Secondary Prevention of Cardioembolic Stroke

62 

Secondary Prevention of Cardioembolic Stroke Karen Furie, Muhib Khan

KEY POINTS • Cardioembolic stroke is a major etiology accounting for one-fifth of all ischemic strokes. • Recent advances in technology have enabled us to monitor heart rhythm remotely and detect paroxysmal atrial fibrillation. • Newer risk stratification scores like CHADS2-Vasc and HAS-BLED have been developed to predict ischemic stroke due to atrial fibrillation as well as bleeding risk on anticoagulation. • Rheumatic mitral valve disease has the highest risk of ischemic stroke of all native valvular heart disease. • CLOSURE, RESPECT, and PC trials have shown that device closure of patent foramen ovale (PFO) is not superior to medical therapy in preventing recurrent stroke. • Newer oral anticoagulants have shown equal or superior efficacy to warfarin in preventing ischemic stroke in non-valvular atrial fibrillation expanding treatment options for this patient population. • Intracerebral hemorrhage due to anticoagulant therapy has higher morbidity and mortality needing further research in this particular area.

Cardioembolic stroke is a major stroke subtype accounting for one-fifth of all ischemic strokes.1,2 Advanced imaging technology has enabled us to easily identify potential cardiac sources of emboli. Since, the underlying cardiac condition is often evident before stroke occurs and antithrombotic therapies are notably effective, cardiogenic emboli to the brain are among the most preventable causes of stroke. With a thorough cardiac evaluation, a potential source of cardiogenic emboli can be identified in at least 30% of all patients with ischemic stroke.3,4 However, potential cardioembolic sources often coexist with other cardiovascular disease risk factors.5–7 During the past two decades, new and better non-invasive cardiac imaging became available; therefore, new potential cardioembolic sources have been recognized. This situation is reflected in the increased frequency of cardioembolic stroke over time. Aggregate data from stroke registries conducted between 1988 and 1994 show mean frequency of cardioembolic stroke to be 20% (range, 17–28%).1,6,8–11 Data from later stroke registries (1995–2001) showed a higher mean prevalence of cardioembolic stroke, 25% (range 16–38%).12–16 Cardioembolic stroke is caused by a variety of cardiac disorders, each with a unique natural history and a variable response to antithrombotic therapy (Fig. 62-1). The embolic material originating from the heart and proximal aorta can be

1014

quite diverse. The thrombi may be composed of varying proportions of platelets and fibrin, cholesterol fragments, tumor particles, or bacterial clusters. The natural history and response to antithrombotic therapy of each of these conditions are unique, and, consequently, each source of cardioembolic stroke should be considered separately. Thus cardioembolic stroke is not a single disease; it is a syndrome with diverse causes (see Fig. 62-1). The incidence of ischemic stroke associated with cardioembolic sources varies greatly. Cardioembolic sources of stroke can be divided according to their stroke risk potential as “major-risk sources,” for which the risk for stroke is well established, or “minor-risk sources,” for which the risk for stroke has been incompletely established (Table 62-1). The majorrisk cardioembolic sources carry a substantial annual risk of emboli and a high risk of recurrence, and usually, antithrombotic therapy is warranted for stroke prevention. Conversely, the so-called minor sources of emboli can cause stroke but have a low or uncertain risk of embolism and are more often coincidental than causal; therefore, antithrombotic therapy is usually reserved for selected cases.

ATRIAL FIBRILLATION Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 0.7–0.9% of the general population of the US (2.5 million people).17,18 Its prevalence increases with age, being present in about 5% of persons at age 65 years and in 10% at age 80 years. AF is equally distributed in men and women, and the mean age of individuals affected is about 75 years (Fig. 62-2).17,18 The first-detected episode can proceed along different pathways. It can be self-limited without any recurrence, in which case it is termed “lone AF.” It can adopt a recurrence pattern with intervening sinus rhythm termed as “paroxysmal AF.” If it persists for 7 days, it is termed “persistent.” These forms of AF are proposed by American College of Cardiology (ACC)/ American Heart Association (AHA)/European Society of Cardiology (ESC).19 It is important to note that the AF duration and its persistence can evolve over time either due to ongoing pathophysiological process or treatment. AF can be further divided into valvular vs non-valvular AF. Valvular AF is defined as AF secondary to structural heart disease involving the valves, commonly the mitral valve. Non-valvular AF is defined as AF without evidence of structural valvular heart disease preferably screened by an echocardiogram.19 Non-valvular AF is the etiology in 25% of all ischemic strokes.6,20,21 Older age is a major risk and AF is the diagnosed etiology in more than one-third of patients older than 70 years with ischemic stroke.22 The risk of ischemic stroke increases fivefold (from 1–5% per year) in elderly patients (mean age, 70 years) with non-valvular AF, and about 18-fold in patients with AF and rheumatic mitral stenosis.23 AF accounts for about one-half of presumed cardioembolic strokes. Patients with AF are typically older and have large middle cerebral artery strokes



Secondary Prevention of Cardioembolic Stroke

associated with a high mortality rate during the first 30 days (Table 62-2).24,25 Stroke associated with AF is attributed to embolism of thrombus from the left atrium (LA), the pathogenesis of which is complex.26 Thrombus most frequently forms in the left atrial appendage (LAA).27 This thrombus is a result of stasis, endothelial dysfunction and a hypercoagulable state. Stasis results from the decreased emptying of the LAA due to loss of organized mechanical contraction during the cardiac cycle, as evidenced by the reduced LAA flow velocities.28 Moreover, AF seems to promote a hypercoaguable state and has been associated with biochemical markers of coagulation and platelet activation.29 However, AF alone may not be enough to promote thrombi formation. Other factors may also contribute, because associated cardiovascular disease and age appear to influence the stroke risk in AF and, hence, also to influence the formation of atrial appendage thrombi. This variable risk is reflected by

Ischemic heart disease Rheumatic heart Prosthetic disease cardiac valve (10%) (10%)

Ventricular aneurysm (10%)

the wide range of stroke risk in patients with AF (“lone AF”) a phenomenon not observed with other “high-risk” conditions. Temporal variation in factors that influence thrombus formation may explain the intermittency of embolism in different patients with AF and even within each patient. Embolic events are intermittent in AF, sometimes separated by years. A balance between the formation and inhibition of clot is likely present in the atrial appendage of such patients. This balance is influenced by atrial size, appendage flow velocities, and coagulation factors. Therefore, the type and intensity of antithrombotic therapy needed to inhibit appendage thrombi may differ among patients with AF and over time for the same patient. In summary, complex electrophysiological and thromboembolic processes lead to embolic events in AF. The overall incidence of ischemic stroke among people with AF is about 5% per year. The rate of stroke varies widely, however, ranging from 0.5% per year in young patients with “lone AF” to 12% per year in those with prior transient ischemia attack (TIA) or stroke. This variation depends on coexisting cardiovascular disorders.26,30,31 Therefore, identification of subgroups of patients with AF with relatively high vs low absolute rates of stroke is important for selecting prophylactic antithrombotic therapy.22 Different scores have been developed and validated to predict this risk in an individual. The CHADS2 score is widely used as the most reliable scheme of stratification that allows the separation of AF

12

Other, less common sources (10%)

Nonvalvular atrial fibrillation (45%)

10 9

8

7

6

5

4 2

2 0 Figure 62-1.  Sources of cardioembolic stroke. MI, myocardial infarction.

11

Women Men

10 Prevalence (%)

Acute MI (15%)

1015

0.1 0.2 <55

0.4

1

2

3

7

5

3

1

55–59 60–64 65–69 70–74 75–79 80–84 Age (years)

>85

Figure 62-2.  Prevalence of atrial fibrillation stratified by age and sex.

TABLE 62-1  Cardioembolic Sources by Location

Major-Risk Sources

Minor-Risk Sources

Atrial

Valvular

Ventricular

Atrial fibrillation Left atrial thrombus Left atrial myxoma Sustained atrial flutter Patent foramen ovale Atrial septal aneurysm

Mitral stenosis Prosthetic cardiac valves Infective endocarditis calcification Marantic endocarditis Mitral valve prolapse Calcific aortic stenosis Mitral annular Giant Lambl’s excrescences Fibroelastoma

Left ventricular thrombus (mobile or protruding) Recent anterior wall myocardial infarction Non-ischemic dilated cardiomyopathy Left ventricular regional wall abnormalities Congestive heart failure Akinetic ventricular wall segment

TABLE 62-2  Stroke Risk in Relation to Atrial Fibrillation* Study Framingham (USA) (Wolf, 1991)23 Shibata (Japan) (Nakayama, 1997)23a Reykjavik (Iceland) (Onundarson, 1987)23b *Data from epidemiologic studies.

Mean Age (years)

Stroke Rate %/year AF

Stroke Rate %/year Non-AF

Increased Relative Risk

70 65 52

4.1 5.0 1.6

0.7 0.9 0.2

×6 ×6 ×7

62

1016

SECTION VI  Therapy

TABLE 62-3  CHADS2 Score for Risk Stratification of Stroke

TABLE 62-5  HAS-BLED Score for Bleeding Risk on Anticoagulation36

CHADS2 Score*

Risk

HAS-BLED Score*

0 1 2 3 4 5–6

Low Low Moderate High High Very high

Stroke Rate (%/year) 0.5 1.5 2.5 5 6 7

*For CHADS2 (congestive heart failure, hypertension, age older than 75 year, diabetes mellitus) score and validation, see Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: Results from the national registry of atrial fibrillation. JAMA 2001;285:2864–2870. Level of Evidence Class I.

0 1 2 3 4 5

Bleeding Risk (% per 100 patient-years 1.2 2.8 3.6 6.0 9.5 7.4

*For HAS-BLED (Hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score and validation see Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest. 2010;138:1093–1100. Level of Evidence Class IIb.

TABLE 62-4  CHA2DS2-VASc Score for Risk Stratification of Stroke CHADS2 Score*

Risk

0 1 2 3 4 5 6 7 8 9

Low Low Moderate Moderate High High Very High Very High High Very High

Stroke Rate (%/year) 0 1.3 2.2 3.2 4 6.7 9.8 9.6 6.7 15.2

*For CHA2DS2-VASc (congestive heart failure, hypertension, age older than 65 yr, diabetes mellitus, vascular disease and sex) score and validation, see Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on atrial fibrillation. Chest. 2010;137:263–272. Level of Evidence Class IIa.

patients according to the risk of stroke.32 This scheme was validated in an independent cohort. The acronym stands for: • C = congestive heart failure (1point) • H = hypertension (1 point) • A = age older than 75 (1 point) • D = DM (1 point) • S2 = history of stroke or transient ischemic attack (TIA) (2 points). In a large validation cohort the estimated risk of stroke per year based on CHADS2 score is shown in Table 62-3. A limitation of the CHADS2 score applies to secondary prevention in patients with prior stroke or TIA and no other risk factors.32 Therefore, recently CHA2DS2-VASc index was developed to further refine the risk calculation of CHADS2 by including additional variables of Vascular Disease, Age > 65 and female gender.33,34 The score is calculated as below: • C = congestive heart failure (1 point) • H = hypertension (1 point) • A2 = age older than 75 (2 point) • D = DM (1 point) • S2 = history of stroke or transient ischemic attack (TIA) (2 points) • V = vascular disease (previous myocardial infarction, peripheral artery disease, aortic plaque) (1 point) • Age = 65–74 (1 point) • Sex = female (1 point). The estimated risk of stroke per year based on CHA2DS2VASc score is shown in Table 62-4.33,34

The short-term risk of stroke recurrence after an acute stroke in patients with AF is about 5% in 2 weeks which is a value much lower than previously considered.35 The goal of anticoagulation is to prevent ischemic events but also to minimize the risk of bleeding related to anticoagulation. In this regard HAS-BLED score was developed to predict risk of hemorrhage in patients on anticoagulation. The score is calculated as below: • H = history of uncontrolled hypertension (>160 mm Hg) • A = abnormal renal/liver function (one point for presence of renal or liver impairment, maximum two points) • S = stroke (previous history, particularly lacunar) • B = bleeding history or predisposition (anemia) • L = labile international normalized ratio (INR) (i.e., therapeutic time in range, 60%) • E = elderly ( >65 years) • D = drugs/alcohol concomitantly (antiplatelet agents, nonsteroidal anti-inflammatory drugs; one point for drugs plus one point for alcohol excess, maximum two points). The estimated risk of bleeding events per 100 patient-years based on HAS-BLED score is shown in Table 62-5.36,37

Long-term Monitoring for Detection   of Atrial Fibrillation The risk of stroke recurrence as highlighted above makes it imperative to diagnose AF promptly to provide effective stroke prevention therapy. Paroxysmal AF (PAF) is a major hindrance in achieving this goal and has been suggested as a cause for cryptogenic strokes.38 Brief asymptomatic PAF events may remain undetected by traditional methods of screening. Recent technological advances have made it possible to perform longterm invasive and non-invasive cardiac rhythm monitoring up to months or even years after a stroke.39 The diagnostic yield of these monitoring strategies is high (an average of 11.5%; 95% confidence interval [CI], 8.9–14.3%) and enables detection of AF in large number of cryptogenic stroke patients.39–42 The currently underway CRYSTAL-AF study is investigating the value of longer-term monitoring with an implantable loop recorder in patients with cryptogenic stroke.43 Moreover, IMPACT study is also evaluating the impact of therapeutic intervention implied after detection of these events which is the final goal of any diagnostic evaluation in secondary stroke prevention.44

