IMPLEMENTATION OF A WARFARIN DOSING PROTOCOL IN RURAL PRIMARY CARE
Shannon N. Scearce
A Doctor of Nursing Practice Project submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Nursing
Practice in the School of Nursing.
Chapel Hill 2018
ABSTRACT
Shannon N. Scearce: Implementation of a Warfarin Dosing Protocol in Rural Primary Care (Under the direction of Carrie Palmer)
Warfarin is an anticoagulant used to prevent blood clots in at-risk patients. Although it is highly effective, determining the appropriate warfarin dosage for an individual patient can be challenging. Frequent blood monitoring is needed to maintain the patient’s International Normalized Ratio (INR) within the therapeutic range. Incorrect warfarin dosing can result in an INR outside of the therapeutic range. This can lead to hemorrhage or thrombosis and result in permanent disability or death. Studies show that use of a warfarin dosing protocol can increase the INR time within the therapeutic range (TTR) and decrease warfarin-related morbidity and mortality. The problem for this Doctor of Nursing Practice project was identification of a low percent TTR of INR values in patients whose warfarin was managed at the host site, with no clinic-wide dosing protocol in place.
The purpose of this project was to improve the percent TTR of INR values by
implementing a warfarin dosing protocol to be used consistently by all providers. The primary goal was to achieve 85% use of the protocol, with a secondary goal to increase TTR by 10% or more.
post-intervention percent TTR values were compared. Statistical analysis was conducted using the Chi-Square test.
The primary and secondary goals were exceeded. Protocol use was 97.3%, and the TTR improved from 55.5% to 71.2%. A post-hoc analysis was conducted to evaluate INR variability that expanded the therapeutic ranges by 0.1 on both ends. The post-hoc TTR improved from 62.8% to 81.5%. The primary and post-hoc analyses were statistically significant with a p value of 0.019 and 0.0000923, respectively.
ACKNOWLEDGEMENTS
This Doctor of Nursing Practice project could not have been possible without the consistent love and support of my family and friends. Thank you - To my husband, Brandon, who amazes me daily with his unselfishness, his steadfast love, and his genuine interest,
enthusiasm, and support of my work. He spent countless hours by my side through this process and I am truly grateful to have him as my life partner. To my children, Jacob, Bailey, and
Griffin, who inspire me to pursue my dreams and give me reason to push through the hard days. To my parents, who taught me to have grit and to aspire for greatness. And to my classmates, who challenged and encouraged me, and who understood firsthand the many emotions of balancing school, home, and work.
Thank you to the faculty of the University of North Carolina at Chapel Hill. A special thank you to Dr. Carrie Palmer, my project chair, and Dr. Julee Waldrop for having confidence in me and helping me for the duration of this project.
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND SYMBOLS ... viii
CHAPTER 1: INTRODUCTION ... 1
Description of the Problem ... 1
Available Knowledge... 3
Theoretical Framework ... 10
Specific Aims ... 11
CHAPTER 2: METHODS ... 12
Context ... 12
Intervention ... 12
Study of the Intervention ... 18
Measures ... 18
Analysis... 19
Ethical Considerations ... 19
Funding ... 19
CHAPTER 3: RESULTS ... 21
Key Findings ... 21
Post-Intervention Changes Over Time ... 21
Expanding the Therapeutic Range ... 22
Plan-Do-Study-Act ... 23
CHAPTER 4: DISCUSSION ... 24
Interpretation ... 24
Barriers ... 26
Limitations ... 28
CHAPTER 5: CONCLUSIONS ... 29
Implications for Practice ... 29
Sustainability... 29
Future Changes ... 30
Further Study ... 31
APPENDIX A: SEARCH TERM COMBINATIONS ... 32
APPENDIX B: PRISMA FLOW DIAGRAM ... 33
APPENDIX C: WARFARIN DOSING FORM ... 34
APPENDIX D: WARFARIN DOSING PROTOCOL FOR THERAPEUTIC INR RANGE 2.0-3.0 ... 35
APPENDIX E: WARFARIN DOSING PROTOCOL FOR THERAPEUTIC INR RANGE 2.5-3.5 ... 36
APPENDIX F: PATIENT THROUGHPUT AND WORKFLOW ... 37
APPENDIX G: INTERVAL POST-INTERVENTION DATA ... 39
APPENDIX H: RESULTS WITH STATISTICAL ANALYSIS ... 40
LIST OF ABBREVIATIONS AND SYMBOLS
α Alpha
2 Chi-square
CINAHL Cumulative Index of Nursing and Allied Health Literature DNP Doctor of Nursing Practice
DOI Diffusion of Innovations EBP Evidence-Based Practice EMR Electronic Medical Record FDA Food and Drug Administration
GRADE Grading of Recommendations Assessment, Development, and Evaluation INR International Normalized Ratio
IRB Institutional Review Board
ISMP Institute of Safe Medication Practices JNC-8 Eighth Joint National Committee NQF National Quality Forum
p Probability
PDSA Plan-Do-Study-Act
PICO Population, Intervention, Comparison, Outcome
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analysis RCT Randomized Controlled Trial
RE-LY Randomized Evaluation of Long-Term Anticoagulation Therapy RMA Roxboro Medical Associates
TJC The Joint Commission
TTR Time within the Therapeutic Range
US United States
USDHHS United States Department of Health and Human Services
CHAPTER 1: INTRODUCTION
Description of the Problem
The vitamin K antagonist, warfarin, is used for the prevention of venous
thromboembolism and systemic embolism, most often associated with atrial fibrillation and prosthetic heart valves. Atrial fibrillation is the most common heart arrhythmia in the United States (Centers for Disease Control and Prevention, 2017). In addition, every year approximately 100,000 people in North America undergo heart valve replacement procedures (Leiria, Lopes, Williams, Katz, Kalil, Alexander, 2011). Prevention of potential life-threatening and/or debilitating thrombotic events is imperative for these patients at increased risk of thrombus formation. Although other options are now available for anticoagulation for patients with non-valvular atrial fibrillation, warfarin remains the only anticoagulant approved by the United States (US) Food and Drug Administration (FDA) for the prevention of thrombus formation in patients with a prosthetic heart valve. It also remains the cheapest anticoagulant option for most patients and is currently the only generic option available in the United States. Despite the introduction of alternative anticoagulants, warfarin remains the most commonly prescribed oral anticoagulant in the US (Andreica & Grissinger, 2015; Theodorou, Palmieri, Szychowski, Sehman, & Swarn, 2012).
dosing errors (Piazza et al., 2011; Wysowski, Nourjah, & Swartz, 2007). It is considered a high-alert medication by the Institute for Safe Medication Practices (ISMP) and requires special attention due to its potential for significant patient harm if used erroneously (Andreica &
Grissinger, 2015; ISMP, 2011) Frequent blood monitoring of the International Normalized Ratio (INR) is required, and frequent dose changes to maintain the INR within the therapeutic range are common. If dosed incorrectly, too much warfarin may cause excessive bleeding and too little may result in blood clots.
