Open access peer-reviewed chapter

Knowledge, Adherence, and Quality of Life among Warfarin Therapy Users

Written By

Laila Mahmoud Ali Matalqah

Submitted: 18 March 2019 Reviewed: 16 April 2019 Published: 29 July 2019

DOI: 10.5772/intechopen.86371

From the Edited Volume

Anticoagulation Drugs - the Current State of the Art

Edited by Mina Kelleni

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Patient knowledge and understanding of the therapy are an important factor in treatment success. Multiple factors were identified to cause a treatment failure such as side effects of the medications, rejection of the diagnosis by patients, lack of patient understanding about their medication, noncompliance, and the cost of medication. In addition, improvements in patient medication counseling and education may help in prevention of many adverse drug interactions, drug-drug or food-drug interactions, in turn enhancing medication adherence which depends basically on a patient’s acceptance of the information about the health threat itself. For these reasons, an evaluation of patients’ knowledge of medicine and its use may help screen for problems in therapy and improve therapeutic outcomes. The results of this evaluation may also be used to educate providers about areas of potential problems in which they may be able to influence change.


  • warfarin
  • knowledge
  • adherence
  • quality of life

1. Anticoagulation therapy

Coumarins have been used clinically since the 1950s and are likely the most widely studied medicines currently in clinical use [1, 2]. Anticoagulation therapy with warfarin has been a standard clinical practice to prevent ischemic stroke in patients associated with atrial fibrillation (AF) [3, 4, 5, 6]. A meta-analysis demonstrates that adjusted-dose warfarin reduces stroke risk by 64% when compared to placebo, which is corresponding to an absolute annual risk reduction in all strokes of 2.7%, while antiplatelet agents reduce stroke risk by 22% [7]. In the ACTIVE W trial, anticoagulation therapy had a relative risk reduction of all strokes by 40% when compared to the combination of clopidogrel and aspirin, with no difference in bleeding events between both treatments [8]. Furthermore, anticoagulants may reduce the risk of death rate in AF patients by 38% [9], so about 70–80% patients with AF are suitable for the long-term use of warfarin [10, 11].

However, it increases the risk for major bleeding. Clinical studies revealed that the risk of intracranial hemorrhage, the most common type of bleeding, is as great as that of thromboembolic events warfarin is used to prevent [12, 13].

Therefore, the optimal use of warfarin for atrial fibrillation requires precise assessment of established risk factors of bleeding, such as advanced age, hypertension, stroke, alcoholism, and malignancy [14]. In addition, rigorous reporting of warfarin-associated bleeding is warranted, as patients who bleed often discontinue treatment, which put them at a higher risk of thromboembolism [15, 16].

1.1 Warfarin pharmacodynamics

Warfarin is a drug derived from 4-hydroxycoumarin group and acts by inhibiting vitamin K epoxide reductase, an enzyme which recycles vitamin K into its reduced form (Figure 1). Reduced vitamin K is responsible for carboxylation of the specific blood clotting factors II (prothrombin), VII, IX, and X as well as anticoagulant factor protein C and protein S [18, 19, 20]. Thus warfarin is not a direct antagonist of vitamin K but rather acts by depletion of reduced vitamin K in tissues.

Figure 1.

Mechanism of action of warfarin [17].

As shown in Figure 2, inhibition of the reduction of vitamin K results in a reduction in the conversion of fibrinogen to fibrin which in turn reduces clot formation.

Figure 2.

Warfarin’s effects on the clotting cascade [21].

1.2 Warfarin pharmacokinetics

Warfarin is a racemic mixture of two optically active isomers, the R and S enantiomers [18]. Warfarin is highly water soluble and rapidly absorbed from the gastrointestinal tract and has high bioavailability [22, 23]. The bioavailability of warfarin is more than 95% [24, 25], and some reports had applied 100% bioavailability when developing models [26, 27].

Warfarin reaches maximal blood concentrations about 1.5 hours after oral administration [22, 28]. The plasma half-life of racemic warfarin mixture is 36–42 hours [29], and this means that it takes 5–7 days to reach steady state since warfarin is started or when the dosage is adjusted.

The antithrombotic effect of vitamin K anticoagulants has conventionally been attributed to their anticoagulant effect, which in turn is mediated by the reduction of the four vitamin K-dependent coagulation factors (II, VII, IX, and X). The vitamin K-dependent clotting factors have varying half-lives: 6 hours for factor VII, 24 hours for factor IX, 36 hours for factor X, and 60–72 hours for factor II (prothrombin). Thus, the anticoagulant effect (reduce coagulation of blood, prolonging the clotting time) develops in 2 days, whereas an antithrombotic effect (reduce formation of blood clots (thrombi)) of warfarin requires 6 days of treatment [30].

Numerous environmental factors such as drugs, diet, and various disease states were identified to affect warfarin by altering its kinetics and dynamics [31]. Drugs such as cholestyramine can reduce the absorption of warfarin, thus reducing its anticoagulant effect. R-warfarin is metabolized primarily by CYP1A2 and CYP3A4, while S-warfarin is metabolized primarily by CYP2C9 [32]. Potential warfarin drug interactions could occur with a concomitant administration of medicines that are metabolized by these P450s, and as a consequence, a number of metabolic medicine interactions have been reported for warfarin. For example, drugs such as cimetidine, amiodarone, and omeprazole potentiate the anticoagulant effect of warfarin by inhibiting its metabolism, whereas some drugs like barbiturates, rifampin, azathioprine, and carbamazepine inhibit the anticoagulant effect by enhancing its clearance [33]. In addition, long-term alcohol consumption has a similar potential to increase the clearance of warfarin [34].

Aspirin [35] and nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of warfarin-associated bleeding by inhibiting platelet function [36].

1.3 Dietary vitamin K

As the action of warfarin is modified by vitamin K, a variable dietary intake of vitamin K may alter the extent of the anticoagulation effect. An increased intake of dietary vitamin K (foods high in vitamin K include leafy green vegetables (cooked and raw), broccoli, brussels sprouts, cabbage, pickled cucumber, asparagus, kiwifruit, okra, green beans, and salad greens like lettuce) or vitamin K-containing supplements will increase the production of functional coagulation factors depending on vitamin K which is sufficient to reduce the anticoagulant response to warfarin [37]. Furthermore, patients with poor dietary intake of vitamin K often have a less stable control of anticoagulation [38]. It has been suggested to provide these unstable anticoagulated patients (with poor vitamin K intake) with oral vitamin K supplementation. However, unrecognized intake of such can lead to warfarin resistance [37].

The drug-grapefruit juice interaction enhances plasma concentration (Cmax) of orally concomitantly administered drugs. This interaction has been reported with 40 pharmaceutical products, including the vitamin K antagonist [39]. Grapefruit can affect the metabolism of a variety of medications through the cytochrome P450 enzyme system located in the small intestine and liver. The enzymes that are affected are 3A4, 1A2, and 2A6. The (R) enantiomer of warfarin is metabolized by CYP1A2 and CYP3A4, which could contribute to this theoretical interaction of warfarin with grapefruit [40].

1.4 Warfarin monitoring

The relation between blood clotting and coumarin derivatives was established by Dam and Doisy who shared the Nobel Prize in 1943 for their work [41, 42]. Warfarin has a narrow therapeutic index in which effectiveness and safety are a tight balance between stroke risk and bleeding risk; hence, careful dose titration and monitoring are required.

The prothrombin time (PT) test is the most common test used to monitor vitamin K anticoagulant therapy [43]. The normal prothrombin time is 12–14 seconds [44]. As PT monitoring of warfarin treatment is not standardized when expressed in seconds, a calibration model which was adopted in 1982 is now used to standardize reporting by converting the PT ratio measured with the local thromboplastin into an international normalized ratio (INR) [45]. INR is calculated by raising the prothrombin time ratio (PT; the patient’s prothrombin time divided by a reference normal prothrombin time to the power of international sensitivity index (ISI)) as follows (Eq. (1)):

INR=PatientPTMean normalPTISIE1

where ISI relates the sensitivity of a given thromboplastin (a tissue factor used as a reagent in PT test) to the sensitivity of the World Health Organization’s first primary international reference preparation of thromboplastin, which was assigned an ISI of 1.0 [46]. Each manufacturer assigns an ISI value for any tissue factor they manufacture which is usually between 1.0 and 2.0.

