Search

Purpose: This systematic review and meta-analysis aimed to determine whether tramadol intake increases the risk of bleeding in patients receiving oral anticoagulants. Methods: This systematic review was registered on PROSPERO, CRD42022327230. We searched PubMed and Embase up to 14 April 2022, and references and citations of included studies were screened. Comparative and non-comparative studies exploring bleeding complications among adult patients on oral anticoagulants and tramadol were included. Risk of bias was assessed using an adaptation of the Drug Interaction Probability Scale for case reports and case series and the Newcastle–Ottawa Scale for comparative studies. A meta-analysis was performed for the risk of serious bleeding (leading to hospitalisation or death) associated with tramadol in patients on vitamin K antagonists. Results: A total of 17 studies were included: 1 case series, 12 case reports, 2 case–control studies and 2 cohort studies. Most of the studies described tramadol-vitamin K antagonists' concomitant use; one case–control study also assessed dabigatran and rivaroxaban; one case report involved dabigatran. Among case reports/series, a total of 33 patients had a bleeding complication while using tramadol and an oral anticoagulant. The 4 comparative studies reported an increased bleeding risk during tramadol and vitamin K antagonist intake which was statistically significant in one study; the pooled risk ratio of serious bleeding was 2.68 [95% CI: 1.45 to 4.96; p < 0.001]. Conclusion: This systematic review confirms an association between tramadol use and risk of bleeding in patients on vitamin K antagonists. Evidence is too limited to assess whether this risk extends to patients on direct oral anticoagulants, and further studies are needed. [ABSTRACT FROM AUTHOR]

Purpose: Warfarin-associated coagulopathy commonly occurs in patients undergoing treatment with this anticoagulant. This trial aimed to determine the efficacy of using low-dose orally administered vitamin K1 to lower international normalized ratio (INR) values into the target range in a cohort of Chinese patients with mechanical heart valves. Methods: This was a double-blind, placebo-controlled, randomized trial. Chinese patients with mechanical heart valves who were undergoing warfarin treatment and who had INR values from 4.0 to 10.0 without bleeding were the subjects of this study. These patients were randomized into two treatment groups and were orally administered either vitamin K1 (2.5 mg) or placebo. Warfarin was discontinued in both groups until INR values were ≤ 2.5. INR values on the day following treatment were the primary study outcome, with INR values on the following days and adverse clinical events over a 3-month follow-up serving as secondary study outcomes. Results: In total, 80 patients were enrolled in the present study, and 40 patients each were assigned to the placebo and vitamin K1 treatment groups. Patients administered vitamin K1 exhibited a quick reduction in INR values relative to patients administered placebo (29 of 40 [72.5%] vs. 0 of 44 [0%] patients exhibiting INR values from 1.5–2.5 on the day following treatment, respectively, p = 0.000). Lower bleeding incidence was observed among patients administered vitamin K1 relative to those administered placebo during follow-up (4 [10%] vs. 12 [30%] patients, respectively, p = 0.045). There were no instances of thromboembolic complications or warfarin resistance in either group. Conclusion: Low-dose oral vitamin K1 can be effectively administered to Chinese patients with mechanical heart valves taking warfarin to rapidly reduce elevated INR values. [ABSTRACT FROM AUTHOR]

Purpose: Phenprocoumon is the most frequently used vitamin K antagonist in Germany. The aim of this study was to estimate the risk of serious bleeding as a result of the use of drugs with potential interaction with phenprocoumon. Methods: We conducted a nested case-control study in a cohort of 246,220 phenprocoumon users in the German Pharmacoepidemiological Research Database. Cases were patients hospitalised for haemorrhage of different kinds. Ten controls were matched to each case by health insurance, birth year and sex using incidence density sampling. Odds ratios (OR) with 95% confidence intervals (CI) of the risk of serious bleeding associated with combined use of phenprocoumon and potentially interacting drugs versus phenprocoumon alone were estimated using conditional logistic regression analysis. Our analyses considered multiple risk factors, such as bleeding history, other comorbidities or co-medication. Results: Our study included 2,553 cases and 25,348 matched controls. An increased risk of bleeding was observed for the combined use of phenprocoumon and clopidogrel vs phenprocoumon use alone (OR: 1.83, 95% CI: 1.41-2.36). Antibiotic drugs associated with an increased risk of haemorrhage in the population of phenprocoumon users included the group of quinolones with ORs ranging from 2.74 (95% CI: 1.80-4.18) for ciprofloxacin to 4.40 (95% CI: 2.45-7.89) for levofloxacin, amoxicillin plus clavulanic acid (OR: 2.99, 95% CI: 1.39-6.42) and cotrimoxazole (OR 3.57, 95% CI: 2.36-5.40). Among non-steroidal anti-inflammatory drugs (NSAIDs), ketoprofen and naproxen were associated with the highest risks. Conclusion: Significantly elevated risks of major bleeding were mainly observed for drugs with known pharmacodynamic interaction with phenprocoumon, and less for drugs with possible pharmacokinetic interaction. [ABSTRACT FROM AUTHOR]

