Health Systems and Policy Research

Keywords

Warfarin; Willingness to switch; New oral anticoagulants; Patient satisfaction; Patient knowledge

Introduction

In the past warfarin, a vitamin K antagonist (VKAs), was the only available oral agent to prevent blood clots. While it has proven efficacy in treating and preventing thrombotic conditions (stroke and venous thromboembolism [VTE]), warfarin is also associated with several disadvantages such as frequent lab monitoring, multiple drug interactions, narrow therapeutic index and interpersonal variability in metabolism and target effect due to genetic polymorphisms [1-7]. These factors correlate to a 40-fold difference in the individual maintenance dose requirement (0.5-20 mg daily) to achieve exactly the same effect [1]. In addition to these disadvantages, warfarin carries the risk of intracranial hemorrhage which occurs in 0.4% of patients per year and has a mortality of approximately 50% [5-7]. Overall these disadvantages have resulted in apprehension in physicians’ prescribing and patients’ uptake of this medication.

This delicate balance of risk versus benefit plays a significant role in the hesitation of many prescribers to prescribe warfarin and discourages many patients from taking the drug [8]. Current evidence suggests that almost 50% of patients with an indication for anticoagulation for stroke prophylaxis in atrial fibrillation are not treated [8,9]. Therefore, alternative anticoagulants were much needed to potentially better serve this population. These agents include the oral thrombin inhibitor dabigatran, and the factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban. Although these medications lack the above mentioned disadvantages of warfarin (need for frequent monitoring, less drug interactions), patients and prescribers must be aware of potential drawbacks such as (monitoring difficulty, availability/cost of effective antidotes in the event of severe bleeding, and less forgiving in those with poor adherence) [10].

Gaps in existing studies in the area of patient preferences to anticoagulation treatments include limited assessment of the collective impact of patient knowledge and satisfaction on therapy choices, inadequate inclusion of minorities, and limited scope of patient population to atrial fibrillation patients only.

In order to fill the aforementioned knowledge gaps the goal of this study was to determine if patient warfarin knowledge, their satisfaction with therapy, or any other patient characteristics impact a patient’s decision to switch to one of the new oral agents in a majority African American population of patients with thrombolytic conditions. The secondary goals of the study were to assess the level of patient knowledge and satisfaction with warfarin therapy in an urban university-affiliated pharmacist-run clinic.

Methods and Materials

Study design and patient population

A cross sectional study of warfarin treated patients attending the outpatient anticoagulation management services clinic at Howard University Hospital from August 2014 to February 2015 was conducted. Patients were eligible for the study if they were 18 or older, currently taking warfarin, attended the outpatient anticoagulation clinic, and provided informed consent to participate in the study. Patients with all indications for warfarin therapy were included in the study. No financial incentive was provided for participation in the study. The project was approved by the Howard University Institutional Review Board. The sample size was determined based on the concept of saturation which was predetermined to be 100 participants based on factors such as heterogeneity of the population, number of selection criteria, data collection method, budget and resources available.

Patient recruitment

Recruitment was clinic-based and at the point of care. Procedurally, patients were invited to participate in the study in the evaluation room where they would normally receive their INR reading. Prior to obtaining a blood sample, the investigator informed the patient about the study and invited them to participate. Patients were informed that the study would take approximately 10 minutes. After agreeing to participate, patients were informed of the study procedures and provided informed consent. Patients that declined to participate proceeded with their normally scheduled INR monitoring visit.

Study variables

The primary outcome of this study was patient willingness to switch to a new oral anticoagulant. Other study variables of interest collected through the investigator-administered survey included patient knowledge of warfarin therapy, patient satisfaction with warfarin therapy, employment status, marital status, highest completed education, alcohol consumption, smoking status, physical activity assessment, frequency of bleeding episodes in past year, sum of missed doses over past month, average days the patient consumes green vegetables per week, duration of warfarin therapy, and whether the patient was involved in decision to use warfarin. Data abstracted from patients’ charts included age, ethnicity, gender, insurance, indication for warfarin, number of total medications, warfarin dose, comorbid conditions, percent of appointments patient’s INR within target range over last 4 visits, number of appointments kept and missed over the past 6 months.

