Continuing Education Activity

An estimated 26 million people suffer a stroke each year, making it a significant source of mortality and long-term disability. Up to two-thirds of strokes are ischemic in origin, and approximately 25 percent of all ischemic strokes are cardioembolic. Cardioembolic strokes are frequently more severe than atherothrombotic strokes. Additionally, they are more prone to both early and late recurrences. This activity reviews the etiology, evaluation, and management of cardioembolic strokes and highlights the role of interprofessional teams in caring for affected patients.

Objectives:

• Describe the etiology of cardioembolic stroke.
• Explain the evaluation of a cardioembolic stroke.
• Review the treatment options for cardioembolic strokes.
• Summarize the importance of improving coordination amongst the interprofessional team to enhance care for patients affected by cardioembolic strokes.

Introduction

Historically, one landmark of societal progress has been the pattern of disease - specifically, the emergence of non-communicable diseases as significant health problems, replacing infections. Strokes may well represent the flagship of these non-communicable diseases. That said, it is worth mentioning that the heavy burden of stroke continues to be in low-to-middle-income countries.[1] An estimated 26 million people suffer from a stroke every year, making it one of the most significant contributors to both mortality and long-term disability. Up to two-thirds of these are ischemic.[1] Approximately 25% of all ischemic cases are believed to be cardioembolic in origin.[2] However, despite accounting for a relatively small proportion of all ischemic strokes, cardioembolic strokes are particularly important as they are frequently more severe than atherothrombotic strokes. Additionally, they are more prone to both early and late recurrences.[3]

Cardioembolic strokes can occur from at least a dozen specific cardiac disorders, including atrial fibrillation, left ventricular thrombi, cardiac tumors, valvular vegetations, and paradoxical emboli. For the most part, cardioembolic strokes can be prevented.

Etiology

Cardioembolic strokes can occur as a consequence of any cardiac insult that could cause the fulfillment of Virchow triad of endothelial injury, stasis, and hypercoagulability.

Commonly encountered causes include:

• Atrial disease:
  • Arrhythmias:
    • Atrial fibrillation, specifically non-valvular atrial fibrillation, is believed to be the most prevalent cause of cardioembolic strokes.[3] Considered the most frequently encountered sustained arrhythmia, it occurs in approximately 5% of people aged 65 years and above. In western populations, most cases are believed to occur secondary to ischemic or hypertensive heart disease. Other contributing factors include hyperthyroidism and heavy alcohol consumption. The contribution of valvular heart disease, particularly the involvement of the mitral valve, is on the decline in terms of the number of cases. However, concerning relative risk, patients with valvular atrial fibrillation have a 17-fold increased risk of cardioembolic stroke, as opposed to the 2-7 fold increased risk in patients with non-valvular atrial fibrillation.[4] The CHADS2 risk stratification tool is often used to predict the stroke risk in patients with atrial fibrillation
    • Sick sinus syndrome, also known as a bradycardia-tachycardia syndrome, is also associated with an increased risk of stroke.
  • Structural disease:
    • Patent foramen ovale:[5] The role of a patent foramen ovale in strokes, particularly the so-called "cryptogenic strokes," is currently an area of great interest. Current evidence is insufficient to conclude about its role as a causative factor, or merely as a conduit for paradoxical emboli.
• Valvular heart disease: Even with the absence of arrhythmias, valvular heart diseases correlate with an increased risk of stroke. These include:
  • Rheumatic valvular disease; the most common is rheumatic mitral stenosis. Without anticoagulation, the risk of stroke is very high.
  • Infective endocarditis: Approximately 10% of cases of infective endocarditis develop embolic strokes. The risk of stroke occurrence is highest before instituting, or within the first two weeks of antibiotic therapy.[4] Anticoagulation is contraindicated because, usually, they are associated with superimposed microhemorrhages. However, current recommendations are to start anticoagulation seven days after a stroke.
  • Non-infective endocarditis such as marantic endocarditis
  • Valvular calcifications: Native valvular calcification, particularly of the mitral valve, increases the risk of developing a cardioembolic stroke. Mitral annular calcification correlates with a relative risk of 2.1 for the development of embolic stroke.[6]
  • Mechanical prosthetic heart valves have a stroke rate of 2% to 4%, even in patients maintained on oral anticoagulation. Permanent anticoagulation with an INR between 2.5-3.5 is mandatory. Bioprosthetic heart valves have a lower risk of stroke, and aspirin is recommended unless the patient has atrial fibrillation.
  • Mitral valve prolapse has a low risk of stroke, and anticoagulation is not recommended. However, long-term aspirin is recommended.
• Structural and functional ventricular diseases:
  • Ventricular aneurysms
  • Septal aneurysms
  • General ventricular hypokinesia (heart failure with reduced ejection fraction): The annual rate of stroke in patients with heart failure with reduced ejection fraction (HFrEF) is approximately 2%, with a direct correlation between the risk of a stroke, and the degree of ventricular compromise.[7]
• Myocardial infarction: The occurrence of myocardial infarction increases the risk of the development of a stroke, with the degree of left ventricular dysfunction, the presence of a ventricular aneurysm or mural thrombus, and the presence of arrhythmias significantly influencing the degree of risk. Approximately 2.5% of cases will develop a stroke within the first four weeks of the infarction, and nearly 10% will over six years.[4]

