Hospital Practice

ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20

Non—Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation and Venous Thromboembolism: Where are we Now? Reza Hajhosseiny MBBS, BSc, Ian Sabir MA, PhD, MRCP & Gregory Y.H. Lip MD, FRCP, FDM, FACC, FESC To cite this article: Reza Hajhosseiny MBBS, BSc, Ian Sabir MA, PhD, MRCP & Gregory Y.H. Lip MD, FRCP, FDM, FACC, FESC (2014) Non—Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation and Venous Thromboembolism: Where are we Now?, Hospital Practice, 42:4, 153-162 To link to this article: http://dx.doi.org/10.3810/hp.2014.10.1152

Published online: 13 Mar 2015.

Submit your article to this journal

Article views: 5

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Universite Laval]

Date: 28 October 2015, At: 00:40

C L I N I C A L F E AT U R E S

Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation and Venous Thromboembolism: Where Are We Now?

Downloaded by [Universite Laval] at 00:40 28 October 2015

DOI: 10.3810/hp.2014.10.1152

Reza Hajhosseiny, MBBS, BSc 1 Ian Sabir, MA, PhD, MRCP 1 Gregory Y.H. Lip, MD, FRCP, FDM, FACC, FESC 2 BHF Centre of Cardiovascular Excellence, St. Thomas Hospital, Westminster Bridge Road, London, UK; 2University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK 1

Abstract: Four non–vitamin-K antagonist oral anticoagulants (NOACs) are now available and are variously approved for stroke prevention in atrial fibrillation and the management of venous thromboembolism. On the whole, these drugs offer clear benefits over warfarin, overcoming problems with unpredictable individual responses and avoiding the need for frequent and resource-intensive monitoring. Sufficient data are now available to recommend the use of particular NOACs in defined settings. As a group these drugs offer a real alternative to warfarin; their more widespread use for stroke prevention in atrial fibrillation, in the management of venous thromboembolism, and perhaps in other settings promises to bring real clinical gains for at-risk populations worldwide. This review highlights the growing importance of effective anticoagulation therapy at a time when cardiovascular risk profiles are evolving, discusses the relative merits of the NOACs over warfarin, and describes the use of specific agents in specific patient populations. Keywords: atrial fibrillation; non–vitamin-K antagonist oral anticoagulant; venous thromboembolism; warfarin

Introduction

Correspondence: Gregory Y.H. Lip, MD, FRCP, FDM, FACC, FESC, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham, UK. E-mail: [email protected]

Thromboembolic disease, most importantly embolic stroke and pulmonary embolism, represents a major public health concern.1 Whether in the arterial or venous circulations, thrombi most often form in the setting of blood stasis.2,3 In the arterial circulation, atrial fibrillation (AF) is the most common precipitating cause.2,4 By disrupting the coordinated contraction of the atria, AF results in stasis within the left atrial appendage.5 Resulting thrombi may then embolize and travel to the cerebral arteries; this sequence of events is responsible for at least one fifth of all ischemic strokes.6 As the most common cardiac arrhythmia, AF affects some 1% of the global population, and 9% of those aged . 80 years.7 Atrial fibrillation is expected to become 5 times more common over the coming decades, with global deaths from stroke expected to rise from just under 6 million per year in 2005 to . 8 million per year by 2030.6,8–10 Along with hypercoagulability and alterations in the blood vessel wall, stasis is also a key contributor to the formation of venous thrombi.3 With a prevalence of 1 in 1000 in the general population, venous thromboembolism (VTE) is the third most common cardiovascular cause of death.11 The prevalence of VTE is projected to more than double by 2050.12 Increases in the prevalence of disease related to arterial and venous thromboembolism are primarily driven by 2 main factors: population aging and increases in the

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 153 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Downloaded by [Universite Laval] at 00:40 28 October 2015

Hajhosseiny et al

prevalence of lifestyle-related risk factors. Populations are aging the world over.13 Studies have shown that advanced age is a clear risk factor for both the development of AF and for AF-associated stroke.14,15 There is a continuous relationship between AF prevalence and age: , 1% of 55- to 59-yearolds have AF, whereas . 11% of those . 85 years old have a diagnosis.15 The prevalence of VTE rises exponentially with age, from , 5 cases per 100 000 persons in those , 15 years old to . 500 per 100 000 persons in those . 80 years old.16,17 The impact of population aging is particularly striking in the developing world. For instance, in Brazil the population aged . 60 years is expected to double from 15 million in 2002 to 30 million by 2020.18 The prevalence of lifestylerelated cardiovascular risk factors such as diabetes, hypertension, obesity, and hyperlipidemia is increasing globally19,20; these factors are strongly associated with increased risk of AF21 and of ischemic stroke.21 The prevalence of these risk factors is significantly higher among patients with VTE than in those without a history of venous or arterial thrombosis.22 Together obesity, hypertension, and diabetes approximately double the VTE risk, although after adjustment for body mass index, the association of the metabolic syndrome with VTE was no longer statistically significant (P = 0.056).22 This finding is also supported by other large studies.23,24 For decades vitamin K antagonist–based therapies such as warfarin were the only effective strategy for achieving anticoagulation; when used well, warfarin significantly reduces both AF-related stroke and VTE risk.25,26 The safety and efficacy of warfarin is potentially undermined by its unpredictability, driven by both individual variation and the impact of food–drug and drug–drug interactions, however.27–29 What is more, warfarin therapy necessitates frequent monitoring, a requirement for which both provision and compliance are often poor. Non–vitamin K antagonist oral anticoagulants (NOACs) now provide an alternative.30 This review highlights recent findings and compares early results with the 4 currently available NOACs in relation to stroke prevention in AF and the management of VTE.

