Influence of Atrial Fibrillation on Risk of Stroke: Evaluation of Experiment Results

Abstract

Background

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and it significantly increases the risk of stroke. AF is also associated with an increased risk of morbidity and mortality (Ment, 2015). AF is independently associated with an approximately 5-fold increase in a patient’s stroke risk (Dobesh & Fanikos, 2015). Therefore, along with the appropriate management of AF, effective anticoagulation therapy is essential for reducing the risk of stroke in patients. However, clinicians often find it challenging when trying to differentiate between DOACs to appropriately treatment patients due to the lack of head to head comparisons and this knowledge gap may lead to clinical consequences (Beyer-Westendorf et al., 2017). Although several indirect comparisons have been carried out using meta-analytic or network meta-analytic techniques, the results obtained are often misleading due to the differences in trial design and patient selection criteria for each of the trials.

Aim

The aim of this review is to establish the similarities and differences in the clinical trials for the two direct oral anticoagulants (DOACs) Apixaban (ARISTOTLE) and Rivaroxaban (ROCKET-AF) for stroke prevention in patients with nonvalvular Atrial Fibrillation (NVAF) while focusing on the importance of trial design and patient selection and its impact on the outcomes to provide clinicians with a well-rounded understanding of the trials when selecting a DOAC in clinical practice.

Methods

The trials ARISTOTLE and ROCKET-AF were randomised, double-blind, double-dummy, event-driven, with the primary efficacy endpoint consisting of stroke (haemorrhagic or ischemic) or systemic embolism (Granger et al., 2011 & Patel et al., 2011). Both trials compared their respective DOAC with dose adjusted warfarin as the control drug. This review compares the results for the two DOAC arms as well as the warfarin arms in the two trials to demonstrate the impact of the study design and population on the results and the final outcome of the trials.

Results

In ROCKET AF the rate of primary efficacy endpoint was 1.7% per year in the rivaroxaban arm and 2.2% per year in the warfarin arm. Whereas the rate of primary efficacy endpoint in ARISTOTLE was 1.27% per year in the apixaban arm and 1.60% per year in the warfarin arm. The rate of major bleeding or clinically relevant non-major bleeding in the ROCKET AF trial was 14.9% per year in the rivaroxaban arm and 14.5% per year in the warfarin arm, whereas, in the ATISTOTLE trial it was 4.07% in the apixaban arm and 6.01% in the warfarin arm. The rate of primary efficacy endpoint and primary safety endpoint for both DOACs were similar to warfarin in their respective trials. However, when the results from the two trials were compared, the rate of primary efficacy and safety were different in the DOAC arm as well as the warfarin arm. The difference in the results for warfarin arm suggests that the differences in the trial design and population affected the outcomes as both trials used warfarin as the control drug.

Conclusion

The differences in the two trials such as study design, population studied, and the bleeding definitions as well as the process in which the bleeding rates were recorded had a significant impact on the outcomes in the trials ROCKET AF and ARISTOTLE which can be seen by the results of the control arm in both trials. ROCKET AF had a stricter inclusion and exclusion criterion fitting a higher risk population that reflects the clinical practice. Therefore, the use of Rivaroxaban may demonstrate better outcomes in patients who are at higher risk of stroke and at a higher risk of bleeding, except those with GI complications.

Introduction

1.1 Overview

Atrial fibrillation is the most common cardiac arrhythmia and is a one of the leading causes of stroke (Ment, 2015) and can be diagnosed on an ECG by lack of a P-wave and irregular QRS complexes. Appropriate anticoagulation can assist in the prevention of strokes associated with AF. Stroke risk stratification system, such as CHADS2 is often used for the measure of the risk of stroke in patients with AF. Historically vitamin K antagonists (VKAs) such as warfarin have been used as an oral anticoagulant for the prevention of stroke, despite its efficacy warfarin is associated with several limitations (Saraiva, 2018). The development of direct oral anticoagulants DOACs has helped overcome these limitations while maintaining or surpassing the efficacy and safety profiles of warfarin (Dobesh & Fanikos, 2015). All oral anticoagulants present an increased risk of bleeding which can be measured using the HAS-BLED risk stratification system. The clinical trials for all DOACs had several similarities and differences which impacted the outcome. However, irrespective of the differences; DOACs are often compared against each other in clinical practice as they all used warfarin as the control drug. The differences in the trials discussed in this review illustrate how the outcome was impacted.

