Annals of Medicine, 2015; Early Online: 1–11 © 2015 Informa UK, Ltd. ISSN 0785-3890 print/ISSN 1365-2060 online DOI: 10.3109/07853890.2015.1015600
review ARTICLE
Effective practical management of patients with atrial fibrillation when using new oral anticoagulants Jafna L. Cox
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Division of Cardiology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; Department of Medicine and Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada; Capital Health, Halifax, Nova Scotia, Canada
Practical management of stroke prevention in patients with non-valvular atrial fibrillation (AF) requires physicians to find the optimal balance between maximizing prevention of ischaemic stroke and minimizing the risk of bleeding. Vitamin K antagonists have traditionally been used for stroke prevention in patients with AF; however, they have been associated with increased risk of bleeding, particularly intracranial haemorrhage. New oral anticoagulants (OACs) have shown similar efficacy to the vitamin K antagonist warfarin but with a reduced risk of bleeding, particularly life-threatening bleeding such as intracranial haemorrhage. Decisions about which new OAC therapy to use may be influenced by patient characteristics such as age, renal function, co-medication use, and bleeding risk. This review uses a case-based approach to highlight the practical management issues to be considered by the physician when selecting a new OAC for stroke prevention in patients with nonvalvular AF. Key words: Apixaban, atrial fibrillation, dabigatran, new oral anticoagulant, rivaroxaban, stroke prevention
Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence of 10 million in Europe and 3 million in the United States (1,2). By 2050, this prevalence is expected to increase in both regions to approximately 25–30 million and 8 million, respectively (1). The risk of AF increases with age, from 0.3% in those aged 18–27 years to 2.1% and 17.6% in those aged 50–55 years and 80 years, respectively (3). Patients with AF can have an increased risk of stroke up to seven times that of those without AF, resulting in an incidence of approximately 5% (4). The risk of stroke attributable to AF also increases with age, from 1.5% in those aged 50–59 years to 23.5% in those aged 80–89 years (5). Overall, approximately 15% of strokes are due to AF (6), and these are often associated with more severe outcomes in terms of morbidity and mortality than non-AF-related strokes. Vitamin K antagonists (VKAs), such as warfarin, have traditionally been the oral anticoagulants (OACs) used for stroke
Key messages •• The new oral anticoagulants apixaban, dabigatran, and rivaroxaban are approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; this approval is a result of their favourable benefit–risk profiles compared with that of warfarin, the current standard of care. •• All of the new oral anticoagulants have demonstrated non-inferiority to warfarin in reducing the risk of stroke and systemic embolism and in reducing the risk of major bleeding, particularly intracranial haemorrhage or fatal bleeding. •• Practical management of stroke prevention in patients with atrial fibrillation is no longer about whether to choose between warfarin and a new oral anticoagulant, but rather which new oral anticoagulant is appropriate for use in a particular patient and what its limitations are.
prevention in patients with AF, with warfarin specifically shown to reduce this risk by 64% compared with placebo or no treatment (7). However, VKAs are associated with substantial challenges. Most notable is the difficulty in achieving adequate time spent in therapeutic range, defined by the international normalized ratio (INR; target range 2.0–3.0). In controlled clinical trials, VKAtreated patients have been within this INR range only 55%–65% of the time (8–10), but this falls to below 50% in routine clinical practice, which may offset the benefits of VKAs (11). VKAs also have significant interactions with food, alcohol, and drugs (11). New OACs, such as apixaban, dabigatran, and rivaroxaban, have all shown efficacy and safety profiles similar to those of warfarin, but are uniformly more easily and dependably used. Table I (12–15) shows a comparison of the basic pharmacological properties of warfarin with those of the new OACs. This review will use a case-based approach to focus on the practical management of stroke prevention in patients with AF using the currently licensed new OACs.
Correspondence: Professor Jafna L. Cox, MD, FRCPC, FACC, Division of Cardiology, Queen Elizabeth II Health Sciences Centre, New Halifax Infirmary Site, Room 2147, 1796 Summer Street, Halifax, Nova Scotia, B3H 3A7, Canada. Fax: 1 902-473-8616. E-mail: [email protected] (Received 5 November 2014; accepted 30 January 2015)
2 J. L. Cox Table I. Comparison of pharmacological properties of oral anticoagulants. Warfarin (12) Mode of action Tmax (hours) T1/2 (hours) Routine monitoring Administration Drug interaction Renal excretion
Apixaban (13)
Dabigatran (14)
Inhibits production of vitamin K-dependent coagulation factors 72–96 20–60
Direct inhibitor of Factor Xa 3–4 ∼12
Direct inhibitor of Factor IIa 0.5–2 12–14
Required with INR Adjusted dose (based on INR), od CYP2C9, CYP1A2, CYP3A4 inhibitors; dietary vitamin K ∼92% excreted as metabolites in urine
Not required 5 mg bid Potent CYP3A4 and P-gp inhibitors ∼27% renal elimination
Not required 150 mg bid P-gp inhibitors 85% renal elimination
Rivaroxaban (15) Direct inhibitor of Factor Xa 2–4 5–13 (5–9 healthy; 11–13 elderly) Not required 20 mg od Potent CYP3A4 and Pgp inhibitors 33% renal elimination
id twice daily; CYP cytochrome P450; INR international normalized ratio; od once daily; P-gp P-glycoprotein; T1/2 half-life; Tmax time to b maximum concentration.
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Patient case study Figure 1A introduces our patient case study, with various additional scenarios detailed in Figure 1B. This will provide a context to highlight the practical management issues and challenges associated with stroke prevention in patients with AF using the new OACs.
Balancing stroke prevention and bleeding risk What does this all mean? Anticoagulant therapy for any indication, including stroke prevention in patients with AF, is associated with an increased risk of bleeding. Therefore, it is important to weigh treatment
benefit versus hazard, and risk stratification schemes have been developed to support this objective. The original risk predictor for stroke was the CHADS2 score (16); however, this score fails to identify many patients at intermediate risk. For example, the patient described in Figure 1A would have a CHADS2 score of 0 and, therefore, would not previously have been considered as an obvious candidate for anticoagulation (although the patient’s nominal annual stroke risk would be 1.9%, the confidence interval ranges from a low risk of 1.2% to a risk as high as 3.0%). The CHA2DS2-VASc score was subsequently developed to incorporate additional risk factors known to contribute to the overall risk of stroke, including female sex and vascular disease. Most importantly, however, it emphasized the relevance of increasing age as a risk factor, awarding 1 point for an age of 65–74 years and 2 points for an age 75 years. This has improved
(A) • • •
• •
67-year-old female with a 1-month history of intermittent palpitations Past medical history: - Stable CAD, prior GI bleeding event, hyperlipidaemia Physical examination: - 5´2˝ (1.58 m) tall, 122 lbs (55.3 kg) - HR 102 bpm, irregularly irregular; BP 134/80 mmHg - Chest and CV examinations otherwise normal Medication: - ASA, metoprolol, rosuvastatin, Acetominophen extra strength Investigations: - CBC, liver function tests, TSH all normal; CrCl 40 mL/min - ECG: AF at 96 BPM, otherwise unremarkable - Echo: mild LA enlargement, normal RV and LV size and function
(B) • • •
• •
88-year-old female, severely kyphotic but ambulatory with a cane, presenting with a 1-month history of intermittent palpitations Past medical history: - Stable CAD, prior GI bleeding event, frequent falls, hyperlipidaemia Physical examination: - 5´2˝ (1.58 m) tall, 122 lbs (55.3 kg) - HR 102 bpm, irregularly irregular; BP 134/80 mmHg - Chest and CV examinations otherwise normal Medication: - ASA, metoprolol, rosuvastatin, Acetominophen extra strength Investigations: - CBC, liver function tests, TSH all normal; CrCl 35 mL/min - ECG: AF at 96 BPM, otherwise unremarkable - Echo: mild LA enlargement, normal RV and LV size and function
Figure 1. A: Patient case study. B: Different scenario of patient case study (changes shown in italics). AF atrial fibrillation; ASA acetylsalicylic acid; BP blood pressure; bpm, beats per minute; CAD coronary artery disease; CBC complete blood count; CrCl creatinine clearance; CV cardiovascular; ECG electrocardiogram; GI gastrointestinal; HR heart rate; ICH, intracranial haemorrhage; LA left atrial; LV left ventricle; RV right ventricle; TSH thyroid stimulating hormone.