The NOACs Versus Warfarin

In large clinical trials, warfarin treatment to a target international normalized ratio of 2.5 and a tolerated therapeutic range of 2.0 to 3.0 reduces the risk of stroke by up to 64%.31 Similarly, warfarin dose adjusted to the same range has been shown in large clinical trials to significantly reduce the risk of recurrent VTE.32,33 Despite its benefits, warfarin has limitations in real clinical practice. Warfarin metabolism shows considerable day-to-day and individual 154

variation, necessitating frequent international normalized ratio monitoring and dose adjustment.27,28 The issues of lack of practicality and the inevitable lack of compliance by patients often result in over- or under-anticoagulation.29 Time in therapeutic range (TTR) is critical to the effectiveness of warfarin therapy,34 and is influenced by a host of factors, including pharmacogenomics, pharmacokinetics, drug–drug interactions, and drug–food interactions; an average TTR of  .  70% is recommended in a European position document.35 However, in large studies of patients on warfarin, mean TTR varied between 38% and 69%.29,36 The issue of monitoring and compliance is particularly problematic in developing countries, where patient education and monitoring facilities are limited.37 Random blood samples in patients with AF receiving warfarin in Latin America suggest TTRs as low as 16%.9,38 Physicians and patients in these countries therefore have legitimate concerns about the safe use of warfarin; this is reflected by the poor warfarin uptake in these countries despite a clear clinical need.9 The NOACs offer a clear alternative to warfarin therapy.30 Importantly, they do not require regular monitoring, have many fewer drug–drug interactions than warfarin, and their use does not appear to be impacted by the choice of food or by fasting.39 This said, they come with their own issues. Foremost among these is reversibility: specific antidotes for these agents are not currently available, although an antibody that binds the direct thrombin inhibitor dabigatran40 and a specific antidote for the factor Xa inhibitors41 rivaroxaban, apixaban, and edoxaban are currently in development. Dialysis may be of value for removing dabigatran,42 but not for the other agents, as they are more highly protein bound. Administration of prothrombin complex concentrates may be of use.43 The other key practical issue is cost. Although there is no doubt that drug costs are markedly higher for NOACs than for warfarin, it is notable that NOAC therapy does not require the complex and expensive monitoring and support infrastructure necessary for safe and effective treatment with warfarin. One must remain mindful, of course, that such an infrastructure is already in place for many patients. Leaving this point aside for a moment, a recent cost-effectiveness analysis suggested that for a simulated patient with AF there was only a ∼10% difference in total with a NOAC as compared with warfarin.44 Robust data from large and well-conducted trials demonstrate that these agents are, in all, at least as safe and effective as warfarin for stroke prevention in the broader AF population,45–49 as well as in the setting of VTE.50–58 The AF trials ranged from 14 264 to 21 105 patients, with median follow

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

NOACs in AF and VTE

ups of 1.8 to 2.8 years. Such variations were also notable with the main VTE trials, with participant numbers varying between 2564 and 8292 and median follow-up ranging between 6 months and 2 years. Inevitably there were also differences in the inclusion and exclusion criteria used in these trials, though these do not preclude comparisons (Tables 1A and 1B). Table 2 summarizes the heterogeneity of treatment regimens in the VTE trials.

Importantly, fixed-dose therapy with each of the NOACs results in a lower risk of intracerebral hemorrhage—the most feared complication of anticoagulation—as compared with warfarin.46–48,59,60 This said, treatment with higher dose dabigatran, rivaroxaban, and edoxaban increases the risk of gastrointestinal bleeding.46,48,49,59,61,62 There is also an indication that dabigatran may somewhat increase the risk of acute myocardial infarction.63,64 As for their use in wider

Table 1A.  Inclusion and Exclusion Criteria Used in the Main Trials of NOACs for Stroke Prevention in AF

