Cardiac embolism causes up to 30 % of all ischemic strokes [1–4] with an incidence ranging from 20 to 40 per 100,000 in the US population. Cardioembolic stroke is disproportionately more disabling and potentially fatal than nonembolic-mechanism stroke, due to occlusion of larger intracranial arteries and larger ischemic brain volume [5]. Atrial fibrillation (AF) remains the most common cause of cardioembolic stroke (Fig. 12.3) and has a steep age-related increase in incidence. AF accounts for 1.5 % of strokes among patients in their 50s but increases to 23.5 % among patients in their 80s [2, 3, 5, 6]. However, there are a variety of other causes of cardioembolic stroke, which include acute myocardial infarction (AMI), ventricular thrombus (20 %), structural heart defects, cardiac tumors (15 %), and valvular heart disease (15 %) (see Table 12.1) [3]. Cardioembolic stroke affecting the posterior circulation accounts for ≤25 % of all posterior circulation ischemic events in some registries [7–15].

The clinical presentation of cardioembolic stroke is typically indistinguishable from other clinical strokes, namely a sudden neurologic deficit with maximal symptomatology at onset [16, 17]. However, clinical predictors of cardioembolic stroke include rapid or “dramatic” improvement of a major neurologic deficit [18], a maximal deficit from onset [16, 17], simultaneous ischemic strokes in different vascular territories (especially anterior and posterior circulation), and hemorrhagic transformation of an ischemic infarct that suggests recanalization and reperfusion injury. Patients with cardioembolic stroke are less likely to have had a transient ischemic attack (TIA) as a harbinger of their stroke than patients with another high-risk mechanism, large-vessel (e.g., carotid artery) atherosclerosis [16]. Also, cardioembolic strokes may present with a “stuttering” or fluctuating pattern of neurologic deficits, especially those that display features of alternating right or left hemisphere or anterior and posterior circulatory localization. Cardioembolic ischemic stroke may occlude a larger-sized intracranial artery (e.g., proximal middle cerebral artery [M1] segment occlusion) compared to small vessel disease or perforator vessel disease and so the former stroke type tends to often come with greater neurological symptom severity [16, 19]. Seizures are more likely to occur from embolism to distal cortical brain tissue as compared to small vessel disease infarcts in deep locations [20]. Thromboembolic events may also exhibit a characteristic distal cortical wedge-shaped pattern of infarction on CT or MRI (Fig. 12.2) [21]. Embolic events also typically have a scattered pattern of infarction that suggest an embolus fractured or shattered into several pieces before traversing the downstream vascular territory [17, 18]. It should be noted that these radiographic patterns are not pathognomonic for cardiac embolism, per se, as these patterns can occur with emboli arising from other sources including aortic or cervical arterial atherosclerosis that travel through the intracranial circulation.

The clinical approach to cardioembolic stroke patients is systematic but not algorithmic. As with all neurologic evaluations, it hinges on a detailed history and physical examination. It also includes neuroimaging, cardiac rhythm monitoring, laboratory and echocardiographic data. The history should screen for symptomatic palpitations, unexplained bradycardic or tachycardic episodes, assessment of the patient’s history of cardiac disease or heart failure, and family history of cardiac disease or arrhythmias. Asymptomatic patients should be screened during routine annual examinations for risk factors for cardiac embolism by cardiac auscultation for murmurs and assessment for an irregular heart rhythm [22].

