Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients

Accepted Manuscript A Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients Israel Gotsman, MD, Orly Ezra, RN, Bruria Hirsh-Rokach, Pharm.D, Dan Admon, MD, Chaim Lotan, MD, Freda DeKeyser Ganz, PhD, RN PII:

S0002-9343(17)30255-3

DOI:

10.1016/j.amjmed.2017.02.030

Reference:

AJM 13971

To appear in:

The American Journal of Medicine

Received Date: 24 January 2017 Revised Date:

31 January 2017

Accepted Date: 1 February 2017

Please cite this article as: Gotsman I, Ezra O, Hirsh-Rokach B, Admon D, Lotan C, Ganz FD, A PatientSpecific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2017.02.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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A Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients

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Israel Gotsman MD1, Orly Ezra, RN1,3, Bruria Hirsh-Rokach Pharm.D1,2, Dan Admon MD1, Chaim Lotan MD1 and Freda DeKeyser Ganz, PhD, RN3

Heart Failure Center, Heart Institute, Hadassah University Hospital, Jerusalem, Israel.

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1

School of Pharmacy, Hadassah Hebrew University Medical Center, Jerusalem, Israel;

3

Henrietta Szold Hadassah - Hebrew University School of Nursing, Jerusalem, Israel.

Word count: 2553 Address all communications to: Israel Gotsman, MD

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Heart Institute,

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Hadassah University Hospital

P.O.B 12000, Jerusalem, Israel IL-91120 Tel: 972-2-6776564;

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Fax: 972-2- 6411028;

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E-mail: [email protected]

Running title: Tailored intervention to control anticoagulation in heart failure Keywords: Tailored Intervention; INR; Heart failure

Funding: None

Conflicts of interest: none of the authors have a conflict of interest. All authors have read and approved the manuscript and take full responsibility for the integrity of the data as presented.

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Abstract Background: Many patients with heart failure need anticoagulants including Warfarin. Good control is particularly challenging in heart failure patients, with less than 60% of International

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Normalized Ratio (INR) measurements in the therapeutic range, thereby increasing the risk of complications.

Objective: To evaluate the effect of a patient-specific tailored intervention on anticoagulation

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control in patients with heart failure.

Methods: Patients with heart failure on Warfarin therapy (N=145) were randomized to either

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standard care or a one-time intervention assessing potential risk factors for lability of INR, where they received patient-specific instructions. Time in therapeutic range (TTR) using Rosendaal’s linear model was assessed 3 months prior and after the intervention. Results: Patient-tailored intervention significantly increased anticoagulation control. The

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median TTR levels pre intervention were suboptimal in the interventional and control groups (53% vs. 45%, P=0.14). Post intervention, the median TTR increased significantly in the interventional group compared to the control group (80% (62-93 inter-quartile range) vs. 44%

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(29-61), P<0.0001). The intervention resulted in a significant improvement in the interventional group pre vs. post intervention (53% vs. 80%, P<0.0001) but not in the control

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group (45% vs. 44%, P=0.95). The percentage of patients with a TTR ≥ 60%, considered therapeutic was substantially higher in the interventional group: 79% vs. 25% (P<0.0001). INR variability (standard deviation of each patient’s INR measurements) decreased significantly in the interventional group from 0.53 to 0.32 (P<0.0001) after intervention but not in the control group. Conclusions: Patient-specific tailored intervention significantly improves anticoagulation therapy in patients with heart failure.

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Background Approximately a third of the patients with heart failure require anticoagulants, usually due to atrial fibrillation. Many are prescribed Warfarin. In order for Warfarin to be effective, the

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International Normalized Ratio (INR) that measures anticoagulation levels needs to be kept in a very narrow therapeutic window. Achieving this is challenging as many factors effect INR levels. Numerous factors influence the metabolism of Warfarin and are associated with

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fluctuations in the INR level. Such factors include medications, nutrition, smoking, alcohol consumption, physical activity, use of tobacco and acute illness including heart failure 1.

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Despite efforts to control the INR, less than 60% of INR measurements in the general patient population are in the therapeutic range2-5. This has been shown to be directly associated with reduced net benefit of the medication and increased complications6, 7. Recently this has also been shown in heart failure patients8 . Quality of anticoagulation is even lower and more

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challenging in patients with heart failure due to interactions with medication, nutrition and liver congestion9 . Patients with heart failure have shown to be at an increased risk of overanticoagulation10.

