Influence of Vitamin K intake on INR and Anticoagulation in outpatients taking Warfarin

 

Norisca Aliza Putriana1, Taofik Rusdiana1*, Tina Rostinawati2, Mohammad Rizki Akbar3

1Department of Pharmaceutical and Formulation Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jalan Raya Bandung-Sumedang KM 21, Jatinangor 45363, Indonesia.

2Department of Biology Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran,

Jalan Raya Bandung-Sumedang KM 21, Jatinangor 45363, Indonesia.

3Department of Cardiovascular, Faculty of Medicine, Universitas Padjadjaran,

Jalan Raya Bandung-Sumedang KM 21, Jatinangor 45363, Indonesia.

*Corresponding Author E-mail: t.rusdiana@unpad.ac.id

 

ABSTRACT:

Warfarin is a type of vitamin K antagonist anticoagulant used to thromboembolic prevention and its maintenance dose differs significantly among patients. Moreover, the factor influencing the dose calculation is known as genetic polymorphism, while the influence of vitamin K intake while the effect of vitamin K intake is still a matter of debate. This study aims to provide an overview of several studies on the effect of vitamin K intake on the stability of the PT-INR value and anticoagulation in warfarin therapy patients. A study was conducted on the effect of vitamin K intake on the PT-INR value stability and anticoagulation in warfarin therapy patients. One study showed that there was no significant correlation between vitamin K usual intake and the anticoagulant effect, while in another, it was found that the stability of this effect is achievable with adequate amounts of the vitamin intake. Furthermore, another study showed that the anticoagulant effect is more stable in patients with excessive vitamin K intake on long-term warfarin use. However, other study showed that INR values will stabilize if vitamin K intake is relatively low. The results from various studies were different, therefore, there is a debate regarding the influence of vitamin K intake on the PT-INR value and anticoagulation.

 

KEYWORDS: Anticoagulation, PT-INR, Thromboembolism, Vitamin K, Warfarin.

 

 


INTRODUCTION:

Oral anticoagulation has been used for over 50 years to prevent thromboembolism1. However, it is known that the effectiveness of these anticoagulants in clinical practice is limited. Most patients are not well maintained within the recommended therapeutic range2, despite the great efforts by health care providers to educate and carefully adjust warfarin doses. Meanwhile, the risk of major bleeding that occurs at 2% to 3% per year has become a major concern, especially, in the elderly population3–5.

 

Furthermore, increase in the elderly population is estimated to increase the prevalence of atrial fibrillation6. Warfarin is a therapy used by patients who are at high risk of developing blood clots and belongs to the group of vitamin K. antagonists. In patients with venous thromboembolism, chronic atrial fibrillation, and mechanical heart valves, long-term anticoagulation therapy with warfarin is required7. Since warfarin has a narrow therapeutic range, physicians are expected to monitor the dose carefully for proper maintenance of anti-coagulation effect, while minimizing bleeding complications. Several factors, such as genetic factors, liver function, nutritional status, intestinal malabsorption, ethnicity, drugs-drugs interaction, vitamin K intake, knowledge and adherence can influence intra- and inter-individual variations in warfarin doses7–12.

 

Vitamin K is one of the fat-soluble vitamins sourced from dark green vegetables, spices and vegetable oils13. Vitamin K acts as an important cofactor for the post-translational carboxylation of various proteins involved in blood clotting14. During the carboxylation reaction, vitamin K hydroquinone is oxidized to vitamin K epoxide. Vitamin K epoxide must be reduced before it can be reused and the process is catalyzed by vitamin K epoxide reductase (VKOR). The use of vitamin K antagonists can inhibit VKOR and reduce active vitamin K stores in the liver. This leads to the desired anticoagulation effect due to decreased production of vitamin K-dependent coagulation factors. Meanwhile, the antagonists inhibit VKOR, block vitamin K turnover, and deplete active stores in the liver, which leads to the desired anticoagulant effect due to decreased production of dependent clotting factors15.