The history and physical examination may disclose a potential risk factor or cause for cardioembolic stroke, such as AF. However a substantial number of patients who present with stroke will not display AF during the inpatient setting, even on telemetry, but may require prolonged monitoring, such as Holter monitoring or event monitoring to detect occult AF. In such patients for whom a clinician has a high degree of clinical suspicion for arrhythmia, a 12-lead electrocardiogram, inpatient telemetry, or outpatient Holter monitor [23] or event recorder may be necessary to capture intermittent paroxysmal AF or sick sinus syndrome. Prolonged outpatient Holter monitoring up to 7 days after an index cerebrovascular event can also be considered for patients with unexplained cerebral ischemia, which has a higher yield of occult AF detection compared to 24 or 48 h Holter monitoring (12.5 % compared with 4–6 %) [24]. Long-term continuous electrocardiographic monitoring or 30-day event recorders show a 9–23 % detection rate of occult AF among those without known AF or with previously diagnosed cryptogenic stroke [25–27]. A recent meta-analysis of trials and observational studies focused on the utility of prolonged outpatient cardiac telemetry suggested an overall rate of detection of AF at 11.5 %, noting higher rates in selected vs. unselected patients [28]. Furthermore, the use of automated detection algorithms is preferred over patient-triggered detection because AF is often asymptomatic [29]. The results of the CRYptogenic STroke and underlying Atrial Fibrillation (CRYSTAL AF) trial, which tested an implantable monitor (REVEAL XT, Medtronic, Minneapolis, MN) vs. standard monitoring (as described above) in a randomized fashion for detection of occult AF of greater than 30 s within 6 months of randomization, were reported at the 2014 International Stroke Conference [30]. The investigators reported that the primary end point, which was time to first detection of atrial fibrillation lasting more than 30 s, was reached in 8.9 % of patients with the implanted device vs. 1.4 % of control patients. The end points for longer monitoring were even more robust with detection rates of 12.4 % vs. 2 % and 30 % vs. 3 % for implanted vs. control subjects at 12 months and 36 months, respectively. The expense and current clinical heterogeneity of cardiac monitoring to detect atrial fibrillation has some physicians questioning the utility of monitoring in general and instead advocating for empiric anticoagulation with NOACs, which have similar bleeding rates as antiplatelet agents (the latter antithrombotic agents being more typically used if cardioembolism is suspected but a source is not found) [31].

Stroke onset after Valsalva (e.g., cough, sneeze, bowel movement) is suggestive of intracardiac or intrapulmonary right-to-left shunt such as large patent foramen ovale or other cardiac septal (atrial or ventricular) defects. In such cases, echocardiogram with a bubble study or alternative means of detecting shunt physiology may disclose this source of potential cardiac embolism. Standard laboratory investigations include complete blood cell count with platelets, prothrombin time, and aPTT [22]. B-type natriuretic peptide (BNP) elevation rises to >76 pg/mL at stroke admission has a greater association with cardioembolic stroke as compared to other stroke types (odds ratio [OR] 2.3, confidence interval [CI], 1.4–3.7; p = 0.001), and BNP elevation was highest in the cardioembolic stroke cohort (as high as 410 pg/mL) among all stroke subtypes [32, 33].

Young patients without vascular risk factors who experience cardioembolic stroke or especially TIA, and who have a family history suggestive of thrombophilia, should undergo a prothrombotic workup. A standard prothrombotic laboratory workup for younger patients includes Prothrombin G20210A (prothrombin gene) mutation, factor V Leiden mutation, protein C or S deficiency, anti-thrombin III deficiency, and anti-phospholipid antibodies (e.g., anticardiolipin antibodies, beta-2 glycoprotein antibodies, and the lupus anticoagulant), and serum homocysteine. Recently, hypercoagulable blood testing has come into question, given recent meta-analyses showing a weak association with arterial stroke [34]. However, this may be considered in young patients with no other cause of stroke.

In patients with incident stroke, echocardiography is advised to evaluate the source of cardioembolism. Transesophageal echocardiogram (TEE) remains the diagnostic “gold-standard” to evaluate cardiac structural sources of stroke [22, 35, 36]. TEE has been shown to be superior to transthoracic echocardiography (TTE) in detecting cardiac sources of embolism [36]. Some clinicians prefer to perform TTE first, and if positive for cardioembolic stroke proceed with treatment, depending on the cause. However, if TTE is negative and TEE is not obtained, it is possible to fail to identify the source of cardiac embolism as a TEE can identify high-risk structural abnormalities including intracardiac thrombus (particularly in the left atrial appendage), high-grade aortic plaque and valvular sources of embolism that cannot routinely be identified with TTE [37, 38]. The risks of TEE include local irritation or injury to the oropharynx and esophagus and respiratory decompensation, especially in those with poor cardiopulmonary status (e.g., end-stage cardiopulmonary disease). The hypopnea from sedating medications and Valsalva can increase intracranial pressure, perhaps dangerously in patients who are at risk such as those with large space-occupying intracranial lesions. Structural changes such as wall hypokinesis, septal aneurysm, valvular masses and atrial abnormalities are of particular interest. The presence of left atrial enlargement, although it is nonspecific, is typically seen in patients with atrial fibrillation and one series suggested a greater than sixfold difference in presence of left atrial enlargement in patients with cardioembolic stroke than patients with small vessel disease [39]. The sensitivity for both TTE and TEE in detecting right-to-left shunting can be greatly enhanced by intravenous injection of saline mixed with air (e.g., the saline bubble study or agitated saline study) as compared to detection by color flow imaging alone [40]. Saline bubble study transcranial Doppler ultrasonography can also detect right-to-left shunting with great sensitivity and specificity when intravenous microbubbles are detected as they pass through the middle cerebral artery segment (M1) [41–44]. In addition, paradoxical embolism should be considered in stroke patients with a known right-to-left shunt in whom deep vein thrombosis (DVT) is detected.