Many national organizations provide recommendations for improvement of warfarin management. The American College of Chest Physicians has developed evidence-based guidelines to facilitate high-quality anticoagulation management (Holbrook, et al., 2012). The Joint Commission (TJC), The US Department of Health and Human Services (USDHHS), and the National Quality Forum (NQF) recommend use of a systematic approach to manage warfarin, such as use of a dosing protocol, for clinical decision making (NQF, 2010; TJC, 2017;
USDHHS, 2014).
guidelines efficiently (Zipkin, Greenblatt, & Kushinka, 2012). Simple evidence-based protocols can facilitate integration of evidence into daily practice. Evidence-based practice guidelines and protocols are not intended to override provider clinical judgment. They are intended to improve standardization and communication and support clinical decision making that can reduce patient harm and improve outcomes (American College of Obstetricians and Gynecologists, 2015).
Available Knowledge
Search terms. The following Population, Intervention, Comparison, Outcome (PICO) question was developed to perform a review of current available literature: Does use of a
warfarin dosing protocol in primary care increase the time within the therapeutic range (TTR) of INRs in adult patients taking warfarin compared to usual warfarin dosing without use of a protocol? To answer this question, a search of PubMed, CINAHL, Embase, and Cochrane databases was conducted. The following key word sets were used in the search: warfarin OR coumadin OR anticoagula*; protocol OR nomogram OR algorithm; dosing OR administration; time within therapeutic range OR TTR; International Normalized Ratio OR INR; outpatient OR primary care OR ambulatory care. Only studies conducted within the past 15 years, in English language, and in an adult population in outpatient settings were included. Studies that focused on inpatient or specialty management of warfarin, only addressed initiation of warfarin, involved patients on hemodialysis, or used genotype-guided protocols were excluded. The same
studies was that they did not directly relate to the PICO question. Of the remaining 10 studies, two were removed after reading the full text because they were looking at different outcome measures. A total of eight studies remained (Dolan, Smith, Collins, & Plumb, 2008; Franke, Dickerson, & Carek, 2008; Kim, et al., 2009; Nantha, 2015; Nieuwlaat, et al., 2014; Rose, et al., 2017; Van Spall, et al., 2012, & Wilson, Constantini, & Crowther, 2007). The Preferred
Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) diagram for this literature review is provided in Appendix B.
Data extraction. Data were extracted from each of these eight studies focusing on what was relevant to the PICO question. The extracted study data included aims/objectives, design, sample, setting, outcome variables, measurement of variables, statistical analyses (when
available), results, and quality of evidence. The outcome measure for seven of these studies was TTR of INR in patients taking warfarin (Dolan, et al., 2008; Franke, et al., 2008; Kim, et al., 2009; Nantha, 2015; Niewlaat, et al., 2014; Rose, et al., 2017; Wilson, et al., 2007). The TTR of INR was defined as the proportion, percentage, or mean time the patient’s serum INR level was within the predetermined target range. The outcome measure for the remaining study was how strongly algorithm-specific dosing predicted TTR (Van Spall, et al., 2012).
included in the review (Wilson, et al., 2007). And, there was one retrospective cohort study that used data from a prior study (Van Spall, et al., 2012).
The systematic review had several strengths (Dolan, et al., 2008). It included a meta-analysis of 36 studies including 13 RCTs, conducted a secondary meta-analysis for sensitivity data, considered confounding factors, considered areas of bias, and compared the results to other studies for consistency of data (Dolan, et al., 2008). One possible area of concern identified in the SR report was that they were not able to perform more advanced statistics on their data to control for all confounding factors and further evaluate heterogeneity because they were not able to access patient-level data (Dolan, et al., 2008).
Although the systematic review had several strengths, the quality of evidence varied among the other studies. Evidence in two of these studies was strong due to large samples sizes, one of which also had thorough statistical analyses (Kim, et al., 2009; Rose, et al., 2017). Two of the pre-test/post-test studies had a small sample size, which could decrease their power (Franke, et al., 2008; Nantha, 2015). Weaknesses were found in the studies using a
The cluster-RCT is a strong study design; however, the Nieuwlaat, et al. (2014) study had several areas of potential bias. Patient selection bias was likely present because not all patients within the practice were required to participate; therefore, those that chose to participate could have been more compliant or generally more stable. Patients in the algorithm group that were on multiple warfarin dose strengths were required to switch to one dose strength, but the control group was not required to do this. The providers were not blinded to study groups, which could have affected their dosing practice because they were aware that they were being monitored.
The randomized blinded clinical trial had limited power (Wilson, et al., 2007). Even though the study duration was 2.7 years and blinding was used to increase power, there was no statistical analysis included in the report (presumably not conducted) and the sample size was small and limited by their inclusion criteria. These results could still be considered clinically meaningful because there was an improvement in TTR with use of a protocol that is also consistent with other evidence (Wilson, et al., 2007).
Sample characteristics. A total of 11,510 patients were examined within 995 practice sites in seven of the studies collectively, including outpatient primary care and anticoagulation clinics (Franke, et al., 2008; Kim, et al., 2009; Nantha, 2015; Nieuwlaat, et al., 2014; Rose, et al., 2017; Van Spall, et al., 2012; Wilson, et al., 2007). The SR did not provide a specific number of patients, but rather provided data based on 35,199 patient-years spread among numerous practice settings, including general community practices, specialty and non-specialty clinics, and
anticoagulation clinics (Dolan, et al., 2008). Two of the studies took place in the US (Franke, et al., 2008). Three of them took place in Canada (Kim, et al., 2009; Nieuwlaat, et al., 2014;
Wilson, et al., 2007). One study was done in Malaysia (Nantha, 2015). The SR was conducted in the United Kingdom, but reviewed studies done in multiple countries (Dolan, et al., 2008). One study included a total of 44 countries, spanning all continents except Antarctica (Van Spall, et al., 2012).
2015; Nieuwlaat, et al., 2014; Rose, et al., 2017). One study only included patients with
antiphospholipid antibodies and a previous episode of thrombosis (venous or arterial) (Wilson, et al., 2007). One study included only patients with nonvalvular atrial fibrillation (Van Spall, et al., 2012).
