Novel oral anticoagulants for stroke prevention in atrial fibrillation: a focus on the older patient

Figures & data

Figure 1 Impact of atrial fibrillation (AF) by increasing age: overall prevalence of AF and annual incidence of stroke in patients with AF.

Notes: Line indicates the prevalence of AF with increasing age as a percentage of the general population of US adults. Prevalence is plotted on the primary axis and is based on data from Go et al. Copyright © (2001) American Medical Association. All rights reserved. Adapted with permission from Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370–2375.³ Bars provide the incidence of stroke among patients with AF, expressed as a percentage of patients with AF per year. Stroke incidence is plotted on the secondary axis and is based on data from Wolf et al. Copyright © (1987) American Medical Association. All rights reserved. Adapted with permission from Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med. 1987;147(9):1561–1564.⁹⁴

Figure 2 Rates of anticoagulation by patient age group.

Notes: Proportion of patients admitted with electrocardiography-verified atrial fibrillation (AF) who were prescribed warfarin therapy at hospital discharge by patient age. Data from Hylek et al.²⁰

Table 1 Summary of drug–drug interactions for warfarin and the novel oral anticoagulants dabigatran, rivaroxaban, and apixaban

Anticoagulant agent	Drug–drug interactions
Warfarin^Citation27	Do not use witha • Drugs used for thrombosis treatment or prophylaxis, or other drugs with adverse effects on hemostasis • Fibrinolytic drugs • St John’s wort
	Use caution with • Alcohol • Inhibitors of CYP2C9, 1A2, or 3A4 and drugs known to potentiate the effects of warfarin, including: acetaminophen, allopurinol, amiodarone, antibiotics (eg, ciprofloxacin, erythromycin, metronidazole, sulfamethoxazole), azole antimycoticsb, caffeine, statins (excluding pravastatin), tamoxifen • Inducers of CYP2C9, 1A2, or 3A4 and drugs known to antagonize the effect of warfarin, including: azathioprine, barbiturates, carbamazepine, griseofulvin, rifampin, phenytoin, primidone • NSAIDs, platelet aggregation inhibitors, heparins, other antithrombotic agents • Oral contraceptives • Serotonergic agents, including SSRIs and SNRIs • Antidepressants
Dabigatran^Citation54	Avoid coadministration with • P-gp inducer rifampin • In patients with moderate renal impairment (CrCl 30–50 mL/min), consider a reduced dose (75 mg twice daily) if coadministered with P-gp inhibitors dronedarone and systemic ketoconazole
	Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including drugs such as • NSAIDs used chronically • Antiplatelet agents, heparin, or fibrinolytic therapy
Rivaroxaban^Citation55	Avoid concomitant use with • Combined P-gp and strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, or St John’s wort) • Combined P-gp and strong CYP3A4 inhibitors (eg, azole antimycoticsb or HIV protease inhibitors)
	Concomitant use of other drugs affecting hemostasis increases the risk of bleeding, including drugs such as • Aspirin, platelet aggregation inhibitors, other antithrombotic agents • NSAIDs
Apixaban^Citation56	Avoid concomitant use with • Strong dual inducers of CYP3A4 and P-gp (eg, rifampin, phenytoin, carbamazepine, or St John’s wort)
	Decrease dose of apixaban when coadministered with^e • Strong dual inhibitors of CYP3A4 and P-gp (eg, azole antimycoticsb or HIV protease inhibitorsc)
	Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including drugs such as • NSAIDs used chronically • Platelet aggregation inhibitors or other antithrombotic agents • SSRIs or SNRIs

Notes: ^aWarfarin is associated with a number of drug–drug and drug–food interactions. Consult the prescribing information for warfarin and any drugs used concurrently for a complete list.

b Azole antimycotics include ketoconazole, itraconazole, voriconazole, and posaconazole.

c If apixaban is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp, the dose of apixaban should be decreased to 2.5 mg twice daily. In patients already taking a reduced dose of apixaban, concomitant use of apixaban with strong dual inhibitors of CYP3A4 and P-gp should be avoided.