Cardiac CT and MRI are emerging diagnostic tools and have identified sources of cardioembolism missed by conventional echocardiography [45, 46], especially for left atrial thrombi. However, cardiac MRI is not typically utilized in routine practice, because it is not widely available, knowledge among physicians with regard to its approved indications is limited, and it so far it has received poor reimbursement [45]. Current guidelines [45, 47] provide the following indications for cardiac MRI: (1) TTE study is questionable for the presence of left ventricular thrombus; (2) a cardiac mass suspected on TTE requires further evaluation; (3) patients cannot tolerate TEE and/or cannot undergo TEE secondary to medical reasons; (4) the TEE study was inconclusive; and (5) suspected false-negative TEE results, in which a cardiac MRI can adequately image potentially missed sources of embolus, such as left ventricular thrombus, cardiac masses, aortic plaque, or left atrial appendage thrombus.

Neuroimaging of cardioembolic stroke is typically performed acutely via noncontrast head CT for patients presenting to the emergency room. Noncontrast head CT has wide availability, quick turnaround time, and an ability to exclude intracranial hemorrhage which is why it is typically used in the decision making process regarding eligibility for intravenous tissue plasminogen activator (tPA) for patients who present within 3–4.5 h of symptom onset [22]. However, patients who present with subacute to chronic stroke symptoms or TIA, or when CT is nondiagnostic, MRI is often used. MRI with diffusion-weighted image sequences has superior sensitivity in detecting small areas of ischemia or infarction that are often missed on initial CT, particularly in the posterior fossa. The neuroimaging pattern of a cardioembolic infarct is typically a cortical or a cortical-subcortical pattern of ischemia on diffusion-weighted imaging, if within roughly 2 weeks of the event. In comparison, small deep penetrator infarcts of the lenticulostriate or brainstem (<1 cm in size) are typically not cardioembolic in origin and most likely relate to small vessel (≤100 μm in diameter) disease processes, such as lipohyalinosis secondary to hypertension or diabetes. However, reports of migratory cardioembolic events that occlude penetrating vessel ostia are reported, but their parenchymal involvement is typically greater than 1 cm in size.

AF is the most common source of cardiac embolism (~45 %) and has an incidence that increases with age [6, 48–50]. Approximately 2.3–3.2 million people are currently affected in the USA, and based on epidemiologic data from Olmsted County in Minnesota, the USA, the future projections of patients with AF could exceed 12 million by 2050 [48], which has tremendous potential to impact societal and healthcare costs attributed to stroke. According to the American College of Cardiology, the American Heart Association, and the European Society of Cardiology [49], AF is classified into different forms: (1) paroxysmal AF (PAF), a self-terminating or intermittent form that generally last less than 7 days and usually less than 24 h; (2) persistent AF, which fails to self-terminate and lasts longer than 7 days; and (3) permanent AF, which lasts for more than 1 year. However, it is important to note that the ischemic stroke risk is similar for persistent, sustained, and PAF based on data within the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W) [51, 52] and anticoagulation is recommended for patients with both chronic and PAF. Detection of PAF can be particularly elusive and sometimes it is first detected during embolic stroke. AF causes ineffective atrial contractions, which lead to stagnation of blood within the left atrium and within the left atrial appendage, which later embolizes to the brain and sometimes viscera. Another classification for AF is either “valvular” or “nonvalvular” AF. Valvular AF refers to AF in the setting of mitral valve disease (e.g., rheumatic mitral valve stenosis) or prosthetic valve [49]. Nonvalvular AF refers to AF without any underlying structural valve disease or prosthetic valve. Nonvalvular AF occurs in approximately 0.7 % of the general population and incidence increases steeply with age [6, 50, 53, 54].