Interventions. The four quasi-experimental pre-test/post-test studies collected baseline proportion, percentage, or mean TTR of INR data in participants with warfarin management by usual care without a dosing protocol (pre-test) and then recollected the same data from another sample within the same population after implementation of a dosing protocol (post-test) (Franke, et al., 2008; Kim, et al., 2009; Nantha, 2015; Rose, et al., 2017). The SR extracted pooled mean TTR data in a primary and secondary sensitivity analysis (Dolan, et al., 2008). The primary data set separated the patients with atrial fibrillation and secondary data included a mix of indications to provide a sensitivity analysis. Groups were separated by infrequent monitoring (usual care) and frequent monitoring (use of a protocol) (Dolan, et al., 2008). In the cluster-RCT, practices were randomized to a usual care group (without use of a protocol) or an algorithm group (with use of protocol) with mean TTR collected (Nieuwlaat, et al., 2014). In the random blinded clinical trial, patients were randomly assigned to two groups (for goal INR ranges 2.0-3.0 and 3.1-4.0) with two paper-based warfarin dosing protocols (one for each desired goal range) with the proportion of total percent patient-time spent within this goal range collected and compared to prior study results of usual medical care without use of a dosing protocol with no true
Outcomes. Among these eight studies, there was consistency of evidence showing an increase in TTR with protocol use, although not all studies had statistically significant findings. Three of the studies, including the SR secondary analysis, showed a statistically significant increase in TTR when using a dosing protocol compared to usual care/no protocol (Dolan, et al., 2008; Franke, et al., 2008; Kim et al., 2009). In the SR, there was a statistically significant increase in the frequent monitoring (use of protocol) group compared to the infrequent
monitoring (usual care) group in the secondary analysis, but was not statistically significant in the primary analysis (Dolan, et al., 2008). The secondary analysis included a mix of clinical indications for warfarin (compared to only atrial fibrillation in the primary analysis) and expanded the upper limit of the therapeutic INR range from 3.0 to 3.5, which was considered acceptable because occasional INR results up to 3.5 require no dose adjustments per guidelines (Dolan, et al., 2008). The Nantha (2015) and Nieuwlaat, et al. (2014) studies showed an increase in TTR with protocol use, but were not statistically significant. Two of the studies showed increase in TTR with use of a protocol, but did not provide statistics to determine significance (Rose, et al., 2017; Wilson, et al., 2007). The final study was statistically significant but looked at the data differently, showing that each 10% increase in algorithm-consistent dosing
independently predicted a 6.21% increase in TTR (Van Spall, et al., 2012).
showing increased TTR in the groups using a protocol and one showing an association between improved TTR and algorithm-consistent dosing. Although the smaller studies did not show a statistically significant difference, the clinical significance may still be important. None of these studies showed a decrease in TTR following implementation of a dosing protocol. Based on this body of evidence, using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria, the quality of evidence available for the PICO question was considered moderate (Balshem, et al., 2011).
Application and summary. Several studies report that increased TTR decreases warfarin-related morbidity and mortality (Kim, et al., 2009; Lip, et al., 2015; Rose, 2012; Van Spall, et al., 2012). Use of TTR has been identified as an appropriate marker and quality indicator for predicting adverse events from oral anticoagulation therapy and is an independent predictor of patient clinical outcomes (Kaatz, 2007; Van Spall, et al., 2012). Based on this review of literature, use of a warfarin dosing protocol does increase TTR of INR in adult patients taking warfarin compared to usual warfarin dosing without a protocol. Furthermore, as stated
previously, several professional organizations recommend use of a systematic approach to manage warfarin, such as with use of a dosing protocol (NQF, 2010; TJC, 2017; USDHHS, 2014).
Theoretical Framework
promote practice change (Gale & Schaffer, 2009). Rogers (2003) proposed that “diffusion of an innovation is an uncertainty reduction process” (p. 232). The DOI theory provides characteristics that predict adoptability, a five-stage innovation-decision process, and categories of adopters based on innovativeness to guide communication for each type of adopter (Rogers, 2003). This theory applied because this project required providers to adopt an innovation, a warfarin dosing protocol, into their daily clinical practice. Specific uses of this theory are explained in Chapter 2 of this report.
Specific Aims
The purpose of this quality improvement project was to improve percent TTR of INR in patients taking warfarin by implementing a clinic-wide warfarin dosing protocol to be used consistently by all providers at the host site. The primary measure or process indicator was provider use of the warfarin dosing protocol (measured as yes/no). The secondary measure was percent TTR before and after implementation of the protocol.
CHAPTER 2: METHODS
Context
This project took place at Roxboro Medical Associates (RMA) in Roxboro, North
Carolina. Roxboro Medical Associates is a rural, family-owned, private, adult primary care clinic consisting of four providers (three physicians and one nurse practitioner), four nurses, two
laboratory (referred to as “lab” for the remainder of this paper) technicians, three front office secretaries, a billing specialist, and an office manager. This practice serves patients with mostly Medicare and private/commercial insurance, with very few patients having Medicaid or no insurance. According to the office manager of the practice, the patient breakdown based on insurance type at the time of project implementation was estimated at 60% Medicare, 30% private/commercial insurance, 5% Medicaid, and 5% no insurance.
Intervention
Improving protocol adoptability. Rogers’ DOI theory provides guidance for predicting and minimizing potential barriers for acceptance and sustainability of an innovation and may increase the likelihood that the innovation will be adopted (De Civita & Dasgupta, 2007). For this project, the innovation was the warfarin dosing protocol. According to DOI theory, innovation characteristics that increase adoptability include relative advantage, compatibility, complexity, trialability, and observability (Rogers, 2003).
objective data available to the providers, especially individualized data, motivated them to change their practice and was a significant influence on provider buy-in.
Compatibility is the degree to which the adopter perceives the innovation as consistent with their existing values, beliefs, structures, needs, and past experiences (Rogers, 2003). It is common for healthcare professionals to use algorithms and/or protocols from evidence-based guidelines to guide clinical decision making. In fact, providers at the host site already used other algorithms, such as the Eighth Joint National Committee (JNC-8) Hypertension Management Algorithm. Therefore, use of a protocol was considered compatible with the host site’s current structure and the providers’ prior experience. The chosen protocols were already in use at another outpatient practice that was considered similar in function to the host site, which further supported its compatibility there.
Complexity is the degree to which a potential adopter perceives the innovation as
difficult to understand or use (Rogers, 2003). The protocol was a simple paper-based format that was easy to follow, and a documentation template that was already available in the EMR was used to simplify the documentation process. Workflow adjustments were made as a result of discussions with stakeholders to decrease the perceived complexity of the protocol and its implementation.