Instead of a specific value of the INR target, a therapeutic window is utilized as the recommended target range for specific diagnosis, e.g., in atrial fibrillation the clinical benefits of warfarin are highly dependent on maintaining the INR within the therapeutic range of between 2 and 3, while mechanical heart valve replacement often requires a slightly higher target range of INR (2.5–4.0) [47, 48, 49, 50]. As shown in Figure 3, INRs below this range increase the risk of stroke, while INR values above 3 or 4 are associated with increased bleeding rate [51].

Figure 3.

Maintaining INR in the therapeutic range is crucial to prevent strokes and avoid bleeding [51].

Further quality assessment of the treatment involves calculation of time spent in the therapeutic range (TTR). In Rosendaal method, the difference between two consecutive INR readings, which was within the target range, was divided by the total difference between them [52].

1.5 Warfarin-related adverse drug events

The most common side effect from over-anticoagulation is bleeding from any anatomical site. There are many risk factors that increase the risk of hemorrhage in patients on oral anticoagulant therapy, such as increasing age (≥60); previous stroke; comorbidities, i.e., diabetes mellitus; recent myocardial infarction; anemia (defined as hematocrit <30%); the presence of malignancy; concomitant; antiplatelet usage; uncontrolled hypertension; liver/renal failure; and previous gastrointestinal bleed [53].

The most feared hemorrhagic complication of anticoagulants is the intracranial hemorrhage (ICH) which accounts for approximately 90% of deaths from warfarin-associated hemorrhage and for the majority of disability among survivors [54]. Nonetheless, ICH rates in clinical trials conducted in AF patients on oral anticoagulant therapy are small, reported to be between 0.3 and 0.6% per year [55], and the absolute increase in major extracranial hemorrhages is even smaller, at ≤0.3% per year [56]. The risk of ICH associated with warfarin use was twice that of aspirin, but the absolute risk was small at 0.2% per year [7].

Other than hemorrhage, other important side effects of warfarin are acute thrombotic complications, such as skin necrosis and limb gangrene [57, 58].


2. Patients’ knowledge about warfarin therapy

2.1 Factors impacting patient’s knowledge about warfarin therapy

Evidence from the literatures suggests that patients’ knowledge about their warfarin therapy is generally poor with many demographic and clinical factors influencing their level of knowledge [2, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74].

IN the USA, a 52-item questionnaire related to the knowledge of warfarin was administered to 100 patients with atrial fibrillation in a face-to-face interview with a dietitian [69]. The survey questions were compiled based on five categories: general warfarin knowledge, compliance, drug interactions, herbal or vitamin interactions, and diet. For the total population, the average percentage of correct responses was 36%. The average score by category was 64% (general knowledge), 71% (compliance), 17% (drug interactions), 7% (herbal or vitamin interactions), and 23% (diet). Results from the former study suggested that in general, patients on warfarin, especially those at highest risk of stroke, had a poor understanding of their medication.

In Germany, in a study aimed to investigate the patients’ knowledge on anticoagulants and the patient characteristics associated with low knowledge, an 8-item multiple-choice test was developed and distributed to 59 anticoagulated medical inpatients of a German university hospital [66]. The scoring range was 0–8 points (each correct answer giving 1 point). The average knowledge was 55% with the most often wrong answers about questions regarding drug-drug and drug-food interactions. The former study revealed no significant correlation between the total test score and any of the patient characteristics.

McCabe and colleagues [68] described the self-management knowledge and behaviors of patients with recently detected AF. One hundred subjects were interviewed by telephone to assess knowledge after 2-week hospitalization. They found a knowledge deficit related to the purpose of medication and complications of warfarin. The knowledge deficits were greater in older subjects and in subjects with less formal education. The patients aged between 65 and 74 years had knowledge scores of 26.6 (out of a possible 50), as compared to 19.1 for those aged between 75 and 94 years (P = 0.001); this may be due to cognition disorders. Despite knowledge deficits among the patients, they were high adherent to taking medication and anticoagulation monitoring.

In England, a pilot study to examine patient’s knowledge and perceptions of AF and their anticoagulant treatment before and after a brief educational intervention was conducted [67]. Thirty-three patients completed the baseline interview; by then, they were given an information booklet which explained about AF, treatment options and their benefits/risks, and what the INR is and what factors may affect it. They were reassessed to their knowledge and perceptions of AF in a follow-up assessment session. Out of 33 (35.5%) patients that completed the follow-up assessment, 52% were aware about anticoagulants preventing blood clots, which increased to 70% post-intervention. However, few patients were aware of the benefit of stroke prevention associated with anticoagulants. The intervention significantly improved patient’s knowledge of the target INR range and factors that may affect INR levels (P = 0.001 and P = 0.014, respectively); however, it had little effect on increasing awareness of the bleeding risks associated with anticoagulants.

To measure patient’s knowledge about warfarin and to identify factors related to higher level of knowledge, Hu et al. [64] conducted a telephone survey among 100 patients with mitral valve replacement (MVR) using a validated 20-item questionnaire. They found that about 61% of participants had insufficient knowledge of warfarin therapy (score ≤ 80%). Among all variables studied, age was negatively related to warfarin knowledge scores, while family incomes greater than US$25,000, education greater than grade 8, and being employed significantly related to higher warfarin knowledge scores (P < 0.05). However, gender and ethnicity were not related to warfarin knowledge scores.

Besides all literatures mentioned above, the knowledge of warfarin therapy was tested in a sample of 122 patients attending at the warfarin clinic using 9 questions with a maximum score of 1.0 [71]. They found the level of knowledge was generally poor with more obvious knowledge deficient about the possible consequences of under- or over-anticoagulation, drugs that might interact with warfarin, and management of a missed dose. In their study, they found that increasing age negatively impacts upon knowledge about warfarin therapy. The mean warfarin knowledge scores declined with advancing age; <65-year-olds scored 0.47; 65–74-year-olds scored 0.44; and >75-year-olds scored 0.39. Other sociodemographic factors such as lower family income, limited health literacy, unemployment status, and lower education levels appeared to negatively influence patients’ knowledge. However, they did find a weak but positive correlation between patients’ knowledge of warfarin therapy and the number of INR values that were within the target range (Correlation coefficient r 0.20, P = 0.024).

Roche-Nagle et al. [2] evaluated the patient perception of anticoagulation risks, tablet recognition skills, and complications of warfarin therapy in 150 patients attending the anticoagulation clinic. Majority of the patients (n = 125, 83%) were able to identify the 1 mg tablet correctly, 105 (70%) identified the 3 mg tablet, and 98 (65%) identified the 5 mg tablet correctly. In addition, about 60% were aware about the potential complications from over- and underdosage with warfarin; however, only 33 (22%) were unaware that restrictions on alcohol use are required when taking warfarin. This study suggested that patient knowledge regarding anticoagulation therapy is not optimal, and consequently, a significant group may be at risk from serious complications because of this inadequate knowledge.

To investigate whether the knowledge and perceptions of antithrombotic therapy differ between ethnic groups in the UK, Nadar et al. [75] conducted a cross-sectional questionnaire survey among 180 patients attending anticoagulation clinic (135 white European, 29 Indo-Asian, and 16 Afro-Caribbean). The average knowledge score among all participants was 5.5 out of 9, with no significant differences between all ethnic groups. However, this study highlighted the gaps in the knowledge of patients from ethnic minorities and suggested that these groups should receive a special attention in the provision of information. Moreover, they have identified age as a negative factor of warfarin knowledge with the lowest score among patients older than 61 years.

In a historical cohort with questionnaires to 242 patients discharged from hospital, identified from hospital pharmacy records as being prescribed warfarin frequency of testing and levels of INR within 6 months of discharge, the level of INR aimed at by GP, complication rates, and patient knowledge about anticoagulation were measured [72]. Only 27% of all patients answered more than 8 out of 10 questions correctly. In this study, higher education level was identified as a predictor of high knowledge, but there was no relationship between the knowledge level and the INR control.

In Qatar, a cross-sectional survey using a 20-question questionnaire was delivered to 140 patients who were taking warfarin for at least 2 months [76]. Out of 12 questions about warfarin knowledge, 10 questions were derived from the Oral Anticoagulation Knowledge (OAK) test that was developed by Zeolla et al. [77]. The OAK questions covered the topics on warfarin drug interaction; interpretation of INR value, food, and vitamin K; effect of missing a dose; and when to seek a medical attention. In this study, the satisfactory level was considered answering 10 out of 12 questions (≥75%). They found that 79 patients (56%) had a satisfactory level of knowledge. The lowest score was in the knowledge of management of missing a dose and drug-drug interaction.

