Evaluation of Efficacy and Determining Various Factors Associated with the Effective Use of Vitamin-K Antagonist Therapy in the Indian Population

Darisi S; Ahmed T; George J; Ramaiah B

Research Article

Austin J Clin Cardiolog. 2021; 7(2): 1080.

Evaluation of Efficacy and Determining Various Factors Associated with the Effective Use of Vitamin-K Antagonist Therapy in the Indian Population

Darisi S¹*, Ahmed T², George J³ and Ramaiah B⁴

¹Pharm D, Rajiv Gandhi University of Health Sciences, Karnataka, India

²Consultant Cardiologist, Bangalore Baptist Hospital, Karnataka, India

³Assistant Professor, Karnataka College of Pharmacy, Karnataka, India

⁴HOD of Pharmacy Practice, Karnataka College of Pharmacy, Karnataka, India

*Corresponding author: Srikanth Darisi, Department of Pharmacy Practice, Karnataka College of Pharmacy, 76-11, Bapuji Road, Guntur, India

Received: July 26, 2021; Accepted: August 13, 2021; Published: August 20, 2021

Abstract

Aim: To assess the efficacy of Vitamin K antagonist to maintain stable INR in a tertiary care hospital.

Methodology: All the patients who are on Vitamin K antagonists therapy for more than 6 months before the initiation of the study were included. Data, which include demographics, Personal history, medical history, medication history, Dietary habits, laboratory data (INR), and other relevant data, are collected. The laboratory results are further evaluated using the Rosendaal method and Time in Therapeutic Range, which was obtained which is evaluated, for assessing the use of medication, and other correlations were further made.

Results and Discussion: The study showed a mean TTR of 25.638%, the mean TTR above and below the therapeutic range is 19.23% (±17.14), 55.11% (±29.64) respectively, this represents that the patients in the sample population are at higher risk of developing a new clot during the therapy with VKA, various chronic conditions such as Diabetes mellitus, the use of NSAIDs, PPI also showed a statistically significant difference on the patients TTR.

Conclusion: Despite patients being therapeutically anticoagulated, based on the available data, many patients in the study population are at high risk of developing complications of anticoagulants and also the development of new clots even during the treatment, there are not many reports of TTR measurement in INDIAN population, The use of Vitamin K Antagonist comes with many limitations, many Newer Oral Anticoagulants (NOAC) can be used in patients as they are proven to be providing better control of TTR.

Keywords: Vitamin K Antagonist; Warfarin; Acitrom; Time in Therapeutic Range; Rosendaal method; Vitamin K Diet; Anticoagulation; Bleeding; Atrial Fibrillation

Abbreviations

VKA: Vitamin K Antagonist; TTR: Time in Therapeutic Range; AF: Atrial Fibrillation; HTN: Hypertension; CKD: Chronic Kidney Disease; DM-II: Diabetes Mellitus; NSAIDs: Non-Steroidal Anti Inflammatory Drugs; PPI’s: Proton Pump Inhibitors

Introduction

Vitamin K is a fat-soluble vitamin, the most naturally occurring K Vitamins are phylloquinone, which is called Vitamin k1, this Vitamin K1 is mostly available from green leafy vegetables, and Phylloquinone in plants is helpful for photosynthesis. Menaquinone is Vitamin K2; this Vitamin K2 differs from that of K1 with variation in the length of the side chain, which is formed from intestinal bacteria. There is another form of Vitamin K, which is Menadione which is not a naturally occurring substrate, but it can be manufactured synthetically [1,2].

Vitamin-K cycle

Vitamin K is itself is an inactive form (quinine) when reduced into quinol form with the help of vitamin k1 quinone reductase. This helps in forming the active form of Vitamin k1 and this active form is used as a substrate in posttranslational modification of the aminoterminal of glutamic acid. Which residues to 4-carboxyglutamic acid (GLA) in the vitamin K-dependent clotting factors II, VII, IX, X, protein S, C, Z [3] with help of carboxylate epoxidase to its active forms. Thereafter, carboxylation Vitamin k1 (active form i.e. quinol) is converted into an inactive form which is Vitamin k1 2,3 epoxide, and with the help of vitamin k1 2,3 epoxide reductase that results in the formation of the Quinone form of Vitamin K which is again the parent compound [4-6].

