Overanticoagulation associated with combined use of lactulose and acenocoumarol or phenprocoumon

Abstract

Some medical textbooks on drug interactions take note of the potential interaction between laxatives and coumarin anticoagulants, but epidemiological evidence that this interaction is of practical importance is lacking. We conducted a follow-up study in a large population-based cohort to investigate which laxatives are associated with overanticoagulation during therapy with coumarins. Of the 1124 patients in the cohort, 351 developed an International Normalized Ratio ≥6.0. The only laxative with a moderate but significantly increased relative risk of overanticoagulation was lactulose (relative risk 3.4, 95% confidence interval 2.2, 5.3). In view of the widespread use of lactulose, especially among the elderly, awareness of this potential drug interaction is required.

Introduction

Coumarin anticoagulants are extensively used for the treatment and long-term prevention of thromboembolic diseases [1]. The risk of bleeding, the main complication of coumarin anticoagulants, is influenced by the intensity of anticoagulant therapy [2, 3], by the underlying clinical disorders of the patient [3], and by the concomitant use of other drugs [4]. This risk sharply increases when the International Normalized Ratio (INR) is ≥6.0 [5]. Several drugs can affect the INR during oral anticoagulant therapy by different mechanisms [4]. Laxatives, which shorten the transit time in the gut, might be expected to decrease the absorption of both vitamin K and oral anticoagulants. Despite warnings in the medical literature, there seems to be no epidemiological evidence that this interaction is of any practical importance [6].

Therefore, we conducted a follow-up study in a large population-based cohort to investigate whether laxatives are associated with overanticoagulation during therapy with coumarins.

Methods

The study cohort consisted of all 1124 patients in one anticoagulation clinic, who were treated with acenocoumarol or phenprocoumon in the study period between 1 April 1991 and 31 December 1998 and for whom there were INR data during their treatment. All cohort members were followed until the first occurrence of an INR ≥6.0, the last INR assessment because of the end of their treatment, death or end of the study period, whichever came first. For laxatives for which an association was found, a dose and duration effect was studied. The duration of exposure to a laxative on the day of overanticoagulation was divided into tertiles: ≤27 days; >27 days to ≤97 days; and >97 days. Doses were divided into tertiles: ≤7.5 g; >7.5 g to ≤12 g; and >12 g. The following baseline patient characteristics were considered as potential determinants for affecting the response of the INR to oral anticoagulants: gender, age, hepatic dysfunction, hypoalbuminaemia, malignancies, hyperthyroidism, hypertension, congestive heart failure, and low dietary daily intake of vitamin K. Incidence rates were calculated by dividing the number of cases of an INR ≥6.0 by the number of days on combined use of a coumarin anticoagulant and a laxative. To assess laxatives which were independently associated with an INR ≥6.0, all occurring combinations of a coumarin anticoagulant and a laxative were included separately in a Cox proportional hazards regression model for time-dependent variables to compute relative risks and their 95% confidence intervals (95% CI) [7]. To adjust for potential confounding, cofactors, which were associated with an INR ≥6.0 in the univariate analysis, were included in the multivariate model, in addition to gender and age, if this caused a change in the point estimate of >5%.

Results

Of the 1124 patients in the cohort, 351 developed an INR ≥6.0 after 1 April 1991. The incidence rate was 6.9 per 10 000 treatment days. Women and old patients had a higher risk of an INR ≥6.0. The risk of overanticoagulation was lowest with phenprocoumon. Hepatic dysfunction, malignancies, congestive heart failure and a low dietary daily intake of vitamin K were associated with an increased risk of an INR ≥6.0 in the univariate analysis.

Eight different laxatives were used during the study period, of which three were not used in cases. The remaining five laxatives and the relative risks of overanticoagulation are given in Table 1. Fifty-one cases (15%) used laxatives on the index date. Lactulose was the one agent which was univariately as well as multivariately associated with overanticoagulation. After adjustment for confounding factors the relative risk was 3.4 (95% CI 2.2, 5.3).

