OD'ing on a Warfarin and Cranberry Cocktail?
Abstract & Commentary
By Francis Brinker, ND. Dr. Brinker is Clinical Assistant Professor, Department of Medicine, College of Medicine, University of Arizona; he is a retained consultant for Eclectic Institute, Inc.
Synopsis: Regular consumption of substantial amounts of cranberry juice or sauce by patients stabilized on warfarin (Coumadin®, Jantoven®) has been implicated in several cases of otherwise inexplicable increases of International Normalized Ratio (INR), including a few with serious hemorrhages. Garlic has been similarly implicated. This human study investigates parameters that reflect the most probable mechanisms. The findings suggest that those with an increased sensitivity to warfarin due to a genetic variant of vitamin K epoxide reductase may be at increased risk of bleeding from regular use of cranberry products, but not garlic.
Source: Mohammed Abdul MI, et al. Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. Br J Pharmacol 2008;154:1691-1700.
This open-label, randomized, crossover, three-treatment trial with 12 healthy males (18-34 years of age) utilized one dose of 25 mg racemic warfarin alone as a baseline. Daily blood draws were taken at the same time beginning two days before warfarin dosing to seven days after, as well as at 0, 1, 2, 4, 8, and 12 hours post-dosing. Following two-week washout periods, pretreatment with one of two Australian proprietary products for two weeks utilized either two capsules of 500 mg cranberry juice concentrate (GNC brand) three times daily or one enteric-coated garlic tablet (Garliplex 2000, equivalent to 3.7 mg allicin/tablet) twice daily. After the same warfarin dose was taken, the cranberry capsules or garlic tablets were continued for a third week. Warfarin enantiomer concentrations, plasma protein binding, INR, and clotting Factor II, VII, and X activity were monitored with the blood samples.
No platelet aggregation or baseline INR changes occurred after two weeks of cranberry juice concentrate or garlic alone. The protein binding and pharmacokinetics (PK) of the S- and R-warfarin enantiomers were not affected by use of either botanical, neither for subjects with wild nor with variant CYP2C9 genotypes. No bleeding resulted from combining the drug with the botanical products.
No changes in INR or clotting factors were detected in the garlic group. On the other hand, pharmacodynamic (PD) effects of warfarin combined with cranberry juice concentrate included a nonsignificant trend toward a greater decrease in activity of clotting Factors II, VII, and X. More importantly, a 30% increased area under the INR-time curve was significant both statistically and clinically. Population PK-PD modeling estimated a mean decrease in the effective S-warfarin dose for the cranberry product compared to control. This estimated decrease was significant for the eight subjects with a vitamin K epoxide reductase subunit 1 gene (VKORC1) variant, but not for the four subjects with the wild-type VKORC1, whereas a significant increase in the effective dose of S-warfarin was estimated for the garlic product in those with wild-type genes.
Commentary
One value of this study lies in its documenting a lack of hemodynamic effects from relatively normal doses of a specific cranberry juice concentrate and garlic product after two weeks. Another is its comparison of genotypic subpopulations for CYP2C9 and VKORC1. However, the strength of the findings is limited by the small sample and the even smaller group sizes for specific genotypes.
Another important concern for interpreting the results is the poor characterization of the cranberry juice concentrate, whose daily dose was described as "equivalent to 57 g of dry fruit." The authors indicate this amount "is less than the dose employed" in another study that used 300 mL/d of cranberry juice cocktail (consisting of only 33% juice, a fact that the authors may not have taken into account). A qualitative thin layer chromatographic assay of the juice concentrate indicated it contained anthocyanins and quercetin, as did other similar products tested. Unfortunately, differences between preparations cannot be accurately estimated as "equivalent" unless bioassays are performed and/or unless a specific amount of the responsible component(s) have been measured. While the garlic tablets employed were described as enteric-coated and standardized to an allicin content "obtained from 2 g fresh garlic," no independent verification was provided to substantiate the label claims.
The findings of this study verify and help put in context results from two other pharmacological studies on cranberry juice. A previous PK study with 10 healthy subjects consuming 200 mL of cranberry juice or water three times daily for five days before and five days after taking 10 mg R,S-warfarin also found no changes in bioavailability for either warfarin isomer. The combination with the juice did not alter hemodynamics.1 An earlier crossover PD investigation of seven men with atrial fibrillation stabilized on warfarin for three months did not find prothrombin time or INR changes when 250 mL of cranberry juice cocktail or placebo was given for seven days, though the short time and small sample size again limit the study. These authors suggest that up to 250 mL (1 cup) cranberry juice cocktail daily need not be eliminated in patients on warfarin if INRs are closely followed.2
The demand for this research is based on a series of adverse event case reports involving warfarin and implicating cranberry juice. Concern over the potential interaction of cranberry juice with warfarin has grown since one of the first reported cases with this combination was a fatal hemorrhage, involving a man in his 70s with an INR initially reported to be > 50.3 A recently published (and more detailed) report of this case describes how this elderly man had been taking a stable warfarin dosage for four years along with digoxin and phenytoin.4 He suffered a deadly gastrointestinal hemorrhage along with profuse hemopericardium after he consumed about 300-400 mL of cranberry juice daily for six weeks. However, due to a chest infection he had eaten almost no solid food for two weeks prior to his death, but continued his medication and the juice. On admission to the hospital a few hours before expiring his status included: INR > 15, hemoglobin 5 g/dL, an immeasurable prothrombin time, and blood pressure 70/40 mmHg. Autopsy revealed 950 mL of bloody fluid in his pericardial sac, extensive superficial bruising on his limbs, and blood throughout his gut due to erosive pan-gastritis. The association of cranberry juice with this outcome was dismissed by some, due to an almost complete lack of nutrition including vitamin K as well as prior seven-day use of the antibiotic cephalexin, which can alter the intestinal flora and vitamin K biosynthesis.5,6
In another case, a 71-year-old man was stabilized on warfarin for three months prior to using 24 oz cranberry juice daily for two weeks.7 Doctors found blood in his sputum and stools, a prothrombin time > 120 seconds (instrument limit), and an INR of > 18. The bleeding stopped within one day of transfusion, and cessation of warfarin and cranberry juice. The INR went from 7 the next day to 2.6 in another three days. A 78-year-old man on a stable warfarin dose for six years had never had an INR > 3.0 before drinking a half gallon of cranberry/ apple juice in the week prior to registering an INR of 6.45.8 After warfarin dosing adjustments and refraining from cranberry juice, the INR was normalized in two weeks. A 75-year-old man taking a stable dose of warfarin for 10 months with INRs of 2.0-3.0 registered a 4.8 INR following Thanksgiving and consumption of about 113 g of cranberry sauce over the prior week.9 After discontinuing the cranberry sauce, the INR returned to 2.2 within a week.