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Various methods and interventions have been devised to improve TTR rates: anticoagulation specific centers, monitoring by a clinical pharmacist or nurse, self-management programs and

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educational programs11-16. Most have led to some improvement, although with moderate success17. No intervention has yet targeted heart failure patients, a more complex and challenging patient population. We devised an intervention strategy specifically designed for each patient, using a tailored technique in order to improve TTR levels and decrease patient complications associated with Warfarin. This technique is based on the patient centered care approach18 that has been found to be most applicable to the chronically ill patient. The

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objective of this study was to examine the influence of a tailored intervention aimed at improving TTR levels in patients with heart failure. Methods

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Participants and study design: The study was a randomized controlled trial that recruited patients with heart failure on Warfarin therapy. Patients were recruited from the heart failure center and cardiology outpatient clinic at Hadassah University hospital with a diagnosis of

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heart failure. Patients were eligible if they were prescribed Warfarin on a regular basis for at least 3 months prior to recruitment. All patients gave written informed consent to participate

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in the study. The size of the study was calculated based on an assumption of a 10% increase in the primary endpoint (TTR) due to the intervention. Assuming a baseline TTR of 60%±20% based on a recent study on heart failure patients8, to achieve a power (1-β) of 80% with a twosided α≤0.05, a minimum of 64 patients in each group were needed to achieve the primary

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endpoint. Due to possible patient dropout, a sample size of 70 patients in each group was selected as the size of the study. Patients were randomized to either the control group that received standard care (N=75) or to the treatment group that received a one-time intervention

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(N=70) assessing potential risk factors for lability of INR and then receiving patient-specific instructions. Randomization was based on the patient’s unique national identity card number.

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Patients with an even number were allocated to the control group and patients with an odd number were allocated to the interventional group. Interventional protocol: All interventions were conducted by a registered nurse with expertise and knowledge in anticoagulation management. Patients in the treatment group were interviewed by the nurse to determine what risk factors affecting anticoagulation control were relevant for the specific patient. Risk factors assessed included demographic and clinical

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factors such as background diseases, dietary habits, smoking and alcohol consumption and interactions with medications known to affect INR. The nurse then reviewed with the patient the recommended actions needed for each relevant risk factor pertinent to the specific patient.

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Specific actions included: keeping to a recommended stable diet with a stable vitamin K content and if changed then the need to check INR; increased monitoring of INR due to a change in medical condition, for example an infection or change in medications that affect

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INR. After each recommendation the patient was queried if the recommendation was understood and if not, the recommendation was repeated. The average time for the instruction

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was approximately 30 minutes. Beyond the one-time intervention, none of the subjects in either group were advised regarding anticoagulation therapy thereafter. Anticoagulation assessment: Anticoagulation therapy was monitored by their treating physician at regular intervals as indicated per the standard care. Time in therapeutic range

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(TTR) was assessed in all subjects 3 months prior and 3 months after the intervention. Individual TTR was calculated based on Rosendaal’s linear interpolation method19. This method adds each patient’s time within the therapeutic range by incorporating the frequency of

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INR measurements and their actual values assuming that changes between consecutive INR measurements are linear over time and divides by the total time of observation. The target INR

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therapeutic range was specific in each patient based on the target range recommended by the treating physician per standard practice guidelines (either INR between 2 to 3 or 2.5 to 3.5). The majority (139 patients) had a recommended target INR of 2 to 3. Clinical data were collected from the patients on enrollment to the study. We used the recently developed SAMeTT2R2 score (Sex female, Age<60 years, Medical history [more than two comorbidities], Treatment [interacting drugs, e.g., amiodarone for rhythm control], Tobacco use [doubled],

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Race [doubled]) from the AFFIRM study20 that predicted quality of anticoagulation control in patients with atrial fibrillation on Warfarin to assess the type of patients enrolled in the study. All patients recruited to the study completed the follow-up and were included in the final

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analysis. The institutional committee for human studies of the Hadassah Medical Center approved the study protocol.