AF ischemic stroke risk is stratified by concomitant independent risk factors, including age (>75 years), history of prior transient ischemic attack or stroke, hypertension, diabetes, and heart failure. Multiple studies have identified these risk factors for stroke in patients with AF. These include the Atrial Fibrillation Investigators (AFI), the Boston Area Anticoagulation Trial of Atrial Fibrillation Investigators (BAATAF) [55], Stroke Prevention in Atrial Fibrillation (SPAF) [56, 57], Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) [58], Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study (AFASAK) [59], and Canadian Atrial Fibrillation Anticoagulation (CAFA) study [60]. Several stroke risk stratification schemes have been proposed [61, 62], and one scheme has not been definitely proven superior to another scheme or 100 % predictive of ischemic stroke risk. For clinical purposes, we find the CHADS₂ risk stratification scheme [62] easy to use in patients identified with AF. “CHADS” is an acronym of the particular risk factor and is weighed for each to estimate the annual ischemic stroke risk (Table 12.2). The letters stand for Congestive heart failure, Hypertension, Age >75 years, Diabetes, and Stroke or transient ischemic attack. All facets of the score count for a single point toward the total score except the stroke/TIA component which confers 2 points, for a possible total of 6 points. We find the CHADS₂ scale simple and easy to use, especially when discussing the risk-benefit ratio of anticoagulation therapy. There are several other, more clinically nuanced scales that were designed to add granularity for individual patients, but a recent comparison [63] suggested that no one scale was superior to another for risk prediction in high-risk patients, although the CHA₂DS₂-VASc [64] score was the best at clarifying low risk, which is important for deciding for or against oral anticoagulation for stroke prevention. The American Academy of Neurology recently published an evidence-based guideline for evaluation and management of non-valvular (e.g., not in association with rheumatic heart disease or other valvular defects) atrial fibrillation, and the contents of this section are informed by that publication [29].

Several large prospective trials and meta-analyses have demonstrated the superiority of oral vitamin K antagonist anticoagulation (predominately warfarin in the USA) compared to antiplatelet (chiefly aspirin internationally) therapy in reducing stroke for high-risk AF patients. Overall, the optimal therapy for each patient is individualized based on ischemic stroke risk factors against hemorrhage risks, such as prior intracranial hemorrhage or gastrointestinal bleeding. Review of all data supporting this assertion comparing warfarin to antiplatelet agents will not be fully outlined, but references and a table (Table 12.3) are provided to the reader [65–79].

