Am J Cardiovasc Drugs DOI 10.1007/s40256-013-0050-3

REVIEW ARTICLE

Novel Oral Anticoagulants for Stroke Prevention in the Geriatric Population Daniel Kim • Richard Barna • Mary Barna Bridgeman • Luigi Brunetti

Ó Springer International Publishing Switzerland 2013

Abstract Prior to the availability of several newer anticoagulant medications, there had been no new advances in anticoagulation management for stroke prevention since the advent of warfarin in the 1950s. The availability of the novel oral anticoagulants (NOACs) dabigatran, rivaroxaban, and apixaban represent improvements over warfarin in many respects, including the elimination of the need for therapeutic drug monitoring, fewer drug and food interactions, and favorable efficacy; however, these agents are not without risk. Specifically, the use of the NOACs in the geriatric population, who are more likely to have an increased risk of stroke due to atrial fibrillation and other medical comorbidities, is not without risk. The objective of this review is to update the clinician on the use of the NOACs in the geriatric population and introduce the controversies and risks surrounding these newer therapies.

D. Kim  M. B. Bridgeman (&)  L. Brunetti Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA e-mail: [email protected] R. Barna Partners Pharmacy of New Jersey, Cranford, NJ, USA M. B. Bridgeman Robert Wood Johnson University Hospital, New Brunswick, NJ, USA L. Brunetti Somerset Medical Center, Somerville, NJ, USA

1 Introduction According to the National Vital Statistics Report for 2009 and 2010, cerebrovascular diseases (strokes) represent the fourth leading cause of death in the USA [1, 2]. It is estimated that more than 795,000 individuals experience a stroke in the USA each year, attributing to approximately 130,000 deaths annually [3]. Ischemic strokes, most often attributed to atrial fibrillation (AF), represent the most common type of stroke and account for an estimated 87 % of all cases of stroke [3]. The total annual healthcare expense attributed to stroke is estimated to approach $US38.6 billion dollars [4]. In 2009, of the near 1 million hospitalizations for stroke, two-thirds were for patients aged 65 years or older [5]. The increasing prevalence of AF, a comorbidity that accounts for approximately half of all cardioembolic stroke events, is associated with aging and is thought to be a major modifiable contributing factor to the increased risk of stroke in the older adult population [3]. Complicating management are chronic comorbidities and risk factors for AF, such as (but not limited to) heart failure, hypertension, and diabetes [6, 7]. Vitamin K antagonists (e.g., warfarin) have been the mainstay treatment for primary and secondary prevention of stroke in patients with AF. Warfarin therapy is fraught with several limitations, including variable effects, required therapeutic monitoring of the international normalized ratio (INR), and numerous interactions with both medications and foods. These intricacies have been the impetus for the development of novel oral anticoagulants (NOACs) with improved safety and elimination of routine therapeutic monitoring. While these newer agents, including apixaban, dabigatran, edoxaban, and rivaroxaban, have some desirable characteristics for use, special consideration

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for the use of these agents in the geriatric population is warranted. The importance of judicious use of these agents is highlighted by post-marketing reports of toxicity, namely bleeding complications, in geriatric patients [8]. The comparative safety and efficacy of the NOACs are summarized in this review. Additionally, special considerations for the use of these novel agents with respect to the geriatric population are outlined. 1.1 Epidemiology of Atrial Fibrillation AF represents the most common sustained cardiac rhythm disturbance, with a worldwide prevalence estimated at 1.5–2 % of the global population [9]. In the USA, an estimated 2.3 million adults have AF, with an expected increase to more than 5.6 % by 2050 [10]. Notably, the average age of onset of AF occurs between 75 and 85 years of age [3]. The prevalence of AF increases with age from 0.1 % in individuals aged 20–55 years of age to 9 % in those aged greater than 80 [10]. Approximately 82 % of patients with AF in the USA are 65 years of age or older [10]. This cardiac arrhythmia is associated with a fivefold risk of stroke and a threefold incidence of congestive heart failure; patients with AF experience a higher mortality rate than those with other medical conditions and often must be hospitalized for treatment [9]. Approximately 95 % of AF cases in the SUA are due to nonvalvular disease [10]. 1.2 Risk Stratification of Thrombosis and Bleeding Management of AF must address several clinical issues, including the identification of underlying causes or precipitating factors; a decision as to whether conversion to sinus rhythm is a possible or desirable goal; rate control of rapid ventricular response rhythm control for maintenance of sinus rhythm; and initiation of antithrombotic therapy for stroke prophylaxis according to the patient’s past medical history and stroke risk. Stroke risk may be predicted by the calculation of the patient’s CHADS2 Score (see Table 1). The current American College of Chest Physicians (ACCP) antithrombotic therapy guideline

recommends oral anticoagulant therapy in patients with a CHADS2 score of 1 or greater [11, 12]. More recently, the CHA2DS2VasC score has been endorsed by the European Society of Cardiology as a more comprehensive tool to predict the risk of stroke [13]. This validated tool is similar to the CHADS2 score; however, it also includes vascular disease and female sex as risk factors (1 point each). Furthermore, the tool considers age between 65 and 74 years a risk factor for AF (1 point). Age greater than or equal to 75 years is weighted more heavily and receives 2 points. These tools may aid the clinician in quantification of stroke risk and justification of anticoagulant therapy. The lifetime probability of experiencing a stroke dramatically increases with age, from 3.0 and 5.9 % at 55–59 years, to 23.9 and 22.3 % at 80–84 years in women and men, respectively [14]. Furthermore, for each decade of life beyond age 55 years, the stroke rate more than doubles in both men and women [14, 15]. A high risk of stroke is common in the elderly, with one analysis reporting 27 % of patients as high risk when classified according to CHADS2 [16]. Moreover, the remaining 73 % of patients were classified as moderate risk. In another analysis using the CHA2DS2-VASc to assess patient risk, all patients over the age of 65 years were classified as high risk [17]. The increased risk may be related to an increased prevalence of conventional risk factors, including having previously experienced a stroke or transient ischemic attack or having comorbid hypertension, diabetes, heart failure, left ventricular dysfunction, and coronary artery disease [18, 19]. Additionally, there may be an interaction between age and comorbidity, resulting in an even greater risk of embolism [19]. Other factors that may predispose the elderly to stroke include increased brain inflammation, neuronal vulnerability to ischemia, and decline in blood– brain barrier function and integrity [20–22]. Advanced age is not a contraindication to anticoagulation. Nonetheless, the elderly are frequently undertreated due the fear of hemorrhagic complications [23–25]. Go et al. estimated that warfarin is prescribed for prevention of stroke secondary to AF in only 55 % of eligible patients [26]. Prescribing of anticoagulation is further reduced in