 

Variability of vitamin K intake may influence intra-individual variability in anticoagulant response in patients taking warfarin16. Therefore, a study was carried out on the relationship between dietary intake of vitamin K, plasma concentration, and anticoagulation response to warfarin in individual patients. In this study, the contribution of dietary vitamin K to the different doses required for warfarin between individuals.

 

MATERIALS AND METHODS:

This study was conducted using a literature review approach that is related to the effect of foods containing vitamin K on INR values and anticoagulation in patients receiving warfarin therapy. The literature used as a reference was from the NCBI database, Science Direct, and Google Scholar, using the keywords anticoagulation, INR, vitamin K, and warfarin. Meanwhile, the inclusion criteria are journals with the categories research and review article as well as International Journals Finally, 8 journals published in 2008-2022 were collected as primary and supporting literatures, respectively. Figure 1 depicts the flowchart of the methodology.

 

Figure 1. Flow Chart of the Literature Review


RESULT:

Table 1. The results of the study of the relationship of vitamin K intake from food to INR and anticoagulant effects

S. No.

Study design

Anticoagulant

Anticoagulant Measurement

Analyzed nutrients

Population

Result

Reference

1.

Observation

Warfarin

TTR and CV of INR

Vitamin K

50 patients on warfarin therapy

There is no significant corelation  between routine vitamin K intake and the anticoagulant

17

2.

Intervention

Warfarin and Phenprocoumon

INR

Vitamin K

132 outpatients (58% mechanical cardiac prosthesis and 35% atrial fibrillation)

INR value of 74% of patients was on target compared to 58% of conventionally managed patients (P = 0.04)

18

3.

Observation

Warfarin

CV of INR

Vitamin K

66 patients taking warfarin regularly for years

Patients with high vitamin K intake have a more stable long-term of INR

19

4.

Observation

Warfarin

INR, vitamin K plasma level, triglycerides, warfarin enantiomer concentration, and CYP2C9

Vitamin K

53 patients on stable and controlled warfarin therapy

Dietary vitamin K intake had no effect on warfarin dose, but CYP2C9 genotype and age had an influence on warfarin dosing.

16

5.

Observation

Warfarin and Phenprocoumon

INR

Vitamin K

39 outpatients

Subjects with low vitamin K intake, the INR value increased on day 7 (P = 0.005) and decreased on day 4 (P = 0.04) for subjects with high vitamin K intake

20

6.

Case-control

Warfarin, Phenprocoumon and Acenocoumarol

INR

Vitamin K

1157 patients visited the anticoagulation clinic

High vitamin K intake reduces low INR values

21

7.

Observation-Cross sectional

Warfarin

INR

Vitamin K

244 patients (warfarin maintenance dose)

Vitamin K intake is related to warfarin dose

22

8.

Observation

Warfarin and Phenprocoumon

INR

Vitamin K

132 outpatients from the anticoagulation clinic

INR stability can be accomplished with low vitamin K intake

23

 


 

Figure 2. Vitamin K cycle blocked by warfarin.

 

Warfarin exerts anticoagulation effect by interfering with the vitamin K cycle and its epoxides. In vitamin K cycle, with the participation of Ca 2+ , CO 2 , and O 2 , hydroquinone of vitamin K achieves oxidation accompanied with carboxylation. The epoxidation of vitamin K reverted into vitamin K hydroquinone in the role of VKOR and vitamin K quinine reductase through vitamin K. Warfarin blocks up the vitamin K cycle via VKOR, resulting in incomplete carboxylation, and terminates in a series of adverse consequenc 31

 

DISCUSSION:

A previous study by Park et al. found a statistically relationship between normal vitamin K intake in patients receiving warfarin and TTR as well as the CV/INR. Some of the possible causes for the results of this study are as follows: there is a potential that the exactitude of assessment of vitamin K intake decreases. In this study, the treatment used as phylloquinone (vitamin K1) intake only, therefore, vitamin K2 (menaquinone) intake was not rate due to lack of data17. Furthermore, some of the menaquinones synthesized by the bacterial flora were absorbed by the body24 and their dietary intake was ignored. Ultimately, there are potential intra-individual differences in the bioavailability of dietary vitamin K25. Therefore, further studies need to be done by considering the content of vitamin K plasma.