Oral anticoagulants (OA) are a leading cause of fatal haemorrhagic adverse events in relation with an important interindividual variability of response to these drugs. Besides several clinical factors, this interindividual variability of response to OA has a pharmacogenetic basis. Carriers of cytochrome P450 2C9 ( CYP2C9)-deficient alleles have a reduced clearance of warfarin and are exposed to dramatic overdoses in the first weeks of treatment. Genetic polymorphisms of vitamin K epoxide reductase ( VKORC1), the target of OA, identify patients with a high sensitivity to OA who are at risk of early overdose. Most pharmacogenetic evidence is presently restricted to warfarin. Several warfarin dosing algorithms have been constructed, adapted on CYP2C9 and VKORC1 genotypes and clinical factors, to predict the best dose for each patient. Carriers of one of allelic variant need a 20–30% reduction of warfarin dose. However, definite evidence concerning the usefulness of these algorithms in terms of reducing the frequency of major bleeding episodes is still lacking. Ongoing prospective randomised trials will ascertain definitive answer over the coming years. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of lornoxicam co-administration on acenocoumarol pharmacokinetics and pharmacodynamics. Methods: In an open crossover study, six healthy male volunteers received racemic acenocoumarol (10 mg) orally without/with lornoxicam co-administration (8 mg twice daily). Results: The median (range) areas under the concentration-time curve (AUC) for ( R)-acenocoumarol were 3458 (3035–7312) μg · h l−1 in the absence of and 3667 (2907–7741) μg · h l−1 in the presence of lornoxicam. The corresponding values for ( S)-acenocoumarol were 479 (381–853) μg · h l−1 and 612 (425–1241) μg · h l−1. The differences were not statistically significant. Lornoxicam co-administration did not influence the free fractions or acenocoumarol's effect on factor II and VII activities. Simulations based on the results of a model-based analysis predicted that in the case of lornoxicam co-administration, the factor VII activity of a person in steady-state at 26% will remain between 14% and 32%. Conclusion: Co-administration of lornoxicam at the upper limit of recommended doses does not alter the pharmocokinetics of the clinically relevant ( R)-acenocoumarol or the anticoagulant activity of acenocoumarol. These data clearly differ from the results of previous studies, which showed clinically relevant influences of lornoxicam on warfarin kinetics and of piroxicam on acenocoumarol kinetics. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of co-administration of the non-steroidal anti-inflammatory drug (NSAID) lornoxicam on the pharmacokinetics of ( R)- and ( S)-phenprocoumon and their effect on factor II and VII activities. Methods: Six healthy male volunteers completed an open crossover study. Plasma concentrations of ( R)- and ( S)-phenprocoumon and activities of coagulation factors II and VII were measured after a single oral dose of 9 mg phenprocoumon racemate. In the second session, lornoxicam administration was started 3 days before phenprocoumon administration and continued twice daily until the last blood sample was drawn. Results: Lornoxicam co-administration resulted in a statistically significant increase of the area under the concentration-time curve (AUC) of the more potent ( S)-isomer of phenprocoumon from a median value of 100 (range 68–146) mg · h · l−1 to 124 (92–239) mg · h · l−1. For the ( R)-isomer, the AUC increase from 96 (70–142) mg h · l−1 in the absence to 108 (75–155) mg · h · l−1 in the presence of lornoxicam was not statistically significant. In a model-based analysis, an increase of ( S)-phenprocoumon and ( R)-phenprocoumon bioavailability of 14% [95% CI (9%, 19%)] and 6% (2%, 10%) and a decrease of their clearances by 15% (8%, 21%) and 6% (0%, 13%) was obtained. Lornoxicam co-administration did not influence the free fractions of ( R)- or ( S)-phenprocoumon. Contrary to what was expected from the changes in pharmacokinetics, a statistically significant decrease in the effect of phenprocoumon on factor II and VII activity was observed for the sessions with lornoxicam co-administration. For factor VII, lornoxicam was found to increase the concentration causing half-maximal effect (C50) of phenprocoumon by 70% [95% CI (38%, 111%)]. Conclusion: Co-administration of lornoxicam at the upper limit of recommended doses mainly altered the pharmacokinetics of the more potent ( S)-isomer and to a lesser degree those of ( R)-phenprocoumon. Despite these changes in pharmacokinetics, a decrease of the effect on factor II and VII activity was observed. These results suggest that in the case of lornoxicam co-administration in a patient treated with phenprocoumon the prothrombin time should be monitored closely. [ABSTRACT FROM AUTHOR]

Ten healthy subjects were given 20 mg of warfarin orally before, and after a daily intake of 400 g of brussels sprouts for 2 weeks. The brussels sprouts diet stimulated warfarin disposal as evidenced by a 29% increase in mean elimination rate constant, accompanied by a 27% increase in metabolic clearance rate and a 16% decrease in plasma AUC. It is concluded that a high intake of brussels sprouts, a cruciferous vegetable, accelerates warfarin disposal, and thereby might contribute to less anticoagulation. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the role of colchicine in potentiating the anticoagulant effect of fluindione.