Stroke Prevention in Atrial Fibrillation The efficacy of antithrombotic therapies to prevent stroke in non-valvular AF has been well established by randomized



clinical trials. An aggregate analysis showed that anticoagulation with warfarin reduces ischemic stroke by 64% in comparison with the rate in untreated patients, and an efficacy analysis indicated an even greater benefit. Warfarin was effective in preventing disabling stroke by 59% and nondisabling stroke by 61%. The absolute risk reduction in all strokes by the use of warfarin was 2.7% per year for primary prevention (NNT for 1 year to prevent one stroke = 37) and 8.4% per year for secondary prevention (NNT = 12).45 When only ischemic strokes were considered, adjusted-dose warfarin was associated with a 67% relative risk reduction (RRR) (95%CI, 54–77%). In addition, the increase in rate of major bleeding among elderly patients with AF undergoing anticoagulation in these trials was only 0.3–2.0% per year with a target international normalized ratio (INR) of 1.5–4.0. The risk of major hemorrhage in elderly patients with AF who are taking oral anticoagulants seems to be related to the intensity of anticoagulation, patient age, and fluctuation in INR.46 The efficacy of aspirin, with doses ranging from 50 to 1300 mg per day, for stroke prevention in patients with AF has been tested in eight trials that included 4876 participants. Comparing aspirin alone with placebo or no treatment, aspirin was associated with a 19% reduction in incidence of stroke (95%CI, 1–35%). For primary prevention, there was an absolute risk reduction of 0.8% per year (NNT = 125) and for secondary prevention trials a reduction of 2.5% per year (NNT = 40). When only ischemic strokes are considered, aspirin results in a 21% reduction in strokes (95%CI, 1–38%). When all antiplatelet agents are considered, stroke was reduced by 22% (95%CI, 6–35%).45 Eight trials compared warfarin and other vitamin K antagonists with various dosages of aspirin, other antiplatelet agents in three trials and aspirin combined with low-fixed-dose warfarin in two trials. For the 11 trials that compared adjusteddose warfarin with antiplatelet therapy alone, warfarin was associated with a 37% reduction in strokes (95%CI, 23–48%).45 In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W), anticoagulation therapy was superior to the combination clopidogrel plus aspirin (RRR, 40%; 95%CI, 18–56%).47 The risk of intracranial hemorrhage with adjusted-dose warfarin was double that with aspirin. The absolute risk increase, however, was small (0.2% per year).45 Unquestionably, warfarin is highly efficacious for preventing stroke in patients with AF and relatively safe for selected patients. Aspirin offers less benefit, possibly by decreasing non-cardioembolic strokes in these patients. The choice of antithrombotic prophylaxis is based on the risk stratification (see Tables 62-3 and 62-4). Long-term anticoagulation cannot be recommended for all unselected patients with AF, because most of them would not experience strokes even if untreated. Patients with AF with a relatively low risk of subsequent stroke would not substantially benefit from the use of warfarin, because the absolute risk reduction would be small (RRR, 1% per year). In these patients, anticoagulation may not be warranted. On the contrary, patients with AF who have a high risk for ischemic stroke (higher than 7%) because of a history of hypertension, prior TIA or stroke, or ventricular dysfunction would have a significantly lower stroke rate if they received anticoagulation.48 High-risk patients who are good candidates for anticoagulation realize remarkable benefit from warfarin. For high-risk patients 75 years or younger, a target INR of 2.5 (range, 2.0– 3.0) is effective and safe; for those older than 75 years, choosing a slightly lower target (INR 2.0–2.5), with the hope of minimizing bleeding complications, appears appropriate. Patients younger than 60 years with “lone AF” may not require

Secondary Prevention of Cardioembolic Stroke

1017

long-term anticoagulation, and because their intrinsic risk for stroke is small, aspirin may be sufficient. Paroxysmal atrial fibrillation (PAF), with underlying causes similar to those in sustained or constant AF, constitutes between 25% and 60% of all cases of AF.49 Epidemiologic data have suggested that the risk of stroke for patients with PAF is intermediate between those of patients with constant AF and patients with sinus rhythm. However, when data are controlled for stroke risk factors, PAF involves a stroke risk similar to that of constant AF.50 The risk–benefit ratio for antithrombotic therapy in patients with PAF has not been evaluated in clinical trials. Therefore, the recommendations are based on indirect data from AF trials, so the approach to patients with PAF should be the same as that to patients with sustained AF.49

Warfarin Combined with Antiplatelet Agents The risks and benefits of combination of an oral anticoagulant and an antiplatelet agent compared with an oral anticoagulant alone for secondary prevention of cardioembolic stroke have not been clearly established. Turpie et al. studied young patients with prosthetic valves and showed a significant reduction of embolic events in those assigned to combination therapy and no significant increase in the incidence of ICH (seven patients vs three patients, respectively).51 However, in view of the occurrence of only a few events and the patients’ ages, these results cannot be generalized to different groups of patients (i.e., elderly with established cerebrovascular disease). Recent meta-analyses comparing warfarin plus antiplatelet with warfarin alone in different populations found that the addition of antiplatelets to warfarin significantly increased the risk of ICH specially in elderly populations and risk–benefit ratio of combination therapy was higher for elderly patients with prior ischemic strokes than that for young patients with prosthetic valvular disease.52,53 This becomes a major issue in patients who undergo coronary artery stenting and require dual-antiplatelet therapy for drug-eluting stents and also have indication for anticoagulation due to atrial fibrillation. WOEST trial addressed this particular dilemma and found that the risk of bleeding complications is highest with triple therapy and recommended using clopidogrel for warfarin in patients with coronary stents and need for anticoagulation.54

NEW ANTITHROMBOTIC AGENTS Although warfarin is highly efficacious in preventing systemic emboli in AF patients, its use is restricted by the narrow therapeutic window, multiple drug interactions, and the need for permanent INR monitoring.55 Consequently, owing to the inherent limitations for the use of oral anticoagulants in patients with AF, there is a need to develop and test novel antithrombotic agents with a much safer profile and wider therapeutic window than warfarin. Recently three new oral anticoagulants dabigatran, rivaroxaban and apixaban have been approved by FDA for use in non-valvular atrial fibrillation patients48,56 (Table 62-6).

Dabigatran Dabigatran etexilate is an oral pro-drug that is converted to dabigatran, a direct, competitive inhibitor of factor IIa (thrombin). The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) compared open-label warfarin with two fixed, blinded doses of dabigatran (110 mg or 150 mg twice daily) in patients with AF and at least one additional stroke risk factor (previous stroke or TIA, left ventricular ejection fraction <40%, New York Heart Association heart

62

1018

SECTION VI  Therapy

TABLE 62-6  Novel Anticoagulant Agents for Prevention of Stroke in Atrial Fibrillation Drug

Target

Dosing

Apixaban Rivaroxaban Dabigatran

Factor Xa Factor Xa Thrombin

Twice a day Once a day Twice a day

failure classification of II or higher, age ≥75 years, or age 65–74 years plus diabetes mellitus, hypertension, or coronary artery disease). The primary outcome was stroke or systemic embolism; secondary outcomes included stroke, systemic embolism, and death. The primary safety outcome was major hemorrhage. A net clinical benefit was defined as an unweighted composite of stroke, systemic embolism, pulmonary embolism, MI, death, or major hemorrhage.57 For the primary outcome of stroke or systemic embolism, both dabigatran 110 mg twice daily (1.53% per year) and dabigatran 150 mg twice daily (1.11% per year) were noninferior to warfarin (1.69% per year); dabigatran 150 mg twice daily was also superior to warfarin (RR, 0.66; 95%CI, 0.53– 0.82). Compared with warfarin, the risk of hemorrhagic stroke was lower with both dabigatran 110 mg twice daily (RR, 0.31; 95%CI, 0.17–0.56) and dabigatran 150 mg twice daily (RR, 0.26; 95%CI, 0.14–0.49). Major bleeding in RE-LY was lower with dabigatran 110 mg twice daily (2.71% per year; RR, 0.80; 95%CI, 0.69–0.93), but similar for dabigatran 150 mg twice daily (3.11% per year; RR, 0.93; 95%CI, 0.81–1.07) compared with warfarin (3.36% per year).58 The rate of gastrointestinal bleeding was higher with dabigatran 150 mg twice daily (1.51% per year) than with warfarin (1.02% per year) or dabigatran 110 mg twice daily (1.12% per year; P < 0.05).58 Rates of life-threatening and intracranial bleeding, respectively, were higher with warfarin (1.80% and 0.74%) than with either dabigatran 110 mg twice daily (1.22% and 0.23%) or dabigatran 150 mg twice daily (1.45% and 0.30%).57 It is interesting to note that Food and Drug Administration (FDA) only approved the 150 mg twice daily dose and the 75 mg twice daily regimen for patients with low creatinine clearance (15–30 mL/min). This decision raised comment in the medical community, since the 110 mg twice daily dose was approved both in Canada and Europe.58 Moreover, the 110 mg twice daily dose showed better safety profile in terms of bleeding events, as mentioned earlier.57 The 75 mg twice daily dose was approved only on pharmacokinetic and pharmacodynamics modeling.48 FDA responded to this concern by highlighting the superiority of the 150 mg twice daily dose over warfarin, assuming normal renal function.59 Measuring the anticoagulant effect of dabigatran is difficult. Activated partial thromboplastin time, endogenous thrombin potential lag time, thrombin time, and ecarin clotting time can be used.60 Ecarin clotting time is a clinical assay which can be used to measure the thrombin activity and subsequently is affected by thrombin inhibitors.60 Activated recombinant factor VIIa or purified factor replacement products have been proposed for reversal of dabigatran.61 Emergency dialysis for rapid reversal of the antithrombotic effect has been recommended.61 However, there are limited data and there is no widespread consensus on the reversal techniques at this point.62,63

Rivaroxaban Rivaroxaban is a direct factor Xa inhibitor. The Rivaroxaban vs Warfarin in Non valvular Atrial Fibrillation (ROCKET AF) Trial was a double-blind non inferiority trial in randomized patients with non-valvular AF who were at moderate-to-high risk of

Onset (h)

Half-Life (h)

3 3 1–2

12 9 12–17

Antidote No No No

stroke to rivaroxaban (20 mg/d) or warfarin.64 The primary end point was the composite of ischemic and hemorrhagic stroke and systemic embolism. In the rivaroxaban group 1.7% of subjects per year reached the primary end point as compared to 2.2% per year in the warfarin group (HR, 0.79; 95%CI, 0.66–0.96; P < 0.001 for non-inferiority). The primary safety end point was a composite of major and non-major clinically relevant bleeding. Primary safety end point occurred in 14.9% of patients per year in the rivaroxaban group and 14.5% in the warfarin group (HR, 1.03; 95%CI, 0.96–1.11; P = 0.44). Lower rates of intracranial hemorrhage (0.5% vs 0.7%; P = 0.02) and fatal bleeding (0.2% vs 0.5%; P = 0.003) occurred in the rivaroxaban group than in the warfarin group.64 J-ROCKET AF (Japanese Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) was a prospective, randomized, double-blind phase 3 study in Japanese subjects with AF.65 This study evaluated the safety of rivaroxaban 15 mg once daily (10 mg daily in patients with moderate renal impairment) vs dose-adjusted warfarin. The primary safety end point in J-ROCKET was the time to first major or non-major clinically relevant bleeding event in both the rivaroxaban and warfarin arms. There were 11 vs 22 bleeding events in the rivaroxaban and warfarin arms, respectively (1.26 vs 2.61 events per 100 patients per year; HR, 0.48; 95%CI, 0.23–1.00).65 The effect of rivaroxaban can be measured through prothrombin time, endogenous thrombin potential and anti-thrombin activity.66 Thrombelastography can also be used to detect the activity of thrombin inhibitors for emergent decisions such as intravenous thrombolysis in acute stroke patients.67 Prothrombin complex concentrate has been reported to reverse the effect of rivaroxaban.62 Caution is advised regarding these reversal strategies as their clinical efficacy hasn’t been adequately evaluated.

Apixaban Apixaban is a direct and competitive factor Xa inhibitor. The Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial was a randomized, double-blind trial comparing the efficacy and safety of apixaban to aspirin in patients with non-valvular AF who were unsuitable for vitamin K antagonist therapy primarily on the basis of physician judgment or patient preference.68 The dose tested was 5 mg twice daily (94%) or 2.5 mg twice daily (6%). The dose of aspirin was 81 mg (64%), 162 mg (27%), 243 mg (2%), or 324 mg (7%) at the discretion of the investigator. The study was terminated when an interim analysis found that apixaban was superior to aspirin for prevention of stroke or systemic embolism (1.6% per year vs 3.7% per year; HR, 0.45; 95%CI, 0.32–0.62) with a similar rate of major bleeding (1.4% per year vs 1.2% per year; HR, 1.13; 95%CI, 0.74–1.75). Apixaban was superior to aspirin in preventing a disabling or fatal stroke (1% per year vs 2.3% per year; HR, 0.43; 95%CI 0.28–0.65). The net clinical benefit, a composite outcome of stroke, systemic embolism, MI, death of a vascular cause or major bleeding, supported apixaban as



being superior to aspirin (5.3% per year vs 7.2% per year; HR, 0.74; 95%CI, 0.6–0.9).68 The ARISTOTLE trial was a phase 3 randomized trial comparing apixaban to warfarin for the prevention of stroke (ischemic or hemorrhagic) or systemic embolization among patients with AF or atrial flutter.69 The doses tested were 5 mg twice daily as well as 2.5 mg twice daily. Warfarin dose was adjusted to achieve a therapeutic INR of 2.0–3.0. Additionally, patients in both groups were permitted to receive up to 162 mg of aspirin daily if clinically indicated. In the apixaban group 1.27% of the patients experienced the primary outcome of stroke or systemic embolization compared with 1.60% of warfarin group (HR, 0.79; 95%CI, 0.66–0.95). Both non inferiority (P < 0.001) and superiority (P = 0.01) of apixaban were demonstrated.69 There was significant reduction in hemorrhagic stroke (49% reduction) compared with ischemic or uncertain types of stroke (8% reduction). Secondary end points of death (3.52% vs 3.94%; HR, 0.89; 95%CI, 0.80–0.99; P = 0.047) and major bleeding (2.13% vs 3.09%; HR, 0.69; 95%CI, 0.60–0.80; P < 0.001) favored apixaban.69

Comparison of New Oral Anticoagulants There is no direct comparison between the anticoagulants. However, some features distinguish these new oral anticoagulants from each other. The rate of myocardial infarction appears to be slightly higher with dabigatran than with warfarin.70 Moreover, gastrointestinal bleeding was higher with both dabigatran and rivaroxaban than with warfarin.57,64 Apixaban use was not associated with higher gastrointestinal bleeding as compared to warfarin.69 Dabigatran (150 mg twice daily) reduced both the rates of hemorrhagic and ischemic stroke compared with warfarin.57 Apixaban, in addition to reduction of hemorrhagic and ischemic stroke also reduced major systemic bleeding.69 Patients who are non-compliant with warfarin should not be switched to the new agents because missed doses of these short-acting anticoagulants have the potential to be more detrimental than missed doses of warfarin, which has a half-life of several days.71 Patients who prefer once-daily drugs, or are poorly compliant with twice-daily dosing regimens, can be prescribed rivaroxaban. Patients with hepatic dysfunction should not be given the new anticoagulants because all three agents undergo some degree of hepatic metabolism. It has been theorized that the reversal of AF and maintenance of sinus rhythm might reduce the risk of stroke. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study compared the outcomes of patients with AF randomly assigned to treatment with a rhythm-control strategy and with a rate-control strategy.72 One objective of this study was to describe any differences in stroke occurrence in the two groups. The AFFIRM study was designed to compare mortality rates of patients managed with rate control only and those managed with rhythm control utilizing cardioversion and pharmacologic efforts along with anticoagulation. The rate-control and rhythm-control groups did not differ significantly in the primary endpoint, that is, mortality (P = 0.078).72 At 5 years, 94% of patients in both treatment arms remained free of ischemic stroke.73 Treatment assignment had no significant effect on the occurrence of ischemic stroke.