Downloaded by [Universite Laval] at 00:40 28 October 2015

RE-LY (dabigatran)46

ROCKET-AF (rivaroxaban)47

ARISTOTLE (apixaban)59

ENGAGE TIMI 48 (edoxaban)48

Inclusion Criteria

Exclusion Criteria

1. Atrial fibrillation: documented on electrocardiography performed at screening or within 6 months beforehand 2. In addition to above, $ 1 of: -Previous stroke, TIA, systemic embolism -Ejection fraction , 40% -New York Heart Association class II or higher heart failure symptoms within 6 months of screening -Age $ 75 years -Age 65-74 years plus diabetes mellitus, hypertension, or coronary artery disease 1. Nonvalvular AF: documented on electrocardiography within 30 days of randomization 2. History of prior ischemic stroke, TIA, or non-CNS systemic embolism believed to be cardioembolic in origin, or $ 2 of the following risk factors: -Heart failure or left ventricular ejection fraction # 35% -Hypertension -Diabetes -Age $ 75 years (ie, CHADS2 score of $ 2)

1. Severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months before screening 2. A condition that increased the risk of hemorrhage (eg, surgery within 1 month, gastrointestinal bleed within 1 year) 3. A creatinine clearance of , 30 mL/min 4. Active liver disease 5. Pregnancy 6. Active infective endocarditis 7. Anemia (hemoglobin , 100 g/L) 8. Thrombocytopenia (platelets , 100 × 109/L) 9. Reversible causes of AF (eg, pulmonary embolism) 1. Cardiac-related conditions (eg, active endocarditis, valvular heart disease, reversible AF, atrial myxoma, left ventricular thrombus) 2. Hemorrhage risk factors (eg, active bleeding, planned surgery, platelets , 90 × 109/L at the screening visit, uncontrolled hypertension of systolic . 180 mm Hg or diastolic . 100 mm Hg 3. Stroke within 14 days, severe stroke within 3 months or TIA within 3 days of randomization 4. A creatinine clearance of , 30 mL/min 5. Active liver disease 6. Pregnancy 7. Anemia (hemoglobin , 100 g/L) 8. On . 100 mg of aspirin/day 1. AF due to a reversible cause 2. Moderate or severe mitral stenosis 3. Conditions other than atrial fibrillation requiring anticoagulation (eg, a prosthetic heart valve) 3. Stroke within the previous 7 days 4. Aspirin at a dose . 165 mg a day or both aspirin and clopidogrel 5. Severe renal insufficiency (creatinine level of . 2.5 mg/dL [221 μmol/L] or calculated creatinine clearance , 25 mL/min)

1. AF or flutter at enrollment or $ 2 episodes of AF or flutter, as documented by electrocardiography, $ 2 weeks apart in the 12 months before enrollment 2. In addition to the above, $ 1 of the following: -Age $ 75 years -Previous stroke, TIA, or systemic embolism -Symptomatic heart failure within the previous 3 months or left ventricular ejection fraction of # 40% -Diabetes mellitus -Hypertension 1. AF documented on electrocardiography performed within 12 months of randomization 2. A score of $ 2 on the CHADS2 risk assessment

1. AF due to a reversible cause 2. High risk of bleeding 3. Use of dual antiplatelet therapy 4.Valvular heart disease 5. Acute coronary syndromes, coronary revascularization, or stroke within 30 days of randomization 6. A creatinine clearance , 30 mL/min

Abbreviations: AF, atrial fibrillation; CNS, central nervous system; NOAC, non–vitamin-K antagonist oral anticoagulant; TIA, transient ischemic attack. © Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 155 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Hajhosseiny et al

Table 1B.  Inclusion and Exclusion Criteria used in the Main Trials of NOACs for VTE Treatment Inclusion Criteria

Exclusion Criteria

EINSTEIN-DVT

Acute, symptomatic, objectively confirmed proximal DVT without symptomatic PE

1. Received treatment for . 48 hours with therapeutic doses of heparin 2. Received . 1 dose of a vitamin K antagonist 3. Treated with thrombectomy, a vena cava filter, or a fibrinolytic agent for the current episode of thrombosis 4. A creatinine clearance , 30 mL/min 5. Clinically significant liver disease 6. Bacterial endocarditis 7. Active bleeding or a high risk of bleeding 8. Uncontrolled hypertension of systolic . 180 mm Hg or diastolic . 100 mm Hg 9. Use of strong CYP3A4 inhibitors

EINSTEIN-PE52

Acute, symptomatic PE with objective confirmation, with or without symptomatic DVT

1. Received a therapeutic dose of low molecular weight heparin, fondaparinux, or unfractionated heparin . 48 hours or . 1 dose of a vitamin K antagonist before randomization 2. Thrombectomy, vena cava filter, or fibrinolytic agent administered for treatment of the current episode 3. A creatinine clearance , 30 mL/min 4. Clinically significant liver disease 5. Bacterial endocarditis 6. Active bleeding 7. Pregnancy 8. Use of a strong inhibitor of CYP3A4 or CYP3A4 inducer 9. Uncontrolled hypertension of systolic . 180 mm Hg or diastolic . 100 mm Hg