Table 1 CHADS2 thrombosis risk assessment tool [9] C

Congestive heart failure

H

Hypertension (BP [140/90 mmHg or if currently receiving antihypertensives)

1 point 1 point

A

Age C75 years

1 point

D

Diabetes mellitus

1 point

S

Prior stroke, TIA, or thromboembolism

2 point

Score indicates an individual’s annual stroke risk; a score of 0 indicates the patient is at low risk of stroke, a score of 1–2 indicates a moderate stroke risk, and a score of 3 or greater indicates that they are at a high risk of stroke BP blood pressure, TIA transient ischemic attack

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the very elderly, with only 35 % of eligible patients aged 85 years or older receiving treatment. These statistics are concerning given that outcomes tend to be poorer in the elderly population [27]. With the high risk of stroke in the elderly, and the proven benefits of anticoagulation, clinicians should reconsider excluding patients from treatment due to age alone. In addition to assessing patient stroke risk, clinicians should also consider patient bleeding risk. Several tools are available to predict patient bleeding risk, including the ATRIA (Anticoagulation, and Risk Factors in Atrial Fibrillation) [28], HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, and concomitant Drug/ alcohol use) [29], 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) [30], and ORBRI (Outpatient Bleeding Risk Index) [31]. Although ATRIA, HAS-BLED, and HEMMORR2HAGES have only modest predictive value for clinically relevant bleeding, the HAS-BLED index significantly predicts intracranial hemorrhage [32]. HAS-BLED also outperforms the other scoring tools in terms of prediction accuracy and is easier to perform [33]. These tools may aid the clinician in deciding whether the risks of bleeding shadow the benefits of anticoagulant therapy, but they do not obviate individual patient evaluation. Current ACCP guidelines recommend against the use of these risk assessment tools alone when deciding against prescribing anticoagulant therapy [12]. Age is an independent risk factor for major bleeding events. Several of the available bleeding risk assessment tools include age as a risk factor. Major bleeding increases significantly with age (approximately 50 %) for every 10-year increase in age [40 years compared with age \40 years [34]. Also potentiating risk are the concomitant comorbidities, polypharmacy, and organ dysfunction commonly encountered in the geriatric patient. Several analyses have confirmed that advanced age is a significant predictor of bleeding. One study reported that approximately 40 % of patients 65 years and older were classified as high risk according to the HAS-BLED score [17]. Pengo et al. performed a multivariate analysis that identified predictors of bleeding in patients receiving warfarin therapy. In this analysis, age greater than or equal to 75 years was the only patient characteristic independently associated with primary bleeding, defined as bleeding unrelated to an organic lesion (relative risk [RR] 6.6; 95 % CI 1.2–37; p = 0.032) [35]. Similarly, Palareti and colleagues [36] reported a 75 % increase in RR of bleeding in patients aged 70 years or older versus those less than 70 years of age (RR 1.75; 95 % CI 1.21–2.37;

p \ 0.001) who were treated with warfarin. A systemic review of the risk of bleeding performed by Hutten et al. also showed that the percentage of patients with major bleeding was considerably higher in patients aged 75 years or older (8.1 vs. 5.0 %); the incidence of bleeding per treatment year was more than two times higher in these older adults (4.2 vs. 1.7 %) [37]. 1.3 Growth of Elderly and Very Elderly Populations The elderly and very elderly populations are projected to increase [38]. An increase of 18 % in individuals aged 65 years or older has been reported from the year 2000 to 2011 (6.3–41.4 million) in the USA. Furthermore, it is projected that, by 2040, 79.7 million Americans will be 65 years of age or older. Similarly, the very elderly population (age 85 years or older) is projected to increase from 5.7 million in 2011 to 14.1 million in 2040. These populations are more vulnerable to iatrogenic effects of medications [39]. The increased vulnerability may be related to increased risk of both pharmacodynamic and pharmacokinetic drug interactions in the setting of polypharmacy or the presence of comorbidities [40]. Hospital admission in the elderly population related to adverse drug events is common, with a reported incidence in the literature ranging from 8 to 30 % [41–46]. In one analysis, warfarin toxicity was the most common reason for emergency department visit in patients aged 65 years or older [47]. Fortunately, phytonadione, fresh frozen plasma, and prothrombin complex concentrate have established efficacy in reversing warfarin-related bleeding. Conversely, the NOACs do not have any reliable method for reversal of effect. As the elderly population increases, one can expect that the number of medication-related iatrogenic events would also increase. Special focus should be placed on improving the utilization of high-risk medications (e.g., anticoagulants) in order to shift the balance in favor of benefit.

2 Performance of Novel Oral Anticoagulants (NOACs) versus Warfarin The NOACs differ significantly in terms of pharmacologic profile compared with warfarin. Table 2 provides a summary of the pharmacologic characteristics of each agent [48–53]. While warfarin targets several vitamin K-dependent clotting factors, each of the NOACs is specific for a particular clotting factor (Fig. 1) [50]. The safety and efficacy of apixaban, dabigatran, rivaroxaban, and edoxaban have been independently evaluated in large randomized controlled trials (Table 2) [51–54]. These landmark studies are further discussed in the specific drug sections that follow.

