November 2010 Newsletter
The 11th National Conference on Anticoagulant Therapy will be held at the Sheraton Boston Hotel in Boston, MA, May 5-7, 2011. Conference registration is now open!
Register now to receive the Early Bird rate.
More details available on our website. Please be sure to check out the links on the right hand menu for the conference brochure, instructions for abstract preparation, abstract submission form, travel award application, and more.
Jack Ansell, M.D.
There is no creditable scientific evidence to link an interaction between the moderate consumption of cranberry juice and warfarin.
In September 2003, the UK Committee on Safety of Medicines (CSM) issued a warning of a possible interaction between warfarin and cranberry juice. This warning was based on five spontaneous brief case descriptions (nothing more than a few sentences) suggesting such an interaction, leading to changes in INR values. The Committee indicated that the interaction is biologically plausible since cranberry juice contains various antioxidants, including flavonoids, which are known to inhibit specific cytochrome P450 enzymes. They acknowledged that further investigation was needed and recommended that until this matter was concluded, it would be prudent for patients taking warfarin to be advised to limit or avoid drinking cranberry juice. Similar warnings appeared on the labels for the FDA-approved products Coumadin® (warfarin, Bristol-Myers Squibb) and several generic warfarin products.
A review of all 16 suspected reports from the UK reported to the Medicines and Healthcare products Regulatory Agency (MHRA) via spontaneous reporting schemes found that the cases were poorly documented.1 There are several other factors that could have been responsible for the changes in INR observed in these patients, including multiple co-morbidities, nutritional impairment, use of a number of other drugs, and exorbitant amounts of cranberry juice consumed. In one case, the INR actually decreased, the opposite of what is attributed to the interaction. The number of reports is also remarkably small considering the extensive use of warfarin and cranberry juice, often concurrently, by the elderly.
Against this anecdotal and poorly documented evidence from spontaneous reports is the overwhelming and ever-accumulating evidence from well-designed specific drug interaction studies. Recent publications have concluded that there is no interaction between cranberry juice and warfarin. There are seven separate interaction studies assessing valid and accepted pharmacodynamic (PD) and/or pharmacokinetic (PK) endpoints, examining a total exposure of 75 patients and healthy volunteers, of which six concluded that a cranberry juice-warfarin interaction is unlikely. The studies are summarized in Table 1.
Summary of Results
The data show that, in both healthy subjects and patients, there is no evidence of a PK or PD interaction between cranberry juice and warfarin – with the exception of the Abdul study. Abdul and colleagues2 claimed a potential PD interaction on the basis of assessment of an inappropriate and unconventional AUC-based PD parameter and the use of a single, very high dose (25 mg) of warfarin in healthy volunteers. An integrated assessment of the seven formal drug interactions studies, investigating an interaction between cranberry juice and warfarin in vitro and in vivo leads to the following conclusions:
- Using flurbiprofen or diclofenac as the probe substrates, studies indicate that, overall, there is no consistent in vitro evidence of a significant inhibition of CYP2C9 by normal quantities of cranberry juice (i.e., two 250 ml glasses of CJ/day or less). The evidence for in vitro inhibition of CYP2C9 by cranberry juice is conflicting at best. In any case, in vitro performance of cranberry juice is not predictive of its in vivo performance.
- Li et al3 showed that cranberry juice does not inhibit the in vivo activities of CYP1A2 or CYP3A4.
- Evidence consistently shows that cranberry juice does not affect the PK of either warfarin or other probe substrates of CYP2C9.
- Evidence consistently shows that cranberry juice does not affect warfarin-induced changes in INR or vitamin K-dependent clotting factors unless the data analysis employs PD AUC, whose clinical relevance is uncertain.
- Consumption of cranberry juice at a daily volume of 250 ml (used in most studies) or even as high as 200 ml t.i.d for 10 days, as used by Lilja et al4, or 250 ml of pure cranberry juice twice daily, as used by Mellen et al5, is without effect on the in vivo pharmacological properties of warfarin. At present, no conclusions can be drawn on the effect of larger volumes.
Conclusions
In conclusion, there is no evidence of risk of a clinically relevant interaction between warfarin and cranberry products from peer-reviewed interaction studies when cranberry juice is consumed in moderation. One cannot exclude the possibility of an interaction with the consumption of excessive quantities of cranberry products. Thus, it does not appear necessary to avoid normal levels of usage of cranberry products (two 8 oz glasses/day).
