 Vitreous hemorrhage (Ocular)
      GI:
      456.0, .20 Esophageal varices with bleeding (GI)
      530.21 Esophageal ulcer with bleeding (GI)
      530.82 Esophageal hemorrhage (GI)
      531.0x Gastric ulcer – acute with hemorrhage (GI)
      531.2x Gastric ulcer – acute with hemorrhage and perforation (GI)
      531.4x Gastric ulcer – chronic or unspecified with hemorrhage (GI)
      531.6x Gastric ulcer – chronic or unspecified with hemorrhage and perforation (GI)
      532.0x Duodenal ulcer – acute with hemorrhage (GI)
      532.2x Duodenal ulcer – acute with hemorrhage and perforation (GI)
      532.4x Duodenal ulcer – chronic or unspecified with hemorrhage (GI)
      532.6x Duodenal ulcer – chronic or unspecified with hemorrhage and perforation (GI)
      533.0x Peptic ulcer, site unspecified – acute with hemorrhage (GI)
      533.2x Peptic ulcer, site unspecified – acute with hemorrhage and perforation (GI)
      533.4x Peptic ulcer, site unspecified – chronic or unspecified with hemorrhage (GI)
      533.6x Peptic ulcer, site unspecified – chronic or unspecified with hemorrhage and perforation (GI)
      534.0x Gastrojejeunal ulcer – acute with hemorrhage (GI)
      534.2x Gastrojejeunal ulcer – acute with hemorrhage and perforation (GI)
      534.4x Gastrojejeunal ulcer – chronic or unspecified with hemorrhage (GI)
      534.6x Gastrojejeunal ulcer – chronic or unspecified with hemorrhage and perforation (GI)
      535.01 Acute gastritis with hemorrhage (GI)
      535.11 Atrophic gastritis with hemorrhage (GI)
      535.21 Gastric mucosal hypertrophy with hemorrhage (GI)
      535.31 Alcoholic gastritis with hemorrhage (GI)
      535.41 Other gastritis with hemorrhage (GI)
      535.51 Unspec. gastritis with hemorrhage (GI)
      535.61 Duodenitis with hemorrhage (GI)
      535.71 Eosinophilic gastritis with hemorrhage (GI)
      537.83 Gastric angiodysplasia with hemorrhage (GI)
      537.84 Hemorrhagic Dieulafoy lesion of stomach/duodenum (GI)
      562.02 Small intestine diverticulosis with hemorrhage (GI)
      562.03 Small intestine diverticulitis with hemorrhage (GI)
      562.12 Colonic diverticulosis with hemorrhage (GI)
      562.13 Colonic diverticulitis with hemorrhage (GI)
      568.81 Hemoperitoneum – non-traumatic (GI)
      569.3 Hemorrhage of the rectum and anus (GI)
      569.85-6 Angiodysplasia with hemorrhage, Dieulafoy lesion (hemorrhagic)(GI)
      578 GIhemorrhage (GI)
      578.0 Hematemesis (GI)
      578.1 Blood in the stool (melena) (GI)
      578.9 Hemorrhage GI tract, unspecified (GI)
      GU:
      595.0 Hemorrhagic cystitis (GU)
      596.7 Hemorrhage into bladder wall (GU)
      599.7 Hematuria (GU)
      626.2 Excessive menstruation (GU)
      626.6 Metrorrhagia (GU)
      Nonspecific:
      36430 Transfusion, blood or blood components (nonspecific)
      99.03 Transfusion of blood (whole) NOS (nonspecific)
      99.04 Transfusion of packed cells (nonspecific)
      285.1 Acute posthemorrhage anemia (nonspecific)
      287.9 Hemorrhagic diathesis (nonspecific)
      459.0 Hemorrhage, unspecified/spontaneous hemorrhage (nonspecific)
      Pulmonary:
      786.3 Hemoptysis
      Other:
      719.1x Hemarthrosis (other)
      784.7 Epistaxis (other)
      784.8 Hemorrhage from throat (other)

      References

      1. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators.
        N Engl J Med. 1990; 323: 1505-1511
        • Ezekowitz M.D.
        • Bridgers S.L.
        • James K.E.
        • et al.
        Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.
        N Engl J Med. 1992; 327: 1406-1412
      2. Stroke Prevention in Atrial Fibrillation Study. Final results.
        Circulation. 1991; 84: 527-539
        • Petersen P.
        • Boysen G.
        • Godtfredsen J.
        • et al.
        Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
        Lancet. 1989; 1: 175-179
        • Bonow R.O.
        • Carabello B.A.
        • Chatterjee K.
        • et al.
        2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease.
        Circulation. 2008; 118: e523-e661
        • Kearon C.
        • Kahn S.R.
        • Agnelli G.
        • et al.
        Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
        Chest. 2008; 133: 454S-545S
        • Schulman S.
        • Beyth R.J.
        • Kearon C.
        • Levine M.N.
        Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
        Chest. 2008; 133: 257S-298S
        • Fang M.C.
        • Chang Y.
        • Hylek E.M.
        • et al.
        Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation.
        Ann Intern Med. 2004; 141: 745-752
        • Hirsh J.
        • Dalen J.
        • Anderson D.R.
        • et al.
        Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.
        Chest. 2001; 119: 8S-21S
        • Gage B.F.
        • Lesko L.J.
        Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues.
        J Thromb Thrombolysis. 2008; 25: 45-51
        • Gage B.F.
        • Eby C.
        • Johnson J.A.
        • et al.
        Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.
        Clin Pharmacol Ther. 2008; 84: 326-331
        • Schulman S.
        Clinical practice. Care of patients receiving long-term anticoagulant therapy.
