Effect of high-dose cranberry juice on the pharmacodynamics of warfarin in patients

Abstract

AIM

To determine if high-dose cranberry juice (240 ml twice daily) alters the pharmacodynamic action of warfarin.

METHODS

Ten male patients taking stable doses of warfarin were given cranberry juice at 240 ml twice daily for 7 days. Prothrombin times were drawn at baseline and days 2, 6 and 8 after administration of the juice. Prothrombin times were averaged for each day and mean times were compared from each study day to baseline using repeated measures anova.

RESULTS

There was no statistical difference between mean prothrombin time at baseline and any day tested during juice administration.

CONCLUSIONS

Cranberry juice (240 ml twice daily for 1 week) did not alter the pharmacodynamics of warfarin in patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

Case reports suggest an association between cranberry juice and potentiation of warfarin. Studies using 240 ml of cranberry juice daily demonstrated no interaction. It is unknown if higher amounts of cranberry juice will interact with warfarin.

WHAT THIS STUDY ADDS

Cranberry juice at 240 ml twice daily does not alter the pharmacodynamics of warfarin.

Introduction

A 2005 study identified 205 citations with original data containing interactions between warfarin and drug or food interactions [1]. One of these potential interactions was cranberry juice. An interaction with cranberry products and warfarin is listed in the product information produced by the manufacturer of warfarin and patient information sheets [2]. It states that cranberries may increase the international normalized ratio (INR) and that all cranberry products should be avoided in patients taking warfarin. Literature reviews of the possible interaction of warfarin and cranberry juice have resulted in conflicting conclusions [3, 4]. The bulk of the evidence of the possible interaction of cranberry juice and warfarin is based solely on peer reviewed case studies [5–8]. One study found an increase in the INR–time curve with the use of cranberry capsules and a single large dose of warfarin [9]. However, it appears that cranberry juice does not interfere with the function of CYP 2C9, an enzyme responsible for metabolism of S-warfarin [9, 10]. In addition, randomized studies with cranberry juice have found no pharmacodynamic interaction with warfarin, although the dose of cranberry juice in these studies was only 240 ml daily [11–13].

Since cranberry juice may be used more frequently as a nutrition supplement and to prevent urinary tract infections [14], it is important to determine if this food product interacts with warfarin, especially in amounts greater than 240 ml day⁻¹ The purpose of this study was to determine if 240 ml twice daily of cranberry juice interfered with the pharmacodynamics of warfarin.

Methods

The project was a prospective open-labelled study of patients on chronic warfarin therapy at the central anticoagulation clinic at the Southern Arizona VA Health Care System. Patients were required to be on chronic warfarin therapy to be considered for the study. The patients were on stable low-intensity warfarin therapy with a goal INR of 2–3. Patients were considered stable if there were no changes in warfarin doses for a 4 week period and no more than a 10% fluctuation in two consecutive INR laboratory values. Patients with any changes in alcohol consumption, diet, or medication in the prior month were excluded. Patients who consumed cranberry juice on a regular basis defined as greater than 240 ml three times per week were also excluded. Finally, patients with hepatic or renal impairment were not included in the study. Informed consent was required from all eligible patients prior to participation. This study was approved by an Institutional Review Board at the University of Arizona Medical Center.

Patients were provided with a week's supply of whole cranberry juice, not from concentrate (Mountain Sun, Pure Cranberry Juice). The patients consumed 240 ml of cranberry juice twice a day for 7 days. Patients were instructed to continue their daily stable dose of warfarin and to take the medication in the late afternoon. Prothrombin times (PTs) and INRs were obtained on the day before cranberry juice ingestion (day 0), day 2, day 6 and day 8 of the study by an outpatient laboratory service. The target INR range for all patients included in the study was 2–3. The normal laboratory range of PT was 12.9 to 15.0 s with a mean of 14.0.

Prothrombin times were collected by this facilities' central laboratory and analyzed using the STAR instrument by Diagnostica Stago. Adherence of warfarin and cranberry juice were assessed by asking the subject to complete a check off sheet following every ingestion. Patients were removed from the study if not adherent to taking the cranberry juice. Adherence was defined as 80% ingestion of the doses of cranberry juice.

