Clinical Review Dabigatran for Stroke Prevention in Nonvalvular Atrial Fibrillation: Focus in the Geriatric Population Luigi Brunetti, Clement Chen, Jentora White Objective: To evaluate the safety and efficacy of dabigatran for stroke prevention in the elderly population. Data Sources: MEDLINE (1948-June 2013), Web of Science (1980-June 2013), and Google Scholar were used to identify relevant literature. Search terms included dabigatran, dabigatran etexilate, geriatric, elderly. Study Selection: All articles evaluating the use of dabigatran in the elderly were considered for inclusion. Data derived from controlled clinical studies were given priority for inclusion. Data Extraction: Only the Randomized Evaluation of LongTerm Anticoagulant Therapy trial has evaluated dabigatran etexilate for the prevention of stroke in nonvalvular atrial fibrillation. A post hoc analysis of this study was completed to identify the risks and benefits of therapy in patients 75 years of age and older. Numerous case reports and case series have been published that suggest an increased risk of bleeding in the elderly. Large observational studies, however, have not supported the hypotheses generated by these case reports. Data Synthesis: Since the approval of dabigatran etexilate, numerous case reports have suggested the potential dangers of bleeding complications, especially given that there is no known antidote. Observational studies have challenged these case reports and suggest that the increased risk of bleeding is similar or lower compared with warfarin therapy. The increased reporting of bleeding complications may be a result of reporting bias. Conclusions: Advanced age alone should not exclude the use of dabigatran. Clinicians should base their decision on patient characteristics and careful assessment of risk versus benefit.

Key words: Anticoagulation, Atrial fibrillation, Bleeding,

Dabigatran, Nonvalvular atrial fibrillation, Stroke. Abbreviations: ACCF = American College of Cardiology Foundation, ACCP = American College of Chest Physicians, AF = Atrial fibrillation, AHA = American Heart Association, apt = Activated partial thromboplastin time, ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation, CHADS2 = Congestive heart failure, hypertension, age > 75 years, diabetes mellitus, stroke, CI = Confidence interval, Clcr = Creatinine clearance, ECT = Ecarin clotting time, FDA = Food and Drug Administration, FEIBA = Factor eight inhibitor bypass activity, FFP = Fresh frozen plasma, GI = Gastrointestinal, HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile INR, Elderly and concomitant drug/alcohol use, HEMORR2HAGES = Hepatic or Renal disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Rebleeding, Hypertension, Anemia, Genetic factors, Excessive fall risk and Stroke, HR = Hazard ratio, INR = International normalized ratio, ISMP = Institute for Safe Medication Practices, NVAF = Nonvalvular atrial fibrillation, OBRI = Outpatient Bleeding Risk Index, PCC = Prothrombin complex concentrate, P-gp = P-glycoprotein, RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy, rVIIa = Recombinant factor VIIa, sCr = Serum creatinine, TT = Thrombin time. Consult Pharm 2014;29:169-78.

Introduction Atrial fibrillation (AF) affects approximately 0.4% to 1% of the general population of the United States.1 The incidence of AF increases with age, affecting more than 8% of patients older than 80 years.1 A diagnosis of AF confers a higher risk for a cardioembolic event such as a stroke or systemic embolism. Furthermore, patients with AF who develop a stroke have a higher mortality rate compared with those without AF suffering a stroke.1 Anticoagulation therapy is of great importance in mitigating the risk of stroke in high-risk AF patients, particularly the elderly.2 Although the elderly are inherently at an increased risk of bleeding regardless of anticoagulant choice, they are also at an increased risk of stroke.2 This population, however, is

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Clinical Review often not anticoagulated despite proven efficacy in reducing stroke.3 There is some hesitancy to use anticoagulants in this population because of the greater fear of causing a potential bleed from anticoagulants rather than the fear of causing a stroke from lack of treatment.3-7 Since the introduction of target-specific anticoagulants to the treatment armamentarium, case reports of bleeding complications have been widespread. Many of these reports fail to clearly delineate patient risk factors for bleeding, including age and renal function.8 Nonetheless, the case reports provide clinicians heightened awareness when assessing a patient’s risk of bleeding. Recent observational studies suggest that the risk of bleeding with dabigatran may be lower compared with warfarin.8-11 Ultimately, appropriate patient selection and prevention of complications is critical to reduce the likelihood of patient harm. The aim of this review is to summarize the dabigatran literature pertaining to the geriatric population, identify risk factors for dabigatran-related bleeding, and provide recommendations for the management of bleeding complications.