        N Engl J Med. 2003; 349: 675-683
        • Holbrook A.M.
        • Pereira J.A.
        • Labiris R.
        • et al.
        Systematic overview of warfarin and its drug and food interactions.
        Arch Intern Med. 2005; 165: 1095-1106
        • Jacobs L.G.
        Warfarin pharmacology, clinical management, and evaluation of hemorrhagic risk for the elderly.
        Cardiol Clin. 2008; 26 (v): 157-167
        • Glasheen J.J.
        • Fugit R.V.
        • Prochazka A.V.
        The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens.
        J Gen Intern Med. 2005; 20: 653-656
        • Visser L.E.
        • Penning-van Bees F.J.
        • Kasbergen A.A.
        • et al.
        Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants.
        Thromb Haemost. 2002; 88: 705-710
        • O'Reilly R.A.
        The stereoselective interaction of warfarin and metronidazole in man.
        N Engl J Med. 1976; 295: 354-357
        • Kunze K.L.
        • Wienkers L.C.
        • Thummel K.E.
        • Trager W.F.
        Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.
        Drug Metab Dispos. 1996; 24: 414-421
        • Black D.J.
        • Kunze K.L.
        • Wienkers L.C.
        • et al.
        Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies.
        Drug Metab Dispos. 1996; 24: 422-428
        • Israel D.S.
        • Stotka J.
        • Rock W.
        • et al.
        Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin.
        Clin Infect Dis. 1996; 22: 251-256
        • Lane G.
        Increased hypoprothrombinemic effect of warfarin possibly induced by azithromycin.
        Ann Pharmacother. 1996; 30: 884-885
        • Woldtvedt B.R.
        • Cahoon C.L.
        • Bradley L.A.
        • Miller S.J.
        Possible increased anticoagulation effect of warfarin induced by azithromycin.
        Ann Pharmacother. 1998; 32: 269-270
        • Recker M.W.
        • Kier K.L.
        Potential interaction between clarithromycin and warfarin.
        Ann Pharmacother. 1997; 31: 996-998
        • Udall J.A.
        Human sources and absorption of vitamin K in relation to anticoagulation stability.
        JAMA. 1965; 194: 127-129
        • Hochman R.
        • Clark J.
        • Rolla A.
        • et al.
        Bleeding in patients with infections. Are antibiotics helping or hurting?.
        Arch Intern Med. 1982; 142: 1440-1442
        • Lane M.A.
        • Devine S.T.
        • McDonald J.R.
        High-risk antimicrobial prescriptions among ambulatory patients on warfarin.
        J Clin Pharm Ther. 2012; 37: 157-160
        • Arnason T.
        • Wells P.S.
        • van Walraven C.
        • Forster A.J.
        Accuracy of coding for possible warfarin complications in hospital discharge abstracts.
        Thromb Res. 2006; 118: 253-262
        • Baillargeon J.
        • Holmes H.M.
        • Lin Y.-L.
        • Raji M.A.
        • Sharma G.
        • Kuo Y.F.
        Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults.
        Am J Med. 2012; 125: 183-189
        • Penning-van Beest F.
        • Erkens J.
        • Petersen K.U.
        • et al.
        Main comedications associated with major bleeding during anticoagulant therapy with coumarins.
        Eur J Clin Pharmacol. 2005; 61: 439-444
        • Linkins L.A.
        • Choi P.T.
        • Douketis J.D.
        Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis.
        Ann Intern Med. 2003; 139: 893-900
        • Landefeld C.S.
        • Goldman L.
        Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy.
        Am J Med. 1989; 87: 144-152
        • Douketis J.D.
        • Foster G.A.
        • Crowther M.A.
        • et al.
        Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy.
        Arch Intern Med. 2000; 160: 3431-3436
        • Fihn S.D.
        • McDonell M.
        • Martin D.
        • et al.
        Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group.
        Ann Intern Med. 1993; 118: 511-520
        • Fischer H.D.
        • Juurlink D.N.
        • Mamdani M.M.
        • et al.
        Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study.
        Arch Intern Med. 2010; 170: 617-621
        • Schelleman H.
        • Bilker W.B.
        • Brensinger C.M.
        • et al.
        Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding.
        Clin Pharmacol Ther. 2008; 84: 581-588
        • Clark N.P.
        • Delate T.
        • Riggs C.S.
        • et al.
        Warfarin interactions with antibiotics in the ambulatory care setting.
        JAMA Intern Med. 2014; 174: 409-416
        • Altman R.
        • Rouvier J.
        • Gurfinkel E.
        • et al.
        Comparison of two levels of anticoagulant therapy in patients with substitute heart valves.
        J Thorac Cardiovasc Surg. 1991; 101: 427-431
        • Hull R.
        • Hirsh J.
        • Jay R.
        • et al.
        Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.
        N Engl J Med. 1982; 307: 1676-1681
        • Saour J.N.
        • Sieck J.O.
        • Mamo L.A.
        • Gallus A.S.
        Trial of different intensities of anticoagulation in patients with prosthetic heart valves.
        N Engl J Med. 1990; 322: 428-432
        • Turpie A.G.
        • Gunstensen J.
        • Hirsh J.
        • et al.
        Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement.
        Lancet. 1988; 1: 1242-1245
        • Singer D.E.
        • Chang Y.
        • Fang M.C.
        • et al.
        Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study.
        Circ Cardiovasc Qual Outcomes. 2009; 2: 297-304
        • Cunningham A.
        • Stein C.M.
        • Chung C.P.
        • Daugherty J.R.
        • Smalley W.E.
        • Ray W.A.
        An automated database case definition for serious bleeding related to oral anticoagulant use.
        Pharmacoepidemiol Drug Saf. 2011; 20: 560-566