Background

Stroke is the fifth leading cause of mortality and the primary cause of long-term disability in the United States, according to the Centers for Disease Control (CDC).1 Embolic or ischemic type strokes occur when a blood clot or plaque travels to the brain, impairing blood flow. Damaging results from ischemia of the brain then lead to cognitive and physical impairments.2 The CDC reports that 85% of strokes are ischemic or caused by a blood clot, blocking blood flow.1

There are multiple risk factors that place a person at greater risk for an embolic stroke, including hypertension, hyperlipidemia, diabetes and cardiovascular diseases, including atrial fibrillation (AF).2 Twenty percent of stroke incidents are attributed to AF, and AF increases stroke risk five folds.3 A stroke caused by AF is associated with a higher mortality compared with those caused by other factors.4 In addition, after a non-fatal stroke caused by AF, the probability of long-term disability increases by 50%.4

Atrial fibrillation is a common cardiac rhythm disturbance seen in the clinical-practice setting with prevalence of more than 10% in those older than 70.5,6,13 Males are more commonly affected by AF than females.3 Over the last 20 years, AF-related hospital admissions in the United States increased by 66%.6 This increase is thought to be attributed to an aging population, increased prevalence of chronic heart disease and increased frequency of diagnosis.6

Defined as a supraventricular tachyarrhythmia with irregular atrial electrical activity and activation, AF has multiple classifications (paroxysmal, persistent or permanent).5 One of the consequences of AF is changes in the hemodynamic state of the patient due to loss of coordination in atrial contractions, changes in ventricular rate control and variability in ventricular filling.5 In AF, the irregular and poorly coordinated atria leads to blood pooling in the heart and the formation of clots.7 When the heart contracts, the clots are forced out of the heart into the vascular system creating risk for embolic stroke and pulmonary embolism.7,8

Oral anticoagulation therapy can reduce the incidence of embolic stroke in AF patients by over 50%.13 Coumadin (warfarin), a vitamin K antagonist, has been the "gold standard" in prevention of stroke in AF patients since 1950.13 Although this drug is effective in reducing stroke risk in patients with AF, it is a complex medication that poses challenges for both prescribers and patients. Coumadin (warfarin) has multiple drug and food interactions, blood level monitoring requirements and there are difficulties predicting individual dosing related to individual drug metabolism.13 The complexities associated with this medication option have led to the development of newer pharmacotherapeutic options, including direct factor Xa inhibitors.

Direct factor Xa inhibitors

In November 2011, the US Food and Drug Administration (FDA) approved Xarelto (rivaroxaban), a direct factor Xa inhibitor, for the use of stroke prevention in patients with non-valvular AF.7 In December 2012, the FDA approved Eliquis (apixaban), a direct factor Xa inhibitor, for stroke prevention in patients with non-valvular AF.8 Savaysa (edoxoban), another direct factor Xa inhibitor, was approved for the use of stroke prevention in patients with non-valvular AF in the US by the FDA in January 2015.9 Direct factor Xa inhibitors specifically target factor Xa, whereas warfarin targets several other factors contributing to coagulation.10 In terms of pharmacodynamics and pharmacokinetics, direct factor Xa inhibitors have "good oral bioavailability" and "rapid onset of action", which eliminate the need for bridge therapy when using warfarin.10^(p.1072)

Candidates for anticoagulation therapy

Adults with AF are at a higher risk for stroke; therefore, it is important to quantify their risk into categories from low to high to appropriately manage the risk.11 Selection of antithrombotic therapy for AF patients should be based on relative risk for stroke events regardless of classification and risk stratification.5 The fundamental aspect in making a decision to anticoagulate a patient with AF, "requires identifying those patients in whom the risk of ischemic stroke without anticoagulants is sufficiently high to outweigh the increase risks of intracranial and major extracranial hemorrhage" associated with anticoagulant therapies.12^(p.170)

Based on FDA indications and drug manufacturing guidelines, direct factor Xa inhibitors are only to be prescribed to patients with AF of a non-valvular etiology.8 Atrial fibrillation caused by valvular diseases or the presence of prosthetic valves requires specific management and strict international normalized ratio (INR) control.3 There is no routine blood monitoring for direct factor Xa inhibitors based on the clotting cascade in which they affect; therefore, it is unknown if a required INR of 2.0-3.0 can be maintained on these drugs.13

As a part of clinical management of AF, a risk assessment index for risk stratification of ischemic stroke is recommended in the 2010 US clinical practice guidelines, written by the American College of Cardiology Foundation/American Heart Association.6 The European Society of Cardiology, the governing body that established the AF management guidelines, recommends the CHADS₂ [cardiac failure, hypertension, age, diabetes, stroke, (Doubled)] Index as the initial easily memorized tool for assessing stroke risk.3 The CHADS₂ is an acronym that represents risk factors for ischemic stroke, including congestive heart failure history, hypertension history, age >= 75, diabetes mellitus history and stroke or transient ischemic attack (TIA) symptoms previously. The guidelines recommend the practice of providing chronic oral anticoagulant therapy to patients with a CHADS₂ score >=2 to improve outcomes in routine care.3