Tablet 5 mg by mouth bid

Dosage form

Dose for NVAF

CrCl 30–50 mL/min: 15 mg PO od (currently only available in Japan)

CrCl \30 mL/min: 75 mg PO bid

Warfarin: N = 241, %/year = 2.2; p value \0.001

Warfarin: N = 199, %/ year = 1.69; p value \0.001 (noninferiority)

Warfarin: N = 265, %/ year = 1.60; p value = 0.01

RELY Dabigatran (150 mg): N = 134, %/year = 1.11;

ARISTOTLE Apixaban: N = 212, %/ year = 1.27;

Efficacy: stroke and systemic embolism

ROCKET AF Rivaroxaban: N = 188, %/year = 1.7;

ENGAGE AF-TIMI 48 Data not yet available

15 and 20 mg tablets: take with largest meal of the day

10 mg tablets: may be taken with or without food;

Landmark trial

Not affected by food

Can be crushed and mixed with applesauce and administered via NG tube

Not affected by food

No information

Effects of food

Cannot be crushed, opened, broken, or chewed; bioavailability and bleeding risk significantly increased May be taken with or without food

Best absorbed in the stomach

CrCl 15–50 mL/min: 15 mg PO od with evening meal

CrCl [50 mL/min: 20 mg PO od with evening meal

Tablet

Yes (36 %); contraindicated in CrCl \15 mL/min

Substrate

30 % CYP3A4, CYP2J2

Half-life: 5–9 h

Onset of effect: within 4 h

No information

No information

CrCl [50 mL/min: 30 mg PO od

CrCl [30 mL/min: 150 mg PO bid

Prodrug (needs to be converted to its active form to work); high-fat meal will delay absorption but not affect amount absorbed

Tablet

Yes (35 %); contraindicated in CrCl \30 mL/min (currently only available in Japan)

Substrate

Capsule

Yes (80 %); contraindicated in CrCl \30 mL/min

Substrate

\4 %

Half-life: 8–10 h

Tmax: 2–4 h

Bioavailability: 80–100 % (10 mg); 66 % (20 mg)

Direct inhibitor of FXa

Rivaroxaban [50, 53, 81, 82]

Can it be crushed? Administered via NG tube?

Absorption

Yes (27%); AHA recommends avoidance in CrCl \25 mL/min

Renal elimination?

For individuals with two or more of the following characteristics: aged C80 years, weight of B60 kg, serum creatinine of C1.5, dose is 2.5 mg PO bid Absorbed throughout the GI tract (small bowel and colon *55 % of absorption)

Substrate

P-glycoprotein

Half-life: 12–17 h

Half-life: 12 h No

Onset of effect: within 2 h

Onset of effect: within 3 h

25 % CYP3A4

Tmax: 1–2 h

Tmax: 1–2 h

Tmax: 3–4 h

CYP metabolism

Bioavailability: 62 %

Bioavailability: 3–7 % Protein binding: 50 %

Direct inhibitor of FXa

Direct factor IIa inhibitor

Direct inhibitor of FXa Bioavailability: 50 %

Edoxaban [48, 49, 54, 92]

Pharmacokinetics

Dabigatran [50, 51, 55]

Mechanism of action

Apixaban [52, 88, 89]

Table 2 Comparison of apixaban, dabigatran, edoxaban, and rivaroxaban

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AF atrial fibrillation, AHA American Heart Assocation, bid twice daily, Cmax maximum plasma concentration, CrCl creatinine clearance, CYP cytochrome P450, FXa factor Xa, GI gastrointestinal, NG naso-gastric, NVAF nonvalvular AF, od once daily, PO by mouth, Tmax time to Cmax,

p value 0.58 p value 0.003 p value \0.001

Warfarin: N = 386, 100 patient-year = 3.4; Warfarin: N = 397, %/ year = 3.36; Warfarin: N = 462, %/ year = 3.09;

Rivaroxaban: N = 395, 100 patient-year = 3.6; Data not yet available Dabigatran (150 mg): N = 375, %/year = 3.11; Apixaban: N = 327, %/ year = 2.13;

Rivaroxaban [50, 53, 81, 82]

Safety: major bleeding

Table 2 continued

Apixaban [52, 88, 89]

Dabigatran [50, 51, 55]

Edoxaban [48, 49, 54, 92]

Novel Oral Anticoagulants in the Elderly

Fig. 1 Mechanisms of action of the novel oral anticoagulants versus vitamin K antagonists (VKA, warfarin). Reprinted with permission from Steffel and Braunwald [50]

2.1 Dabigatran Etexilate Dabigatran was the first oral direct thrombin inhibitor anticoagulant approved by the US FDA for the prevention of stroke and systemic embolism in patients with nonvalvular AF (NVAF). Dabigatran etexilate is a prodrug of dabigatran, a competitive and reversible direct thrombin inhibitor [55]. The standard dose of dabigatran etexilate is 150 mg twice daily. Anticoagulant effect is exerted through binding of both free and fibrin-bound thrombin via hydrophobic interactions [56]. Dabigatran reaches its maximum plasma concentration (Cmax) at approximately 1 h post-administration and has a half-life of 12–17 h. In a pharmacokinetic evaluation of dabigatran in healthy elderly subjects, the half-life was approximately 12–14 h and Cmax was reached after a median of 3 h [57]. Compared with young healthy subjects, bioavailability of dabigatran is approximately 1.7- to 2-fold greater in the elderly [57]. Although no dosage adjustment is recommended for advanced age in the USA, both Canada and Europe recommend a reduced dose (110 mg twice daily) in patients over the age of 80 years [55, 58, 59]. Dabigatran is primarily renally eliminated. In Canada and Europe, the use of dabigatran is considered contraindicated in patients with a creatinine clearance (CrCl) of \30 mL/min, whereas, in the USA, a threshold of 15 mL/ min has been set [55, 58, 59]. The US product labeling recommends that a reduced dose of 75 mg twice daily is prescribed in patients with a CrCl of 15–29 mL/min. This recommendation was based on pharmacokinetic modeling and has not been evaluated in an actual study to date [60, 61]. Dabigatran has several advantages over warfarin, including a fixed dosing regimen, no INR monitoring, and less potential for drug and food interactions [55]. Although no coagulation monitoring is required, since dabigatran is highly dependent on renal elimination, clinicians should