Dabigatran Overview For more than 50 years, warfarin has been the mainstay of anticoagulant therapy for the prevention of thromboembolic events. It is, however, fraught with many intricacies making patient management challenging. Dabigatran etexilate, a prodrug of dabigatran, is a novel, oral, direct thrombin-inhibitor approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).12 Dabigatran binds to both bound and unbound fibrin and prevents the conversion of fibrinogen into fibrin.13 Additionally, the amplification of the coagulation cascade, cross-linking of fibrin monomers, platelet activation, and inhibition of fibrinolysis are attenuated with dabigatran.13,14 Of the currently approved oral anticoagulants, dabigatran is the only direct thrombin-inhibitor (Figure 1).15,16 Some of the limitations of dabigatran include the lack of an antidote in the event of bleeding, limited outcome data in special populations, and a paucity of clearly defined parameters to gauge the degree of anticoagulation.17 In comparison with warfarin, dabigatran offers

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many advantages, making it a more ideal anticoagulant.18 Some of the advantages of dabigatran include fixed dosing, predictable pharmacokinetics, no routine monitoring of coagulation assays, fewer drug interactions, and rapid onset of action. The 2011 American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society (AHA/ACCF/HRS) treatment guideline endorses dabigatran as an alternative option for prevention of stroke secondary to NVAF.19 The American College of Chest Physicians (ACCP) guideline suggests that for patients with NVAF (including paroxysmal AF) requiring oral anticoagulation, dabigatran should be used over adjusted-dose warfarin in patients without mitral stenosis, coronary artery disease, and stent-placement (Grade 2B, weak recommendation).20 The safety and efficacy of dabigatran was established in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial.21 Patients were randomized to either warfarin targeted to an international normalized ratio (INR) of 2-3 (N = 6,022), dabigatran 150 mg twice daily (N = 6,076), or dabigatran 110 mg twice daily (N = 6,015). Patients treated with dabigatran 150 mg twice daily had a 35% relative reduction in stroke or systemic embolism versus warfarin (hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.52-0.81; P = 0.0001). Major bleeding was similar between patients receiving dabigatran 150 mg twice daily and standard warfarin therapy (3.11%/ year versus 3.36%/year, respectively; P = 0.31). Major gastrointestinal (GI) bleeding was significantly higher in patients treated with dabigatran 150 mg twice daily compared with warfarin (1.51%/year versus 1.02%/year, respectively; P < 0.001). All-cause mortality was 4.13% per year with warfarin compared with 3.75% per year with dabigatran 110 mg and 3.64% per year with dabigatran 150 mg, although these were not statistically significant. A large proportion of geriatric patients were enrolled in the RE-LY trial. The mean age of patients enrolled in RE-LY was 71 years; however, only 16.7% (3,016/18,113) of the patients were older than 80 years of age.22 Few patients weighed less than 63 kg, and less than 20% had a creatinine clearance (Clcr) of ≤ 50 mL/min. In terms of stroke

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Figure 1. Overview of Steps in the Coagulation Cascade and Mechanism of the Target Specific Oral Anticoagulants

In response to an endothelial injury, tissue factor (TF) is released and reacts with Factor VII to initiate coagulation. The prothrombinase complex (Factor Xa and Factor Va) leads to the production of thrombin (Factor IIa). Thrombin is responsible for fibrin generation and ultimately the formation of a hemostatic plug. Dabigatran is a direct thrombin inhibitor (Factor IIa). Apixaban and rivaroxaban are direct Factor Xa inhibitors. Source: References 13,15.

