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Dietary vitamin K intake and anticoagulation in elderly patientsLuis Eduardo Rohde, Michelli Cristina Silva de Assis and Eneida Rejane Rabelo Vitamin K is an essential co-factor for the synthesis of Chronic oral anticoagulation has been used to prevent several coagulation factors. Oral anticoagulants thromboembolic events for more than 6 decades competitively inhibit enzymes that participate in vitamin K Although several clinical trials have attested the metabolism. The purpose of this review is to evaluate the efficacy of anticoagulants in different clinical scenarios, potential interaction of dietary vitamin K and coagulation it is well recognized that the effectiveness of such stability, particularly in the elderly patient.
strategy is limited in clinical practice by an inherent and persistent risk of bleeding and thrombotic events.
Recent prospective evidences suggest that dietary vitamin Oral anticoagulation of the elderly imposes a particular K plays an essential role in anticoagulation stability. Vitamin challenge, as the therapeutical window may be even K intake of more than 250 mg/day was shown to decrease narrower in the aging patient. Despite an allegedly warfarin sensitivity in anticoagulated patients consuming increased risk of bleeding, however, clinical benefits in regular diets. In a randomized crossover study, brief periods elderly patients are also particularly well established. In of changes on vitamin K intake also had significant effects addition, clinical indications of chronic oral anticoagula- on coagulation parameters. Patients that were allocated to tion is expanding in elderly people as atrial fibrillation an 80% decrease of intake increased International prevalence is exponentially associated with aging and Normalized Ratio (INR) by almost 30% 7 days after the prosthetic valvular heart surgery is increasingly being intervention. Similarly, it was estimated by dietary records that for each increase in 100 mg of vitamin K intake, the INRwould be reduced by 0.2. A recent study also demonstrated Unfortunately, anticoagulation parameters outside the that over-the-counter multivitamin supplements contain therapeutic range are exceedingly common in outpatient enough vitamin K1 to significantly alter coagulation clinics worldwide, despite major efforts from healthcare providers to meticulously adjust drug dosages and edu- cate patients. Genetic and environmental factors that Contemporary data strengthen the concept that the might interfere with coagulation stability are the focus interaction between dietary vitamin K and coumarin of intense basic and clinical research Dietary derivatives is clinically relevant and plays a major role in INR vitamin K is one player of this complex interplay that fluctuations in chronic anticoagulated patients.
has been greatly overlooked by physicians, nurses andpharmacists. The theoretical background that supports the potential interaction between vitamin K and cou- marin derivatives has been well established for a longtime, but data on how this interaction actually works in Curr Opin Clin Nutr Metab Care 10:1–5. ß 2007 Lippincott Williams & Wilkins.
clinical practice have only recently begun to emerge Cardiovascular Division of Hospital de Clı´nicas de Porto Alegre, Post-GraduationProgram in Cardiovascular Sciences and Cardiology, Federal University of Elderly patients who are eligible for chronic oral anti- Correspondence to Luis E. Rohde, MD, Cardiovascular Division, Hospital de coagulation therapy are gradually increasing in number, as Clı´nicas de Porto Alegre, Rua Ramiro Barcelos 2350, Sala 2061, Porto Alegre, RS, longevity of the population is steadily expanding. Atrial Brazil 90035-903Tel: +55 51 21018344; e-mail: fibrillation – one of the most common indications for suchtherapy – affects nearly 10% of subjects on their 80s Supported in part by grants from Conselho Nacional de Desenvolvimento Cientı´ficoe Tecnolo´gico (CNPq), Fundac¸a˜o de Amparo a Pesquisa do Rio Grande do Sul Similarly, prosthetic valvular surgery is increasingly being (FAPERGS) and Fundo de Incentivo a Pesquisa (FIPE-HCPA).