CARDIOMYOPATHIES A cardiomyopathy is the second most common cause of cardiogenic stroke after AF, with a threefold increase in relative risk.74 The ejection fraction (EF) is a reliable measurement of left ventricular function, with the normal value between 50% and

Secondary Prevention of Cardioembolic Stroke

1019

70%. A decline in EF produces an elevated left ventricular filling pressure and a drop in stroke volume with a consequent reduction of systemic blood flow. The reduced stroke volume creates relative stasis within the left ventricle that promotes thrombus formation and an increased risk of thromboembolic events. Cardiomyopathies can be dilated or hypertrophic. Dilated cardiomyopathy is present if the diastolic dimension of the left ventricle becomes enlarged and hypertrophic when wall thickness is increased. In patients with CHF who are treated with aspirin or warfarin, the aggregate stroke risk per year has been found to be between 1% and 4%.75,76 The stroke rate was inversely proportional to the EF in two studies.75,77 In the Survival And Ventricular Enlargement trial (SAVE) trial, patients with EF of 32% had a stroke rate of 1% per year; with an EF of 28% or less, the rate increased up to 2% per year. This translates into an 18% increment in the risk of stroke for every 5% decline in EF.77 Ventricular thrombus formation occurs in about 30–50% of patients with dilated cardiomyopathy.78 The underlying mechanism for thrombus formation in patients with dilated cardiomyopathy is probably complex and multifactorial, including mechanical factors such as low velocity in the left ventricle and activation of hemostatic factors.79,80 The intracavitary flow velocity is chronically reduced in these patients; therefore the risk of thrombus formation is constant. The Study of Left Ventricular Dysfunction (SOLVD) clarified the relation between embolic stroke risk and worsening ventricular function.75 In SOLVD, warfarin and aspirin were associated with a lower rate of death or hospitalization for heart failure than aspirin, but only warfarin reduced death from worsening heart failure. Although embolic stroke risk when left ventricular EF declines below 28% is double that for a value of 35%, patients with the lower values also benefit from aspirin alone (56% RRR in SAVE trial77) and without the bleeding complications. The Warfarin and Aspirin Therapy in Chronic Heart Failure (WATCH) trial compared aspirin 160 mg/day, clopidogrel 75 mg/day, and warfarin (INR 2.5–3.0) in patients with poor LV function.81 The primary composite outcome of time to first occurrence of death, non-fatal myocardial infarction, or nonfatal stroke was not significantly different between the groups (P = 0.57).81 Although the rate of nonfatal ischemic strokes was lower in the Warfarin group than aspirin, this benefit was offset by higher bleeding complications in the Warfarin group.81 The Warfarin vs Aspirin in patients with Reduced Cardiac Ejection Fraction (WARCEF) trial was a randomized, doubleblind, multicenter trial studying the efficacy of warfarin (INR, 2.5–3.0; target, 2.75) vs aspirin (325 mg per day) in all-cause mortality and stroke (both ischemic and hemorrhagic) in patients with left ventricular EF of 35% or less.82 The rates of the primary outcome were not significantly different between the two groups (P = 0.40).82 In the light of these trials oral anticoagulation (INR intensity, 2.0–3.0) in patient with severe heart failure should be reserved for those with AF and previous episodes of thromboembolism (systemic or pulmonary embolism), or documented left ventricular thrombus. However, certain high-risk patients with stroke and imaging suggestive of cardioembolism may be considered for anticoagulation but such decisions should be made on an individual basis with extensive discussion with the patient about the risk and benefit of such an approach.

MYOCARDIAL INFARCTION The stroke rate in survivors of MI is about 1–2% per year. The risk of stroke is particularly high during the first 3 months after MI.83,84

62

1020

SECTION VI  Therapy

The use of long-term anticoagulants after MI is associated with a 75% risk reduction in the incidence of stroke; however, this value represents an absolute risk reduction of only 1% per year. At the same time, anticoagulation (INR, 2.5–4.5) has an associated tenfold higher risk of intracerebral hemorrhage (ICH), or 0.4% per year. In addition, ICHs have a higher mortality and are more disabling than ischemic strokes.85 In summary, we would need to treat 1000 unselected MI survivors to prevent approximately ten strokes per year, and of those 1000 patients treated, four would suffer a disabling or fatal ICH; therefore, the net benefit is minimal. Aspirin reduces the incidence of stroke in patients with prior MI, with an RRR of 30%, but a very small absolute risk reduction (less than 0.5%). Because of such small net benefit, oral anticoagulation cannot be routinely recommended to prevent stroke in unselected MI survivors. There are, however, specific subsets of patients with prior MI who are at higher risk of ischemic stroke and benefit from anticoagulation. Patients suffering anterior wall MI have a higher risk for stroke than patients with MI in other locations.86 The presence of left ventricular thrombi after MI is associated with a much higher incidence of embolic stroke (approximately 5–10% over the following 6 to 12 months).87 Left ventricular mural thrombus occurs in 20% of all MIs and up to 40% of anterior infarctions involving the apex. Formation of mural thrombi is almost exclusively limited to mural infarctions.88 The risk of thromboembolism is greatest in the first week after infarction.89 The presence of thrombus mobility, proximity to a hypokinetic segment, and protrusion appear to raise the risk of embolism.90 Additional risk factors predisposing to thrombus formation are EF less than 35%, apical dyskinesia, and anterior infarction.90 In short, when ventricular thrombus is present, anticoagulants reduce the stroke risk by 60%. Therefore, anticoagulation therapy is indicated for 3–6 months after detection of ventricular thrombi. Chronic thrombi (more than 6 months old) have less emboligenic potential, so anticoagulation after this period would be reasonable only for a patient in whom a thrombus is mobile or protruding.91 The presence of AF in MI survivors markedly raises the risk for embolic stroke.92 Therefore, anticoagulation is routinely recommended in this situation. Patients who experience anterior wall myocardial infarction and are found to have ventricular wall thrombus should receive warfarin therapy, aiming for an INR ranging from 2 to 3, for up to 6 months. Prolonged anticoagulation decreased stroke risk up to 40% over 3 years in the Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) trial, although major bleeding complications were increased.93 Therefore, aspirin should be used after 6 months. In summary, oral anticoagulation (INR, 2.5–4.8) to prevent stroke does not substantially benefit unselected patients with acute MI. Patients with prior MI and AF or acute left ven­ tricular thrombi are at higher risk of embolic stroke; anticoagulation (INR, 2.0–3.0) is routinely recommended for stroke prevention in these patients. On the basis of the available evidence, oral anticoagulation in the patient with left ventricular thrombus should be administered for at least 6 months; the patient should then be reassessed for the presence and characteristics of left ventricular thrombi by means of echocardiography.

VALVULAR HEART DISEASE Before the use of surgical replacement of heart valves, valvular disease, especially rheumatic mitral valve disease, was associated with a very high risk of systemic emboli. Now almost all the patients with congenital or acquired valvular disease

undergo surgical implantation of prosthetic heart valves. Hence, for most patients with valvular heart disease, the requirement for antithrombotic therapy depends on the thromboembolic risk associated with valve replacement. Data on antithrombotic therapy in patients with native valvular disease is limited, and all published recommendations are based on clinical experience. Lambl’s excrescence (GLE) and valvular strands consists of valvular abnormalities that have a frond-like appearance and a stalk-like attachment that arises mostly from left-sided valvular surfaces (aortic more than mitral) and are of unclear cause (neoplastic, hamartomatous, or reparative).94 Embolic risk is difficult to quantify for GLE but appears directly proportional to size and mobility. Medical therapy is typically an antiplatelet agent first, and if recurrent cerebral ischemic events occur, anticoagulation or surgical resection is considered for large (more than 1 cm), mobile lesions.95,96

Rheumatic Mitral Valve Disease Of all native valvular diseases, rheumatic mitral valve disease carries the highest risk of systemic emboli. The incidence of systemic emboli ranges from 2% to 5% per year.97 In short, it can be assumed that a patient with rheumatic mitral valve disease has at least one chance in five of having a symptomatic systemic embolus during his or her life.97 Mitral stenosis carries a higher risk of embolization than mitral regurgitation, and the presence of AF increases the risk of embolism by about sevenfold.97 In addition, the risk of systemic emboli in patients with rheumatic heart disease increases with age and is higher in those with associated low EF.97 After a first episode of embolization, recurrent emboli occur in 30–65% of patients; more than half of recurrences are seen during the first year, most during the first 6 months.97 Although long-term anticoagulation was never examined in randomized trials in this population, observational studies have established the effectiveness of this intervention in reducing systemic emboli. In view of these data, all patients with rheumatic mitral valve disease and AF should be treated with long-term anticoagulation if possible. Patients with rheumatic heart disease and prior ischemic stroke should also receive anticoagulation in view of the high recurrence rate.97 The recommended intensity of anticoagulation is a target INR of 2.5. If recurrent embolism occurs despite adequate anticoagulation, the target INR should be increased to 3.0 or aspirin, 81 mg per day, should be added.

PROSTHETIC CARDIAC VALVES Systemic embolism is a serious threat in patients who have undergone heart valve replacement. The rate of embolism is high in patients with mechanical prosthetic cardiac valves, being 2% per year even in those with proper anticoagulation.98 Embolism occurs at estimated rates of 0.5% per year with prosthetic aortic valves, 1% per year with mitral valves, and 1.5% per year for both.98 Embolism is more frequent with valves in the mitral position, with multiple valves, and with caged-ball valves. Atrial stasis, a risk factor for thrombogenicity, is influenced by valve type and position, coexistent AF, and ventricular pacemakers. AF and enlargement of the left atrium are more common in patients with mitral valve disease.98 Permanent anticoagulation is generally recommended to prevent embolic stroke and valve thrombosis with all mechanical prosthetic valves. In addition, anticoagulation is also recommended for bioprosthetic valves in the mitral position in the first 3 months post-operatively. Aspirin can replace anticoagulation after 3 months provided that the patient doesn’t



have AF, enlarged (more than 55 mm) left atrium, ventricular pacemakers, or evidence of atrial thrombi or prior thromboembolism.99 Anticoagulation may not be required for bioprosthetic valves in the aortic position in patients with sinus rhythm because the stroke rate is relatively low.99 In the past, the intensity of anticoagulation for mechanical valves was a target INR between 3.0 and 4.5. Now it is believed that a lower intensity (INR, 2.0–3.0) for aortic mechanical valves and (INR 2.5–3.5) for mitral mechanical valves would be as effective.99 Adding an antiplatelet agent such as aspirin to warfarin further reduces embolism risk in mitral mechanical valves; however, this therapeutic strategy may raise the risk of bleeding (mostly minor bleeds when aspirin is added).99 The success of antithrombotic therapy in primary stroke prevention in patients with prosthetic valves is influenced by the type of prosthesis, factors associated with left atrial stasis, underlying cardiovascular disease, and tolerability of antithrombotic therapies. The optimal or appropriate intensity of anticoagulation and the decision to use additional antiplatelet agents in individual patients depend on the presence of some of the previously mentioned risk factors and the valve type. The current recommendations are as follows: Oral anticoagulation with a target INR between 2 and 3 should be used in all patients with mechanical prosthetic valves (St. Jude Medical bileaflet valve or Medtronic ball tilting disk mechanical valve) in the aortic position and with sinus rhythm. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, the intensity of anticoagulation is a target INR of 2.5 to 3.5. Addition of antiplatelet (low dose aspirin) therapy to both the aortic and mitral mechanical valves is recommended if the bleeding risk is low.99 In patients with full anticoagulation, the incidence of stroke is about 1% per year and most of the emboli are minor, leaving mild residual deficits.99 When stroke occurs in patients receiving anticoagulation, transesophageal echocardiography (TEE) should usually be performed to search for infective valve vegetations, thrombi, spontaneous echodensities, and atrial thrombi.100 Anticoagulation may be increased if embolism from the left atrium is suspected, but adding an antiplatelet agent might be useful if the stroke is attributed to cerebrovascular disease or valve-related thrombi.99 In patients at high risk of thromboembolism, the interruption of anticoagulant therapy before invasive procedures often presents a challenge to clinicians. It is recommended that warfarin therapy be stopped approximately 5 days before surgery, allowing the INR to return to a normal level. Full-dose LMW heparin is begun as the INR falls (about 2 days before surgery). The LMW heparin can be stopped about 6 hours before surgery and restarted between 8 and 12 hours after the procedure.101

NON-BACTERIAL THROMBOTIC ENDOCARDITIS Non-bacterial thrombotic endocarditis (NBTE) or marantic endocarditis is a non-infectious process affecting normal or degenerative cardiac valves that is due to fibrin thrombi deposits in patients with hypercoagulable states associated with adenocarcinomas of the lung, colon, or pancreas that produce mucin.99,102 Patients with NBTE may present with arterial and venous thromboembolism and disseminated intravascular coagulation. Heparin, but not warfarin, has been associated with benefit99,102 as well as treatment of the underlying neoplastic disorder. Libman-Sacks endocarditis is a non-infectious valvular abnormality associated with autoimmune disorders such as systemic lupus erythematosus and the antiphospholipid

Secondary Prevention of Cardioembolic Stroke

1021

antibody syndrome.103 The choice of antiplatelet or anticoagulation doesn’t affect the progression of these lesions.103 Aspirin is recommended for primary prevention and warfarin should be reserved for patients who experience an ischemic stroke in presence of these valvular lesions.104

INFECTIOUS ENDOCARDITIS Infectious seeding of heart valves or endocarditis prior to the advent of antibiotics was associated with a very high cerebral embolic rate (70–90%), which decreased (12–40%) with the advent of antibiotics.105,106 Specific antibiotic therapy for endocarditis remains the first-line treatment on the basis of blood culture results, whereas anticoagulation remains controversial or contraindicated105–107 given the early rates of cerebral hemorrhage and the fact that anticoagulation does not reduce the incidence of embolism in native valve endocarditis. Patients with mechanical prosthetic valves, however, may be at higher risk if anticoagulation is discontinued.108 Controversy remains about the duration and intensity of anticoagulation in patients with prosthetic valve endocarditis, given the risk of embolism vs intracranial hemorrhage.107 Prosthetic endocarditis also may embolize to the brain, where an infected microscopic nidus (especially when there is Staphylococcus aureus) or microaneurysm prone to cerebral hemorrhage may develop. The patient with prosthetic valve endocarditis may be thought of as an anticoagulation dilemma because the ischemic stroke risk must be balanced against cerebral hemorrhagic risk. We recommend careful consideration of the patient’s valve type and location and presence or absence of AF to weigh the ischemic and hemorrhagic risks. For example, if the patient had a large ischemic stroke from endocarditis, anticoagulation becomes higher risk for brain hemorrhage and may need to be delayed or not administered at all.107 Moreover, intracranial vascular imaging is helpful in risk stratification since it can reveal occult mycotic aneurysms at high risk of rupture.109,110 An attempt should be made to treat these aneurysms before anticoagulation is considered.107 Early surgery was historically reserved for heart failure, uncontrolled infection and prevention of recurrent embolic events.111 Recently there has been an increase in early elective surgery with improved outcomes particularly related to systemic embolization.112 This approach needs to be validated in a larger randomized controlled trial before it becomes the standard of care.