Another study using the OAK test was conducted in Jordan among 117 patients using warfarin, who were selected randomly [78]. They found that the majority (64%) of respondents can distinguish between different strengths of warfarin tablets by color. However, a deficit in knowledge was obvious in the areas of vitamin K and drug interactions with warfarin, skipping dose management, and PT/INR test. It was suggested that including clinical pharmacist services in the anticoagulation clinics may result in the improvement of patients’ knowledge toward warfarin use and PT/INR test.

In a study sought to determine the level of knowledge and to what extent patients adhere to OAC therapy, Van Damme et al. [79] developed a questionnaire comprising 10 multiple-choice questions, including 2 questions about each of the 5 knowledge domains: (1) general information about the functioning of the medication, (2) possible side effects, (3) interactions with food, (4) drug interactions, and (5) lifestyle. For each question, four possible answers were given, one of which was correct. In this cross-sectional study which included 57 patients, the median total score on the knowledge questionnaire was 7 on a scale of 0–10 with only 9 patients (15.7%) answering more than 8 questions correctly. They found that the participants had moderate to poor knowledge regarding the kinds of medication that can be taken in case of headaches, the sports to be avoided, what to do when a dose of medication is missed, symptoms related to uncontrolled level of medication in the blood, the effect of alcohol in blood-thinning, and the influence of certain vitamins on the medications.

Finally, another study aimed to collect information on six items of anticoagulation counseling (mode of action of warfarin, adverse effects of over or under anticoagulation, drugs to avoid, action if bleeding or bruising occurs, and alcohol consumption) from 70 consecutive patients on anticoagulant therapy [74]. They found that most patients reported are being clearly advised on five of the six items, but their knowledge about anticoagulation was generally poor. Few patients were able to correctly identify adverse conditions associated with poor control of anticoagulation: bleeding was identified by only 30 (60%), and bruising by 23 (56%), and only 7 (14%) could identify 3 or more self-prescribed agents which may interfere with warfarin.

2.2 Relation of patients’ warfarin knowledge to their therapeutic outcomes

To date, there are important published literatures that highlight the level of patients’ knowledge about warfarin and its relation to the therapeutic outcome, as well as education strategies and their impact on therapy outcomes. In these literatures, there is a general consensus that improved patient knowledge about warfarin therapy improving therapeutic outcomes [59, 66, 71, 80, 81, 82].

Kagansky et al. [80] have measured patient’s knowledge about warfarin by a warfarin knowledge-testing questionnaire. The questionnaire was submitted to elderly patients (n = 323) to assess their knowledge and impression on the quality of the relevant education that they received from the medical system on the following: risk of thromboembolic complications, prevention of thromboembolic complications by oral anticoagulation (OAC) therapy, the significance of OAC monitoring, and risk of bleeding. Among all participants, only 21.3% of the patients are satisfied about the education on OAC therapy that they received from the medical staff. In their study, patients with insufficient education on OAC therapy were more likely to increase major bleeding events (5.2 per 1000 patient-months) compared with no education (1.1 per 1000 patient-months). This study also showed that older patients with better knowledge about their warfarin therapy had 45% of their INR values within the therapeutic range than patients with poorer knowledge (35%); P < 0.001.

These findings were supported by another study [81] which reported that older patients (n = 125) who possessed a better understanding of warfarin therapy spent about 70% of the time within the therapeutic INR range than those with a poorer understanding (63%). The results of this latter study, however, were not statistically significant, reflecting the large amount of variability within each group and also possibly due to the limited number of patients included.

In Italy, Barcellona and colleagues [82] developed a questionnaire concentrated mainly on the patients’ understanding of why they were taking oral anticoagulants, the mechanism of the therapy through its regular assumption, dietary behavior (vegetable intake), current diseases that did not require hospitalization, interactions with other drugs, and assumption of other drugs. It was administered to a group of 219 consecutive anticoagulated patients attending the thrombosis center. The percentage time spent in the therapeutic range was calculated using the INR Day Program by Rosendaal et al. [52]. The difference in time spent in the range between patients who knew why they were taking the oral anticoagulant and those who did not was statistically significant only in the older group (89% vs. 76%, P = 0.04).

In another study of Barcellona et al. [59], the time spent within the therapeutic range by patients taking oral anticoagulants was improved by two different, consecutive educational approaches on the crucial aspects of oral anticoagulant therapy. In this study, 240 patients were randomly allocated into three groups; a course that focused on the questions in the interview was given to the first group (n = 80); a brochure containing the correct answers to questions was given to the second (n = 81); nothing was provided for the third (n = 79). A significant difference was found in the TTR between the quarters preceding and following the interview with 13% increase in the mean TTR among all groups.

Not all studies have found a positive correlation between patient knowledge and outcomes of warfarin therapy. In a sample of 52 patients, knowledge of warfarin therapy was assessed with an 18-question multiple-choice test and associated with anticoagulation control [62]. The anticoagulation control was defined as the number of blood tests in the appropriate therapeutic range divided by the number of blood tests performed during the 60-day period. This study showed no significant association between knowledge or education and the proportion of INRs within the therapeutic range. Moreover, insufficient education on OAC as perceived by the patient or caregiver was one of the significant predictive factors for bleeding complications (OR 8.83).

In Fang et al.’s [83] study, health literacy was measured using the bilingual short-form Test of Functional Health Literacy in Adults (s-TOFHLA), dichotomized as “limited” (score 0–22) and “adequate” (score 23–36) among 179 anticoagulated English- or Spanish-speaking patients. INR control was assessed by calculating the time in therapeutic range for each patient using an adapted linear interpolation method [52], defined as the proportion of person-time within the target therapeutic range over the total person-time of follow-up. It was found that patients with limited health literacy were more likely to have incorrect answers to most questions addressing warfarin-related knowledge and numeracy with incorrect answers to questions about warfarin’s mechanism of action, side effects, medication interactions, and frequency of monitoring, after adjusting for age, sex, ethnicity, education, cognitive impairment, and years on warfarin. However, limited health literacy was not significantly associated with TTR over the previous 12 months.

In the USA, another study aimed to explore the association between literacy and numeracy skills among patients on warfarin, and their anticoagulation control was conducted among 143 patients older than 50 years attending 2 anticoagulation clinics [84]. They found that The INR variability was higher among patients with lower literacy (P = 0.009) and lower numeracy skills (P = 0.004). The time in the range was similar among patients at different literacy levels (P = 0.9); however, patients with lower numeracy level spent more time above their therapeutic range (P = 0.04) and had a trend of less time spent in range (P = 0.10).

In Malaysia, two previous studies have been conducted to assess the patients’ knowledge and relate their knowledge to INR control [85, 86]. Hasan et al. [85] assessed the anticoagulation knowledge and INR control among patients on warfarin. In this cross-sectional study, 156 randomly sampled patients were interviewed using a validated interviewer-administered questionnaire, and all patients’ INR readings were recorded from 2008 to 2010. The authors found the average score of patients knowledge was 66.5% + 36.0% on how warfarin works, 42.9% + 44.9% for interaction between warfarin and alcohol, and 49.2% + 21.1% for adverse effects. Among all variable studied, they found a negative correlation between patients’ knowledge and age (P = 0.001, r = −0.293) and a positive correlation between patients’ knowledge and their education level (P = 0.001, r = 0.365). Furthermore, no significant correlation was found between patients’ INR control and their knowledge on the mechanism of action of warfarin, the interaction between warfarin and alcohol, and the side effects of warfarin.

Another cross-sectional survey was conducted at the Warfarin Clinic of Hospital Teluk Intan, Malaysia, and tended to determine the factors that correlated with the patient’s knowledge of warfarin therapy, the level of medication adherence, and INR control [86]. A total of 52 patients were interviewed with a mean ± SD age of 58.73 ± 9.55 years. Only 44.2% of patients knew about their medications, but the medication adherence was fairly good at 76.1%. The study showed that age, income level, level of education, and literacy in various languages were significantly associated with the patient’s knowledge on warfarin therapy (P < 0.05). The study did not find any association between anticoagulation and the level of knowledge of anticoagulation. However, the major limitation of the former two studies is the limited sample size used.