Data collection

Data collection for this study was done via an intervieweradministered survey and chart abstraction. Data collection in the former case was initiated immediately after study recruitment and at the start of their face to face clinic consultation. Only one interviewer, the clinical pharmacist, was responsible for conducting the interviewer-administered surveys. The interviewer-administered survey contained four sections: 1) patient demographics and characteristics questionnaire, 2) patient satisfaction assessment, 3) patient knowledge assessment, and 4) patient willingness to switch to new oral anticoagulation assessment.

The scales used in the assessment of patient satisfaction, knowledge, willingness to switch have been widely used by other researchers and have high reliability and validity [11-15].

The assessment of satisfaction was done using the validated Anti-Clot Treatment Scale (ACTS) [16]. The ACTS was selected on the basis of its good psychometric properties (Chronbach’s alpha 0.90 to 0.93). It was also used in 2 large randomized controlled trials and was included as an outcome in both the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation and the Global Anticoagulant Registry in the FIELD prospective longitudinal AF patient registries [17,18]. The modified scale contains 12 questions about respondents opinions of warfarin risk, benefits, burdens, and overall satisfaction. The questions on the assessment were comprised of 5 item Likert scales ranging from 1 to 5 (1=“not at all”, to 5=“extremely”). For the first 9 questions, higher scores represented less favorable perceptions and for questions 10-12, higher scores will represent favorable perceptions. Patients were considered to be satisfied if they responded to question 11 “How satisfied are you with your warfarin therapy” with a rating of 4 or above.

The assessment of warfarin knowledge was done using a 10- item multiple choice scales which has items derived from the validated Oral Anticoagulant Knowledge Survey (OAKS) [19]. The modified OAKS consist of questions that determine a patient’s knowledge of warfarin interactions, warfarin side effects, and monitoring parameters. A score over 75% (at least 8 correct responses) constitutes high knowledge of warfarin therapy while a lower score represent lower knowledge of warfarin therapy. The OAKS was selected because it has good internal consistency reliability as determined by the Kuder–Richardson 20 value [19].

The willingness to switch assessment was based on items obtained from a survey created by Elewa et al. [20]. This instrument was selected because of the topic specificity in measuring willingness to switch to new anticoagulation medications and its prior use in a similar care setting. From this survey, a total of 7 items assessed willingness to switch on the basis of opinions and awareness of new anticoagulant medications as well as perceived conveniences and barriers related to current warfarin therapy. The 7 items were Likert type and inquired willingness to switch based on a likelihood of switching. The response options ranged from 1 to 5 (1=“Very unlikely”; to 5=“Very likely”). For analytic purposes, willingness to switch was assessed in two ways. First patients were considered willing to switch based on a rating of 4 or above for each of the 7 items. Secondly, patients’ responses to these items were summed up in order to examine willingness to switch as a summary score. Ratings for each individual item were also summarized as a mean score. Higher scores represented a higher willingness to switch. Willingness to pay for a new treatment was also assessed in an item that queried the patients on an amount the participant would be willing to pay for a new treatment.

Several measures were taken in order to reduce the influence of bias in the study. Acquiescence and Social desirability bias was avoided by asking neutral questions with no perceived right answers and creating a comfortable judgment-free environment which encouraged honest responses. The use of set predetermined answer choices for respondents to choose avoids confirmation bias. Also following a script and not providing immediate feedback of answer choices prevent leading question and wording bias.

Statistical analysis

Descriptive statistics were used to describe patients’ characteristics, along with their knowledge, satisfaction, and willingness to switch scores. Pearson’s chi-square test and independent sample t-test were used to determine the associations between socio-demographic and willingness to switch ratings (willing vs. unwilling). A linear regression analysis was conducted to examine predictive factors of willingness to switch. Simple linear regression was first conducted to examine unadjusted effects. Study variables evaluated were age, yearly bleeds, missed doses, weekly intake of green vegetables, duration of therapy, number of comorbid conditions, number of medications taken, percent of time in therapeutic range, number of missed appointments, number of kept appointments, average warfarin dose, number of dose changes, knowledge score, satisfaction score, employment status, marital status, smoking status, alcohol intake, highest education level, exercise habits, responsibility to take medication, ethnicity, insurance, indication, and gender. The factors that had p<0.2 in simple linear regression analysis and those of clinical importance were then eligible for entry into the multiple linear regression. These factors were entered simultaneously (enter method) into the model and adjusted odds ratios reported. All analyses were conducted using (Statistical Package for the Social Sciences (SPSS) version 22.0 at an alpha level of 0.05.

