Elsevier

American Heart Journal

Volume 173, March 2016, Pages 143-158
American Heart Journal

Curriculum in Cardiology
Individualized approaches to thromboprophylaxis in atrial fibrillation

https://doi.org/10.1016/j.ahj.2015.10.021Get rights and content

Atrial fibrillation (AF) is the most common arrhythmia worldwide. The prevalence of AF in persons older than 55 years is at least 33.5 million globally and is predicted to more than double in the next half-century. Anticoagulation, heart rate control, and heart rhythm control comprise the 3 main treatment strategies in AF.

Anticoagulation is aimed at preventing debilitating stroke, systemic embolism, and associated mortality. Historically, anticoagulation in AF was achieved with a vitamin K antagonist such as warfarin, which is supported by evidence demonstrating reduced incident stroke and all-cause mortality. However, warfarin has unpredictable pharmacokinetics with many drug-drug interactions that require regular monitoring to ensure patients remain in the therapeutic anticoagulant range.

Non–vitamin K antagonist oral anticoagulants including dabigatran, rivaroxaban, apixaban, and edoxaban provide a possible solution to these issues with their more predictable pharmacokinetics, rapid onset of action, and greater specificity. Results from large randomized, controlled trials indicate that these agents are at least noninferior to warfarin in prevention of stroke. These trials also demonstrate a consistently lower incidence of intracranial hemorrhage, almost always all life-threatening bleeds, and many forms of major bleeds with the possible exception of gastrointestinal and some other forms of mucosal bleeding, compared with warfarin.

Patients with AF are a heterogeneous population with diverse risk of stroke and bleeding, and different subgroups respond differently to anticoagulation. Important clinical questions have arisen regarding optimal anticoagulation drug selection in distinct populations such as those with renal impairment, older age, coronary artery disease, and heart failure as well as those at particularly high risk for bleeding or thromboembolism. In this review, treatment strategies in AF management are discussed in the context of different individual subgroups of patients.

Section snippets

Classification of AF

Atrial fibrillation is not a homogenous arrhythmia and has been classified by presentation and duration of the arrhythmia. The ESC has adopted the following 5 types10:

  • 1.

    First diagnosed with AF

  • 2.

    Paroxysmal AF

  • 3.

    Persistent AF

  • 4.

    Long-standing persistent AF

  • 5.

    Permanent AF

The American Heart Association/American College of Cardiology/Heart Rhythm Society 2014 guidelines do not recognize first-diagnosed AF as a distinct entity but instead include an additional group named “nonvalvular AF,” in whom there is absence

Anticoagulation therapies—a multitude of choice

Warfarin is an excellent anticoagulant in AF that reduces stroke by 64% and all-cause mortality by 26%,8, 25 but despite this, physicians underuse it, particularly in elderly patients.26 This may be partly explained by the properties of warfarin: slow onset, narrow therapeutic range, drug and food interactions,27 requirement for close monitoring and patient comorbidities. Even when patients are maintained in the therapeutic range of INR (2.0-3.0), there is still the important problem of

Direct thrombin inhibitors

Thrombin forms from prothrombin by enzyme cleavage by FXa, which initiates the final common pathway of the coagulation cascade. Thrombin undergoes positive feedback and simultaneously cleaves fibrinogen to fibrin enabling the development of the polymeric protein structure around which the fibrin clot can form. Thrombin is therefore pivotal in the formation of a clot and forms an attractive therapeutic target for anticoagulation.33

Factor Xa inhibitors

Factor Xa inhibitors block the conversion of prothrombin to thrombin, preventing the final common pathway of the coagulation cascade; FXa is referred to as the “gatekeeper of coagulation.”29 The suitability of FXa in humans as a target was confirmed by large clinical trials with fondaparinux, an indirect FXa inhibitor, shown to be safe and effective in acute coronary syndrome and pulmonary embolism.34, 35, 36 After high-throughput screening and identification of the crystal structure of FXa,37

Meta-analyses of NOAC trial results

Meta-analysis of 4 RCTs investigating the NOACs in AF (N = 71,683) found that NOACs significantly reduced stroke and systemic emboli by 19% compared with warfarin; this was primarily driven by a reduction in hemorrhagic stroke rates (RR 0.49, 95% CI 0.38-0.64, P < .0001).39 Although NOACs increased the risk of GI bleeding (RR 1.25, 95% CI 1.01-1.55, P = .04), they significantly improved rates of ICH (RR 0.48, 95% CI 0.39-0.59, P < .0001).39 NOACs also significantly reduced all-cause mortality

Individualized anticoagulation: which agent in which patient?