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check renal function at baseline and then periodically [9, 62]. Patients with underlying renal disease should have more frequent monitoring of renal function. Disadvantages of dabigatran compared with warfarin include twice-daily dosing, frequent reports of dyspepsia and gastritis, higher rates of gastrointestinal bleeding, and higher rates of major bleeding in patients over the age of 75 years [51, 63]. Dabigatran is a substrate of P-glycoprotein (P-gp), and thus dabigatran exposure may be influenced by strong P-gp inhibitors (verapamil, amiodarone, quinidine, clarithromycin, atorvastatin) and inducers (rifampin, St. John’s Wort) [55]. If dabigatran is used concomitantly with a strong P-gp inhibitor and the patient has moderate renal impairment (CrCl 30–50 mL/min), a reduced dosage should be used [55]. Concomitant use in patients with a CrCl\30 mL/min should be avoided. The approval of dabigatran for the prevention of stroke in NVAF was based primarily on the results of the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, in which dabigatran was directly compared with warfarin [51]. Patients were randomized to dabigatran 110 mg twice daily (n = 6,015), dabigatran 150 mg twice daily (n = 6,076), or warfarin targeted to an INR of 2–3 (n = 6,022). The primary efficacy outcome was a composite of stroke or systemic embolism. Both dabigatran etexilate dosages were noninferior to warfarin (p \ 0.001) for the primary outcome measure. Dabigatran 150 mg twice daily was found to be superior to warfarin (RR 0.66; 95 % CI 0.53–0.82; p \ 0.001). The rates of hemorrhagic stroke were also lower with both dabigatran doses than with warfarin (p \ 0.001). Major bleeding (defined as a drop in hemoglobin [20 g/L, transfused C2 units of packed red blood cells, or symptomatic bleeding in a critical area or organ) was significantly lower with dabigatran 110 mg and similar with dabigatran 150 mg versus warfarin (2.87 and 3.32 % per year vs. 3.57 % per year). The rate of myocardial infarction was higher in the dabigatran groups (0.72 % per year in the dabigatran 110 mg group, 0.75 % per year in the dabigatran 150 mg group, 0.53 % per year with warfarin). A re-analysis of the data did not find a significant difference in the rate of myocardial infarction between groups [64]. Observational studies have provided conflicting evidence on the dabigatran myocardial infarction risk [65–67]. Interpretation of these studies requires careful assessment; by nature, observational studies are often clouded by confounding. This statement is strengthened by the fact that one analysis reported a 70 % increase in myocardial infarction with dabigatran, while another reported a 60 % reduction in myocardial infarction [65, 67]. The risk of myocardial infarction may be unrelated to dabigatran, but rather a function of superior protection against myocardial infarction from warfarin therapy [68, 69]. A significantly higher

rate of major gastrointestinal bleeding was found in patients receiving dabigatran 150 mg twice daily when compared with warfarin. Patients enrolled in the RE-LY trial provided good representation of the typical AF population. The mean CHADS2 score was 2.1; therefore, patients did not have significant comorbidity. Furthermore, patients with a CrCl \30 mL/min were excluded. Additional data are needed to confirm the safety and efficacy of dabigatran in the elderly population, particularly patients with multiple comorbidities/risk factors for AF. Eikelboom et al. [63] performed a post hoc analysis of the RE-LY trial to evaluate the impact of age on bleeding. Patients C75 years of age had a greater incidence of gastrointestinal bleeding (but not intracranial), irrespective of renal function, compared with patients on warfarin (1.85 vs. 1.25 % per year, respectively; p \ 0.001). Gelbricht et al. [70] performed an observational study evaluating the safety and efficacy of dabigatran in NVAF. Data from a patient registry (New Oral Anticoagulants [NOAC]) of 200 private practice and hospital physicians in Saxony, Germany, were included in the analysis. Patients were enrolled until 31 July 2012 and had follow-up phone calls at 30 days, then quarterly (e.g., at 3 and 6 months) after enrollment. Of the 938 patients enrolled at the time of analysis, 201 received dabigatran for NVAF. The authors point out that these patients were older than patients in whom dabigatran use had been studied previously (average age 74.2 years) and had a higher CHADS2 score (average 2.7). According to this study, bleeding was frequently reported (14.9 %), although major bleeding was rare (1.5 % or three patients). No patients died from bleeding complications. In this study, after 6 months of treatment, almost 20 % of patients had switched from dabigatran to other anticoagulants because of side effects. Since the approval of dabigatran, numerous reports of hemorrhagic complications have been published [71–77]. The increased reporting is expected, given the excitement for the first NOAC in over 50 years. Reporting bias is likely [78, 79]. Nonetheless, the case reports highlight the importance of patient selection and dosage adjustment and remind clinicians that, although dabigatran is closer to an ideal anticoagulant than warfarin, it is still a high-risk medication. The FDA performed a post-marketing analysis of dabigatran adverse events using administrative claims data from the Mini-Sentinel Pilot of the Sentinel Initiative [78]. The analysis shows that, from October 2010 to December 2011, the incidence of gastrointestinal hemorrhage events per 100,000 days of drug exposure was 1.6–2.2 times higher for new warfarin users than for new dabigatran users. The incidence rate of intracranial hemorrhage events per 100,000 days of drug exposure was 2.1–3.0 times higher for new warfarin users than for new

