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Dimensions of Critical Care Nursing:
doi: 10.1097/DCC.0000000000000022
Clinical DIMENSION

Bleeding Risk Factors Affecting Warfarin Therapy in the Elderly With Atrial Fibrillation

Darnell, Stan W. MS, APRN, AGPCNP-BC, CCRN; Davis, Stephanie C. PhD, RN, FNP, BC; Whitcomb, John J. PhD, RN, CCRN, FCCM; Manfredi, Joseph A. MD; McLaurin, Brent T. MD

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Author Information

Stan W. Darnell, MS, APRN, AGPCNP-BC, CCRN, is an adult-gerontology nurse practitioner at the Southeastern Neurosurgical & Spine Institute of the Greenville Health System, South Carolina.

Stephanie C. Davis, PhD, RN, FNP, BC, is graduate coordinator and associate professor at Clemson University School of Nursing, South Carolina.

John J. Whitcomb, PhD, RN, CCRN, FCCM, is second degree coordinator and assistant professor at Clemson University School of Nursing, South Carolina.

Joseph A. Manfredi, MD, is a clinical cardiac electrophysiologist at AnMed Health Arrhythmia Specialists, Anderson, South Carolina.

Brent T. McLaurin, MD, is a cardiologist at Anderson Heart, AnMed Health, Anderson, South Carolina. He also serves as director for the Research Division at Anderson Heart and the AnMed Research Division.

The authors have disclosed that they have no significant relationships with, or financial interest, in any commercial companies pertaining to this article.

Address correspondence and reprint requests to: Stephanie C. Davis, PhD, RN, FNP, BC, 433 Edwards Hall, Clemson, SC 29634 (stephad@clemson.edu).

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Abstract

Purpose: Inadequate anticoagulation among elderly individuals with atrial fibrillation (AF) is a common problem. This synthesis of the literature review describes the pathophysiology of AF, explains the mechanism of action of warfarin (Coumadin), identifies factors that contribute to warfarin (Coumadin)–associated bleeding in the elderly population, and explores alternatives to warfarin (Coumadin) therapy. Implications for advanced practice nurse practice, education, and research will be discussed.

Methods: A literature search was conducted using Academic Search Premier, CINAHL Plus with Full Text, and Medline from 1999 to 2012. Search terms included warfarin (Coumadin), warfarin (Coumadin) genetics, diet, interactions, bleeding, atrial fibrillation, genetics, anticoagulation clinic, dabigatran, apixaban, rivaroxaban, and elderly.

Results: The literature indicates that the potential bleeding risk associated with warfarin (Coumadin) therapy limits its use in the elderly population. However, some studies have found warfarin (Coumadin) to be more effective than aspirin in preventing stroke. The safety profiles of both medications were comparable; also, effective alternatives to warfarin (Coumadin) that do not require routine testing are now available.

Conclusions: Atrial fibrillation increases the probability of an embolic stroke, especially for the elderly population. Stroke risk and bleeding risk tools, in conjunction with patient preference, determine the best stroke prevention treatment. Anticoagulant clinics manage long-term warfarin (Coumadin) therapy effectively. Newer anticoagulants offer effective alternatives to warfarin (Coumadin) therapy.

Atrial fibrillation (AF), a common arrhythmia, results from irregular electrical activity within the atria of the heart. Atrial fibrillation is characterized by interrupted blood flow into the ventricles.1 Blood flow interruption instigates blood pooling, which contributes to the risk for thromboembolism formation.2

Individuals aged 80 to 89 years with AF have a 23.5% chance of thrombus formation. This is sharply higher than in individuals 50 to 59 years of age, who have a 1.5% probability of thrombus formation.3 In 2010, it was projected that approximately 2.66 million people would experience AF.4 The 2005 estimated cost associated with treatment of AF was $6.65 billion.4 Atrial fibrillation is estimated to affect approximately 12 million individuals by the year 2050.4 Forty-five percent of individuals with AF are older than 75 years,5 and AF has been implicated in 25% of strokes in individuals 80 years or older.2 The fear of adverse bleeding has led to inadequate thromboprophylaxis within the elderly population despite a greater risk for thromboembolism.2

Warfarin (Coumadin), an oral vitamin K antagonist, is often prescribed to individuals with AF to decrease the risk of developing a thromboembolism. Warfarin (Coumadin), at a therapeutic level, can reduce the risk of stroke.5-8 The purpose of this article was to describe the pathophysiology of AF, describe the warfarin (Coumadin) mechanism of action, and identify factors that potentially increase bleeding risk with concurrent warfarin (Coumadin) use. Implications for advanced practice nursing (APN) practice, education, and research will be discussed.