Both trials ARISTOTLE and ROCKET-AF had a primary efficacy endpoint consisting of stroke (haemorrhagic or ischemic) or systemic embolism (Granger et al., 2011 & Patel et al., 2011). This thesis will evaluate the results from the two trials and compare the control group and discuss how the differences impacted the outcomes of the two trials against warfarin (Urbonas et al., 2019). Below, within this introduction, I endeavour to set some context and then establish the specific aims and objectives of the thesis.

1.2 Atrial fibrillation (AF)

Atrial fibrillation (AF) is characterised by rapid and disorganised atrial activation leading to impaired atrial function, usually associated by another chronic medical condition, such as coronary artery disease or high blood pressure (Pellman & Sheikh, 2015). AF is one of the most common cardiac arrhythmias, affecting 1% to 2% of the general population, and can be diagnosed on an ECG by lack of a P-wave and irregular QRS complexes as shown in Figure 1. (Xu et at., 2016). AF is independently associated with an approximately 5-fold increase in a patient’s stroke risk (Dobesh & Fanikos, 2015), substantial morbidity and mortality and it is also a risk factor for worsening heart failure (Ment, 2015). AF is often prevalent in the following; male gender, elderly, Caucasian race, patients with hypertension, diabetes mellitus type II, valvular heart disease, and other forms of underlying heart disease. Recently, some newer risk factors for AF have been identified including the metabolic syndrome, obstructive sleep apnea, and obesity as well as genetic factors (Balouch et al., 2014). Lone AF is AF without the underlying diseases such as hypertension and structural heart disease. Lone AF accounts for almost 10–30% of all AF patients and AF can usually develop through various pathways in patients with and without co-morbidities (Balouch et al., 2014).

Figure 1. ECG trace of lead II showing Sinus rhythm (left) and Atrial fibrillation (right) (Houghton, 2014)

AF has been categorised into three forms depending on duration. The first type is paroxysmal AF which consists of irregular heart rhythm, which occurs spontaneously and generally resolves by itself or with treatment within 7 days (Hickey et al., 2018). Persistent AF consists of an abnormal heart rhythm for more than 7 days even with treatment or direct current cardioversion. Permanent AF is long standing persistent AF lasting longer than 12 months when all means of treatment to restore normal heart rhythm have failed (Pellman & Sheikh, 2015).

The mechanism of AF has been researched and discussed in a number of studies. The electrical abnormalities were first discussed by Garrey in 1924, which include the same patterns observed today. In a sinus rhythm, the sinoatrial (SA) node acts as the normal pacemaker of the heart and generates an electrical current that leads to the contraction of the atria and the blood is pumped from the atrial chambers into the ventricles. The signal then travels to the atrioventricular (AV) node, then through the ventricle walls, and causes the ventricles to contract, pumping blood into the body and lungs (Pellman & Sheikh, 2015). In AF however, many different impulses are fired from the walls of the left atrium, causing a very fast and chaotic rhythm, which causes the atria to quiver (Informedhealth, 2017). This prevents the regular contraction of the atria preventing the blood to be effectively pumped into the ventricles and the blood starts to accumulate in the atria. The multiple impulses from the atria do not travel in an orderly manner and are essentially competing for a chance to travel through the AV node. The number of impulses that travel to the ventricles are limited by the AV node, however, many impulses get through in a disorganised way. This leads to an irregular contraction of the ventricles, which in turn causes a rapid and irregular heartbeat (Pellman & Sheikh, 2015).