 

Assis et al stated, to get a more stable anticoagulation effect, it is recommended to take oral vitamin K regularly. Based on a semiquantitative questionnaire assessing routine vitamin K consumption, anticoagulant patients outside the target INR were oriented to reduce or increase intake. The intrinsic validity of this pragmatic and clinical approach is confirmed by its remarkable impact in correcting INR in low and high anticoagulant patients. After 90 days of dietary orientation, patients in the vitamin K diet group were 16% more on target INR than the conventional. More detailed studies and regulation of vitamin K consumption can enhance the magnitude of the benefits of the proposed intervention and limit clinical application. In addition, short -term follow -up of this protocol does not guarantee that the clinical benefits for achieving the INR goal will be sustainable for three months. The data obtained show that changing the intake of foods rich in vitamin K is an effective strategy to increase the likelihood of reaching therapeutic INR range18.

 

As the vitamin K increases, the INR value of the dependent dose decreases. If the K1 supplementation dose in females at 150µg/day and in males at 200µg/day has been reached, there will be a statistically significant change in INR value from baseline. However, the verge for the effect of vitamin K intake is apparently not true for patients in clinical practice, because patients were asked to refrain from eating foods that are rich in vitamin K but only their daily K1 was counted19.

 

Furthermore, the results of a study conducted by Kim et al showed that high dietary intake of vitamin K increases the anticoagulant effect. Patients in the highest vitamin K intake group showed the most stable anticoagulant effect in the long term. The CV of INR and warfarin dose as parameters were used to represent the anticoagulation stability19. Based on the study, there are limitations in the use of WSI to estimate the stability of the anticoagulation effect of warfarin. Since the WSI was calculated with INR and warfarin at one time after stabilization, there was no reflection of variability, which is the stability of anticoagulation. Moreover, CV is defined as SD divided by the mean score, is used to examine the accuracy of laboratory tests and the value is a series of INR together with warfarin dose. This value was adopted to compare INR ranges and warfarin dose fluctuations, which is the effect of anticoagulation stability. These results showed that the large reserves of daily vitamin K intake, several changes in the intake have no significant impact on the anticoagulant effect of warfarin. In this study, the general threshold value of 196µg/day vitamin K intake for the high group was equal to the effect of warfarin in previous reports26–28 and slightly higher than the stabilizing dose of the vitamin supplementation29.

 

Furthermore, the results of a study by Khan et al., showed age and CYP2C9 genotype affected warfarin requirements, whereas dietary vitamin K is not effective16. This result is in line with a study by Loebstein et al., which stated that under optimized conditions, CYP2C9 genotype and age affect individual sensitivity to warfarin but vitamin K has no such effect. Meanwhile, there is a possibility that the deficit of vitamin K effect on the dose requirements of warfarin was due to the adjustment of the dose for each patient according to the vitamin K status, which is likely to impact the pharmacodynamic response to warfarin at the beginning of therapy30.

 

The variation in the anticoagulation response to warfarin among patients based on a previous study showed that for every 100g increase in vitamin K intake in the 4 days, 0.2 of the INR decreased before measurement, which helps to clarify the extent of the interrelationship between dietary vitamin K and INR16.

 

The results of another study showed that the variation of vitamin K intake was independently and directly related with INR instability. Meanwhile, the vitamin K-fortified diet had a faster effect on INR than the depleted, which was statistically significant on the day 4 compared to day 7. This difference is due to a 500% enhance in vitamin K intake means larger absolute variation in µg/d than an 80% decrease20.