RE-COVER I53

Acute, symptomatic, objectively verified proximal DVT of the legs or PE

1. Symptoms . 14 days 2. PE with hemodynamic instability or requiring thrombolytic therapy 3. A creatinine clearance , 30 mL/min 4. Clinically significant liver disease 5. High risk of bleeding 6. Aspirin at a dose . 100 mg a day

RE-COVER II57

Acute, symptomatic, objectively verified proximal DVT of the legs or PE

1. Symptoms . 14 days 2. PE with hemodynamic instability or requiring thrombolytic therapy 3. A creatinine clearance , 30 mL/min 4. Clinically significant liver disease 5. High risk of bleeding 6. Aspirin at a dose . 100 mg a day

RE-MEDY54

Objectively confirmed, symptomatic, proximal DVT or PE that had already been treated with an approved anticoagulant

1. Symptomatic DVT or PE at screening 2. Actual or anticipated use of vena cava filter 3. Excessive risk of bleeding 3. Known anemia (hemoglobin , 100 g/L) 4. Unstable cardiovascular disease, such as uncontrolled hypertension at the time of enrollment 5. Active liver disease 6. A creatinine clearance , 30 mL/min 7. Acute bacterial endocarditis 8. Pregnancy

AMPLIFY55

Objectively confirmed, symptomatic proximal DVT or PE

1. Active bleeding 2. High risk of bleeding 3. Use of dual antiplatelet therapy 4. Aspirin at a dose . 165 mg a day 5. Inhibitors of CYP3 A4 6. Received . 2 doses of a once-daily low molecular weight heparin regimen, fondaparinux, or a vitamin K antagonist 7. Hemoglobin level of , 9 mg per decilitre 8. A platelet count , 100 000 per cubic millimeter 9. A serum creatinine level . 2.5 mg/dL (220 μmol/L), or a calculated creatinine clearance , 25 mL/min

Downloaded by [Universite Laval] at 00:40 28 October 2015

58

(Continued)

156

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

NOACs in AF and VTE

Table 1B.  (Continued) Hokusai-VTE56

Inclusion Criteria

Exclusion Criteria

Objectively diagnosed, acute, symptomatic DVT involving the popliteal, femoral, or iliac veins or acute, symptomatic pulmonary embolism

1. Received treatment . 48 hours with therapeutic doses of heparin 2. Received . 1 dose of a vitamin K antagonist 3. A creatinine clearance , 30 mL/min 4. Aspirin at a dose . 100 mg a day 5. Dual antiplatelet use

Downloaded by [Universite Laval] at 00:40 28 October 2015

Abbreviations: CYP, cytochrome P-450; DVT, deep vein thrombosis; NOAC, non–vitamin-K antagonist oral anticoagulant; PE, pulmonary embolism;VTE, venous thromboembolism.

patient populations, issues around difficulty in quantifying the degree of anticoagulation with readily available tests and the lack of availability of antidotes remain. Results from the main clinical trials are summarized in Figures 1 and 2.46–48,52–59 Relative risks are reported for dabigatran, and hazard ratios for the other drugs. The P values are for noninferiority unless marked with an asterisk. Lowdose dabigatran is 110  mg taken twice daily; high-dose dabigatran is 150 mg taken twice daily; standard-dose rivaroxaban is 20 mg taken once daily; low-dose edoxaban is 30 mg taken once daily; high-dose edoxaban is 60 mg

taken once daily; and standard-dose apixaban is 5  mg taken twice daily. The mean time in the therapeutic range for warfarin was 64% for the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (dabigatran), 55% for the Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKETAF) (rivaroxaban), 62% for the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial (apixaban), and 65% for the

Table 2.  Heterogeneity of the Treatment and Standard Regimens Used in the Main Trials of NOACs for VTE Treatment Treatment Regimens

Standard Regimens

EINSTEIN-DVT

Rivaroxaban 15 mg twice daily for the first 3 weeks, followed by 20 mg once daily

EINSTEIN-PE52

Rivaroxaban 15 mg twice daily for the first 3 weeks, followed by 20 mg once daily

RE-COVER I53

Dabigatran (150 mg twice daily) Parenteral anticoagulant (unfractionated heparin administered intravenously or low molecular weight heparin administered subcutaneously) started before random assignment; stopped after randomization Dabigatran (150 mg twice daily) Parenteral anticoagulant (unfractionated heparin administered intravenously or low molecular weight heparin administered subcutaneously) started before random assignment; stopped after randomization Dabigatran (150 mg twice daily) 10 mg of apixaban twice daily for the first 7 days, followed by 5 mg twice daily