Novel Oral Anticoagulants in the Elderly

dabigatran users. Other large observational studies have also provided reassuring data on the safety of dabigatran [67, 80]. Cautious interpretations of these data are warranted, as the use of claims data for analyses is fraught with confounding and potential coding inaccuracies. 2.2 Rivaroxaban Rivaroxaban was the first available orally active factor Xa (FXa) inhibitor approved for use in the USA. It is currently approved for prevention of stroke in NVAF, as well as for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) [81]. Rivaroxaban is rapidly absorbed with 60–80 % bioavailability and a Cmax occurring 2.5–4 h following oral administration [82]. The half-life of rivaroxaban is 7–11 h for young healthy subjects and 11–13 h in elderly subjects [83, 84]. While approximately twothirds of rivaroxaban undergoes metabolic degradation in the liver, one-third is excreted unchanged by the kidneys [85]. As such, rivaroxaban requires dosage adjustment in moderate renal impairment. The usual dosage of 20 mg daily with a meal is reduced to 15 mg daily if the patient’s CrCl is 15–49 mL/min. The approval of rivaroxaban was based on the results of the ROCKET-AF (Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation) trial [53]. The double-blind trial studied the effects of fixed-dose 20-mg once-daily rivaroxaban (15 mg/day if CrCl 30–49 mL/min) versus adjusted-dose warfarin in patients with NVAF and attempted to determine noninferiority. The study included patients who currently had NVAF and were at moderate-tohigh risk of stroke. Increased risk was determined by a score of 2 or more in the CHADS2 scoring system, which includes history of stroke, transient ischemic attack, or systemic embolism, or at least two of the following risk factors: heart failure or a left ventricular ejection fraction of 35 % or less, hypertension, an age of 75 years or more, or the presence of diabetes mellitus. The primary efficacy endpoint was the number of strokes (ischemic or hemorrhagic) and systemic embolism, while the primary safety endpoint was the total number of clinically relevant bleeding events. Secondary efficacy endpoints consisted of a composite of stroke, systemic embolism, or death from cardiovascular causes or myocardial infarction. In regards to the primary outcome, stroke or systemic embolism occurred in the per-protocol population at a rate of 1.7 % per year in rivaroxaban versus 2.2 % per year in warfarin (hazard ratio [HR] 0.79, 95 % CI 0.66–0.96; p \ 0.001 for noninferiority). Clinically, bleeding seemed to occur in a similar fashion in the rivaroxaban group and warfarin group (14.9 and 14.5 % per year, respectively; HR 1.03; 95 % CI 0.96–1.11; p = 0.44). However, fewer instances of intracranial

bleeding occurred in the rivaroxaban group than in the warfarin group (0.8 and 1.2 %, respectively; HR 0.67; 95 % CI 0.47–0.93; p = 0.02). Fewer instances of fatal bleeding were also recorded in rivaroxaban versus warfarin (0.4 and 0.8 %, respectively; HR 0.5; 95 % CI 0.31–0.79; p = 0.003). Thus, rivaroxaban was deemed as noninferior to warfarin, with a potentially safer bleeding profile. In a post hoc analysis of ROCKET-AF, an increased risk of stroke and bleeding was observed in patients with moderate renal impairment (CrCl 30–49 mL/min) versus patients mild to no renal impairment (CrCl C50 mL/min) [86]. Outcomes in patients with moderate renal impairment did not differ from the overall study participants. The average participant in the ROCKET AF trial fell into the geriatric category, with the average age for both rivaroxaban and warfarin groups being 73 years. While the inclusion criteria were important for measuring the primary and secondary outcomes, the exclusion criteria prevented direct real-world applicability. The trial excluded those with renal impairment (CrCl \30 mL/min) and known liver impairment (e.g., hepatitis, cirrhosis) or alanine transaminase (ALT)[39 the upper limit of normal (ULN). As previously discussed, comorbidities commonly exist in the geriatric population, which would require additional considerations. One study determined that the AUC of rivaroxaban was significantly higher in subjects [75 years versus subjects 18–45 years [87]. Total and renal clearance was also found to be decreased. However, time to maximum FXa inhibition and Cmax were unaffected by age. Further clinical evaluation of rivaroxaban is necessary to determine the need for dose adjustment and to more clearly define its efficacy and safety in the geriatric population, since patients with a CrCl \30 mL/min were excluded from ROCKET-AF. 2.3 Apixaban Apixaban is a recently approved novel anticoagulant agent indicated for reducing the risk of stroke and systemic embolism associated with NVAF. Apixaban is administered orally (usual dose 5 mg twice daily) and works by directly inhibiting FXa [88]. Apixaban is rapidly absorbed after oral administration and has a time to Cmax of approximately 1 h, with a half-life of about 5–6 h, which increases to 12 h with repeated dosing. Apixaban is eliminated in the urine and feces, with up to 27 % renally excreted [89]. Dosage adjustment to 2.5 mg twice daily is required in patients who have any two of these characteristics: age C80 years, body weight B60 kg, or a serum creatinine C1.5 mg/dL. In 2011, the results of the ARISTOTLE (Apixaban versus Warfarin in Patients with Atrial Fibrillation) trial were published; a large-scale, landmark clinical trial that