Statistical analyses: SPSS version 17.0 for Windows (SPSS Inc., Chicago, Illinois, USA) was

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used for all analyses. Comparison of the clinical characteristics was performed using the Mann-Whitney U test for continuous variables and the Chi-Square Test for categorical

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variables. The primary endpoint was the effect of the intervention on TTR. Differences between the two groups were determined based on the unit of analysis of the dependent variable (TTR) using the Mann-Whitney U test. Additional analysis included evaluation of the difference in percent INR tests in range and INR variability as determined by the standard

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deviation of INR measurements. Analysis of the impact of the intervention on INR control before and after intervention in each group separately was performed by the Wilcoxon signedrank test. Clinical predictors of INR control before and after the intervention were evaluated by

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multiple linear regression analysis with TTR as the dependent variable and relevant clinical and demographic characteristics as the predictors. Predictors that were significant on simple

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linear regression analysis were included in the multiple linear regression analysis. The fit of multiple linear regression models was determined by examination of residuals. A two sided p value of <0.05 was considered statistically significant. Results

The study cohort included 145 heart failure patients. Table 1 presents the clinical characteristics of the patients divided into the two experimental groups. Patients were well

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balanced with regard to key clinical parameters with the exclusion of years of education and physical activity that were somewhat higher in the interventional group. The median SAMeTT2R2 score was similar in both groups with a median score of 2. Results of the intervention

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on INR control are presented in Table 2. There was no difference in the median number of INR tests performed during the 3 months before or after the study between the two groups, Table 2. Effect of intervention on TTR

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Patient-tailored intervention significantly increased anticoagulation control (Table 2). The median TTR levels prior to intervention were suboptimal in the interventional and control

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groups (53% (33-68 inter-quartile range) vs. 45% (18-68) respectively, P=0.14). This was also the case with percent INR Tests in range (50% vs. 43%). Post intervention, the median TTR increased significantly in the interventional group compared to the control group (80% (62-93) vs. 44% (29-61), P<0.0001); Figure 1. A similar results was seen with percent INR Tests in

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range (83% vs 40%, P<0.0001). Separately comparing the effect of the intervention on the TTR before and after intervention in each group demonstrated that there was a significant improvement in the interventional group (53% vs. 80%, P<0.0001) but not in the control group

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(45% vs. 44%, P=0.95); Figure 1. A very similar result was demonstrated when analyzing percent INR Tests in range, where we found a significant change in the interventional group

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(50% vs 83%, P<0.0001) but not in the control group (43% vs. 40%, P=0.5). The percentage of patients with a TTR ≥ 60%, the minimal TTR percentage considered therapeutic before the intervention was low in both groups: 40% vs. 33%. After the intervention it was substantially higher in the interventional group: 79% vs. 25% (P<0.0001), Table 2. The difference in control of INR due to the intervention was even higher when analyzing the percent of patients with percent INR Tests in range ≥ 60% (91% vs. 23%, P<0.0001).

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Effect of intervention on INR variability The INR variability, as determined by standard deviation of the INR results, was slightly higher in the interventional group prior to intervention (0.53 vs. 0.45, P=0.01). Post

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intervention, INR variability was reduced in the interventional group compared to the control group (0.32 vs. 0.43, P=0.05). Comparing the effect of the intervention on the INR variability before and after intervention in each group separately by the Wilcoxon signed-rank test

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demonstrated a significant reduction of INR variability in the interventional group (0.53 vs. 0.32, P<0.0001) but not in the control group (0.45 vs 0.43, P=0.7).

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Predictors of TTR

Multivariable linear regression analysis for predictors of TTR are presented in Table 3. Predictors of a low pre-intervention TTR (negative impact) were ischemic heart disease, current smoker and amiodorone therapy. Formal education of more than 10 years was a

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predictor of increased TTR. The regression model demonstrated a significant F statistic (F = 8.1; P <0.0001), with an R2 = 0.19. Interventional group allocation was not associated with TTR levels, affirming that the baseline experimental group allocation was well balanced.

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Predictors of TTR post-intervention were interventional group allocation (positive) and amiodorone therapy (negative); (F = 44.3; P<0.0001, R2 = 0.385). Other predictors including

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smoking were no longer significant predictors. This is consistent with study primary endpoint outcome that the intervention had a significant impact on TTR. Discussion

In the present randomized controlled trial, a tailored intervention aimed at improving TTR levels in patients with heart failure, significantly increased TTR levels. The majority of patients in the interventional group achieved what is considered a minimal therapeutic INR

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(TTR>60%) post intervention. INR variability, another measure of anticoagulation control, also significantly improved in the interventional group. The present study utilized an intervention strategy specifically designed for each patient, using

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a tailored technique in order to improve TTR levels. This technique is based on the patient centered care approach that is most applicable to the chronically ill patient. Such an approach is personalized and targets the specific issues of each patient. This enables to focus on and

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address specific issues that are most relevant for the individual patient. This is particularly relevant in patients with a chronic disease such as heart failure that have multiple co-

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morbidities and are prescribed numerous medications.