It is also important to highlight that some of the aforementioned studies, regardless of their results, are limited by the use of a non-validated warfarin knowledge-testing instruments or questionnaire to evaluate patient knowledge [2, 66, 67, 68, 69, 73, 74, 75, 86]. Validation indicates that the questionnaire has been thoroughly tested for content validity, measures of question difficulty, readability, and item/person reliability. Only after a knowledge assessment instrument has been validated can sound scientific conclusions be drawn from its results [87]. The appropriate psychometric methodology must be followed to ensure that an assessment measure is valid and reliable for testing the specific objectives or constructs. In theory, this process demonstrates that an instrument’s results are accurate, consistent, reproducible, and stable over time [87, 88, 89].

To date, only two questionnaires measuring patient knowledge of warfarin therapy have been validated: the Oral Anticoagulation Knowledge test, created and validated by Zeolla et al. [77], and the Anticoagulation Knowledge Assessment (AKA) questionnaire, designed and validated by Briggs et al. [90].

In Zeolla et al. [77], the Oral Anticoagulation Knowledge, a new instrument, was developed by four nationally recognized anticoagulation experts to ensure content validity. The test was administered to 72 subjects on warfarin and 27 from a group of age-matched subjects not on warfarin to assess construct validity. Subgroups of warfarin subjects were retested approximately 2–3 months after initial testing to assess test-retest reliability. The OAK test was administered to 74 subjects taking warfarin and 27 age-matched subjects not on warfarin. In this study, subjects taking warfarin scored significantly higher than those not on warfarin (72% vs. 52%, respectively; P < 0.001), supporting the construct validity of the instrument. Test-retest reliability was acceptable, with a Pearson’s correlation coefficient of 0.81, and the internal consistency reliability was 0.76. However, the association between the level of knowledge and clinical outcomes was not tested.

Another validated tool is the Anticoagulation Knowledge Assessment test, which was developed by Briggs et al. [90]. It is a 29-multiple-choice instrument that measures patient knowledge in 9 content areas, each worth 3.45 points. The validity of the instrument was assessed among 60 patients managed in two anticoagulation clinics who had received warfarin therapy for a mean of 28 months. The majority (80%) of patients who participated in the study had 12 or more years of education. The instrument was designed to be self-administered at a sixth grade reading level. Content validity of the instrument verified that the AKA instrument contains a variety of questions of varying levels of cognitive difficulty. However, the authors did not report whether they performed key reliability assessments (e.g., internal reliability or test-retest reliability); furthermore, they did not examine the relationship between patient’s knowledge and the anticoagulation control.

In literature, Baker et al. [91] used the validated AKA questionnaire. Correctly answering 21 questions (72.4%) or more was needed for the determination of adequate knowledge of anticoagulation therapy (passing score). Interestingly, this cross-sectional study showed that 74% (n = 185) of patients receiving long-term warfarin therapy had achieved a pass rate. Statistically, no significant correlation between warfarin knowledge and INR control was found. These results may have been inflated as the questionnaire is a self-completed questionnaire at home and there is a possibility of assistance from others.

On the other hand, the impact of educational program in reducing the clinical adverse event rates was tested by a randomized trial [92]. They reported a decrease in the adverse event rates by threefold less in the educated group compared to the control group. This supports the significant and independent impact of the educational program on the reduction in risk of events (OR 0.25, 95% CI 0.1–0.7).

Similarly, other studies showed that patient knowledge has a positive effect in the clinical outcomes with the highest rate of major bleeding events among patients who had poor knowledge about warfarin [80, 93]. In Beyth et al.’s [93] study, there was a reduction in hospitalizations among patients receiving structured warfarin education compared to those in a control group (3 vs. 9 hospitalizations, respectively, out of a total of 12 hospitalizations; P = 0.08). Moreover, the time spent within the therapeutic range was higher in the educated group than in the control normal care group (56% vs. 32%; P < 0.001).

In summary, evidence from previous studies, such as Davis et al. [62] (n = 52), Fang et al. [83] (n = 139), Estrada et al. [84] (n = 143), Group TNAS [72] (n = 242), and Baker et al. [91] (n = 260) suggested no association between patients’ warfarin knowledge and anticoagulation control. Some of the results of these latter studies, however, cannot be generalized because of their use of small sample sizes [62], number of variables relating to patient knowledge measured [62], and use of non-standardized data collection techniques [91].

The inverse relationship between the individual patient’s level of knowledge about warfarin and the rate of adverse outcome events has been reported in other literatures [2, 68, 71, 80, 92].


3. Health-related quality of life of warfarin users

The term health-related quality of life (HRQoL) has been used when the concern of researchers is to investigate the influence of the disease and treatment on the quality of life of the individual [94]. This narrower concept has been used to avoid ambiguity between the definition of quality of life in the common sense and that used in clinical and medical trials.

Warfarin use is challenging [18], since it has a narrow therapeutic index; it interacts with other drugs, alcohol, and food [31, 95]; and the clinical response to it is affected by many factors such as patients’ compliance and overall knowledge of therapy [74, 82]. Therefore, warfarin therapy requires a special care in order to control the desirable levels of blood coagulation and to prevent hemorrhagic and thromboembolic complications. Such care can lead to changes in the lifestyle of warfarin users since this involves changes in the dietary habits, the use of alcohol, and the performance of physical activity [96, 97], as well as the need to adhere strictly to the treatment regimen, the inconvenience of dosing adjustments, and the need for regular blood tests to monitor INR levels, together with the fear of complications such as the risk of minor or major bleeding and stroke [98]. All these changes caused by the use of anticoagulant treatment negatively affect the patient’s HRQoL. Perceived reduction in HRQoL is an important factor, which may influence the physician’s prescription and patient’s use of warfarin therapy.

To study the HRQoL of OAC users, authors have used different types of instruments. In a literature review regarding specific instruments available to evaluate the HRQoL of patients using OACs, the authors identified seven instruments [99]. In Brazil, a new specific instrument, the Duke Anticoagulation Satisfaction Scale (DASS), was developed by Samsa et al. [100] and recently validated by Pelegrino [101]. Some authors used a measurement of HRQoL obtained through the generic instrument such as the Medical Outcomes Survey 36-item Short Form (SF-36) [96, 100, 102, 103] and found that the more impaired HRQoL domains were physical aspects and vitality [96, 102], pain [100], physical functioning, and general health status [96].

In a cross-sectional study aimed to analyze the HRQoL and its relationship with gender, age, duration, and indication for the use of OAT, a total of 178 patients were interviewed, and the HRQoL was assessed through 8 domains of the SF-36 [104]. The means of the domains of the SF-36 ranged from 82 (social aspects) to 54.8 (physical aspects). In their study, the men had higher scores than the women in the majority of the domains of the SF-36, except for general health status. However, these differences were only significant in the domains, mental health, and pain. Elderly patients diagnosed with atrial fibrillation and with less than 1 year of medication use presented a worse HRQoL evaluation.

The HRQoL was also evaluated through a cross-sectional study with a sample composed of 72 patients with atrial fibrillation and mechanical heart valve at the anticoagulation outpatient unit of the Federal University of Bahia’s University Hospital [105]. The patients were submitted to two quality of life evaluation questionnaires: SF-36 and DASS. The quality of life perception of the patients studied, based on both instruments, was positive regarding the treatment with OAC. The SF-36 presented an average score of 62.2 (±20.0). Among the SF-36 evaluated domains, the physical-emotional aspect was the most compromised one. The DASS presented an average score of 67.1 (±18.2), and the domain presenting a greater compromise was the one related to the treatment inconveniences. The authors identified many factors impacting patients’ HRQoL; previous hemorrhagic event, comorbidities, drug interactions with medicines that increase the anticoagulant effect, lower education level in the SF-36, and younger age group influence a more negative perception of the QoL, whereas lower education level in the DASS and the duration of treatment for more than 1 year offer a more positive perception.

In a randomized, controlled trial including 333 atrial fibrillation patients using warfarin for stroke prevention, the impact of the long-term use of warfarin in their quality of life was assessed [97]. The results for their trial showed no significant differences between warfarin-treated and control patients on well-validated measures of functional status, well-being, and health perceptions. The mean score of health perceptions was 68.8 in the warfarin-treated group vs. 66.6 in the control group (scale of 0 to 100; 95% CI). In contrast, patients taking warfarin who had a bleeding episode had a significant decrease in health perceptions (−11.9; 95% CI). The authors concluded that warfarin therapy is not usually associated with a significant decrease in perceived health, unless a bleeding episode has occurred.