risk, 31.9% of patients had a CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke) score of 0-1. Although the RE-LY study did include geriatric patients, the patients included were relatively low risk in terms of stroke risk and had mild-to-moderate renal impairment. Extrapolation of the RE-LY study results warrants caution, especially in higher-risk patients with additional risk factors for bleeding complications, namely renal impairment. Furthermore, based on findings from RE-LY, clinicians should be cautious if contemplating the use of dabigatran in a patient with a history positive for GI pathology. The risk-to-benefit ratio may be unfavorable in this setting and, therefore, dabigatran may be best avoided.

Evaluating Stroke and Bleeding Risk The CHADS2 score may be used to calculate stroke risk.23 Patients receive one point for having any of the following conditions: heart failure, hypertension, 75 years of age or older, or diabetes mellitus. Patients with a history of prior stroke, transient ischemic attack, or thromboembolism receive two points: the higher the score, the greater the stroke risk. A calculated score of 1 correlates with an annual stroke risk of 2.8% (95% CI 2.0-3.8). The ACCP antithrombotic therapy guideline recommends oral anticoagulant therapy in patients with a CHADS2 score of 1 or greater.24 More recently, the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes

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Clinical Review mellitus, stroke, vascular disease, 65 to 74 years of age, gender category) has been proposed. This scoring system has better predictive value and accounts for additional risk factors.25 The European Society of Cardiology endorses the CHA2DS2-VASc scoring system and it is gaining popularity in the United States as well. The geriatric population is at a greater risk of bleeding irrespective of the anticoagulant used. Some inherent risk factors in this population include greater risk for renal impairment, drug interactions, and the presence of comorbidities. Several tools are available to gauge the patient’s risk of bleeding including OBRI (Outpatient Bleeding Risk Index), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), HEMORR2HAGES (Hepatic or renal disease, Ethanol abuse, Malignancy, Older age, Reduced platelet count or function, Re-bleeding, Hypertension, Anemia, Genetic factors, Excessive fall risk and Stroke), and HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, and concomitant Drug/alcohol use).23,26-28 These tools may help the clinician determine if the benefit of anticoagulation outweighs the risk of bleeding. The current ACCP guideline recommends against using these validated tools alone to determine whether to anticoagulate patients.24 Clinicians should use these tools in addition to clinical judgment when determining bleeding risk. Of the risk stratification tools, HAS-BLED appears to have the greatest accuracy and best correlation with intracranial hemorrhage.29,30

Risk Factors for Bleeding in the Elderly Renal Disease Renal dysfunction increases the risk of stroke formation and bleeding, as platelets become more dysfunctional secondary to exposure to increased uremic-like toxins.31 Dabigatran is highly dependent on renal clearance (~ 80%).12 As such, renal dysfunction results in altered pharmacokinetics (Table 1). The Food and Drug Administration (FDA)-approved dosing strategy for dabigatran is 150 mg twice daily in patients with a Clcr > 30 mL/min, 75 mg twice daily in patients with severe renal impairment