Observability is the degree to which one can see positive results of the innovation (Rogers, 2003). Data were made available to stakeholders every two weeks showing consistent improvement following protocol implementation. Continuing to present this data to stakeholders over time, perhaps at longer intervals, could also increase sustainability moving forward,
Innovation-decision process. Rogers’ DOI theory describes a five-stage innovation-decision process, which includes knowledge, persuasion, innovation-decision, implementation, and
confirmation (Rogers, 2003). These stages suggest that the decision to adopt an innovation is a process that occurs over time, moving through each stage until eventual adoption or rejection occurs (Rogers, 2003).
The knowledge stage begins when a potential adopter gains awareness of innovation and the need for change and begins to understand how the innovation functions (Rogers, 2003). This project included an education session for providers and nurses. During this session, providers were given information showing current guidelines and research evidence that use of a protocol improves patient outcomes and their individual percent TTR data from 2017. A toolkit
highlighting these points was distributed to stakeholders for reference. A demonstration was provided on how to use the specific protocol to be implemented and the nurses were trained on how to calculate dose adjustments based on the protocol.
The persuasion stage begins when a favorable or unfavorable attitude is formed about the innovation and an individual seeks to gain more information and determine what is credible (Rogers, 2003). The difference here is that there is an affective component, compared to
cognitive component in the prior stage (Rogers, 2003). It is within this stage that change agents are essential (Gale & Schaffer, 2009). The change agent develops a relationship with the
Following this stage, the decision stage begins when the choice is made to adopt or reject the innovation (Rogers, 2003). If the decision is to adopt, the implementation stage will occur, and the providers will begin using the protocol (Rogers, 2003). If the decision is to reject, further adaptation of the project will be performed and reviewed by stakeholders resulting in later adoption or continued rejection (Rogers, 2003). The confirmation stage is the final stage during which the decision to maintain the change or not occurs (Rogers, 2003). The change agents provided continued support to the stakeholders and progress reports were given at regular 2-week intervals that showed results of their efforts during the 13-2-week project lifespan. This reinforced continued use of the protocol during the project implementation phase and, continuing these progress reports should increase sustainability moving forward.
2003). The project leader attempted to identify each stakeholder’s adopter category and used communication techniques recommended by the DOI theory to facilitate effective
communication and promote buy-in.
Supporting materials. A form was created, as requested by the providers, for nurses to complete for each patient presenting for INR point-of-care testing during project implementation. These forms were titled “Warfarin Dosing” and made into a tear pad for each nurse. Each one-page document included a blank line to write the patient’s name, date of service, indication for warfarin, INR therapeutic range, current warfarin tablet strength, current warfarin dosing schedule, current weekly dose, the INR result for that date of service, the protocol
recommendation with dose adjustment calculation if applicable, and whether the provider followed the protocol (yes/no) with space at the bottom of the page for handwritten calculations (See Appendix C). These forms were completed by the nurse and given to the provider who reviewed the information and determined if they wanted to accept or decline the protocol recommendation. It was then returned to the nurse to file in a folder labeled “Warfarin Protocol Project”. These forms were collected by the project leader and used to compare with data extracted from the EMR.
documents, and tear pad. Every provider and nurse received their own binder toolkit with contact information for the project leader on the front cover. A meeting was held by the project leader with all providers and nurses to review this information, practice using the protocol, receive feedback, and address any concerns regarding this practice change plan prior to project implementation.
Dosing protocols. The warfarin dosing protocols, based on the American College of Chest Physicians evidence-based clinical practice guidelines, were used with permission from The University of North Carolina at Chapel Hill General Internal Medicine Clinic. There were two protocols, one for an INR therapeutic range of 2.0 to 3.0 (See Appendix D) and one for an INR therapeutic range of 2.5 to 3.5 (See Appendix E). The protocol for therapeutic INR range of 2.0 to 3.0 was used for patients with atrial fibrillation or a history of deep venous thrombosis, pulmonary embolism, or embolic stroke. The protocol for therapeutic INR range of 2.5 to 3.5 was used for patients with a history of prosthetic valve replacement.
Patient throughput and workflow. Patient throughput and workflow was detailed for staff, nurses, and providers (See Appendix F). The specific workflow was determined with input from RMA providers at pre-implementation meetings. The workflow document was laminated and provided to all affected employees for reference.
Evaluation and feedback. The Plan-Do-Study-Act (PDSA) model was used as a means for evaluation and improvement of the project throughout implementation (Institute for
Study of the Intervention
To assess protocol usage and its impact on percent TTR for this practice, data were analyzed before, during, and after protocol implementation. The project leader extracted the data. Data were extracted from the “Warfarin Dosing” forms and were compared to the EMR for accuracy. Data were analyzed on three separate occasions to verify accuracy of results. Baseline data were extracted pre-intervention to include all INR results on all patients taking warfarin who presented to the clinic for an INR test between July 1, 2017 and September 30, 2017 and whether the INR value was within that patient’s therapeutic range (yes/no). Post-intervention data were extracted following implementation of the protocol and included all INR results on all patients taking warfarin who presented to the clinic for INR point-of-care testing after protocol
implementation between July 1, 2018 and September 30, 2018, whether the provider used the protocol recommendation (yes/no), and whether the INR value was within that patient’s
therapeutic range (yes/no). Pre-intervention data were collected for the same dates the year prior in an attempt to control for seasonal dietary differences that could alter INR results.
Measures
The primary aim of this project was measured by determining the percent of protocol use with a goal of 85% or more. The secondary aim was measured by determining the percent TTR with a goal of a 10% or more increase from the pre-intervention TTR within the 13-week span of the project. For this project, an increase in percent TTR that was clinically meaningful for this practice was desired, which did not require a statistically significant increase to determine project success. The expectation was to achieve an increase in TTR of INR values following
Analysis
Post-intervention data were collected and analyzed every two weeks following
implementation and continued for a total of 13 weeks from July 1, 2018 to September 30, 2018. Descriptive statistics were reported as percent TTR which was calculated from dichotomous variables of yes or no regarding whether the INR was or was not within the therapeutic range. If the INR was within the therapeutic range, it was labeled as “yes” and if not, it was labeled as “no”. The Chi-square (2) test was used to determine statistical significance with α equal to
0.05.