In an attempt to find the strategies to improve the HRQoL of patients undergoing anticoagulation therapy, a previous study found that patient self-management improves general treatment satisfaction and decreases patients’ perception of treatment-related daily hassles, distress, and strain on their social network (Gadisseur et al., 2004). This is supported by other researchers who noted an improvement in many of treatment-related areas of QoL through patient self-management in comparison with routine anticoagulant care through family physicians [106, 107, 108].


4. Adherence toward warfarin

An assessment of warfarin adherence is important in improving patient’s warfarin-taking behavior and INR control. Nonadherence includes not only a cessation of medication therapy but also taking the medication other than as prescribed (i.e., under-adherence, over-adherence, or not taking the dose at the prescribed time). Most studies reported medication adherence as a percentage of doses taken out of those prescribed over a specific period of time. While there is no general consensus on what constitutes adherence or nonadherence.

Nonadherence to OAC medication is generally problematic in practice. In a cohort study in the USA, 1005 patients with AF and taking warfarin are included, and there was a 32% reduction (from 65 to 44%) in the number of patients taking warfarin after 30 months [109].

Poor patient adherence to the prescribed drug regimen is often cited as an explanation for out-of-range INR measurements [110]. Despite this, there is little rigorous evidence of the level of adherence to warfarin, particularly among a broad spectrum of patients and anticoagulation practices. One reason for the lack of data on adherence to warfarin is the difficulty in measuring adherence [111].

In a prospective study of warfarin adherence, both under-adherence and over-adherence were measured among a sample of 145 patients at 3 anticoagulation clinics. The mean percentage of nonadherent days was 21.8% as measured by electronic medication event monitoring system (MEMS) [112].

In Singapore, another cross-sectional survey aimed to validate a patient-reported medication adherence measure, the MMAS-8, within a convenience sample of 151 patients taking warfarin [113]. It was found that respondents with higher MMAS-8 scores are more likely to have a higher percentage of INRs within the therapeutic range (P = 0.01), higher adherence to diet recommendations (P = 0.02), and less perceived difficulty in taking all medications (P < 0.001); they were also more likely to take warfarin at the same time every day (P < 0.001). This study showed that the 8-item MMAS has good validity and moderate reliability in patients taking warfarin.

In the International Normalized Ratio Adherence and Genetics (IN-RANGE) study of 111 adults taking warfarin, factors impacting patient adherence toward warfarin were studied [114]. It was found that demographic factors like education and occupation and psychosocial factors (such as lower levels of mental health functioning and poor cognitive functioning) are associated with nonadherence. Specifically, nonadherence was greater among those with educational levels beyond high school and those currently employed (compared with those unemployed and retired).

In a literature review by Brown et al. [115], many factors associated with OAC adherence among patients with AF were summarized as disease- and drug-related; patient knowledge, beliefs, and abilities; health system-related; economics; patient-physician relationship; and patient demographic, psychosocial, and personality traits.

In another review article that identified many factors associated with nonadherence in older adults, Murray et al. [116] developed a conceptual model of general medication adherence to improve adherence, assist in adherence research, and facilitate the development of multidimensional adherence improvement interventions. They concluded from an extensive literature search that older adults are at special risk due to the burden of multiple chronic diseases and age-related factors, such as cognitive impairment and other environmental and social factors.

To assess barriers to OAC medication use among patients with AF, a new questionnaire was developed by Ingelgård et al. [65]. The authors identified 41 barriers to warfarin use and classified them into 4 groups: patient medical characteristics, healthcare system factors, patient capability, and patient preference. On the other hand, Cohen et al. [117] summarized the factors that affect adherence to anticoagulation medication as factors related to disease (e.g., symptoms, long-term therapy, morbidities), drug (e.g., adverse events, duration, dose frequency and complexity, polypharmacy, cost), patient (e.g., lack of support, lack of disease knowledge, concerns, difficulty comprehending instructions, inability to adhere to restrictions), follow-up (e.g., shortage of time, costs associated with INR monitoring, patient unwilling to repeat testing, delay in laboratory reporting), and health system (e.g., patient-doctor relationship, reimbursement, lack of proper facilities or experience to manage therapy).

Added to the previous literature, Arnsten et al. [118] found significant relationships between various demographic characteristics and adherence. Noncompliance patients were more likely than warfarin-adherent patients to be younger (mean age 53.7 vs. 68.7 years), male, and nonwhite. Non-adherent patients were also more likely to report a lack of understanding or knowledge of the reason for taking warfarin and were also less likely to have a regular physician.

In Korea, a cross-sectional survey involving 204 patients aimed to identify factors affecting medication adherence and their relationships with anticoagulation control in Korean patients taking warfarin [119]. They found that 56 (27.5%) of 204 respondents were adherent. Their results showed that knowledge about warfarin exerts significant influence on medication adherence; however, medication adherence was not associated with good anticoagulation level as measured by INR.

The association between medication adherence and the clinical outcome of warfarin was also studied previously. In Davis et al. [62], adherence was found as one of the many factors that contribute to anticoagulation control. In this cross-sectional survey, the 4-item Morisky survey was used to assess self-reported adherence. The researchers found that adequate adherence was reported by 50% of patients and it was significantly associated with good anticoagulation control (P = 0.01) [120, 121].

In addition, this relationship between medication adherence and the clinical outcome of warfarin was also studied by Kimmel et al. [122]. In this prospective cohort study involving three coagulation clinics in Pennsylvania, 136 patients treated with warfarin for various indications (with a goal INR of 2–3), adherence to anticoagulation therapy was monitored using electronic MEMS medication bottle caps. The authors found patients who fail to adhere to warfarin therapy as prescribed are more likely to experience problems with anticoagulation control. Patients who missed >20% of bottle openings are two times more likely to have under-coagulation (adjusted OR 2.10). On the other hand, a significant effect on INR with over-adherence was also demonstrated; patients who had >10% extra pill bottle openings had a statistically significant increase in over-coagulation (adjusted OR 1.73). Furthermore, the authors estimated that poor patient adherence to medications is responsible for more than 53% of all hospital admissions.

In contrast, another cross-sectional study studied the relationship between adherence and other factors with the INR stability [123]. Among all patients, 90% (n = 156) had high and medium adherence, and 117 (75%) had INR stability up to 50% and 39 (25%) ≥ 75%. It was found that factors like adherence, age, level of education, socioeconomic level, interaction with other drugs, comorbidities, and vitamin K intake did not influence INR stability. However, longer anticoagulation time and drug cost were the factors related to the anticoagulation stability.

In studies among patients with diagnoses other than AF and on anticoagulation therapy, other psychosocial factors associated with poorer adherence were identified. These factors include depressive symptoms, pessimism, and a perceived lack of social support [111, 124, 125].


5. Factors impacting anticoagulation control

A retrospective cross-sectional study was conducted in community clinics in Israel aimed to assess the level of anticoagulation control achieved in patients with AF and to explore patient factors that influence the anticoagulation control [126]. The univariate and multivariate analyses were performed to explore the association of patient variables with anticoagulation control. They found that the mean TTR was 48.6% with about two-thirds of patients had poor anticoagulation control, as evidenced by TTR of <60%. Poor control was significantly associated with female sex, advancing age, and comorbid conditions. Heart failure was found to be an independent predictor of poor control (OR: 1.63).

A different cohort methodology was applied for assessing the likelihood of poor INR control among AF patients [127]. They used linear regression analysis to detect clinical factors associated with TTR and binary logistic regression to evaluate the predictive factors for different cut-off values of TTR. They explored various variables as independent predictors of poor TTR: female gender, age <50 years, ethnic minority status, smoking, more than two comorbidities, and being treated with a beta blocker, verapamil, or, inversely, amiodarone use.


