New Standards of Care in Ischemic Stroke

Ischemic arterial strokes of the ophthalmic artery and its branches and posterior cerebral artery are common causes of visual disability. Etiologies of stroke affecting the retina, optic nerve, optic radiation, and visual cortex overlap with other types of ischemic strokes. Stenosis of the internal carotid is the most common cause of central retinal artery occlusion (CRAO). One-fourth of patients with CRAO have cerebral strokes. We report recent developments in the acute treatment and secondary prevention of ischemic stroke of relevance to clinicians who encounter patients with acute vision loss. A search of Pubmed and practice guidelines over the past 5 years was performed, with a focus on significant changes in treatment and prevention of ischemic stroke. Recent randomized controlled trials provide Level I evidence for the use of endovascular therapy with current stent retriever devices for patients with large vessel anterior circulation occlusions within 6 hours of presentation. Number needed to treat to achieve one additional patient with an independent functional outcome was in the range of 3-7, and benefit was additive to that of intravenous tissue plasminogen activator alone. Paroxysmal atrial fibrillation (AF) is a major cause of cryptogenic stroke with incidence expected to rise with the aging population. Since 2014, prolonged 30-day cardiac monitoring has been recommended as a part of transient ischemic attack and stroke workup in patients with cryptogenic stroke. Even longer term monitoring of 6 months to 1 year with external and implantable loop recorders improves rates of diagnosing AF. First available in 2010, the novel anticoagulants-dabigatran, apixaban, rivaroxaban, and edoxaban-have been compared with warfarin in the prevention of stroke in patients with nonvalvular AF. Apixaban demonstrated superiority in safety and efficacy, with the novel anticoagulants as a group having favorable risk-benefit profile at higher dosages compared with standard warfarin therapy. Endovascular therapy is now standard of care for eligible patients with anterior large vessel occlusions. Prolonged cardiac monitoring is recommended for patients with cryptogenic stroke. The novel anticoagulants are an alternative to warfarin in patients with AF.

State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD New Standards of Care in Ischemic Stroke Bree K. Chancellor, MD, MBA, Koto Ishida, MD Background: Ischemic arterial strokes of the ophthalmic artery and its branches and posterior cerebral artery are common causes of visual disability. Etiologies of stroke affecting the retina, optic nerve, optic radiation, and visual cortex overlap with other types of ischemic strokes. Stenosis of the internal carotid is the most common cause of central retinal artery occlusion (CRAO). One-fourth of patients with CRAO have cerebral strokes. We report recent developments in the acute treatment and secondary prevention of ischemic stroke of relevance to clinicians who encounter patients with acute vision loss. Evidence Acquisition: A search of Pubmed and practice guidelines over the past 5 years was performed, with a focus on significant changes in treatment and prevention of ischemic stroke. Results: Recent randomized controlled trials provide Level I evidence for the use of endovascular therapy with current stent retriever devices for patients with large vessel anterior circulation occlusions within 6 hours of presentation. Number needed to treat to achieve one additional patient with an independent functional outcome was in the range of 3-7, and benefit was additive to that of intravenous tissue plasminogen activator alone. Paroxysmal atrial fibrillation (AF) is a major cause of cryptogenic stroke with incidence expected to rise with the aging population. Since 2014, prolonged 30-day cardiac monitoring has been recommended as a part of transient ischemic attack and stroke workup in patients with cryptogenic stroke. Even longer term monitoring of 6 months to 1 year with external and implantable loop recorders improves rates of diagnosing AF. First available in 2010, the novel anticoagulants- dabigatran, apixaban, rivaroxaban, and edoxaban-have been compared with warfarin in the prevention of stroke in patients with nonvalvular AF. Apixaban demonstrated superiority in safety and efficacy, with the novel anticoagulants as a group having favorable risk-benefit profile at higher dosages compared with standard warfarin therapy. Conclusions: Endovascular therapy is now standard of care for eligible patients with anterior large vessel occlusions. Prolonged cardiac monitoring is recommended for patients Department of Neurology, New York University Medical Center, New York, NY. The authors report no conflicts of interest. Address correspondence to Bree Chancellor, MD, MBA, Department of Neurology, New York University Medical Center, 530 First Avenue, HCC Suite 5A, New York, NY 10016; E-mail: Breehan. [e-mail] 320 with