Introduction 9 11 5 12 12 21 24 13 19 20 1 reactive The aim of the present study was to examine the management of the interaction between coumarin anticoagulants and antibiotics by anticoagulation clinics and its consequences for users of co-trimoxazole and other antibiotics. To this end, we conducted a prospective follow-up study at four anticoagulation clinics in The Netherlands. Materials and methods Study design This was a follow-up study conducted at four anticoagulation clinics in The Netherlands. We included patients who were stabilised on one of the coumarin anticoagulants acenocoumarol or phenprocoumon and who had started using one of the following antibiotics between January 2001 and October 2003: co-trimoxazole, amoxicillin, amoxicillin-clavulanic acid, clarithromycin, doxycyclin, nitrofurantoin, norfloxacin or trimethoprim. In addition to co-trimoxazole, we chose the other antibiotics based on their use for the same kind of infections, mainly those of the urinary and respiratory tract. 12 21 We excluded subjects from our analyses in whom the INR was not measured during the course of the antibiotic and who used the antibiotic for a period shorter than 3 days and longer than 14 days. If the INR was not measured during the course, an interaction effect of the antibiotic could be missed. Antibiotics used for less than 3 days or more than 14 days are usually prescribed for prophylaxis not for acute infections. written Setting and attitudes of anticoagulation clinics on antibiotic use All anticoagulation clinics in The Netherlands monitor the INR in outpatients at a frequency varying from a few days to maximally 6 weeks. The two target therapeutic ranges are the normal therapeutic range (INR: 2.0–3.5) and the high therapeutic range (INR: 2.5–4.0). The initiation of the use of an antibiotic is usually reported to the anticoagulation clinics by the patients, their pharmacists and/or the prescribing physicians. The four anticoagulation clinics participating in this study had different attitudes on the management of the interaction between coumarins and antibiotics. The approach of three of the anticoagulation clinics was to decrease the coumarin dose preventively if co-trimoxazole was prescribed; one of the anticoagulation clinics applied a PDR of 20–25% in the case of co-trimoxazole use. If one of the other antibiotics examined in this study was prescribed, the application of a PDR would depend on the seriousness of the disease and on the occurrence of fever. The fourth anticoagulation clinic had no established protocols for dose reduction but indicated that it would monitor the INR of every user of co-trimoxazole within 3–5 days after initiation of the course. Data collection preventive after Outcomes The end points of our study were chosen to assess the effectiveness of the management of the interaction between coumarin anticoagulants and co-trimoxazole and other antibiotics. occurrence of moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0); time spent within, above and under the therapeutic INR range from the starting date of the antibiotic until the last INR measurement within 6 weeks following the starting date of the antibiotic. Calculations and statistical analysis We assessed the effects of the PDR within the group of users of co-trimoxazole and within the group of users of other antibiotics by comparing the occurrence of overanticoagulation in patients for whom a PDR had been applied with the occurrence of overanticoagulation in patients for whom PDR had not been applied (logistic regression models). We also compared the occurrence of overanticoagulation and time spent within, under and above the therapeutic range of co-trimoxazole users with users of other antibiotics (reference group). These comparisons were made for patients with PDR and for patients without PDR. Finally, we compared the time spent within, under and above the therapeutic range in patients for whom a PDR had been applied with those for whom a PDR had not been applied (reference) within the groups of co-trimoxazole users and users of other antibiotics (linear regression models). In all models we adjusted for the potential confounding covariates sex, age, target therapeutic range and fever, as indicated by the patient. Covariates were added to the statistical models one at a time. We adjusted for a covariate if it changed the point estimation of the outcome of interest by 5% or more upon inclusion in the model. 15 Although all patients were stable when they were included in our study, we re-analysed our statistically significant outcomes after excluding patients in whom destabilisation could be due to factors other than those of infection and/or fever (presence of thyroid disease, malignancy or use of other enzyme-inhibiting or-inducing drugs).  