  1. 1. Link KP. The discovery of dicumarol and its sequels. Circulation. 1959;19:97-107
  2. 2. Roche-Nagle G, Chambers F, Nanra J, Bouchier-Hayes D, Young S. Evaluation of patient knowledge regarding oral anticoagulants. Ireland Medical Journal. 2003;96(7):211-213
  3. 3. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian atrial fibrillation anticoagulation study. Journal of American College of Cardiology. 1991;18:349-355
  4. 4. Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. New England Journal of Medicine. 1992;327:1406-1412
  5. 5. Katritsis DG, Gersh BJ, Camm AJ. Anticoagulation in atrial fibrillation—Current concepts. Arrhythmia & Electrophysiology Review. 2015;4.2:100-107. PMC. Web. 15 Jan. 2018
  6. 6. Xu J, Luc JG, Phan K. Atrial fibrillation: Review of current treatment strategies. Journal of Thoracic Disease. 2016;8(9):E886
  7. 7. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of Internal Medicine. 2007;146:857-867
  8. 8. Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): A randomised controlled trial. Lancet. 2006;367:1903-1912
  9. 9. Alpesh A. Oral anticoagulation to reduce risk of stroke in patients with atrial fibrillation: Current and future therapies. Clinical Interventions in Aging. 2013;8:75-84. DOI: 10.2147/CIA.S37818
  10. 10. Darcy RF, Allan ER, Richard CB, Timothy ST. CYP2C9 genotype-dependent warfarin pharmacokinetics: Impact of CYP2C9 genotype on R- and S-warfarin and their oxidative metabolites. Journal of Clinical Pharmacology. 2017;57:382-393. DOI: 10.1002/jcph.813
  11. 11. Liu XB, Huang HM, Yu JH, Gao GL, Feng LL, Xu Q , et al. Warfarin compared with aspirin for older Chinese patients with stable coronary heart diseases and atrial fibrillation complications. International Journal of Clinical Pharmacy and Therapeutics. 2014;52:454-459. DOI: 10.5414/CP201996
  12. 12. Mittal MK, Rabinstein AA. Anticoagulation-related intracranial hemorrhages. Current Atherosclerosis Reports. 2012;14(4):351-359. DOI: 10.1007/s11883-012-0258-8 [Review]
  13. 13. Senoo K, Lane D, Lip GY. Stroke and bleeding risk in atrial fibrillation. Korean Circulation Journal. 2014;44(5):281-290. DOI: 10.4070/kcj.2014.44.5.281
  14. 14. Hughes M, Lip GY. Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: A systematic review guideline development group for the NICE national clinical guideline for management of atrial fibrillation in primary and secondary care. Quarterly Journal of Medicine. 2007;100(10):599-607
  15. 15. Healey JS, Oldgren J, Ezekowitz M, et al. Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: A cohort study. Lancet. 2016;388:1161-1169
  16. 16. Steinberg BA, Piccini JP. Anticoagulation in atrial fibrillation. British Medical Journal. 2014;348:g2116. DOI: 10.1136/bmj.g2116
  17. 17. Pharmaceutical Information. 2013. Available from:
  18. 18. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, et al. Pharmacology and management of the vitamin K antagonists. Chest. 2008;133:160-198
  19. 19. Malhotra OP, Nesheim ME, Mann KG. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins. The Journal of Biological Chemistry. 1985;260:279-287
  20. 20. Friedman PA, Rosenberg RD, Hauschka PV, Fitz-James A. A spectrum of partially carboxylated prothrombins in the plasmas of coumarin-treated patients. Biochimica et Biophysica Acta. 1977;494:271-276
  21. 21. The use of dabigatran in general practice: A cautious approach is recommended. Best Practice Journal. 2011. Available from: [Accessed: March 2013]
  22. 22. Breckenridge AM. Oral anticoagulant drugs: Pharmacokinetic aspects. Seminars in Hematology. 1978;15:19-26
  23. 23. O’Reilly RA. Vitamin K and other oral anticoagulant drugs. Annual Review of Medicine. 1976;27:245-261
  24. 24. Juno Y, Rengarajan B, Yoo BK. Self-nanoemulsifying drug delivery system of lutein: Physicochemical properties and effect bioavailability of warfarin. Biomolecules & Therapeutics. 2013;21:173-179. DOI: 10.4062/biomolther.2013.011
  25. 25. Mark K, Dennis G, Veronica M. Warfarin bioavailability with feeding tubes and enteral formula. Journal of Parenteral and Enteral Nutrition. 2010;34:300-304. DOI: 10.1177/0148607109337257
  26. 26. Hamberg AK, Dahl ML, Barban M, Scordo MG, Wadelius M, Pengo V, et al. A PK-PD model for predicting impact of age, CYP2C9 and VKORC1 genotype on individualization of warfarin therapy. Clinical Pharmacology and Therapeutics. 2007;81:529-538. DOI: 10.1038/sj.clpt.610008
  27. 27. Steven L, Sameh AZ, Ellen H, Ivan M, Andrea LJ, Panos D, et al. The population pharmacokinetics of R- and S-warfarin: Effect of genetic and clinical factors. British Journal of Clinical Pharmacology. 2011;73:66-76. DOI: 10.1111/j.1365-2125.2011.04051.x
  28. 28. Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clinical Pharmacokinetics. 1979;4:1-15
  29. 29. O’Reilly RA. Warfarin metabolism and drug-drug interactions. In: Wessler S, Becker CG, Nemerson Y, editors. The New Dimensions of Warfarin Prophylaxis: Advances in Experimental Medicine and Biology. New York, NY: Plenum; 1986. pp. 205-212
  30. 30. Zivelin A, Rao VM, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin-K dependent clotting factors. Journal of Clinical Investigation. 1993;92:2131-2140
  31. 31. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, et al. Systematic overview of warfarin and its drug and food interactions. Archives of Internal Medicine. 2005;165:1095-1106
  32. 32. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacology and Therapeutic Journal. 1997;73(1):67-74
  33. 33. Orme M, Breckenridge A. Enantiomers of warfarin and phenobarbital. New England Journal of Medicine. 1976;295:1482-1483
  34. 34. O’Reilly RA. Lack of effect of fortified wine ingested during fasting and anticoagulant therapy. Archives of Internal Medicine. 1981;141:458-459
  35. 35. Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. American Heart Journal. 1980;99:746-751
  36. 36. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Archives of Internal Medicine. 2005;165:189-192
  37. 37. O’Reilly RA, Rytand D. Resistance to warfarin due to unrecognized vitamin K supplementation. New England Journal of Medicine. 1980;303:160-161
  38. 38. Sconce E, Khan T, Mason J, Noble F, Wynne H, Kamali F. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Journal of Thrombosis & Homeostasis. 2005;93(5):872-875
  39. 39. Saito M, Hirata-Koizumi M, Matsumoto M, Urano T, Hasegawa R. Undesirable effects of citrus juice on the pharmacokinetics of drugs. Drug Safety. 2005;28:677-694
  40. 40. Sterling ES, Smith KM. What’s the scoop with grapefruit? Orthopedics. 2005;28:31-34
  41. 41. Dam H. The antihaemorrhagic vitamin of the chick. Biochemistry Journal. 1935;29:1273-1285
  42. 42. MacCorquodale DW, Binkley SB, Thayer SA, Doisy EA. On the constitution of vitamin K1. Journal of American Chemistry & Society. 1939;61(7):1928-1929
  43. 43. Quick AJ. The prothrombin time in haemophilia and in obstructive jaundice. The Journal of Biological Chemistry. 1935;109:73-74
  44. 44. Hoffbrand AV. Essential Haematology. Oxford: Blackwell Science; 2002. p. 248
  45. 45. Kirkwood TBL. Calibration of reference thromboplastins and standardisation of the prothrombin time ratio. Journal of Thrombosis & Haemostasis. 1983;49:238-244
  46. 46. Dzung TL, Weibert RT, Sevilla BK, Donnelly KJ, Rapaport SI. The international normalized ratio (INR) for monitoring warfarin therapy: Reliability and relation to; other monitoring methods. Annual Internal Medicine. 1994;120:552-559
  47. 47. Oake N, Jennings A, Forster AJ, Fergusson D, Doucette S, van Walraven C. Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: A systematic review and meta-analysis. Canadian Medical Association Journal. 2008;179:235-244
  48. 48. Odén A, Fahlén M, Hart RG. Optimal INR for prevention of stroke and death in atrial fibrillation: A critical appraisal. Thrombosis Research. 2006;117:493-499
  49. 49. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1):8S-21S