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resulted in the approval of apixaban for reducing the risk of stroke and systemic embolism in patients with NVAF. ARISTOTLE was a randomized, double-blind, doubledummy study that directly compared apixaban (5 mg twice daily) with warfarin (titrated to a target INR 2.0–3.0) in 18,201 patients with NVAF and at least one additional risk factor for stroke (e.g., age of 75 years or older; previous stroke, transient ischemic attack, or embolism; symptomatic heart failure or an ejection fraction of no more than 40 %; or hypertension treated with antihypertensives) [52]. The primary objective of this study was to determine whether apixaban was noninferior to warfarin at reducing the risk of stroke in this patient population; the primary efficacy outcome measured was the incidence of ischemic or hemorrhagic stroke or systemic embolism. While the study was primarily designed to test for noninferiority, a secondary objective was to prove superiority for the primary outcome of major bleeding and death from any cause. The results of the trial showed that the rate of the primary outcome was lower in patients treated with apixaban versus those who received warfarin (1.27 vs. 1.60 % per year; p \ 0.001 for noninferiority, p = 0.01 for superiority). Although the composite primary endpoint favored apixaban, the endpoint was driven by a significant reduction in hemorrhagic stroke and not ischemic stroke. The rate of major bleeding was also lower in patients treated with apixaban (2.13 vs. 3.09 % per year; p \ 0.001). The authors concluded that apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. In terms of the elderly, one study was conducted to measure the differences in sex and age regarding the pharmacokinetics and pharmacodynamics of apixaban [90]. While the study found that age did not affect the Cmax, the area under the concentration–time curve to infinity was 32 % higher in the elderly (aged 65 years or older) than in the younger subjects (younger than 40 years). These pharmacokinetic data indicate that apixaban achieves greater total serum concentrations in the elderly; dosage adjustment is thus recommended in individuals aged 80 years or older with either low body mass (weight less than or equal to 60 kg) or renal impairment (serum creatinine 1.5 mg/dL or higher). While hepatic impairment was shown to not affect the pharmacokinetics of apixaban [91], individuals with any degree of renal impairment showed an increase in plasma concentrations without evidence of altered anti-FXa activity.

Edoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation) trial was completed in mid-2013. Edoxaban is also an oral direct FXa inhibitor that has a Cmax of 1–3 h and a half-life of 8–10 h [92]. While the results of phase III trials are currently pending, several phase II trials have published their results. One study directly compared the effects of various doses of edoxaban with warfarin in Japanese patients with NVAF (average age 69.4 years for warfarin-treated patients compared with 69.4, 69.5, and 68.4 years, respectively, for edoxaban 30, 45, and 60 mg daily) [93]. The primary outcome of this study was the incidence of any type of bleeding, including asymptomatic intracranial hemorrhage, while secondary outcomes included thromboembolic events, such as stroke, pharmacodynamic parameters, and plasma concentrations at 4 and 8 weeks into treatment. Adverse events and adverse drug reactions were set as the safety endpoints. While higher doses of once-daily edoxaban (administered at either 45 or 60 mg) had higher rates of bleeding than dose-adjusted warfarin (22.4, 27.7, and 20 %, respectively), the lower dose of once-daily edoxaban (30 mg) had a lower incidence of bleeding at 18.5 %. Adverse events were also dose-related, as the 30-mg edoxaban group had fewer incidences than warfarin and the 45- and 60-mg groups. Another phase II trial evaluated various doses of edoxaban (30-mg once daily, 60-mg once daily, 30-mg twice daily, and 60-mg twice daily) in patients with NVAF and a CHADS2 score of at least 2 for 12 weeks [54]. The mean age of the safety population evaluated in this study was 65 ± 8.7 years. In this analysis, twice-daily edoxaban doses had higher rates of clinically relevant bleeding events than did warfarin. However, the patients receiving edoxaban dosed at either 30 or 60 mg once daily had similar rates of bleeding to warfarin-treated patients (7, 11, and 8 %, respectively). The patients receiving edoxaban dosed at either 30 or 60 mg once daily also showed a lower incidence of stroke than those receiving warfarin (0.4, 0.4, and 1.6 %, respectively). Final results from the phase III studies of edoxaban have yet to be published, although, based on phase II data, it has promising efficacy in the treatment of NVAF with incidence of bleeding similar to warfarin. Additional data are needed to determine the role of edoxaban in the prevention of stroke in AF, particularly in the elderly population.

2.4 Edoxaban

3 Risk Factors for Treatment Complications with NOACs

Edoxaban is another novel anticoagulant that is currently undergoing phase III trials in the USA. The ENGAGE-AF (Global Study to Assess the Safety and Effectiveness of

Pharmacologic thromboprophylaxis is not without risk. Hemorrhagic episodes are a well known and feared treatment complication associated with anticoagulant therapy [94].

Novel Oral Anticoagulants in the Elderly

Although bleeding can be defined in a variety of ways, major bleeding is generally classified as such if it is intracranial or retroperitoneal, results in death, or results in hospitalization. While bleeding is a common, yet potentially serious, adverse event associated with all anticoagulants, there are a number of independent risk factors that can increase an individual patient’s risk of bleeding during treatment. Recognition of these risks can help the clinician optimize the use of the NOACs and potentially reduce the risk of serious complications by prompting dosage adjustment. Although the NOACs offer several advantages over warfarin therapy, specific therapeutic concerns and potential disadvantages also exist. First and foremost, unlike warfarin, no antidote exists for these agents. Additionally, although monitoring is not required, coagulation assays may be beneficial in certain circumstances, such as toxicity, interruption of therapy, and to assess compliance. The optimal method for monitoring anticoagulation for the NOACs requires further evaluation. Over 80 % of adverse drug reactions causing hospital admission are categorized as type A (dose related) [40]. This figure supports the importance of appropriate drug dosing, particularly with high-risk medications such as the NOACs. Renal dysfunction, drug interactions, and/or age may require dosage adjustment. The shorter halflives of these agents also mandate strict patient compliance. Finally, cost is of particular significance, as all of these agents are significantly more expensive than warfarin. However, it should be noted that the NOACs are cost effective when looking at the overall cost of care in addition to drug-acquisition costs [95].

