What Can I Take for Diarrhea While on Warfarin

Abstract

Astute diarrhea is associated with a reduced absorption of both vitamin K antagonists (VKA) and vitamin K itself. To date, the cyberspace consequence on the coagulation status of subjects with VKA remains elusive. Nosotros performed a systematic retrospective single-center assay using an electronic data extraction approach to identify subjects with plasmatic anticoagulation (either VKA or straight oral anticoagulant (DOAC)) and diarrhea in a German Academy Hospital over a flow of eight years. Acute diarrhea and complete documentation of coagulation status on admission were defined equally inclusion criteria, anticoagulation other than VKA/DOAC and obvious inadherence as exclusion criteria. Subjects with VKA/DOAC admitted for hypertension served equally control group. Data extraction yielded 356 subjects with gastrointestinal diagnoses and 198 hypertensive subjects, 55 and 83 of whom fulfilled all in- and exclusion criteria. INR values of subjects with VKA were significantly higher in subjects with diarrhea than in hypertensive controls (four.3 ± 3.seven vs. two.iii ± 0.7, p < 0.001). The distribution of subjects having INR values lower, college or within the target range differed significantly among groups with a substantially college prevalence of overanticoagulation in the diarrhea grouping (46.4% vs. xiv.iii%, p < 0.001). In a multinomial logistic regression model, astute diarrhea was significantly associated with overanticoagulation (odds ratio 7.two, 95% confidence interval two.163–23.921; p < 0.001), whereas age, sex, creatinine, and indication of anticoagulation were not (p > 0.05 each). Acute diarrhea is associated with a highly increased risk for overanticoagulation in patients with VKA. Thus, gastroenteritis necessitates a close monitoring of INR in society to place subjects needing a temporary pause of VKA therapy.

Introduction

Phenprocoumon and warfarin exert their anticoagulatory furnishings by inhibiting the vitamin K dependent synthesis of clotting factors in the liver. In that location are numerous factors that may alter the resorption, metabolism and response to Vitamin K antagonists (VKA). Thus, liver disease, hyperthyroidism, and chronic kidney disease or acute states like decompensated heart failure and fever can increase the response to VKA¹. Moreover, several drug interaction take to be taken into account. E. m., antibiotics like chinolons and contrimoxazole are associated with an increased risk of haemorrhageⁱⁱ.

Although these drugs have been standard of care for decades, little is known about the effects of astute episodes of diarrhea on the coagulation condition of subjects with VKA. On the ane paw diarrhea leads to decreased absorption of the drug, potentially resulting in ineffective anticoagulation. On the other hand, diarrhea reduces the assimilation of vitamin K itself, which could atomic number 82 to temporary overanticoagulation. Information technology remains elusive, which issue overweighs the other.

So far, just isolated instance reports are bachelor on this topic. In 1994, a physician reported about himself taking warfarin and suffering from overanticoagulation with excessively increased international normalized ratio (INR) values during an episode of giardiasisⁱⁱⁱ. Over the following 20 years four further case reports indicated that diarrhea may atomic number 82 to overanticoagulation in subjects taking VKA^4,5,6,7. Despite the high clinical relevance of this upshot, there is neither a case series nor a systemic retrospective analysis on this upshot so far. The nowadays work constitutes the first systematic assay on the effects of new-onset diarrhea on coagulation parameters in patients with VKA.

Methods

Blueprint and protocol

Subjects with oral anticoagulation that were admitted to the Medical Department of a High german University Hospital from 2011–2018 for acute gastroenteritis were enrolled in this retrospective analysis. Subjects admitted for hypertension served every bit control group.