Abbreviations: CrCl, creatinine clearance; CYP, cytochrome P450; HIV, human immunodeficiency virus; NSAID, non-steroidal anti-inflammatory drug; P-gp, P-glycoprotein; SNRI, serotonin/norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Table 2 Summary of study results for RE-LY, ROCKET-AF, ARISTOTLE, and AVERROES, for stroke and systemic embolism rates, major bleeding rates, and all-cause mortality

Study	Rate of stroke or SE	Major bleeding rates	All-cause mortality
RE-LY^Citation60,Citation61 summary	Significant reduction in the risk of stroke or SE with 150 mg dabigatran compared with warfarin; 110 mg dabigatran had similar rates to warfarin	Similar rates of major bleeding with 150 mg dabigatran compared with warfarin; lower rate of major bleeding with 110 mg dabigatran compared with warfarin	No significant difference
Event rate	Stroke or SE rate (% per year)	Major bleeding rate (% per year)	Rate of death (any cause, % per year)
Dabigatran 110 mg	1.54	2.87	3.75
Dabigatran 150 mg	I.I1	3.32	3.64
Warfarin	1.71	3.57	4.13
Relative risk (dabigatran 110 mg vs warfarin)	0.90(0.74–1.10)	0.80 (0.70–0.93)	0.91 (0.80, 1.03)
P value	<0.00l for non-inferiority 0.30 for superiority	0.003	0.13
Relative risk (dabigatran 150 mg vs warfarin)	0.65(0.52–0.81)	0.93 (0.81, 1.07)	0.88 (0.77, 1.00)
P value	<0.001 for non-inferiority <0.001 for superiority	0.32	0.051
ROCKET-AF^Citation66 summary	Non-inferiority in the prevention of stroke or SE demonstrated for rivaroxaban compared with warfarin	No significant difference	No significant difference
Event rate	Stroke or SE rate (% per year)	Major bleeding rate (% per year)	Rate of death (any cause, % per year)
Rivaroxaban	2.1	14.9	4.5
Warfarin	2.4	14.5	4.9
Hazard ratio	0.88 (0.75, 1.03)	1.03 (0.96, 1.11)	0.92 (0.82, 1.03)
P value	<0.001 for non-inferiority 0.12 for superiority	0.44	0.15
ARISTOTLE^Citation68 summary	Significant reduction in the risk of stroke or SE with apixaban compared with warfarin	Significant lower risk of major bleeding with apixaban compared with warfarin	Significant reduction in all-cause mortality with apixaban compared with warfarin
Event rate	Stroke or SE rate (% per year)	Major bleeding rate (% per year)	Rate of death (any cause, % per year)
Apixaban	1.27	2.13	3.52
Warfarin	1.60	3.09	3.94
Relative risk	0.79 (0.66, 0.95)	0.69 (0.60, 0.80)	0.89 (0.80, 0.998)
P value	0.01	<0.00l	0.047
AVERROES^Citation70 summary	Significant reduction in the risk of stroke or SE with apixaban compared with aspirin	No significant difference	No significant difference
Event rate	Stroke or SE rate (% per year)	Major bleeding rate (% per year)	Rate of death (any cause, % per year)
Apixaban	1.6	1.4	3.5
Aspirin	3.7	1.2	4.4
Hazard ratio	0.45 (0.32, 0.62)	1.13 (0.74, 1.75)	0.79 (0.62, 1.02)
P value	<0.00l	0.57	0.07

Note: Data in parentheses are 95% confidence intervals.

Abbreviations: ARISTOTLE, Apixaban for Reduction In STroke and Other Thromboembolic Events in atrial fibrillation; AVERROES, Apixaban Versus acEtylsalicylic acid to pRevent stROke in atrial fibrillation patients who have failed or are unsuitablE for vitamin K antagonist treatment; RE-LY, Randomized Evaluation of Long-term anticoagulation therapY; 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; SE, systemic embolism.

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