CARDIAC TUMORS Primary cardiac tumors are rare (less than 0.2% in unselected autopsy series) and the majority of them benign (50% myxomas and papillary fibroelastoma) but associated with a high frequency of embolic events. Myxomas commonly occur in the left atrium and arise from the interatrial septum. They may embolize to the systemic circulation, particularly to the brain, when tumor pieces break off or there is secondary thrombus formation. TEE is invaluable in defining tumor location, size, and morphology. To prevent embolization, surgical resection of the tumor is recommended in all cases of myxoma.113,114 Papillary fibroelastomas are benign tumors that tend to originate on cardiac valves in single or multiple masses. Embolic events are typically the first clinical manifestation, because they are present on highly mobile valve leaflets. The embolic mechanism is the same as myxomas, being tumor fragmentation or secondary thrombus generation. Surgical resection is also indicated for fibroelastomas.115 Metastatic tumors to the heart are 20–40 times more frequent than primary cardiac tumors, which are rare (e.g.,

62

1022

SECTION VI  Therapy

angiosarcoma, rhabdomyosarcoma).116 Cerebral embolization can occur from these tumors as well. Surgical treatment can be offered but depends on the underlying tumor type and prognosis.116

PATENT FORAMEN OVALE The high frequency of patent foramen ovale (PFO) is in part the result of advances that have been made in cardiac imaging techniques. PFO has been associated with stroke in several case-control studies, particularly in young individuals without an alternative recognized cause of stroke. PFO is a potential conduit for paradoxical embolism.117–119 However, its relationship to stroke, its prognosis, and the therapeutic implications are not clearly established. Precordial contrast echocardiography detects some interatrial shunting in about 18% of normal controls120 especially during early systole or Valsalva maneuver– provoking activities such as coughing.121 The fossa ovalis and the size of PFO can be directly visualized by TEE, considered the diagnostic “gold standard”.122 Transcranial Doppler (TCD) ultrasonography can detect injected microbubbles that bypass the pulmonary capillaries and enter the cerebral circulation, an observation that correlates well with the TEE evidence of PFO in the majority of patients.123 The size of the PFO patency varies from 1 to 9 mm at autopsy.124 The volume of shunting depends on the size of the PFO and the difference in atrial pressures. Several studies have now shown that the prevalence of PFO in young adults with TIA or ischemic stroke has increased (about 40%; range 32–48%)125 especially among those with cryptogenic ischemic stroke, in whom the prevalence in some series exceeds 50%.125 The wide range of PFO prevalence may reflect in part the interobserver variability in the diagnosis of septal abnormalities. Hence, the frequency of PFO is increased twofold to threefold among young adults with cerebral ischemia, and PFO is clearly associated with cryptogenic stroke in young adults, who are less likely to have traditional risk factors for stroke. In older patients with stroke, the prevalence of PFO is lower, probably because its importance as an independent risk factor is offset by the higher prevalence of other stroke mechanisms.126 PFO is significantly associated with ischemic stroke usually in patients younger than 55 years.127 Because PFO is also common in normal subjects, it is important to characterize the cases associated with stroke. Therefore, it is possible that patients with PFO plus atrial septal aneurysm (ASA) constitute a subgroup of patients at increased risk of stroke.128 An ASA is a sustained 15-mm segmental bowing of the interatrial septal membrane in the fossa ovalis of at least 11–15 mm beyond the plane of the interatrial septum or may be a phasic excursion to either side of the same distance.128 Therefore, an ASA may be the substrate for in-situ thrombus to form, which later passes through the PFO (rightto left-sided circulation). The mechanism of PFO-associated stroke is thought to be due to paradoxical embolism in many patients. Paradoxical embolism occurs when embolic material originating in the venous system or right heart chambers migrates into the systemic circulation through vascular shunts that bypass the pulmonary vasculature. However, this mechanism has been well documented in only a few cases, in which the embolus was seen in its passage through a PFO. A venous source of thromboembolism is rarely found in patients with stroke and PFO.129,130 The failure to document a venous source does not rule out paradoxical emboli, because in many cases, deep venous thrombosis in the pelvis or legs is under-recognized.129,130 Another potential mechanism for stroke is direct embolization from thrombi formed locally within the PFO or in an associated ASA.130 In a prospective study of 503 patients with stroke, PFO

or PFO-ASA was detected in 34% and 14% of the patients classified with cryptogenic stroke by Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria vs 12% and 4%, respectively, with stroke of known type (P < 0.001).131 The study also compared 131 younger patients (less than 55 years) with 372 older patients (more than 55 years) and found that the PFO-ASA combination was more strongly associated with cryptogenic stroke in younger (P < 0.049) and older (P < 0.001) patients than with known stroke subtype. In addition to the unclear mechanism of stroke in patients with PFO, the risk of recurrent stroke remains unsettled owing to the lack of prospective data. Studies have reported stroke recurrence between 1% and 2% in patients with PFO.132,133 A prospective study of 581 patients with cryptogenic stroke treated with aspirin reported that at 4 years, the risk of recurrent stroke was 2% in those with PFO (n = 216), 15% in those with both PFO and ASA (n = 51), and 4% in those with neither. Only 10 patients in the study had ASA alone, and no recurrence was seen in this group. In this study, only the presence of both abnormalities was associated with a significant risk of stroke (relative risk [RR] 4; 95%CI, 1–12). PFO alone, regardless of its size, did not influence the risk of stroke.134 Results of the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), a substudy of the Warfarin-Aspirin Recurrent Stroke Study (WARSS), were reported in 2002. The 630 patients first underwent TEE, which documented PFO in 34%, and then were randomly assigned to receive either warfarin (INR, 2.0) or aspirin. The stroke rates were similar for the two interventions, and the presence of PFO did not alter the event rate when associated with all or cryptogenic strokes. There was no benefit to using warfarin in patients with large PFO or in those with PFO and ASA (12% of the total).125 It is sensible to speculate that closure of PFO by surgical or device-mediated procedures would prevent stroke recurrence in patients with paradoxical emboli. Three major clinical trials have been published since 2012: CLOSURE I, RESPECT, and PC comparing the efficacy of medical therapy vs device closure of PFO.135–137 CLOSURE I trial used STARFLEX device while RESPECT and PC trials sued AMPLATZER device. There was no significant difference in outcomes between the two approaches in these trials.135–137 One of the major reasons for no significant difference being found between the two treatment groups was the low risk of recurrence in this subset of population.135–137 The current data therefore do not support routine device closure of PFO to prevent recurrent stroke. Closure can be considered in young patients with recurrent cryptogenic stroke, deep venous thrombosis or hypercoaguable state, but such decisions should be extensively discussed with patients in light of the known risk and questionable benefits of such an approach. In short, the role of PFO as a cause of stroke is still unsettled; therefore, the optimal treatment remains undetermined. On the basis of current evidence, every patient with stroke and PFO should receive antiplatelet therapy. In addition, if there is evidence of deep venous thrombosis, pulmonary embolism, hypercoagulable state or recurrent stroke, the use of long-term anticoagulation seems appropriate.

AORTIC ARCH DISEASE An overlooked but a potentially serious source of embolic stroke is the aortic arch.138 Aortic embolic events may be misclassified as cryptogenic unless adequate transesophageal echocardiography of the aorta is performed. Patients with ascending aorta or proximal arch plaques of 4 mm thickness are up to seven times more likely to have cerebral infarction than controls (14.4% vs 2%; P < 0.001).138,139 For non-mobile aortic plaque, statin therapy may be protective in preventing



stroke,140 whereas uncertainty remains about the optimal antithrombotic therapy, aspirin or warfarin.140

ACUTE ANTICOAGULANT AGENTS Heparin, Low-Molecular-Weight Heparin,   and Heparinoids Heparin is the most commonly used parenteral anticoagulant. Unfractionated heparin is derived from bovine lung or porcine gut tissue. A glycosaminoglycan of varying molecular weight, heparin binds to antithrombin III to inactivate factors IIa and Xa.141 Its major anticoagulant effect comes from a unique pentasaccharide with high-affinity binding to antithrombin. Unfractionated heparin is quite heterogeneous, containing saccharides ranging in molecular weight from 5000 to 30,000 daltons. Only about one-third of the unfractionated heparin molecules have anticoagulant activity. This heterogeneity is one of the reasons for the variability in the anticoagulant effect of heparin administration among individuals. The most common side effect of heparin administration is bleeding. Other complications are thrombocytopenia, osteoporosis, skin necrosis, alopecia, hypersensitivity reactions, and hypoaldosteronism. Thrombocytopenia is somewhat more common with heparin derived from bovine lung than from porcine gut. The thrombocytopenia is thought to occur because of the binding of immunoglobulin (Ig) G to heparin. Thrombocytopenia occurs in between 0.3% (in prophylactic use) and 2.4% (with higher therapeutic doses) of treated patients. Low-molecular-weight heparin (LMWH) represents a fragment of a standard heparin with lower molecular weight, higher bioavailability, longer half-life, and more predictable anticoagulant effects. LMWH is said to cause fewer bleeding complications and fewer interactions with platelets, but this issue remains somewhat controversial. Heparinoids are analogues of heparin that inhibit factor Xa, have a longer half-life than unfractionated heparin, and cause fewer bleeding complications. LMWH is as effective as, if not more effective than, unfractionated heparin, has the advantage of being given in fixed subcutaneous doses, and does not require monitoring or dose adjustment.141 Patients who are not candidates for heparin or heparnoids due to heparin-induced thrombocytopenia (HIT) can benefit from new-generation intravenous anticoagulants.142 Argatroban and bivalirudin are approved for the treatment of heparin-induced thrombocytopenia. Direct thrombin inhibitors cause a dose-dependent increase in the activated partialthromboplastin time, which allows for simple monitoring. Argatroban is a synthetic direct thrombin inhibitor derived from the amino acid L-arginine that reversibly binds to the active site of thrombin, inhibiting its catalytic activity. The standard regimen is an intravenous infusion of 2 µg per kilogram of body weight per minute.143 Bivalirudin is a hirudin analogue that binds to both the active and fibrin-binding sites of circulating and clot-bound thrombin. It is administered intravenously by continuous infusion. A regimen of 0.15 mg per kilogram per hour, adjusted for the activated partialthromboplastin time, has been suggested.144

INTRACEREBRAL HEMORRHAGE ASSOCIATED WITH ANTICOAGULATION ICH is the most serious complication of anticoagulant therapy because of its high associated mortality. Anticoagulation with INR targets between 2.5 and 4.5 increases the risk of ICH 7 to 10 times145,146 representing an absolute rate of 1% per year in stroke-prone patients.46 The mortality related to

Secondary Prevention of Cardioembolic Stroke

1023

oral anticoagulants in patients with ICH exceeds 50%. The cerebellum is frequently involved, and simultaneous ICHs at multiple sites can occur, particularly with excessive anticoagulation. One of the unique features of intracerebral hematomas related to anticoagulation is that they can continue to enlarge for 12–24 hours; therefore, anticoagulation should be reversed immediately, even in patients with minimal deficits and small hematomas. ICH-related anticoagulation is usually managed by the following approaches: • Cessation of anticoagulation therapy • Administration of vitamin K; the INR is not affected for several hours, and the dose should not exceed 10 mg because higher doses lead to refractoriness to further anticoagulant therapy for days • Administration of plasma derivatives containing vitamin-Kdependent clotting factors, such as fresh frozen plasma (FFP), cryoprecipitates and prothrombin complex concentrates (PCC). FFP reverses anticoagulation immediately, but it has the disadvantage of requiring a large infusion to correct the INR, which could be a problem in patients with poor cardiac function. Factor concentrates (factor II, VII, IX, and X) are an alternative for patients who cannot tolerate large volume of fluids but should not be used in patients with liver failure. The hemostatic agent recombinant activated factor VII (rFVIIa) has been used for the management of hemorrhages in the central nervous system associated with anticoagulation. In the phase 2B randomized controlled trial, Mayer et al. and the Novo Nordisk investigators studied the effect of recombinant factor VIIa (rFVIIa) on early hematoma growth.147 Three hundred and ninety-nine patients with acute ICH were randomly assigned to placebo or to 40 µg/kg, 80 µg/kg, or 160 µg/kg of rFVIIa within 1 hour after a baseline CT scan. The primary outcome of the study was to assess hematoma growth at 24 hours. A dose-dependent effect on reducing hematoma growth was noticed, with a mean increase of 29%, 16%, 14%, and 11% in the placebo, 40 µg/kg, 80 µg/kg, and 160 µg/kg groups, respectively (P = 0.01). The modified Rankin Scale (mRS) performed at 90 days found 69% of placebo-treated patients dead or severely disabled (mRS = 4 to 6), compared with 49–55% for the rFVIIa-treated patients (P = 0.004). Mortality at 90 days was 29% for placebo-treated patients, compared with 18% for rFVIIa-treated patients. Thromboembolic events (MI or ischemic stroke) occurred in 7% of rFVIIa-treated patients, compared with 2% of placebotreated patients (P = 0.12).147 To address safety and to find an optimal dose, Novo Nordisk and the NovoSeven Investigators completed the phase 3 Factor Seven for Acute Hemorrhagic Stroke (FAST) study in the United States and Europe, which involved 821 patients randomly assigned to receive placebo or 20 µg/kg or 80 µg/kg of rFVIIa.148 The investigators reported reduced growth of the hematoma and a safety profile similar to results of the phase 2B study. However, the FAST study failed to confirm that rFVIIa given within 4 hours of onset improves survival or functional outcome in ICH and has not gained a U.S. Food and Drug Administration (FDA) label indication for that purpose.148 In summary, with the available evidence, the use of rFVIIa for the management of ICH is not indicated outside clinical trials. It remains an off-label indication for this agent. Prothrombin complex concentrate has been shown recently to be effective in warfarin reversal. Effective hemostasis was achieved in 72.4% of patients receiving PCC vs 65.4% receiving plasma. Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving PCC vs 9.6% receiving plasma. The safety profile (adverse events, serious

