| Summary: | 碩士 === 臺灣大學 === 臨床藥學研究所 === 98 === Background
Gastrointestinal (GI) bleeding was the most frequent complication of warfarin. Drug-drug interactions may increase this risk. In Taiwan, there is no comprehensive study to investigate the risk of GI bleeding associated with potentially significant warfarin drug interactions.
Objective
Using National Health Insurance Database of Taiwan to evaluate the incidence rate of GI bleeding in warfarin users, risk of GI bleeding associated with potentially significant warfarin drug interactions, and characteristics of warfarin users who were hospitalized due to bleeding.
Methods
This retrospective cohort study analyzed National Health Insurance Database with one million randomly selected individuals from January, 1997 until December, 2007. The study population (warfarin new users) started warfarin after January, 1998. They were followed from the first day of warfarin prescribing until the firtst GI bleeding complication requiring hospitalization or the last claim data befor December 2007. We collected all claim data of warfarin, 56 potentially significant interacting drugs (PIDs), risk medication and comorbidity.
We calculated the crude incidence of GI bleeding events during warfarin exposure alone period (without PIDs) and periods of concomitant exposure (with PIDs), and also analyzed characteristics of patients with bleeding events.
The time dependent Cox proportional hazard model was performed to determine the hazard ratio (HR) of risk factors associated with GI bleeding, adjusted with age, sex, risk medication and comorbidity.
Results
There were 5251 warfarin new users in the 10 year study period. Their mean age was 63.3 years old. More than half (53.8%) were male. A total of 189 patients were hospitalized for GI bleeding. The major etiology, peptic ulcer bleeding, was found in 60 patients (31.7%). The crude incidence rate of total warfarin users was 2.9 per 100 person-year (per 100 PY). During warfarin exposure alone, the incidence rate was 4.6 per 100 PY. Forty-three (76.8%) out of 56 PIDs were taken concomitantly by warfarin users. Among 43 PIDs, GI bleeding events occurred during combinationof 19 PIDs and warfarin. The incidence rate of the PIDs with more than 3 bleeding events were ketoprofen (51.5 per 100 PY), naproxen (23.6 per 100 PY), fenofibrate (12.6 per 100 PY) , cilostazol (5.5 per 100 PY), aspirin (4.7 per 100 PY) , celecoxib (4.1 per 100 PY), ginkgo biloba (3.6 per 100 PY), clopidogrel (2.4 per 100 PY) and amiodarone (2.1 per 100 PY).
Patients who suffered from bleeding were usually older than 70 years old without dosing adjustment (reduction), more comorbidities prone to GI bleeding and taking risk medication.
The Cox model analysis revealed that adjusted HRs of warfarin-PID for GI bleeding were 2.614 (1.779-3.842), 1.232(1.017-1.494), 1.027(1.010-1.044), 1.025 (1.016-1.033), 1.187 (1.035-1.362), for increasing 1 defined daily dose (DDD, 10000U) of heparin, increasing one DDD (500 mg) of levofloxacin, increasing one DDD (100 mg) of aspirin, increasing 1 mg of carboplatin, increasing one day of ketoprofen, respectively. In addition, patients with comorbidity (congestive heart failure, coagulopathy, peptic ulcer or bleeding, esophagitis, gastritis, duodenitis, esophageal varices, Mallory-weiss tear, renal dialysis), or using risk medication (NSAIDs, corticosteroid, spironolactone) had a higher risk of bleeding.
Conclusions
Warfarin users in this study used 43 PIDs and only 5 PIDs (11.6%) significantly increased the risk of GI bleeding. On the other hand, some risk medication or comorbidities caused higher risk than warfarin and PIDs. This study, however, was limited by not able to access data regarding patient adherence, drug-food or herb interactions. Although the risk of PIDs was not as high as we expected, physicians or pharmacists should pay attention to elderly (age>70 years old), patients taking risk medications or with history of peptic ulcer or bleeding. It may ensure medication safety in these patient populations by close monitoring and adjusting warfarin dosing.
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