Use of Hypoprothrombinemia-Inducing Cephalosporins and the Risk of Hemorrhagic Events: A Nationwide Nested Case-Control Study

Objective Existing data regarding the risk of hemorrhagic events associated with exposure to hypoprothrombinemia-inducing cephalosporins are limited by the small sample size. This population-based study aimed to examine the association between exposure to hypoprothrombinemia-inducing cephalosporins and hemorrhagic events using National Health Insurance Research Database in Taiwan. Design A nationwide nested case-control study. Setting National Health Insurance Research database. Participants We conducted a nested case-control study within a cohort of 6191 patients who received hypoprothrombinemia-inducing cephalosporins and other antibiotics for more than 48 hours. Multivariable conditional logistic regressions were used to calculate the adjusted odds ratio (aOR) and 95% confidence interval (CI) for hemorrhagic events associated with exposure to hypoprothrombinemia-inducing cephalosporins (overall, cumulative dose measured as defined daily dose (DDD), and individual cephalosporins). Results Within the cohort, we identified 704 patients with hemorrhagic events and 2816 matched controls. Use of hypoprothrombinemia-inducing cephalosporins was associated with increased risk of hemorrhagic events (aOR, 1.71; 95% CI, 1.42-2.06), which increased with higher cumulative doses (<3 DDDs, aOR 1.62; 3-5 DDDs, aOR 1.78; and >5 DDDs, aOR 1.89). The aOR for individual cephalosporin was 2.88 (95% CI, 2.08-4.00), 1.35 (1.09-1.67) and 4.57 (2.63-7.95) for cefmetazole, flomoxef, and cefoperazone, respectively. Other risk factors included use of anticoagulants (aOR 2.08 [95% CI, 1.64-2.63]), liver failure (aOR 1.69 [1.30-2.18]), poor nutritional status (aOR 1.41 [1.15-1.73]), and history of hemorrhagic events (aOR 2.57 [1.94-3.41]) 6 months prior to the index date. Conclusions Use of hypoprothrombinemia-inducing cephalosporins increases risk of hemorrhagic events. Close watch for hemorrhagic events is recommended when prescribing these cephalosporins, especially in patients who are at higher risk.