By Joanna Becker
Faculty Peer Reviewed
Patients who are placed on long-term warfarin (Coumadin) therapy are sent home with a lengthy list of restrictions to minimize variations in warfarin efficacy. The agents that can alter warfarin levels can be divided into 2 categories: (1) those that interact with cytochrome P450, which metabolizes warfarin and (2) those that alter phytonadione (vitamin K) levels. The majority of inter- and intra-individual warfarin dose variability is attributable to the agents in category 1 above, which include everything from antibiotics, antihistamines, and barbiturates to alcohol and antacids. However, once one controls for these variables, oral intake of vitamin K persists as an integral factor in anticoagulation stability.
Warfarin functions by inhibiting vitamin K epoxide reductase, which halts the recycling of vitamin K and subsequently prevents the synthesis of vitamin-K-dependent coagulation factors II, VII, IX, and X. As a result, for probably the first time since childhood, patients are steered away from all dark green vegetables, which are rich in the vitamin K that blunts the anticoagulant effect of warfarin, lowering the international normalized ratio (INR). The logic is that if patients restrict vitamin K in their diet there will be less dietary fluctuation of vitamin K and it will be less of a challenge to manage warfarin’s narrow therapeutic index. So, should we continue to give all patients taking warfarin permission to pass on the broccoli? Not exactly.
Although it may seem counter-intuitive, increasing evidence has shown that the common anti-green vegetable lecture imparted to all patients starting warfarin may actually be doing more harm than good. Such advice may be setting up patients for a widely variable and difficult to manage INR. Low-dose vitamin K supplementation may actually improve the stability of anticoagulation therapy.
What is therapeutic stability and what factors influence it?
A patient’s ability to achieve a stable INR on anticoagulation with warfarin is essential for protection against thromboembolic and hemorrhagic events. Stability is generally quantified by the standard deviation (SD) of measured INR over a certain period of time. In one study, the median standard deviation of INR in a single clinic population was 0.3 over 6 months. The researchers classified patients as unstable if they had a SD >0.5 and at least 3 changes in warfarin dose over the prior 6 months. Of note, patients with instability attributable to factors such as poor adherence to therapy, other medications, comorbidities, or excess alcohol consumption were excluded. In addition to these controllable factors, stability depends on a number of uncontrollable factors including age and CYP2C9 and VKORC1 polymorphisms. Although genotype can aid in determining anticoagulation initiation doses by being plugged into dose-optimizing algorithms, genotype is not a factor in the ability to maintain stability once it is achieved. On the other hand, vitamin K intake still plays an independent role and thus represents a controllable factor that we can manipulate to improve stability.
What is the relationship between low dietary vitamin K and INR stability?
In a 2010 review in the British Journal of Clinical Pharmacology, the authors contend that, “Older recommendations for diets low in vitamin K as appropriate for warfarin-treated patients should now be considered outdated.” Their conclusion is based on research such as the 2004 study by Kurnik and colleagues, which found that vitamin K-depleted patients had significantly greater fluctuation in INR when given vitamin K supplementation when compared with non-depleted patients. In other words, low vitamin K levels cause a patient’s warfarin requirement to vary with even minor changes in vitamin K intake. In 2005, Sconce and colleagues went one step further and demonstrated that patients with low dietary intake of vitamin K were more likely to have unstable control of anticoagulation. These results were then replicated in a 2010 study by Kim and colleagues. When taken together, these studies conclude that patients with low vitamin K intake are more sensitive to minor changes in vitamin K intake and thus more likely to have therapeutic instability.
Does vitamin K supplementation improve stability?