Subcutaneous enoxaparin, 1.0 mg/kg body weight twice daily, and either warfarin or acenocoumarol, started within 48 hours after randomization. Enoxaparin discontinued when INR $ 2.0 for 2 consecutive days and the patient had received $ 5 days of enoxaparin treatment. Subcutaneous enoxaparin, 1.0 mg/kg body weight twice daily, and either warfarin or acenocoumarol, started within 48 hours after randomization. Enoxaparin discontinued when INR $ 2.0 for 2 consecutive days and the patient had received $ 5 days of enoxaparin treatment. Warfarin with target INR 2.0–3.0 Parenteral anticoagulant (unfractionated heparin administered intravenously or low molecular weight heparin administered subcutaneously) started before random assignment. Stopped once the parenteral anticoagulant had been given $ 5 days and the INR was recorded as $ 2.0 on 2 consecutive days. Warfarin with target INR 2.0–3.0 Parenteral anticoagulant (unfractionated heparin administered intravenously or low molecular weight heparin administered subcutaneously) started before random assignment. Stopped once the parenteral anticoagulant had been given $ 5 days and the INR was recorded as $ 2.0 on 2 consecutive days. Warfarin with target INR 2.0–3.0 Subcutaneous enoxaparin, 1.0 mg/kg body weight twice daily, and warfarin started concomitantly. Enoxaparin discontinued when INR $ 2.0 for 2 consecutive days and the patient had received $ 5 days of enoxaparin treatment. Initial therapy with enoxaparin or unfractionated heparin $ 5 days

58

RE-COVER II57

RE-MEDY54 AMPLIFY55

Hokusai-VTE56

Initial therapy with enoxaparin or unfractionated heparin for $ 5 days Edoxaban 60 mg once daily or 30 mg once daily in renal impairment, weight , 60 kg, or use of P-glycoprotein inhibitors

Warfarin concomitantly with target INR 2.0–3.0

Abbreviations: INR, international normalized ratio; NOAC, non–vitamin-K antagonist oral anticoagulant;VTE, venous thromboembolism. © Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 157 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Hajhosseiny et al

Downloaded by [Universite Laval] at 00:40 28 October 2015

Figure 1.  (A) Efficacy of the novel oral anticoagulants in comparison to warfarin for stroke prevention in AF. (B) Safety of the novel oral anticoagulants in comparison to warfarin for stroke prevention in AF. (C) Safety of the novel oral anticoagulants in comparison to warfarin for stroke prevention in AF. (D) Safety of the novel oral anticoagulants in comparison to warfarin for stroke prevention in AF.

**Annual event rates were significantly lower with rivaroxaban than with warfarin (3.2% vs 2.2%, P , 0.001). Abbreviation: AF, atrial fibrillation.

Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction (ENGAGE-TIMI) trial (edoxaban). Relative risks are reported for apixaban, and hazard ratios for other drugs. The P values are for noninferiority unless marked with an asterisk. Mean time in therapeutic range for warfarin was 58% in the EINSTEIN deep vein thrombosis (DVT) trial, 63% in the EINSTEIN pulmonary embolism (PE) trial, 60% in the RE-COVER (Efficacy and Safety of Dabigatran Compared to Warfarin for 6-Month Treatment of Acute Symptomatic Venous Thromboembolism) I trial, 57% in the RE-COVER II trial, 65% (the median) in the RE-MEDY (Secondary Prevention of Venous Thrombo Embolism with Dabigatran) trial, 61% in the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, and 64% in the Hokusai venous thromboembolism (VTE) trial. Practical aspects of the use of NOACs in everyday clinical practice have been the subject of recent comprehensive reviews.50,65–67 The following section summarizes the key points, focusing on factors that might prompt the choice of 1 agent over another. 158

Choosing Among the NOACs:The Right Drug for the Right Patient

Trial data demonstrate that each of the 4 NOACs studied are safe and effective in the study setting; there is little to choose among them as regards their safety and efficacy in broad populations. There is a great deal to be said, however, for individualizing the NOAC choice for specific patients based on such factors as comorbidities and the other medications they are prescribed. These considerations are summarized in Figure 3. The use of warfarin, especially for maintaining a stable level of anticoagulation, is particularly challenging in patients with kidney and liver failure.39,68 Frustratingly, data on NOACs in these groups are limited. Dabigatran is predominantly excreted by the kidney, whereas renal clearance is rather less important for apixaban, rivaroxaban, and edoxaban.69,70 Apixaban is relatively well established as safe in patients with moderately impaired renal function; no dose adjustment is needed in patients with a creatinine clearance of .  30  mL/min.39 Notably these agents have not been studied in patients with creatinine clearances of # 30 mL/min. Patients with active liver disease or evidence

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

NOACs in AF and VTE

Downloaded by [Universite Laval] at 00:40 28 October 2015

Figure 2.  (A) Efficacy of the novel oral anticoagulants in comparison to warfarin in the treatment of VTE. (B) Safety of the novel oral anticoagulants in comparison to warfarin in the treatment of VTE. (C) Safety of the novel oral anticoagulants in comparison to warfarin in the treatment of VTE.