A few similar case reports involving elderly men with increased INRs with or without bleeding after using cranberry juice with warfarin have been published in the last several years.6 Brief descriptions of seven other potential interactions of warfarin with cranberry juice indicate that INRs increased in four, were unstable in two, and decreased in one.3 In a randomized placebo-controlled double-blind trial of 30 patients on warfarin with stable INRs, 14 used 9 oz cranberry juice daily for two weeks. No differences in mean INR and R- or S-warfarin peak levels between groups were found during the lead-in or treatment phases, except on day 11 when the cranberry group INR was significantly higher (P < 0.02). Of the 14 cranberry juice subjects, four developed slightly higher INRs and one had a low INR, while four of 16 in the placebo group had slightly higher INRs.10 At least 30% of patients using warfarin are commonly outside of the normal therapeutic range.5
Despite the existence of equivocal evidence in support of an interaction between cranberry products and warfarin, the United Kingdom's Committee on Safety of Medicines alerted clinicians of this potentially risky combination and advised patients to avoid concurrent use of warfarin with cranberry juice. While large volumes of juice may destabilize the therapy, small amounts are not expected to cause a serious interaction, though patients should be counseled and monitored.6 This current study suggests that the risks from this combination appear greatest for a specific subpopulation set, those with variant VKORC1 genotypes.
Aside from dietary vitamin K sources, herb-drug combinations, and drug-drug interactions, the inherent risks from warfarin use due to genetic polymorphisms has led to development of a dose algorithm based on genetic information combined with clinical variables. Compared to dosing based only on clinical information, this pharmacogenetic algorithm was found to be significantly better at predicting those in the 46.2% of the population who require either lower (< 21 mg weekly) or higher (> 49 mg weekly) therapeutic doses to achieve the target INR range (P < 0.001).11 This new algorithm is now publicly available for free from the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB).12 Several clinical tests for CYP2C9 and VKORC1 variants to assess warfarin sensitivity (and potentially identify those with cranberry-heightened sensitivity) have been approved by the FDA in the past year and a half. These include TrimGen, Nanosphere, Autogenomics, ParagonDx, and Osmetech.13
References
1. Lilja JJ, et al. Effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin, tizanidine, and midazolamprobes of CYP2C9, CYP1A2, and CYP3A4. Clin Pharmacol Ther 2007;81:833-839.
2. Li Z, et al. Cranberry does not affect prothrombin time in male subjects on warfarin. J Am Diet Assoc 2006;106: 2057-2061.
3. Suvarna R, et al. Possible interaction between warfarin and cranberry juice. BMJ 2003;327:1454.
4. Griffiths AP, et al. Fatal haemopericardium and gastrointestinal haemorrhage due to possible interaction of cranberry juice with warfarin. J R Soc Health 2008; 128:324-326.
5. Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol 2005;45:127-132.
6. Aston JL, et al. Interaction between warfarin and cranberry juice. Pharmacotherapy 2006;26:1314-1319.
7. Rindone JP, Murphy TW. Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding. Am J Ther 2005;13:283-284.
8. Paeng CH, et al. Interaction between warfarin and cranberry juice. Clin Ther 2007;29:1730-1735.
9. Mergenhagen KA, Sherman O. Elevated International Normalized Ratio after concurrent ingestion of cranberry sauce and warfarin. Am J Health Syst Pharm 2008;65: 2113-2116.
10. Ansell J, et al. A randomized, double-blind trial of the interaction between cranberry juice and warfarin. J Thromb Thrombolysis 2008;25:112.
11. International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009:360:753-764.
12. Warfarin Dosing. Available at:www.warfarindosing.org/Source/Home.aspx.
13. TrimGen gets FDA OK for warfarin genotyping test. GenomeWeb Daily News. Feb. 17, 2009. Available at:www.genomeweb.com/newsletter/genomeweb-daily-news.
Regular consumption of substantial amounts of cranberry juice or sauce by patients stabilized on warfarin (Coumadin, Jantoven) has been implicated in several cases of otherwise inexplicable increases of International Normalized Ratio (INR), including a few with serious hemorrhages.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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