Results

Patient characteristics

A total of 130 patients were recruited to participate in the survey, of them 30 patients declined to participate. A total of 100 patients completed the survey (76.9%). The majority of participants were retired/disabled (59%), mostly African American (86%), male (55%). The average age of the participants was 62.58 ± 13.90 years old and 87% receive either Medicare or Medicaid as their primary source of insurance. The indications for taking warfarin included deep venous thrombosis and/ or pulmonary embolism (59%), atrial fibrillation (23%), or other indication (18%). The average time in therapeutic range among participants was 38.75% ± 30.64 based on patients last 4 INR readings. A detailed description of patient demographics information is provided in Table 1.

Table 1: Participant Characteristics in Warfarin Study (N=100).

Willingness to switch

The overall mean willingness to switch score was 21.59 (maximum score=35) A summary of patient responses to the willingness to switch items is shown in Figure 1. As shown, willingness to switch to an anticoagulant with equal/lower cost, fewer drug interactions, less monitoring frequency and equal efficacy was each over 50%.

Figure 1: Willingness to switch chart.

Higher scores on the willingness to switch scale represented a more willingness to switch to a new medication while lower scores represent an unwillingness to switch. The mean willingness to switch scores was 3.19 ± 1.50 for expressed willingness to switch to an agent that had equal efficacy as warfarin, 3.10 ± 1.54, for a treatment with a similar risk profile as warfarin, 3.55 ± 1.77 for a treatment that required less frequent follow up and 3.75 ± 1.67 for a treatment that had fewer drug-drug and no drug-food interactions.

Notable barriers to switching to a new anticoagulant for respondents were the need to take the medication twice daily instead of once daily (mean willingness to switch score=2.5 ± 1.6) and higher patient co-pays (mean willingness to switch score=2.06 ± 1.55). When asked to quantify the amount of out-of-pocket cost participants were willing to pay to switch to these new agents, 82% responded less than $10 a month, 13% agreed to pay up to $49 per month, 3% agreed to pay up to $99 per month, while 2% would be willing to pay over $100 per month in order to switch medications.

Factors associated with willingness to switch

Findings on factors associated with major barriers to willingness to switch are presented in Table 2. Willingness to switch if cost was similar was associated with age. Specifically the mean age was lower for the willingness to switch patient group versus the not willing to switch group (59.6 years vs. 67.1 years, p=0.008). Satisfaction was also associated with willingness to switch if cost was similar with patients reporting lower satisfaction having a higher proportion of willingness (85.7% vs. 50%, p=0.001)

*P<0.05

Table 2: Associations between major barriers to willingness to switch and patient characteristics.

Willingness to switch if monitoring frequency was less was associated with ethnicity and satisfaction. Ethnicity was associated with willingness to switch if monitoring frequency was less with African Americans having a higher proportion of willingness compared to non-African Americans (72.1% vs. 28.6%, p=0.018). Satisfaction was also associated with willingness to switch if monitoring frequency is less with patients reporting lower satisfaction having a higher proportion of willingness to switch (85.7% vs. 58.3%, p=0.009).

Willingness to switch if concerned with drug-drug and drug-food interactions was associated with age, warfarin dose, responsibility for taking medications, and satisfaction. Age was associated with willingness to switch if concerned with drug interactions with younger patients having a higher proportion of willingness to switch (67.1 vs. 60.5, p=0.033). Warfarin dose was associated with willingness to switch if concerned with drug interactions with the mean warfarin dose being higher for the willingness to switch patient group versus the not willing to switch group (6.13 mg vs. 7.32 mg, p=0.046). Responsibility for taking medications was associated with willingness to switch if concerned with drug interactions with patients who report being solely responsible for taking their medications having a higher proportion of willingness to switch (71.7% vs. 37.5%, p=0.045). Satisfaction was associated with willingness to switch if concerned with drug interactions with patients who report lower satisfaction having a higher proportion of willingness to switch (85.7% vs. 62.5%, p=0.024).