In an attempt to keep this QI project as simple as possible for the stakeholders, additional data, such as reason for deviating from the protocol, was not required to be reported although there was a blank line on the “Warfarin Dosing” form for this information if the nurse or provider wished to include it. A chart review was conducted by the project leader when the protocol was not used to obtain more information regarding protocol deviation with the intent of discovering protocol limitations and addressing possible future issues with sustainability.
Ethical Considerations
This project was submitted to the Institutional Review Board (IRB) of The University of North Carolina at Chapel Hill. The IRB determined that this was non-human subject research and their approval for this project was not required. There were no ethical concerns with this quality improvement project and no potential conflicts of interest identified.
Funding
CHAPTER 3: RESULTS
Key Findings
A total of 247 point-of-care INR tests were obtained from July 1, 2017 to September 30, 2017. Of these, 137 INR values were within the therapeutic range and 110 were not. This resulted in a TTR pre-intervention baseline of 55.5%. A total of 146 point-of-care INR tests were obtained from July 1, 2018 to September 30, 2018 following protocol implementation. The protocol was used for 142 of these encounters and not used for four of them. This resulted in 97.3% protocol use and exceeded the desired goal of 85%. Of the 146 post-intervention INR values, 104 were within the therapeutic range and 42 were not. This resulted in a post-intervention TTR of 71.2%, an improvement of 15.7% from the pre-post-intervention TTR. This exceeded the desired goal of a 10% improvement in TTR.
To conduct Chi-square analysis on this data, the descriptive data were converted back to dichotomous variables of yes/no. The INR value was labeled as “yes” when it was within the therapeutic range and “no” when it was not. Chi-square testing was completed using Excel with an α of 0.05. There was a statistically significant difference in the pre-intervention percent TTR and post-intervention percent TTR with p=0.019 (See Appendix H).
Post-Intervention Changes Over Time
were compared to the pre-intervention TTR. Six data points were obtained with each consisting of two weeks of data with the exception of the final data point, which included an extra week for a total of 13 weeks of implementation. Each of these data points included protocol use (yes/no) converted into percent protocol use, number of INR values inside and outside of the therapeutic range (yes/no) converted into percent TTR for those weeks and the to-date percent protocol use and to-date percent TTR from July 1, 2018 for those weeks. Data point TTRs ranged from 60.9% to 82.6%. To-date TTRs ranged from 64.7% to 75%. All data point TTRs were higher than the baseline TTR of 55.5%. A linear trendline was calculated using Excel, showing an upward slope that predicts continued improvement over time (See Appendix G).
Expanding the Therapeutic Range
To further evaluate INR variability before and after protocol implementation, a post-hoc analysis was conducted with the INR therapeutic ranges expanded by 0.1 at both ends. The initial INR therapeutic range of 2.0 to 3.0 was expanded to 1.9 to 3.1 and the initial INR therapeutic range of 2.5 to 3.5 was expanded to 2.4 to 3.6. Expanding these ranges was also acceptable because the protocol did not recommend warfarin dose adjustments for occasional INR values within these ranges. A new total pre-intervention TTR and total post-intervention TTR were determined with these expanded therapeutic ranges. This resulted in a new baseline pre-intervention TTR from July 1, 2017 to September 30, 2017 of 62.8% and a new
post-intervention TTR from July 1, 2018 to September 30, 2018 of 81.5%, an improvement of 18.7% following protocol implementation. This further demonstrated improvement in INR variability with use of a warfarin dosing protocol.
significant difference between the expanded range pre-intervention TTR and the expanded range post-intervention TTR with p=0.0000923 (See Appendix H).
Plan-Do-Study-Act
CHAPTER 4: DISCUSSION
Summary
Both primary and secondary aims were achieved for this quality improvement project. The primary aim of 85% protocol use was exceeded with actual protocol use of 97.3%. The secondary aim of a 10% improvement in TTR was also exceeded with improvement in primary TTR of 15.7%, and improvement in the post-hoc analysis TTR of 18.7%. Both the primary and post-hoc pre-intervention and post-intervention differences were clinically and statistically significant.
Interpretation
Outcomes. The results of this project confirmed that consistent use of a warfarin dosing protocol can significantly improve TTR of INR values in primary care. This is consistent with other studies in the current literature as previously discussed in this report. The results also demonstrated that consistent use of a warfarin dosing protocol by all providers at RMA was a needed and successful practice change. This practice change is also clinically significant as it should improve patient outcomes for this rural primary care practice because increased TTR decreases warfarin-related morbidity and mortality (Kim, et al., 2009; Lip, et al., 2015; Rose, 2012; Van Spall, et al., 2012).
Observed difference in groups. The number of INR values in the post-intervention group was 101 less than the pre-intervention group. There are several possible explanations for this. Patients return for repeat INR testing less frequently when their INR is within the
and therefore fewer INR values to collect. Approximately five patients taking warfarin in 2017 had passed away prior to project implementation. The cause of death for these patients was not collected for the purposes of this project. Some of the patients taking warfarin in 2017 were switched to direct oral anticoagulant medications prior to or during protocol implementation in 2018. The exact number of patients is not known but was estimated to be around 10 total patients.
Deviation from protocol. The protocol was used in 97.3% of total opportunities during project implementation; this equates to the protocol not being used in only four of 146
opportunities. A review of the EMR and “Warfarin Dosing” forms was conducted by the project leader for possible explanations for not using the protocol. The protocol was not used in three of these occurrences because the patient had missed scheduled doses prior to their INR test. For one of these three, the patient had not taken his warfarin for five days prior due to having a colonoscopy the week before the office visit, so the provider restarted his prior dose and did not use the protocol to adjust the warfarin dose. For another one of these three, the patient forgot to take the warfarin dose the night before and had recently been discharged from the hospital. That patient’s dose was adjusted to match what they had been taking during their hospital stay and not based on the protocol. For the last one of these three, the patient had intentionally not taken several doses of warfarin because he was unsure of taking it when he started another new medication. The patient’s warfarin was restarted at the intended dose instead of adjusting it based on the protocol. For the remaining one occurrence, the patient’s INR value was slightly low, and the dose was not adjusted because the patient received a prescription for an antibiotic the day of the office visit, leading to a potential drug interaction that could cause a
Out-of-range values. The post-intervention post-hoc analysis TTR using the expanded therapeutic range was 81.5%. This indicates that 18.5% of the INR values were not within the expanded therapeutic range. A review of the EMR and “Warfarin Dosing” forms was conducted by the project leader for possible explanations of these out-of-range INR values. There were 146 total INR values with 119 values within the expanded therapeutic range and 27 out-of-range values. Of these 27 out-of-range values, 15 were above the therapeutic range and 12 were below. Three were from the same patient that was on hemodialysis, six were from patients who had been on antibiotics or started new medications since the last INR test, eight were from patients taking the warfarin incorrectly or had missed recent warfarin doses, and ten were unable to be explained by chart review. All three of the INR values for the patient on hemodialysis were low. Dialysis can alter metabolism of warfarin, leading to a subtherapeutic INR value despite use of the protocol for dose adjustments (Abe, Maruyama, Suzuki, Okada, & Soma, 2012). The protocol did not include dose considerations specifically for patients on
hemodialysis. Multiple medications, especially antibiotics, can interact with warfarin and alter INR levels which could potentially explain the six INR values that were out-of-range for patients who had received antibiotics or new medications since the last INR test (Bungard, Yakiwchuk, Foisy, & Brocklebank, 2011). The protocol did not include dose considerations for patients starting new medications or on antibiotics.