4 Strategies to Minimize Treatment Complications As previously described, the geriatric population is at a greater risk for treatment complications, such as bleeding, independent of a specific anticoagulant therapy. While experience with the NOACs is limited, several case reports and series highlight the importance of patient selection to minimize bleeding risks [71–74, 96, 97]. In regards to use of these agents in patients with impaired renal function, reducing the standard dose of these agents may be effective in this population; not all agents have robust clinical data to support renal dosage adjustment recommendations, as is the case with dabigatran. Given the lack of data in severe renal impairment (CrCl \30 mL/min) with all of the NOACs, warfarin may be preferred. 4.1 Renal Disease as an Independent Risk Factor for Bleeding The presence of renal disease has been implicated as an independent risk factor for anticoagulant-related

hemorrhage [98, 99]. Platelets become dysfunctional secondary to exposure to increased uremic-like toxins in renal dysfunction, thus increasing the risk of bleeding [100, 101]. Limdi and colleagues [102] were the first to perform a prospective study comparing various degrees of reduced kidney function and the effects on risk for hemorrhage and found that patients with severe chronic kidney disease (CKD), defined as having an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m2, had a higher incidence of major hemorrhage than those with either no kidney disease or mild CKD (RR 4.9; 95 % CI 2.6–9.1; p \ 0.0001). A retrospective cohort study conducted by McMahan et al. [103] also showed that patients with chronic renal insufficiency, defined as having a serum creatinine level above 1.5 mg/dL, had a RR of bleeding 2.6 (95 % CI; 1.5–5.2; p = 0.008). This finding is particularly distressing, as a report by the National Health and Nutrition Examination Survey estimated the prevalence of CKD in patients aged 65 years or older to be 39.4 % [104]. The Cockroft–Gault equation is often used to estimate GFR, and is commonly used when determining appropriate dose adjustments in patients with kidney disease [105]. This method of estimating renal function may overestimate renal function in the elderly, as overestimation may be more pronounced in patients with low serum creatinine as a result of decreased muscle mass [106]. Overexposure due to inaccurate assessment of renal function is a concern in the elderly, but is not limited to the NOACs. Further study is warranted to determine which method of estimating renal function is best correlated with therapeutic drug levels. Monitoring of renal function in the setting of use of the NOACs in the elderly population should be determined in accordance with the patient’s baseline degree of renal impairment. For those individuals with normal renal function or mild impairment (CrCl [60 mL/min), periodic assessment of renal function could be proposed (e.g., annual basic metabolic panel to evaluate serum creatinine) [62]. For those individuals with moderate renal impairment or a baseline CrCl between 30 and 60 mL/min or who are receiving dabigatran and are aged 75 years or older or are fragile, it has been recommended that re-assessment of renal function occur every 6 months to maximize efficacy and minimize the risk of toxicity associated with the NOACs requiring dosage adjustment in renal impairment [62, 107]. For those individuals with a CrCl 15–30 mL/min, monitoring of renal function every 3 months may be prudent; alternative treatments beside dabigatran could be considered [62, 107]. For those individuals likely to experience an acute change in renal function (e.g., acutely hospitalized, receiving intravenous contrast, initiating therapy with angiotensin-converting enzyme [ACE] inhibitor or angiotensin-receptor blocker), more frequent monitoring of renal function may be warranted.

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4.2 Patient Comorbidities as Independent Risk Factors for Bleeding Patient comorbidities and characteristics should also be carefully evaluated prior to selection of a NOAC. For example, if the patient has liver dysfunction with elevated INR, or poor compliance, the NOACs may not be optimal [68]. Furthermore, in patients with structural heart disease (e.g., mechanical heart valve, valvular heart disease), use of the NOACs are not indicated. Recent data indicate increased rates of thromboembolic events and bleeding with the use of dabigatran versus warfarin in the setting of AF with mechanical heart valves [108]. Warfarin may be preferred in all of these scenarios. Although the NOACs have not been directly compared, clinical studies provide some rationale to personalize NOAC selection. Dabigatran was associated with high rates of dyspepsia in the RE-LY trial, therefore, apixaban or rivaroxaban may be better options in patients with upper gastrointestinal disorders. Of the NOACs, only dabigatran was superior to warfarin for reduction of ischemic stroke [51]. In patients presenting with ischemic stroke previously receiving warfarin, clinicians should consider dabigatran over the other NOACs. Finally, rivaroxaban or apixaban should be considered over dabigatran in patients with recent acute coronary syndrome. Although inconclusive, dabigatran may be associated with an increased risk of myocardial infarction. 4.3 Drug Interactions as Independent Risk Factors for Bleeding It is also important to consider concomitant medications during dose adjustment, especially given the geriatric population’s increased chance of comorbidities. Dabigatran exposure is reduced when administered with inducers of P-gp, such as rifampin. Co-administration with P-gp inducers should be avoided and, while certain P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin) generally do not require a dose adjustment, coadministration of P-gp inhibitors should be avoided in any patient with severe renal impairment. The dabigatran dosage should be reduced in patients receiving strong P-gp inhibitors with moderate renal impairment. Rivaroxaban is a substrate of cytochrome P450 (CYP) 3A4/5, CYP2J2, and the P-gp and adenosine triphosphate (ATP)-binding cassette G2 (ABCG2) transporters and is susceptible to multiple interactions. Rivaroxaban should not be administered with combined P-gp and strong CYP3A4 inhibitors, unless data suggest there is no increase in bleeding risk (e.g., clarithromycin). On the other hand, concomitant administration with combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) decreases efficacy and should also be avoided.