Willingness to switch if concerned about taking more doses of medications per day was associated with age, number of comorbid conditions, time in therapeutic range, alcohol use, and satisfaction. Age was associated with willingness to switch if concerned about taking more doses of medications per day with mean age being lower for the willingness to switch patient group versus the not willing to switch group (65.5 years vs. 57.1 years, p=0.003). Comorbid conditions was associated with willingness to switch if concerned about taking more doses of medications per day with mean number of comorbid conditions being lower for the willingness to switch patient group versus the not willing to switch group (3.3 vs. 2.5, p=0.021). Percent time in therapeutic range was associated with willingness to switch if concerned about taking more doses of medications per day with patients spending less time with INR in therapeutic range having a higher proportion of willingness to switch (43.5% vs. 30.0%, p=0.044). Alcohol use was associated with willingness to switch if concerned about taking more doses of medications per day with patients who report drinking alcohol having a higher proportion of willingness to switch (55% vs. 30%, p=0.036). Satisfaction was associated with willingness to switch if concerned about taking more doses of medications per day with patients who report lower satisfaction having a higher proportion of willingness to switch (53.6% vs. 27.8%, p=0.015).

Predictors of willingness to switch are shown in Table 3. The only predictor of willingness to switch was low patient satisfaction (p=0.002). Based upon the beta coefficient, those with high satisfaction had a lower willingness to switch score compared to those with low satisfaction. Other factors the trended toward predicting willingness to switch included less time in therapeutic range (p=0.068) and higher warfarin dose (p=0.60). Knowledge was found to not be a predictor of willingness to switch (p=0.249).

Table 3: Predictors of Willingness to Switch Score.

Discussion

The primary goal of this study was to determine if patient knowledge or satisfaction with warfarin therapy or other patient characteristics impacted a patient’s decision to switch to one of the new oral agents in a predominantly African American population.

Patient satisfaction was determined to be a significant predictor of patient willingness to switch to a new oral anticoagulant with patients with high satisfaction having lower willingness to switch scores compared to those with low satisfaction. The authors were unable to find a comparative study that examined the predictive effect of patient satisfaction on willingness to switch to the newer anticoagulation therapies so our findings would be the first to have examined such an effect. These findings were expected as patients dissatisfied with warfarin could likely have reduced quality of life due to associated complications and would be more willing to switch. Our findings reflect a general sentiment of willingness to switch based on dissatisfaction with therapy and additional studies could be done to further quantify the effect of satisfaction. Several studies have examined patient satisfaction after switching to warfarin alternatives [21,22]. In a RE-LY sub study, it was determined that healthrelated quality of life scores between dabigatran and warfarin were comparable.21 These results illustrate that patients were willing to switch to the new oral anticoagulants and when they do, maintain equal satisfaction with their therapy. Another study found that patients taking the new oral anticoagulants were more satisfied compared to warfarin users, even though they experienced more adverse events [22].

Based on these findings targeted efforts can be made to identify patients who are dissatisfied with current therapy as they would be those most likely to benefit from a switch to a newer anticoagulation.

Our study did not find a predictive effect of knowledge on willingness to switch. These findings were contradictory to our original hypothesis, as we had expected higher knowledge about warfarin therapy would lead to more willingness to switch to newer therapy. These expectations were based on prior research that have shown patient knowledge being a factor modulating treatment acceptance [23,24]. It was possible that patients knowledge of their therapy may simply reflect awareness of its disadvantages and limitations but may not be a driver of action towards change to seeking newer therapies. More studies would need to be conducted to confirm these findings.

Despite the high satisfaction with warfarin therapy, many patients showed interest in switching to a new oral anticoagulant that required less frequent monitoring, fewer drug interactions, with similar efficacy and safety. The lack of drug interactions was the leading reason for the preference to switch therapies. Patients preferred freedom of diet over less rigorous monitoring schedule. The biggest barrier to patients’ willingness to switch from warfarin to one of the newer agents in a previous study was the increased cost to the patient. This was reflected in our study with a reduction in willing to switch occurred when informed that the warfarin alternatives could cost more. The vast majority were unwilling to pay over $10 more per month for the conveniences afforded with the new oral anticoagulants.