The ACTIVE A trial [80] and ACTIVE W trial [51] investigated the role of aspirin and clopidogrel against AF-related thromboembolic events and hemorrhagic events. The ACTIVE A trial studied 7,554 patients with AF at risk for stroke who were unsuitable for warfarin anticoagulation randomized to clopidogrel (75 mg daily) or a placebo in addition to aspirin (75–100 mg daily). The primary outcome measure was a composite end point of stroke, myocardial infarction (MI), extra-cerebral embolic events, and vascular death. The combination of aspirin and clopidogrel reduced the risk of ischemic stroke (relative risk [RR], 0.68; 95 % CI, 0.57–0.80; p < 0.001; number needed to treat [NNT] 111) and myocardial infarction (RR, 0.78; 95 % CI, 0.59–1.03; p = 0.08; NNT 500), but also increased the risk of major bleeding in the clopidogrel group (2.0 % per year) compared to aspirin-placebo group (1.3 % per year) (RR, 1.57; 95 % CI, 1.29–1.92; p < 0.001; number needed to harm [NNH] 143). The ACTIVE W trial randomized more than 6,600 patients with AF with at least 1 risk factor for stroke to aspirin (75–100 mg daily) plus clopidogrel (75 mg daily) or dose-adjusted warfarin (target INR, 2.0–3.0). The primary outcome measure for the study was incident stroke, extra-cerebral embolic event, MI, and vascular death. The study was stopped early due to the findings of superiority of oral anticoagulation compared to the aspirin plus clopidogrel group in preventing primary events (RR, 1.44; 95 % CI, 1.18–1.76; p = 0.0003), and less major bleeding with oral anticoagulation therapy (RR, 1.30; 95 % CI, 0.94–1.79; p = 0.03). These data from the ACTIVE studies suggest clopidogrel and aspirin reduces ischemic stroke and MI (2.4 % stroke rate per year for clopidogrel plus aspirin vs. 3.3 % for aspirin alone), but at the cost of increased bleeding events compared to aspirin alone (2.0 % had major bleeds per year for clopidogrel and aspirin vs. 1.3 % for aspirin alone). Also the combination of aspirin and clopidogrel increases bleeding risk compared to warfarin (major bleeds, 2.42 % vs. 2.21 % per year, respectively) and is inferior to oral anticoagulation in preventing ischemic stroke (2.1 % vs. 1.0 % per year, respectively).

The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial [81] is another recent important study. BAFTA studied 973 elderly patients (aged 75 years or older) with AF, which is significant given that, broadly speaking, an older cohort has more medical comorbidity and increased risk of hemorrhage [82]. The study randomized patients to either low-dose aspirin (75 mg/day) or dose-adjusted warfarin (target INR, 2.0–3.0). The primary end point was ischemic stroke, fatal or disabling hemorrhagic event (such as intracranial hemorrhage [ICH]), or clinically significant arterial embolic event. The mean period of follow-up was 2.7 years in a primary care setting in the UK. The primary event rate was 3.8 % per year in the aspirin group compared to 1.8 % per year in the warfarin group (RR, 0.48; 95 % CI, 0.28–0.80; p = 0.003). The annual absolute risk reduction using warfarin compared to aspirin was only 2 % (95 % CI, 0.7–3.2). However, it is important to note this study included all AF patients, regardless of stratified risk (e.g., CHADS₂ or other scale). The findings demonstrate a “net clinical benefit” (“fatal or disabling stroke” regardless of ischemic or hemorrhagic origin) in older patients (48 % RR reduction) in overall stroke events treated with warfarin compared to aspirin. The annual risk of extracranial bleeding was not significantly different between the groups (e.g., 1.6 % in the aspirin group compared to 1.4 % in the warfarin group [RR, 0.87; 95 % CI, 0.43–1.73]).

The National Study for Prevention of Embolism in Atrial Fibrillation (NASPEAF) trial studied various antithrombotic modalities for stroke risk reduction. Patients deemed high risk (previous embolism, >60 years of age and/or mitral stenosis, n = 495) were randomized to anticoagulation with INR goal of 2.0–3.0 (n = 259) or a combination of the antiplatelet medication triflusal (600 mg daily) plus moderately dose anticoagulation (INR goal 1.40–2.40, n = 236). Patients considered to be of intermediate risk (not meeting criteria for high or low risk by SPAF III [83] criteria), were randomized in a 1:1:1 fashion to triflusal (600 mg daily) alone (n = 242), anticoagulation with target INR 2.0–3.0 (n = 237), or combination triflusal (600 mg daily) with moderate anticoagulation (target INR 1.25–2.00, n = 235). The primary outcome was a composite of vascular death and nonfatal stroke or systemic embolism. Median follow-up was 2.76 years. The primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate- (HR 0.33 [95 % CI 0.12–0.91]; p = 0.02) and the high-risk group (HR 0.51 [95 % CI 0.27–0.96]; p = 0.03). The primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group but not the high risk group. Interestingly, the nonvalvular and mitral stenosis patients—two groups not often included in the same trial—had similar embolic event rates during anticoagulation therapy. This study demonstrated that combined antiplatelet therapy and moderate anticoagulation was effective in reducing vascular events and death in patients with nonvalvular AF and was safe as compared to standard anticoagulation or antiplatelet medication alone [77]. That said, it is not the authors’ practice nor impression of guideline-based care that utilization of dual antiplatelet therapy and lower-intensity anticoagulation be used routinely in this setting.