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Practical management of new oral anticoagulants for AF 3 stroke risk stratification in patients with AF (17). Assessing our patient (Figure 1A) using CHA2DS2-VASc results in a score of 3 (vascular disease, age 65–74 years, and female sex) and a nominal annual stroke risk of 3.2%, which is sufficient to require an OAC for stroke prevention according to all guidelines (11,18–20). Bleeding risk calculators have also been created. The HASBLED score was specifically developed to estimate the 1-year risk of major bleeding in patients with AF (21). This score has an advantage over other bleeding risk scores, such as HEMORR2HAGES, in that it does not require any laboratory or genetic testing and can be assessed from medical records or routine testing in patients newly diagnosed with AF (21). Referring back to our patient (Figure 1A), we can see that she has had a prior gastrointestinal (GI) bleeding event, is aged 65 years, and is currently taking acetylsalicylic acid (ASA). The HAS-BLED score defines abnormal renal function as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 mmol/L (21). However, the new OAC clinical trials and label recommendations all used creatinine clearance (CrCl) to assess renal function (22). Our patient has a CrCl of 40 mL/min, which is classified as moderate renal impairment. If an additional point is given for this, then our patient has a HAS-BLED score of 4, putting her at high risk of an estimated 8.7 bleeding events per 100 patient-years (21). Because this is almost three times the patient’s apparent stroke risk, the appropriateness of antithrombotic therapy might be questioned. Bleeding risk is often cited as one of the main reasons not to prescribe anticoagulants to patients with AF (23). However, stroke risk is often underestimated, whereas the risk of bleeding with anticoagulants such as VKAs and new OACs is often overestimated. In general, the benefits of stroke prevention in most cases outweigh the risk of bleeding. A Canadian survey of physicians treating patients with AF and patients at high risk of developing AF found that, compared with physicians, patients placed more value on stroke avoidance than bleeding risk. The mean thresholds for the minimum number of strokes to be prevented and the maximum increase in the risk of acceptable excess bleeding in 100 patients treated with warfarin over 2 years were 2.5 and 10.3 in physicians, respectively, and 1.8 and 17.4 in patients, respectively (24).
How to reduce the risk of bleeding in patients receiving OAC therapy It is important to recognize that the risk of bleeding in patients receiving OACs can often be reduced, whereas the risk of stroke cannot be improved. For example, the nominally high bleeding risk of our patient can be positively modified by simply withdrawing ASA therapy, thereby reducing the HAS-BLED score to 3 and putting our patient at the lower estimated risk of 3.74 bleeding events per 100 patient-years (21). The HAS-BLED risk score can also be modified, as applicable, with adequate control of hypertension (itself an important contributor to stroke risk), reducing alcohol consumption, and monitoring renal function. Other methods to reduce bleeding risk include the provision of balance and mobility aids to patients with a history of falls and the use of proton pump inhibitors in patients at risk of a GI bleeding event. The major concern with warfarin is the increased risk of bleeding—in particular, intracranial haemorrhage (ICH); the risk of death is significantly increased in any patient treated with warfarin who suffers an ICH (25). All of the new OACs have been associated with significantly lower rates of ICH compared with warfarin in phase III clinical studies. Increasing the intensity of warfarin treatment (from INR 2.0 towards INR 3.0) is also strongly associated with an increased risk of death (P 0.01 for trend) (25). As a result, VKAs tend to be under-used in patients
requiring anticoagulation. Aggravating matters is the fact that patient adherence to warfarin therapy is poor, with one population-based cohort study in Canadian patients from 1997 to 2008 finding a discontinuation rate of 31.8% within 1 year of treatment commencement, which rises to 61.3% within 5 years (26).
Selecting a new oral anticoagulant What has been demonstrated in clinical studies? Clinical trials of the new OACs have shown efficacy and safety profiles that are similar to, and in some cases better than, those of warfarin. Key data from these clinical trials are presented in Table II (8–10,27–31). In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, apixaban was found to reduce the rates of stroke and systemic embolism compared with warfarin (1.27% versus 1.60%, respectively; P 0.01 for superiority) (8). Major bleeding was also reduced with apixaban in comparison with warfarin (2.13% versus 3.09% per year, respectively; P 0.001) (8). In the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, two doses of dabigatran (110 mg and 150 mg twice daily [bid]) were compared with warfarin (9). Both doses of dabigatran were found to be non-inferior to warfarin in the prevention of stroke in patients with AF (P 0.001), but only the dabigatran 150 mg bid dose was found to be superior to warfarin (P 0.001) (9). Rates of major bleeding were 2.71% and 3.11% per year for the dabigatran 110 mg and 150 mg bid doses, respectively, compared with 3.36% per year with warfarin (9). There were significantly higher rates of GI bleeding with dabigatran 150 mg bid compared with warfarin (P 0.001) (9). Results from ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) found rivaroxaban to be non-inferior to warfarin. In the intention-to-treat analysis, the primary efficacy end-point of stroke or systemic embolism occurred in 269 patients in the rivaroxaban group (2.1% per year) and 306 patients in the warfarin group (2.4% per year; P 0.001 for non-inferiority; P 0.12 for superiority) (10). Major and non-major clinically relevant bleeding occurred in 14.9% and 14.5% of patients per year in the rivaroxaban- and warfarin-treated groups, respectively (10). A significant increase in the rate of GI bleeding was noted with rivaroxaban compared with warfarin (3.2% versus 2.2% per year, respectively; P 0.001) The major clinical recommendations for antithrombotic management in patients with AF are presented in Table III (11,20,22) and are similar. Patients who are eligible for, but not currently on, any anticoagulant should be immediately started on such therapy, preferably one of the new OACs as per international practice guideline recommendations. Switching patients already on warfarin to a new OAC may be considered, especially in those who are poorly maintained on warfarin. In this instance, the directions given in the relevant product monographs are that warfarin must be stopped and the patient’s INR must be 2.0 before starting therapy with apixaban or dabigatran (13,14) or 3.0 when switching to rivaroxaban. Switching from a parenteral anticoagulant to a new OAC can be done 0–2 hours before the next scheduled dose of the parenteral anticoagulant or at the time of discontinuation for continuous parenteral anticoagulants (e.g. unfractionated heparin) (14,15). In the event of a missed dose, patients treated with rivaroxaban should take a dose immediately and carry on with the schedule as normal