Epidemiology

Cardioembolic strokes appear to occur more frequently with increasing age. Studies have estimated that they account for 14.6% of cases below the age of 65 years, but this proportion has gone up to 36% for patients aged 85 years and older.[4]

About 20% of strokes are considered to cardioembolic. The risk of these strokes increases with age.

Pathophysiology

As with any thrombus, the fundamental pathophysiology is vested within Virchow's triad. Stasis of blood, as occurs with ventricular akinesia or aneurysms, predisposes to thrombus formation. Similarly, the lack of atrial contractility in atrial fibrillation results in an increased predisposition to clot formation, particularly in the left atrial appendage. These thrombi can either remain indolent and later undergo organization or embolize to systemic circulation - stroke is a potential consequence. With atrial fibrillation, this risk is greatest when converting a patient back to sinus rhythm.

The endothelial injury that accompanies valvular lesions also predisposes to hypercoagulability and thrombus formation, with similar potential consequences.

The cardiac emboli may consist of cholesterol, thrombus, platelet thrombi, calcium, or even bacterial clumps. Emboli from the heart can be distributed anywhere in the body, but more than 80% migrate to the brain. Of the emboli to the brain, the majority involve the anterior circulation, with only about 20% involving the vertebrobasilar circulation.

When emboli enter the brain, they not only obstruct blood flow but may become detached and migrate further distally. Thus, reperfusion is another form of injury.

History and Physical

The classic clinical scenario is that of an abrupt onset neurologic deficit that reaches maximal intensity within minutes and then gradually improves.

As with all strokes, the clinical features depend on the extent and location of neurovascular compromise. However, depressed consciousness is usually a factor favoring a cardioembolic etiology instead of an atherothrombotic stroke.[8] Further, eliciting a history of a Valsalva-like maneuver provoking the stroke also supports a cardioembolic etiology.[4] Cardioembolic strokes cause more seizures due to distal ischemia. 

Classic features of cardioembolic stroke include the following:

• Abrupt decline in mental status
• Change in the level of consciousness
• Presence of neurological deficits

Cardiac findings may include:

• Atrial fibrillation
• Presence of a cardiac murmur
• Signs of congestive heart failure
• Recent myocardial infarction
• Recent diagnosis of infective endocarditis

Evaluation

Cardiac Evaluation

The preliminary cardiac evaluation must be directed towards evaluating both the electrophysiologic status of the heart as well as structural and functional status. As such, workup must include a 12-lead ECG and transthoracic echocardiography for all patients.

Electrophysiologic Assessment

• A 12-lead ECG is useful only to the extent of detecting ongoing arrhythmias. Additionally, it may provide useful insight into ventricular myocardial status (evidence of ventricular hypertrophy) as well as indicate prior cardiac ischemic episodes. However, transient arrhythmias, particularly paroxysmal atrial fibrillation, will be missed.
• Holter monitoring has now become a part of the baseline evaluation of all cases of suspected cardioembolic strokes. Fundamentally similar to an ECG, it has the same drawback of evaluating the conduction system for a relatively limited period of 24 hours.
• Implantable loop recorders (ILRs) can record activity for as long as three years. Thus, their utility in clinical practice continues to increase, and their use has helped identify several cases of "missed" atrial fibrillation. Also, it is very important to note that a patient on oral anticoagulation with atrial fibrillation has to fall 295 times per year for the risk of traumatic subdural hematoma. 