Risk stratification is highly important to correctly identify patients with AF for antithrombotic therapy.14 Appropriately categorizing low-, moderate- and high-risk patients enables the provider to weigh the risk versus benefit of drug therapy.14 The CHADS₂ Index (Appendix I) is a risk stratification schema used to categorize level of stroke risk in non-valvular AF patients.14 The stroke risk CHADS₂ Index is based on a point system that assigns a patient a score.6 A single point is given for each of the following: recent heart failure, hypertension history, diabetes and/or age over 75.6 Two points are given for a history of transient ischemic attack or stroke.6 The points are added together to create to the patients CHADS₂ score and then categorized into low, moderate or high risk.6 Clinical practice guidelines provide providers with recommendations for no treatment, antiplatelet therapy or anticoagulation therapy for AF patient based on the CHADS₂ score.6

Current US clinical practice guidelines recommend anticoagulation for patients who are at moderate-to-high risk (score >=2) based on the CHADS₂ score (Appendix II).6 The studies to be included in this systematic review use the CHADS₂ score to identify patients who are appropriate for anticoagulation (either warfarin or new pharmacotherapeutic option) in stroke prevention.

Although there is current research that establishes the efficacy of direct Xa inhibitors and the efficacy of warfarin in the prevention of stroke incidence with AF patients, there is not a systematic review that is comparative between the drugs in terms of stroke incidence. The authors searched and found no prior systematic reviews in the Cochrane Library or JBI Database of Systematic Reviews and Implementation Reports. Therefore a systematic review to determine the efficacy of direct factor Xa inhibitors compared with warfarin in preventing the incidence of stroke in adults with non-valvular atrial fibrillation is warranted.

Inclusion criteria

Types of participants

This review will consider studies that include adult patients with non-valvular AF receiving anticoagulation therapy for the purpose of stroke prevention. Studies investigating stroke prevention among patients with AF utilize the CHADS₂ to determine appropriateness for anticoagulation therapy. Studies with subjects with a CHADS₂ score of >=1 will be included in this review. Studies including participants with valvular etiology of AF will be excluded because direct factor Xa inhibitors are not indicated for use in these patients. Atrial fibrillation originating from valvular cause requires strict INR control that cannot be achieved from a direct factor Xa inhibitor.

Types of intervention(s)

This review will consider studies that evaluate the efficacy of the three direct factor Xa inhibitors, rivaroxaban, apixaban and edoxaban versus warfarin in studies of patients receiving rivoroxaban, apixaban or edoxaban for the management of AF. Doses will vary in each individual based on age, diagnosis, duration of therapy and direct Xa inhibitor initated.7-9

Comparators

The efficacy of direct factor Xa inhibitors will be compared with the standard treatment of warfarin in patients with non-valvular AF and moderate-to-high risk of stroke.

Outcomes

This review will consider studies that include the following outcome measure: incidence of stroke. Several published studies have measured stroke in terms of the percentage of events per treatment group in one year.

Types of studies

This review will consider only randomized controlled trials for inclusion in this review.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of PubMed and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search will be conducted using identified keywords. Third, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English from 2011 to present will be considered for inclusion in this review, as 2011 is when the first Xa inhibitor clinical trial was published. The three FDA-approved Xa inhibitors for use in non-valvular AF were approved in the US in 2011 (rivoraxaban), 2012 (apixaban) and 2015 (edoxaban).

The databases to be searched include: PubMed, CINAHL, EMBASE, Clinical Trials.gov, Controlled Clinical Trials and Google Scholar

The search for unpublished studies will include: The CDC and Prevention, FDA, American Heart Association, American College of Cardiology and Google

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review, using standardized critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix III). Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.

Data extraction

Data will be extracted from papers included in the review, using the standardized data extraction tool from JBI-MAStARI (Appendix IV). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. In the event that data are missing or unclear, the authors will contact the investigators.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data), and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard chi-square. In cases in which statistical pooling is not possible, the findings will be presented in narrative form, including tables and figures to aid in data presentation where appropriate.

Acknowledgements

The author would like to acknowledge the assistance and support of the following in the development of this protocol:

* Dr Reena Haymond, Adjunct Assistant Professor at the Samuel Merritt University, Oakland, California, USA.

* Dr Daphnne Stannard, Director of Institute of Nursing Excellence at UCSF Centre for Evidence-based Patient Care Quality Improvement, San Francisco, California, USA.

* Adam Cooper, Nurse Educator at Institute of Nursing Excellence at UCSF Centre for Evidence-based Patient Care Quality Improvement, San Francisco, California, USA.

Appendix I: CHADS₂ index

Appendix II: CHADS₂ score

Appendix III: Appraisal instruments

MAStARI appraisal instrument

Appendix IV: Data extraction instruments

MAStARI data extraction instrument

References