Journal of Gerontological Nursing

Geropharmacology 

Moving Beyond Warfarin—Are We Ready?: A Review of the Efficacy and Safety of Novel Anticoagulant Agents Compared to Warfarin for the Management of Atrial Fibrillation in Older Adults

Kelechi C. Ogbonna, PharmD, CGP; Kalin M. Clifford, PharmD

Abstract

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias seen in clinical practice. Stroke risk in patients diagnosed with AF increases from 1.5% in the fifth decade of life to 23.5% in patients older than 80, emphasizing the need for effective and appropriate therapies. Over the past 50 years, vitamin K antagonists—namely warfarin (Coumadin®)—have been the mainstay for stroke prevention. The introduction of dabigatran (Pradaxa®), rivaroxaban (Xarelto®), and apixaban (Eliquis®) has caused both patients and providers to question whether better alternatives to warfarin therapy exist. These agents have shown to be at least as effective as warfarin in stroke risk reduction with no need for international normalized ratio monitoring. This review will examine these newer anticoagulant agents’ safety and efficacy and provide clinical considerations for treating older adults with AF. Clinicians with patients unable to tolerate warfarin or with difficulty managing therapy will need to consider patient characteristics, cost, adherence, lack of a reversal agent, and long-term efficacy before prescribing these agents. [Journal of Gerontological Nursing, 39(7), 8–17.]

Dr. Ogbonna is Assistant Professor, Geriatrics, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, and Dr. Clifford is PGY2 Geriatric Pharmacy Practice Resident, University of Maryland School of Pharmacy, Baltimore, Maryland.

The authors have disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Kelechi C. Ogbonna, PharmD, CGP, Assistant Professor, Geriatrics, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University School of Pharmacy, 410 N. 12th Street, PO Box 980533, Richmond, VA 23298-0533; e-mail: Kcunegbuogbo@vcu.edu.

Posted Online: June 12, 2013

Abstract

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias seen in clinical practice. Stroke risk in patients diagnosed with AF increases from 1.5% in the fifth decade of life to 23.5% in patients older than 80, emphasizing the need for effective and appropriate therapies. Over the past 50 years, vitamin K antagonists—namely warfarin (Coumadin®)—have been the mainstay for stroke prevention. The introduction of dabigatran (Pradaxa®), rivaroxaban (Xarelto®), and apixaban (Eliquis®) has caused both patients and providers to question whether better alternatives to warfarin therapy exist. These agents have shown to be at least as effective as warfarin in stroke risk reduction with no need for international normalized ratio monitoring. This review will examine these newer anticoagulant agents’ safety and efficacy and provide clinical considerations for treating older adults with AF. Clinicians with patients unable to tolerate warfarin or with difficulty managing therapy will need to consider patient characteristics, cost, adherence, lack of a reversal agent, and long-term efficacy before prescribing these agents. [Journal of Gerontological Nursing, 39(7), 8–17.]

Dr. Ogbonna is Assistant Professor, Geriatrics, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, and Dr. Clifford is PGY2 Geriatric Pharmacy Practice Resident, University of Maryland School of Pharmacy, Baltimore, Maryland.

The authors have disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Kelechi C. Ogbonna, PharmD, CGP, Assistant Professor, Geriatrics, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University School of Pharmacy, 410 N. 12th Street, PO Box 980533, Richmond, VA 23298-0533; e-mail: Kcunegbuogbo@vcu.edu.

Posted Online: June 12, 2013

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias seen in clinical practice (European Heart Rhythm Association et al., 2006  ). More than 2 million patients in the United States have been diagnosed with AF, and 70% of all diagnosed patients are between ages 65 and 85 (Feinberg, Blackshear, Laupacis, Kronmal, & Hart, 1995  ; Zarraga & Kron, 2013  ). Stroke risk in patients diagnosed with AF increases from 1.5% in the fifth decade of life to 23.5% in patients older than 80, emphasizing the need for effective and appropriate therapies (Hylek, 2013  ). In clinical practice, risk assessment scales (e.g., CHADS2, HAS-BLED) are used to guide decision making, taking into account the patient’s overall risk for stroke and bleeding. Over the past 50 years, vitamin K antagonist agents—namely warfarin (Coumadin®)—have been the mainstay of anticoagulation therapy for stroke prevention in those patients determined to be high risk.