SPSS Results A total of 424 patients who met the inclusion criteria gave their informed consent to participate in our study. Of these patients, 81 did not have assesment of the INR during the antibiotic course, 14 used the antibiotic for less than 3 days, and 3 used the antibiotic for more than 14 days. 1 Table 1 n Characteristic n a n b n c n b n c n Men, no. (%) 22 (78.6) 10 (66.7) 30 (50.0) 114 (51.1) Age in years, mean (SD) 75.4 (10.9) 75.1 (8.2) 72.6 (10.9) 71.4 (11.2) Users of acenocoumarol, no. (%) 24 (85.7) 10 (66.7) 52 (86.7) 169 (75.8) Follow-up time, mean (SD)  33.2 (5.6) 28.9 (8.0) 30.4 (7.2) 30.2 (7.2) Fever, no. (%) 18 (64.3) 6 (40.0) 27 (45.0) 120 (53.8) d 19 (67.9) 5 (33.3) 30 (50.0) 112 (50.2) Respiratory infections, no. (%) 8 (28.6) 3 (20.0) 33 (55.0) 116 (52.0) Urinary tract infections, no. (%) 13 (46.4) 8 (53.3) 11 (18.3) 53 (23.8) Malignancies, no. (%) 1 (3.6) 3 (20.0) 3 (5.0) 9 (4.0) Thyroid diseases, no. (%) 0 0 1 (1.7) 11 (4.9) Users of inhibiting drugs, no. (%) 0 1 (6.7) 5 (8.3) 17 (7.6) Users of inducing drugs, no. (%) 1 (3.6) 0 1 (1.7) 4 (1.8) INR measurements, mean no. (SD) 3.5 (0.9) 3.9 (1.5) 3.5 (1.1) 3.1 (1.1) Acenocoumarol, mean dose, mg/day (SD) 2.42 (1.26) 2.41 (1.41) 2.61 (1.06) 2.60 (1.12) Percentage PDR applied, mean (SD) in acenocoumarol users 15.0 (7.6)  10.3 (11.1)  Phenprocoumon, mean dose, mg/day (SD) 2.81 (0.86) 2.53 (1.02) 2.99 (1.31) 2.36 (1.00) Percentage PDR applied, mean (SD) in phenprocoumon users 17.9 (15.8)  11.4 (7.0)  Percentage PDR applied, all coumarins, mean (SD) 15.4 (8.8)  10.5 (10.6)  a n n n n n n n b c d  P  t P  t 1 2 3 Table 2 a Outcome Co-trimoxazole Other antibiotics  b n b n b n b n INR >4.5, no. (%) 3 (10.7) 25 (89.3) 9 (15.0) d INR > 6.0, no. (%) 1 (3.6) 4 (26.7) 5 (8.3) e c 71.1 (60.4–81.8) 51.8 (34.6–69.0) 76.2 (69.5–82.9) f Time above therapeutic range, mean % (95%CI) 15.0 (5.7–24.3) 20.3 (10.7–29.8) 12.3 (6.8–17.7) g Time under therapeutic range, mean % (95%CI) 14.0 (5.6–22.2) 27.9 (7.7–48.1) 11.5 (6.9–16.1) h a b c d e f g h Table 3 Odds ratios for effect of preventive dose reduction (PDR) and for (severe) overanticoagulation in users of co-trimoxazole compared with users of other antibiotics   Odds ratios (95%CI) P a P b  Co-trimoxazole    PDR applied, INR >4.5 0.10 (0.02–0.50) 0.005* 0.06 (0.01–0.51) 0.010*    PDR applied, INR >6.0 0.10 (0.01–1.02) 0.051 c 0.042*    PDR not applied Reference  Reference   Other antibiotics    PDR applied, INR >4.5 0.70 (0.32–1.52) 0.37 d     PDR applied, INR >6.0 1.36 (0.47–3.93) 0.57 N.A     PDR not applied Reference    Risk of overanticoagulation  PDR not applied    Co-trimoxazole, INR >4.5 4.52 (1.56–13.1) 0.006* 3.96 (1.33–11.8) 0.013*    Co-trimoxazole, INR >6.0 5.43 (1.53–19.2) 0.009* 3.86 (1.03–14.6) 0.046*    Other antibiotics Reference  Reference   PDR applied    Co-trimoxazole, INR >4.5 0.68 (0.17–2.73) 0.59 N.A.     Co-trimoxazole, INR >6.0 0.41 (0.04–3.66) 0.42 e 0.30    Other antibiotics Reference  Reference  P a b c d e 2 3 2 4 Table 4 a  Mean difference P b P PDR applied c −5.1 (−17.2 to 6.9) 0.40 −4.2 (−17.1 to 8.6) 0.51   Co-trimoxazole, % time above TR 2.7 (−7.3 to 12.7) 0.60 1.9 (−8.9 to 12.7) 0.73   Co-trimoxazole, % time under TR 2.4 (−6.3 to 11.1) 0.58 d    Other antibiotics Reference  Reference  PDR not applied   Co-trimoxazole, % time within TR −23.8 (−38.2 to –9.6) < 0.001* e 0.002*   Co-trimoxazole, % time above TR 1.4 (−11.7 to 14.5) 0.83 N.A.    Co-trimoxazole, % time under TR 22.5 (14.4 to 30.6) < 0.001* f < 0.001*   Other antibiotics Reference  Reference  Co-trimoxazole   PDR applied, % time within TR 19.3 (0.7 to 37.9) 0.042* f 0.16   PDR applied, % time above TR −5.3 (−19.6 to 9.0) 0.46 g 0.55   PDR applied, % time under TR −14.0 (−31.6 to 3.6) 0.16 g 0.24   PDR not applied Reference  Reference  Other antibiotics   PDR applied, % time within TR 0.5 (−7.0 to 8.1) 0.89 0.6 (−6.8 to 8.2) 0.87   PDR applied, % time above TR −6.6 (−13.5 to 0.3) 0.061 N.A.    PDR applied, % time under TR 6.1 (2.0 to 10.1) 0.003* N.A.    