be undertreated.31 Physician concerns over bleeding in the elderly, in particular the risk of intracranial hemorrhage associated with falls, remains the most cited reason for inappropriate undertreatment.71 With a more stable therapeutic profile and lower rates of intracranial hemorrhage as compared with warfarin, the NOACs have a particularly important role in the elderly.72 The bioavailabilities of dabigatran, rivaroxaban, and apixaban increase with age; dose reductions are therefore recommended in the elderly for NOACs other than edoxaban.39,69 Compliance issues are common in the elderly and are particularly problematic for drugs taken more than once daily.73 This argues for the use of once-daily drugs such as rivaroxaban, edoxaban, or, indeed, warfarin. Body weight has a particular impact on the choice of NOAC.69 Apixaban is present at 20% to 30% lower concentrations in the plasma of those weighing over 120 kg than in controls.74 In contrast, rivaroxaban exposure does not appear to differ between those weighing . 120 kg and those weighing less.49 A recent report suggests that in patients who are morbidly obese, the standard once-daily dose of rivaroxaban provides sufficient anticoagulant cover.75 Limited information is available regarding dabigatran and edoxaban dosing in the overweight.69

Conclusion

Abbreviation: VTE, venous thromboembolism.

of liver impairment were excluded from the major trials of rivaroxaban, dabigatran, and apixaban.46,47,59 As it stands, rivaroxaban, dabigatran, and apixaban should be avoided in patients with liver impairment.69 The recently published ENGAGE-TIMI-48  study of edoxaban for stroke prevention in AF was the first major trial to include patients with liver dysfunction.48 Edoxaban therapy did not result in an increase in rates of bleeding events and also was not associated with elevations in liver enzymes. Edoxaban, therefore, represents the best choice in this group based on currently available data. Although older patients are at highest risk of AF (and stroke) and of VTE, they are also the group most likely to

There are now robust data demonstrating that the NOACs as a group offer a safe and effective alternative to warfarin for stroke prevention in AF and for the management of VTE. Recent clinical guidelines provide clear recommendations as to how NOACs agents should be used, as well as hinting at which NOACs should be chosen for specific patients. 76,77 Early modeling work suggests that broad prescription of dabigatran for stroke prevention in AF according to European Union labeling recommendations should result in its bringing a clear net clinical benefit over warfarin.78 Interest remains in using NOACs for other indications, whether as a substitute for warfarin or in addition to standard therapies. Recently published data on the first point are disappointing: dabigatran is markedly inferior to warfarin for the prevention of thrombus formation on mechanical heart valves, as well as being associated with increased bleeding risk.78 As a counterpoint, however, treatment with low-dose rivaroxaban improves outcomes in patients with recent acute coronary syndrome79; it has recently been approved by the European Medicines Agency for this indication.80 Trial data suggest that the NOACs offer a welcome alternative to warfarin for large groups of patients: the challenge

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 159 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Hajhosseiny et al

Downloaded by [Universite Laval] at 00:40 28 October 2015

Figure 3.  Factors that should be considered when prescribing novel oral anticoagulants as part of the decision making tailored to the individual patient.

1. Pokorney SD, Sherwood MW, Becker RC. Clinical strategies for selecting oral anticoagulants in patients with atrial fibrillation. J Thromb Thrombolysis. Aug 2013;36(2):163–174. 2. Giuliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. Nov 28 2013;369(22):2093–2104. 3. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. Mar 3 2011;364(9):806–817. 4. Mahlmann A, Gehrisch S, Beyer-Westebdorf J. Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis. Nov 2013;36(4):533–353. 5. U.S. Food and Drug Administration. Briefing information for the September 20, 2010 meeting of the cardiovascular and renal drugs advisory committee. Available from htt:// www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugAdvisoryCommittee/UCM226011.pdf. Accessed 27/03/2014. 6. Albert NM. Use of novel oral anticoagulants for patients with atrial fibrillation: Systematic review and clinical implications. Heart Lung. Jan-Feb 2014;43(1):48–59. 7. Medell J, Zahir H, Matsushima N, et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs. Oct 2013;13(5):331–342. 8. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial filbrillation: design and rationale for the Effective aNticoaGulation with factor xA next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarcation study 48 (ENGAGE AF-TIMI 48). Am Heart J. Oct 2010;160(4):635–641. Abbreviations: CrCl, creatinine clearance; CYP3A4, cytochrome P-4503A4.

will now be to ensure that these positive results are realized in a real-world setting.

Conflict of Interest Statement

Ian Sabir, MA, PhD, MRCP, is a consultant to DaiichiSankyo. Gregory Y.H. Lip, MD, FRCP, FDM, FACC, FESC, has been a consultant to Bayer, Astellas, Merck, Sanofi, BMS/ Pfizer, Daiichi-Sankyo, Biotronik, Medtronic, Portola and Boehringer Ingelheim, as well as a member of the speaker’s bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, and Sanofi Aventis. Reza Hajhosseiny, MBBS, BSc, has no conflict of interest to declare.