Based on the above data, it can be hypothesized that vitamin K supplementation is particularly useful in achieving therapeutic stability in patients with low vitamin K intake. In such patients, daily fluctuations in vitamin K intake lead to significant and proportional changes in INR that can be avoided by oral supplementation. A 2007 study by Sconce and colleagues put this hypothesis to the test in the first randomized, blinded, placebo-controlled trial investigating the effects of vitamin K supplementation in 70 unstable patients over 6 months. When patients with unstable anticoagulation were given 150 mcg of vitamin K supplementation per day, they spent a greater amount of time within target INR range and had decreased daily variability in INR when compared with placebo. These findings were consistent with other literature including a 2005 trial by Reese and colleagues as well as a 2007 study by Rombouts and colleagues using phenprocoumon (a longer-acting vitamin K antagonist) as the anticoagulation agent. Finally, a recent 2010 study by Gebuis and colleagues looked at patients taking phenprocoumon or acenocoumarol and compared the effects of placebo with 100-, 150-, or 200-mcg vitamin K supplementation. Although the supplementation provided improved stability, there was little difference between the doses. Ultimately, low-dose vitamin K supplementation, regardless of dose, was shown to improve therapeutic stability in patients with unstable anticoagulation with warfarin or its derivatives.
What should we tell our patients? When and in whom should we start supplementation?
It is clear from the research outlined here that cutting out vitamin K is not the answer for achieving stable anticoagulation. Instead, inform your patients of the vitamin-K rich foods and advise them to maintain a steady dietary pattern. If they have any planned dietary changes or adjustments in multivitamin use, these should be reported. According to the 2008 clinical practice guidelines published in Chest by Ansell and colleagues: “For patients receiving long-term warfarin therapy with a variable INR response not attributable to any of the usual known causes for instability, we suggest a trial of daily low-dose oral vitamin K (100 to 200 mcg), with close monitoring of the INR and warfarin dose adjustment to counter an initial lowering of the INR in response to vitamin K (Grade 2B).”
In summary, patients no longer have an excuse to avoid leafy green vegetables, missing out on all the other nutrients they harbor as well as vitamin K’s role in slowing vascular calcification. Vitamin K will help rather than hinder the chances of achieving long-term stable anticoagulation. If a patient has a consistent diet and all other causes of instability have been eliminated, try vitamin K supplementation.
Comment by Dr. Wasserman
Time in the therapeutic range (TTR) is a key determinant of outcomes for patients receiving anticoagulation with warfarin. The relative risk of adverse outcomes for patients with atrial fibrillation whose TTR is <60% is 1.5 for ischemic stroke and 2.3 for hemorrhagic stroke when compared with patients with a TTR >60%. TTR is also important for patients with a history of venous thrombosis or embolism. Those with a TTR <45% have a relative risk of recurrent venous thromboembolism or major bleeding of 2.8 compared to those with TTR >65%. Unfortunately, we in the US miss the mark. A study of a large laboratory’s national database reveals that INR measurements are within target only 52% of the time for patients with atrial fibrillation and 45% of the time for patients with venous thromboembolism.
Ms. Becker’s excellent review of dietary and supplemental vitamin K intake in patients requiring warfarin is most welcome. Based upon estimates of fresh food availability, the citizens of New York City probably have a high rate of relative vitamin K deficiency. Vitamin K1, which accounts for approximately 95% of our vitamin K intake, is most readily available in leafy green vegetables. Approximately 3 million people living in New York City live in “food deserts,” where there is limited availability of fresh or healthy food. Patients who reside in food deserts probably have low vitamin K intake and higher variability in warfarin requirements, like the subjects in the articles by Sconce  and Kim . Dietary advice will be of limited value unless these patients are willing to find the fresh vegetables lacking in their neighborhoods. Alternatively, vitamin K 100 microgram supplements may be had for approximately $4 for 100 tablets. The largest benefit with vitamin supplementation occurred in studies that excluded patients with other obvious reasons for variability of INR (eg, alcohol abuse, medication non-adherence, and changes in concurrent medications). Targeting advice to patients like these would provide the most benefit.
Dr. Joanna Becker is a 4th year medical student at NYU School of Medicine
Faculty peer reviewed by Lloyd Wasserman, MD, Clinicial Instructor, Department of Medicine, NYU Langone Medical Center
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