Patients who present without symptoms of AF are often not diagnosed and therefore go untreated as AF can be missed through conventional monitoring approaches such as pulse check, 12-lead ECGs, and ambulatory electrocardiography device monitoring. These methods only capture the activity of the heart for a short period, therefore, the use of devices such as the AliveCor device can prove to be beneficial. The AliveCor device is highly sensitive (94%) and specific (98%) in capturing AF episodes and is easy to use. ECGs can be recorded independently using the AliveCor device by patients after a brief training session and devices such as the AliveCor can benefit patients whose AF may go undetected. A case report of a 58-year-old patient who was suffering from AF and was undetected. The patient also had several CVD risk factors, the patient was given the AliveCor device to monitor their rhythm and their AF was successfully detected (Hickey et al., 2018).

Figure 2. KardiaMobile device demonstrating a patient’s heart rhythm (AliveCor, 2019).

Once diagnosed, the management of a patient with AF is dependent on multiple factors, including the clinical presentation, the frequency, and duration of AF and there are several factors that need to be investigated before a treatment is initiated. Management of AF may involve rate control and rhythm control strategies. The aim of rate control therapy is to alleviate symptoms and preserve ventricular function due to tachycardia as we as the prevention of tachycardia‐associated cardiomyopathy. Clinicians may use drugs such as Beta-blockers and/or calcium channel blockers such as metoprolol, propranolol and verapamil. (Lip & Tello-Montoliu 2006). Drugs such as Digoxin may be used along with rate control drugs in patients with heart failure. Rhythm control strategy in AF aims to restore sinus rhythm and reduce recurrences of AF and may be offered to patients depending on the severity of the AF. Electrical cardioversion can be performed by a synchronised direct current (DC) shock or pharmacologically. Catheter ablation may also be an appropriate therapy in those patients who cannot achieve rate control with medications (Hickey et al., 2018). Studies have found that catheter ablation had an estimated 80% success compared with pharmacologic interventions in persistent and paroxysmal AF (Lip & Tello-Montoliu 2006).

If the AF is not managed appropriately, the quivering of the atrial walls can cause the blood to start accumulating within in the atria as the blood is not pumped into the ventricles. This can potentially lead to the formation of thrombi. Left atrial appendage (LAA) is a common site where these thrombi may form. Formation of a thrombus outside the LAA is uncommon in NVAF without the presence of a LAA thrombus. Formation of these thrombi can often lead to various CVDs and increases the risk of stroke (Melillo et al., 2019).

Figure 3. The Watchman device for the left atrial appendage occlusion (Alshehri, 2019).

The watchman device for left atrial appendage (LAA) occlusion as shown in figure 2 has been suggested as a preventative measure for thrombi formation within the LAA. Studies such as PROTECT AF found that stroke, systemic embolism, and cardiovascular death was lower for patients with Watchman device when compared to patients who were treated with warfarin (Holmes et al., 2009). However, the study also found that major bleeding and procedure related complications were more common in the watchman arm. Another study PREVAIL, however, found that the major bleeding and procedure related complications were less in patients with the watchman device compared to that found in the PROTECT AF. Therefore, it can be concluded that the watchman device can be cost-effective method of prevention of thrombi and for stroke prevention in patients with NVAF (Holmes et al., 2014).

1.3 Burden of AF and the risk of Stroke

The term “burden” in AF is often used in different contexts, such as “arrhythmia burden”, “disease burden”, “clinical burden” and “economic burden”. These “burdens” may change depending the disease progression and the therapy used. Arrhythmia burden is often used by electrophysiologists to describe the percentage of time that a patient is in AF – calculated from the total time in AF divided by the total monitored time (Euler, & Friedman 2003). In the TRENDS study the risk of thromboembolism associated with AF burden was assessed and it was found that the risk of thromboembolism doubled if AF burden was ≥ 5.5 hours on any given day during the prior 30 days (Glotzer et al., 2009). Disease Burden in patients with AF is often defined as the recurrences of AF and the frequency, duration, and severity of episodes. The clinical burden can be defined as the outcomes due to AF such as visits to the General practitioner (GP) or hospital visits, the effects of AF symptoms, the treatment required, and or the consequences of AF e.g. stroke, heart failure. The economic burden reflects the total cost both direct and indirect associated with AF symptoms, consequences, treatments, and/or resultant complications (Rosner et al., 2012).