Recently, the U.S. Food and Drug Administration (FDA) approved three oral anticoagulant agents—dabigatran (Pradaxa®), rivaroxaban (Xarelto®), and apixaban (Eliquis®)—for multiple indications related to thrombus treatment and prophylaxis. Although these agents have broader applications in clinical practice, this review will focus on their use for the prevention of stroke and systemic embolism in older adults with nonvalvular AF. Alternatives to warfarin therapy have been long awaited; however, prior to declaring a warfarin successor, health care providers must determine if the benefit of switching therapy outweighs the risk. Factors such as drug-drug interactions, dietary concerns, adverse reactions, renal function, ease of medication use, and potential complications need to be evaluated within the older adult population to determine safe and effective use. This review will examine current strategies for assessing stroke and bleeding risk, the safety and efficacy of each novel anticoagulant agent, and provide clinical considerations when deciding to use warfarin or a novel anticoagulant agent in older adults with nonvalvular AF.

Risk Assessment Scales

Stratifying stroke and bleeding risks can be challenging in the older adult population. Older age is not only a risk factor for AF and stroke secondary to AF, but it is also a risk factor for bleeding events while taking any anticoagulant agent (Rockson & Albers, 2004  ). The CHADS2 risk score is one of many tools used for determining therapeutic recommendations for patients with AF (Gage et al., 2001  ). This tool is based on risk factors proven to increase the risk of stroke in patients diagnosed with AF. In the past 3 years, the CHADS2 score has been modified as additional risk factors have been found to also have a significant impact on stroke. The CHA2DS2-VASc includes additional risk factors such as vascular disease, female gender, and age (Table ) (Guyatt, Akl, Crowther, Gutterman, & Schuünemann, 2012  ; Lip, Nieuwlaat, Pisters, Lane, & Crijns, 2010  ). The additional risk factors allow clinicians to more precisely identify those patients who may benefit from anticoagulant therapy.

 
CHADS2 Versus CHA2DS2-VASc Risk Assessments for Stroke in Atrial Fibrillation 

Table 1: CHADS2 Versus CHA2DS2-VASc Risk Assessments for Stroke in Atrial Fibrillation

During the Euro Heart Survey on Atrial Fibrillation, the new CHA2DS2-VASc risk assessment was validated using the Danish National Registry. This study analyzed more than 73,000 patients diagnosed with nonvalvular AF or atrial flutter without a history of mitral or aortic valve surgery. The researchers used the CHADS2 and CHA2DS2-VASc scoring systems to evaluate the difference in risk assessment between the two tools. Applying the CHADS2 scoring to this patient population resulted in 22% of patients being classified as low risk; however, when using the CHA2DS2-VASc scoring tool for the same low-risk patient population, 39.5% met the criteria for intermediate risk (score of 1) and 21.7% met the criteria for high risk (score ⩾2), which would warrant the use of an anticoagulant agent (Olesen et al., 2011  ; Zarraga & Kron, 2013  ). The results of this study reinforce the need to reassess those patients deemed to be low or intermediate risk using more detailed tools such as the CHA2DS2-VASc score before selecting therapy (Olesen et al., 2011  ).

It is based on these risk categories that nationally recognized guidelines (i.e., Guyatt et al. [2012  ]) provide treatment recommendations (Table ). A CHADS2 score of 1 allows the provider to choose between aspirin or an anticoagulant agent, whereas, a score ⩾2 requires the use of anticoagulation (Guyatt et al., 2012  ). Currently, the American College of Chest Physicians recommends dabigatran over warfarin therapy in patients with a CHADS2 score of ⩾1.