Structural and Functional Assessment

• Transthoracic echocardiography: Transthoracic echocardiography forms the cornerstone of cardiac evaluation. Ventricular hypo- or akinesia, aneurysms, as well as most valvular lesions, can be identified. However, aA key limitation is that visualization of the left atrial appendage is rarely possible using this imaging modality.
• Transesophageal echocardiography: The transesophageal approach permits the use of higher-frequency probes that provide a significantly higher image resolution, and permit visualization of very minute pathologies, including intra-valvar abscesses. A steeper learning curve and lack of universal availability limit its utility as a primary modality of cardiac imaging. An echocardiogram may detect the following pathologies:
• Atrial septal defect
• Patent foramen ovale
• Atrial septal aneurysm
• Atrial thrombus
• Atrial myxoma
• Aortic arch thrombi
• Mitral valve vegetations

Neurologic Evaluation

Although the imaging modality of choice will differ based on the time of presentation of the patient (i.e., within the window period or outside it), the following principles govern the process of evaluation:

• Parenchymal assessment:
  • MRI scans are, by far, the best available imaging modality to evaluate neural parenchymal status. The increasingly available 3 Tesla devices provide an unrivaled image resolution. Various imaging sequences help not only delineate the infarcted area but also help provide a temporal frame where history is sketchy. For instance, diffusion-weighted imaging (DWI) can help identify even hyper-acute infarcts by selecting the appropriate b-value. The presence of cortical stroke in multiple vascular territories should give suspicion for a cardioembolic etiology. The appearance of an infarct in the fluid-attenuated inversion recovery (FLAIR) sequence indicates that the infarct has developed, at least partially, over 6 hours back. MRI scans can even accurately detect hemorrhagic infarcts by means of susceptibility-weighted imaging (SWI). Key limitations, however, are the relatively long duration required for the scan - a formidable contraindication in hemodynamically unstable patients - and ensuring compliance in claustrophobic patients. The increasing availability of "open MRIs" and "virtual-reality based systems" help alleviate the latter, but the former remains a major problem.
  • CT scans: CT scans are excellent imaging modalities for detecting or ruling out hemorrhage. Rapid imaging and ease of reporting, even in settings with limited expertise, remain its key redeeming features. That said, it shows limited sensitivity in detecting infarcts early on in their evolution. Large infarcts may exhibit subtle signs such as sulcal effacement or "the hyperdense middle cerebral artery (MCA) sign," although these are inconsistent features that may easily be missed.
• Vascular status assessment:
  • MR angiography: Magnetic resonance angiography is a useful imaging modality, particularly in patients with renal impairment, as it does not require the use of intravenous contrast media. However, it is prone to various artifacts, including potentially overestimating stenotic lesions.
  • CT angiography: CT angiography remains the investigation of choice for evaluating cerebral vasculature; it's only drawback being that it is not an option in patients with renal impairment. 

Serological Assessment

Although most standard guidelines recommend against instituting this as a routine practice, the evaluation of patients for hyper-homocysteinemia secondary to metabolic vitamin B12 deficiency continues to have a role in the evaluation of a patient of stroke.[9] This is particularly significant in patients known to be following a vegan lifestyle.

Treatment / Management

The cornerstone of the management of cardioembolic strokes involves the use of anticoagulants for secondary prevention.

However, the exact timing of the initiation of anticoagulation remains a matter of controversy. The intention is to strike a delicate balance between the risk of recurrence on the one hand and the risk of a hemorrhagic transformation of the infarct on the other.