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AF Pathophysiology

Atrial fibrillation can have numerous cardiac and noncardiac causes. Cardiac causes include ischemia, hypertension, and cardiomyopathy. Infection, thyroid disease, electrolyte imbalance, and pulmonary disease are noncardiac etiologies that may trigger AF.9,10 Paroxysmal AF terminates without intervention and lasts less than 7 days. Atrial fibrillation that lasts more than 7 days and either terminates without intervention or requires cardioversion is termed persistent AF. Atrial fibrillation that persists for more than a year is classified as permanent AF.9

Electrical disturbances originate throughout the atria, with most arising from the left atrium. Abnormal electrical disturbances develop within the atria that reduce the amount of blood ejected into the ventricles.9,11 Atrial conduction rates of 300 to 600 beats/min are possible. A secondary increase in the ventricular rate may subsequently impair the emptying of the ventricles. As a result, an individual may experience chest pain, fatigue, and shortness of breath.9 Blood pooling within the atria may cause a thrombus formation or blood clot. The blood clot may travel to the circulatory system and result in embolic stroke.9

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Warfarin Mechanism of Action

Warfarin (Coumadin) prevents thrombus formation by interrupting vitamin K metabolism. Vitamin K, a vital component of thrombus formation, acts as a cofactor that facilitates conversion of glutamic acid to γ-carboxyglutamic acid residues in 6 proteins. These 6 proteins promote clotting factors II, VII, IX, and X and proteins C and S. The γ-carboxyglutamic acid residues bind calcium. Calcium normally controls the binding process of proteins to the phospholipid membrane where injury occurs. Vitamin K is oxidized to a dormant form during the γ-gluatamyl carboxylation process and is later reactivated by a redox reaction with enzyme vitamin K 2,3-epoxide reductase. Warfarin (Coumadin) blocks the action of vitamin K 2,3-epoxide reductase and results in lower amounts of active vitamin K. Decreased availability of vitamin K prevents the conversion of glutamic acid to γ-carboxyglutamic acid residues, which prevents the activation of clotting factors. Vitamin K–enriched vegetables replenish vitamin K and can antagonize the effect of warfarin.12 Other contributing factors are genetics and the availability of albumin.

The most plentiful protein in circulating plasma is human serum albumin (HSA). Human serum albumin binds and transports compounds to specific bodily sites. Long-chain fatty acids, heme, bilirubin, and hydrophobic organic anions of medium size bind especially well to it.13 Three homologous primary domains constitute the amino acid sequence of HSA, noted as domain I, domain II, and domain III. Two subdomains, noted as A and B, further define each primary domain. This configuration facilitates HSA to have ligand-binding site variability. This subsequently enables HSA to bind to warfarin (Coumadin) effectively at a specific region on HSA known as Sudlow site.13 The binding mechanism between HSA and warfarin (Coumadin) depends on hydrophobic interactions and electrostatic interactions.13

Ninety-nine percent of warfarin (Coumadin) is bound to protein when the drug is at a therapeutic level.14 This strong affinity of warfarin (Coumadin) for HSA results in low amounts of unbound warfarin (Coumadin). Any condition that causes a decrease in HSA can result in an accumulation of unbound warfarin (Coumadin).14 The unbound portion of a drug produces the pharmacological effect.15 Thus, an increased amount of unbound warfarin (Coumadin) can lead to an increased international normalized ratio (INR). The competition between warfarin (Coumadin) and other Sudlow site I binding–dependent drugs, including phenylbutazone, tolbutamide, and indomethacin, can result in an increased amount of unbound warfarin (Coumadin).14

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REVIEW OF LITERATURE

Limited evidence is available describing why warfarin (Coumadin) is withheld in the absence of clinical contraindications. A systematic literature review was performed using electronic databases CINAHL Plus with Full Text, Academic Search Premier, and Medline and the search terms warfarin (Coumadin), warfarin (Coumadin) genetics, diet, interactions, bleeding, atrial fibrillation, genetics, anticoagulation clinic, dabigatran, apixaban, rivaroxaban, and elderly. Studies not published in English were excluded.

Bleeding risk is the major factor affecting warfarin (Coumadin) treatment in elderly individuals.16-18 Individual patient factors, drug interactions, and dietary intake affect the risk of bleeding.