Data extraction was performed electronically in an anonymized style based on the diagnosis coded at discharge and submitted to the health insurance. The study was canonical by the ethics commission of the Ruhr-Academy Bochum (20-6963-BR) and informed consent was waived by the ethics committee of the Ruhr-Academy Bochum. The protocol was in accordance with institutional and national guidelines. All subjects with a diagnosis related group (DRG) lawmaking "G67A-C" between 2011 and 2022 were identified. These DRGs comprise eastward. k. astute gastroenteritis, esophagitis, gastrointestinal haemorrhage, diverticulitis, ulcera ventriculi and duodeni. Those ones with coincident documentation of the code for plasmatic anticoagulation (Z92.1) were enrolled in the analysis. In a 2nd step, those ones with acute diarrhea were identified by the patient's nautical chart (gastroenteritis group). The other subjects were excluded from further analysis. Finally, it was checked, whether the subject was administered a VKA, a directly oral anticoagulant (DOAC), low molecular heparin or other anticoagulants until admission to the hospital. Acute diarrhea was divers as mandatory inclusion criterion, obvious inadherence (either documented in patient'southward history or INR < 1.iii despite VKA), anticoagulation other than VKA/DOAC, and lack of INR data at access were divers as exclusion criterion. Subjects admitted to infirmary due to a hypertensive episode (I10.01/I10.11) receiving plasmatic anticoagulation served as command population. Overanticoagulation was defined as an INR > 3.5 for subjects with mechanical center valves and > 3.0 for atrial fibrillation, venous thrombosis, and pulmonary embolism.

Statistical assay

Numeric data are presented as mean ± standard deviation. Data were tested for normal distribution by the Kolmogorov–Smirnov test. Intergroup differences (gastroenteritis with VKA, gastroenteritis with DOAC, control with VKA, command with DOAC) in numeric ordinarily distributed data were analyzed by ANOVA. Chiselled data were compared by Pearson Chi squared test. Multinomial logistic regression analysis with "overanticoagulation" as dependent variable was performed for patients with VKA using creatinine, age, C-reactive protein (CRP), diarrhea, indication for anticoagulation, and sex equally covariates/factors. The distribution of subjects with over-, under-, and normoanticoagulation in the gastroenteritis vs. control grouping was compared by Pearson Chi squared test. INR values among VKA patients with diarrhea vs. control were compared using unpaired 2-tailed Educatee'south t test. All statistical analyses were done using SPSS Statistics 25 (SPSS Inc, Chicago, Illinois, USA) and Prism 5 (GraphPad Software, La Jolla, California, The states). p < 0.05 was regarded statistically significant.

Results

Electronic information extraction yielded an overall population of 554 subjects with the code for anticoagulation, who were admitted to hospital for either a bowel-related diagnosis (G67A-C, n = 356) or hypertension (I10.01/I10.11, n = 198). 83 of those ones with the primary diagnosis of hypertension fulfilled in- and exclusion criteria and served as control group. seventy (84.3%) were administered phenprocoumon, 13 (15.7%) received a DOAC. Among those with a bowel-related diagnosis, 55 suffered from acute diarrhea, had INR information on admission, anticoagulation with either VKA or DOAC and no obvious inadherence. These subjects constituted the gastroenteritis group. 28 (l.9%) were administered a VKA, 27 (49.ane%) received a DOAC. A flow canvass of the composition of the report population is provided in Fig. 1.

Mean age of the overall study population was 77.0 ± 10.7 years. Age differed significantly between the four groups (gastroenteritis with VKA, gastroenteritis with DOAC, command with VKA, control with DOAC; p 0.04). Subjects with DOACs were older than those ones with VKA. Atrial fibrillation was the near frequent indication for anticoagulation (81.nine%). vii.2% of the patients had anticoagulation due to prosthetic valves, the balance for either venous thrombosis or pulmonary embolism. There was no intergroup difference in the indications of anticoagulation. Moreover, gastroenteritis and control group were homogenous for sexual activity and white blood prison cell count (p > 0.05 each). Gastroenteritis was associated with higher CRP and creatinine values (p < 0.05 each). Noteworthy, none of the patients with VKA and diarrhea had antibiotics at the time of laboratory examinations (admission). Table 1 presents the epidemiological data and the coagulation status of the study population. Norovirus, rotavirus, Campylobacter jejuni, enteropathogenic Escherichia coli (EPEC), and clostridioides were identified as infectious agents.

Table 1 Label of study population. Subjects with gastroenteritis versus subjects with hypertension serving every bit control group.