Current guidelines propose an arbitrary deferral of anticoagulation for two weeks after the event, based on the extrapolation of trials based on heparin use.[4]

Conventionally, vitamin K antagonists like warfarin are used for oral anticoagulation. Therapeutic response is monitored by serial assessment of prothrombin time and the international normalized ratio (PT/INR). The target INR is between 2.0 to -3.0. However, this target is scaled up to 2.5 to 3.5 for cases with metallic mitral valves. Although universally available and inexpensive, a poorly predictable dose-response curve, a penchant for drug interactions, and a heavy dependence on patient dietary compliance are key drawbacks of these agents.

Direct oral anticoagulants (DOACs) represent the new generation of oral anticoagulants that overcome the shortcomings of vitamin K antagonists. Available agents include apixaban, rivaroxaban, dabigatran, and edoxaban. These newer agents are believed to have a more predictable dose-response curve, and their use obviates the need for repeated monitoring. A key drawback of these DOACs was the lack of availability of a reversal agent; however, this is no longer always the case. Reversal agents for dabigatran (idarucizumab) and rivaroxaban and apixaban (recombinant factor Xa - andexanet alfa) have received FDA approval and are available for clinical use.

Various devices have also received approval for stroke prevention, such as the "WATCHMAN" device for left atrial appendage closure. Such devices are useful in patients with atrial fibrillation unable to tolerate anticoagulation. By sealing off the left atrial appendage, these devices reduce the risk of atrial thrombi, that develop due to atrial fibrillation, embolizing into the systemic circulation.

Closure of the patent foramen ovale is also gaining recognition as a vital tool to prevent stroke recurrence. It has shown a clear superiority to antiplatelet therapy, and non-inferiority to anticoagulation.[10] Any patient who had a cardioembolic stroke less than 60 years old should evaluate for patent foramen ovale.

For patients with left ventricular thrombus and myocardial infarction, we usually recommend anticoagulation at least for three months due to embolization risk.

Differential Diagnosis

• Atherothrombotic strokes
• Hemorrhagic stroke
• Transient ischemic attack
• Stroke mimic syndromes

Pertinent Studies and Ongoing Trials

The TIMING study, undertaken in 2017, is likely to provide useful clinical information regarding the optimal time of initiation of anticoagulation.

Prognosis

If not treated appropriately, cardioembolic strokes have a higher tendency than atherothrombotic strokes to show both early and late recurrences.

Complications

Hemorrhagic transformations, both spontaneous and post-anticoagulation therapy, are potentially grave consequences of this condition. In addition, long-term disability, bed-rest related complications such as pressure sores, may all occur but vary depending on the severity and extent of neuro deficit.

Deterrence and Patient Education

Avoiding excessive alcohol, adopting a Mediterranean-like or DASH (dietary approaches to stop hypertension) diet, and other measures that can combat both hypertension, as well as eliminate triggers of atrial fibrillation, are likely to be beneficial.

Patients on warfarin should be provided with a list of foods that contain vitamin K (avocado, broccoli, etc) which can limit the efficacy of warfarin.

Enhancing Healthcare Team Outcomes

Cardioembolic stroke is a devastating disease with a high risk of recurrence and complications if it is not identified and treated properly. The treatment involves multiple levels of evaluation, drugs, and therapy to optimize patient recovery. An interprofessional team of clinicians, nurses, pharmacists, and physical therapists is needed to treat these patients effectively.

Most hospitals have an interprofessional team dedicated to the management of patients with stroke. This stroke team consisting of a cardiologist, a neurologist, a dedicated radiologist (potentially an interventional neuro-radiologist if thrombectomy is warranted), and an internal medicine physician, is vital in improving outcomes. The clinicians need to maintain a high degree of suspicion for underlying arrhythmias or cardiac diseases that can lead to an embolic etiology of the stroke. Due diligence with thorough evaluation is warranted to rule out this disease.

In addition, a stroke nurse is needed to monitor the patient's neurologic status during the hospital stay and to assist the medical team in educating the patient to prevent a recurrence. The clinical pharmacist is needed to assist the team in educating the patient on drug compliance and to adjust medications to minimize adverse outcomes. An integrative and collaborative interprofessional team can greatly improve outcomes for patients with this disease. [Level V]

Current evidence regarding when to initiate treatment is still sketchy. Trials such as the TIMING study are likely to add valuable information to the existing knowledge base.