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Individual Patient Factors

Fall risk, poor cognition, and altered sensory skills potentiate the risk of bleeding due to risk for injury.16 Studies show rates of hemorrhage from 6% to 12.5% in geriatric populations taking warfarin (Coumadin).3,19 Jacobs et al19 reported a death rate of 20% for elderly patients with AF being treated with warfarin (Coumadin). It was undetermined whether death was associated with hemorrhage, ischemia, or other cause. However, mortality was higher for participants with dementia and for participants who experienced falls. Determination of cause of death could have influenced the findings. Inclusion criteria between the studies varied, including the geriatric age definition, which ranged from 65 to 80 years.

Genetics can strongly influence warfarin (Coumadin) requirements. Variations in the CYP2C9 genes can affect the required warfarin (Coumadin) dosage. The CYP2C9*1, or wild-type allele, is the most common form. The most common variations of the CYP2C9 gene that occur are CYP2C9*2 and CYP2C9*3. These variants occur approximately 15% to 30% in whites but are seen much less in African, African American, and Asian populations. The presence of either of the variant alleles is associated with decreased warfarin (Coumadin) metabolism. Variations of the CYP2C9 gene can affect warfarin (Coumadin) dosage by approximately 15%. Thus, individuals who possess these allele variations may require a lower dosage of warfarin (Coumadin).20

The VKORC1 gene can also affect warfarin (Coumadin) response. The required warfarin (Coumadin) dosage can be affected by single nucleotide polymorphisms of the VKORC1 gene. Approximately 20% to 35% of the variability of warfarin (Coumadin) dosage among patients on stable therapy can be explained by polymorphism of this gene. VKORC1 polymorphism can affect warfarin (Coumadin) dosage by approximately 25%.20 Thus, individuals who have polymorphic expression of the VKORC1 gene may require a lower dosage of warfarin (Coumadin) to prevent bleeding complications.

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Drug Interactions

Drug-to-drug interactions (DDIs) may also potentiate the risk of bleeding with individuals taking warfarin (Coumadin). Analgesic and anti-inflammatory medications (such as salicylates and nonsteroidal anti-inflammatories) potentiate warfarin (Coumadin), causing higher than therapeutic INR levels.21-23 Similarly, Obreli-Neto et al24 found that warfarin (Coumadin) and nonsteroidal anti-inflammatory drug interactions were among the most prevalent medications implicated in adverse drug reactions. A limitation to this finding was the inability to control for medication durations and dosages. Salicylate doses greater than 1.5 g/d can potentiate anticoagulation. Salicylates might potentiate anticoagulation by altering the metabolism of vitamin K or by displacing warfarin (Coumadin) from its binding site on albumin.21

Broad-spectrum antibiotics destroy normal intestinal flora, which subsequently impairs vitamin K production.25 Antibiotics can also alter the metabolism of warfarin (Coumadin) with subsequent elevation of warfarin (Coumadin) drug levels.21,23 Certain antibiotics can inhibit the clearance of warfarin (Coumadin) from an individual. Metronidazole and trimethoprim-sulfamethoxazole are 2 antibiotics that interact this way with warfarin (Coumadin). Other antibiotics with the same effect include ciprofloxacin, cotrimoxazole, erythromycin, fluconazole, clarithromycin, azithromycin, and amoxicillin.21

Centrally acting medications that affect the central nervous system can potentiate the effect of warfarin (Coumadin). These medications include citalopram, entacapone, and sertraline. Barbiturates, rifampicin, azathioprine, and carbamazepine decrease the effectiveness of warfarin (Coumadin) and increase the rate of hepatic clearance of warfarin (Coumadin).21

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Dietary Intake

Vitamin K ingestion is especially important to warfarin (Coumadin) response and subsequent degree of anticoagulation. Vitamin K is a fat-soluble vitamin required for the production and regulation of procoagulant factors (VII, IX, and X), anticoagulant factors (proteins C and S), and prothrombin.26 Vitamin K is found in green leafy vegetables such as arugula, asparagus, broccoli, collard greens, cucumbers, cabbage, green tea, turnip, and watercress.27 Consumption of these vitamin K–enriched foods can decrease the effectiveness of warfarin (Coumadin). Conversely, the omission of these foods causes excessive anticoagulation.28 Thus, consistent vitamin K intake is necessary to accurately dose warfarin (Coumadin).