Table 1. Summary of studies examining a potential cranberry juice-warfarin interaction from the literature
|
Study |
Participant numbers |
Study design |
Treatment groups |
Duration of cranberry juice exposure |
PK result* |
PD result* |
|
Li et al (2006)3 |
7 patients (warfarin for AF)* |
Crossover |
Warfarin + cranberry juice/placebo |
Extended |
Not determined |
No effect (INR) |
|
Greenblatt et al (2006)5 |
14 healthy volunteers |
Crossover |
Flurbiprofen (single dose) (preceded by cranberry juice, placebo, grape juice, tea or fluconazole) |
Short-term |
No effect |
N/A |
|
Lilja et al (2007)4 |
10 healthy volunteers |
Parallel |
R-S warfarin, tizanidine, midazolam (5 days) + cranberry |
Extended |
No effect |
No effect (thromboplastin time) |
|
Abdul et al (2008)2 |
12 healthy male volunteers |
Open label, randomized crossover |
Single dose 25 mg warfarin, alone or after 2 weeks of cranberry juice concentrate capsules or garlic tablets |
Extended |
No effect |
INR AUC increased by 28% (max 8% difference at any individual time point) in warfarin/cranberry juice group |
|
Ansell et al (2009)7 |
30 patients (16 placebo; 14 cranberry juice) |
Parallel |
Cranberry juice vs. placebo |
Extended |
No effect |
No significant effect on INR |
|
Ushijima et al (2009)8 |
6 male, 2 female healthy volunteers, mean age 30.5 (range 23–44 years) |
Open-label, two-period, crossover design with a wash-out period of >2 weeks |
Cranberry juice vs. water with or without diclofenac (a medication metabolized by CYP2C9) |
Medium duration (5 days), dosing of cranberry juice 180 ml, twice a day |
No effect in healthy volunteers |
No interaction with diclofenac in vivo, although inhibition of CYP2C9 in microsomal preparation in vitro |
|
Mellen, et al (2010)5 |
10 patients, ages 62–86, on warfarin for AF (3), PE (5), DVT-stroke or DVT and AF (1 each)* |
Open-label, prospective |
On stable warfarin dose, INR 2-3. |
Cranberry juice (100%), 240 ml, twice/day x 7 days |
N/A |
No significant difference found in the mean PT at |
*AF = atrial fibrillation; DVT = deep vein thrombosis; PE = pulmonary embolism; VHD = valvular heart disease; CVD = cerebrovascular disease; CHF = congestive heart failure; AUC = area under the curve; PT = prothrombin time.
References
- MHRA/CSM. Possible interaction between warfarin and cranberry juice. Current Problems in Pharmacovigilance. 2003;29:8.
- Abdul MI, Jiang X, Williams KM, et al. Pharmacodynamic interaction of warfarin with cranberry juice but not garlic in healthy subjects. Br J Pharmacol. 2008; 154:1691-1700.
- Li Z, Seeram NP, Carpenter CL, Thames G, Minutti C, Bowerman S. Cranberry does not affect prothrombin time in male subjects on warfarin. J Amer Diet Assoc. 2006; 106(12):2057-2061.
- Lilja JJ, Backman JT, Neuvonen PJ. Effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin, tizanidine, and midazolam probes of CYP2C9, CYP1A2, and CYP3A4. Clin Pharmacol & Ther. 2007; 81(6):833-839.
- Mellen CK, Ford M, Rindone JP. Effect of high-dose cranberry juice on the pharmacodynamics of warfarin in patients. Br J Clin Pharmacol. 2010;70(1):139-142.
- Greenblatt DJ, von Moltke LL, Perloff ES, Luo Y, Harmatz JS, Zinny MA. Interaction of flurbiprofen with cranberry juice, grape juice, tea and fluconazole: in vitro and clinical studies. Clin Pharmacol Ther. 2006; 79:125-133.
- Ansell J, McDonough M, Zhao Y, Harmatz JS, Greenblatt DJ. The absence of an interaction between warfarin and cranberry juice: A randomized double blind trial. J Clin Pharmacol. 2009; 49:824-830.