80 mL/min eGFR: 0.99% vs 1.12% (HR 0.88; 95% CI 0.64–1.22) 50 to 80 mL/min eGFR: 1.24% vs 1.69% (HR 0.74; 95% CI 0.56–0.97) 50 mL/min eGFR: 2.11% vs 2.67% (HR 0.79; 95% CI 0.55–1.14) P value for interaction: 0.705 (30) 80 mL/min eGFR: 1.46% vs 1.84% (HR 0.80; 95% CI 0.61–1.04) 50 to 80 mL/min eGFR: 2.45% vs 3.21% (HR 0.77; 95% CI 0.62–0.94) 50 mL/min eGFR: 3.21% vs 6.44% (HR 0.50; 95% CI 0.38–0.66) P value for interaction: 0.03d (30)
Patients with renal impairment: Primary efficacy end-point (stroke and SE) vs warfarin
Patients with renal impairment: Principal safety outcome vs warfarin
CrCl 50 mL/min: 5.45% vs 5.49% per year (HR 0.99; 95% CI 0.77–1.28) CrCl 50 to 80 mL/min: 2.84% vs 3.70% per year (HR 0.76; 95% CI 0.62–0.94) CrCl 80 mL/min: 1.48% vs 2.43% (HR 0.61; 95% CI 0.44–0.84) per year P value for interaction: 0.06e (31)
CrCl 50 mL/min: 5.50% vs 5.49% per year (HR 1.01; 95% CI 0.79–1.30) CrCl 50 to 80 mL/min: 3.35% vs 3.70% per year (HR 0.91; 95% CI 0.75–1.11) CrCl 80 mL/min: 1.48% vs 2.43% (HR 0.84; 95% CI 0.62–1.13) per year P value for interaction: 0.64e (31)
18,113 Dose-adjusted warfarin (target INR 2.0–3.0) 110 mg bid 150 mg bid 1.53% vs 1.69% (RR 0.91; 95% CI 1.11% vs 1.69% (RR 0.66; 95% CI 0.74–1.11; P 0.001) 0.53–0.82; P 0.001) 2.71% vs 3.36% (HR 0.80; 95% CI 3.11% vs 3.36% (HR 0.93; 95% CI 0.69–0.93; P 0.003e 0.81–1.07; P 0.31)e 75 years: 1.32% vs 1.43% (RR 0.93; 75 years: 0.90% vs 1.43% (RR 0.63; 95% CI 0.70–1.22) 95% CI 0.46–0.86) 75 years: 1.89% vs 2.14% (RR 0.88; 75 years: 1.43% vs 2.14% (RR 0.67; 95% 95% CI 0.66–1.17) CI 0.49–0.90) P value for interaction: 0.81 (28) P value for interaction: 0.81 (28) 75 years: 1.89% vs 3.04% (RR 0.62; 75 years: 2.12% vs 3.04% (RR 0.70; 95% CI 0.50–0.77) 95% CI 0.57–0.86) 75 years: 4.43% vs 4.37% (RR 1.01; 75 years: 5.10% vs 4.37% (RR 1.18; 95% CI 0.83–1.23) 95% CI 0.98–1.42) P value for interaction: 0.001e (28) P value for interaction: 0.001e (28) CrCl 50 mL/min: 2.15% vs 2.78% CrCl 50 mL/min: 1.52% vs 2.78% per per year year CrCl 50 to 79 mL/min: CrCl 50 to 79 mL/min: 1.20% vs 1.76% per 1.70% vs 1.76% per year year CrCl 80 mL/min: 0.94% vs 0.98% CrCl 80 mL/min: 0.75% vs 0.98% per per year year P value for interaction: 0.60 P value for interaction: 0.54
RE-LY (dabigatran) (9)
20 mg odb 2.1% vs 2.4% (HR 0.88; 95% CI 0.75–1.03; P 0.001) 14.9% vs 14.5% (HR 1.03; 95% CI 0.96–1.11; P 0.44)f 75 years: 2.00% vs 2.10% (HR 0.96; 95% CI 0.78–1.19) 75 years: 2.29% vs 2.85% (HR 0.80; 95% CI 0.63–1.02) P value for interaction; 0.31d (29) 75 years: 2.69% vs 2.79% (HR 0.96; 95% CI 0.78–1.19) 75 years: 4.86% vs 4.40% (HR 1.11; 95% CI 0.92–1.34) P value for interaction: 0.34f (29) CrCl 50 mL/min 1.57 vs 2.00 events per 100 patient-years (HR 0.78; 95% CI 0.63–0.98) CrCl 30 to 49 mL/min: 2.32 vs 2.77 events per 100 patient-years (HR 0.84, 95% CI 0.57–1.23) P value for interaction: 0.76 CrCl 50 mL/min: 14.24 vs 13.67 events per 100 patient-years (HR 1.04; 95% CI 0.96–1.13) CrCl 30 to 49 mL/min 17.82 vs 18.28 events per 100 patient-years (HR 0.98; 95% CI 0.84–1.14) P value for interaction: 0.45
14,264
ROCKET AF (rivaroxaban) (10)
aReduced dose of 2.5 mg bid was tested for a subset of patients with two or more of the following criteria: age 80 years, body weight 60 kg, serum creatinine 1.5 mg/dL (133 mmol/L). bReduced dose of 15 mg od was tested in patients with renal impairment (CrCl 30–49 mL/min). cIn intention-to-treat population. dMajor bleeding defined according to the ISTH criteria as clinically overt bleeding accompanied by a decrease in the haemoglobin level of 2 g/dL or transfusion of 2 units of packed red cells, occurring at a critical site or resulting in death. eDefined as major haemorrhage. fPrincipal safety outcome defined as composite of major and non-major clinically relevant bleeding. bid twice daily; CI confidence interval; CrCl creatinine clearance; eGFR estimated glomerular filtration rate; HR hazard ratio; INR international normalized ratio; ISTH International Society on Thrombosis and Haemostasis; od once daily; RR relative risk; SE systemic embolism; vs versus.
65 years: 1.17% vs 1.51% 65 to 75 years: 1.99% vs 2.82% 75 years: 3.33% vs 5.19% P value for interaction: 0.63d (27)
5 mg bida 1.27% vs 1.60% (HR 0.79; 95% CI 0.66–0.95; P 0.001) 2.13% vs 3.09% (HR 0.69; 95% CI 0.60–0.80; P 0.001)d 65 years: 1.00% vs 0.86% 65 to 75 years: 1.25% vs 1.73% 75 years: 1.56% vs 2.19% P value for interaction: 0.11 (27)
18,201
ARISTOTLE (apixaban) (8)
Elderly patients: principal safety outcome vs warfarin
Elderly patients: primary efficacy end-point (stroke and SE) vs warfarin
Patients randomized Comparator Doses tested Primary efficacy end-point (stroke and SE) vs warfarinc Principal safety outcome vs warfarin
Table II. Key data from new oral anticoagulant phase III trials.
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4 J. L. Cox
Practical management of new oral anticoagulants for AF 5 Table III. Major clinical recommendations for antithrombotic management in patients with atrial fibrillation. Canadian guidelines Low stroke risk (CHADS2 0)
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Intermediate stroke risk (CHADS2 1)
High stroke risk (CHADS2 2)
American guidelines
European guidelines
CCS (19) Lower-risk patients (no additional risk factors)—no therapy Low-risk patients (additional risk factors of female sex/vascular disease)—ASA recommended Higher-risk patients (age 65 years or combination of female sex and vascular disease)—OAC recommended (dabigatran, rivaroxaban, and apixaban recommended over warfarin)a OAC is recommended (dabigatran, apixaban, and rivaroxaban recommended over warfarin)a
ACCP (20) No therapy is preferable, but patients who choose therapy should be given ASA 75–325 mg od or in combination with clopidogrel
AHA/ACC/HRS (18) No antithrombotic therapy is recommended
ESC (11,22) No antithrombotic therapy is needed
OAC is recommended over ASA (dabigatran is recommended over warfarin)b
OAC therapy recommended; ASA may be considered
OAC is recommended (dabigatran, apixaban, and rivaroxaban recommended over warfarin)a
OAC therapy is preferable to ASA Dabigatran 150 mg bid is preferable to VKA therapyb
OAC therapy is recommended (warfarin, dabigatran, apixaban, and rivaroxaban)
VKA therapy or ASA 75–325 mg daily in patients who refuse or have a clear contraindication to OAC therapy Or a direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban or apixaban), recommended over VKA when OAC is required VKA therapy, dose adjusted to achieve target INR of 2.0–3.0 Or a direct thrombin inhibitor (dabigatran) Or oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban)
ACC American College of Cardiology; ACCP American College of Chest Physicians; AHA American Heart Association; ASA acetylsalicylic acid; bid twice daily; CCS Canadian Cardiovascular Society; ESC European Society of Cardiology; HRS Heart Rhythm Society; INR international normalized ratio; OAC oral anticoagulant; od once daily; VKA vitamin K antagonist. a Preference for newer agents is less clear in patients treated with warfarin with stable INR and no bleeding complications. bOnly dabigatran had received regulatory approval for use in atrial fibrillation when the 2012 ACCP guidelines were published; therefore, the guidelines did not make any recommendations for apixaban or rivaroxaban.