Additionally, clinicians should be aware of the various dosing regimens for rivaroxaban, depending on the indication for use (see Table 2). Apixaban is also a substrate of both CYP3A4 and P-gp. The dose should be reduced to 2.5 mg twice daily when co-administered with combined P-gp and strong CYP3A4 inhibitors, due to an increased risk of bleeding. Patients who already fit the criteria for a reduced dose based on the previously discussed characteristics, should avoid co-administration altogether. Combined P-gp and strong CYP3A4 inducers should also be avoided so as not to decrease efficacy. Edoxaban is also a substrate of CYP3A4 and P-gp, but specific interactions have yet to be determined. Concurrent usage of the NOACs with other anticoagulants, antiplatelets (e.g., clopidogrel), and NSAIDs may increase bleeding risk and should be avoided, unless benefit outweighs risk. Recently, the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) trial suggested that triple therapy (e.g., oral anticoagulant plus aspirin plus clopidogrel) is associated with greater risks than benefits in individuals with AF and coronary stents [109]. Careful evaluation of risks and benefits of dual and triple therapy is imperative; the scope of these controversies is beyond that of this review article [12]. 4.4 NOACs and Therapeutic Drug Monitoring The response to usual coagulation testing may be varied with the use of the NOACs. Specifically, unlike warfarin, the need for routine therapeutic monitoring of the INR or any other value is not routinely required to assure efficacy with these newer drugs. Moreover, the predictable pharmacokinetic profiles of these agents negate the need for routine therapeutic monitoring. Refer to Table 3 for a comparison of the effects of the NOACs on various laboratory tests used for monitoring anticoagulant effect. If the use of such testing is desired due to a clinically emergent situation or concern for therapeutic failure, certain laboratory tests may be utilized as a qualitative assessment to determine whether or not anticoagulant effect is present; test results are generally not useful in quantifying the degree of anticoagulation achieved [107]. 4.5 Management of Bleeding Complications In the event of a hemorrhagic complication during NOAC treatment, it is advisable to initiate appropriate clinical support, discontinue the treatment, and investigate the source of bleeding. Activated charcoal may be administered if ingestion occurred within 2 h. Hemodialysis may be an option to remove dabigatran but data supporting this method are presently limited to case reports and anecdotal

Novel Oral Anticoagulants in the Elderly Table 3 Effect of novel oral anticoagulants on laboratory tests [107] Test

Prothrombin time (PT)

Dilute thrombin time

Activated partial thromboplastin time (aPTT)

International normalized ratio (INR)

Ecarin clotting time (ECT)

AntiXa chromogenic assay

Dabigatran

Not accurate for monitoring

Quantitative; at trough: [200 ng/ ml or [65 sec: excess bleeding risk

Elevated trough value (more than 2 9 ULN) suggestive of excessive bleeding risk

Not accurate for monitoring

Elevated trough value (more than 3 9 ULN) suggestive of excessive bleeding risk

Not applicable

Rivaroxaban

Prolonged; may correlate with bleeding risk, local calibration required

Not useful

Not accurate for monitoring

Not accurate for monitoring

No effect

Quantitative; values not yet correlated with efficacy or safety

Apixaban

Not accurate for monitoring

Not useful

Not accurate for monitoring

Not accurate for monitoring

No effect

Not reported

Edoxaban

Prolonged; does not correlate with bleeding risk

Not useful

Prolonged; does not correlate with bleeding risk

Not accurate for monitoring

No effect

Quantitative; values not yet correlated with efficacy or safety

ULN upper limit of normal

evidence [110]. More detailed reviews specifically addressing the management of bleeding complications secondary to NOACs have been published elsewhere [8, 107, 111, 112]. 4.6 Cardioversion in the Setting of NOAC Use Data evaluating the safety of cardioversion in the presence of the NOACs are limited. A post hoc analysis of the RELY study has provided some reassuring data that the stroke rate with dabigatran is similar to that with warfarin [113]. Data are also limited in terms of dabigatran as an alternative to warfarin for peri-procedural anticoagulation for AF ablation. Several authors have reported protocols for peri-procedural use of dabigatran with varying success [114–116]. Current evidence suggests that this strategy should be limited to younger patients with relatively good renal function [117]. Data published only in abstract form suggest that cardioversion is safe and effective with apixaban or rivaroxaban [107]. 4.7 Peri-Operative Management in the Setting of NOAC Use Patients undergoing surgical procedures require special consideration regarding cessation of use of NOACs in order to minimize bleeding risks. For those individuals undergoing minor surgical procedures (e.g., dental cleaning or extraction, cataract extraction, or skin biopsy), NOAC therapy need not be discontinued prior to the procedure.

Rather, these procedures can be performed when serum concentrations of the NOAC in question are at a trough (e.g., 10–12 h after the last dose of dabigatran and apixaban, 20–24 h after the last dose of rivaroxaban) [107, 111, 112]. For other surgical procedures, consideration must be given to the NOAC in use, bleeding risk associated with the procedure, and the patient’s underlying renal function. See Table 4 for a description of strategies for holding NOAC therapy in the peri-operative setting. In the post-operative period, NOAC therapy can generally be restarted 6–8 h after the surgical procedure if immediate and complete hemostasis is achieved. In those individuals undergoing invasive procedures or who require immobilization postTable 4 Temporary cessation of novel oral anticoagulants for surgical procedures [107, 111] Last intake of drug before elective surgical intervention Low risk of bleeding

High risk of bleeding

Estimated CrCl (mL/min) Dabigatran [80

1–1.5 days

2–3 days

50–80

1–2 days

2–3 days

30–50

1.5–2 days

3–4 days

\30

2–3 days

4–6 days

Rivaroxaban and apixaban [30

1 day

2 days

\30

1.5 days

2 days

CrCl creatinine clearance

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operatively, initiation of a reduced-dose low-molecularweight heparin 6–8 h after surgery if hemostasis is achieved is recommended, with the NOAC therapy resuming 48–72 h after the procedure as clinically indicated [111].

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5 Conclusions The elderly represent a heterogeneous population at increased risk of morbidity and mortality secondary to ischemic stroke and vascular disease as well as a population inherently at risk for medication misadventures secondary to declining renal and hepatic function and predisposed to drug–drug interactions due to other medical comorbidities. The advent of novel agents that require minimal therapeutic monitoring and that have few restrictions on dietary or concomitant medication use represent significant advantages over the use of warfarin in this subpopulation. Intimate understanding of the nuances to use of each of these new agents is essential to assure optimal safety and efficacy in the prevention of stroke. Acknowledgments The authors report no funding was received for the preparation of this paper. The authors report no relevant conflicts of interest. The authors have no additional acknowledgements.

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Novel oral anticoagulants for stroke prevention in the geriatric population.

Prior to the availability of several newer anticoagulant medications, there had been no new advances in anticoagulation management for stroke preventi...
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