  50. 50. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. New England Journal of Medicine. 1996;335:540-546
  51. 51. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation. 2006;114:e257-e354
  52. 52. Rosendaal FR, Cannegieter SC, van der Meer FJM. A method to determine the optimal intensity of oral anticoagulant therapy. Journal of Thrombosis & Homeostasis. 1993;69:236-239
  53. 53. Tay KH, Lane DA, Lip GY. Bleeding risks with combination of oral anticoagulation plus antiplatelet therapy: Is clopidogrel any safer than aspirin when combined with warfarin? Journal of Thrombosis & Haemostsis. 2008;100:955-957
  54. 54. Fang MC, Go AS, Chang Y, Hylek EM, Henault LE, Jensvold NG, et al. Death and disability from warfarin-associated intracranialand extracranial haemorrhages. American Journal of Medicine. 2007;120:700-705
  55. 55. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: Recent data and ideas. Stroke. 2005;36:1588-1593
  56. 56. Lip GY, Lim HS. Atrial fibrillation and stroke prevention. The Lancet Neurology. 2007;6(11):981-993
  57. 57. Weinberg AC, Lieskovsky G, McGehee WG, Skinner DG. Warfarin necrosis of the skin and subcutaneous tissue of the male genitalia. Journal of Urology. 1983;130:352-354
  58. 58. Verhagen H. Local hemorrhage and necrosis of the skin and underlying tissues at starting therapy with dicumarol or dicumacyl. Acta Medica Scandinavica. 1954;148:455-467
  59. 59. Barcellona D, Contu P, Marongiu F. A “two-step” educational approach for patients taking oral anticoagulants does not improve therapy control. Journal of Thrombosis and Thrombolysis. 2006;22:185-190
  60. 60. Cheah GM, Martens KH. Coumadin knowledge deficits: Do recently hospitalized patients know how to safely manage the medication? Home Healthcare Nurse. 2003;21(2):94-100
  61. 61. Dantas GC, Thompson BV, Manson JA, Tracy CS, Upshur RE. Patients’ perspectives on taking warfarin: Qualitative study in family practice. BMC Family Practice. 2004;5(1):15
  62. 62. Davis NJ, Billett HH, Cohen HW, Arnsten JH. Impact of adherence, knowledge, and quality of life on anticoagulation control. Annals of Pharmacotherapy. 2005;39(4):632-636
  63. 63. Engova D, Duggan C, MacCallum P, Bates I. Patients’ understanding and perceptions of treatment as determinants of adherence to warfarin treatment. International Journal of Pharmacy Practice. 2002;10(suppl):R69
  64. 64. Hu A, Chow C, Dao D, Errett L, Keith M. Factors influencing patient knowledge of warfarin therapy after mechanical heart valve replacement. Journal of Cardiovascular Nursing. 2006;21(3):169-175
  65. 65. Ingelgård A, Hollowell J, Reddy P, Gold K, Tran K, Fitzmaurice D. What are the barriers to warfarin use in atrial fibrillation? Development of a questionnaire. Journal of Thrombosis & Thrombolysis. 2006;21(3):257-265
  66. 66. Jank S, Bertsche T, Herzog W, Haefeli WE. Patient knowledge on oral anticoagulants: Results of a questionnaire survey in Germany and comparison with the literature. International Journal of Pharmacology & Therapeutic. 2008;46(6):280-288
  67. 67. Lane DA, Ponsford J, Shelley A, Sirpal A, Lip GYH. Patient knowledge and perceptions of atrial fibrillation and anticoagulant therapy: Effects of an educational intervention programme The West Birmingham Atrial Fibrillation Project. International Journal of Cardiology. 2006;110:354-358
  68. 68. McCabe PJ, Schad S, Hampton A, Holland DE. Knowledge and self-management behaviors of patients with recently detected atrial fibrillation. Heart & Lung. 2008;37(2):79-90
  69. 69. Smith MB, Christensen N, Wang S, Strohecker J, Day JD, Weiss JP, et al. Warfarin knowledge in patients with atrial fibrillation: Implications for safety, efficacy, and education strategies. Cardiology. 2010;116:61-69
  70. 70. St-Louis L, Robichaud-Ekstrand S. Knowledge level and coping strategies according to coagulation levels in older persons with atrial fibrillation. Nursing & Health Science. 2003;5:67-75
  71. 71. Tang EO, Lai CS, Lee KK, Wong RS, Cheng G, Chan TY. Relationship between patients’ warfarin knowledge and anticoagulation control. Annual of Pharmacotherapy. 2003;37:34-39
  72. 72. Group TNAS: The Newcastle Anticoagulation Study Group. Effectiveness of anticoagulation among patients discharged from hospital on warfarin. Medical Journal of Australia. 1998;169:243-246
  73. 73. McCormack PM, Stinson JC, Hemeryck L, Feely J. Audit of an anticoagulant clinic: doctor and patient knowledge. Ireland Medicine Journal. 1997;90(5):192-193
  74. 74. Taylor FC, Ramsay ME, Tan G, Gabbay J, Cohen H. Evaluation of patients knowledge about anticoagulation treatment. Quality in Health Care. 1994;3(2):7985
  75. 75. Nadar S, Begum N, Kaur B, Sandhu S, Lip GY. Patients’ understanding of anticoagulant therapy in a multiethnic population. Journal of Royal Society & Medicine. 2003;96:175-179
  76. 76. Khudair IF, Hanssens YI. Evaluation of patients’ knowledge on warfarin in outpatient anticoagulation clinics in a teaching hospital in Qatar. Saudi Medical Journal. 2010;31(6):672-677
  77. 77. Zeolla MM, Brodeur MR, Dominelli A, Haines ST, Allie ND. Development and validation of an instrument to determine patient knowledge: The oral anticoagulation knowledge test. Annual of Pharmacotherapy. 2006;40(4):633-638
  78. 78. Yassien AM, Khataybeh OY, Aleyadeh A, Al-kurdi NE, TA AL-S. Patients’ experiences and knowledge about using coumarine and coagulation test. Zagaziq University Medical Journal. 2012;18(6):1118-1122
  79. 79. Van Damme S, Van Deyk K, Budts W, Verhamme P, Moons P. Patient knowledge of and adherence to oral anticoagulation therapy after mechanical heart-valve replacement for congenital or acquired valve defects. Heart & Lung. 2011;40(2):139-146
  80. 80. Kagansky N, Knobler H, Rimon E, Ozer Z, Levy S. Safety of anticoagulation therapy in well-informed older patients. Archives of Internal Medicine. 2004;164:2044-2050
  81. 81. Khan T, Kamali F, Kesteven P, Avery P, Wynne H. The value of education and self-monitoring in the management of warfarin therapy in older patients with unstable control of anticoagulation. British Journal of Haematology. 2004;126:557-564
  82. 82. Barcellona D, Contu P, Marongiu F. Patient education and oral anticoagulation therapy. Hema. 2002;87(10):1081-1086
  83. 83. Fang MC, Machtinger EL, Wang F, Schillinger D. Health literacy and anti- coagulation-related outcomes among patients taking warfarin. Journal of General Internal Medicine. 2006;21(8):841-846
  84. 84. Estrada CA, Martin-Hryniewicz M, Peek BT, Collins C, Byrd JC. Literacy and numeracy skills and anticoagulation control. American Journal of Medical Science. 2004;328(2):88-93
  85. 85. Hasan SS, Shamala R, Syed IA, Basariah N, Chong DW, Mei TK, et al. Factors affecting warfarin-related knowledge and INR control of patients attending physician- and pharmacist-managed anticoagulation clinics. Journal of Pharmacy Practice. 2011;24(5):485-493
  86. 86. Yahaya AHM, Hassali MA, Awaisu A, Shafie AA. Factors associated with warfarin therapy knowledge and anticoagulation control among patients attending a warfarin clinic in Malaysia. Journal of Clinical Diagnostic Research. 2009;3:1663-1670
  87. 87. Devellis RF. Scale Development: Theory and Applications. Newbury Park, CA: Sage Publications; 1991
  88. 88. Kline P. A Handbook of Test Construction: Introduction to Psychometric Design. New York: Methuen & Co; 1986
  89. 89. Streiner DL, Norman GR. Health Measurement Scales: A Practical Guide to Their Development and Use. New York: Oxford University Press; 1989
  90. 90. Briggs AL, Jackson TR, Bruce S, Shapiro NL. The development and performance validation of a tool to assess patient anticoagulation knowledge. Research of Social & Administrative Pharmacy. 2005;1(1):40-59
  91. 91. Baker WJ, Pierce KL, Ryals CA. INR goal attainment and oral anticoagulation knowledge of patients enrolled in an anticoagulation clinic in a veterans affairs medical Center. Journal of Managed Care Pharmacy. 2011;17(2):133-142