(13,15). Missed apixaban and dabigatran doses can be taken up to 6 hours before the next scheduled dose (14). However, the dose should be omitted if there is 6 hours left before the next scheduled dose. Double dosing is not recommended for any of the new OACs (14,15). No international guideline recommends any specific new OAC over the others; however, it is acknowledged that patient characteristics, drug compliance, and tolerability, as well as cost, may influence which new OAC is chosen (22). The recommended doses of apixaban and dabigatran for stroke prevention in patients with AF are 5 mg and 150 mg, respectively; both are taken orally bid (13,14). However, the dose of dabigatran is reduced to 110 mg bid in patients aged 80 years. In patients aged between 75 and 80 years, or in those with an increased risk of bleeding, moderate renal impairment, gastritis, oesophagitis, or gastro-oesophageal reflux, either the 150 mg or 110 mg bid dose of dabigatran can be given at the discretion of the physician (14), with the lower dose tending to be favoured. The 110 mg dose of dabigatran is not approved in the United States for the prevention of stroke in patients with AF. Instead, the recommended dose for patients with CrCl 15–30 mL/min is 75 mg bid orally (20), but this is based on pharmacological assumptions because this dose has not been tested in patients with AF. In Europe, dabigatran is contraindicated in patients with AF who have severe renal impairment (CrCl 30 mL/min) (14). The usual apixaban dose is 5 mg bid, although it should be reduced to 2.5 mg bid if two or more of the following risk factors are present: age 80 years, weight 60 kg, or creatinine 133 mmol/L. Rivaroxaban has a recommended dose of 20 mg, but differs from apixaban and dabigatran in that it has a oncedaily (od) dosing regimen (15). With CrCl 15– 50 mL/min, the
rivaroxaban dose is reduced to 15 mg od. To ensure high bioavailability, rivaroxaban at either the 15 mg or the 20 mg dose should be taken with food (15). Note that a full meal is not a requirement in this regard, nor does the meal need to be dinner. Ultimately, there is an evolving treatment paradigm for stroke prevention in patients with AF. Increasingly, the issue is not whether to choose warfarin or a new OAC, but rather which new OAC to select for treatment. A suggested approach is summarized in Table IV.
Adherence to new OACs Compliance with new OAC regimens is crucial because the anticoagulant effect fades after 12–24 hours (32). A retrospective analysis in four therapeutic classes of drugs (antidiabetic, antihyperlipidaemic, antiplatelet, and cardiac) found that adherence with od regimens was generally higher than for bid regimens, by approximately 14% (33). Results of another study showed lower persistence with warfarin compared with dabigatran therapy in patients with newly diagnosed AF at 6 months: 50% and 64%, respectively, falling to 24% and 41%, respectively, at 12 months (34). New data from a prospective registry of new OACs have shown even higher rates of adherence to dabigatran therapy, as well as high rates of adherence to rivaroxaban therapy: after 6 months of follow-up, 74.3% of patients were still on dabigatran (bid) therapy, and 90.9% were still on rivaroxaban (od) therapy (32,35). The issue of whether a missed dose with the once-daily regimen of rivaroxaban is more consequential than missing a dose of one of the new OACs with bid dosing has often been raised; however, to put matters in perspective, enoxaparin is generally dosed once daily for thromboembolic prevention
6 J. L. Cox Table IV. Summary of choice of oral anticoagulants based on patient characteristics. From reference (36) with permission.
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Characteristic
Drug choice
Rationale
Mechanical or valvular AF Liver dysfunction with elevated INR Stable on warfarin CrCl 30 mL/min
Warfarin Warfarin Warfarin Warfarin
CrCl 30–50 mL/min
Rivaroxaban or apixaban
Dyspepsia/upper GI complaints Recent GI bleeding event
Rivaroxaban or apixaban Apixaban
Recent ischaemic stroke on warfarin
Dabigatran
Recent ACS Poor compliance with bid dosing or request for an od regimen
Rivaroxaban or apixaban Rivaroxaban
New OACs not studied New OACs require hepatic metabolism Consider switching at patient request Such patients were excluded from trials with new agents Oral Factor Xa inhibitors are less affected by impaired renal function than dabigatran Dyspepsia in up to 10% given dabigatran More GI bleeding with dabigatran (150 mg bid) or rivaroxaban than with warfarin Dabigatran (150 mg bid) associated with lowest risk of ischaemic stroke versus warfarin Small MI signal with dabigatran Only oral agent that is currently od
ACS acute coronary syndrome; AF atrial fibrillation; bid twice daily; CrCl creatinine clearance; GI gastrointestinal; INR international normalized ratio; MI myocardial infarction; OAC, oral anticoagulant; od once daily.
or treatment, yet its half-life is somewhat shorter than that of rivaroxaban (36). Although the new OACs are generally well tolerated, both dabigatran doses in the RE-LY trial were associated with significantly higher levels of dyspepsia compared with warfarin (11.8% and 11.3% with 110 mg and 150 mg dabigatran, respectively, compared with 5.8% for warfarin; P 0.001 for both comparisons) (9). This may affect adherence to dabigatran. However, dyspepsia with dabigatran therapy may be eased by taking the drug with food or using proton pump inhibitors (22), although this presents a further pill burden for patients. Patient education is necessary to ensure compliance particularly at each prescription renewal (37).
Patients with declining renal function Treating patients with impaired renal function Figure 1B shows that our patient has moderate renal impairment (CrCl 35 ml/min), which could easily develop into severe renal impairment. This patient may be at an increased risk of bleeding according to the HAS-BLED score. One way to reduce bleeding risk is to monitor renal function at least yearly in patients with normal renal function or mild renal impairment (CrCl 50 mL/min) and ensure that new OACs are being appropriately dosed. If a patient has moderate renal impairment (CrCl 30–50 mL/min), such as our patient case, monitoring should be conducted at least every 6 months, with a further increased frequency of monitoring in patients with a CrCl of 30 mL/min (every 3 months) (22). Additionally, renal function must be monitored at the time of any acute, especially dehydrating, illness. Results from the key new OAC trials related to renal impairment are shown in Table II. Overall, the results show that patients with renal impairment treated with new OACs experienced fewer primary efficacy end-point events than those treated with warfarin. Figure 2 shows the total drug exposure with the new OACs in patients with declining renal function (13–15). None of the European, Canadian, or Australian guidelines recommend new OACs for use in patients with a CrCl 30 mL/min (19,22,38), although in Europe both rivaroxaban and apixaban may be used with caution in patients with CrCl 15–29 mL/min (13,15) (use in patients with CrCl 15 mL/min is not recommended).
Stroke prevention in elderly patients with atrial fibrillation Challenges associated with treating elderly patients with AF Findings from a literature review showed that physicians are reluctant to recommend warfarin for elderly patients with AF, despite evidence of increased benefit in these patients versus younger patients (23). The risk of falls and a history of bleeding events were also shown to be disproportionate barriers to warfarin prescription such that antiplatelet drugs were more commonly the antithrombotic agents used (23). Elderly patients are more likely to have renal impairment, other co-morbidities, and frequent co-medications that increase the risk of stroke and/or the risk of bleeding. Sub-analyses carried out for different age groups help to clarify the current clinical data for the physician (Table II). Imagine that the case study were revised such that our patient is now 88 years of age, with kyphosis and a risk of falls (Figure 1B). This clearly puts her at increased risk of bleeding. However, as mentioned previously, the risk of stroke also increases with age such that any hazard related to falls is generally exceeded—often markedly so—by the stroke risk. Indeed, the average elderly patient would need to fall almost 300 times a year before the strokerelated risk of a subdural haematoma outweighed the risk of stroke with AF (39). Warfarin therapy in the elderly is specifically associated with an increased risk of ICH (25); this risk of ICH is significantly reduced with the new OACs, as shown in Table III.
Stroke prevention in very elderly patients Given that the incidence of cognitive impairment increases with age and global populations are living longer, very elderly patients with at least some cognitive impairment and a multitude of medical problems, including atrial fibrillation, are becoming ever more commonly seen in medical practice. In the past, using warfarin in such patients raised concerns about their inherent bleeding risk (40), but also about their adherence to both the drug and its regular monitoring, such that its use in this clinical context was particularly limited. An advantage of the new OACs in this specific patient population is their relative ease of use and, as such, should allow greater comfort with their being prescribed to the very elderly, including those with cognitive impairment. Clearly, it is preferable to have a cognitively impaired elderly patient still able to ambulate and follow basic directions than one who is bedridden and wholly dependent on others after a major disabling stroke.