PDR not applied Reference  Reference  Co-trimoxazole, PDR applied   % time within TR −4.7 (−15.1 to 5.6) 0.37 f 0.58   % time above TR −2.4 (−11.9 to 7.1) 0.61 h 0.46   % time under TR 7.2 (1.2 to 13.1) 0.018* h 0.022*   Other antibiotics      PDR applied + PDR not applied Reference  Reference  P a b c d e f g h  P The application of a PDR differed between anticoagulation clinics. Three of the four anticoagulation clinics participating in this study applied PDR as a rule in co-trimoxazole users (83.3–85.7%). In terms of users of other antibiotics, the application of a PDR was more varied: in three of the anticoagulation clinics PDR was sometimes applied (in 17.6–50.8% of all cases), whereas one anticoagulation clinic did not apply the PDR approach at all. The overall percentage of time spent within the therapeutic range during the first 6 weeks after initiation of an antibiotic ranged from 73.7 to 78.0% at all four anticoagulation clinics. In the anticoagulation clinic that did not apply a PDR, overanticoagulation (INR>4.5) occurred most frequently for the all antibiotics class (26.9 vs.10.8–22.7% in the other clinics), with the difference being most marked for co-trimoxazole (54.4 vs. 14.3–16.7% in the other clinics). n n 5 Table 5 Main outcomes stratified for users of acenocoumarol and phenprocoumon Outcome n n Protective effect of PDR a P a P Co-trimoxazole    PDR applied, INR >4.5 0.08 (0.01–0.70) 0.022* 0.16 (0.01–4.48) b    PDR not applied Reference  Reference  Risk of overanticoagulation    PDR not applied    Co-trimoxazole, INR >4.5 4.40 (1.15–16.8) 0.030* 3.83 (0.55–26.7) 0.18    Other antibiotics Reference  Reference  % Time within or under TR Mean difference (95%CI)  Mean difference (95%CI)     Co-trimoxazole, % time within TR −22.1 (−39.1 to –5.0) 0.011* −21.4 (−49.4 to 6.6) 0.13    Co-trimoxazole, % time under TR 20.3 (10.9–29.7) <0.001* 22.6 (5.7–39.5) 0.010*    Other antibiotics Reference  Reference     Co-trimoxazole, PDR applied    % time under TR 9.1 (3.0–15.1) 0.004* −6.7 (−23.0 to 9.6) 0.42    Other antibiotics       PDR applied + PDR not applied Reference  Reference  P a b Re-analysis of our results after excluding patients with thyroid diseases and malignancy or those using enzyme-inhibiting or -inducing drugs gave similar point estimates or trends, significance for severe overanticoagulation in users of co-trimoxazole compared to other antibiotics and for time spent within the therapeutic range for users of co-trimoxazole in whom PDR was not applied (data not shown). Discussion The results of the present study, in which we evaluated the management of the interaction between antibiotics and coumarin anticoagulants by anticoagulation clinics, demonstrated that a PDR reduces the risk of overanticoagulation in co-trimoxazole users to the level of other antibiotic users, but also that management of the interaction between coumarins and co-trimoxazole results in a significantly longer period of undertreatment during the first 6 weeks after initiation of the antibiotic. 2 3 6 8 10 12 21 24 Although PDRs as applied in clinical practice are effective in reducing the overanticoagulation risk in co-trimoxazole users, the price that has to be paid for the concurrent use of co-trimoxazole is a significantly prolonged period of underanticoagulation compared with the use of other antibiotics during the first 6 weeks after the antibiotic course. This difference was more marked in the subgroup of subjects in whom PDR was not applied. Possible explanations for this result are (1) the usually shorter time span between PDR and the first INR measurement (always within the course) compared to the time span between a reactive dose reduction following supratherapeutic INR and subsequent INR measurement (usually after the course) and (2) the higher reactive dose reduction which is applied in the case of severe overanticoagulation (INR >6.0). However, even co-trimoxazole users for whom the PDR had been applied had a significantly prolonged period of underanticoagulation compared with all of the users of other antibiotics (PDR applied and PDR not applied taken together). This last comparison is totally logical because our results strongly suggest that a PDR should always be applied in co-trimoxazole users, whereas this is as a rule not required in users of other antibiotics. The adjusted difference in time spent under the therapeutic range – ranging from 6.9 (PDR applied) to 22.5% (PDR not applied) – corresponds to about 2–7 days of the mean follow-up time of 30 days in otherwise stabilised patients; this time interval is clinically relevant and can be avoided by substituting co-trimoxazole. 20 22 18 CYP2C9 16 22 VKORC1 4 14 17 23 CYP2C9 VKORC1 In conclusion, if co-trimoxazole is prescribed to users of coumarin anticoagulants, the interaction can be managed by applying PDR, which adequately decreases the risk of overanticoagulation, but this successful management comes at the cost of a prolonged period of underanticoagulation after the course. Consequently, rather than managing the interaction it is better to avoid prescribing co-trimoxazole as a therapeutically equivalent alternative is always available.