62

1024

SECTION VI  Therapy

adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (PCC group), and 71 of 109 (plasma group) patients experienced ≥1 adverse event.149,150 Well-established risk factors for ICH in patients who have been receiving anticoagulants include advanced age (particularly more than 75 years), hypertension, prior ischemic stroke151 and intensity of anticoagulation (perhaps also fluctuations in the level of anticoagulation).152 The significance of high INR levels in influencing the development of ICH was demonstrated in an observational study and in the Stroke Prevention in Reversible Ischemia Trial (SPIRIT) study. In this study, the absolute rate of ICH was 3% per year in patients receiving anticoagulation, particularly those with INR values exceeding 4.0.153,154 White matter abnormalities, identified by neuroimaging studies in patients with established cerebrovascular disease, were found to be an independent risk factor for ICH associated with anticoagulation.155,156 Small hemosiderin deposits (indicative of asymptomatic “microbleeds”) are frequently detected by gradient echo MRI in patients with stroke, particularly those with small vessel disease (i.e., lacunar stroke, primary ICH, and white matter abnormalities).157 It is likely that the presence of microbleeds predisposes to ICH in patients taking anticoagulants.158–160 Currently, the presence of white matter abnormalities or microbleeds does not preclude the use of anticoagulants; more data are needed to stratify the risk of ICH on the basis of MRI findings. A prospective inception cohort study (CROMIS-2) is underway in UK to answer to address this issue (www.ucl.ac.uk/cromis-2).160 Cerebral amyloid angiography (CAA) is characterized by deposition of congophilic amyloid beta protein in cortical and leptomeningeal vessels. ICH associated with CAA is typically seen in an older individual after the age of 55 (predominantly more than 80 years), lobar, often multiple, with a tendency to be located in the posterior half of brain, and prone to recurrence.160 It is a well-established risk factor for non-coagulopathic ICH, and this information might also apply to WICH.160

ANTICOAGULATION IN ACUTE   CARDIOEMBOLIC STROKE Hemorrhagic transformation is defined as the presence of petechiae or confluent petechial hemorrhage confined to the ischemic zone. It is a relatively common consequence of developing cerebral infarction, being present in about 15% of all ischemic strokes and up to 30% of cardioembolic strokes.161– 163 The proposed mechanism for hemorrhagic transformation is the distal migration or lysis of an embolus resulting in reperfusion of the ischemic tissue, which can become hemorrhagic depending on the extent of the ischemic vascular injury. Detection of hemorrhagic transformation depends on the neuroimaging technique used. MRI with T2-weighted sequences as well as diffusion- and perfusion-weighted imaging has higher sensitivity than CT for early detection of hemorrhagic transformation.164,165 A prospective MRI study that imaged patients 3 weeks after cardioembolic stroke reported a 60% incidence of hemorrhagic transformation.162 Autopsy series showed hemorrhagic transformation in even higher numbers (50–70%) of patients undergoing anticoagulation.166 The great majority of hemorrhagic transformations are asymptomatic in patients not receiving anticoagulants. The visualization of hemorrhagic transformation in a patient with ischemic stroke is important in that it may provide guidance as to the possible underlying mechanism of stroke (i.e., cardioembolic) and may influence the selection of antithrombotic therapy. Because of the high incidence of secondary hemorrhagic transformation in patients with cardioembolic stroke, early anticoagulation is potentially risky. At

present, it is impossible to formulate firm guidelines for anticoagulation in acute cardioembolic stroke because of a paucity of adequate data. The risk–benefit ratio of early anticoagulation is influenced by the specific cardioembolic source of the stroke as well as the size of the infarct. In the past, the risk of early recurrent stroke or systemic embolism after a recent cardioembolic stroke in untreated patients was estimated to be around 10% during the first week and to be especially high during the first 5 or 6 days after an acute cardioembolic stroke.167 However these data were not supported by later studies, in which the risk of recurrent stroke within the first 14 days of stroke in patients with AF was between 5% and 8% without anticoagulation.35 Pooled data from case-series and one small controlled trial suggest that heparin reduces early stroke recurrence by about 70% in patients with cardioembolic stroke. However, the higher risk of symptomatic ICH in patients in whom anticoagulation is begun early offsets the benefit conveyed by the therapy.168 It has been shown that these patients can be safely bridged with aspirin until the target INR is achieved.169 The relationship between anticoagulants and clinically significant delayed hemorrhage is controversial. The occurrence and timing of asymptomatic hemorrhagic transformation do not seem to be affected by anticoagulation;170 however, the magnitude and likelihood of associated clinical deterioration are augmented.170 The incidence of symptomatic hemorrhagic transformation in patients receiving early anticoagulation varies widely (from 1% to 25%).171 Patients with a large infarct, excessive anticoagulation, and detection of hemorrhagic infarction on initial CT scan are at higher risk for symptomatic hemorrhagic transformation. Small case-series have advocated the use of anticoagulants even in patients with early CT visualization of hemorrhagic infarction.172 It appears that hemorrhagic infarction may not be an absolute contraindication to anticoagulation, especially in individual patients who are at high risk of recurrent embolism. Given the lack of prospective studies and the relatively small number of patients in these case-series, however, early anticoagulation in hemorrhagic infarction cannot be routinely recommended without assessment of the risk of recurrent stroke. Delaying the start of anticoagulation for 1–2 weeks after detection of hemorrhagic infarction may be prudent. For patients at relatively low risk of early stroke recurrence, including those with non-valvular AF or recent MI without associated ventricular thrombi, deferring anticoagulation for several weeks may reduce the risk of hemorrhagic deterioration, particularly for patients with moderate-to-large infarcts or uncontrolled hypertension. Initiation of anticoagulation with oral warfarin (without the use of heparin) is an alternative for these patients. Thus, the “typical” patient with ischemic stroke and AF is unlikely to benefit from initiation of anticoagulation within the first day or two, especially if the stroke is large. In the interest of management efficiency, some physicians initiate oral anticoagulation within the first day or two, assuming that therapeutic and, therefore, dangerous levels of anticoagulation will not be achieved for a few days, when the period of increased risk for symptomatic hemorrhage has past. Since there are no specific studies to address this issue, individualized care is recommended. Presence of blood products on imaging, larger infarct size, mass effect, contrast enhancement on neuroimaging indicating disruption of blood–brain barrier and leukoariaosis may be taken into consideration when deciding about anticoagulation since these factors have been associated with hemorrhagic transformation.173,174 Moreover, newer oral anticoagulants are therapeutic immediately, in contrast to warfarin, which takes days to weeks to achieve a therapeutic effect. This should also be considered when starting treatment in these patients. Bridging is not recommended



when newer oral anticoagulants are started. It has been proposed that even in the presence of hemorrhagic transformation initiation of anticoagulation does not lead to adverse outcomes but we advise caution in such an approach because of the small number of patients studied.175 Some patients with AF might benefit from early anticoagulation because their recurrent stroke risk is increased – for example, the patient with documented thrombi in the left atrium. The randomized clinical trials that included patients with AF have not studied this subgroup and other potentially important subgroups to establish with certainty whether atrial thrombi or other predictors might identify a subpopulation at sufficiently increased risk of early stroke recurrence to justify prompt initiation of anticoagulation.35 For patients at high risk of recurrent embolization (i.e., mechanical prosthetic valve, intracardiac thrombus, AF with valvular disease or CHF), early anticoagulation is recommended, particularly if there are no associated risk factors for brain hemorrhage. Intravenous boluses of heparin and excessive anticoagulation should be avoided. The value of antiplatelet agents and low-dose subcutaneous heparin in this setting has not been systematically assessed. Both could be alternatives to intravenous heparin, particularly in patients at low risk of early recurrent stroke (e.g., nonvalvular AF). Patients with prosthetic valves who are in full anticoagulation at the time of stroke represent a management challenge. Reversing anticoagulation should be considered in patients with large infarcts or with infarcts already visible on early CT scan (less than 6–12 hours). Anticoagulation is not indicated for embolic stroke secondary to infective endocarditis of native valves.

RESUMPTION OF ANTICOAGULATION IN THE PRESENCE OF INTRACEREBRAL HEMORRHAGE The risk of ICH in the general population ranges from 0.5% to 2% per year. In patients undergoing anticoagulation, the risk of hemorrhage is about 10 times higher.176 However, the risk of cerebral emboli in patients with major cardioembolic sources (e.g., left ventricular thrombi, prosthetic valve disease) who are without the protection offered by anticoagulation is high. Therefore, it is essential to estimate the risks and benefits of anticoagulation in this particular group of patients. So far, data are insufficient for firm recommendations to be made in these situations. Results of several small series and retrospective studies have suggested that, when absolutely necessary, resumption of oral anticoagulation after 1 or 2 weeks is associated with a low short-term risk of embolism and no major complications, worsening, or recurrence of ICH.177,178 The use of intravenous heparin or continuation of oral anticoagulant therapy in a patient who has ICH or a cerebral infarct with hemorrhagic transformation and a high-risk embolic source is less clear and continues to be a challenge for physicians. There are no large, prospective trials addressing the issue of when to restart anticoagulation after warfarinassociated ICH. The literature ranges from recommendations to withhold warfarin anticoagulation for 4–6 weeks177 or 1–2 weeks179 to the use of intravenous heparin immediately after the INR is corrected to normal.180 The risk of thromboembolism (underlying indication to use anticoagulation) and the risk of recurrent ICH (i.e., lobar vs deep location of the initial ICH vs hemorrhagic infarct) are key factors to be considered. When to initiate anticoagulation and whether to continue anticoagulant therapy in patients with ICH remain controversial, and it is unlikely that these important issues will be

Secondary Prevention of Cardioembolic Stroke

1025

settled by a large study.181 In view of the lack of evidence, we recommend that each case be assessed individually through balancing of the risks and benefits of the intervention.

SUMMARY Emboli arising from the heart account for at least 20% of ischemic strokes. Cardiac sources of emboli are being detected with increasing ease with modern echocardiography and longterm cardiac rhythm monitoring. The common clinical dilemma is whether the detection of one of the “minor” cardiac sources of emboli bears any responsibility for causing a stroke in a given patient. Long-term oral anticoagulation is highly effective in preventing recurrent stroke in patients with “major” cardiac abnormalities, including AF, in patients who have received prosthetic cardiac valves and in patients with intracardiac thrombi due to MI or cardiomyopathy. In the near future, likely novel antithrombotic agents with superior safety and efficacy profile will replace warfarin as alternative agents to prevent cardioembolic stroke.

Definitions of Classes and Levels of Evidence Used Class I: Conditions for which there is evidence for and/or general agreement that the procedure or treatment is useful and effective Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment Class IIa: The weight of evidence or opinion is in favor of the procedure or treatment Class IIb: Usefulness/efficacy is less well established by evidence or opinion Class III: Conditions for which there is evidence and/or general agreement that the procedure or treatment is not useful/ effective and in some cases may be harmful THERAPEUTIC RECOMMENDATIONS Level of Evidence A: Data derived from multiple randomized clinical trials or meta-analyses Level of Evidence B: Data derived from a single randomized trial or non-randomized studies Level of Evidence C: Consensus opinion of experts, case studies, or standard of care Adapted from Furie et al.48 For more details refer to “Evidence box index” in the FM.

The complete reference list can be found on the companion Expert Consult website at www.expertconsult.inkling.com. KEY REFERENCES 1. Foulkes MA, Wolf PA, Price TR, et al. The stroke data bank: Design, methods, and baseline characteristics. Stroke 1988;19: 547–54. 2. [No authors listed]. Cardiogenic brain embolism. The second report of the cerebral embolism task force. Arch Neurol 1989;46: 727–43. 4. Albers GW, Comess KA, DeRook FA, et al. Transesophageal echocardiographic findings in stroke subtypes. Stroke 1994;25: 23–8. 12. Arboix A, Vericat MC, Pujades R, et al. Cardioembolic infarction in the Sagrat Cor-Alianza Hospital of Barcelona stroke Registry. Acta Neurol Scand 1997;96:407–12. 13. Vemmos KN, Bots ML, Tsibouris PK, et al. Stroke incidence and case fatality in Southern Greece: The Arcadia Stroke Registry. Stroke 1999;30:363–70.