AUC ratio versus normal renal function
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Practical management of new oral anticoagulants for AF 7 7
7
7
6
6
6
5
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5 Dabigatran (85% cleared renally)
Apixaban (27% cleared renallya)
Rivaroxaban (33% cleared renallyb)
4
4
4
3
3
3
2
2
2
1
1
1
0
Normal renal function (≥80 mL/min)
Mild renal impairment (50–79 mL/min)
Moderate renal impairment (30–49 mL/min)
Severe renal impairment (
review ARTICLE
Effective practical management of patients with atrial fibrillation when using new oral anticoagulants Jafna L. Cox
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Division of Cardiology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; Department of Medicine and Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada; Capital Health, Halifax, Nova Scotia, Canada
Practical management of stroke prevention in patients with non-valvular atrial fibrillation (AF) requires physicians to find the optimal balance between maximizing prevention of ischaemic stroke and minimizing the risk of bleeding. Vitamin K antagonists have traditionally been used for stroke prevention in patients with AF; however, they have been associated with increased risk of bleeding, particularly intracranial haemorrhage. New oral anticoagulants (OACs) have shown similar efficacy to the vitamin K antagonist warfarin but with a reduced risk of bleeding, particularly life-threatening bleeding such as intracranial haemorrhage. Decisions about which new OAC therapy to use may be influenced by patient characteristics such as age, renal function, co-medication use, and bleeding risk. This review uses a case-based approach to highlight the practical management issues to be considered by the physician when selecting a new OAC for stroke prevention in patients with nonvalvular AF. Key words: Apixaban, atrial fibrillation, dabigatran, new oral anticoagulant, rivaroxaban, stroke prevention
Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence of 10 million in Europe and 3 million in the United States (1,2). By 2050, this prevalence is expected to increase in both regions to approximately 25–30 million and 8 million, respectively (1). The risk of AF increases with age, from 0.3% in those aged 18–27 years to 2.1% and 17.6% in those aged 50–55 years and 80 years, respectively (3). Patients with AF can have an increased risk of stroke up to seven times that of those without AF, resulting in an incidence of approximately 5% (4). The risk of stroke attributable to AF also increases with age, from 1.5% in those aged 50–59 years to 23.5% in those aged 80–89 years (5). Overall, approximately 15% of strokes are due to AF (6), and these are often associated with more severe outcomes in terms of morbidity and mortality than non-AF-related strokes. Vitamin K antagonists (VKAs), such as warfarin, have traditionally been the oral anticoagulants (OACs) used for stroke
Key messages •• The new oral anticoagulants apixaban, dabigatran, and rivaroxaban are approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; this approval is a result of their favourable benefit–risk profiles compared with that of warfarin, the current standard of care. •• All of the new oral anticoagulants have demonstrated non-inferiority to warfarin in reducing the risk of stroke and systemic embolism and in reducing the risk of major bleeding, particularly intracranial haemorrhage or fatal bleeding. •• Practical management of stroke prevention in patients with atrial fibrillation is no longer about whether to choose between warfarin and a new oral anticoagulant, but rather which new oral anticoagulant is appropriate for use in a particular patient and what its limitations are.
prevention in patients with AF, with warfarin specifically shown to reduce this risk by 64% compared with placebo or no treatment (7). However, VKAs are associated with substantial challenges. Most notable is the difficulty in achieving adequate time spent in therapeutic range, defined by the international normalized ratio (INR; target range 2.0–3.0). In controlled clinical trials, VKAtreated patients have been within this INR range only 55%–65% of the time (8–10), but this falls to below 50% in routine clinical practice, which may offset the benefits of VKAs (11). VKAs also have significant interactions with food, alcohol, and drugs (11). New OACs, such as apixaban, dabigatran, and rivaroxaban, have all shown efficacy and safety profiles similar to those of warfarin, but are uniformly more easily and dependably used. Table I (12–15) shows a comparison of the basic pharmacological properties of warfarin with those of the new OACs. This review will use a case-based approach to focus on the practical management of stroke prevention in patients with AF using the currently licensed new OACs.
Correspondence: Professor Jafna L. Cox, MD, FRCPC, FACC, Division of Cardiology, Queen Elizabeth II Health Sciences Centre, New Halifax Infirmary Site, Room 2147, 1796 Summer Street, Halifax, Nova Scotia, B3H 3A7, Canada. Fax: 1 902-473-8616. E-mail: [email protected] (Received 5 November 2014; accepted 30 January 2015)
2 J. L. Cox Table I. Comparison of pharmacological properties of oral anticoagulants. Warfarin (12) Mode of action Tmax (hours) T1/2 (hours) Routine monitoring Administration Drug interaction Renal excretion
Apixaban (13)
Dabigatran (14)
Inhibits production of vitamin K-dependent coagulation factors 72–96 20–60
Direct inhibitor of Factor Xa 3–4 ∼12
Direct inhibitor of Factor IIa 0.5–2 12–14
Required with INR Adjusted dose (based on INR), od CYP2C9, CYP1A2, CYP3A4 inhibitors; dietary vitamin K ∼92% excreted as metabolites in urine
Not required 5 mg bid Potent CYP3A4 and P-gp inhibitors ∼27% renal elimination
Not required 150 mg bid P-gp inhibitors 85% renal elimination
Rivaroxaban (15) Direct inhibitor of Factor Xa 2–4 5–13 (5–9 healthy; 11–13 elderly) Not required 20 mg od Potent CYP3A4 and Pgp inhibitors 33% renal elimination
id twice daily; CYP cytochrome P450; INR international normalized ratio; od once daily; P-gp P-glycoprotein; T1/2 half-life; Tmax time to b maximum concentration.
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Patient case study Figure 1A introduces our patient case study, with various additional scenarios detailed in Figure 1B. This will provide a context to highlight the practical management issues and challenges associated with stroke prevention in patients with AF using the new OACs.
Balancing stroke prevention and bleeding risk What does this all mean? Anticoagulant therapy for any indication, including stroke prevention in patients with AF, is associated with an increased risk of bleeding. Therefore, it is important to weigh treatment
benefit versus hazard, and risk stratification schemes have been developed to support this objective. The original risk predictor for stroke was the CHADS2 score (16); however, this score fails to identify many patients at intermediate risk. For example, the patient described in Figure 1A would have a CHADS2 score of 0 and, therefore, would not previously have been considered as an obvious candidate for anticoagulation (although the patient’s nominal annual stroke risk would be 1.9%, the confidence interval ranges from a low risk of 1.2% to a risk as high as 3.0%). The CHA2DS2-VASc score was subsequently developed to incorporate additional risk factors known to contribute to the overall risk of stroke, including female sex and vascular disease. Most importantly, however, it emphasized the relevance of increasing age as a risk factor, awarding 1 point for an age of 65–74 years and 2 points for an age 75 years. This has improved
(A) • • •
• •
67-year-old female with a 1-month history of intermittent palpitations Past medical history: - Stable CAD, prior GI bleeding event, hyperlipidaemia Physical examination: - 5´2˝ (1.58 m) tall, 122 lbs (55.3 kg) - HR 102 bpm, irregularly irregular; BP 134/80 mmHg - Chest and CV examinations otherwise normal Medication: - ASA, metoprolol, rosuvastatin, Acetominophen extra strength Investigations: - CBC, liver function tests, TSH all normal; CrCl 40 mL/min - ECG: AF at 96 BPM, otherwise unremarkable - Echo: mild LA enlargement, normal RV and LV size and function
(B) • • •
• •
88-year-old female, severely kyphotic but ambulatory with a cane, presenting with a 1-month history of intermittent palpitations Past medical history: - Stable CAD, prior GI bleeding event, frequent falls, hyperlipidaemia Physical examination: - 5´2˝ (1.58 m) tall, 122 lbs (55.3 kg) - HR 102 bpm, irregularly irregular; BP 134/80 mmHg - Chest and CV examinations otherwise normal Medication: - ASA, metoprolol, rosuvastatin, Acetominophen extra strength Investigations: - CBC, liver function tests, TSH all normal; CrCl 35 mL/min - ECG: AF at 96 BPM, otherwise unremarkable - Echo: mild LA enlargement, normal RV and LV size and function
Figure 1. A: Patient case study. B: Different scenario of patient case study (changes shown in italics). AF atrial fibrillation; ASA acetylsalicylic acid; BP blood pressure; bpm, beats per minute; CAD coronary artery disease; CBC complete blood count; CrCl creatinine clearance; CV cardiovascular; ECG electrocardiogram; GI gastrointestinal; HR heart rate; ICH, intracranial haemorrhage; LA left atrial; LV left ventricle; RV right ventricle; TSH thyroid stimulating hormone.