performed in the elderly patient. Anticoagulation of the Current Opinion in Clinical Nutrition and Metabolic Care 2007, 10:1–5 ageing patient, however, poses a particular challenge, asthere is an increased fear of bleeding events and loss of compliance – factors that are related in part to concomi- tant clinical co-morbidities. Notably, although mosthealthcare professionals believe that the risk of bleeding ß 2007 Lippincott Williams & Wilkins1363-1950 is augmented in elderly patients, the strict associationbetween bleeding and coumarin-induced events isnot consensual in the literature Recently, Fang Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
and co-workers have suggested that the odds for intra- cranial hemorrhage are increased particularly in anti- coagulated patients with atrial fibrillation over 85 years Vitamin K is an essential co-factor for the synthesis of of age. More importantly, however, the net clinical carboxyglutamic acid, which is required to activate benefit of anticoagulation in elderly people is expected not only coagulation factors II, VII, IX and X, but also to be at least similar to younger patients and, in some proteins C and S Syntheses of these factors are scenarios, even greater. For instance, the risk, morbidity limited by the presence of vitamin K on its hydro- and mortality associated with atrial fibrillation are quinone form – an essential co-factor for a specific increased in elderly people, so that most clinical practice microssomic carboxylase. This enzyme inserts a car- guidelines are consensual to point out that age of greater boxyl group in certain residues of glutamic acid on than 75 years identifies a subgroup of patients who would polypeptide chains. This step is essential to allow derive the greatest benefit in stroke prevention calcium binding that is needed to activate vitaminK-dependent coagulation factors. Through this process,reduced vitamin K1 is oxidized to its epoxide form and enzymatic regeneration by a reductase system The above topic will be thoroughly explored in another is needed to produce new hydroquinone vitamin K manuscript of this issue of Current Opinion in Clinical and to allow de-novo activation of other vitamin Nutrition and Metabolic Care. For the current discussion, K-dependent factors. This cycle is inhibited by several however, it is relevant to point out some particularities of coumarin derivatives (warfarin, phenprocoumon and vitamin K metabolism. Most vitamin K comes from acenocoumarol), through the interaction with funda- dietary intake as phylloquinone, although small and mental regenerating enzymes: KO reductase and unpredictable amounts may be endogenously produced K reductase ). Each of these drugs substantially by the small bowel flora Recommendations for adult intake are approximately of 1 mg/kg – an amount that can regard to its biological half time and protein binding.
be easily obtained from a normal balanced diet. Most The dose – response relationship of coumarin deriva- food items rich in vitamin K are of vegetarian origin, tives has a substantial intra-individual and inter- although animal viscera (e.g. liver) can also have individual variability, but accountable factors that significant amounts of the vitamin. Among commonly could explain over and undercoagulation commonly consumed foods, deep yellow and dark green leafy veg- etables are the major sources of dietary vitamin K practice It is consensual, however, that dose especially spinach, broccoli and cabbage (vitamin K1 requirements decrease greatly with age, so that content between 50 and 800 mg/100 g). Hidden sources of weekly maintenance doses are usually decreased by vitamin K such as multivitamin supplements are of approximately 50% in octogenarians when compared specific concern in the elderly, as they can dramatically increase daily intake . Also, common clinical co-morbidities of ageing people may lead to vitamin Kdeficiency, as they can substantially interfere with overall Figure 1 Role of vitamin K and its cycle in the activation ofcoagulation factors appetite, liver function and nutrition status.
Population-based estimates of vitamin K intake are not well established worldwide. Although estimates of daily intake in the US population vary substantially, recent studies indicate that phylloquinone intake is below the recommended dietary allowance in specific agegroups, particularly adults of 18–44 years of age. The elderly population reports significantly higher intakes of vitamin K, but with substantial intra-group variability, sothat it is likely that some ageing subjects will also have intakes below the recommended dietary allowance. Moreimportantly, studies on stability of phylloquinone con-sumption over longer periods of time are surprisingly scarce in the literature. Bioavailability of different (warfarin, phenprocoumon and acenocoumarol) dietary sources of vitamin K also has been evaluated inelderly people. These analyses have shown equiv- Oral coumarins competitively inhibit the enzymes that participate in ocal results depending on the use of different approaches vitamin K metabolism, resulting in failure to synthesize carboxyglutamicacid.
for the assessment of vitamin K absorption.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Dietary vitamin K intake Rohde et al.