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(Clcr 15-29 mL/min), and is contraindicated in patients with a Clcr < 15 mL/min.12 By comparison, the Canadian and the European Medicines Agencies have listed patients with a Clcr < 30 mL/min (severe renal impairment) as a contraindication for dabigatran therapy.32,33 Furthermore, the RE-LY study excluded patients with a Clcr < 30 mL/min.21 The RE-LY trial evaluated two dosage strengths: 1) 150 mg by mouth twice daily and 2) 110 mg by mouth twice daily. The 110 mg dosage strength has not been approved in the United States although it demonstrated noninferiority to warfarin with a similar safety profile. Some clinicians have suggested that the FDA review its prior decision since many of the postmarketing bleeding events have been reported in elderly patients with renal impairment.34-36 Geriatric patients will have some degree of renal impairment ranging from mild to severe and often have multiple risk factors placing them at risk for bleeding complications.37 Further, dosage selection may be complicated by the overestimation of renal function in the elderly with the Cockcroft-Gault equation.38 Additional research is warranted to determine what method for renal assessment correlates best with dabigatran pharmacokinetics. The United States-approved dosage for severe renal impairment was derived during the approval phase of dabigatran using a simulation pharmacokinetic model.39,40 Pharmacokinetic simulations estimated that dabigatran 75 mg twice-daily in severe renal impairment will produce similar peak and trough concentrations compared with the 150 mg twice-daily dosage in moderate renal impairment. However, these simulations were performed based on data from a very small number of subjects with severe renal impairment.39 These predictions have not been confirmed in an actual pharmacokinetic study to date. Clinicians should consider choosing alternative therapies in elderly patients with a Clcr < 30 mL/min until clinical data confirming the safety and efficacy of dabigatran 75 mg twice daily are available.

Advanced Age Changes in pharmacokinetics and pharmacodynamics are common in the geriatric population. Some changes in pharmacokinetics include a reduced renal or hepatic

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Table 1. Impact of Renal Impairment on Dabigatran Pharmacokinetics Renal Function Normal Mild Moderate Severe*

Clcr (mL/min) ≥ 80 50-80 30-50 15-30

Increase in AUC

1x 1.5x 3.2x 6.3x

T 1/ (h)

Increase in Cmax

1x 1.1x 1.7x 2.1x

2



13 15 18 27

*Patients with severe renal impairment were not studied in RE-LY. Dosing recommendations in subjects with severe renal impairment are based on pharmacokinetic modeling. Abbreviations: AUC = Area under the curve, Clcr = Creatinine clearance, Cmax = Peak plasma concentration, RE-LY = Randomized Evaluation of Long Term Anticoagulant Therapy, T1/2 = Half-life. Source: Reference12.

clearance and an increase in the volume of distribution of drugs.41 These changes can prolong the elimination halflife. Furthermore, geriatric patients may also have a greater sensitivity to many medications, comorbidity burden, and medication burden. As age increases, the risk of bleeding increases as does the risk of AF and subsequent stroke. The increased risk of bleeding likely results from the increased risk of falls and the number of comorbidities.3 Estimating the benefits of anticoagulation in terms of stroke prevention versus the risk of bleeding is a dilemma that influences both physicians’ willingness to prescribe and patients’ willingness to take anticoagulation. Overestimating the risks of bleeding in electing against using anticoagulants puts patients at a much higher risk for stroke.3 Clinicians should evaluate the patient’s desire to take anticoagulants and his/her likelihood to remain compliant to the medication. Addressing patient parameters is especially important in mitigating the inherent risks of bleeding and can help address the hesitance involved in prescribing anticoagulants. There are limited data evaluating dabigatran in the elderly. To date only one pharmacokinetic study evaluated the pharmacokinetic and pharmacodynamic profile of dabigatran in healthy “elderly” (defined as older than 65 years of age) subjects. The study found that the time to steady state ranged from 2 to 3 days, correlating to a half-life of 12-14 hours, and peak concentrations

(256 ng/mL females, 255 ng/mL males) were reached after a median of 3 hours (range, 2.0-4.0 hours).42 A historical comparison of these data with young healthy subjects indicates an increased bioavailability of 1.7- to 2-fold in elderly subjects. The clinical impact of advanced age was evaluated in a post hoc analysis of the RE-LY trial. Eikelboom and colleagues reported that patients 75 years of age and older had a greater incidence of GI bleeding (but not intracranial), irrespective of renal function, compared with patients on warfarin (1.85%/year versus 1.25%/year, respectively; P < 0.001).43 Additional data are needed to justify dabigatran dosing strategies in the elderly population. In particular, the United States strategy to use full-dose dabigatran in elderly patients requiring anticoagulation requires confirmation.44 In both Canada and Europe, product labeling suggests a dosage reduction in patients of advanced age.32,33 Bleeding complications can occur at any time after the initiation of anticoagulants. The complications are more prevalent in the first several months after initiation; therefore, patient education and early follow-up are crucial.45 In the elderly population, providing medication counseling to the caregiver may also help mitigate the bleeding risk.