  92. 92. Pernod G, Labarère J, Yver J, Gross R, Metlay JP, Christie JD, et al. EDUC’AVK: Reduction of oral anticoagulant-related adverse events after patient education: A prospective multicenter open randomized study. Journal of General Internal Medicine. 2008;23(9):1141-1146
  93. 93. Beyth RJ, Quinn L, Landefeld CS. A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin: A randomized, controlled trial. Annals of Internal Medicine. 2000;133(9):687-695
  94. 94. Fayers PM, Machin D. Scores and measurements: Validity, reliability and sensitivity. In: Quality of Life: Assessment, Analysis and Interpretation. 2nd ed. Chichester, England: John Wiley & Sons; 2007
  95. 95. Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances and foods. Journal of Clinical Pharmacology. 2005;45:127-132
  96. 96. Casais P, Meschengieser SS, Sanchez-Luceros A, Lazzari MA. Patients’ regarding oral anticoagulation therapy and its effect on quality of life. Current Medicine Research Opinions. 2005;21(7):1085-1090
  97. 97. Lancaster TR, Singer DE, Sheehah MA, Oertel LB, Maraventano SW, Hughes RA, et al. The impact of long-term warfarin therapy on quality of life-evidence from a randomized trial. Archives of Internal Medicine. 1991;151:1944-1949
  98. 98. McCahon D, Murray ET, Holder RL, Fitzmaurice DA. Does self-management of oral anticoagulation therapy improve quality of life and anxiety? Family Practice. 2011;28(2):134-140
  99. 99. Wild D, Murray M, Shakespeare A, Reaney M, von Maltzahn R. Patient-reported treatment satisfaction measures for long-term anticoagulant therapy. Expert Review of Pharmacoeconomics & Outcomes Research. 2008;8:291-299
  100. 100. Samsa G, Matchar DB, Dolor RJ, Wiklund I, Hedner E, Wygant G, et al. A new instrument for measuring anticoagulation-related quality of life: Development and preliminary validation. Health and Quality of Life Outcomes. 2004;2:22
  101. 101. Pelegrino FM. Cultural Adaptation and Validation of Duke Instrument Anticoagulation Satisfaction Scale (DASS): Version for Brazilian in Use of Oral Anticoagulation. Ribeirão Preto: School of Nursing, University of São Paulo; 2009. p. 168
  102. 102. Howes CJ, Reid MC, Brandt C, Ruo B, Yerkey MW, Prasad B, et al. Exercise tolerance and quality of life in elderly patients with chronic atrial fibrillation. Journal of Cardiovascular Pharmacology & Therapeutics. 2001;6(1):23-29
  103. 103. Matchar DB, Jacobson AK, Edson RG, Lavori PW, Ansell JE, Ezekowitz MD, et al. The impact of patient self-testing of prothrombin time for managing anticoagulation: Rationale and design of VA cooperative study #481—The home INR study (THINRS). Journal of Thrombosis & Thrombolysis. 2005;19(3):163-172
  104. 104. Corbi ISA, Dantas RAS, Pelegrino FM, Carvalho ARS. Health related quality of life of patients undergoing oral anticoagulation therapy. Revista Latino-Americana de Enfermagem. 2011;19(4):865-873
  105. 105. Almeida GQ , Noblat LD, Passos LCS, Nascimento HF. Quality of life analysis of patients in chronic use of oral anticoagulant: An observational study. Health and Quality of Life Outcomes. 2011;9:91
  106. 106. Cromheecke ME, Levi M, Colly LP, de Mol BJ, Prins MH, et al. Oral anticoagulation self-management and management by a specialist anticoagulation clinic: A randomised cross-over comparison. The Lancet. 2000;356(9224):97-102
  107. 107. Kulinna W, Ney D, Wenzel T, Heene DL, Harenberg J. The effect of self-monitoring the INR on quality of anticoagulation and quality of life. Seminars in Thrombosis and Hemostasis. 1999;25:123-126
  108. 108. Sawicki PT. A structured teaching and self-management program for patients receiving oral anticoagulation: A randomized controlled trial. Working Group for the Study of patient self-management of oral anticoagulation. Journal of American Medical Association. 1999;281:145-150
  109. 109. Reynolds MR, Shah J, Essebag V, et al. Patterns and predictors of warfarin use in patients with new-onset atrial fibrillation from the FRACTAL registry. American Journal of Cardiology. 2006;97(4):538-543
  110. 110. Kutner M, Nixon G, Silverstone F. Physicians’ attitudes toward oral anticoagulants and antiplatelet agents for stroke prevention In elderly parents with atrial fibrillation. Archives of Internal Medicine. 1991;151:1950-1953
  111. 111. Osterberg L, Blaschke T. Adherence to medication. New England Journal of Medicine. 2005;353(5):487-497
  112. 112. Parker CS, Chen Z, Price M, Gross R, Metlay JP, Christie JD, et al. Adherence to warfarin assessed by electronic pill caps, clinician assessment, and patient reports: Results from the IN-RANGE study. Journal of General Internal Medicine. 2007;22(9):1254-1259
  113. 113. Wang Y, Kong MC, Ko T. Psychometric properties of the 8-item Morisky medication adherence scale in patients taking warfarin. Journal of Thrombosis &. Homeostasis. 2012;108(4):789-795
  114. 114. Platt AB, Localio AR, Brensinger CM, Cruess DG, Christie JD, Gross R, et al. Risk factors for nonadherence to warfarin: Results from the IN-RANGE study. Pharmacoepidemiology & Drug Safety. 2008;17(9):853-860
  115. 115. Brown TM, Siu KWD, Pladevall-Vila M, Sande S, Mordin M. Development of a conceptual model of adherence to oral anticoagulants to reduce risk of stroke in patients with atrial fibrillation. Journal of Managed Care Pharmacy. 2012;18(5):351-362
  116. 116. Murray MD, Morrow DG, Weiner M, Clark DO, Tu W, Deer MM, et al. A conceptual framework to study medication adherence in older adults. American Journal of Geriatric Pharmacotherapy. 2004;2(1):36-43
  117. 117. Cohen AT, Maillarde L, Yavin Y. Will a once-weekly anticoagulant for the treatment and secondary prevention of thromboembolism improve adherence? Journal of Thrombosis & Haemostasis. 2009;101(3):422-427
  118. 118. Arnsten JH, Gelfand JM, Singer DE. Determinants of compliance with anticoagulation: A case-control study. American Journal of Medicine. 1997;1103(1):11-17
  119. 119. Kim JH, Kim GS, Kim EJ, Park S, Chung N, Chu SH. Factors affecting medication adherence and anticoagulation control in Korean patients taking warfarin. Journal of Cardiovascular Nursing. 2011;26(6):466-474
  120. 120. Morisky DE, Ang A, Krousel- Wood M, Ward H. Predictive validity of a medication adherence measure for hypertension control. Journal of Clinical Hypertension. 2008;10:348-354
  121. 121. Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measurement of medication adherence and long-term predictive validity of blood pressure control. Medical Care. 1986;24:67-74
  122. 122. Kimmel SE, Chen Z, Price M, Parker CS, Metlay JP, Christie JD, et al. The influence of patient adherence on anticoagulation control with warfarin: Results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) study. Archives of Internal Medicine. 2007;167:229-235
  123. 123. Ávila CW, Aliti GB, Feijó MKF, Rabelo ER. Pharmacological adherence to Oral anticoagulant and factors that influence the international normalized ratio stability. Revista Latino-Americana de Enfermagem. 2011;19(1):18-25
  124. 124. Cruess DG, Localio AR, Platt AB, Brensinger CM, Christie JD, Gross R, et al. Patient attitudinal and behavioral factors associated with warfarin non-adherence at outpatient anticoagulation clinics. International Journal of Behavior Medicine. 2010;17(1):33-42
  125. 125. Rieckmann N, Gerin W, Kronish IM, Burg MM, Chaplin WF, Kong G, et al. Course of depressive symptoms and medication adherence after acute coronary syndromes: An electronic medication monitoring study. Journal of American College of Cardiology. 2006;248(11):2218-2222
  126. 126. Melamed OC, Horowitz G, Elhayany A, Vinker S. Quality of anticoagulation control among patients with atrial fibrillation. The American Journal of Managed Care. 2011;17(3):232-237
  127. 127. Apostolakis S, Sullivan RM, Olshansky B, Lip GY. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: The SAMe-TT2R2 score. Chest. 2013;144(5):1555-1563

Written By

Laila Mahmoud Ali Matalqah

Submitted: 18 March 2019 Reviewed: 16 April 2019 Published: 29 July 2019