 
Anticoagulation Based on the CHADS2 and CHA2DS2-VASc Score 

Table 2: Anticoagulation Based on the CHADS2 and CHA2DS2-VASc Score

The importance of stroke prevention cannot be overstated; however, the likelihood of bleeding must also be taken into account when considering anticoagulation. Several bleeding risk assessment scales have been created to aid clinicians in interpreting the risks of initiating therapy (i.e., HEMOR2RHAGES, Outpatient Bleeding Risk Index, and ATRIA). One scale that is widely used in clinical practice is the HAS-BLED risk assessment (Table ) (Lip et al., 2010  ; Olesen et al., 2011  ). The HAS-BLED mnemonic incorporates known risk factors that could potentially predispose a patient to bleeding. In the Euro Heart Survey on Atrial Fibrillation, researchers were able to verify the positive correlation between bleeding risk and presence of each of the HAS-BLED risk factors. This study lacked a large sample and lost a number of patients to follow up, potentially underestimating bleeding risk in this population. Despite these limitations, the HAS-BLED score can be used in conjunction with other assessment tools to better evaluate the benefit and risk of proposed therapies. A patient with a CHA2DS2-VASc score of 3 and a HAS-BLED score of 3 has an estimated stroke risk of 5.92% per 100 person years. Conversely, that same patient has an estimated bleeding risk of approximately 3.74% per 100 person years (Pisters et al., 2010  ; Zarraga & Kron, 2013  ). This estimation would inform the provider that the patient has a higher risk of having a stroke than bleeding, and anticoagulation is likely warranted. Clinicians should use risk assessment tools for bleeding and stroke to better inform decision making, which will optimize patient outcomes.

 
HAS-BLED Score for Bleeding Risk in Atrial Fibrillation 

Table 3: HAS-BLED Score for Bleeding Risk in Atrial Fibrillation

Warfarin

Warfarin is the most frequently prescribed oral anticoagulant agent in the United States, accounting for approximately 32 million prescriptions per year (IMS Institute for Healthcare Informatics, 2011  ). Despite these numbers, warfarin therapy remains underutilized for stroke prevention in older adults. Clinicians tend to weigh the risk of bleeding more heavily than the risk of thrombosis as patients increase in age (McCormick et al., 2001  ). Although highly effective in preventing stroke, the bleeding risks and complexities associated with warfarin therapy remain barriers to appropriate and effective management of AF in older adults (The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators, 1990  ; Connolly et al., 1991  ; Ezekowitz et al., 1992  ; “Risk Factors,” 1994  ; “Stroke Prevention,” 1991  ).

Mechanism and Efficacy

Warfarin’s erratic and at times unpredictable pharmacokinetic profile can be attributed to its inhibition of vitamin K–dependent clotting factors II, VII, IX, and X (Guyatt et al., 2012  ). Warfarin’s extended half life (20 to 60 hours), metabolism through the cytochrome P450 enzyme system, and renal elimination results in delayed and variable activity. However, a benefit of warfarin is that its effects can be reversed by administering vitamin K (Guyatt et al., 2012  ).

Warfarin therapy has been studied extensively and its efficacy has been well established for multiple indications such as prophylaxis of venous thrombosis, treatment of venous thromboembolism, and AF (Guyatt et al., 2012  ). The safety and efficacy of warfarin for primary stroke prevention in patients with AF was established by five pivotal randomized controlled trials. Each of the five trials observed a decrease in the risk of stroke by approximately 68% with low rates of hemorrhagic complications when international normalized ratio (INR) was well maintained (The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators, 1990  ; Connolly et al., 1991  ; Ezekowitz et al., 1992  ; Petersen, Boysen, Godtfredsen, Andersen, & Andersen, 1989  ; “Stroke Prevention,” 1991  ). For most indications, an INR of 2.0 to 3.0 is now recommended (Guyatt et al., 2012  ). It is the difficulty in maintaining an appropriate therapeutic INR that frustrates both patients and providers.

Challenges Associated with Warfarin Management

The anticipation surrounding the development of the three novel anticoagulants has stemmed from the challenges that accompany warfarin therapy. Not only are patients at risk for bleeding complications, which is to be expected with any anticoagulant agent, but there are also significant care-coordination aspects to warfarin management a patient must endure. Initiation of warfarin therapy often requires frequent blood tests, patient–provider communication, dose adjustments, and potential dietary changes, all of which may be more difficult for an older adult. Drug-drug interactions, differences in absorption, clearance, and genetic variations can also have a significant impact on the ability to maintain a patient’s INR (Mangoni & Jackson, 2004  ). Due to the challenges and the need for ongoing care coordination, the stage has been set for new anticoagulant agents that have similar efficacy but less burden for the health care team and patient.

Novel Anticoagulant Agents

Dabigatran

Dabigatran is the first new oral anticoagulant agent to be approved by the FDA since approval of warfarin in 1954. It also provides a novel approach to anticoagulation therapy, as it acts as a competitive reversible direct thrombin inhibitor (Table ). The inhibition of thrombin prevents formation of thrombi (clots), which in turn prevents strokes in AF patients. Dabigatran inhibits both free-floating and clot-bound thrombin in the blood stream to inhibit further aggregation of platelets to the clot.