Prothrombin times and INRs were averaged at baseline and during the study (days 2, 6 and 8). The mean PT at baseline was compared with mean PTs during the study using repeated measures analysis of variance. Ten patients should be sufficient to detect a 2.5 s difference in PT assuming a standard deviation of 2 s, using an alpha of 0.05 and a beta of 0.2 [15]. An alpha of <0.05 was considered significant.

Results

Ten male patients were enrolled into the study and nine completed the protocol. The demographic and clinical characteristics of the patients are included in Table 1. Compliance to both cranberry juice and warfarin was reported at 100% by all patients.

Table 1.

Demographic and clinical characteristics of patients

Mean age (years)	73.4 (range 62–86)
Mean weight (kg)	99.3 (range 72.3–122.5)
Mean weekly dose (mg)	33.2 (range 20–52.5)
Indication
Atrial fibrillation	n = 3
Pulmonary embolism	n = 5
Deep vein thrombosis/stroke	n = 1
Deep vein thrombosis/atrial flutter	n = 1

No significant difference was found in the mean PT at baseline and any time during the study. The time course of INR for each patient is depicted in Figure 1. One patient developed diarrhoea soon after starting the protocol and had an elevated INR on day 2 of the study. The cranberry juice was stopped and warfarin held. On day 6 his INR was 2.3 and his diarrhoea had resolved. No further adverse events such as bleeding or bruising were reported, with only complaints of sour taste from the juice by all patients.

Figure 1.

The effect of cranberry juice on INR in individual patients

Discussion

Our results showed that 240 ml twice daily of cranberry juice did not significantly change the PT of patients on chronic stable warfarin therapy. The results contribute to the existing findings of previous randomized, placebo-controlled studies that found no effect of cranberry juice on the anticoagulant properties of warfarin, albeit at a lower dose.

The only randomized, placebo-controlled study to suggest an interaction utilized cranberry capsules [9]. Healthy subjects consumed two cranberry capsules or placebo three times daily for 2 weeks and then took a one time dose of warfarin 25 mg. The cranberry capsules significantly increased the area under the INR–time curve. However, this pharmacodynamic finding did not appear to have a significant clinical impact, as the magnitude of the effect on the prolongation of the INR was small. The study design also was not indicative of the daily dosing schedule of warfarin used in actual warfarin patients. Finally, the contents of over the counter herbal capsules challenge the ability to ascertain that cranberries alone are affecting warfarin.

One patient was required to stop consuming cranberry juice due to a supratherapeutic INR. After further discussions with the patient, we determined he fell ill with gastroenteritis the day before the study with stomach distress and diarrhoea ensuing over the next 2 days. In our experience, patients who are stable on warfarin and fall ill tend to have an increase in their INR. Case reports have also demonstrated elevated INRs and near fatal bleeding in conjunction with diarrhoea [16–18]. A case-control study associated an increase in elevated INRs in patients on warfarin with decreased intake of vitamin K and diarrhoea [19]. It is hypothesized that the absorption of vitamin K in the proximal small intestine may be affected by diarrhoea, resulting in an increased risk for bleeding [17]. Although one could argue that the cranberry juice caused the INR elevation, we felt his illness was the likely cause.

It is difficult to reconcile the numerous case reports describing an interaction and the negative prospective trials. Possibly the amount of cranberry juice in these trials was insufficient to elicit an interaction. In the best described case report, the patient ingested 720 ml of cranberry juice daily for 2 weeks before the interaction was documented [7]. Our trial used the largest amount of cranberry juice (480 ml day⁻¹) studied to date, and was negative. We feel it would be difficult to do a trial with larger amounts of juice due to patient acceptance. Another reason for this discrepancy is that the interaction may be unpredictable and rare, and nine patients, perhaps, is an insufficient sample size to demonstrate this possibility.

There were limitations to this prospective open-labelled study. Cranberry products are available in multiple dosage forms not included in the study. The heterogeneity of the patients makes it difficult to generalize to all patients on warfarin. The patients were not blinded, leading to the possibility of bias. Assessment of compliance required subjects to report consumption, with no ability to verify ingestion. Finally, the study was unable to assess the polymorphisms of VCORC1 and CYP 2C9 of the patients, which may affect the metabolism of warfarin and its potential interaction with cranberry juice.

In conclusion, no significant pharmacodynamic interaction was found between cranberry juice and warfarin when dosed at 240 ml twice daily for 1 week.

Competing interests

There are no competing interests to declare.