Coagulation pathway

The mechanism of formation of a blood clot (Hemostasis) involves different pathways, which include the intrinsic pathway and the extrinsic pathway. The intrinsic pathway consists of coagulation factors I, II, IX, X, XI, and XII, and the extrinsic pathway includes factors I, II, VII, and X. Factor II is prothrombin which when activated in turn increases the activity of Factor XI, VIII, V, XIII which leads to the formation of a stable clot. The extrinsic pathway is activated by the tissue factors, which are released from the endothelial cells after external damage; the intrinsic pathway is activated when exposed through endothelial collagen [7].

Oral anticoagulants

These drugs act through different mechanisms for preventing clot formation, which can be chiefly classified as [10]:

• Direct thrombin Inhibitors: Argatroban, Bivalirudin, Dabigatran, Desirudin [11,12].

• Direct factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban [13,14].

• Vitamin k antagonist: Warfarin, Acenocoumarol [15].

Time in therapeutic Range (TTR)

When patients are being treated with Vitamin K antagonists, the effect of these drugs should be monitored closely as there is an increased risk of bleeding in these patients.

The effectiveness of these drugs can be monitored by checking PT, INR of the patients at regular intervals for most of the indications such as Prophylaxis for DVT, Treatment for DVT, Post CABG patients, Heart failure, Peripheral vascular diseases, Atrial Fibrillation. The required therapeutic INR is 2-3 [16,17], but for some indications such as Myocardial Infarction, the Therapeutic INR requires to be 3.0 to 4.0 for the optimal effectiveness of drug therapy [18,19].

Measurement of TTR

Linear interpolation methods (Rosendaal method): This method involves the calculation of TTR by incorporating the frequency of INR measurements and their actual values and assuming that changes between consecutive INR measurements are linear over time [20].

Factors affecting TTR

Many factors influence the TTR such as age, body weight, nutrition status, acute and chronic disease, Polypharmacy [21], high vitamin k diet, vitamin k supplements [22], adherence to the therapy [23,24], awareness about the therapy [25], which can result in therapeutic failure [26,27].

Methodology

All the patients who were prescribed Vitamin K antagonists and who were on the therapy for more than 6 months before the initiation of the study were included. Data includes demographics, personal history, medical history, medication history, dietary habits, laboratory data (INR), and other relevant data were collected. The laboratory results were further evaluated using the Rosendaal method and Time in Therapeutic Range, which were obtained which was evaluated, for assessing the use of medication, and other correlations were further made.

Statistical analysis

Data were analyzed using Minitab software, 2 sample t-test, a p-value of <0.05 is considered to be statistically significant, the data obtained in the study was analyzed by 2 sample t-test

Results

The patients were classified into 3 groups based on the TTR; TTR of >70% is considered to be good Control, TTR of 50%-70% is considered to be intermediate control, TTR of <50% is considered to be poor control, the mean (±SD) TTR of the patients involved in the study was 25.64% (±20.82),

Fifty patients were enrolled over 6 months, the mean TTR among the sample population was 25.46%, a total of 23 males, 27 female patients were enrolled.

The good control group had 1 patient with a mean TTR of 88.9%, the intermediate control group had 7 patients with a mean TTR of 56.74%, 42 patients were having poor control of TTR with a mean TTR of 18.94%.

The demographics of the patients involved in the study are described in (Table 1) as seen in the below table there is no statistically significant difference between the patients based on age and gender (P= 0.664, 0.456 respectively).

Table 1: Demographic parameters and personal history of the studied patients.