 
Characteristics of Novel Anticoagulant Agents Pertaining to Atrial Fibrillation (AF) 

Table 4: Characteristics of Novel Anticoagulant Agents Pertaining to Atrial Fibrillation (AF)

Dabigatran was approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. The key clinical trial that garnered dabigatran’s FDA approval was the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (Connolly et al., 2009  ). This trial compared two fixed doses of dabigatran, 110 mg and 150 mg, with warfarin therapy to target an INR range of 2 to 3. More than 18,000 patients took part in the study. Participants were included if they had AF with another risk factor such as previous stroke, left ventricular ejection fraction <40%, or were categorized as a New York Heart Association Class II or higher. Study participants also had to be at least age 75 or ages 65 to 75 with a diagnosis of diabetes mellitus, hypertension, or coronary artery disease. The average age for participants was 71 with a mean CHADS2 score of 2.1. Also important to note, the time in therapeutic range (TTR), or the percentage of time the INR is within the goal range of 2 to 3, was 65%. Dabigatran 150 mg twice daily was superior to warfarin therapy with significantly decreased rates of stroke and systemic embolism (1.11% versus 1.69%; p < 0.001) without any significant change in bleeding rates (3.31% versus 3.57%; p = 0.32). The lower dabigatran dose of 110 mg twice daily was noninferior, as it had similar stroke and systemic embolism prevention rates (1.53% versus 1.69%; p < 0.001) with a statistically significant decrease in the risk of bleeding (2.71% versus 3.36%; p = 0.003) (Connolly et al., 2009  ).

The results for dabigatran in the RE-LY trial were positive; however, specific factors need to be evaluated as it pertains to the geriatric population. More than 80% of dabigatran is excreted renally. In the RE-LY trial, potential participants with a creatinine clearance (CrCl) less than 30 mL/minute were excluded, so data on patients with severe renal dysfunction is lacking. The FDA approved a 75-mg dose to be administered twice daily for patients with a CrCl of 15 to 30 mL/minute; however, this was never studied in clinical trials and was approved based on analysis of preclinical data (Hunchuck & Lake, 2011  ). Patients 80 and older in the 150-mg arm had similar stroke risk reduction when compared to the same patient population in the 110-mg arm while experiencing higher rates of bleeding.

RE-LY showed dabigatran was at least as effective as warfarin with similar rates of bleeding. There was a statistically significant reduction in intracranial hemorrhage (ICH) associated with the 110-mg dose (0.23%) and 150-mg dose (0.3%) (p values < 0.001) compared to warfarin. This is an important finding, particularly in a population where ICH results in death in approximately half of all cases (Connolly et al., 2009  ).

The primary reasons for discontinuation were due to gastrointestinal symptoms (i.e., abdominal pain, vomiting, and diarrhea) and gastrointestinal bleeding. The most common adverse effect reported by study participants was dyspepsia, which was reported more often in the dabigatran arm of the trial (11.8% in dabigatran 110 mg, 11.3% in dabigatran 150 mg, and 5.8% in warfarin, p < 0.001). This is thought to be due to the tartaric acid core that is formulated with dabigatran to improve acidity and in turn bioavailability (Ogbonna & Jeffery, 2013  ). Caution should be exercised in patients who have a history of ulcers or gastroesophageal reflux disease, as dabigatran may aggravate these disorders.

Recent postmarketing surveillance has revealed numerous reports of major gastrointestinal (GI) bleeding (Institute for Safe Medication Practices [ISMP], 2012  ). According to the ISMP (2012  ), 932 serious adverse drug events (ADEs) have been reported, and 293 ADEs were classified as gastrointestinal hemorrhage. Patients and providers will need to discuss the potential dyspepsia and risk of GI bleeding, and twice-daily dosing prior to initiating therapy. Dabigatran’s role in therapy remains limited due to issues discussed above as well as the lack of a reversal agent.

Rivaroxaban

Rivaroxaban is the second oral anticoagulant agent approved by the FDA. It provides an alternative mechanism from both warfarin and dabigatran. Rivaroxaban is a Factor Xa inhibitor that blocks both free-floating and bound Factor Xa within the prothrombinase complex (Table ). The prothrombinase complex functions to create thrombin (Factor II), which in turn creates clots. By inhibiting Factor Xa, this decreases clot production.

