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Anticoagulation Therapy for Stroke Prevention

AF and stroke

Read time: 60 mins
Last updated:16th Jun 2022
Published:24th Nov 2021

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, and strokes seem to be becoming more prevalent1–3. Discover more on the:

  • Increased risk of stroke in AF patients
  • Increasing prevalence and burden of AF and stroke
  • Pathophysiology of stroke in AF4

Atrial fibrillation: an important stroke risk factor

Atrial fibrillation (AF) patients can present with a wide range of sometimes debilitating symptoms, disease patterns and comorbidities. Even when asymptomatic, AF can cause irreversible remodelling of the atria, which can perpetuate the arrhythmia and mean that over time, AF becomes progressively more difficult to treat5,6. As a result, early detection and rapid effective treatment are the cornerstones of care to alleviate symptoms and to reduce the risk of complications, including AF-related stroke5.

Association between atrial fibrillation and stroke

AF is an important risk factor for stroke. In AF, the disrupted rhythm may cause blood to pool in the atria and form clots. If a blood clot forms, it could dislodge from the heart and travel to the brain, blocking the blood flow and causing a stroke (Figure 1). Identifying and managing AF early and effectively can therefore help to prevent AF-related stroke.

T1_Stroke_Fig1.png

Figure 1. How atrial fibrillation can lead to stroke (Adapted7).

It is now well known that atrial fibrillation (AF) and stroke are associated8. This association is based on three concepts:

  1. AF causes stroke
  2. Stroke causes AF
  3. AF is associated with other factors that can cause stroke


AF as a cause of stroke

AF markedly increases the risk of stroke and systemic embolism6. For instance, AF increases stroke risk five-fold compared with people without the arrhythmia2,6. The risk associated with AF is even higher in people with other stroke risk factors9. Overall, AF may cause up to half of cardioembolic strokes and 10–30% of acute ischaemic strokes4,10,11

Stroke risk does not seem to depend on AF severity: stroke risk with paroxysmal AF is the same as that with permanent or persistent AF4. Even a brief episode of subclinical AF doubles the risk of stroke in older patients with vascular risk factors8.

Nevertheless, some patient groups seem to be especially vulnerable to developing AF-related strokes. For instance, stroke risk is 17-fold higher in AF patients with rheumatic mitral valve stenosis compared with people in sinus rhythm4,10. Older people are at increased risk: 25% of all stroke in people older than 80 years occur in AF patients2. Women are also at higher risk of experiencing a cardioembolic stroke from AF compared with men (Figure 2)6,12

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Epidemiology of stroke and atrial fibrillation

Stroke

Stroke is ranked as the second leading cause of death worldwide with an annual mortality rate of about 5.5 million. The burden of stroke not only lies in the high mortality, but also in the high morbidity, since up to 50% of survivors end up being chronically disable16.

Age-adjusted stroke incidence varies from 95–290 per 1,000,000 of the European population annually25. About 1.1 million people experience a stroke in Europe each year. Transient ischaemic attacks (TIAs) are also common: the age-adjusted incidence ranged from 28–59 per 100,000 of the European population each year25

Despite improved prevention, rapid diagnosis and prompt treatment, stroke remains common. Many stroke survivors develop serious complications and demographic changes mean that strokes and TIAs are likely to become even more common over the next few decades25.

Stroke incidence, for example, increases 100-fold between 40 and 80 years of age, while the age-adjusted incidence is 1.2–2.0 times higher in men than women, but life-expectancy is lower in males than females. Epidemiologists predict that, if current trends continue, by 2025, 1.5 million people in Europe will experience a stroke each year25.

Types of stroke and outcomes following stroke

Despite advances in management, strokes generally show a poor prognosis including a high case fatality rate

Ischaemic strokes account for about 80% of cases in Europe, although this varies from 55% to 90% depending on the study. Intracerebral and subarachnoid haemorrhages account for 10–25% and 0.5–5% of strokes respectively3. Numerous well-established factors contribute to the risk of developing a stroke including hypertension, dyslipidaemia, carotid stenosis and atrial fibrillation (AF)17. Nevertheless, cryptogenic strokes and TIAs with an unknown aetiology account for between 25% and 39% of strokes18.

Ischaemic strokes interrupt the cerebral blood supply, causing areas of cell death in the brain19. The reduction in cerebral blood can fall beneath the threshold for brain function, generally 25–50% of the perfusion before the stroke. These areas generally recover if blood flow returns. A further decrease to about 20% or less of the flow before the stroke can lead to irreversible tissue damage, which is generally closer to the area of reduced blood supply. The penumbra refers to the range between these thresholds. The infarction develops from the core of ischaemia propagating a wave of irreversible tissue damage that spreads through the penumbra reaching areas less severely affected by the reduced blood flow20

In ischaemic stroke, the necrotic core can arise in three ways19:

  • small vessel disease, which may be non-atherosclerotic or atherosclerotic, arises from blockages in the small cerebral perforating arteries
  • large vessel disease results from occlusions or emboli released by the rupture of atherosclerotic plaques in the carotid artery or another large blood vessel
  • cardioembolic stroke arises typically from emboli that travel from the heart to the cerebral arteries

AF may cause up to half of cardioembolic strokes10.

Outcomes following stroke

Case fatality rates after a stroke increase from about 15% at 1 month, to 25% at 1 year and 50% at 5 years. Following intracerebral haemorrhage, case fatality rates increase from 55% at 1 year to 70% after 5 years17

Despite advances in management – such as tissue plasminogen activator, which, when used promptly, reduces the propagation of the ischaemic penumbra – strokes generally show a poor prognosis (Table 1), including a high case fatality rate. About 40% of people who survive are disabled, defined as a modified Rankin Scale score of 3–5, 1 month and 5 years after the stroke17.