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Clinical Review Drug Interactions Dabigatran has a fairly low oral bioavailability of 3% to 7%.12 Dabigatran etexilate (but not dabigatran) is a substrate of the P-glycoprotein (P-gp) efflux transport system, but does not have major associations with the cytochrome P450 system.12,46 Once dabigatran etexilate is converted to active form, it is no longer subject to P-gp-mediated drug interactions. Administration of dabigatran two hours or more before a P-gp inhibitor or inducer should minimize the impact of dabigatran absorption.47 This strategy should be more beneficial when dabigatran is administered concomitantly with short-acting P-gp inhibitors and inducers. Medications that inhibit P-gp increase the level of dabigatran absorption and may increase the risk of bleeding. Ketoconazole, amiodarone, verapamil, quinidine, dronedarone, and clarithromycin are P-gp inhibitors that increase dabigatran peak plasma concentration and area under the curve. In patients with severe renal impairment (Clcr 15-29 mL/min), it is best to avoid concomitant P-gp inhibitors.12 For the systemic azole antifungals and dronedarone, consider reducing the dose of dabigatran to 75 mg twice daily in patients with moderate renal impairment (Clcr 30-50 mL/min). Observational data are reassuring and confirm that clinicians often reduce the dabigatran dose in the setting of P-gp interactions.48 Antiplatelet agents do not have direct effects on dabigatran pharmacodynamic parameters such as thrombin time (TT) and ecarin clotting time (ECT), but have an additive risk of bleeding. Unlike warfarin, bridge therapy with heparin is unnecessary in most cases with dabigatran and may unnecessarily increase bleeding risk.

Postmarketing Reports of Bleeding Complications: Real or Reporting Bias? Although dabigatran possesses many of the attributes of an ideal anticoagulant, several postmarketing reports of bleeding complications have challenged the safety of dabigatran, especially in vulnerable populations.36,37,49-56 The increased reporting may be a result of the Weber effect associated with the launch of a new drug and/or temporal bias secondary to increased media attention.8,10,57 More recently, large observational studies have affirmed that

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dabigatran is as safe as or safer than warfarin therapy.8,9,11 Berger and colleagues reported that in the 15 and 25 patients who presented with bleeding complications and were selected for randomization during a six-month period to receive dabigatran or warfarin, respectively, mortality was similar and those in the dabigatran group had a shorter length of stay (3.5 vs. 6.0 days).10 Patients in the dabigatran group also received fewer units of fresh frozen plasma (FFP), were older, received less red blood cell transfusions, and had fewer major bleeding events. It is also interesting to note that patients were older, 77 and 70 years of age, in the dabigatran and warfarin groups, respectively. An Institute for Safe Medication Practices (ISMP) medication safety alert provided a summary of serious dabigatran adverse events voluntarily reported through the FDA MedWatch program in the first quarter of 2011.34 The report stated that of the 932 cases, there were 120 deaths, 25 cases of permanent disability, and 543 cases requiring hospitalization. Of those events, 505 cases involved a hemorrhage associated with dabigatran. ISMP describes these patients as having a median age of 80, and a quarter of those were 84 years of age or older. The alert highlights the need for a reversal agent, the limitations associated with the approved dosages, and the generalizability of the RE-LY trial results. Harper and colleagues reported that during a two-month period, an audit of bleeding events revealed 22 patients who had a bleeding episode while receiving a reduced dose. Two-thirds of those patients were older than 80 years of age, 58% had at least moderate renal impairment defined as Clcr of 30-50 mL/ min, and one-half weighed less than 60 kg.37 Although valuable, the generalizability of these reports is limited by small sample size, potential confounding, and reporting bias. Recently, several observational studies provided more reassuring data.8,9,11 Larsen and colleagues performed a prospective propensity-matched cohort study comparing dabigatran 150 mg and 110 mg twice daily (4,978) with warfarin (treatment-naive) (8,936) using data from the Danish National Patient Register.9 In their analysis, stroke and systemic embolism were not statistically different, and adjusted mortality was significantly lower in both the dabigatran 150 and 110 mg twice-daily groups when