62

1026

SECTION VI  Therapy

14. Vemmos KN, Takis CE, Georgilis K, et al. The Athens Stroke Registry: Results of a five-year hospital-based study. Cerebrovasc Dis 2000;10:133–41. 15. Lee BI, Nam HS, Heo JH, et al. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. Cerebrovasc Dis 2001;12:145–51. 16. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: The German Stroke Data Bank. Stroke 2001;32:2559–66. 18. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The anticoagulation and risk factors in atrial fibrillation (atria) study. JAMA 2001;285: 2370–5. 19. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e269–367. 24. Saxena R, Lewis S, Berge E, et al. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the international stroke trial. Stroke 2001;32:2333–7. 32. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: Results from the national registry of atrial fibrillation. JAMA 2001;285: 2864–70. 33. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on atrial fibrillation. Chest 2010;137:263–72. 34. Lip GY, Frison L, Halperin JL, et al. Identifying patients at high risk for stroke despite anticoagulation: A comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010;41:2731–8. 35. Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: Analysis of randomized clinical trials. Stroke 2002;33:2722–7. 36. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010;138: 1093–100. 37. Lip GY, Frison L, Halperin JL, et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score. J Am Coll Cardiol 2011;57:173–80. 38. Seet RC, Friedman PA, Rabinstein AA. Prolonged rhythm monitoring for the detection of occult paroxysmal atrial fibrillation in ischemic stroke of unknown cause. Circulation 2011;124: 477–86. 39. Kishore A, Vail A, Majid A, et al. Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: A systematic review and meta-analysis. Stroke 2014. 40. Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: Detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke 2013;44:1449–52. 41. Etgen T, Hochreiter M, Mundel M, et al. Insertable cardiac event recorder in detection of atrial fibrillation after cryptogenic stroke: An audit report. Stroke 2013;44:2007–9. 42. Flint AC, Banki NM, Ren X, et al. Detection of paroxysmal atrial fibrillation by 30-day event monitoring in cryptogenic ischemic stroke: The stroke and monitoring for PAF in real time (SMART) registry. Stroke 2012;43:2788–90. 43. Sinha AM, Diener HC, Morillo CA, et al. Cryptogenic stroke and underlying atrial fibrillation (CRYSTAL AF): Design and rationale. Am Heart J 2010;160:36–41 e31. 44. Ip J, Waldo AL, Lip GY, et al. Multicenter randomized study of anticoagulation guided by remote rhythm monitoring in patients with implantable cardioverter-defibrillator and CRT-D devices: Rationale, design, and clinical characteristics of the initially enrolled cohort the impact study. Am Heart J 2009;158:364–70, e361.

45. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. 46. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995;26: 1471–7. 47. Investigators AWGotA, Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903–12. 48. Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: A science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:3442–53. 49. Lip GY, Hee FL. Paroxysmal atrial fibrillation. QJM 2001;94: 665–78. 50. Hart RG, Pearce LA, Rothbart RM, et al. Stroke with intermittent atrial fibrillation: Incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 2000;35:183–7. 52. Dentali F, Douketis JD, Lim W, et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: A meta-analysis of randomized trials. Arch Intern Med 2007;167: 117–24. 53. Johnson SG, Rogers K, Delate T, et al. Outcomes associated with combined antiplatelet and anticoagulant therapy. Chest 2008; 133:948–54. 54. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An openlabel, randomised, controlled trial. Lancet 2013;381:1107–15. 55. Sobieraj-Teague M, O’Donnell M, Eikelboom J. New anticoagulants for atrial fibrillation. Semin Thromb Hemost 2009;35: 515–24. 56. Alberts MJ, Eikelboom JW, Hankey GJ. Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation. Lancet Neurol 2012;11:1066–81. 57. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 2009;361:1139–51. 58. Kowey PR, Naccarelli GV. The food and drug administration decision not to approve the 110 mg dose of dabigatran: Give us a way out. Am J Med 2012;125:732. 59. Beasley BN, Unger EF, Temple R. Anticoagulant options – why the FDA approved a higher but not a lower dose of dabigatran. New Engl J Med 2011;364:1788–90. 60. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Heamost 2010;103:1116–27. 61. Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. New Engl J Med 2011;365:2039–40. 62. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. 63. Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 2012;126:2428–32. 64. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 2011;365: 883–91. 65. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. Warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study. Circ J 2012;76:2104–11. 66. Steiner T, Bohm M, Dichgans M, et al. Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACS), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 2013;102:399–412. 67. Bowry R, Fraser S, Archeval-Lao JM, et al. Thrombelastography detects the anticoagulant effect of rivaroxaban in patients with stroke. Stroke 2014;45:880–3.



Secondary Prevention of Cardioembolic Stroke 68. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. New Engl J Med 2011;364:806–17. 69. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2011; 365:981–92. 70. Hohnloser SH, Oldgren J, Yang S, et  al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of longterm anticoagulation therapy) trial. Circulation 2012;125: 669–76. 71. Weitz JI, Gross PL. New oral anticoagulants: Which one should my patient use? Hematology Am Soc Hematol Educ Program 2012;2012:536–40. 72. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. New Engl J Med 2002;347:1825–33. 73. Sherman DG, Kim SG, Boop BS, et al. Occurrence and characteristics of stroke events in the atrial fibrillation follow-up investigation of sinus rhythm management (AFFIRM) study. Arch Intern Med 2005;165:1185–91. 77. Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. New Engl J Med 1997;336:251–7. 80. Maze SS, Kotler MN, Parry WR. Flow characteristics in the dilated left ventricle with thrombus: Qualitative and quantitative Doppler analysis. J Am Coll Cardiol 1989;13:873–81. 81. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: The warfarin and antiplatelet therapy in chronic heart failure (WATCH) trial. Circulation 2009;119:1616–24. 82. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. New Engl J Med 2012;366:1859–69. 83. Dexter DD Jr, Whisnant JP, Connolly DC, et al. The association of stroke and coronary heart disease: A population study. Mayo Clin Proc 1987;62:1077–83. 84. Tanne D, Goldbourt U, Zion M, et al. Frequency and prognosis of stroke/TIA among 4808 survivors of acute myocardial infarction. The Sprint Study Group. Stroke 1993;24:1490–5. 85. The Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 1996;156:409–16. 86. Bodenheimer MM, Sauer D, Shareef B, et al. Relation between myocardial infarct location and stroke. J Am Coll Cardiol 1994;24:61–6. 87. Keren A, Goldberg S, Gottlieb S, et al. Natural history of left ventricular thrombi: Their appearance and resolution in the posthospitalization period of acute myocardial infarction. J Am Coll Cardiol 1990;15:790–800. 88. Friedman MJ, Carlson K, Marcus FI, et al. Clinical correlations in patients with acute myocardial infarction and left ventricular thrombus detected by two-dimensional echocardiography. Am J Med 1982;72:894–8. 89. Mooe T, Eriksson P, Stegmayr B. Ischemic stroke after acute myocardial infarction. A population-based study. Stroke 1997;28:762–7. 90. Mooe T, Teien D, Karp K, et al. Long term follow up of patients with anterior myocardial infarction complicated by left ventricular thrombus in the thrombolytic era. Heart 1996;75:252–6. 93. Anticoagulants in the secondary prevention of events in coronary thrombosis (ASPECT) research group. Effect of longterm oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 1994;343: 499–503. 94. Roldan CA, Shively BK, Crawford MH. Valve excrescences: Prevalence, evolution and risk for cardioembolism. J Am Coll Cardiol 1997;30:1308–14. 95. Cohen A, Tzourio C, Chauvel C, et al. Mitral valve strands and the risk of ischemic stroke in elderly patients. The French Study of Aortic Plaques in Stroke (FAPS) investigators. Stroke 1997;28: 1574–8. 96. Aziz F, Baciewicz FA Jr. Lambl’s excrescences: Review and recommendations. Tex Heart Inst J 2007;34:366–8. 97. Salem DN, Daudelin HD, Levine HJ, et al. Antithrombotic therapy in valvular heart disease. Chest 2001;119:207S–219S.

1027

98. Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. New Engl J Med 1995;333:11–17. 99. Whitlock RP, Sun JC, Fremes SE, et al., American College of Chest P. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141:e576S–600S. 100. Scott PJ, Essop R, Wharton GA, et al. Left atrial clot in patients with mitral prostheses: Increased rate of detection after recent systemic embolism. Int J Cardiol 1991;33:141–8. 101. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141:e326S–350S. 102. Katsouli A, Massad MG. Current issues in the diagnosis and management of blood culture-negative infective and noninfective endocarditis. Ann Thorac Surg 2013;95:1467–74. 103. Roldan CA, Sibbitt WL Jr, Qualls CR, et al. Libman-sacks endocarditis and embolic cerebrovascular disease. JACC Cardiovasc Imaging 2013;6:973–83. 104. Lockshin M, Tenedios F, Petri M, et al. Cardiac disease in the antiphospholipid syndrome: Recommendations for treatment. Committee consensus report. Lupus 2003;12:518–23. 105. Hart RG, Foster JW, Luther MF, et al. Stroke in infective endocarditis. Stroke 1990;21:695–700. 106. Davenport J, Hart RG. Prosthetic valve endocarditis 1976–1987. Antibiotics, anticoagulation, and stroke. Stroke 1990;21: 993–9. 107. Molina CA, Selim MH. Anticoagulation in patients with stroke with infective endocarditis: The sword of Damocles. Stroke 2011; 42:1799–800. 108. Yau JW, Lee P, Wilson A, et al. Prosthetic valve endocarditis: What is the evidence for anticoagulant therapy? Intern Med J 2011;41:795–7. 109. Okazaki S, Yoshioka D, Sakaguchi M, et al. Acute ischemic brain lesions in infective endocarditis: Incidence, related factors, and postoperative outcome. Cerebrovasc Dis 2013;35:155–62. 110. Goulenok T, Klein I, Mazighi M, et al. Infective endocarditis with symptomatic cerebral complications: Contribution of cerebral magnetic resonance imaging. Cerebrovasc Dis 2013;35: 327–36. 111. Hoen B, Duval X. Clinical practice. Infective endocarditis. New Engl J Med 2013;368:1425–33. 112. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. New Engl J Med 2012; 366:2466–73. 113. Bhan A, Mehrotra R, Choudhary SK, et al. Surgical experience with intracardiac myxomas: Long-term follow-up. Ann Thorac Surg 1998;66:810–13. 114. Garatti A, Nano G, Canziani A, et al. Surgical excision of cardiac myxomas: Twenty years experience at a single institution. Ann Thorac Surg 2012;93:825–31. 115. Gowda RM, Khan IA, Nair CK, et al. Cardiac papillary fibroelastoma: A comprehensive analysis of 725 cases. Am Heart J 2003; 146:404–10. 116. Amano J, Nakayama J, Yoshimura Y, et al. Clinical classification of cardiovascular tumors and tumor-like lesions, and its incidences. Gen Thorac Cardiovasc Surg 2013;61:435–47. 117. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992;117: 461–5. 118. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993;24:1865–73. 119. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. New Engl J Med 1988;318: 1148–52. 120. Hausmann D, Mugge A, Daniel WG. Identification of patent foramen ovale permitting paradoxic embolism. J Am Coll Cardiol 1995;26:1030–8. 121. Lynch JJ, Schuchard GH, Gross CM, et al. Prevalence of right-toleft atrial shunting in a healthy population: Detection by valsalva

62

1028

SECTION VI  Therapy

maneuver contrast echocardiography. Am J Cardiol 1984;53: 1478–80. 123. Jauss M, Kaps M, Keberle M, et al. A comparison of transesophageal echocardiography and transcranial Doppler sonography with contrast medium for detection of patent foramen ovale. Stroke 1994;25:1265–7. 124. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: An autopsy study of 965 normal hearts. Mayo Clin Proc 1984;59: 17–20. 125. Homma S, Sacco RL, Di Tullio MR, et al., Investigators PFOiCSS. Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study. Circulation 2002;105:2625–31. 126. Jones EF, Calafiore P, Donnan GA, et al. Evidence that patent foramen ovale is not a risk factor for cerebral ischemia in the elderly. Am J Cardiol 1994;74:596–9. 127. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: Incidental or pathogenic? Stroke 2009;40: 2349–55. 128. Lee JY, Song JK, Song JM, et al. Association between anatomic features of atrial septal abnormalities obtained by omni-plane transesophageal echocardiography and stroke recurrence in cryptogenic stroke patients with patent foramen ovale. Am J Cardiol 2010;106:129–34. 129. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: The PFO-ASA study. Atrial septal aneurysm. Stroke 2002;33:706–11. 130. Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: Results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) Study. Stroke 2004;35:46–50. 131. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. New Engl J Med 2007;357:2262–8. 133. Mas JL, Zuber M. Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischemic attack. French Study Group on Patent Foramen Ovale and Atrial Septal Aneurysm. Am Heart J 1995;130:1083–8. 135. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. New Engl J Med 2012;366:991–9. 136. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. New Engl J Med 2013;368:1092–100. 137. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. New Engl J Med 2013;368:1083–91. 138. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. New Engl J Med 1994;331:1474–9. 139. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. New Engl J Med 1996;334:1216–21. 140. Tunick PA, Nayar AC, Goodkin GM, et al. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002;90:1320–5. 141. Hirsh J, Anand SS, Halperin JL, et al. Guide to anticoagulant therapy: Heparin: A statement for healthcare professionals from the American Heart Association. Circulation 2001;103: 2994–3018. 142. Kelton JG, Arnold DM, Bates SM. Nonheparin anticoagulants for heparin-induced thrombocytopenia. New Engl J Med 2013;368: 737–44. 143. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;103:1838–43. 144. Kiser TH, Burch JC, Klem PM, et al. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy 2008;28:1115–24. 145. Fogelholm R, Eskola K, Kiminkinen T, et al. Anticoagulant treatment as a risk factor for primary intracerebral haemorrhage. J Neurol Neurosurg Psychiatry 1992;55:1121–4.