References 1. Go AS, Mozaffarian D, Roger VL, et  al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–e292.

160

2. Shively BK, Gelgand EA, Crawford MH. Regional left atrial stasis during atrial fibrillation and flutter: determinants and relation to stroke. J Am Coll Cardiol. 1996;27(7):1722–1729. 3. Previtali E, Bucciarelli P, Passamonti SM, Martinelli I. Risk factors for venous and arterial thrombosis. Blood Transfus. 2011;9(2):120–138. 4. Pepi M, Evangelista A, Nihoyannopoulos P, et  al. Recommendations for echocardiography use in the diagnosis and management of cardiac sources of embolism: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr. 2010;11(6):461–476. 5. Medi C, Hankey GJ, Freedman SB. Stroke risk and antithrombotic strategies in atrial fibrillation. Stroke. 2010;41(11):2705–2713. 6. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010;121(7):e46–e215. 7. Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest. 2012;142(6):1489–1498. 8. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006  guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;123(10): e269–367.

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Downloaded by [Universite Laval] at 00:40 28 October 2015

NOACs in AF and VTE 9. How Can We Avoid a Stroke Crisis in Latin America? Working Group Report: Stroke Prevention in Patients with Atrial Fibrillation. http:// www.stopafib.org/downloads/News360.pdf. Accessed March 16, 2014. 10. World Health Organization (WHO). The global burden of disease, 2004 update. http://www.who.int/healthinfo/global_burden_disease/ GBD_report_2004update_full.pdf. Accessed March 21, 2014. 11. Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet. 2012;379(9828):1835–1846. 12. Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol. 2011;86(2):217–220. 13. US National Institute of Health, Division of Behavioral and Social Research, World Population Aging. Clocks illustrate growth in population under age 5 and over age 65. http://www.nia.nih.gov/research/dbsr/ world-population-aging. Accessed May 24, 2014. 14. Panel, Sacco RL, Benjamin EJ, et  al. Risk factors. Stroke. 1997; 28(7):1507–1517. 15. 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. 16. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151(5):933–938. 17. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585–593. 18. Aging the Brazilian context. http://bvsms.saude.gov.br/bvs/ folder/10006003219.pdf. Accessed March 20, 2014. 19. Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J. The metabolic syndrome: a global public health problem and a new definition. J Atheroscler Thromb. 2005;12(6):295–300. 20. Nguyen JT, Benditt DG. Atrial fibrillation susceptibility in metabolic syndrome: simply the sum of its parts? Circulation. 2008;117(10):1249–1251. 21. Tsai CT, Chang SH, Chang SN, et al. Additive effect of the metabolic syndrome score to the conventional CHADS2 score for the thromboembolic risk stratification of patients with atrial fibrillation. Heart Rhythm. 2014;11(3):352–357. 22. Ay C, Tengler T, Vormittag R, et  al. Venous thromboembolism— a manifestation of the metabolic syndrome. Haematologica. 2007;92(3):374–380. 23. Vaya A, Martinez-Triguero ML, Espana F, Todoli JA, Bonet E, Corella D. The metabolic syndrome and its individual components: its association with venous thromboembolism in a Mediterranean population. Metab Syndr Relat Disord. 2011;9(3):197–201. 24. Steffen LM, Cushman M, Peacock JM, et al. Metabolic syndrome and risk of venous thromboembolism: longitudinal investigation of thromboembolism etiology. J Thromb Haemost. 2009;7(5):746–751. 25. Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation. 2004;109(4):551–556. 26. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–2497. 27. Amerena JV, Walters TE, Mirzaee S, Kalman JM. Update on the management of atrial fibrillation. Med J Aust. 2013;199(9):592–597. 28. Holbrook AM, Pereira JA, Labiris R, et  al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095–1106.