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Practical management of new oral anticoagulants for AF 3 stroke risk stratification in patients with AF (17). Assessing our patient (Figure 1A) using CHA2DS2-VASc results in a score of 3 (vascular disease, age 65–74 years, and female sex) and a nominal annual stroke risk of 3.2%, which is sufficient to require an OAC for stroke prevention according to all guidelines (11,18–20). Bleeding risk calculators have also been created. The HASBLED score was specifically developed to estimate the 1-year risk of major bleeding in patients with AF (21). This score has an advantage over other bleeding risk scores, such as HEMORR2HAGES, in that it does not require any laboratory or genetic testing and can be assessed from medical records or routine testing in patients newly diagnosed with AF (21). Referring back to our patient (Figure 1A), we can see that she has had a prior gastrointestinal (GI) bleeding event, is aged 65 years, and is currently taking acetylsalicylic acid (ASA). The HAS-BLED score defines abnormal renal function as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 mmol/L (21). However, the new OAC clinical trials and label recommendations all used creatinine clearance (CrCl) to assess renal function (22). Our patient has a CrCl of 40 mL/min, which is classified as moderate renal impairment. If an additional point is given for this, then our patient has a HAS-BLED score of 4, putting her at high risk of an estimated 8.7 bleeding events per 100 patient-years (21). Because this is almost three times the patient’s apparent stroke risk, the appropriateness of antithrombotic therapy might be questioned. Bleeding risk is often cited as one of the main reasons not to prescribe anticoagulants to patients with AF (23). However, stroke risk is often underestimated, whereas the risk of bleeding with anticoagulants such as VKAs and new OACs is often overestimated. In general, the benefits of stroke prevention in most cases outweigh the risk of bleeding. A Canadian survey of physicians treating patients with AF and patients at high risk of developing AF found that, compared with physicians, patients placed more value on stroke avoidance than bleeding risk. The mean thresholds for the minimum number of strokes to be prevented and the maximum increase in the risk of acceptable excess bleeding in 100 patients treated with warfarin over 2 years were 2.5 and 10.3 in physicians, respectively, and 1.8 and 17.4 in patients, respectively (24).
How to reduce the risk of bleeding in patients receiving OAC therapy It is important to recognize that the risk of bleeding in patients receiving OACs can often be reduced, whereas the risk of stroke cannot be improved. For example, the nominally high bleeding risk of our patient can be positively modified by simply withdrawing ASA therapy, thereby reducing the HAS-BLED score to 3 and putting our patient at the lower estimated risk of 3.74 bleeding events per 100 patient-years (21). The HAS-BLED risk score can also be modified, as applicable, with adequate control of hypertension (itself an important contributor to stroke risk), reducing alcohol consumption, and monitoring renal function. Other methods to reduce bleeding risk include the provision of balance and mobility aids to patients with a history of falls and the use of proton pump inhibitors in patients at risk of a GI bleeding event. The major concern with warfarin is the increased risk of bleeding—in particular, intracranial haemorrhage (ICH); the risk of death is significantly increased in any patient treated with warfarin who suffers an ICH (25). All of the new OACs have been associated with significantly lower rates of ICH compared with warfarin in phase III clinical studies. Increasing the intensity of warfarin treatment (from INR 2.0 towards INR 3.0) is also strongly associated with an increased risk of death (P 0.01 for trend) (25). As a result, VKAs tend to be under-used in patients
requiring anticoagulation. Aggravating matters is the fact that patient adherence to warfarin therapy is poor, with one population-based cohort study in Canadian patients from 1997 to 2008 finding a discontinuation rate of 31.8% within 1 year of treatment commencement, which rises to 61.3% within 5 years (26).
Selecting a new oral anticoagulant What has been demonstrated in clinical studies? Clinical trials of the new OACs have shown efficacy and safety profiles that are similar to, and in some cases better than, those of warfarin. Key data from these clinical trials are presented in Table II (8–10,27–31). In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, apixaban was found to reduce the rates of stroke and systemic embolism compared with warfarin (1.27% versus 1.60%, respectively; P 0.01 for superiority) (8). Major bleeding was also reduced with apixaban in comparison with warfarin (2.13% versus 3.09% per year, respectively; P 0.001) (8). In the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, two doses of dabigatran (110 mg and 150 mg twice daily [bid]) were compared with warfarin (9). Both doses of dabigatran were found to be non-inferior to warfarin in the prevention of stroke in patients with AF (P 0.001), but only the dabigatran 150 mg bid dose was found to be superior to warfarin (P 0.001) (9). Rates of major bleeding were 2.71% and 3.11% per year for the dabigatran 110 mg and 150 mg bid doses, respectively, compared with 3.36% per year with warfarin (9). There were significantly higher rates of GI bleeding with dabigatran 150 mg bid compared with warfarin (P 0.001) (9). Results from ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) found rivaroxaban to be non-inferior to warfarin. In the intention-to-treat analysis, the primary efficacy end-point of stroke or systemic embolism occurred in 269 patients in the rivaroxaban group (2.1% per year) and 306 patients in the warfarin group (2.4% per year; P 0.001 for non-inferiority; P 0.12 for superiority) (10). Major and non-major clinically relevant bleeding occurred in 14.9% and 14.5% of patients per year in the rivaroxaban- and warfarin-treated groups, respectively (10). A significant increase in the rate of GI bleeding was noted with rivaroxaban compared with warfarin (3.2% versus 2.2% per year, respectively; P 0.001) The major clinical recommendations for antithrombotic management in patients with AF are presented in Table III (11,20,22) and are similar. Patients who are eligible for, but not currently on, any anticoagulant should be immediately started on such therapy, preferably one of the new OACs as per international practice guideline recommendations. Switching patients already on warfarin to a new OAC may be considered, especially in those who are poorly maintained on warfarin. In this instance, the directions given in the relevant product monographs are that warfarin must be stopped and the patient’s INR must be 2.0 before starting therapy with apixaban or dabigatran (13,14) or 3.0 when switching to rivaroxaban. Switching from a parenteral anticoagulant to a new OAC can be done 0–2 hours before the next scheduled dose of the parenteral anticoagulant or at the time of discontinuation for continuous parenteral anticoagulants (e.g. unfractionated heparin) (14,15). In the event of a missed dose, patients treated with rivaroxaban should take a dose immediately and carry on with the schedule as normal