Various methods and interventions have been devised to improve TTR rates: anticoagulation specific centers 11, monitoring by a clinical pharmacist

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, self-management programs15, and

educational programs 16. Most lead to some improvement, although with moderate success17. A 11

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higher percent in therapeutic range can be achieved in specific anticoagulation centers

national registry from Sweden achieved a high therapeutic percent (76%)12, as most patients are treated in anticoagulation centers in Sweden. These dedicated anticoagulation clinic

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services are associated with an increase in INR control compared with standard community care. However, these services require specific resources and are not always available to the

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entire population of appropriate patients. Self-management programs have shown improvement in anticoagulation control; but most studies enrolled patients with a high level of education that is important for this type of management. No intervention has yet targeted heart failure patients, a more complex and challenging patient population. A recent post-analysis of a randomized study8 showed that heart failure patients had a mean TTR of only 57% and achieving a high TTR percent was a predictor of reduced

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stroke or death. The mean TTR in the real world is probably even lower. The baseline TTR percent in the present study was only 49%. The median SAMe-TT2R2 score, which is a recently validated predictor of poor anticoagulation control, was 2 in the present study. This

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score was associated with a reduced TTR prior to intervention in the present study (B = -7.7, P<0.001; R2=0.065, F=10 for linear regression model). A score of ≥2 is considered a high score, predicting poor anticoagulation control and warrants some type of intervention to help

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achieve acceptable anticoagulation control. It is therefore not surprising that the participants of the present study achieved a limited baseline anticoagulation control. Furthermore, the baseline

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TTR in the present study was similar to a recent Israeli nationwide observational study that showed that the average TTR was only 42% in all Warfarin users due to atrial fibrillation5. TTR levels in the real world are on average below the minimally expected therapeutic level of 60%, emphasizing the importance of improving TTR levels in the general population and even

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more in patients with heart failure.

The groups in the present study were allocated randomly according to a predefined protocol and the patients were evenly balanced in the majority of the clinical characteristics. However,

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the patients in the experimental group had on average more years of education and this may have affected the study results. We cannot preclude this completely; however baseline TTR

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were not significantly different between the groups despite differences in educational levels. In addition, in the secondary end-point, the experimental group served as a control for itself and the experimental intervention increased TTR in this group comparing before and after the intervention. Furthermore, while education had an association with the TTR pre-intervention, it was not a predictor post-intervention, supporting the assumption that education was not a major determinant of the interventional outcome.

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Limitations of this study: While the present study demonstrated that a onetime intervention had a significant impact on anticoagulation control, there are several limitations and questions that need to be addressed. The study was a randomized controlled study performed on an

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adequately sized group that was powered to demonstrate the end point and resulted in a positive outcome. Despite this, it was not a large study. Furthermore, the intervention was performed by a specific nurse in one center on a particular although not unique population.

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Can this be inferred to other, perhaps less educated patients or from diverse cultural backgrounds is unknown. Can it be implemented with the same success in a large population

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of patients with heart failure needs to be determined. Another question is related to the long term effects of the intervention. The impact of the intervention was evaluated at 3 months, focusing on short term outcome. Does the intervention have a sustained effect on long term control of anticoagulation? This also needs to be evaluated.

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In conclusion, a patient-specific tailored intervention significantly improved anticoagulation therapy in patients with heart failure. This relatively simple intervention may be an additional

complications.

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Disclosures

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therapeutic option to increase anticoagulation control in patients with heart failure and reduce

None.

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anticoagulation on major clinical outcomes. Ann Intern Med 2011;154(7):472-82. 16. Clarkesmith DE, Pattison HM, Lip GY, Lane DA. Educational intervention improves anticoagulation control in atrial fibrillation patients: the TREAT randomised trial. PLoS One 2013;8(9):e74037.

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17. van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest 2006;129(5):115566.

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18. Parekh S, Vandelanotte C, King D, Boyle FM. Improving diet, physical activity and other lifestyle behaviours using computer-tailored advice in general practice: a randomised

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controlled trial. Int J Behav Nutr Phys Act 2012;9:108.

19. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993;69(3):236-9.

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Figure legend Figure 1. Effect of the experimental intervention on TTR levels. TTR levels on an individual patient level are depicted in the control and interventional group

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separately before and after the intervention. The intervention resulted in a significant increase in TTR in the interventional group but not in the control group. Box plots denote median and inter-quartile range (IQR); whiskers are of maximum 1.5 IQR. P values between the groups

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were calculated using the Mann-Whitney U test and in each group comparing before and after

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intervention by the Wilcoxon signed-rank test.

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Table 1. Clinical characteristics and pharmacological treatment of the patients stratified according to randomization into control and interventional groups. Total (N=145)

P Value

72 (63-80)

75 (63-81)

73 (63-80)

0.38

42 (56)

34 (49)

76 (52)

0.37

Gender (Male)

0.41

Reason for anticoagulation: Atrial Fibrillation

51 (68)

42 (60)

Mechanical Valve

18 (24)

19 (27)

Thromboembolism

5 (7)

9 (13)

Diabetes mellitus

23 (31)

24 (34)

Hypertension

43 (57)

Ischemic heart disease

32 (43) 3 (4)

Education (years)

10 (6.0-12)

93 (64)

37 (26)

14 (10)

47 (32)

0.64

42 (60)

85 (59)

0.74

29 (41)

61 (42)

0.88

3 (4)

6 (4)

0.93

10 (7.0-14)

10 (6.5-12)

0.04

4 (6)

13 (9)

0.19

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Depression

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Intervention (N=70)

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Age (Years)

Control (N=75)

9 (12)

Alcohol consumption

0 (0.0)

2 (3)

2 (1)

0.14

0 (0.0)

4 (6)

4 (3)

0.003

2.0 (1.0-2.0)

2.0 (1.0-2.0)

2.0 (1.0-2.0)

0.40

59 (36-72)

55 (33-74)

56 (34-73)

0.61

106 (80-146)

110 (83-159)

108 (81-149)

0.74

29 (18-51)

36 (25-57)

35 (22-55)

0.25

12 (11-14)

12 (11-14)

12 (11-14)

0.68

2.2 (1.2-3.7)

2.5 (1.6-4.1)

2.4 (1.4-3.8)

0.25

20 (13-28)

18 (13-27)

19 (13-28)

0.68

Amiodorone

22 (31)

16 (23)

38 (27)

0.3

Simvastatin

16 (21)

24 (35)

40 (28)

0.07

Allopurinol

0 (0.0)

1 (1)

1 (0.7)

0.19

Lansoprazole

2 (3)

3 (4)

5 (4)

0.63

Levothyroxine

18 (25)

22 (31)

40 (28)

0.39

Physical activity SAMe-TT2R2** eGFR (mL/min per 1.73m2)* Urea (mg/dL)

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Creatinine (µmol/L)

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Present smoker

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Hemoglobin (g/dL) TSH (mIU/L)

Alanine aminotransferase (U/L )

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Data is presented as median (inter-quartile range) for continuous variables and counts (percentages) for categorical variables.

categorical variables.

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P value by the Kruskal Wallis Test for continuous variables and the Chi-Square Test for

* Estimated Glomerular Filtration Rate was calculated using the modified Modification of Diet

correction factor is used multiplying by 0.742.)

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in Renal Disease (MDRD) equation (175 * serum creatinine–1.154 * age–0.203. For females a

** SAMe-TT2R2 = Score based on: female sex, age<60 years, medical history (more than two

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(doubled), race (doubled).

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co-morbidities), treatment (interacting drugs, eg, amiodarone for rhythm control), tobacco use

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Table 2. Results of the intervention on anticoagulation parameters stratified according to the study groups

Intervention (N=70)

Total (N=145)

P Value

Number of INR tests

7.0 (5.0-9.0)

8.0 (6.0-9.0)

7.0 (6.0-9.0)

0.18

Median INR

2.2 (1.9-2.7)

2.5 (2.1-2.8)

2.3 (2.0-2.8)

0.02

Percent TTR

45 (18-68)

53 (33-68)

49 (26-68)

0.14

Percent INR Tests in Range

43 (20-67)

50 (32-70)

50 (25-67)

0.20

TTR ≥ 60%

25 (33)

28 (40)

53 (37)

0.4

INR Tests in Range ≥ 60%

23 (31)

26 (37)

49 (34)