Rivaroxaban was approved for a number of indications, specifically, to reduce the risk of stroke and systemic embolism in patients diagnosed with nonvalvular AF in November 2011. The pivotal trial that helped rivaroxaban gain FDA approval was The Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (Patel et al., 2011  ). ROCKET AF was designed to compare rivaroxaban 20 mg daily with warfarin dosed to an INR range of 2 to 3. More than 14,000 participants were enrolled in the study. Patients were included if they were diagnosed with nonvalvular AF and were considered moderate or high risk. ROCKET AF defined moderate or high risk as having a documented history of stroke with two additional risk factors (i.e., hypertension, ejection fraction <35%, age >75 years, and diabetes). The median age for study participants was 73, and the average CHADS2 score was 3.5, representing a higher-risk population as compared to the dabigatran and apixaban trials. The event rate for stroke or systemic embolism was 2.1% per 100 patient years in the rivaroxaban group and 2.4% per 100 patient years in the warfarin group (hazard ratio: 0.88, 95% confidence interval (CI) [0.74, 1.03], p < 0.001), proving rivaroxaban therapy was noninferior. There was no statistically significant difference in overall bleeding events between rivaroxaban and warfarin (14.9% versus 14.5%, p = 0.44). The TTR for the warfarin group throughout the ROCKET AF trial was 55%, demonstrating poor INR control (Patel et al., 2011  ).

Although rivaroxaban was found to be equally efficacious as warfarin therapy, additional drug characteristics must be evaluated. Approximately 66% of rivaroxaban is renally excreted, with the remainder excreted via the feces. Patients with a CrCl of <30mL/minute were excluded from this trial, limiting the utility of this agent in severe renal impairment.

Rivaroxaban decreased the risk of ICH when compared to warfarin (0.8% versus 1.2%, hazard ratio: 0.67, 95% CI [0.47, 0.93], p = 0.02). Major bleeding from the GI tract was more common with rivaroxaban than with warfarin (3.2% versus 2.2%, p < 0.001), and as stated previously, the average CHADS2 score for the ROCKET AF trial was 3.5, signifying that this patient population had more comorbidities and an increased likelihood for the primary outcome event of stroke or systemic embolism. As discussed with dabigatran, TTR is an important parameter to assess quality of warfarin therapy. The TTR of 55% in ROCKET AF is lower than that seen in RE-LY and previous warfarin studies. The authors of ROCKET AF acknowledged the relatively poor control attributing the low TTR values to differences in warfarin management at numerous study facilities across 45 countries (Connolly et al., 2009  ; Patel et al., 2011  ; Rose et al., 2011  ). Nonetheless, this finding questions rivaroxaban’s noninferiority in a patient population with well-managed warfarin therapy.

Additional factors that differentiate rivaroxaban from other novel anticoagulant agents are the once-daily dosing, which may ease medication burden and increase overall adherence to prescribed therapy. As seen with dabigatran, rivaroxaban does not require monitoring and lacks a reversal agent. Rivaroxaban is as effective as warfarin and decreases risk of ICH. Again, the lack of a reversal agent, potential for GI bleeding, and renal dependency limit rivaroxaban’s use in the older adult population.

Apixaban

Apixaban is the newest oral anticoagulant agent approved by the FDA in November 2012. It is classified as an anti-Xa inhibitor, similar to rivaroxaban, except that apixaban is more selective for Factor Xa (Table ). Apixaban inhibits both free-floating and bound Factor Xa within the prothrombinase complex. As mentioned above, by preventing the formation of the prothrombinase complex, apixaban inhibits the formation of thrombin and clots, therefore preventing strokes.