Table 1.

Association between overanticoagulation [International Normalized Ratio (INR) ≥6.0] and use of laxatives

Laxative	Patients with INR ≥ 6.0 n = 351	Total population*n = 1124	RRcrude† (95% CI)	RRadj.‡ (95% CI)
Liquid paraffin	1	135	1.2 (0.2, 8.9)	0.7 (0.1, 5.5)
Colocynthine preparation	4	430	2.3 (0.8, 6.1)	1.9 (0.6, 6.1)
Psyllium seeds	4	983	1.0 (0.4, 2.6)	1.3 (0.3, 5.1)
Wheat fibre	6	975	1.5 (0.7, 3.4)	2.0 (0.6, 6.3)
Lactulose	36	3521	2.6 (1.8, 3.6)	3.4 (2.2, 5.3)

^*In this time-dependent analysis, exposure in case patients and in the rest of the cohort is assessed at the time of the outcome in each case patient (index date). Because control patients can be used multiple times, the number of assessments in the reference group is much larger than the number of individuals. Hence, crude relative risks can not be calculated with the numbers inTable 1.

^†If none of the patients with an INR

^≥6.0 was exposed, P-values are given instead of relative risks.

^‡Adjusted for gender, age, congestive heart failure, low dietary intake of vitamin K.

Stratification by the duration of laxative exposure on the day of overanticoagulation revealed a significantly protective effect of lactulose during the first 27 days of use, the relative risk being 0.5 (95% CI 0.3, 0.8). The relative risk was 1.7 (95% CI 0.9, 3.0) for >27 days to ≤97 days and 2.1 (95% CI 1.2, 3.7) for >97 days of lactulose use. A clear dose–effect relationship could not be detected. The relative risks for the subsequent dose levels were 1.7 (95% CI 0.9, 3.1), 2.0 (95% CI 1.0, 4.9) and 1.9 (95% CI 0.9, 4.0).

Discussion

The main finding in this population-based cohort study is that among laxatives, only lactulose was associated with an increased risk of overanticoagulation during oral anticoagulant therapy with acenocoumarol or phenprocoumon. Laxatives shorten the transit time in the gut and might be expected to decrease the absorption of both the oral anticoagulants and vitamin K. If the absorption of vitamin K is more strongly impaired than that of coumarins, overanticoagulation might occur. It seems likely that such effects on the INR would more or less apply to all laxatives. In addition to that, the long-term oral administration of paraffin may interfere with the absorption of the fat-soluble vitamin K and result in a deficiency of this substance and an increase in INR. The fact that we did not find an association for paraffin may have had two reasons. The first is that there is no real association, all the more as the medical literature mentions only a theoretical possibility that paraffin affects the response to coumarin anticoagulants. The second may be that in our study population paraffin was used only on a short-term basis. With the administration of lactulose the colonic pH will decrease below pH 7.4 [8, 9]. This could theoretically have resulted in an increase in the absorption of phylloquinone (vitamin K1) and menaquinone (vitamin K2) in the colon [10, 11]. This is in line with the observed protective effect during the first month of lactulose therapy. During long-term use, however, another mechanism seems to play a role. We can only speculate about this mechanism, but the biologically most plausible one is that lactulose has its influence on the faecal flora responsible for mena-quinone production. Reported effects of lactulose on the faecal flora are conflicting, but counts of the menaquinone-producing bacteria were reported to decrease after lactulose administration [12]. The fact that only lactulose and none of the other laxatives was associated with a significantly increased risk of overanticoagulation could have been due to the lower exposure to these agents in our study. Although our study pertained to the coumarins acenocoumarol and phenprocoumon, it is likely that the results can be extrapolated to warfarin, because here vitamin K plays a similar role.

In conclusion, in this population-based cohort study among outpatients of an anticoagulation clinic on coumarins, lactulose was associated with overanticoagulation. In view of the widespread use of lactulose, especially among the elderly, awareness of this potential drug interaction is required.