Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction

Abstract

Objective The objective of our study was to examine the management of the interaction between acenocoumarol or phenprocoumon and several antibiotics by anticoagulation clinics and to compare the consequences of this interaction on users of co-trimoxazole with those for users of other antibiotics. Methods A follow-up study was conducted at four anticoagulation clinics in The Netherlands. Data on measurements of the International Normalised Ratio (INR), application of a preventive dose reduction (PDR) of the coumarin anticoagulant, fever and time within or outside the therapeutic INR range were collected. Results The study cohort consisted of 326 subjects. A PDR was given more often to users of co-trimoxazole PDR than to users of other antibiotics. The PDR in co-trimoxazole users resulted in a significantly reduced risk of both moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0) compared with no PDR, with odds ratios (ORs) of 0.06 [95% confidence interval (CI): 0.01-0.51] and 0.09 (95% CI: 0.01-0.92), respectively. In co-trimoxazole users without PDR, the risk of overanticoagulation was significantly increased compared with users of other antibiotics. All co-trimoxazole users spent significantly more time under the therapeutic INR range during the first 6 weeks after the course than users of other antibiotics. Conclusion PDR is effective in preventing overanticoagulation in co-trimoxazole users, but results in a significantly prolonged period of underanticoagulation after the course. Avoidance of concomitant use of co-trimoxazole with acenocoumarol or phenprocoumon seems to be a safer approach than management of the interaction between these drugs.

Interaction of vitamin K antagonists and trimethoprim-sulfamethoxazole: ignore at your patient’s risk

“…Trimethoprim is a relatively selective inhibitor of CYP2C8 [15]. Hauta-Aho et al [16] reported that the risk of bleeding related to VKA drug interactions in hospitalized patients was greatest with CYP 2C9 inhibitors, of which TMP-SMX would appear to be the most potent of interacting antibiotics [17][18][19]. At typically achieved SMX serum concentrations, there is a 20%-30% inhibition of CYPC29, consistent with observed VKA dose reduction requirements when used together.…”

“…In such patients the VKA should be started at lower doses (20%-40% of usual), INR monitored carefully (sooner and more often), and doses titrated slower (due to the interaction-related longer half-life of the S-enantiomer of VKA). Similarly, careful INR monitoring with VKA dose adjustment is needed to avoid undercoagulation if chronic TMP-SMX is discontinued [19,57].…”

Trends in antithrombotic drug use and adherence to non-vitamin K oral anticoagulants in the Netherlands

“…However, in a review of a healthcare claims database in Canada, rivaroxaban was associated with a significantly lower risk of nonadherence compared with warfarin (hazard ratio for cessation = 0.66) [ 34 ]. This could be different from the situation in Netherlands because of the therapeutic VKA monitoring by specialised anticoagulation clinics [ 35 ]. To ensure an optimal antithrombotic effect, continuous and regular intake of NOACs is necessary [ 32 , 33 ].…”

Impact of GATA4 variants on stable warfarin doses in patients with prosthetic heart valves

“…It has been known that environmental and clinical factors, such as age, height, body weight, co-medications and dietary vitamin K intake, influence warfarin dose requirements. [1][2][3][4] In addition, the contribution of genetic factors to interindividual variability has become increasingly appreciated in recent years. Over 40% of the variance in warfarin dose could be attributed to genetic variants in both cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes.…”