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compared with warfarin. Furthermore, pulmonary embolism, intracranial bleeds, and incidence of myocardial infarction were all significantly lower in both dabigatran groups versus warfarin. The risk of GI bleed was lower with dabigatran 110 mg twice daily and similar with dabigatran 150 mg twice daily compared with warfarin. In a subgroup of patients followed for one year, no increased risk of bleeding was evident. This large observational study did not identify any concern with excess bleeding or myocardial infarction in dabigatran-treated patients. Sorensen and colleagues performed a similar analysis using the same dataset and included both warfarin-naive and -experienced patients.11 The study affirmed that dabigatran use was safe in warfarin-naive patients. There was an increased risk of thromboembolism in the dabigatran groups among warfarin-experienced patients. The authors concluded that this increased risk may be related to patient selection and drug-switching practices. The analysis highlighted that there were frequent deviations in the recommended use of dabigatran. FDA performed a review of bleeding rates and warfarin using insurance claim data and administrative data from the Mini-Sentinel database for the time period of October 2010 through December 2011.8 Both GI bleeding (1.6 per 100,000 days at risk vs. 3.5 per 100,000 days at risk) and intracranial hemorrhage (0.8 days at risk vs. 2.4 days at risk) were not higher in patients with AF treated with dabigatran versus warfarin. As with all analyses of claims data, the analysis is limited by the inability to adjust for confounding.

Treatment Options for Managing Dabigatran-Related Bleeding The optimal management of dabigatran-related bleeding has not been adequately defined. Furthermore, dabigatran does not have an antidote.58 A monoclonal antibody is currently in phase II studies and has demonstrated positive results.59 Current approaches to managing bleeding complications are based mainly on preclinical data and case reports. Despite limited data, several treatment options may be considered in addition to discontinuation of therapy. These options include activated charcoal, tranexamic acid,

FFP, prothrombin complex concentrate (PCC), factor eight inhibitor bypass activity (FEIBA®, activated PCC), factor VIIa, and hemodialysis.58,60,61 Before considering any of these treatment options, it is critical to evaluate the risk: benefit ratio of the chosen modality, especially when considering hemostatic agents. Administration of a hemostatic agent to a patient already at risk for thrombosis may further propagate the risk. Determining the severity of the bleeding event will aid in selecting the most appropriate treatment course. Major, life-threatening bleeding requires urgent care and the use of hemostatic agents. Mild-to-moderate nonmajor bleeding may be managed with symptomatic care alone. When a patient presents with a bleeding event, clinicians should establish when the last dose of dabigatran was administered and whether there are any effects of dabigatran still present.61 Several laboratory parameters may help in clinical decision making including serum creatinine (sCr), activated partial thromboplastin time (aPTT), international normalized ratio (PT/INR), complete blood cell count, platelets, TT, and ECT, if available. Although no coagulation assays are approved for monitoring dabigatran in the United States, aPTT and TT serve as qualitative measures of dabigatran activity. If they are normal, there is likely no dabigatran effect present.17,61 ECT and dilute TT (e.g., Hemoclot direct thrombin inhibitor) are quantitative measures of dabigatran activity; however, they are not readily available.62 For nonmajor bleeds, supportive care and symptomatic treatment with fluid replacement and hemodynamic support are generally sufficient. Blood product transfusions can be used in the setting of hemorrhagic shock in which the patient is hypovolemic, of an acute hemorrhage and hemodynamic instability or inadequate oxygen delivery, or a hemoglobin ≤ 7 mg/dL. Liquid charcoal with sorbitol 50 g by mouth for one dose can be used if the patient ingested a target-specific anticoagulant within two hours.63 Hemodialysis can be considered. It should be noted that hemodialysis only removes approximately 62% to 67% of dabigatran, and there are reports of redistribution postdialysis.12,64