Apixaban has been approved for various indications, including risk reduction of stroke and systemic embolism in patients diagnosed with nonvalvular AF. The landmark study demonstrating apixaban’s efficacy is the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation Trial (ARISTOTLE) (Granger et al., 2011  ). This study compared the use of apixaban 5 mg twice daily (also apixaban 2.5 mg twice daily for patients who met two of the three criteria: age older than 80, serum creatinine ⩾1.5 mg/dL, or body weight <60 kg) to warfarin therapy (INR 2 to 3) (Connolly et al., 2011  ; Granger et al., 2011  ). More than 18,000 participants were included with a diagnosis of AF and at least one additional risk factor (age ⩾75, previous stroke, symptomatic heart failure in past 3 months, left ventricular ejection fraction <40%, diabetes mellitus, or hypertension requiring pharmacological therapy). The average age of participants was 70, and the average CHADS2 score of patients was 2.1. Apixaban was proven superior to warfarin therapy in stroke risk reduction (1.27% events per year versus 1.60% events per year; hazard ratio: 0.79, 95% CI [0.66, 0.95], p = 0.01) with a statistically significant reduction in major bleeding (2.13% events per year versus 3.09% events per year; hazard ratio: 0.69, 95% CI [0.60, 0.80], p < 0.001). The TTR in the ARISTO-TLE trial was calculated to be 62% (Granger et al., 2011  ). Based on the study results, apixaban significantly decreased both stroke and bleeding.

ARISTOTLE identified a significant reduction in ICH risk with apixaban therapy (0.33% event rate versus 0.8% event rate, hazard ratio: 0.42, 95% CI [0.30, 0.58], p < 0.001) (Granger et al., 2011  ). Patients were excluded from the ARISTOTLE trial if they had a CrCl <25 mL/minute. Upon subgroup analysis, approximately 500 patients received the renal dosing of apixaban (2.5 mg twice daily) during the study. The authors found a decrease in stroke risk at the reduced dose of apixaban 2.5 mg twice daily (1.7% event rate per year versus 3.3% event rate per year) when compared with warfarin. An important differentiating characteristic from the other novel anticoagulant agents is apixaban’s reduction in mortality. The reduction in all-cause mortality was 3.52% per year for apixaban versus 3.94% per year for warfarin (p = 0.047).

Apixaban requires twice-daily dosing, and approximately 27% of the drug is cleared renally. Regular laboratory monitoring for anticoagulation is not required for apixaban, similar to both dabigatran and rivaroxaban. Apixaban reduces the risk of stroke and bleeding as well as all-cause mortality.

Considerations for Clinical Practice

Anticoagulant Reversal

The lack of a reversal agent for each of the novel anticoagulant agents is a concern for both patients and providers. Unlike warfarin, vitamin K cannot be given to reverse the effects of any of the new agents due to their mechanism of action. If a patient experiences bleeding while taking any of the new agents, activated charcoal, activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of coagulation Factors II, IX, or X may be considered, although their use has not been rigorously evaluated in clinical trials (Kaatz & Crowther, 2013  ). Dialysis may be an option for patients with bleeding on dabigatran therapy due to its low affinity for protein binding, with approximately 60% of the drug dialyzed over 2 to 3 hours.

The development and testing of antidotes for the novel anticoagulant agents is ongoing. Various strategies have been suggested, such as monoclonal antibodies and molecular decoys; however, their availability is not expected any time in the near future (Kaatz & Crowther, 2013  ). Older adults with complex conditions often have multiple comorbidities and an increased risk of injurious falls. These factors alone are often enough for clinicians to prevent the initiation of any anticoagulant therapy. Until an antidote is thoroughly tested and approved, the inability to reverse anticoagulation with the newer agents in this complex patient population warrants careful consideration.

Study Population

When extrapolating trial data to clinical practice it is important to consider the study population. In all three clinical trials (RE-LY, ROCKET AF, ARISTOTLE) less than half of the study participants were older than 75, and less than a quarter were 80 or older (Mannucci, 2013  ) (Table ). The rate of enrollment emphasizes the need to re-evaluate use of the novel anticoagulant agents in the oldest-old population, as we have limited data to support their use.

 
Enrollment Rates of Older Adults in Major Atrial Fibrillation (AF) Clinical Trials 

Table 5: Enrollment Rates of Older Adults in Major Atrial Fibrillation (AF) Clinical Trials