80 mL/min eGFR: 0.99% vs 1.12% (HR 0.88; 95% CI 0.64–1.22) 50 to 80 mL/min eGFR: 1.24% vs 1.69% (HR 0.74; 95% CI 0.56–0.97) 50 mL/min eGFR: 2.11% vs 2.67% (HR 0.79; 95% CI 0.55–1.14) P value for interaction: 0.705 (30) 80 mL/min eGFR: 1.46% vs 1.84% (HR 0.80; 95% CI 0.61–1.04) 50 to 80 mL/min eGFR: 2.45% vs 3.21% (HR 0.77; 95% CI 0.62–0.94) 50 mL/min eGFR: 3.21% vs 6.44% (HR 0.50; 95% CI 0.38–0.66) P value for interaction: 0.03d (30)
Patients with renal impairment: Primary efficacy end-point (stroke and SE) vs warfarin
Patients with renal impairment: Principal safety outcome vs warfarin
CrCl 50 mL/min: 5.45% vs 5.49% per year (HR 0.99; 95% CI 0.77–1.28) CrCl 50 to 80 mL/min: 2.84% vs 3.70% per year (HR 0.76; 95% CI 0.62–0.94) CrCl 80 mL/min: 1.48% vs 2.43% (HR 0.61; 95% CI 0.44–0.84) per year P value for interaction: 0.06e (31)
CrCl 50 mL/min: 5.50% vs 5.49% per year (HR 1.01; 95% CI 0.79–1.30) CrCl 50 to 80 mL/min: 3.35% vs 3.70% per year (HR 0.91; 95% CI 0.75–1.11) CrCl 80 mL/min: 1.48% vs 2.43% (HR 0.84; 95% CI 0.62–1.13) per year P value for interaction: 0.64e (31)
18,113 Dose-adjusted warfarin (target INR 2.0–3.0) 110 mg bid 150 mg bid 1.53% vs 1.69% (RR 0.91; 95% CI 1.11% vs 1.69% (RR 0.66; 95% CI 0.74–1.11; P 0.001) 0.53–0.82; P 0.001) 2.71% vs 3.36% (HR 0.80; 95% CI 3.11% vs 3.36% (HR 0.93; 95% CI 0.69–0.93; P 0.003e 0.81–1.07; P 0.31)e 75 years: 1.32% vs 1.43% (RR 0.93; 75 years: 0.90% vs 1.43% (RR 0.63; 95% CI 0.70–1.22) 95% CI 0.46–0.86) 75 years: 1.89% vs 2.14% (RR 0.88; 75 years: 1.43% vs 2.14% (RR 0.67; 95% 95% CI 0.66–1.17) CI 0.49–0.90) P value for interaction: 0.81 (28) P value for interaction: 0.81 (28) 75 years: 1.89% vs 3.04% (RR 0.62; 75 years: 2.12% vs 3.04% (RR 0.70; 95% CI 0.50–0.77) 95% CI 0.57–0.86) 75 years: 4.43% vs 4.37% (RR 1.01; 75 years: 5.10% vs 4.37% (RR 1.18; 95% CI 0.83–1.23) 95% CI 0.98–1.42) P value for interaction: 0.001e (28) P value for interaction: 0.001e (28) CrCl 50 mL/min: 2.15% vs 2.78% CrCl 50 mL/min: 1.52% vs 2.78% per per year year CrCl 50 to 79 mL/min: CrCl 50 to 79 mL/min: 1.20% vs 1.76% per 1.70% vs 1.76% per year year CrCl 80 mL/min: 0.94% vs 0.98% CrCl 80 mL/min: 0.75% vs 0.98% per per year year P value for interaction: 0.60 P value for interaction: 0.54
RE-LY (dabigatran) (9)
20 mg odb 2.1% vs 2.4% (HR 0.88; 95% CI 0.75–1.03; P 0.001) 14.9% vs 14.5% (HR 1.03; 95% CI 0.96–1.11; P 0.44)f 75 years: 2.00% vs 2.10% (HR 0.96; 95% CI 0.78–1.19) 75 years: 2.29% vs 2.85% (HR 0.80; 95% CI 0.63–1.02) P value for interaction; 0.31d (29) 75 years: 2.69% vs 2.79% (HR 0.96; 95% CI 0.78–1.19) 75 years: 4.86% vs 4.40% (HR 1.11; 95% CI 0.92–1.34) P value for interaction: 0.34f (29) CrCl 50 mL/min 1.57 vs 2.00 events per 100 patient-years (HR 0.78; 95% CI 0.63–0.98) CrCl 30 to 49 mL/min: 2.32 vs 2.77 events per 100 patient-years (HR 0.84, 95% CI 0.57–1.23) P value for interaction: 0.76 CrCl 50 mL/min: 14.24 vs 13.67 events per 100 patient-years (HR 1.04; 95% CI 0.96–1.13) CrCl 30 to 49 mL/min 17.82 vs 18.28 events per 100 patient-years (HR 0.98; 95% CI 0.84–1.14) P value for interaction: 0.45
14,264
ROCKET AF (rivaroxaban) (10)
aReduced dose of 2.5 mg bid was tested for a subset of patients with two or more of the following criteria: age 80 years, body weight 60 kg, serum creatinine 1.5 mg/dL (133 mmol/L). bReduced dose of 15 mg od was tested in patients with renal impairment (CrCl 30–49 mL/min). cIn intention-to-treat population. dMajor bleeding defined according to the ISTH criteria as clinically overt bleeding accompanied by a decrease in the haemoglobin level of 2 g/dL or transfusion of 2 units of packed red cells, occurring at a critical site or resulting in death. eDefined as major haemorrhage. fPrincipal safety outcome defined as composite of major and non-major clinically relevant bleeding. bid twice daily; CI confidence interval; CrCl creatinine clearance; eGFR estimated glomerular filtration rate; HR hazard ratio; INR international normalized ratio; ISTH International Society on Thrombosis and Haemostasis; od once daily; RR relative risk; SE systemic embolism; vs versus.
65 years: 1.17% vs 1.51% 65 to 75 years: 1.99% vs 2.82% 75 years: 3.33% vs 5.19% P value for interaction: 0.63d (27)
5 mg bida 1.27% vs 1.60% (HR 0.79; 95% CI 0.66–0.95; P 0.001) 2.13% vs 3.09% (HR 0.69; 95% CI 0.60–0.80; P 0.001)d 65 years: 1.00% vs 0.86% 65 to 75 years: 1.25% vs 1.73% 75 years: 1.56% vs 2.19% P value for interaction: 0.11 (27)
18,201
ARISTOTLE (apixaban) (8)
Elderly patients: principal safety outcome vs warfarin
Elderly patients: primary efficacy end-point (stroke and SE) vs warfarin
Patients randomized Comparator Doses tested Primary efficacy end-point (stroke and SE) vs warfarinc Principal safety outcome vs warfarin
Table II. Key data from new oral anticoagulant phase III trials.
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4 J. L. Cox
Practical management of new oral anticoagulants for AF 5 Table III. Major clinical recommendations for antithrombotic management in patients with atrial fibrillation. Canadian guidelines Low stroke risk (CHADS2 0)
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Intermediate stroke risk (CHADS2 1)
High stroke risk (CHADS2 2)
American guidelines
European guidelines
CCS (19) Lower-risk patients (no additional risk factors)—no therapy Low-risk patients (additional risk factors of female sex/vascular disease)—ASA recommended Higher-risk patients (age 65 years or combination of female sex and vascular disease)—OAC recommended (dabigatran, rivaroxaban, and apixaban recommended over warfarin)a OAC is recommended (dabigatran, apixaban, and rivaroxaban recommended over warfarin)a
ACCP (20) No therapy is preferable, but patients who choose therapy should be given ASA 75–325 mg od or in combination with clopidogrel
AHA/ACC/HRS (18) No antithrombotic therapy is recommended
ESC (11,22) No antithrombotic therapy is needed
OAC is recommended over ASA (dabigatran is recommended over warfarin)b
OAC therapy recommended; ASA may be considered
OAC is recommended (dabigatran, apixaban, and rivaroxaban recommended over warfarin)a
OAC therapy is preferable to ASA Dabigatran 150 mg bid is preferable to VKA therapyb
OAC therapy is recommended (warfarin, dabigatran, apixaban, and rivaroxaban)
VKA therapy or ASA 75–325 mg daily in patients who refuse or have a clear contraindication to OAC therapy Or a direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban or apixaban), recommended over VKA when OAC is required VKA therapy, dose adjusted to achieve target INR of 2.0–3.0 Or a direct thrombin inhibitor (dabigatran) Or oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban)
ACC American College of Cardiology; ACCP American College of Chest Physicians; AHA American Heart Association; ASA acetylsalicylic acid; bid twice daily; CCS Canadian Cardiovascular Society; ESC European Society of Cardiology; HRS Heart Rhythm Society; INR international normalized ratio; OAC oral anticoagulant; od once daily; VKA vitamin K antagonist. a Preference for newer agents is less clear in patients treated with warfarin with stable INR and no bleeding complications. bOnly dabigatran had received regulatory approval for use in atrial fibrillation when the 2012 ACCP guidelines were published; therefore, the guidelines did not make any recommendations for apixaban or rivaroxaban.