Table 1. Outcomes of stroke in Europe (Adapted3).

Stroke prevention_T1_Table1.png

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Classification of atrial fibrillation 

Atrial fibrillation (AF) can present in several ways and correct classification can guide the choice of treatment. AF can present from a single isolated episode to a constant arrhythmia (Table 2). 

Table 2. Classification of atrial fibrillation (Adapted5). AF, atrial fibrillation.

Stroke prevention_T1_Table2.png

Occasionally, in about 2–3% of patients, AF remains paroxysmal for several decades5. Paroxysmal AF is more common than the persistent arrhythmia in young people and women13. However, AF usually progresses.

Paroxysmal and persistent AF each occur in about 20–30% of patients2. Overall about 40–50% of AF patients develop permanent atrial arrhythmias2.

Up to a third of patients do not experience symptoms during an episode, so-called silent or subclinical AF11. Indeed, people with asymptomatic AF can experience clinically silent episodes5. Symptomatic and silent AF share the same electrophysiological and mechanical pathogenesis. However, as silent AF is generally untreated, the progression from paroxysmal to persistent or permanent AF might be more rapid than in patients with documented AF11.

Mortality is between 1.5 and 1.9-fold higher among AF patients than in people without the arrhythmia after adjusting for other cardiovascular risk factors10, partly because of the increased stroke risk.

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Pathophysiology of atrial fibrillation

A network of pathways influences the onset and persistence of atrial fibrillation

In any particular patient, the onset and persistence of atrial fibrillation (AF) may involve a complex network of mutually reinforcing pathogenic pathways that are influenced by age, genetic factors and acquired risk factors8,27. For example, acute coronary syndrome (ACS), such as myocardial infarction, as well as surgery or infection seem to precipitate a third of AF cases11. Table 3 summaries the possible pathophysiology of different AF types, which may overlap in clinical practice5. This section takes a deep dive into the pathophysiology of this common arrhythmia and its relationship with stroke.

Table 3. Possible pathophysiology of different clinical types of atrial fibrillation (Adapted5). AF, atrial fibrillation; RAAS, renin-angiotensin-aldosterone system.

Stroke prevention_T1_Table3.png

The genetics of atrial fibrillation

Atrial fibrillation (AF) incidence is lower in African Americans, Hispanics and people of Asian descent compared with Caucasians, which may suggest a genetic component6. Further evidence supporting a genetic component emerged in studies from a variety of populations showing that having a parent with AF markedly increases the likelihood of developing the arrhythmia. In one study, the likelihood of developing AF was 1.85 in people with one parent who had the arrhythmia compared with controls. The risk increased to 3.23 in those whose parent developed AF when older than 75 years of age28.

Family studies and genotyping of sporadic cases identified numerous rare genetic variants that seem to contribute to AF27. Moreover, genome-wide association studies link more than 30 common genetic variants with AF, many of which encode loss-of-function or gain-of-function channelopathies (defects in ion channels caused by genetic or acquired factors, such as toxins or drugs)27,29. Other polymorphisms linked to AF are associated with transcription factors (proteins that regulate gene activity by increasing or reducing binding of RNA polymerases to DNA) associated with cardiac genes27. Future investigations of transcription factors might elucidate how developmental abnormalities affecting the heart may predispose to AF in later life27.

Other polymorphisms associated with AF encode27:

  • structural components in the myocardium, such as the light and heavy chains of the contractile protein myosin
  • structural components in gap junctions, which allow a depolarising current to travel between myocytes and help synchronise cardiac contraction
  • proteins involved in signalling or protein turnover

Genetic interactions between AF and stroke

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Burden of atrial fibrillation

Atrial fibrillation (AF) impairs patients’ quality of life and accounts for up to 2% of healthcare budgets; stroke and hospitalisations drive the costs.

AF patients report impaired quality of life (QoL) that is independent of concomitant cardiovascular conditions5. The impairment in QoL associated with AF can be similar to that in congestive heart failure (CHF) and reflects the symptoms of the disease and complications, such as stroke37. AF’s impact on QoL may be especially marked in women, younger patients and those with comorbid conditions, such as coronary artery disease, chronic obstructive pulmonary disease (COPD), obstructive sleep apnoea or New York Heart Association (NYHA) classes II-IV CHF. Some of these factors could be modified and their presence may indicate that the patient requires a thorough QoL assessment37.

Between 10% and 30% of AF patients are hospitalised annually5

AF is present in 3–6% of acute medical admissions, imposing a heavy economic burden9. Most costs associated with AF derive from hospitalisations, management of the associated comorbidities (notably stroke and CHF) and lost economic productivity6.

A study from Denmark suggested that AF accounted for 1.3–1.7% of total healthcare costs, which were highest during the first year after diagnosis. Costs were higher in AF patients with ischaemic stroke (€89,510 per patient) than in those who did not experience a cerebrovascular event (€30,066 per patient). Hospital admissions represented the largest cost driver (Figure 9). The authors concluded that reducing the need for hospitalisations, especially from stroke, is important to help control costs38.

PFI_Stroke_T1_Fig9.png

Figure 9. Total average cost per individual in years 1–3 after a first-time hospital diagnosis of atrial fibrillation (Adapted38).

Discover more on screening and diagnosis for atrial fibrillation

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References

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