Full size table

The prevalence of overanticoagulation at admission was 46.4% in the gastroenteritis and 14.3% in the command group. Figure ii shows the distribution of subjects with hyper-, hypo-, and normoanticoagulation in these ii groups, which differed significantly (p < 0.001). As illustrated by Fig. three, subjects with VKA had significantly higher INR values in the gastroenteritis than in the command group (four.three ± 3.7 vs. 2.3 ± 0.7, p < 0.001). Accordingly, Quick values were lower on access in VKA subjects with gastroenteritis than in hypertensive controls (24.4 ± 12.9% vs. 35.9 ± fourteen.2%, p < 0.001). At belch from hospital, INR values did not differ anymore (p 0.26).

A multinomial logistic regression was used to examine the association of serum creatinine, age, CRP, diarrhea, indication for anticoagulation, and sexual practice on the status of overanticoagulation in patients with VKA. As shown in Tabular array 2, astute diarrhea was highly significantly associated with overanticoagulation (Odds ratio vii.ii, 95% confidence interval 2.163–23.921; p 0.001). None of the other parameters was associated with an INR beyond the target range.

Tabular array two Multinomial logistic regression analysis on patients with VKA using overanticoagulation as dependent binary variable.

Full size table

Discussion

The present work constitutes the outset systematic analysis of the bear on of acute diarrhea on the coagulation status of subjects with VKA. In line with the few available previous case reports it shows that acute episodes of diarrhea are associated with an increased risk of overanticoagulation. Subjects with VKA and diarrhea had a substantially higher run a risk of an INR beyond the target range than subjects with VKA that were admitted to hospital for hypertension. Acute diarrhea was associated with overanticoagulation in near 50% of patients. Consistently, the rate of subjects with INR in the target range was lower than in the control group. These findings are of clinical relevance, since an INR excess is associated with a substantially increased bleeding chance^viii,ix,10.

This insight is of especial importance for subjects receiving anticoagulation for mechanical centre valves. Outset, since the intensity of anticoagulation is higher than in subjects with atrial fibrillation or venous thrombosis, usually with an INR target range of 2.5–3.v vs. two.0–3.0. Thus, the adventure of overanticoagulation is higher than in subjects with a lower INR target. 2nd, even short states of dysanticoagulation are associated with a relevant thrombembolic risk in this indication. Third, vitamin K antagonists are still the only available way of oral anticoagulation in these subjects. Later on the REALLIGN trial has demonstrated an increased risk of both thromboembolic events and bleeding complications for the straight thrombin inhibitor dabigatran compared to warfarin, it is unlikely that manufacturers of other DOACs will initiate another trial in this population¹¹. Hence, VKA volition remain standard of care in subjects with mechanical heart valves for the fourth dimension being.

In the logistic regression model, the odds ratio for overanticoagulation in acute diarrhea was 7.ii. Interestingly, neither age nor kidney function predicted overanticoagulation in this model. The clinical outcome of these findings is that episodes of diarrhea necessitate an intense monitoring of the coagulation state. Subjects who are trained in self-monitoring should be instructed to perform daily INR controls. Subjects without the opportunity of self-controls should exist encouraged to attend their physician for extraordinary checks of INR.

Phenprocoumon is completely absorbed from the gastrointestinal tract. Information technology circulates jump to plasma albumin and is metabolized in the liver¹². Diarrhea is normally associated with a reduction of a drug'south absorption resulting in lower plasma levels. There are few exceptions from this rule, due east.k. for drugs that are metabolized in the intestine. Thus, the immunosuppressive drug tacrolimus is absorbed in the duodenum and jejunum and partially metabolized by cytochrome p450 in the intestinal mucosa. Diarrhea reduces metabolization of the drug, which obviously outweighs a potential subtract in absorption yielding increased plasma concentrations¹³. In the case of phenprocoumon and warfarin, however, in that location is no intestinal inactivation of the drug. It has therefore to be hypothesized that diarrhea has a stronger effect on the absorption of vitamin K than on the absorption of the drug. Indeed, diarrhea leads to a substantial reduction of vitamin K assimilation^xiv.