A single multicenter placebo-controlled trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontané; FFAACS) demonstrated that the risk of hemorrhagic complications was increased in the dose-adjusted vitamin K antagonist plus aspirin group as compared with the vitamin K antagonist alone group (risk difference 14.6 % [95 % CI 5.5–24.8 %]). The study lacked the power to detect important differences in the risk of thromboembolic events. Overall, in patients with nonvalvular AF, the combination of low-dose aspirin and dose-adjusted vitamin K antagonist therapy probably increases the risk of hemorrhagic complications without necessarily favorably affecting the risk of ischemic stroke or other thromboembolic events [84].

The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) trial by Singer et al. [85] demonstrated a net clinical benefit of warfarin anticoagulation in older patients (age > 85) with AF, despite hemorrhagic events. There were 13,559 adult patients with nonvalvular AF who were involved in both retrospective and prospective components of the study. The ATRIA study used the CHADS₂ score to estimate embolic stroke risk. A net clinical benefit was assessed by determining the annual rate of ischemic strokes and systemic emboli prevented by warfarin minus ICH attributable to warfarin, multiplied by an impact factor. An impact factor of 1.5 was used for ICH. The study demonstrated a net weighted benefit of warfarin in AF patients increasing with CHADS₂ score, starting from 0 and increasing to 6, even when accounting for ICH and in older patients. Controversy exists, however, given a more recent retrospective review of spontaneous intracranial hemorrhage in anticoagulated patients that suggests the risk of anticoagulation may approach if not outweigh any benefit in the very elderly or those with other clinical risk factors for hemorrhage [82]. It remains the authors’ recommendation to not consider advanced age a strict contraindication to anticoagulation but perhaps another clinical variable for which a stroke provider must account. The recent American Academy of Neurology guideline on nonvalvular AF suggests the benefit of anticoagulation for stroke prevention likely extends to the elderly based on two Class I studies [29].

Another population of concern is those with AF and chronic kidney disease (CKD). Among patients with CKD participating in the SPAF III trials [86], adjusted-dose warfarin (INR target 2.0–3.0) reduced ischemic stroke and systemic embolism in patients with CKD and a high risk of stroke (relative RR 76 % [95 % CI 42 % − 90 %]) as compared with aspirin or low-dose warfarin, with no difference in major hemorrhage rates. For patients with stage 3 CKD [87], apixaban as compared with aspirin significantly reduced stroke and systemic embolism event rates (HR 0.32 [95 % CI 0.18–0.55], p < 0.001) without an increase in major bleeding (absolute rate apixaban 2.5 % vs. aspirin 2.2 %). So, overall, the benefits of anticoagulation for AF extend to patients with CKD, in spite of the known increased bleeding rates in that population [88].

Ximelagatran, a direct thrombin inhibitor, was studied in Stroke Prevention using Oral Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V trials, but had complications of hepatic dysfunction and was not approved for use by the US Food and Drug Administration [89–91]. The drug was not inferior to warfarin in reducing ischemic stroke in AF patients and had a relatively low incidence of bleeding similar to warfarin. In the SPORTIF trials, ximelagatran had similar rates for major hemorrhage (gastrointestinal and soft tissue) as compared to warfarin, approximately 2.5 % per year.

The Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial [92] studied dabigatran (Pradaxa, Boehringer Ingelheim, Rhein, Germany), another oral direct thrombin inhibitor in AF patients. The study randomized 18,113 patients with AF at risk for ischemic stroke to either dabigatran (fixed doses of 110 or 150 mg twice a day in blinded fashion) or dose-adjusted warfarin (unblinded). Nearly 20 % of the patients in each treatment arm had experienced a stroke or transient ischemic attack prior to enrollment (19.9 % in dabigatran 110 mg arm, 20.3 % in dabigatran 150 mg arm, 19.8 % in warfarin arm). The primary outcome was stroke or systemic embolism. The median duration of follow-up was approximately 2 years. The primary outcome occurred in 1.69 % per year in the warfarin group compared to 1.53 % in the dabigatran group (with 110 mg) (RR with dabigatran, 0.91; 95 % CI, 0.74–1.11; p < 0.001 for non inferiority) and 1.11 % per year in the dabigatran group (with 150 mg) (RR, 0.66; 95 % CI, 0.53–0.82; p < 0.001 for superiority). Major bleeding was reported in 3.36 % per year in the warfarin group compared to 2.71 % in the dabigatran group (with 110 mg) (p = 0.003), and 3.11 % per year in the dabigatran group (with 150 mg) (p = 0.31). ICH occurred at a rate of 0.38 % per year in the warfarin group compared to 0.12 % per year in the dabigatran group (with 110 mg) (p < 0.001), and 0.10 % per year in the dabigatran group (with 150 mg) (p < 0.001). The data suggest the dabigatran group (with 110 mg dose) was not inferior to the dose-adjusted warfarin for stroke prevention, and had less major bleeding complications, particularly ICH (0.38 % warfarin vs. 0.12 % with 110 mg). The higher dose of dabigatran (with 150 mg) was superior to warfarin in ischemic stroke prevention, and had less ICH than warfarin (0.38 % per year with warfarin vs. 0.10 % per year with 150 mg oral dabigatran), but it had similar rates of extracranial major hemorrhage (3.36 % per year with warfarin vs. 3.11 % per year with 150 mg dabigatran). Dabigatran needs to dose-adjusted with renal function and interacts with amiodarone (a P-gp inhibitor), which is commonly used in AF patients. Other P-gp inhibitors ketoconazole, verapamil, quinidine, and clarithromycin do not require dose adjustments. The drug is also a category C in regard to pregnancy. The effects of dabigatran are reduced by rifampin which is a P-gp inducer. The dose used for patients with a creatinine clearance of greater than 30 mL/min is 150 mg orally twice daily, whereas in patients with a creatinine clearance of 15–30 mL/min the suggested dose is 75 mg orally, twice daily [93]. The half-life of dabigatran is approximately 12 h, and there is no known “antidote” to reverse its effects if life-threatening bleeding occurs. Dabigatran was approved by the US Food and Drug Administration in 2010 for use in AF patients for stroke prevention [94], and it was available for prescription by mid-November to December 2010. The drug has been approved and available for use in Europe (prior to approval in the USA) for venous thromboembolism prevention after knee replacement (at a dose of 110 mg, twice a day), which was not for stroke prevention.

Dabigatran prolongs the aPTT. In patients with bleeding, the aPTT test may determine if the drug is present or not, or to assess drug compliance. In areas that in which it is available, a thrombin time or ecarin clotting time may be more sensitive in evaluating, and with the anticoagulant effects of the drug. The prothrombin time (PT) is also prolonged by this drug, but is less sensitive than ecarin clotting time and is not deemed suitable for assessing the anticoagulation effect of the dabigatran. The drug can be dialyzed, and as mentioned there is no antidote to reverse its effects. The manufacturer suggests providing sufficient intravenous fluids to maintain diuresis because the drug has a renal elimination route [93].

Dabigatran was the first of a new line of oral anticoagulants to compete with warfarin for stroke prevention in AF, which has been the anticoagulation mainstay for the past 50 years. However, other newer anticoagulants have either recently been approved or are being actively investigated in trials [95]. These include the recently FDA-approved oral anti-Xa drugs apixaban and rivaroxaban, as well as the drugs still under investigation which include edoxaban [96], darexaban [97], betrixaban [98], and the pro-drug AZD0837 (Table 12.4), which converts into a select and reversible direct thrombin inhibitor (AR-H067637). These drugs have “-xaban” in the name to indicate their mechanism of action (factor Xa inhibition). Edoxaban is the only drug of those still in investigatory phases that has undergone a randomized trial in a large number of patients and has been shown to be non-inferior to warfarin for prevention of stroke in non-valvular AF with significantly less hemorrhagic complication [96]. These newer anticoagulants may provide a wider array for AF patients and ischemic stroke prevention, depending on the results of these trials, which include at least 1 risk factor for stroke, and looking at embolic events both central nervous system (CNS) and non-CNS events, and bleeding.