In the absence of direct comparison data, selecting the most appropriate agent can be based on shared decision making, taking into account some limited information from indirect comparisons, adverse event profiles, specific pharmacokinetic properties, drug-drug interaction profile, renal and hepatic function, other comorbidities, and the TTR if already treated with a VKA.17, 41 Accounting for individualized risk of stroke and bleeding, as described in the CHA2DS2-VASc (congestive heart failure,

Chronic kidney disease

Approximately 1 in 3 patients with AF have proteinuria or chronic kidney disease (CKD),62 which is associated with both increased risk of stroke and hemorrhage, the latter due to uremia-induced platelet dysfunction and coagulation dysregulation.63 Although warfarin therapy confers a significant reduction in stroke risk in CKD,64 it has a poor safety profile in stage 4 CKD with more major bleeding events compared with stage 3 CKD.65 Furthermore, patients with both stage 3 and 4 CKD spend more

Elderly

Atrial fibrillation increases in prevalence with age and affects around 20% of individuals older than 85 years.10, 81 Elderly patients with AF have a greater burden of cardiovascular risk factors82, 83 and excess risk of stroke as reflected in the CHA2DS2-VASc score. Rates of anticoagulation in the elderly are consistently poorer relative to a younger population and physician-cited reasons for this include prior falls, hemorrhage, and patient refusal.84 It has been estimated that a patient

Bleeding prone

Numerous calculators are available to score bleeding risk including ATRIA,89 HEMORR2HAGES,90 and HAS-BLED.91 HAS-BLED has been shown to have the best predictive value of bleeding risk,92, 93 with a score ≥3 indicating high risk. This should prompt care providers to modify reversible risk factors including hypertension, polypharmacy including concomitant aspirin or nonsteroidal anti-inflammatory drug use, and a labile INR. Overestimation of bleeding risk represents a real clinical problem and a

Coronary heart disease

The ACTIVE W and ACTIVE A trials demonstrated that 14% to 17% of AF patients have had a prior myocardial infarction (MI),104, 105 a group in whom antiplatelet and anticoagulant prescriptions are common. Prospective analysis of 7,243 patients with AF demonstrated 95.3% (629/660) of patients on dual antiplatelet, and anticoagulation therapy did not have an accepted indication and exposed patients to inappropriate bleeding risks.106 The combination of anticoagulation and aspirin is associated with

Heart failure

Patients with HF are more likely to develop AF, which is itself an independent risk factor for development of HF.114 Heart failure, even in sinus rhythm, is associated with ischemic stroke. In patients with AF, HF has been linked with increased risk of stroke and death irrespective of left ventricular systolic function.115 Congestive heart failure is included in the CHA2DS2-VASc score representing a higher stroke risk, although this criterion refers only to moderate-to-severe systolic

Asian patients

Asian populations have a lower prevalence of AF relative to the West, and AF results in a more modest 3-fold increase in stroke risk.124, 125, 126, 127 However, Asians appear to be at greatest overall risk for both hemorrhagic and ischemic stroke, secondary to a higher prevalence of risk factors.128

The risk of stroke and hemorrhage is inconsistent among different Asian subgroups; East Asians (China, Japan, Korea, Laos, Thailand, and Vietnam) appear more susceptible to ICH compared with South

Patient adherence

Non–vitamin K antagonist oral anticoagulants have shorter half-lives than warfarin, mandating good adherence if patients are to remain protected.12, 13, 14, 16 Physicians can improve compliance through education around the risks of untreated AF. In the UK, NICE recently released a patient decision aid that helps portray the embolic risk in AF with the associated hemorrhage risk with anticoagulation, based on an individual's CHA2DS2-VASc score.137 Of concern, in a UK survey of 119 inpatients

Cost-effectiveness

In the current economic climate, cost-effectiveness will be a key consideration. Results from RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF–TIMI suggest that NOACs are associated with lower medical costs (excluding drug costs) relative to warfarin,141, 142, 143, 144 and this will be greatest among patients where INR control is poor.145 However, cost-effectiveness is dependent on local factors including resource availability, pricing, and TTR achieved by the specific anticoagulation service.145, 146

Conclusion

The overall burden of AF is rising commensurate with the options to manage it. Despite clear guidance and overwhelming evidence supporting the benefits of anticoagulation, undertreatment persists. Non–vitamin K antagonist oral anticoagulants are as effective as warfarin in prevention of stroke, whereas simultaneously reducing rates of ICH and life-threatening bleeding. Patient involvement in shared decision making around the most appropriate agent for anticoagulation can be facilitated by

Disclosures

O.J.Z. has no conflicts of interest. A.J.C. has acted as an advisor or consultant for Actelion Pharmaceuticals, ARYx Therapeutics, Bristol-Myers Squibb Company, Cardiome Pharma Corporation, CV Therapeutics, Daiichi Sankyo, Menarini Group, Pfizer, Sanofi, and Xention Limited. He has served as a speaker or a member of the speaker's bureau for Cardiome Pharma Corporation, Daiichi Sankyo, Menarini Group, Pfizer, and Sanofi. He has received grants for clinical research from Bristol-Myers Squibb

Contributors

O.J.Z. performed the literature search and prepared the initial draft of the manuscript. A.J.C. contributed to the critical revision of the manuscript. Both authors have approved the final article.

Acknowledgements

We thank Dr Kaivan Khavandi for medical editorial assistance. Financial support for this assistance was provided by Daiichi Sankyo Europe GmbH.

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