AF burden is also imposed on patients due to the potential side effects of their treatment for AF. These include but are not limited to the use of beta blockers for rate control where the patient may start to suffer from fatigue. Anticoagulation for the prevention of stroke can also be considered as a burden on the patients’ quality of life (QOL) as the treatments can be costly, interfere with the patients’ lifestyle and diet, requires monitoring, and are associated with an increased risk of bleeding. However, these are often overlooked when compared with the complications associated with stroke or other thromboembolic events. Families and carers of elderly patients may also have burden placed on them due to AF as they would need to be educated on the importance of anticoagulation and prevention of stroke (Rosner et al., 2012).

There are approximately 100,000 strokes each year and 38,000 deaths from stroke in one year in the UK according to the State of the nation stroke statistics (2018). The costs associated with these strokes were around £25.5 billion in 2015 and is expected to rise to £75.5 billion in 2035 (Stroke Association, 2018). Approximately 15% of all strokes are associated with AF (Ment, 2015) and strokes due to AF often have poorer outcomes, where 70% to 80% patients suffer from disability or death. The risk of stroke in AF patients is also higher than in patients with other cardiovascular diseases. AF related strokes cause devastation for patients, their families, and the health care systems around the world therefore the prevention of AF related strokes is a global priority (Oladiran & Nwosu 2019).

Clinical commissioning groups (CCGs) across the UK are working with the NHS on the Long-Term Plan (10-year plan) which includes measures to prevent 150,000 heart attacks, strokes, and dementia cases (NHS England, 2020). There are national and local pathways set for each CCG which follow a more holistic approach to the management of AF; such as the ABC or Atrial fibrillation Better Care Pathway. ‘A’ Avoid stroke with Anticoagulation; ‘B’ Better symptom care, with patient-centred symptom directed decisions on rate or rhythm control; and ‘C’ Cardiovascular and comorbidity risk management, including attention to risk factors and lifestyle changes (Lip, 2017).

Anticoagulation therapy based on the patients’ stroke risk score using an appropriate stratification system is essential to reduce the risk of stroke in patients with AF. The Framingham scoring system is one of the first stroke risk stratification systems. It is a points-based system that assesses several clinical factors of stroke and the patient receives scores as follows: Age (0–10), female sex (6), systolic hypertension (0–4), diabetes mellitus (5), and prior stroke or transient ischemic attack (TIA) (6). Patients with scores >8 were considered increased risk and required thromboprophylaxis (Fang et al., 2008).

The CHADS2 scoring system was devised in 2001, which then became the commonly used scoring system for estimating the risk of stroke in patients with AF (Gage et al., 2001). Similar to Framingham, in the CHADS2 scoring system, the patient receives 1 point for each of the following; congestive heart failure, hypertension, age ≥75 years, diabetes mellitus and the patient receives 2 points if they have suffered from prior stroke or transient ischemic attack and the patient can receive a maximum score of 6 (Al-Turaiki et al., 2016). Based on CHADS2 cumulative score, the risk of stroke is divided into three strata: low-risk patients with a score of 0, moderate-risk patients with scores of 1–2, and high-risk patients with scores of 3–6 (Oladiran & Nwosu 2019).

In 2010, a revised and more updated version of CHADS2 was introduced. CHA2 DS2–VASc scoring system ranges from 0-9 and is now widely used as a stroke risk stratification system (Lip et al., 2010). It uses the components from the CHADS2 but also considers some additional risk factors of stroke where the patient receives additional points; vascular disease (peripheral vascular disease, myocardial infarction, and aortic plaque), Age 65-74, and female sex and the patient receives 2 points for age ≥75 years. The CHA2 DS2–VASc scoring