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Facilitators

Risk-benefit analysis is the recommended approach for determining if an elderly individual is a candidate for an antithrombotic medication, such as warfarin (Coumadin). Two assessment tools are available to help determine the risk-benefit ratio for stroke and bleeding. The CHA2DS2-VASC (C: congestive heart failure, H: high blood pressure, A: age [75 years or older], D: diabetes, S: previous stroke; the DS2-VASC adds female gender, age 65-75 years, and vascular disease) tool uses a point system to determine an individual’s risk for having a stroke based on age, chronic disease, history of transient ischemic attack/stroke, sex, and vascular disease. Each criterion is worth 1 point, with 2 exceptions. Individuals 75 years or older and/or those with a previous stroke or transient ischemic attack each receive 2 points. A maximum number of 9 points are possible. The total score determines stroke risk and appropriate antithrombotic therapy.29 The second assessment tool is the HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, elderly, and drug therapy or alcohol) rating score. The HAS-BLED scoring system assigns a maximum of 9 points to determine an individual’s bleeding risk based on a history of hypertension, renal/liver function, stroke history, bleeding history or predisposition for bleeding, drug/alcohol use, and age.30 Despite the availability of these screening tools, two-thirds of eligible elderly individuals older than 85 years do not receive vitamin K antagonists.31 Tulner et al32 found advanced age to be the only differing variable that prevented the use of an oral anticoagulant.

Gouin-Thibault et al7 determined that a computer-based dosing program was superior to physician dosing at keeping INR levels within therapeutic range for greater periods of time. Time in therapeutic range was shown to be a prudent indicator of the effectiveness of warfarin (Coumadin) in reducing stroke risk.5 Limitations of this study included a small sample size and inability to control for extraneous variables such as concurrent use of other medications.

Anticoagulation clinics have become increasingly popular to help maintain therapeutic levels of warfarin (Coumadin). The effectiveness of an anticoagulation clinic found that INRs were within their target range 46.1% of the time. Minor hemorrhagic and major hemorrhagic events did occur in 17.3% and 1.8% of patients, respectively.33 Hospitalization from a thromboembolic incident occurred in 2.3% of patients. Point-of-care systems, which allow for home testing of INR levels, may help to reduce potential complications of elevated INR levels by allowing patients to discover elevated levels sooner than a once monthly office visit. The timely discovery allows for quicker intervention, thus reducing the risk of elevated INR levels over a prolonged period.

A dilemma can arise when individuals taking anticoagulants, such as warfarin, need an invasive procedure. Perioperative use of warfarin inherently increases the risk of bleeding complications. Perioperative cessation of warfarin inherently increases the risk of thrombosis formation. Cessation of warfarin in certain high-risk populations for thromboembolism reoccurrence can increase this likelihood by 15% annually if warfarin is discontinued.34 Therefore, the decision to withhold warfarin during a perioperative period should be approached on a case-by-case basis. Published guidelines by the American College of Chest Physicians help direct treatment based on the presence of artificial heart valves, medical history, and nature of the invasive procedure.35

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Warfarin (Coumadin) Alternatives

The decision to use aspirin or warfarin (Coumadin) for intermediate risk of stroke can hinge on preference and anticoagulation risk.36 The landmark Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study by Mant et al37 compared the effectiveness of aspirin with that of warfarin (Coumadin) and concluded that warfarin (Coumadin) was superior to aspirin in preventing strokes in people 75 years or older with AF. The use of warfarin (Coumadin) was associated with a lower rate of intracranial hemorrhage compared with 75 mg of aspirin daily. No evidence suggested that anticoagulants were less safe than aspirin within the same age group.37 These results parallel those of other studies.6,38 A meta-analysis by Agarwal et al38 determined that major bleeding ranged from 1.40% to 3.40% annually for individuals taking warfarin (Coumadin). However, the criteria that defined major bleeding varied among the individual studies. Man-Son-Hing et al6 further remarked that an elderly individual would have to fall almost 300 times per year for warfarin (Coumadin) not to be the appropriate therapy.