Barriers
warfarin therapy and use of a warfarin dosing protocol was not a part of the existing core
meaningful use measures with the Centers for Medicare and Medicaid Services or the practice’s Accountable Care Organization quality measures, the providers did not feel this was a priority for practice improvement. They had numerous other measures they were focused on at the time of the project implementation. The project leader attempted to overcome this major barrier by presenting them with objective data and using communication techniques that reached them, based on DOI theory. This included educating them on the literature review findings, current EBP guidelines, and professional organization recommendations, which support use of a warfarin dosing protocol. It seemed that the providers were willing to use the protocol for this project temporarily and wished to decide afterward as to whether they would sustain this practice change based on the post-implementation data and ease of use. Remaining flexible and positive as a project leader and respecting all stakeholders’ concerns and suggestions was important in engaging them. Adapting the workflow using stakeholder input created a sense of ownership for the project since their ideas shaped the final product and hopefully improved the likelihood of sustainability of the practice change following project completion.
Other barriers included the perceived time commitment required to use the protocol and the perceived threat to provider autonomy for warfarin dose adjustments. The providers’ initial response to the dose adjustment calculations and documentation workflow that was originally presented to them was perceived as too time consuming and complicated when they compared it to their current practice. Workflow adaptations were made using their input to decrease
create consistency of care among all providers at the practice. The providers could override the protocol if there was a specific reason to do so for a specific patient based on their clinical judgment, which was not questioned by the project team.
Limitations
The 13-week duration of the project may be insufficient to gauge long-term results. Retrospective historical data were collected for the pre-intervention group and characteristics of the patients within that group were not compared to those within the post-intervention group to determine similarities and differences between groups. Complex patients whose INR values were more likely to fall outside of the therapeutic range may have had more INR values within the duration of the project because of the need for more frequent INR testing. Despite provider instructions, some patients may not have presented for an INR test during the 13-week project implementation. It is possible that these patients with low adherence to prescribed treatment would be more likely to have INR values outside of the therapeutic range and were potentially not captured during the duration of this project. These potential limitations were difficult to minimize and there were no specific changes identified or conducted to adjust for them.
The protocol itself had limitations. It did not include recommendations for patients who had missed doses, had recently taken or were currently taking antibiotics, or who were on hemodialysis. There are practice tools available to assist providers with medical decision
making in these cases, but they were not included with this protocol or in this project. Some may argue that these perceived protocol limitations could be considered a strength as provider
CHAPTER 5: CONCLUSIONS
Implications for Practice
This quality improvement project resulted in clinically and statistically significant improvements in percent TTR of INR values for patients receiving warfarin management at Roxboro Medical Associates. This project adds to the current body of knowledge regarding implementation of a warfarin dosing protocol and its usefulness in primary care. The results are transferable to most primary care practices who could use this project and report as a guide for implementing a warfarin dosing protocol in their specific setting. Rural primary care settings may particularly benefit from this project and report as they are more likely to manage their patient’s warfarin therapy given the lack of available anticoagulation clinics in rural areas. The results of this project support the recommendation to follow EBP guidelines for warfarin
management that include use of a warfarin dosing protocol. This project validates evaluation of practice to identify problems that can be improved using EBP guidelines and quality
improvement methods.
Sustainability
This project should be highly sustainable as consideration was made to incorporate ideas that would increase the likelihood of sustainability from project conception to completion as stated throughout this report. It did not require extra personnel or new equipment. Sustaining the practice change should remain low cost with no foreseeable additional costs in the future.
increased likelihood of sustainability. The PDSA method could be continued indefinitely at variable intervals to maintain the practice change in the future. Providers are also likely to continue using the protocol given the statistically and clinically significant improvement in percent TTR demonstrated in the primary and post-hoc analyses.
Future Changes
If this quality improvement project was repeated at the host site or was to be replicated at another site, consideration should be made for the following changes:
Consider extending the implementation phase beyond 13 weeks. The 13-week duration was relatively short and, although statistically significant results were obtained, this time frame may make it difficult to gauge long-term results. A time frame of six months or more for post-intervention data collection may provide more information regarding protocol effectiveness and sustainability. In this case, the pre-intervention comparative data collection time frame would also be extended in the same manner for the prior year. Consider formal interval meetings for evaluation and feedback discussions. Informal
meetings were used in this project with nurses and providers stopped randomly during their normal daily patient care schedules and respondents may have felt rushed to speak so they may not have put much thought into their responses.
Consider creating an electronic version of the protocol or somehow integrating the protocol into the EMR but be sure to determine stakeholder preference beforehand. The providers at the host site for this project did not want an electronic version but their paper version created duplicate documentation for the nurses. An electronic version that could be incorporated into the EMR could prevent this duplication and perhaps be more readily available for the providers and nurses who are already using the EMR for every patient visit. An electronic version could also streamline data availability and retrieval, making it more feasible to monitor the practice change on an ongoing basis.
Further Study
This project could be expanded in the future to include issues with warfarin management beyond simple provider dose adjustments. Future projects could include a dosing protocol along with standardized warfarin patient education that may improve adherence to warfarin dose changes, INR testing, and a warfarin friendly diet, and possibly result in an additional increase in TTR of INR values. Additional clinical decision-making tools could be added to the dosing protocol used for this project that may include, for example, recommended dose adjustments when prescribing specific antibiotics for patient’s taking warfarin, guidance on warfarin management for patients receiving hemodialysis, or computer-assisted dose adjustment calculations.