Potential interaction between dietary vitamin Recently, our group prospectively investigated the effect of dietary vitamin K intake on anticoagulation stability in The theoretical bases of interactions between nutrients patients receiving chronic oral anticoagulant therapy .
and coumarin derivatives, particularly vitamin K First, in an observational protocol, clinical characteristics are well established, as described above. Oral coumarins and vitamin K intake, assessed semiquantitatively, were competitively inhibit the enzymes that participate in evaluated in 230 visits to our anticoagulation clinic. In vitamin K metabolism, resulting in failure to synthesize this analysis, the vitamin K intake score was inversely and carboxyglutamic acid. The specific role of vitamin K from progressively associated with different levels of INR diet on International Normalized Ratio (INR) fluctu- Increased vitamin K intake was independently ations and how this interaction works in day-by-day associated in multivariate analysis with undercoagulation clinical practice, however, is still not completely eluci- and decreased intake with overcoagulation. Afterwards, dated. Moreover, recommendations for dietary intake of 12 patients with stable anticoagulation underwent 4-day vitamin K1 in guidelines for chronic oral anticoagulant in-hospital dietary interventions, 1–2 weeks apart, pro- therapy have often been misinterpreted, and many phys- viding a 500% increase and an 80% decrease in vitamin K icians advise their patients to restrict their consumption intake relative to the baseline level. In this randomized crossover protocol, we demonstrated that even briefperiods of increased or decreased vitamin K intake had Udall in 1965, was the first investigator to evaluate statistically significant effects on coagulation parameters.
the effects of dietary vitamin K on coagulation Patients allocated to a decreased vitamin K intake (mean parameters in the clinical arena. He demonstrated a baseline vitamin K intake was 118 Æ 51 mg/day and final small, but significant, increase in prothrombin time in intake was 26 Æ 8 mg/day), for example, increased the healthy subjects who were fed a diet essentially free of INR values by almost 30% 7 days after the intervention vitamin K. Subsequently, the potential association between vitamin K intake and coagulation instability,based on a putative interaction between dietary vitamin Several investigators concur with the concept that to K and coumarin, was illustrated in several case reports pursue stable anticoagulation in patients receiving chronic oral therapy with anticoagulants, dietary intake reported the case of a 42-year-old female with a metallic of vitamin K should be actively evaluated and taken into aortic prosthesis, with stable oral anticoagulation for consideration Findings from our study are consistent the last 2 years that suddenly developed severe conges- with the notion that a constant level of dietary vitamin K1 tive heart failure due to aortic regurgitation. Prosthetic intake is important in achieving stable anticoagulation.
valve dysfunction was diagnosed at the operating room, as The precise amount of dietary vitamin K to be offered, the disk of the aortic prosthesis was fixed, being held bythrombi. A recorded interview about the diet patterns Figure 2 Vitamin K intake score according to different levels of revealed that in the past 4 weeks, the patient was having several meals based on a soup composed of broccoli andporcine liver – two food items with high vitamin Kcontent. The resulting excess of ingested vitamin K was believed to antagonize the effects of warfarin and account for her state of under-anticoagulation . Stu- dies such as these clearly suggest that vitamin K may interfere with coagulation patterns; however, they are intrinsically limited by methodological design flaws and small sample sizes. Most describe extreme variations in nutrient intake, sometimes associated with weight-loss diets or involving patients with severe systemic diseases who were not actually taking oral anticoagulant medi-cations. More recently, dietary and biochemical measures of vitamin K status were associated with warfarin sensi-tivity at the onset of oral treatment in a series of 40 ortho- Bars represent the mean score of all subjects within the INR range. A pedic patients Similarly, vitamin K intake of more score of 0 (zero) indicates stability in intake, a positive score indicates than 250 mg/day decreased sensitivity to warfarin in a greater vitamin K intake and a negative score indicates lower vitamin Kintake. Scores were based on queries contrasting usual consumption of group of anticoagulated patients consuming their usual 11 specific vitamin K-rich foods with the intake of the same items during diets In another study oral phytomenadione the week preceding the prothrombin time test. Area inside the dotted and high vitamin K intake had significant effects on lines delineates anticoagulation therapeutic range. Adapted with per-mission from Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
however, is not well established or completely evidence- and efficacious clinical strategy to adjust minor changes based. In a study of 20 patients with poor coagulation on anticoagulation instability both in young and elderly control, those randomly assigned to a diet with controlled vitamin K1 content had a much higher percentage ofprothrombin times within the therapeutic range thanpatients who had no dietary restrictions. Similarly, Khan and co-workers estimated by dietary records that for Papers of particular interest, published within the annual period of review, havebeen highlighted as: each increase in 100 mg of vitamin K intake averaged over 4 days, the INR would be reduced by 0.2. The same Additional references related to this topic can also be found in the Current group of investigators subsequently demonstrated World Literature section in this issue (p. 93).