In addition to considering age, a patient’s weight is also another important parameter that may dissuade the use of the novel anticoagulant agents. The average weight in RE-LY, ROCKET AF, and ARISTOTLE was 82.5 kg (181.5 lbs), 82.1 kg (180.6 lbs), and 82 kg (180.4 lbs), respectively (Connolly et al., 2009  ; Contractor, Levin, Martinez, & Marchlinski, 2013  ; Frost et al., 2013  ; Granger et al., 2011  ; Patel et al., 2011  ). Dabigatran studies have shown an approximate 20% decrease in trough concentration in patients who weigh more than 100 kg. In patients taking rivaroxaban, a 24% increase in the maximum concentration has been noted in patients who weigh ⩽50 kg. Finally, an increase and decrease in the area under the curve (AUC) for patients taking apixaban has been observed based on patient weight. Apixaban therapy in patients ⩽50 kg resulted in a 20% increase in AUC and patients ⩾120 kg resulted in a 20% decrease in AUC (Connolly et al., 2009  ; Contractor et al., 2013  ; Frost et al., 2013  ; Granger et al., 2011  ; Patel et al., 2011  ). Although the clinical implications are thought to be insignificant, body weight has the potential to influence pharmacokinetics of all three novel anticoagulant agents.

Patient Adherence

The ability for a patient to adhere to a warfarin regimen and maintain a therapeutic INR has always been essential for achieving positive outcomes. Nonetheless, a missed dose is not always detrimental to the patient or to sustaining a therapeutic INR. Warfarin’s extended half life and effect on clotting factors does not cause an immediate cessation in anticoagulant activity. With the newer agents, the half life and duration of activity is well defined. The room for error with dabigatran, rivaroxaban, and apixaban is greatly reduced when compared to warfarin. Patients and providers must understand the importance of adherence and potential consequences of missed doses. Akin to warfarin, rivaroxaban is dosed once per day. Dabigatran and apixaban, however, are dosed twice daily, which may not only increase pill burden but may also be more difficult for an older patient to remember. Adherence is important for any type of medication therapy but essential for patients on dabigatran, rivaroxaban, or apixaban therapy.

Renal Impairment

Patients with CrCl <30 mL/minute were excluded in RE-LY and ROCKET AF, and patients with CrCl <25 mL/minute were excluded in ARISTOTLE. The impact of severe renal dysfunction on dosing and anticoagulant activity has not been thoroughly evaluated. Pharmacokinetics and pharmacodynamics studies of dabigatran have found AUC levels to be 1.5-, 3.2-, and 6.3-fold higher in participants with mild, moderate, and severe renal impairment, respectively (Mueck et al., 2011  ). Patients with CrCl of 30 to 50 mL/minute had a 43% increase in apixaban exposure when compared to patients without renal impairment (Leil et al., 2010  ). These studies highlight the importance of appropriate patient selection and potential impact of drug therapy in patients with declining renal function. Furthermore, suggested dose adjustments for dabigatran are solely based on pharmacokinetic modeling and have not been evaluated in clinical trials. Therefore the FDA’s approval of dabigatran 75 mg twice daily for patients with CrCl of 15 to 29 mL/minute should be used cautiously.

Implications for Geriatric Nurses

Nurses play a critical role in monitoring anticoagulant therapy. They are often on the frontlines assessing patients for signs or symptoms of bleeding and stroke. Adherence to the novel anticoagulant agents is essential for desired therapeutic effect. Unlike warfarin, the inability to monitor INR to determine the degree of anticoagulation is a challenge with these newer agents. Thus, the role of nurses to optimize adherence will become instrumental in ensuring proper anticoagulation.

Preventing ADEs with these novel anticoagulant agents will rely heavily on patient education. As patients begin therapy or transition from one setting to another, nurses can ensure that both the patient and caregiver demonstrate understanding regarding administration and monitoring of these novel anticoagulant agents. Nurses should emphasize the importance of provider notification if the patient experiences a fall or any signs of stroke or bleeding. Because there is no antidote for any of these agents, prompt identification of patients with any sign of bleeding and subsequent referral will be key in preventing complications. Finally, kidney function in older adults decreases over time and can often fluctuate. It is important that nurses monitor for conditions that can affect kidney function such as dehydration, changes in blood pressure, and acute illness. Although routine monitoring is not required, it is imperative that nurses remain vigilant in assessing an older adult’s health status, adherence, and renal function while taking any of these agents.

Conclusion

Dabigatran, rivaroxaban, and apixaban offer an exciting alternative to warfarin therapy. All three agents demonstrate comparable or superior efficacy in large clinical trials when compared to warfarin. The role of these agents in primary stroke prevention for older adults with AF, however, remains uncertain. Although these agents require less monitoring and have shown a decrease in ICH, the lack of a reversal agent and limited evidence in an older adult population with multiple comorbidities suggest a cautious approach by the health care team on weighing the risks and benefits. Patients who are well maintained on warfarin therapy will likely see little to no benefit by switching to one of the newer agents. For those patients unable to tolerate warfarin or with difficulty managing warfarin therapy, the use of novel anticoagulant agents will need to be addressed on a case-by-case basis. Overall, additional evidence is needed evaluating the newer anticoagulant agents in older adults with multiple comorbidities. At this time, we may not be ready to move beyond warfarin, but significant steps have been made to find its successor.