APPENDIX A: SEARCH TERM COMBINATIONS
1. warfarin OR coumadin OR anticoagula* AND protocol OR nomogram OR algorithm
2. warfarin OR coumadin OR anticoagula* AND dosing OR administration
3. warfarin OR coumadin OR anticoagula* AND time within therapeutic range OR TTR
4. warfarin OR coumadin OR anticoagula* AND International Normalized Ratio OR INR
5. warfarin OR coumadin OR anticoagula* AND outpatient OR primary care OR ambulatory care
6. warfarin OR coumadin OR anticoagula* AND outpatient OR primary care OR
ambulatory care AND dosing OR administration AND time within therapeutic range OR TTR AND outpatient OR primary care OR ambulatory care AND International
APPENDIX B: PRISMA FLOW DIAGRAM Records identified through database searching (PubMed=58) (CINAHL=11) (Embase=53) (Cochrane database = 1)
S cr ee n in g In cl u d ed E li gi bi li ty Id en ti fi ca ti
on Additional records identified through
other sources (n=2 - articles identified
from reference list of another article)
Records after duplicates removed (n=116)
Records screened (n=116)
Records excluded after title and abstract
screening (n=106)
Full-text articles assessed for eligibility
(n=10)
Full-text articles read and excluded, with reasons (n=2: different outcome
measure)
35
APPENDIX D: WARFARIN DOSING PROTOCOL FOR THERAPEUTIC INR RANGE 2.0-3.0
36
APPENDIX E: WARFARIN DOSING PROTOCOL FOR THERAPEUTIC INR RANGE 2.5-3.5
*used with permission from The University of North Carolina General Internal Medicine Clinic Signature:
Internal Medicine Clinic Director
Chest. 2012 Feb;141(2 Suppl);e1S-801S. Copyright 2012. UNC Center for Excellence in Chronic Illness Updated August 2012
Major bleed:
• Hold Warfarin and admit patient to hospital
• Rapid reversal of anticoagulation with four-factor prothrombin complex concentrate rather than plasma
• Additionally use vitamin K 5-10 mg administered by slow IV injection
APPENDIX F: PATIENT THROUGHPUT AND WORKFLOW
Patient arrives for INR testing
FRONT OFFICE STAFF
Registers patient & adds patient to provider schedule (reason for visit entered as “INR”) Changes patient status in EMR to “checked in”
Directs patient to main waiting area
LAB TECH
Sees “checked in” status for patient needing INR testing in EMR Retrieves patient from main waiting area & escorts to lab Obtains point-of-care INR blood lab by finger stick Enters INR result in EMR
Escorts patient to lab waiting area & notifies nurse that patient is ready
NURSE
Retrieves patient from lab waiting area & escorts to nursing station
Obtains patient vital signs (blood pressure, heart rate) & documents in EMR Verifies medication list with patient & updates in EMR
Documents changes in diet, current symptoms, side effects of warfarin therapy, & compliance with current warfarin dosing schedule using the warfarin documentation EMR template
Verifies clinical indication for warfarin (updating EMR if needed)
Establishes patient’s therapeutic INR range (i.e. Afib/DVT/PE = 2.0 - 3.0, valve replacement = 2.5 - 3.5) Reviews INR result & uses the appropriate warfarin dosing protocol to determine if a dose change is
needed
Calculates new warfarin dosage, if indicated, and completes the “Warfarin Dosing” form
Discusses with provider the patient’s clinical indication for warfarin, current INR result, and protocol dose adjustment recommendation & gives the provider the “Warfarin Dosing” form
PROVIDER
Reviews patient’s EMR
Determines if a compelling reason to deviate from the protocol recommendation exists
Informs nurse of decision to follow protocol recommendation or not, and reason for protocol deviation if applicable and desired
Legend: INR= International Normalized Ratio; EMR = Electronic Medical Record; Afib = atrial fibrillation; DVT = deep vein thrombosis; PE = pulmonary embolism
NURSE
Enters dose adjustment & recheck time frame in EMR using documentation template as follows: Warfarin strength, dosing directions, recheck time frame (Ex: warfarin 5mg, take 1 tab daily, recheck in 2 weeks) Enters whether protocol recommendation was or was not followed and, if not, reason for deviation if
given as follows: Per protocol OR not per protocol due to [enter reason] Prints office visit summary & gives to patient
APPENDIX G: INTERVAL POST-INTERVENTION DATA
Data
Point Date Protocol Use TTR Protocol To-date
Use
To-date TTR
Yes No % Yes No %
1 July 1 – July 14, 2018 16 1 94.1% 11 6 64.7%
2 July 15 – July 28, 2018 23 0 100% 19 4 82.6% 97.5% 75% 3 July 29 – Aug 11, 2018 22 1 95.7% 14 9 60.9% 96.8% 69.8% 4 Aug 12 – Aug 25, 2018 25 1 96.2% 21 5 80.8% 92.1% 73% 5 Aug 26 – Sept 8, 2018 21 1 95.5% 15 7 68.2% 96.4% 72% 6 Sept 9 – Sept 30, 2018 35 0 100% 24 11 68.6% 97.3% 71.2%
Legend. TTR=Time within the Therapeutic Range
52.79 57.79 62.79 67.79 72.79 77.79 82.79 87.79
Baseline 1 2 3 4 5 6
%
T
TR
Data Point
Post-Intervention TTR Change Over Time
APPENDIX H: RESULTS WITH STATISTICAL ANALYSIS
Primary Analysis
(Original Therapeutic Range) (Expanded Therapeutic Range) Post-hoc Analysis
Pre-Intervention (n=247)
Yes 137 155
No 110 92
TTR 55.5% 62.8%
Post-Intervention (n=146)
Yes 104 119
No 42 27
TTR 71.2% 81.5%
Difference TTR ↑ 15.7% ↑ 18.7%
Chi-square analysis α = 0.05 α = 0.05
REFERENCES
Abe, M., Maruyama, N., Suzuki, H., Okada, K., & Soma, M. (2012). International normalized ratio decreases after hemodialysis treatment in patients with warfarin. Journal of Cardiovascular Pharmacology, 60(6), 502-507. doi: 10.1097/FJC.013e31826f34f3 The American College of Obstetricians and Gynecologists. (2015). Committee Opinion: Clinical
Guidelines and Standardization of Practice to Improve Outcomes. Retrieved from https://www.acog.org/-/media/Committee-Opinions/Committee-on-Patient-Safety-and-Quality-Improvement/co629.pdf?dmc=1
Andreica, I. & Grissinger, M. (2015). Oral anticoagulants: A review of common errors and risk reduction strategies. Pennsylvania Patient Safety Authority, 12(2), 54-61. Retrieved from http://patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2015/jun;12(2)/Pages/5 4.aspx