146. Franke CL, de Jonge J, van Swieten JC, et al. Intracerebral hematomas during anticoagulant treatment. Stroke 1990;21: 726–30. 147. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. New Engl J Med 2005;352:777–85. 148. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. New Engl J Med 2008;358:2127–37. 149. Woo CH, Patel N, Conell C, et al. Rapid warfarin reversal in the setting of intracranial hemorrhage: A comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate. World Neurosurg 2014;81:110–15. 150. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, phase IIIb study. Circulation 2013;128:1234–43. 151. Torn M, Algra A, Rosendaal FR. Oral anticoagulation for cerebral ischemia of arterial origin: High initial bleeding risk. Neurology 2001;57:1993–9. 152. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120: 897–902. 153. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857–65. 154. Hylek EM, Skates SJ, Sheehan MA, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. New Engl J Med 1996;335: 540–6. 155. Smith EE, Rosand J, Knudsen KA, et al. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002;59:193–7. 156. Gorter JW. Major bleeding during anticoagulation after cerebral ischemia: Patterns and risk factors. Stroke Prevention in Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups. Neurology 1999;53:1319–27. 157. Kato H, Izumiyama M, Izumiyama K, et al. Silent cerebral microbleeds on T2*-weighted MRI: Correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke 2002;33: 1536–40. 158. Charidimou A, Kakar P, Fox Z, et al. Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: Systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2013;84:277–80. 159. Charidimou A, Werring DJ. The dilemma of atrial fibrillation in intracerebral haemorrhage: How to balance the risks of ischaemia and bleeding. Eur J Neurol 2014;21:549–51. 160. Kakar P, Charidimou A, Werring DJ. Cerebral microbleeds: A new dilemma in stroke medicine. JRSM Cardiovasc Dis 2012;1: 2048004012474754. 161. Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 1986;17: 586–9. 162. Hornig CR, Bauer T, Simon C, et al. Hemorrhagic transformation in cardioembolic cerebral infarction. Stroke 1993;24: 465–8. 163. Molina CA, Montaner J, Abilleira S, et al. Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke 2001;32:1079–84. 164. Nighoghossian N, Hermier M, Berthezene Y, et al. Early diagnosis of hemorrhagic transformation: Diffusion/perfusionweighted MRI versus CT scan. Cerebrovasc Dis 2001;11:151–6. 165. Hermier M, Nighoghossian N, Derex L, et al. MRI of acute postischemic cerebral hemorrhage in stroke patients: Diagnosis with T2*-weighted gradient-echo sequences. Neuroradiology 2001;43: 809–15. 166. Okada Y, Yamaguchi T, Minematsu K, et al. Hemorrhagic transformation in cerebral embolism. Stroke 1989;20:598–603. 167. Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: Brain hemorrhage and management options. Stroke 1984;15:779–89. 168. Sandercock P. Full heparin anticoagulation should not be used in acute ischemic stroke. Stroke 2003;34:231–2.

169. Hallevi H, Albright KC, Martin-Schild S, et al. Anticoagulation after cardioembolic stroke: To bridge or not to bridge? Arch Neurol 2008;65:1169–73. 170. Cerebral Embolism Study Group. Cardioembolic stroke, early anticoagulation, and brain hemorrhage. Arch Intern Med 1987; 147:636–40. 171. Chamorro A, Vila N, Saiz A, et al. Early anticoagulation after large cerebral embolic infarction: A safety study. Neurology 1995;45:861–5. 172. Pessin MS, Estol CJ, Lafranchise F, et al. Safety of anticoagulation after hemorrhagic infarction. Neurology 1993;43:1298–303. 173. Paciaroni M, Agnelli G, Corea F, et al. Early hemorrhagic transformation of brain infarction: Rate, predictive factors, and influence on clinical outcome: Results of a prospective multicenter study. Stroke 2008;39:2249–56. 174. Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab 2014;34:185–99. 175. Kim JT, Heo SH, Park MS, et al. Use of antithrombotics after hemorrhagic transformation in acute ischemic stroke. PLoS ONE 2014;9:e89798.

Secondary Prevention of Cardioembolic Stroke

1029

176. Gebel JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin 2000;18:419–38. 177. Crawley F, Bevan D, Wren D. Management of intracranial bleeding associated with anticoagulation: Balancing the risk of further bleeding against thromboembolism from prosthetic heart valves. J Neurol Neurosurg Psychiatry 2000;69:396–8. 178. Hacke W. The dilemma of reinstituting anticoagulation for patients with cardioembolic sources and intracranial hemorrhage: How wide is the strait between Skylla and Karybdis? Arch Neurol 2000;57:1682–4. 179. Phan TG, Koh M, Wijdicks EF. Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. Arch Neurol 2000;57:1710–13. 180. Bertram M, Bonsanto M, Hacke W, et al. Managing the therapeutic dilemma: Patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol 2000;247: 209–14. 181. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarinassociated intracerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007;82:82–92.

62



Secondary Prevention of Cardioembolic Stroke

REFERENCES 1. Foulkes MA, Wolf PA, Price TR, et al. The stroke data bank: Design, methods, and baseline characteristics. Stroke 1988;19: 547–54. 2. [No authors listed]. Cardiogenic brain embolism. The second report of the cerebral embolism task force. Arch Neurol 1989; 46:727–43. 3. Comess KA, DeRook FA, Beach KW, et al. Transesophageal echocardiography and carotid ultrasound in patients with cerebral ischemia: Prevalence of findings and recurrent stroke risk. J Am Coll Cardiol 1994;23:1598–603. 4. Albers GW, Comess KA, DeRook FA, et al. Transesophageal echocardiographic findings in stroke subtypes. Stroke 1994;25: 23–8. 5. Ramirez-Lassepas M, Cipolle RJ, Bjork RJ, et al. Can embolic stroke be diagnosed on the basis of neurologic clinical criteria? Arch Neurol 1987;44:87–9. 6. Bogousslavsky J, Cachin C, Regli F, et al. Cardiac sources of embolism and cerebral infarction – clinical consequences and vascular concomitants: The Lausanne Stroke Registry. Neurology 1991;41:855–9. 7. Hornig CR, Brainin M, Mast H. Cardioembolic stroke: Results from three current stroke data banks. Neuroepidemiol 1994;13: 318–23. 8. Ward G, Jamrozik K, Stewart-Wynne E. Incidence and outcome of cerebrovascular disease in Perth, western Australia. Stroke 1988;19:1501–6. 9. Lindgren A, Roijer A, Norrving B, et al. Carotid artery and heart disease in subtypes of cerebral infarction. Stroke 1994;25: 2356–62. 10. Moulin T, Tatu L, Crepin-Leblond T, et al. The Besancon Stroke Registry: An acute stroke registry of 2,500 consecutive patients. Eur Neurol 1997;38:10–20. 11. Czlonkowska A, Ryglewicz D, Weissbein T, et al. A prospective community-based study of stroke in Warsaw, Poland. Stroke 1994;25:547–51. 12. Arboix A, Vericat MC, Pujades R, et al. Cardioembolic infarction in the Sagrat Cor-Alianza Hospital of Barcelona stroke Registry. Acta Neurol Scand 1997;96:407–12. 13. Vemmos KN, Bots ML, Tsibouris PK, et al. Stroke incidence and case fatality in Southern Greece: The Arcadia Stroke Registry. Stroke 1999;30:363–70. 14. Vemmos KN, Takis CE, Georgilis K, et al. The Athens Stroke Registry: Results of a five-year hospital-based study. Cerebrovasc Dis 2000;10:133–41. 15. Lee BI, Nam HS, Heo JH, et al. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. Cerebrovasc Dis 2001;12:145–51. 16. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: The German Stroke Data Bank. Stroke 2001;32:2559–66. 17. Feinberg WM, Blackshear JL, Laupacis A, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–73. 18. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The anticoagulation and risk factors in atrial fibrillation (atria) study. JAMA 2001;285: 2370–5. 19. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e269–367. 20. Broderick JP, Phillips SJ, O’Fallon WM, et al. Relationship of cardiac disease to stroke occurrence, recurrence, and mortality. Stroke 1992;23:1250–6. 21. Sandercock P, Bamford J, Dennis M, et al. Atrial fibrillation and stroke: Prevalence in different types of stroke and influence on early and long term prognosis (Oxfordshire Community Stroke Project). BMJ 1992;305:1460–5. 22. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449–57.

1029.e1

23. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991;22:983–8. 23a.  Nakayama T, Date C, Yokoyama T, et al. A 15.5-year follow-up study of stroke in a Japanese provincial city. The Shibata Study. Stroke 1997;28(1):45–52. 23b.  Onundarson PT, Thorgeirsson G, Jonmundsson E, et al. Chronic atrial fibrillation–epidemiologic features and 14 year follow-up: a case control study. Eur Heart J 1987;8(5):521–7. 24. Saxena R, Lewis S, Berge E, et al. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the international stroke trial. Stroke 2001;32:2333–7. 25. Lamassa M, Di Carlo A, Pracucci G, et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: Data from a multicenter multinational hospital-based registry (the European Community Stroke Project). Stroke 2001; 32:392–8. 26. Hart RG, Halperin JL. Atrial fibrillation and stroke: Concepts and controversies. Stroke 2001;32:803–8. 27. Aschenberg W, Schluter M, Kremer P, et al. Transesophageal twodimensional echocardiography for the detection of left atrial appendage thrombus. J Am Coll Cardiol 1986;7:163–6. 28. Grimm RA, Stewart WJ, Maloney JD, et al. Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: Characterization by simultaneous transesophageal echocardiography. J Am Coll Cardiol 1993;22:1359–66. 29. Mitusch R, Siemens HJ, Garbe M, et al. Detection of a hypercoagulable state in nonvalvular atrial fibrillation and the effect of anticoagulant therapy. Thromb Heamost 1996;75:219–23. 30. Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: A decade of progress in stroke prevention. Ann Intern Med 1999;131:688–95. 31. Albers GW, Dalen JE, Laupacis A, et al. Antithrombotic therapy in atrial fibrillation. Chest 2001;119:194S–206S. 32. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: Results from the national registry of atrial fibrillation. JAMA 2001;285:2864–70. 33. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on atrial fibrillation. Chest 2010;137:263–72. 34. Lip GY, Frison L, Halperin JL, et al. Identifying patients at high risk for stroke despite anticoagulation: A comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010;41:2731–8. 35. Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: Analysis of randomized clinical trials. Stroke 2002;33:2722–7. 36. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010;138: 1093–100. 37. Lip GY, Frison L, Halperin JL, et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score. J Am Coll Cardiol 2011;57:173–80. 38. Seet RC, Friedman PA, Rabinstein AA. Prolonged rhythm monitoring for the detection of occult paroxysmal atrial fibrillation in ischemic stroke of unknown cause. Circulation 2011;124: 477–86. 39. Kishore A, Vail A, Majid A, et al. Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: A systematic review and meta-analysis. Stroke 2014. 40. Ritter MA, Kochhauser S, Duning T, et al. Occult atrial fibrillation in cryptogenic stroke: Detection by 7-day electrocardiogram versus implantable cardiac monitors. Stroke 2013;44:1449–52. 41. Etgen T, Hochreiter M, Mundel M, et al. Insertable cardiac event recorder in detection of atrial fibrillation after cryptogenic stroke: An audit report. Stroke 2013;44:2007–9. 42. Flint AC, Banki NM, Ren X, et al. Detection of paroxysmal atrial fibrillation by 30-day event monitoring in cryptogenic ischemic

62

1029.e2

SECTION VI  Therapy

stroke: The stroke and monitoring for PAF in real time (SMART) registry. Stroke 2012;43:2788–90. 43. Sinha AM, Diener HC, Morillo CA, et al. Cryptogenic stroke and underlying atrial fibrillation (CRYSTAL AF): Design and rationale. Am Heart J 2010;160:36–41 e31. 44. Ip J, Waldo AL, Lip GY, et al. Multicenter randomized study of anticoagulation guided by remote rhythm monitoring in patients with implantable cardioverter-defibrillator and CRT-D devices: Rationale, design, and clinical characteristics of the initially enrolled cohort the impact study. Am Heart J 2009;158:364–70, e361. 45. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. 46. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995;26: 1471–7. 47. Investigators AWGotA, Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903–12. 48. Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: A science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:3442–53. 49. Lip GY, Hee FL. Paroxysmal atrial fibrillation. QJM 2001;94: 665–78. 50. Hart RG, Pearce LA, Rothbart RM, et al. Stroke with intermittent atrial fibrillation: Incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 2000;35:183–7. 51. Turpie AG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. New Engl J Med 1993;329:524–9. 52. Dentali F, Douketis JD, Lim W, et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: A metaanalysis of randomized trials. Arch Intern Med 2007;167: 117–24. 53. Johnson SG, Rogers K, Delate T, et al. Outcomes associated with combined antiplatelet and anticoagulant therapy. Chest 2008;133:948–54. 54. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An openlabel, randomised, controlled trial. Lancet 2013;381:1107–15. 55. Sobieraj-Teague M, O’Donnell M, Eikelboom J. New anticoagulants for atrial fibrillation. Semin Thromb Hemost 2009;35: 515–24. 56. Alberts MJ, Eikelboom JW, Hankey GJ. Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation. Lancet Neurol 2012;11:1066–81. 57. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 2009;361:1139–51. 58. Kowey PR, Naccarelli GV. The food and drug administration decision not to approve the 110 mg dose of dabigatran: Give us a way out. Am J Med 2012;125:732. 59. Beasley BN, Unger EF, Temple R. Anticoagulant options – why the FDA approved a higher but not a lower dose of dabigatran. New Engl J Med 2011;364:1788–90. 60. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Heamost 2010;103:1116–27. 61. Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. New Engl J Med 2011;365:2039–40. 62. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. 63. Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 2012;126:2428–32.

64. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 2011;365: 883–91. 65. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. Warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study. Circ J 2012;76:2104–11. 66. Steiner T, Bohm M, Dichgans M, et al. Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACS), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 2013;102:399–412. 67. Bowry R, Fraser S, Archeval-Lao JM, et al. Thrombelastography detects the anticoagulant effect of rivaroxaban in patients with stroke. Stroke 2014;45:880–3. 68. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. New Engl J Med 2011;364:806–17. 69. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2011;365:981–92. 70. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long- term anticoagulation therapy) trial. Circulation 2012;125: 669–76. 71. Weitz JI, Gross PL. New oral anticoagulants: Which one should my patient use? Hematology Am Soc Hematol Educ Program 2012;2012:536–40. 72. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. New Engl J Med 2002;347:1825–33. 73. Sherman DG, Kim SG, Boop BS, et al. Occurrence and characteristics of stroke events in the atrial fibrillation follow-up investigation of sinus rhythm management (AFFIRM) study. Arch Intern Med 2005;165:1185–91. 74. Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to stroke. The Framingham Study. JAMA 1983;250: 2942–6. 75. Dries DL, Rosenberg YD, Waclawiw MA, et al. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: Evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol 1997;29:1074–80. 76. Cioffi G, Pozzoli M, Forni G, et al. Systemic thromboembolism in chronic heart failure. A prospective study in 406 patients. Eur Heart J 1996;17:1381–9. 77. Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. New Engl J Med 1997;336:251–7. 78. Fuster V, Gersh BJ, Giuliani ER, et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981;47: 525–31. 79. Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. EMERAS (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur) collaborative group. Lancet 1993;342:767–72. 80. Maze SS, Kotler MN, Parry WR. Flow characteristics in the dilated left ventricle with thrombus: Qualitative and quantitative Doppler analysis. J Am Coll Cardiol 1989;13:873–81. 81. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: The warfarin and antiplatelet therapy in chronic heart failure (WATCH) trial. Circulation 2009;119:1616–24. 82. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. New Engl J Med 2012;366:1859–69. 83. Dexter DD Jr, Whisnant JP, Connolly DC, et al. The association of stroke and coronary heart disease: A population study. Mayo Clin Proc 1987;62:1077–83. 84. Tanne D, Goldbourt U, Zion M, et al. Frequency and prognosis of stroke/TIA among 4808 survivors of acute myocardial infarction. The Sprint Study Group. Stroke 1993;24:1490–5. 85. The Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 1996;156:409–16. 86. Bodenheimer MM, Sauer D, Shareef B, et al. Relation between myocardial infarct location and stroke. J Am Coll Cardiol 1994;24:61–6.