29. Wan Y, Heneghan C, Perera R, et  al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circ Cardiovasc Qual Outcomes. 2008;1(2):84–91. 30. De Caterina R, Husted S, Wallentin L, et al. General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013;109(4):569–579. 31. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857–867. 32. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 Suppl):381S–453S. 33. Husted S, De Caterina R, Andreotti F, et al. Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel. Thromb Haemost. 2014;111(5):781–782. 34. Gallego P, Roldan V, Marin F, et al. Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation. Thromb Haemost. 2013;110(6):1189–1198. 35. De Caterina R, Husted S, Wallentin L, et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013;110(6):1087–1107. 36. Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Risk-adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation: results of the Veterans Affairs Study To Improve Anticoagulation (VARIA). Circ Cardiovasc Qual. 2011;4(1):22–U43. 37. Lip GY, Kamath S, Jafri M, Mohammed A, Bareford D. Ethnic differences in patient perceptions of atrial fibrillation and anticoagulation therapy: the West Birmingham Atrial Fibrillation Project. Stroke. 2002;33(1):238–242. 38. Fornari LS, Calderaro D, Nassar IB, et al. Misuse of antithrombotic therapy in atrial fibrillation patients: frequent, pervasive and persistent. J Thromb Thrombolysis. 2007;23(1):65–71. 39. Albert NM. Use of novel oral anticoagulants for patients with atrial fibrillation: Systematic review and clinical implications. Heart Lung. 2014;43(1):48–59. 40. Schiele F, van Ryn J, Canada K, et  al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554–3562. 41. Lu G, DeGuzman FR, Hollenbach SJ, et  al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–451. 42. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013;109(4):596–605. 43. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–1579. 44. Harrington AR, Armstrong EP, Nolan PE Jr, Malone DC. Costeffectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke. 2013;44(6):1676–1681. 45. Hylek EM, Ko D, Cove CL. Gaps in translation from trials to practice: Non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. Thromb Haemost. 2014;111(5):783–788. 46. Connolly SJ, Ezekowitz MD, Yusuf S, et  al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151. 47. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891. 48. Giugliano RP, Ruff CT, Braunwald E, et  al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104. 49. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–817.

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 161 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Downloaded by [Universite Laval] at 00:40 28 October 2015

Hajhosseiny et al 50. Cohen AT, Imfeld S, Rider T. Phase III trials of new oral anticoagulants in the acute treatment and secondary prevention of VTE: comparison and critique of study methodology and results. Adv Ther. 2014;31(5):473–493. 51. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21. 52. Buller HR, Prins MH, Lensin AW, et  al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–1297. 53. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352. 54. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709–718. 55. Agnelli G, Buller HR, Cohen A, et  al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808. 56. Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–1415. 57. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764–772. 58. Bauersachs R, Berkowitz SD, Brenner B, et  al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–2510. 59. Granger CB, Alexander JH, McMurray JJ, et  al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992. 60. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol. 2013;70(12):1486–1490. 61. Desai J, Kolb JM, Weitz JI, Aisenberg J. Gastrointestinal bleeding with the new oral anticoagulants—defining the issues and the management strategies. Thromb Haemost. 2013;110(2):205–212. 62. Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology. 2013;145(1):105–112, e115. 63. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med. 2012;172(5):397–402. 64. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation. 2012;125(5):669–676. 65. Heidbuchel H, Verhamme P, Alings M, et  al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(5):625–651.

162

66. Huisman MV, Lip GY, Diener HC, Brueckmann M, van Ryn J, Clemens A. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost. 2012;107(5):838–847. 67. Turpie AGG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost. 2012;108(11):876–886. 68. Kleinow ME, Garwood CL, Clemente JL, Whittaker P. Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic. J Manag Care Pharm. 2011;17(7):523–530. 69. Pokorney SD, Sherwood MW, Becker RC. Clinical strategies for selecting oral anticoagulants in patients with atrial fibrillation. J Thromb Thrombolysis. 2013;36(2):163–174. 70. Matsushima N, Lee F, Sato T, Weiss D, Mendell J. Bioavailability and Safety of the Factor Xa Inhibitor Edoxaban and the Effects of Quinidine in Healthy Subjects. Clin Pharmacol Drug Dev. 2013;2(4): 358–366. 71. Sellers MB, Newby LK. Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients. Am Heart J. 2011;161(2):241–246. 72. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial [published online ahead of print February 20, 2014]. Eur Heart J. doi:10.1093/eurheartj/ ehu046. 73. Corsonello A, Pedone C, Lattanzio F, et al. Regimen complexity and medication nonadherence in elderly patients. Ther Clin Risk Manag. 2009;5(1):209–216. 74. Product monograph: PrELIQUISTM, apixaban tablets, 2.5  mg and 5  mg, Anticoagulant. http://www.pfizer.ca/en/our_products/products/ monograph/313. Accessed March 18, 2014. 75. Mahlmann A, Gehrisch S, Beyer-Westendorf J. Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis. 2013;36(4):533–535. 76. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719–2747. 77. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published online ahead of print March 28, 2014]. J Am Coll Cardiol. doi:10.1016/j.jacc.2014.03.022. 78. Lip GYH, Clemens A, Noack H, Ferreira J, Connolly SJ, Yusuf S. Patient outcomes using the European label for dabigatran. A post-hoc analysis from the RE-LY database. Thromb Haemost. 2014;111(5): 933–942. 79. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9–19. 80. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Product_Information/human/000944/WC500057108.pdf. Accessed March 25, 2014.

© Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Non-vitamin K antagonist oral anticoagulants in atrial fibrillation and venous thromboembolism: where are we now?

Four non-vitamin-K antagonist oral anticoagulants (NOACs) are now available and are variously approved for stroke prevention in atrial fibrillation an...
1MB Sizes 1 Downloads 7 Views