Alternatives to warfarin (Coumadin) include dabigatran (Pradaxa), an oral direct thrombin inhibitor, and oral direct inhibitors of factor Xa such as rivaroxaban (Xarelto) and apixaban (Eliquis). The benefits of these newer medications include their predictable anticoagulant outcome and a less DDI profile of warfarin (Coumadin). The Randomized Evaluation of Long-term Anticoagulant Therapy trial found dabigatran 150 mg twice a day to be more effective than warfarin (Coumadin) in preventing stroke and systemic embolisms but increased major gastrointestinal bleeding risk. However, the risk of hemorrhagic stroke and intracranial hemorrhage was less than that of warfarin (Coumadin). The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation found rivaroxaban to have similar efficacy in preventing stroke and systemic embolism as compared with warfarin (Coumadin). Rivaroxaban was more efficacious in reducing intracranial hemorrhaging when compared with warfarin (Coumadin). However, the incidence of gastrointestinal bleeding was higher with rivaroxaban. Major bleeding rates between the 2 medications were determined to be similar. The Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation trial found apixaban to be more efficacious in reducing hemorrhagic stroke, major bleeding, and intracranial hemorrhage than warfarin (Coumadin). Warfarin (Coumadin) and apixaban had similar rates of gastrointestinal bleeding.39

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IMPLICATIONS FOR APN

Implications for APN Education

Advanced practice nurses should be aware of factors that hinder warfarin (Coumadin) therapy in the elderly population to ensure that elderly AF patients receive treatment according to evidence-based clinical guidelines. The literature indicates that elderly individuals with AF are at a disadvantage when warfarin (Coumadin) is not prescribed in the absence of contraindications. Advanced practice nurses need to be educated about the ways genetics, diet, and comedications affect warfarin (Coumadin) response. Knowledge of available screening tools, such as CHA2DS2-VASC and HAS-BLED, is necessary to maximize benefit and minimize risk. Warfarin (Coumadin) recipients need to be educated on the importance of INR monitoring and consistent vitamin K intake. Advanced practice nurses should also advise warfarin (Coumadin) recipients to avoid activities that could instigate a bleeding injury.

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Implications for APN Practice

The literature indicates that bleeding is the major barrier to warfarin (Coumadin) use. Medications can interact with warfarin (Coumadin) that potentiates bleeding risk. The risk for DDIs was emphasized by Snaith et al23 and Obreli-Neto et al.24 Therefore, it is imperative for prescribing APNs to assess for the possibility of DDIs. Advanced practice nurses need to use the CHA2DS2-VASC and/or HAS-BLED screening tools to determine stroke risk, recommended therapy, and determine associated bleeding risk. Gouin-Thibault et al7 indicated that computer-based dosing software was superior to traditional dosing methods at maintaining therapeutic INR levels. Advanced practice nurses should apply such technology to successfully manage warfarin (Coumadin) therapy. Dabigatran, rivaroxaban, and apixaban have proven to be effective warfarin (Coumadin) alternatives in stroke prevention according to randomized clinical trials. However, the incidence of gastrointestinal bleeding was higher with dabigatran and rivaroxaban as compared with warfarin (Coumadin). Therefore, individuals with a history of gastrointestinal bleeding may have adverse outcomes from these 2 medications.

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Implications for APN Nursing Research

Further research is indicated to investigate the dilemma of treating elderly individuals with warfarin (Coumadin). Large research studies, such as BAFTA, have demonstrated the greater effectiveness and safety of warfarin (Coumadin) use in older adults. However, the literature continues to point to the underuse of the medication in this population. More research is needed to determine a cost-effective and feasible way to test for CYP2C9 variation and VKORC1 polymorphism in potential warfarin (Coumadin) candidates. This would be a useful screening tool guiding the prescriber in determining warfarin (Coumadin) dosage based on genetic disposition.

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SUMMARY

The incidence of AF increases significantly with age. The onset of AF places an individual at increased risk of thromboembolism. Although the risk for stroke increases in elderly individuals with AF, warfarin (Coumadin) treatment is not always given because of perceived bleeding risk. The risk of bleeding is sometimes exaggerated. The decision to prescribe warfarin (Coumadin) must be determined on an individual basis. The landmark BAFTA study by Mant et al35 strengthened the argument that aspirin was less effective than warfarin (Coumadin) in preventing stroke in persons 75 years or older with AF. The study also indicated that the frequency of intracranial hemorrhage was lower with warfarin (Coumadin) when compared with aspirin. The meta-analysis by Agarwal et al36 also concluded that warfarin (Coumadin) therapy was associated with a low stroke rate. Newer medications, such as dabigatran, rivaroxaban, and apixaban, provide practitioners an alternative to warfarin (Coumadin) that may provide easier dosing schedules without frequent laboratory testing. All practitioners should use the validated CHA2DS2-VASC and HAS-BLED screening tools. Maintenance of safe and therapeutic warfarin (Coumadin) levels in the elderly population is best accomplished through anticoagulant clinics and a working partnership between the prescriber and the patient and/or the patient’s caregiver.

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Keywords:

Atrial fibrillation; Bleeding; Warfarin therapy

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