(13,15). Missed apixaban and dabigatran doses can be taken up to 6 hours before the next scheduled dose (14). However, the dose should be omitted if there is 6 hours left before the next scheduled dose. Double dosing is not recommended for any of the new OACs (14,15). No international guideline recommends any specific new OAC over the others; however, it is acknowledged that patient characteristics, drug compliance, and tolerability, as well as cost, may influence which new OAC is chosen (22). The recommended doses of apixaban and dabigatran for stroke prevention in patients with AF are 5 mg and 150 mg, respectively; both are taken orally bid (13,14). However, the dose of dabigatran is reduced to 110 mg bid in patients aged 80 years. In patients aged between 75 and 80 years, or in those with an increased risk of bleeding, moderate renal impairment, gastritis, oesophagitis, or gastro-oesophageal reflux, either the 150 mg or 110 mg bid dose of dabigatran can be given at the discretion of the physician (14), with the lower dose tending to be favoured. The 110 mg dose of dabigatran is not approved in the United States for the prevention of stroke in patients with AF. Instead, the recommended dose for patients with CrCl 15–30 mL/min is 75 mg bid orally (20), but this is based on pharmacological assumptions because this dose has not been tested in patients with AF. In Europe, dabigatran is contraindicated in patients with AF who have severe renal impairment (CrCl 30 mL/min) (14). The usual apixaban dose is 5 mg bid, although it should be reduced to 2.5 mg bid if two or more of the following risk factors are present: age 80 years, weight 60 kg, or creatinine 133 mmol/L. Rivaroxaban has a recommended dose of 20 mg, but differs from apixaban and dabigatran in that it has a oncedaily (od) dosing regimen (15). With CrCl 15– 50 mL/min, the
rivaroxaban dose is reduced to 15 mg od. To ensure high bioavailability, rivaroxaban at either the 15 mg or the 20 mg dose should be taken with food (15). Note that a full meal is not a requirement in this regard, nor does the meal need to be dinner. Ultimately, there is an evolving treatment paradigm for stroke prevention in patients with AF. Increasingly, the issue is not whether to choose warfarin or a new OAC, but rather which new OAC to select for treatment. A suggested approach is summarized in Table IV.
Adherence to new OACs Compliance with new OAC regimens is crucial because the anticoagulant effect fades after 12–24 hours (32). A retrospective analysis in four therapeutic classes of drugs (antidiabetic, antihyperlipidaemic, antiplatelet, and cardiac) found that adherence with od regimens was generally higher than for bid regimens, by approximately 14% (33). Results of another study showed lower persistence with warfarin compared with dabigatran therapy in patients with newly diagnosed AF at 6 months: 50% and 64%, respectively, falling to 24% and 41%, respectively, at 12 months (34). New data from a prospective registry of new OACs have shown even higher rates of adherence to dabigatran therapy, as well as high rates of adherence to rivaroxaban therapy: after 6 months of follow-up, 74.3% of patients were still on dabigatran (bid) therapy, and 90.9% were still on rivaroxaban (od) therapy (32,35). The issue of whether a missed dose with the once-daily regimen of rivaroxaban is more consequential than missing a dose of one of the new OACs with bid dosing has often been raised; however, to put matters in perspective, enoxaparin is generally dosed once daily for thromboembolic prevention
6 J. L. Cox Table IV. Summary of choice of oral anticoagulants based on patient characteristics. From reference (36) with permission.
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Characteristic
Drug choice
Rationale
Mechanical or valvular AF Liver dysfunction with elevated INR Stable on warfarin CrCl 30 mL/min
Warfarin Warfarin Warfarin Warfarin
CrCl 30–50 mL/min
Rivaroxaban or apixaban
Dyspepsia/upper GI complaints Recent GI bleeding event
Rivaroxaban or apixaban Apixaban
Recent ischaemic stroke on warfarin
Dabigatran
Recent ACS Poor compliance with bid dosing or request for an od regimen
Rivaroxaban or apixaban Rivaroxaban
New OACs not studied New OACs require hepatic metabolism Consider switching at patient request Such patients were excluded from trials with new agents Oral Factor Xa inhibitors are less affected by impaired renal function than dabigatran Dyspepsia in up to 10% given dabigatran More GI bleeding with dabigatran (150 mg bid) or rivaroxaban than with warfarin Dabigatran (150 mg bid) associated with lowest risk of ischaemic stroke versus warfarin Small MI signal with dabigatran Only oral agent that is currently od
ACS acute coronary syndrome; AF atrial fibrillation; bid twice daily; CrCl creatinine clearance; GI gastrointestinal; INR international normalized ratio; MI myocardial infarction; OAC, oral anticoagulant; od once daily.
or treatment, yet its half-life is somewhat shorter than that of rivaroxaban (36). Although the new OACs are generally well tolerated, both dabigatran doses in the RE-LY trial were associated with significantly higher levels of dyspepsia compared with warfarin (11.8% and 11.3% with 110 mg and 150 mg dabigatran, respectively, compared with 5.8% for warfarin; P 0.001 for both comparisons) (9). This may affect adherence to dabigatran. However, dyspepsia with dabigatran therapy may be eased by taking the drug with food or using proton pump inhibitors (22), although this presents a further pill burden for patients. Patient education is necessary to ensure compliance particularly at each prescription renewal (37).
Patients with declining renal function Treating patients with impaired renal function Figure 1B shows that our patient has moderate renal impairment (CrCl 35 ml/min), which could easily develop into severe renal impairment. This patient may be at an increased risk of bleeding according to the HAS-BLED score. One way to reduce bleeding risk is to monitor renal function at least yearly in patients with normal renal function or mild renal impairment (CrCl 50 mL/min) and ensure that new OACs are being appropriately dosed. If a patient has moderate renal impairment (CrCl 30–50 mL/min), such as our patient case, monitoring should be conducted at least every 6 months, with a further increased frequency of monitoring in patients with a CrCl of 30 mL/min (every 3 months) (22). Additionally, renal function must be monitored at the time of any acute, especially dehydrating, illness. Results from the key new OAC trials related to renal impairment are shown in Table II. Overall, the results show that patients with renal impairment treated with new OACs experienced fewer primary efficacy end-point events than those treated with warfarin. Figure 2 shows the total drug exposure with the new OACs in patients with declining renal function (13–15). None of the European, Canadian, or Australian guidelines recommend new OACs for use in patients with a CrCl 30 mL/min (19,22,38), although in Europe both rivaroxaban and apixaban may be used with caution in patients with CrCl 15–29 mL/min (13,15) (use in patients with CrCl 15 mL/min is not recommended).
Stroke prevention in elderly patients with atrial fibrillation Challenges associated with treating elderly patients with AF Findings from a literature review showed that physicians are reluctant to recommend warfarin for elderly patients with AF, despite evidence of increased benefit in these patients versus younger patients (23). The risk of falls and a history of bleeding events were also shown to be disproportionate barriers to warfarin prescription such that antiplatelet drugs were more commonly the antithrombotic agents used (23). Elderly patients are more likely to have renal impairment, other co-morbidities, and frequent co-medications that increase the risk of stroke and/or the risk of bleeding. Sub-analyses carried out for different age groups help to clarify the current clinical data for the physician (Table II). Imagine that the case study were revised such that our patient is now 88 years of age, with kyphosis and a risk of falls (Figure 1B). This clearly puts her at increased risk of bleeding. However, as mentioned previously, the risk of stroke also increases with age such that any hazard related to falls is generally exceeded—often markedly so—by the stroke risk. Indeed, the average elderly patient would need to fall almost 300 times a year before the strokerelated risk of a subdural haematoma outweighed the risk of stroke with AF (39). Warfarin therapy in the elderly is specifically associated with an increased risk of ICH (25); this risk of ICH is significantly reduced with the new OACs, as shown in Table III.
Stroke prevention in very elderly patients Given that the incidence of cognitive impairment increases with age and global populations are living longer, very elderly patients with at least some cognitive impairment and a multitude of medical problems, including atrial fibrillation, are becoming ever more commonly seen in medical practice. In the past, using warfarin in such patients raised concerns about their inherent bleeding risk (40), but also about their adherence to both the drug and its regular monitoring, such that its use in this clinical context was particularly limited. An advantage of the new OACs in this specific patient population is their relative ease of use and, as such, should allow greater comfort with their being prescribed to the very elderly, including those with cognitive impairment. Clearly, it is preferable to have a cognitively impaired elderly patient still able to ambulate and follow basic directions than one who is bedridden and wholly dependent on others after a major disabling stroke.
AUC ratio versus normal renal function
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Practical management of new oral anticoagulants for AF 7 7
7
7
6
6
6
5
5
5 Dabigatran (85% cleared renally)
Apixaban (27% cleared renallya)
Rivaroxaban (33% cleared renallyb)
4
4
4
3
3
3
2
2
2
1
1
1
0
Normal renal function (≥80 mL/min)
Mild renal impairment (50–79 mL/min)
Moderate renal impairment (30–49 mL/min)
Severe renal impairment (