87. Keren A, Goldberg S, Gottlieb S, et al. Natural history of left ventricular thrombi: Their appearance and resolution in the posthospitalization period of acute myocardial infarction. J Am Coll Cardiol 1990;15:790–800. 88. Friedman MJ, Carlson K, Marcus FI, et al. Clinical correlations in patients with acute myocardial infarction and left ventricular thrombus detected by two-dimensional echocardiography. Am J Med 1982;72:894–8. 89. Mooe T, Eriksson P, Stegmayr B. Ischemic stroke after acute myocardial infarction. A population-based study. Stroke 1997; 28:762–7. 90. Mooe T, Teien D, Karp K, et al. Long term follow up of patients with anterior myocardial infarction complicated by left ventricular thrombus in the thrombolytic era. Heart 1996;75:252–6. 91. Cairns JA, Theroux P, Lewis HD Jr, et al. Antithrombotic agents in coronary artery disease. Chest 2001;119:228S–252S. 92. Pizzetti F, Turazza FM, Franzosi MG, et al. Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: The GISSI-3 data. Heart 2001;86:527–32. 93. Anticoagulants in the secondary prevention of events in coronary thrombosis (ASPECT) research group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 1994;343:499–503. 94. Roldan CA, Shively BK, Crawford MH. Valve excrescences: Prevalence, evolution and risk for cardioembolism. J Am Coll Cardiol 1997;30:1308–14. 95. Cohen A, Tzourio C, Chauvel C, et al. Mitral valve strands and the risk of ischemic stroke in elderly patients. The French Study of Aortic Plaques in Stroke (FAPS) investigators. Stroke 1997;28: 1574–8. 96. Aziz F, Baciewicz FA Jr. Lambl’s excrescences: Review and recommendations. Tex Heart Inst J 2007;34:366–8. 97. Salem DN, Daudelin HD, Levine HJ, et al. Antithrombotic therapy in valvular heart disease. Chest 2001;119:207S–219S. 98. Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. New Engl J Med 1995;333:11–17. 99. Whitlock RP, Sun JC, Fremes SE, et al., American College of Chest P. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141:e576S–600S. 100. Scott PJ, Essop R, Wharton GA, et al. Left atrial clot in patients with mitral prostheses: Increased rate of detection after recent systemic embolism. Int J Cardiol 1991;33:141–8. 101. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141:e326S–350S. 102. Katsouli A, Massad MG. Current issues in the diagnosis and management of blood culture-negative infective and noninfective endocarditis. Ann Thorac Surg 2013;95:1467–74. 103. Roldan CA, Sibbitt WL Jr, Qualls CR, et al. Libman-sacks endocarditis and embolic cerebrovascular disease. JACC Cardiovasc Imaging 2013;6:973–83. 104. Lockshin M, Tenedios F, Petri M, et al. Cardiac disease in the antiphospholipid syndrome: Recommendations for treatment. Committee consensus report. Lupus 2003;12:518–23. 105. Hart RG, Foster JW, Luther MF, et al. Stroke in infective endocarditis. Stroke 1990;21:695–700. 106. Davenport J, Hart RG. Prosthetic valve endocarditis 1976–1987. Antibiotics, anticoagulation, and stroke. Stroke 1990;21:993–9. 107. Molina CA, Selim MH. Anticoagulation in patients with stroke with infective endocarditis: The sword of Damocles. Stroke 2011; 42:1799–800. 108. Yau JW, Lee P, Wilson A, et al. Prosthetic valve endocarditis: What is the evidence for anticoagulant therapy? Intern Med J 2011;41:795–7. 109. Okazaki S, Yoshioka D, Sakaguchi M, et al. Acute ischemic brain lesions in infective endocarditis: Incidence, related factors, and postoperative outcome. Cerebrovasc Dis 2013;35:155–62. 110. Goulenok T, Klein I, Mazighi M, et al. Infective endocarditis with symptomatic cerebral complications: Contribution of cerebral magnetic resonance imaging. Cerebrovasc Dis 2013;35: 327–36.

Secondary Prevention of Cardioembolic Stroke

1029.e3

111. Hoen B, Duval X. Clinical practice. Infective endocarditis. New Engl J Med 2013;368:1425–33. 112. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. New Engl J Med 2012;366:2466–73. 113. Bhan A, Mehrotra R, Choudhary SK, et al. Surgical experience with intracardiac myxomas: Long-term follow-up. Ann Thorac Surg 1998;66:810–13. 114. Garatti A, Nano G, Canziani A, et al. Surgical excision of cardiac myxomas: Twenty years experience at a single institution. Ann Thorac Surg 2012;93:825–31. 115. Gowda RM, Khan IA, Nair CK, et al. Cardiac papillary fibroelastoma: A comprehensive analysis of 725 cases. Am Heart J 2003;146:404–10. 116. Amano J, Nakayama J, Yoshimura Y, et al. Clinical classification of cardiovascular tumors and tumor-like lesions, and its incidences. Gen Thorac Cardiovasc Surg 2013;61:435–47. 117. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992;117: 461–5. 118. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993;24:1865–73. 119. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. New Engl J Med 1988;318:1148–52. 120. Hausmann D, Mugge A, Daniel WG. Identification of patent foramen ovale permitting paradoxic embolism. J Am Coll Cardiol 1995;26:1030–8. 121. Lynch JJ, Schuchard GH, Gross CM, et al. Prevalence of right-toleft atrial shunting in a healthy population: Detection by valsalva maneuver contrast echocardiography. Am J Cardiol 1984;53: 1478–80. 122. DeRook FA, Comess KA, Albers GW, et al. Transesophageal echocardiography in the evaluation of stroke. Ann Intern Med 1992;117:922–32. 123. Jauss M, Kaps M, Keberle M, et al. A comparison of transesophageal echocardiography and transcranial Doppler sonography with contrast medium for detection of patent foramen ovale. Stroke 1994;25:1265–7. 124. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: An autopsy study of 965 normal hearts. Mayo Clin Proc 1984;59:17–20. 125. Homma S, Sacco RL, Di Tullio MR, et al., Investigators PFOiCSS. Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study. Circulation 2002;105:2625–31. 126. Jones EF, Calafiore P, Donnan GA, et al. Evidence that patent foramen ovale is not a risk factor for cerebral ischemia in the elderly. Am J Cardiol 1994;74:596–9. 127. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: Incidental or pathogenic? Stroke 2009;40: 2349–55. 128. Lee JY, Song JK, Song JM, et al. Association between anatomic features of atrial septal abnormalities obtained by omni-plane transesophageal echocardiography and stroke recurrence in cryptogenic stroke patients with patent foramen ovale. Am J Cardiol 2010;106:129–34. 129. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: The PFO-ASA study. Atrial septal aneurysm. Stroke 2002;33:706–11. 130. Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: Results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) Study. Stroke 2004;35:46–50. 131. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. New Engl J Med 2007;357:2262–8. 132. Bogousslavsky J, Garazi S, Jeanrenaud X, et al. Stroke recurrence in patients with patent foramen ovale: The Lausanne Study. Lausanne Stroke with Paradoxal Embolism Study Group. Neurology 1996;46:1301–5. 133. Mas JL, Zuber M. Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischemic attack. French Study

62

1029.e4

SECTION VI  Therapy

Group on Patent Foramen Ovale and Atrial Septal Aneurysm. Am Heart J 1995;130:1083–8. 134. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. New Engl J Med 2001;345:1740–6. 135. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. New Engl J Med 2012;366:991–9. 136. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. New Engl J Med 2013;368:1092–100. 137. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. New Engl J Med 2013;368:1083–91. 138. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. New Engl J Med 1994;331:1474–9. 139. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. New Engl J Med 1996;334:1216–21. 140. Tunick PA, Nayar AC, Goodkin GM, et al. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002;90:1320–5. 141. Hirsh J, Anand SS, Halperin JL, et al. Guide to anticoagulant therapy: Heparin: A statement for healthcare professionals from the American Heart Association. Circulation 2001;103:2994–3018. 142. Kelton JG, Arnold DM, Bates SM. Nonheparin anticoagulants for heparin-induced thrombocytopenia. New Engl J Med 2013;368: 737–44. 143. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;103:1838–43. 144. Kiser TH, Burch JC, Klem PM, et al. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy 2008;28:1115–24. 145. Fogelholm R, Eskola K, Kiminkinen T, et al. Anticoagulant treatment as a risk factor for primary intracerebral haemorrhage. J Neurol Neurosurg Psychiatry 1992;55:1121–4. 146. Franke CL, de Jonge J, van Swieten JC, et al. Intracerebral hematomas during anticoagulant treatment. Stroke 1990;21:726–30. 147. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. New Engl J Med 2005;352:777–85. 148. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. New Engl J Med 2008;358:2127–37. 149. Woo CH, Patel N, Conell C, et al. Rapid warfarin reversal in the setting of intracranial hemorrhage: A comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate. World Neurosurg 2014;81:110–15. 150. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: A randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234–43. 151. Torn M, Algra A, Rosendaal FR. Oral anticoagulation for cerebral ischemia of arterial origin: High initial bleeding risk. Neurology 2001;57:1993–9. 152. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120: 897–902. 153. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997;42:857–65. 154. Hylek EM, Skates SJ, Sheehan MA, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. New Engl J Med 1996; 335:540–6. 155. Smith EE, Rosand J, Knudsen KA, et al. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002;59:193–7. 156. Gorter JW. Major bleeding during anticoagulation after cerebral ischemia: Patterns and risk factors. Stroke Prevention in Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups. Neurology 1999;53:1319–27.

157. Kato H, Izumiyama M, Izumiyama K, et al. Silent cerebral microbleeds on T2*-weighted MRI: Correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke 2002;33:1536–40. 158. Charidimou A, Kakar P, Fox Z, et al. Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: Systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2013;84:277–80. 159. Charidimou A, Werring DJ. The dilemma of atrial fibrillation in intracerebral haemorrhage: How to balance the risks of ischaemia and bleeding. Eur J Neurol 2014;21:549–51. 160. Kakar P, Charidimou A, Werring DJ. Cerebral microbleeds: A new dilemma in stroke medicine. JRSM Cardiovasc Dis 2012;1: 2048004012474754. 161. Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 1986;17: 586–9. 162. Hornig CR, Bauer T, Simon C, et al. Hemorrhagic transformation in cardioembolic cerebral infarction. Stroke 1993;24: 465–8. 163. Molina CA, Montaner J, Abilleira S, et al. Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke 2001;32:1079–84. 164. Nighoghossian N, Hermier M, Berthezene Y, et al. Early diagnosis of hemorrhagic transformation: Diffusion/perfusionweighted MRI versus CT scan. Cerebrovasc Dis 2001;11:151–6. 165. Hermier M, Nighoghossian N, Derex L, et al. MRI of acute postischemic cerebral hemorrhage in stroke patients: Diagnosis with T2*-weighted gradient-echo sequences. Neuroradiology 2001;43: 809–15. 166. Okada Y, Yamaguchi T, Minematsu K, et al. Hemorrhagic transformation in cerebral embolism. Stroke 1989;20:598–603. 167. Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: Brain hemorrhage and management options. Stroke 1984;15:779–89. 168. Sandercock P. Full heparin anticoagulation should not be used in acute ischemic stroke. Stroke 2003;34:231–2. 169. Hallevi H, Albright KC, Martin-Schild S, et al. Anticoagulation after cardioembolic stroke: To bridge or not to bridge? Arch Neurol 2008;65:1169–73. 170. Cerebral Embolism Study Group. Cardioembolic stroke, early anticoagulation, and brain hemorrhage. Arch Intern Med 1987; 147:636–40. 171. Chamorro A, Vila N, Saiz A, et al. Early anticoagulation after large cerebral embolic infarction: A safety study. Neurology 1995;45:861–5. 172. Pessin MS, Estol CJ, Lafranchise F, et al. Safety of anticoagulation after hemorrhagic infarction. Neurology 1993;43:1298–303. 173. Paciaroni M, Agnelli G, Corea F, et al. Early hemorrhagic transformation of brain infarction: Rate, predictive factors, and influence on clinical outcome: Results of a prospective multicenter study. Stroke 2008;39:2249–56. 174. Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab 2014;34:185–99. 175. Kim JT, Heo SH, Park MS, et al. Use of antithrombotics after hemorrhagic transformation in acute ischemic stroke. PLoS ONE 2014;9:e89798. 176. Gebel JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin 2000;18:419–38. 177. Crawley F, Bevan D, Wren D. Management of intracranial bleeding associated with anticoagulation: Balancing the risk of further bleeding against thromboembolism from prosthetic heart valves. J Neurol Neurosurg Psychiatry 2000;69:396–8. 178. Hacke W. The dilemma of reinstituting anticoagulation for patients with cardioembolic sources and intracranial hemorrhage: How wide is the strait between Skylla and Karybdis? Arch Neurol 2000;57:1682–4. 179. Phan TG, Koh M, Wijdicks EF. Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. Arch Neurol 2000;57:1710–13. 180. Bertram M, Bonsanto M, Hacke W, et al. Managing the therapeutic dilemma: Patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol 2000;247: 209–14. 181. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarinassociated intracerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007;82:82–92.