In spite of its high clinical relevance, the present study constitutes the offset systematic test on the furnishings of acute diarrhea on the coagulation state in subjects with vitamin K antagonists. The patent on phenprocoumon by Hoffmann–La Roche was granted more than than 60 years ago in 1955. The commencement description of a potential risk of overanticoagulation during diarrhea occurred non until 1994. Interestingly, this instance description—a md that reported on himself during an episode of gastroenteritis—was regarded equally highly relevant and was therefore published in the Lancet³. Notwithstanding, this report did not initiate any initiatives to investigate this consequence systematically and information technology is unlikely that there volition be a prospective evaluation in the future. The present data are therefore the best available evidence to establish sensation in physicians and patients for the demand of an intense laboratory monitoring of the coagulation land during episodes of diarrhea. In line with our results, 3 studies on various factors predicting an increased response to VKA identified diarrhea as one of them as well^{fifteen,sixteen,17}. Interestingly, these studies were published from 1998 to 2008. More recent data is scarce, showing that this issue has not been investigated in more detail despite its loftier clinical relevance.

Our study is limited by its monocentric view and its sample size. Furthermore, the study only enrolled hospitalized patients, which likely have more than intense episodes of diarrhea than outpatients. Thus, the findings might overestimate the effects on INR in outpatients. Moreover, the data extraction approach did not allow to define all the lifestyle features, drug interactions, affliction states or dosing errors that might have an effect on VKA response. Finally, we only focused on acute diarrhea. We therefore cannot draw whatsoever conclusions on states of chronic diarrhea, e.g. in chronic malabsorptive diarrhea. On the other hand, the study systematically covers a range of 8 years in a Medical Department of a University Infirmary and the small study size is the consequence of the strict in- and exclusion criteria. Moreover, the study design provided a control group with a very similar pattern of indications for anticoagulation and comorbidities that was admitted for other reasons. This control group minimized potential confounders factors equally far as possible and immune a quantification of the effect of diarrhea on the take chances of overanticoagulation.

Decision

The findings presented here volition increase sensation for the loftier risk of INR backlog in subjects with VKA and acute diarrhea. They should encourage physicians to closely monitor INR in these patients in order to identify the demand for a temporary pause of VKA therapy. Moreover, physicians should encourage patients, who perform INR cocky-monitoring, to intensify the monitoring during acute diarrhea, e.g. in a daily manner. This arroyo will likely reduce the rate of adverse bleeding events.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding writer on reasonable request.

Abbreviations

VKA:: Vitamin One thousand antagonists
INR:: International normalized ratio
DOAC:: Direct oral anticoagulant
CRP:: C-reactive protein

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Acknowledgements

Nosotros thank Inga Kropf for her tireless work in data extraction and documentation.

Funding

Open Access funding enabled and organized by Projekt DEAL.

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Affiliations

Medical Section I, Marien Hospital Herne, University Infirmary of the Ruhr-University Bochum, Hölkeskampring forty, 44625, Herne, Germany

Johannes Schweinfurth, Alexander Bauer, Frederic Bauer, Felix Sebastian Seibert, Benjamin Rohn, Maximilian Seidel, Sebastian Bertram, Ulrik Stervbo, Nina Boom-boom & Timm Henning Westhoff

Contributions

Conceptualization: T.H.W.; Formal analysis: J.South.; Investigation: J.S. and A.B.; Methodology: B.R., M.Southward., S.B. and T.H.W.; Resources: A.B., F.B., F.Southward.South., B.R., One thousand.Due south., South.B. and U.Due south.; Supervision: N.B. and T.H.W.; Writing—original draft: Due north.B. and T.H.Westward.; Writing—review and editing: U.S., Due north.B. and T.H.W.

Corresponding author

Correspondence to Timm Henning Westhoff.

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Schweinfurth, J., Bauer, A., Bauer, F. et al. The impact of acute diarrhea on the coagulation status of patients with vitamin Grand antagonists. Sci Rep xi, 11726 (2021). https://doi.org/10.1038/s41598-021-91316-10

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Received: 12 July 2020
Accepted: 10 March 2021
Published: 03 June 2021
DOI : https://doi.org/ten.1038/s41598-021-91316-ten

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