that patients with unstable control of oral anticoagulation Ansell JE, Buttaro ML, Thomas OV, Knowlton CH. Consensus guidelines had a mean daily intake of vitamin K significantly lower for coordinated outpatient oral anticoagulation therapy management: than that for stable subjects. These authors suggest that Anticoagulation Guidelines Task Force. Ann Pharmacother 1997; 31:604–615.
daily supplementation with oral vitamin K could be an Ansell J, Hirsh J, Dalen J, et al. Managing Oral Anticoagulant Therapy. Chest adequate strategy to lead to a more stable anticoagulation.
The impact of over-the-counter supplements of vitamin K Hylek EM. Oral anticoagulants: pharmacologic issues for use in the elderly.
on anticoagulation parameters was elegantly explored in a prospective, crossover, controlled trial by Kurnik and co- Vecsler M, Loebstein R, Almog S, et al. Combined genetic profiles of components and regulators of the vitamin K-dependent gamma–carboxyla- workers These authors demonstrated that multi- tion system affect individual sensitivity to warfarin. Thromb Haemost 2006; vitamin supplements contain enough vitamin K1 to A study that evaluates the clinical role of several genetic polymorphisms potentially significantly alter coagulation parameters. In particular, related to coagulation stability and warfarin sensitivity.
vitamin K1-containing multivitamins reduced INR in Bovill EG, Fung M, Cushman M. Vitamin K and oral anticoagulation: thought patients with low plasma levels of the vitamin.
for food. Am J Med 2004; 116:711 –713.
Go AS, Hylek EM, Philips KA, et al. Prevalence of diagnosed atrial fibrillation inadults: national implications for rhythm management and stroke prevention – The potential interaction between dietary vitamin K and the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA coagulation parameters has been questioned in part in a recent study by Schurgers and co-workers These Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity,and risk for intracranial hemorrhage among patients taking warfarin for atrial investigators evaluated the response to weekly incremen- fibrillation. Ann Intern Med 2004; 141:745 –752.
tal doses (50–500 mg) of vitamin K1 supplements taken Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for daily for 7 days in a group of healthy subjects. They the Management of Patients with Atrial Fibrillation: a report of the AmericanCollege of Cardiology/American Heart Association Task Force on Practice identified that the threshold dose causing a significant Guidelines and the European Society of Cardiology Committee for Practice decrease of the INR was 150 mg/day, and in 25% of the Guidelines (Writing Committee to Revise the 2001 Guidelines forthe Management of Patients With Atrial Fibrillation) – developed in collabora- participants, the INR change was regarded as clinically tion with the European Heart Rhythm Association and the Heart Rhythm relevant. They also evaluated the short-lived response to Society. Circulation 2006; 114:e257–e354.
A comprehensive and updated review of the management of atrial fibrillation, two vitamin K-rich foods, however, and suggested that including the indications and risks of oral anticoagulation.
the bioavailability of these two sources was inadequate to Sutie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr cause important fluctuations in INRs.
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modulation of vitamin K intake may be an adequate 18 Shearer MJ. Vitamin K. Lancet 1995; 345:229–234.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Dietary vitamin K intake Rohde et al.
19 Wittkowsky AK, Devine EB. Frequency and causes of overanticoagulation and 31 Chow WH, Chow TC, Tse TM, et al. Anticoagulation instability with life- underanticoagulation in patients treated with warfarin. Pharmacotherapy threatening complication after dietary modification. Postgrad Med J 1990; 20 Garcia D, Regan S, Crowther M, et al. Warfarin maintenance dosing patterns 32 Cushman M, Both SL, Possidente CJ, et al. The association of vitamin K status in clinical practice: implications for safer anticoagulation in the elderly popula- with warfarin sensitivity at the onset of treatment. Br J Haematol 2001; 21 Wells PS, Holbrook AM, Crowther RN, Hirsh J. Interactions of warfarin with 33 Lubetsky A, Dekel-Stern E, Chetrit A, et al. Vitamin K intake and sensitivity to drugs and food. Ann Intern Med 1994; 121:676 –683.
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