Balshem, H., Helfand, M., Schunemann, H.., Oxman, A.D., Kunz, R., Brozek, J., … Guyatt, G.H. (2011). GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology, 64, 401-406. doi: 10.1016/j.jclinepi.2010.07.015
Bungard, T.J., Yakiwchuk, E., Foisy, M., & Brocklebank, C. (2011). Drug interactions
involving warfarin: Practice tool and practical management tips. Canadian Pharmacists Journal, 144(1), 21-25.ed. https://doi.org/10.3821%2F1913-701X-144.1.21
Centers for Disease Control and Prevention. (2017). Atrial Fibrillation Fact Sheet. Retrieved from https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm De Civita, M. & Dasgupta, K. (2007). Using diffusion of innovations theory to guide diabetes
management program development: An illustrative example. Journal of Public Health, 29(3), 263-268. doi: 10.1093/pubmed/fdm033
Dolan, G., Smith, L.A., Collins, S., & Plumb, J.M. (2008). Effect of setting, monitoring intensity and patient experience on anticoagulation control: A systematic review and meta-analysis of the literature. Current Medical Research and Opinion, 24(5), 1459-1472. doi:
10.1185/030079908x297349
Franke, C.A., Dickerson, L.M., & Carek, P.J. (2008). Improving anticoagulation therapy using point-of-care testing and a standardized protocol. Annals of Family Medicine, 6(Suppl. 1), S28-S32. doi: 10.1370/afm/739
Holbrook, A., Schulman, S., Witt, D.M., Vandvik, P.O., Fish, J., Kovacs, M.J., … Guyatt, G.H. (2012). Evidence-based management of anticoagulant therapy. Antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 141(Suppl. 2), e152S-e184S. doi:
10.1378/chest.11-2295
Institute for Healthcare Improvement. (2017). How to Improve. Retrieved from http://www.ihi.org/resources/Pages/HowtoImprove/default.aspx
Institute for Safe Medication Practices. (2011). ISMP list of high-alert medications in
community/ambulatory healthcare. Retrieved from https://www.ismp.org/communityRx/ tools/ambulatoryhighalert.asp
Kaatz, S. (2007). Determinants and of quality in oral anticoagulation therapy. The Journal of Thrombosis and Thrombolysis, 25, 61-66. https://dx.doi.org/10.1007/s11239-007-0106-9 Kim, Y.K., Nieuwlaat, R., Connolly, S.J., Schulman, S., Meijer, K., Raju, N.,… Eikelboom, J.W.
(2009). Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: A pilot study. The Journal of Thrombosis and Thrombolysis, 8, 101-106. doi: 10.1111/j.1538-7836.2009.03652.x
Leiria, T.L.L., Lopes, R.D., Williams, J.B., Katz, J.N., Kalil, R.A., and Alexander, J.H. (2011). Antithrombotic therapies in patients with prosthetic heart valves: Guidelines translated for the clinician. The Journal of Thrombosis and Thrombolysis 31(4), 514-22. doi: 10.1007/s11239-011-0574-9
Lip, G.Y.H., Laroche, C., Popescu, M.I., Rasmussen, L.H., Vitali-Serdoz, L., Dan, G. …Boriani, G. (2015). Improved outcomes with European Society of Cardiology guideline-adherent antithrombotic treatment in high-risk patients with atrial fibrillation: A report from the EORP-AF general pilot registry. Europace, 17, 1777-1786. doi:
10.1093/europace/euv269
Locatelli, F., Andrulli, S., and Del Vecchio, L., (2000). Difficulties of implementing clinical guidelines in medical practice. Nephrology Dialysis Transplantation, 15(9), 1284-1287. Nantha, Y.S. (2015). Anticoagulant management of atrial fibrillation: The influence of dosing
algorithm and recall schedule on time in therapeutic range. Family Practice, 32(5), 514-519. doi: 10.1093/fampra/cmv066
Nieuwlaat, R., Eikelboom, J.W., Schulman, S., van Spall, H.G.C., Schulze, K.M., Connolly, B.J., …Connolly, S.J. (2014). Cluster randomized controlled trial of a simple warfarin
maintenance dosing algorithm versus usual care among primary care practices. Journal of Thrombosis and Thrombolysis, 37, 435-442. doi: 10.1007/s11239-013-0969-x
Piazza, G., Nguyen, T.N., Cios, D., Labreche, M., Hohlfelder, B, Fanikos, J., …Goldhaber, S.Z. (2011). Anticoagulation-associated adverse drug events. The American Journal of Medicine, 124(12), 1136-1142. http://dx.doi.org/10.1016/j.anjmed.2011.06.009 Rogers, E. (2003). Diffusion of innovations (5th ed.). New York, NY: The Free Press. Rose, A.E., Robinson, E.N., Premo, J.A., Hauschild, L.J., Trapskin, P.J., & McBride, A.M.
(2017). Improving warfarin management within the medical home: A health-system approach. The American Journal of Medicine, 130, 365.e7-365.e7-365.e12.
https://dx.doi.org/10.1016/j.amjmed.2016.09.030
Rose, A.J. (2012). Improving the management of warfarin may be easier than we think. Circulation, 126, 2277-2279. doi: 10.1161/CIRCULATIONAHA.112.141887
Sanson-Fisher, R.W. (2004). Diffusion of innovation theory for clinical change. Medical Journal of Australia, 180(Suppl.), S55-S56.
The Joint Commission. (2017). Ambulatory health care 2018 national patient safety goals. Retrieved from https://www.jointcommission.org/assets/1/6/NPSG_Chapter_AHC_ Jan2018.pdf
Theodorou, A.A., Palmieri, A., Szychowski, J.A., Sehman, M.L., & Swarna, V. (2012). Prescription utilization of the oral anticoagulants. American Journal of Pharmacy Benefits, 4(3), 120-123.
U.S. Department of Health and Human Services, Office of Disease Promotion and Prevention. (2014). National action plan for adverse drug event prevention. Retrieved from
https://health.gov/hcq/pdfs/ade-action-plan-508c.pdf
Van Spall, H.G.C., Wallentin, L., Yusuf, S., Eikelboom, J.W., Nieuwlaat, R., Yang, S.,
…Connolly, S.J. (2012). Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: An analysis of patients receiving warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial. Circulation, 126, 2309-2316. doi:
10.1161/CIRCULATIONAHA.112.101808
Wysowski, D.K., Nourjah, P., and Swartz, L. (2007). Bleeding complications with warfarin use: A prevalent adverse effect resulting in regulatory action. Archives of Internal Medicine, 167(13), 1414-1419. doi: 10.1001/archinte.167.13.1414