Our survey findings were also consistent with results of several other studies in which examine patients preferences, warfarin or switch to alternative oral anticoagulants to warfarin [20]. A study in a similar patient population done by Elewa et al. using the same Likert scale ranging from 1 to 5, showed high willingness to switch to an agent with less frequent follow up visits (mean score of 3.9), lacks interaction with food (mean score of 4.1) and was as efficacious as warfarin (mean score of 3.7). 20 In our study those mean scores were 3.75, 3.55, and 3.19, respectively. Other earlier studies have also showed equal or greater preference to switching to new anticoagulation therapies. In the latter case, a survey investigating patient attitudes toward switching from warfarin to newer agents indicated a general willingness to switch to new oral anticoagulants [25].

Our study has several limitations which must be addressed. First, our sample size may not fully represent the general population who are taking warfarin. Being an outpatient anticoagulation clinic located in an inner city of Washington D.C. and affiliated with a historically black university, our patient population comprises of less Caucasians, Hispanics and Asians and more African Americans. The socioeconomic level of our patient population was possibly lower than the general population leading to a more exaggerated response regarding barriers to switching such as cost. Also foods such as collard and turnip greens are a staple in the African American community which may have affected responses regarding patient feelings about drug-food interactions of warfarin. Furthermore, only patients who attended clinic were recruited for the study which excludes patients who were less engaged in their warfarin therapy. Another limitation was that our survey did not include other potential barriers to switching to oral anticoagulants such as lack of reliable monitoring parameters, absence/cost of an antidote, and short duration of action of the medications in comparison to warfarin. In addition, several of our variables were self-reported which could result in reporting bias. Additional bias may have been introduced by using an investigator administered survey model which may prompt patients to report being more satisfied than they truly were with current therapy leading to an overestimation of warfarin satisfaction. Despite these limitations, this study finding adds to our current body of research on willingness to switch in minority patients, and was the first of such a study to determine both knowledge and satisfaction on willingness to switch together.

Conclusion

This study suggest that patients at our pharmacist run outpatient anticoagulation clinic have low knowledge of their warfarin therapy, were overall satisfied with warfarin treatment, but were willing to consider using a new oral anticoagulant that was more convenient. The major barrier to switching was cost and the need to take some of the newer agents twice daily as opposed to once daily. Patient satisfaction with their warfarin therapy was the biggest predictor of the patient’s willingness to switch. Further studies should be directed toward patient preferences when determining optimal regimen to manage anticoagulant conditions.