  
    
    Good    Control N (TTR%) 
    Intermediate    Control N (TTR%) 
    Poor    Control N (TTR%) 
    P-Value 
  
  
    Age 
    >60 Years 
    1 (88.9) 
    2 (52.4) 
    21 (21.4) 
    0.664 
  
  
    <60 Years 
    0 
    5 (58.48) 
    21 (16.48) 
  
  
    Sex 
    Male 
    0 
    4 (54.97%) 
    19 (16.96%) 
    0.456 
  
  
    Female 
    1 (88.9) 
    3 (59.1%) 
    23 (20.91%) 
  
  
    Smoking 
    Yes 
    0 
    1 (57.3%) 
    3 (4.4%) 
    0.570 
  
  
    No 
    1 (88.9) 
    6 (56.65%) 
    39 (20.26%



Table 1: Demographic parameters and personal history of the studied patients.

The effect of various medical conditions, medications on a patient’s TTR are discussed in Table 2, The patients with MVR, Diabetes mellitus, on NSAIDs, PPIs had a significant difference in the mean TTR (P= 0.001, 0.021, 0.004, 0.017 respectively) (Table 2).

Table 2: TTR of the studied population based on various parameters.




  
    
    Good    Control 
    Intermediate    Control 
    Poor    Control 
    Mean    TTR (%) 
    P-Value 
  
  
    AF 
    Yes 
    1 (88.9) 
    2 (52.4) 
    21 (21.4) 
    21.8 
    0.709 
  
  
    No 
    0 
    5 (58.48) 
    21 (16.48) 
    20.2 
  
  
    MVR 
    Yes 
    0 (0) 
    1 (50.9) 
    4 (41.7) 
    43.54 
    0.001 
  
  
    No 
    1 (88.9) 
    6 (57.71) 
    38 (16.55) 
    23.6 
  
  
    DM-II 
    Yes 
    0 
    0 
    20 (17.99) 
    18 
    0.021 
  
  
    No 
    1 (88.9) 
    5 (57.6) 
    24 (23.1) 
    30.7 
  
  
    HTN 
    Yes 
    1 (88.9) 
    2 (59.1) 
    18 (16.73) 
    24.2 
    0.694 
  
  
    No 
    0 
    5 (55.8) 
    24 (20.91) 
    26.7 
  
  
    CKD 
    Yes 
    0 
    0 
    8 (15.46) 
    15.5 
    0.098 
  
  
    No 
    1 (88.9) 
    7 (56.74) 
    34 (19.95) 
    27.6 
  
  
    HYPOTHYROIDISM 
    Yes 
    1 (88.9) 
    0 
    3 (24.7) 
    37.9 
    0.526 
  
  
    No 
    0 
    7 (56.74) 
    39 (18.79) 
    24.6 
  
  
    NSAIDS 
    Yes 
    0 
    0 
    2 (6.35) 
    6.35 
    0.004 
  
  
    No 
    1 (88.9) 
    7 (56.74) 
    40 (19.57) 
    26.4 
  
  
    PPI’s 
    Yes 
    0 
    0 
    9 (13.93) 
    13.9 
    0.017 
  
  
    No 
    1 (88.9) 
    7 (26.74) 
    33 (20.31) 
    28.2



Table 2: TTR of the studied population based on various parameters.

The mean TTR values of patients on various no. of concomitant medication is shown in Figure 2; it shows patients with 3 concomitant medications had a mean TTR of 29.8% followed by patients with 4 concomitant medications with a mean TTR of 29.26., the lowest being patients using only 1 concurrent medication with a mean TTR of 3.8% followed by 15.45% in patients using 5 medications (Figure 2).

Figure 1: Coagulation Cascade [8,9].

    
    
    Figure 1: Coagulation Cascade [8,9].

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Citation: Darisi S, Ahmed T, George J and Ramaiah B. Evaluation of Efficacy and Determining Various Factors Associated with the Effective Use of Vitamin-K Antagonist Therapy in the Indian Population. Austin J Clin Cardiolog. 2021; 7(2): 1080.

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