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CHADS2 Versus CHA2DS2-VASc Risk Assessments for Stroke in Atrial Fibrillation

CHADS2 Risk FactorScoreCHA2DS2-VASc Risk FactorScore
Congestive heart failure (CHF)1CHF or left ventricular ejection fraction <40%1
Hypertension1Hypertension1
Age >751Age >752
Diabetes mellitus1Diabetes mellitus1
Stroke or transient ischemic attack (TIA)2Stroke/TIA/thromboembolism2
Vascular disease1
Age 65 to 741
Female gender1
 

Anticoagulation Based on the CHADS2 and CHA2DS2-VASc Score

Risk CategoryACCP RecommendationESC Recommendation
CHADS2
Score = 0No therapyRefer to CHA2DS2-VASc scoring
Score = 1DabigatranaRefer to CHA2DS2-VASc scoring
Score ⩾2DabigatranaVKA (goal INR = 2.0 to 3.0)
CHA2DS2-VASc
Score = 0No therapy
Score = 1VKA (goal INR = 2.0 to 3.0)
Score ⩾2VKA (goal INR = 2.0 to 3.0)
 

HAS-BLED Score for Bleeding Risk in Atrial Fibrillation

HAS-BLED Risk FactorScore
Hypertension (uncontrolled, systolic blood pressure >160 mm Hg)1
Abnormal renal/hepatic function1 point for each
Stroke1
Bleeding (anemia, predisposition to bleeding)1
Labile INR (time in therapeutic range >60%)1
Age >651
Medications (antiplatelet agents, nonsteroidal anti-inflammatory agents) and alcohol use1 point for each
 

Characteristics of Novel Anticoagulant Agents Pertaining to Atrial Fibrillation (AF)

Drug (Brand Name)TargetDoseFDA-Approved IndicationsDrug-Drug InteractionsSafety ConcernsAdministration Concerns
Dabigatran (Pradaxa®)Thrombin150 mg twice dailyNonvalvular AF: prophylaxisProton pump inhibitors decrease absorption Possible inter-actions with P-glycoprotein inhibitors and inducersIncreased risk of GI bleeding Renal impairment:

Reduce dose to 75 mg twice daily if CrCl <15 to 30

Not recommended if CrCl <15

Do not chew or break capsules Medication should be kept in original bottle (do not store in pill-box) Do not take missed dose if <6 hours before next dose
Rivaroxaban (Xarelto®)Factor Xa20 mg dailyNonvalvular AF: prophylaxis VTE prophylaxis: Patients undergoing hip or knee replacement surgery Treatment of acute DVT/PE and prevention of recurrent VTEPotent 3A4 and P-glycoprotein inhibitors augment anticoagulation effect (e.g., ketoconazole, clarithromycin, ritonavir)Increased risk of GI bleeding Renal impairment:

Reduce dose to 15 mg daily if CrCl = 30 to 49

Avoid in moderate or severe hepatic impairment (Child-Pugh Class B and C)

Caution with abrupt discontinuation (increased risk of stroke)

Should be taken with food If missed dose, take as soon as possible on same day
Apixaban (Eliquis®)Factor Xa5 mg twice dailyNonvalvular AF: prophylaxisPotent 3A4 and P-glycoprotein inhibitors augment anticoagulation effect (e.g., ketoconazole, clarithromycin, ritonavir)Increased risk of GI bleeding Renal impairment:

Reduce dose to 2.5 mg daily if age ⩾80; weight ⩽60 kg, or SCr ⩾1.5

CrCl = 30 to 49

Avoid in moderate or severe hepatic impairment (Child-Pugh Class B and C)
If missed dose, take as soon as possible on same day
 

Enrollment Rates of Older Adults in Major Atrial Fibrillation (AF) Clinical Trials

StudyMedian Age% Age >75% Age >80
RE-LY714117
ROCKET AF734325
ARISTOTLE7031
 
 

10.3928/00989134-20130605-01

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