References

1. Schulman S (2014) Advantages and limitations of the new anticoagulants. J Intern Med 275: 1-11
2. Hart RG, Benavente O, McBride R, Pearce LA (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation; a meta-analysis. Ann Intern Med 131: 492-501.
3. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ (1999) A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N. Engl J Med 340: 901-907.
4. Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, et al. (1997) The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 336: 393-398.
5. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, et al. (2003) Anticoagulation therapy for stroke prevention and atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 290: 2685-2692.
6. Dowlatshahi D, Butcher KS, Asdaghi N, Nahirniak S, Bernbaum ML, et al. (2012) Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 43: 1812-1817.
7. Flaherty ML, Adeoye O, Sekar P, Haverbusch M, Moomaw CJ, et al. (2009) The challenge of designing a treatment trial for warfarin-associated intracerebral hemorrhage. Stroke 40: 1738-1742.
8. McCroyr DC, Matchar DB, Samsa G, Sanders LL, Pritchett EL (1995) Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly. Arch Intern Med 155:277-281.
9. Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT (2000) Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 160:41-46.
10. ACCF/AHF Task Force Members. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guidelines): a report of the American College of Cardiology Foundation/American heart Association Task Force on Practice Guidelines. Circulation 123:104-123.
11. Rahmani P, Guzman C, Blostein M, Tabah A, Muladzanov A (2013) Patients knowledge of anticoagulation and its association with clinical characteristics, INR control and warfarin-related adverse events. Blood Journal 122: 1738.
12. MatalqahL, Radaideh K, Sulaiman S, Hasali MA, Kader MASK (2013) An instrument to measure anticoagulation knowledge among Malaysian community: A translation and validation study of the Oral Anticoagulation Knowledge (OAK) Test. Asian J Biomedical &Pharmasci3: 30-37.
13. Janoly-Dumenil A, Bourne C, Loiseau K, Luauté J, Sancho PO, et al.  (2011) Oral anticoagulant treatment – evaluating  the knowledge of patients admitted in physical medicine and rehabilitation units. Ann PhysRehabil Med 54: 172-180.
14. Cano S, Lamping DL, Bamber L, Smith S (2012) The Anti-Clot Treatment Scale (ACTS) in clinical Trials. Health Qual Life Outcomes 10: 120.
15. Wild D, Murray M, Shakespeare A, Reaney M, von Maltzahn R (2008) Patient reported treatment satisfaction measures for long term anticoagulant therapy.  Expert Rev Pharmacoecon Outcomes Res 8:291-299.
16. Coleman C, Coleman S, Vanderpoel  J (2013) Patient satisfaction with warfarin and non-warfarin containing Thromboprophylaxis regimens for Atrial Fibrillation. J Investig Med 61:878-881.
17. Kakkar AK, Mueller I, Bassand JP, Fitzmaurice DA, Goldhaber SZ, et al. (2012) International longitudinal registry of patients with atrial fibrillation at risk of stroke.: Global Anticoagulant Registry in the FIELD (GARFIELD).  Am heart J 163:13-19.e1.
18. Piccini JP, Fraulo ES, Ansell JE, Fonarow GC, Gersh BJ, et al. (2011) Outcomes registry for better informed treatment or atrial fibrillation: rationale and design of ORBIT-AF. Am heart J 162:606-612.e1.
19. Zeolla MM, Brodeur MR, Dominelli A, Haines ST, Allie ND (2006) Development and validation of an instrument to determine patient knowledge: the oral anticoagulation knowledge test. Ann Pharmacother 40:633-638.
20. Elewa H, DeRemer C, Keller K, Gujral J, Joshua TV (2013) Patients satisfaction with warfarin and willingness to switch to dabigatran: a patient survey. J Throb Thrombolysis 38: 115-120.
21. Attaya S, Bornstein T, Ronquillo N,Volgman R, Braun LT, et al. (2012) Study of warfarin patients investigating attitudes toward therapy change (SWITCH Survey). Am J Ther 19:432-435.
22. Monz BU, Connolly SJ, Korhonen M, Noack H, Pooley J (2013)  Assessing the impact of dabigatran and warfarin on health-related quality of life: results from an RE-LY sub-study. Int J Cardiol 168:2540-2547.
23. Dong Y, Shen X, Guo R, Liu B, Zhu L, et al. (2014) Willingness to participate in HIV therapeutic vaccine trials among HIV-infected patients on ART in China. PLoS One 5: 9.
24. Abu HH, Tohid H, Mohd AR, Long BMB, Muthupalaniappen L, et al. (2013) Factors influencing insulin acceptance among type 2 diabetes mellitus patients in a primary care clinic: a qualitative exploration. BMC FamPract 14: 164.
25. Choi JC, Dibonaventurea M, Kopenhafer L, Nelson WW (2014) Survey of the use of warfarin and the newer anticoagulant dabigatran in patients with atrial fibrillation. Patient Prefer Adherence 8: 167-177.