 

Protocol studies of dietary vitamin K were not suitable for estimating phylloquinone intake in the µg/day range, so this study had some potential limitations. In the observation protocol, a semiquantitative approach was used to simplify the clinical application of the results. In addition, because of factors such as co-treatment, illness, and hospitalization over time, analysis of patient visits was performed to identify predictors of undercoagulation and overcoagulation. The main limitation of this approach is that the behavior of some subjects is successfully changed because of its repetitive patterns, but this behavior is not yet known. The randomized crossover protocol allows a period of 1-2 weeks between feedings to minimize genetic effects that are not excluded. The only bias brought is for higher serum vitamin K levels. In addition, a randomized crossover study evaluated the effect of high volatility on short -term vitamin K intake. Longer diets have not been evaluated for ethical implications, but previous studies indicate that different results are unlikely to be obtained20.

 

In addition, another study showed that vitamin K was lower in unstable than stable patients which indicated that low intake is a risk factor for unstable anticoagulation. Therefore, recommendations for consuming foods with adequate vitamin K content are supported by controlled evidence that low-dose supplementation improves anticoagulation stability. Genetic variation of VKORC1 causes different sensitivity to vitamin K antagonists. Therefore, the improvement in anticoagulant control observed in patients given low-dose of vitamin K supplements are possibly to dependent on the VKORC1 polymorphism. However, the effect of the VKOR genotype on the stability of anticoagulant therapy on vitamin K intake needs to be reinvestigated21.

 

A previous study by Rasmussen et al. showed that there is a negative relationship between vitamin K intake and warfarin maintenance dose. These effect occurs most often in the group of patients who require the least dose. When adjusting for possible confounders in the multivariate analysis, the investigators confirmed that the maintenance dose of warfarin was primarily dependent on pharmacogenetics, important polymorphisms in VKORC1 and CYP2C9, and clinical variables such as body weight and age. This study emphasizes the importance of choosing statistical methods that reflect the complexity of the data in order to interpret the results of observational studies. The multivariate model, on the other hand, seems appropriate to describe the complex relationship between vitamin K intake and VKA dose22.

 

Studies by Zuchinali et al found that patients who took oral vitamin K that had been modified were more likely to achieve the desired INR target than conventional doses (variation in oral anticoagulant dose). Meanwhile, INR stability is achieved in patients receiving only low protein intake, while the variation in vitamin K over a short period affects anticoagulant parameters23.

 

These studies chose a semi-quantitative assessment of vitamin K that was not accurately estimated daily intake. Therefore, an intensive assessment and modulation of vitamin K consumption have the potential to limit the clinical application of the proposed strategy, which describes the relationship between micronutrients and oral anticoagulants more accurately. In addition, the short-term follow-up of the original protocol has relatively limited assessment of the effect of vitamin K intake on the long-term stability of oral anticoagulants23.

 

This sub-analysis shows that INR stability can be achievable with a low amount of vitamin K intake. Meanwhile, most studies that have been conducted stated that patients on anticoagulation are expected to maintain a stable vitamin K intake when INR stability is achieved. A previous study by Zuchinali et al showed that the target daily intake of vitamin K was close (slightly higher) to the internationally accepted RDA (90-120 µg/day), which avoids higher intakes. Therefore, in this case, future studies are recommended to consider these strategies to give the best nutritional advice to patients23.

 

CONCLUSION:

The results from various studies are different, therefore, there is still a debate on the influence of vitamin K intake on PT/INR values and the anticoagulation in patients on warfarin therapy.

 

CONFLICT OF INTEREST:

The authors declared that they have no conflict of interest

 

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Received on 13.08.2021            Modified on 24.12.2021

Accepted on 02.03.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(10):4851-4856.

DOI: 10.52711/0974-360X.2022.00815