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Clinical Review According to the intracerebral hemorrhage guidelines, if there is a major, life-threatening bleed, the patient should receive, as appropriate, a factor replacement therapy as soon as possible.65 The optimal method for treatment of major, life-threatening bleeding secondary to dabigatran has not been definitively established. Expert opinion, with limited supporting data, suggests FEIBA is the best option.58,66 If FEIBA is unavailable, then a 4-factor PCC would be an alternative. If 4-factor PCC is unavailable, combining 3-factor PCC with FFP or rFVIIa would be reasonable. When combining multiple hemostatic agents the risk of thrombosis increases; therefore, this strategy should only be used in life-threatening bleeding. More detailed description of dabigatran bleeding management may be found elsewhere.58,61,63

should be avoided in patients with a Clcr < 30 mL/min until more data are available.69 In special clinical circumstances, coagulation assay monitoring may be useful (e.g., drug interactions, stroke); however, clinical evidence supporting this practice is needed.17 In terms of patient selection, patients with a history of GI reflux disease or any other GI pathology should forego the selection of dabigatran as a treatment modality. Since GI bleeding has been reported to be increased irrespective of renal function in the elderly,43 this may suggest preexisting pathology increasing patient vulnerability to bleeding. Dabigatran has far fewer drug interactions in comparison with warfarin. Nevertheless, its bioavailability may be affected by P-glycoprotein inhibitors and inducers. If concomitant use of these agents can be avoided, they should be.

Summary and Recommendations

Conclusion

Although several postmarketing observational studies support the safety of dabigatran, the large number of case reports should not be disregarded. Patients in the reported cases and case series often had predisposing factors that increased the risk of bleeding. These factors ranged from renal impairment, advanced age, drug interactions (e.g., amiodarone), failure to acknowledge patient parameters (e.g., GI reflux disease), and prescription error such as wrong dose or inappropriate overlap with other anticoagulants.36,49,51,52,56,67 The cases highlight the fact that although dabigatran does not require routine monitoring of coagulation parameters, monitoring and acknowledgement of patient parameters are essential. The lack of routine monitoring of coagulation parameters should not mask that dabigatran, as an anticoagulant, is a high-risk medication. Clinicians should carefully select patients and monitor renal function to optimize safety. A baseline renal assessment with annual reassessments in patients with normal Clcr (≥80 mL/min) or mild (50-79 mL/min) renal impairment, and two to three times per year in patients with moderate (Clcr 30-49 mL/min) renal impairment.62,68 Patients with severe renal impairment (Clcr 15-29 mL/min) on dabigatran 75 mg twice daily should, based on the above guidelines, be monitored more often than three times per year. Some authors have suggested that dabigatran

Clinicians should acknowledge the risks of anticoagulantrelated bleeding in the elderly population regardless of anticoagulant choice. Prevention of stroke in NVAF is a high priority, and advanced age alone should not preclude the use of dabigatran or other anticoagulants. However, careful consideration of patient parameters and dabigatran pharmacologic profile are critical to mitigate the risk of toxicity.

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Luigi Brunetti, PharmD, MPH, is clinical assistant professor, Rutgers, The State University of New Jersey, Piscataway, New Jersey. Clement Chen, PharmD, is PGY1 pharmacy resident, Veterans Affairs Hudson Valley Healthcare System, Castle Point, New York. Jentora White, PharmD, is scientific associate, Phoenix Marketing Solutions, Warren, New Jersey. For correspondence: Luigi Brunetti, PharmD, MPH, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854; Phone: 201-638-5868; Fax: 908-685-2981; E-mail: [email protected]. Disclosures: The authors report no conflicts of interest. No funding was provided to assist in manuscript preparation. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.169.

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