- Ushijima K, Tsuruoka S, Tsuda H, et al. Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects. Br J Clin Pharmacol. 2009 Aug; 68(2):194-200.
Disclosure
Dr. Ansell has been asked by the Cranberry Institute to clarify the relationship between cranberry juice consumption and warfarin affect based on sound clinical science. As such, he is paid a small honorarium for his efforts. The Cranberry Institute is a not-for-profit organization to support cranberry growers through agricultural and environmental research, promotion and education.
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VTE Prevention and Treatment:
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Announcing for the first time. AC Forum Conference Travel Awards. Travel awards will be granted to 10 candidates who best demonstrate a combination of financial need and desire to further their professional knowledge in the field of antithrombotic therapy. See the Travel Award Application for details. |
Jodi Wagner, RPh, CACP
Providence Spokane Anticoagulation Clinics
Providence Spokane Urban Campus Anticoagulation Clinics are a testimony to success for pharmacist run anticoagulation clinics in Washington. These clinics currently serve over 1300 patients and over 400 physicians in the greater Spokane area. The hospital outpatient service is staffed by dedicated pharmacists who work under a collaborative practice agreement, with specialized training and many have received national certification as Certified Anticoagulation Care Providers.
Sacred Heart Anticoagulation Clinic opened in 1999 and Holy Family Hospital Anticoagulation Clinic in 2001, both starting out with a handful of patients in a small basement space, with a single exam room. In 2009, the Sacred Heart Anticoagulation Clinic became affiliated with the Holy Family Anticoagulation Clinic as a result of integration of two hospitals under the Providence Spokane umbrella. Both clinics continue to grow and have a net positive profit margin. The clinics employee one full-time pharmacist supervisor/director, four full-time pharmacists (one is also a family nurse practitioner), five part-time pharmacists and four supplemental pharmacists. Seven of these pharmacists are Certified Anticoagulation Care Providers. A dedicated pharmacist and a pharmacy technician staff the home monitor program four days a week.
The Spokane Providence Anticoagulation Clinics offer a variety of anticoagulation management services. Types of patients serviced include those with thromboembolic disorders requiring treatment and/or prophylaxis with antithrombotics. Services provided include evaluation, assessment, education, follow-up, in-office point of care INR testing and Home INR Monitoring services. The pharmacist provides warfarin, low-molecular weight heparin and unfractionated heparin management, bridge therapy planning, and physician consultation. The clinic operates by appointment only and requires a provider referral prior to the patient's appointment. Patients receive verbal education and printed information from a pharmacist on all aspects of antithrombotics. The clinic has produced its own 9 minute warfarin education video for patients to view. Patients are encouraged to use a pillbox and can receive a complimentary pillbox. The patient is given a new warfarin dosing card and follow-up appointment at each visit. The pharmacists are responsible for all low-molecular weight heparin dosing and teaching, including self-injection technique. The clinic offers adult immunizations for influenza and pneumococcal vaccines. Pharmacists are authorized to order new and/or refills for warfarin and injectable anticoagulants, vitamin k and aminocaproic acid mouth rinse through our collaborative practice agreement.
The AC Forum offers the opportunity for posters to be presented at the 11th National Conference on Anticoagulant Therapy in Boston, MA. The organization seeks abstracts that demonstrate best practices with measurable results, evidence based policies, and the latest findings in research..
Works-in-progress may be submitted. If final results are not yet available, preliminary results must be outlined. We are also interested in lessons learned from programs and projects that worked as well as those that did not work out quite as anticipated. Abstracts must be submitted online at www.acforum.org. Abstracts will be presented on Friday, May 6th from 4:00-6:00 at the conference. Please visit the website for complete details.
Conference participants are also invited to submit written reports of interesting and/or challenging cases. The best four cases will be selected and presented at the conference during a Difficult Cases Panel session. Please email your case, limited to 250 words, to Elizabeth Goldstein by January 15th.
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Our Mission The Anticoagulation Forum is a multidisciplinary nonprofit organization of health care professionals that will improve the quality of care for patients taking antithrombotic medications. Join the Forum There is no charge to join the Forum. If you are not yet a registered member, please take a quick moment to join the AC Forum. Contact Elizabeth Goldstein |
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