References

1. Schulman S (2014) Advantages and limitations of the new anticoagulants. J Intern Med 275: 1-11
2. Hart RG, Benavente O, McBride R, Pearce LA (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation; a meta-analysis. Ann Intern Med 131: 492-501.
3. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ (1999) A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N. Engl J Med 340: 901-907.
4. Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, et al. (1997) The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 336: 393-398.
5. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, et al. (2003) Anticoagulation therapy for stroke prevention and atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 290: 2685-2692.
6. Dowlatshahi D, Butcher KS, Asdaghi N, Nahirniak S, Bernbaum ML, et al. (2012) Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 43: 1812-1817.
7. Flaherty ML, Adeoye O, Sekar P, Haverbusch M, Moomaw CJ, et al. (2009) The challenge of designing a treatment trial for warfarin-associated intracerebral hemorrhage. Stroke 40: 1738-1742.
8. McCroyr DC, Matchar DB, Samsa G, Sanders LL, Pritchett EL (1995) Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly. Arch Intern Med 155:277-281.
9. Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT (2000) Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 160:41-46.
10. ACCF/AHF Task Force Members. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guidelines): a report of the American College of Cardiology Foundation/American heart Association Task Force on Practice Guidelines. Circulation 123:104-123.
11. Rahmani P, Guzman C, Blostein M, Tabah A, Muladzanov A (2013) Patients knowledge of anticoagulation and its association with clinical characteristics, INR control and warfarin-related adverse events. Blood Journal 122: 1738.
12. MatalqahL, Radaideh K, Sulaiman S, Hasali MA, Kader MASK (2013) An instrument to measure anticoagulation knowledge among Malaysian community: A translation and validation study of the Oral Anticoagulation Knowledge (OAK) Test. Asian J Biomedical &Pharmasci3: 30-37.
13. Janoly-Dumenil A, Bourne C, Loiseau K, Luauté J, Sancho PO, et al.  (2011) Oral anticoagulant treatment – evaluating  the knowledge of patients admitted in physical medicine and rehabilitation units. Ann PhysRehabil Med 54: 172-180.
14. Cano S, Lamping DL, Bamber L, Smith S (2012) The Anti-Clot Treatment Scale (ACTS) in clinical Trials. Health Qual Life Outcomes 10: 120.
15. Wild D, Murray M, Shakespeare A, Reaney M, von Maltzahn R (2008) Patient reported treatment satisfaction measures for long term anticoagulant therapy.  Expert Rev Pharmacoecon Outcomes Res 8:291-299.
16. Coleman C, Coleman S, Vanderpoel  J (2013) Patient satisfaction with warfarin and non-warfarin containing Thromboprophylaxis regimens for Atrial Fibrillation. J Investig Med 61:878-881.
17. Kakkar AK, Mueller I, Bassand JP, Fitzmaurice DA, Goldhaber SZ, et al. (2012) International longitudinal registry of patients with atrial fibrillation at risk of stroke.: Global Anticoagulant Registry in the FIELD (GARFIELD).  Am heart J 163:13-19.e1.
18. Piccini JP, Fraulo ES, Ansell JE, Fonarow GC, Gersh BJ, et al. (2011) Outcomes registry for better informed treatment or atrial fibrillation: rationale and design of ORBIT-AF. Am heart J 162:606-612.e1.
19. Zeolla MM, Brodeur MR, Dominelli A, Haines ST, Allie ND (2006) Development and validation of an instrument to determine patient knowledge: the oral anticoagulation knowledge test. Ann Pharmacother 40:633-638.
20. Elewa H, DeRemer C, Keller K, Gujral J, Joshua TV (2013) Patients satisfaction with warfarin and willingness to switch to dabigatran: a patient survey. J Throb Thrombolysis 38: 115-120.
21. Attaya S, Bornstein T, Ronquillo N,Volgman R, Braun LT, et al. (2012) Study of warfarin patients investigating attitudes toward therapy change (SWITCH Survey). Am J Ther 19:432-435.
22. Monz BU, Connolly SJ, Korhonen M, Noack H, Pooley J (2013)  Assessing the impact of dabigatran and warfarin on health-related quality of life: results from an RE-LY sub-study. Int J Cardiol 168:2540-2547.
23. Dong Y, Shen X, Guo R, Liu B, Zhu L, et al. (2014) Willingness to participate in HIV therapeutic vaccine trials among HIV-infected patients on ART in China. PLoS One 5: 9.
24. Abu HH, Tohid H, Mohd AR, Long BMB, Muthupalaniappen L, et al. (2013) Factors influencing insulin acceptance among type 2 diabetes mellitus patients in a primary care clinic: a qualitative exploration. BMC FamPract 14: 164.
25. Choi JC, Dibonaventurea M, Kopenhafer L, Nelson WW (2014) Survey of the use of warfarin and the newer anticoagulant dabigatran in patients with atrial fibrillation. Patient Prefer Adherence 8: 167-177.