0.41

0.45 (0.2-0.7) 0.53 (0.4-0.9)

0.5 (0.3-0.8)

0.01

7.0 (5.0-9.0)

8.0 (6.0-9.0)

7.0 (6.0-9.0)

0.33

2.2 (1.9-2.9)

2.6 (2.4-2.8)

2.5 (2.2-2.8)

0.02

44 (29-61)

80 (62-93)

61 (42-85)

<0.001

40 (25-57)

83 (71-88)

67 (38-83)

<0.001

19 (25)

55 (79)

74 (51)

<0.001

17 (23)

64 (91)

81 (56)

<0.001

M AN U

INR Variability (Standard Deviation)

Median INR Percent TTR

TE D

Post-intervention Number of INR tests

TTR ≥ 60%

EP

Percent INR Tests in Range

AC C

INR Tests in Range ≥ 60% INR Variability (Standard Deviation)

SC

Pre-intervention

RI PT

Control (N=75)

0.43 (0.3-0.6) 0.32 (0.2-0.5) 0.4 (0.2-0.6)

0.05

Data is presented as median (inter-quartile range) for continuous variables and counts (percentages) for categorical variables. P value by the Mann-Whitney U test for continuous variables and the Chi-Square Test for categorical variables.

2

ACCEPTED MANUSCRIPT

Table 3. Predictors of INR control pre and post intervention determined by percent TTR by multivariable linear regression analysis.

Pre-Intervention* (Constant)

53.5 (3.8)

46.01

61.00

Education > 10 yrs

9.8 (4.4)

1.21

18.54

Ischemic heart disease

-9.2 (4.4)

-17.96

Smoker

-28.3 (7.6)

-43.32

Amiodorone treatment

-11.2 (4.9)

(Constant) Interventional Group

P Value

<0.0001 0.03

-0.56

-0.16

0.04

-13.29

-0.28

<0.0001

-20.90

-1.57

-0.18

0.02

48.5 (2.9)

42.79

54.26

32.2 (3.7)

24.74

39.57

0.57

<0.0001

-21.64

-4.93

-0.21

<0.01

M AN U

SC

0.17

TE D

Post-Intervention**

Amiodorone treatment

Standardized Coefficients

RI PT

B coefficient (Std. Error)

95.0% Confidence Interval for B Lower Upper Bound Bound

-13.3 (4.2)

<0.0001

Parameters that were entered into the model included parameters that were significant on

EP

univariable regression.

* Model F statistic = 8.1; P<0.0001, R2 = 0.188.

AC C

** Model F statistic = 44.3; P<0.0001, R2 = 0.385.

3

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Clinical significance:

RI PT

SC M AN U TE D

•

EP

•

Many patients with heart failure require anti-coagulation with Warfarin. Good control is particularly challenging in these patients, increasing the risk of complications. A one-time patient-specific tailored intervention targeting potential risk factors for lability of INR significantly improved anticoagulation therapy in patients with heart failure. This relatively simple intervention may be a promising therapeutic option to increase anticoagulation control in heart failure patients.

AC C

•

ACCEPTED MANUSCRIPT Appendix 1. Intervention protocol

Intervention

Evaluate clinical risk factors that affect INR levels: Smoking, tobacco or alcohol consumption, exercise, worsening heart failure, infection, vomiting, diarrhea or fever.

General instruction on clinical factors that affect INR control.

Check the list of medications and natural remedies the patient takes. Mark drugs that affect INR level *.

General instruction regarding medication interactions with INR.

RI PT

Risk factor evaluation

SC

Instruction regarding patient’s specific risk factors: check INR level more frequently if there is a change in the risk factor.

M AN U

Instruction regarding patient’s specific drugs: check INR level more often if there is a change in drug/remedy intake.

Calculate the daily amount of vitamin K consumption of the patient.

Instruction on the relation between INR and vitamin K consumption.

TE D

Guidance on foods with high vitamin K content. Explain the importance on keeping to a diet containing stable vitamin K levels, based on the patients’ daily consumption.

EP

After each recommendation, the patient was queried if the recommendation was understood and if not, the recommendation was repeated.

AC C

At the completion of the intervention, the patient received a table of foods with vitamin K levels and a summary of the above guidance. * Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug Interactions Involving Warfarin: Practice Tool and Practical Management Tips. Canadian Pharmacists Journal / Revue des Pharmaciens du Canada. 2011;144(1):21-5.e9.