cryptogenic stroke. The novel anticoagulants are an alternative to warfarin in patients with AF. Journal of Neuro-Ophthalmology 2017;37:320-331 doi: 10.1097/WNO.0000000000000449 © 2016 by North American Neuro-Ophthalmology Society troke is the fifth most common cause of death in the United States and a significant source of functional disability, affecting 795,000 Americans a year (Fig. 1) (3,4). Ocular vascular disorders are commonly responsible for severe visual loss (5) and include visual acuity and visual field deficits because of ischemic optic neuropathy and central retinal artery occlusion (CRAO). Ischemia from occlusion of the branches of the middle cerebral artery, the basilar artery, and posterior cerebral artery (PCA) often impairs the visual field. The incidence of CRAO is 1 in 100,000 (6). Patients with CRAO experience acute, painless monocular vision loss with retinal infarction and usually are evaluated in an outpatient setting. Less common than CRAO, but similar in pathophysiology and etiology, branch retinal artery occlusion (BRAO) causes monocular vision loss affecting only part of the visual field. Transient monocular vision loss represents 19% of all transient ischemic attacks (TIAs) and may herald CRAO (7). Morbidity associated with CRAO and infarcts of the visual system are significant (8). Within 7 days of onset, only 22% of patients with nonarteritic CRAO (NA-CRAO) will recover visual acuity of 20/200 or better (9,10). In the 14% of patients with CRAO who have a cilioretinal artery supplying the macula, visual acuity outcome improves to this level in 67% of cases (Fig. 2). Patients with CRAO have "silent" or other infarcts on MRI in 25% of cases (12,13). In a series of 213 patients with CRAO, BRAO, or amaurosis fugax, cerebral infarctions were detected in 23% (14). In patients with concurrent cerebral infarcts, between 10% and 60% report additional neurologic symptoms. Patients with concurrent strokes are more likely to have a cardiac or vascular source of embolism. S Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. A. Etiology of ischemic stroke in a multiethnic population (1) by TOAST criteria (categories: 1, large artery atherosclerosis; 2, cardioembolism; 3, small vessel occlusion; 4, stroke of other determined etiology; 5, stroke of underdetermined etiology). B. Incidence of different types of ischemic strokes (2). CRAO, central retinal artery occlusion. Risk factors for strokes affecting the visual system are similar to those for strokes in other locations, with etiology dependent on the affected vessels. Two-thirds of NACRAO cases are caused by emboli because of atherosclerotic disease in the internal carotid artery (ICA). In patients with CRAO and patent ipsilateral intracranial and extracranial vasculature, a common source is proximal embolic site such as the aortic arch or heart. Undiagnosed cardiovascular risk factors were found in 78% of 84 CRAO patients, most importantly ipsilateral carotid artery stenosis (15). For PCA strokes, cardioembolism accounts for about half of cases, whereas embolism is a less common cause of vertebrobasilar strokes (16). Acute treatments for CRAO, including ocular massage, anterior chamber paracentesis, and vasodilating agents, have not demonstrated reliable benefit in randomized trials (17). Trials of intra-arterial t-PA for CRAO including the EAGLE trial that treated patients up to 20 hours from onset have not yet demonstrated efficacy. Among patients with a proximal vessel occlusion in the anterior circulation, only 20%-40% of patients regain functional independence within 90 days despite t-PA treatment (18). Posterior circulation infarcts may be even more debilitating. Specifically, basilar artery occlusions are associated with death or severe disability in up to 80% of patients (19). After TIA or stroke, risk of recurrence is high. Within a week of TIA, stroke risk is 5% (20) and at 90 days the risk of a recurrent TIA is 11% and stroke is 10% (21). After stroke, the rate of recurrence is 3% at 1 month, 11% at 1 year, and 26% at 5 years (22). Stroke risk in patients presenting with TIA is commonly stratified by ABCD2 score, which is based on age, blood pressure on presentation, clinical features of the TIA, duration of symptoms, and the presence of diabetes (23,24). In 20%-40% of ischemic strokes, etiology after comprehensive workup remains unknown, often referred to as cryptogenic stroke. Cryptogenic stroke is a heterogeneous group. However, many patients are suspected of having FIG. 2. A. Incidence of central retinal artery occlusion by subtype (11). B. Recovery of visual function after central retinal artery occlusion (5). NA, nonarteritic. Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 321 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review undiagnosed or occult atrial fibrillation (AF), the most common arrhythmia leading to stroke. Before 2010, warfarin was the only approved oral anticoagulant for stroke prevention in patients with AF. Warfarin was consistently proven effective in this setting but use in many patients was limited because of food and medication interactions, required longterm monitoring, and narrow therapeutic range. Here we focus on a 3 major clinical advances in the field of vascular neurology. First, in acute stroke, mechanical thrombectomy is now recommended in patients with anterior circulation large vessel occlusions up to 6 hours from onset who have received intravenous (IV) t-PA. Second, prolonged cardiac monitoring using implantable loop recorders increases rates of AF diagnosis in patients with cryptogenic stroke. Finally, in patients with nonvalvular (NV) AF, the novel oral anticoagulants represent a new alternative to warfarin with similar efficacy and reduced risk of major bleeding complications and without the need for monitoring. EMBOLECTOMY FOR ACUTE ANTERIOR LARGE VESSEL OCCLUSIONS For decades, IV t-PA was the mainstay of acute stroke treatment. Approved by the FDA in 1996, t-PA improves disability rates when given within 4.5 hours of stroke onset (25,26). Number needed to treat to confer benefit of a 1-point improvement in the modified Rankin Scale (mRS) at 90 days is between 6 and 14, with even lower number needed to treat for treatment within 3 hours. Nationally, only a small minority of patients with acute stroke, 3%- 5%, receive IV t-PA with most exclusions related to delayed presentation outside the time window (27,28). Since 2014, several multicenter randomized controlled trials have been published comparing functional outcomes in acute ischemic stroke patients who received IV t-PA with or without endovascular thrombectomy (EVT). These trials provide consistent evidence for the use of mechanical thrombectomy in select patients with acute anterior circulation large vessel occlusions (Table 1, Fig. 3). Previous trials of EVT for acute stroke published in 2013 using first-generation devices (IMS III, 34; MR RESCUE, 35; and SYNTHESIS Expansion) (36) failed to show superiority, but established EVT as safe. Although specific inclusion criteria and study design were somewhat variable, as a group, the recent EVT trials- MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, and REVASCAT-all required proof of large vessel occlusion before randomization, rapid treatment times, and a preference for the newer generation stent retrievers. The majority of these patients also received IV t-PA. Complete or near complete recanalization was achieved in 59%-88% of those who underwent endovascular intervention in these recent trials compared with only 25%-41% in some of the earlier trials. 322 MR CLEAN (29), a Netherlands-based trial, enrolled 500 patients for medical plus EVT vs medical therapy alone. Selected patients had evidence of ICA, M1, M2, A1, or A2 occlusion on computed tomographic (CT) angiography (CTA), and primary outcome was improved functional status (mRS) at 90 days. In total, 89% were treated with IV t-PA and 81.5% of the endovascular group were treated with stent retrievers. Mean time from onset to IV t-PA was 85 minutes, and time to arterial puncture was 260 minutes. Functional independence (mRS 0-2) was observed in 32.6% and 19.1% of the EVT and medical treatment groups, respectively (95% confidence interval [CI], 5.9-21.1) with an adjusted common odds ratio (OR) of 1.67 (95% CI, 1.21-2.30). Number needed to treat for one additional patient with independent functional outcome was 7. The number needed to treat for a less disabled outcome (change in mRS by one or more at 90 days) was 3-5 (37). Notably, 16% of patients were 80 years or older, and benefit in this group after EVT was similar to that of the overall cohort (OR, 3.24; 95% CI, 1.21-8.62) (29). ESCAPE AND SWIFT-PRIME also reported consistent benefits for elderly patients. The ESCAPE (18) trial randomized 316 patients to medical therapy with or without endovascular therapy. Notably, ESCAPE included patients up to 12 hours from symptom onset, much longer than the other comparable trials. Patients with a large infarct core or poor collateral circulation on multiphase CTA were excluded. The ESCAPE study was terminated early when interim analysis showed efficacy of EVT, with functional independence (mRS 0-2) in 53% vs 29.3% in the medical arm (P , 0.001) with a number needed to treat of 4. Of the 5 trials, ESCAPE had the fastest average time to arterial puncture time, 185 minutes, relative to the other 4 trials that averaged 241 minutes, perhaps contributing to a statistically significant reduction in mortality between the 2 groups (10.4% vs 19.0%, P = 0.04). EXTEND-IA (31) was stopped early after enrolling 70 patients to IV t-PA vs IV t-PA with EVT. Notably, this was the only trial to require evidence of small ischemic core and favorable penumbra with advanced imaging (CT or MR perfusion). Early reperfusion defined as percentage of ischemic territory that had undergone reperfusion at 24 hours on imaging was greater in the EVT with a median of 100% vs 37% in the control group (P , 0.001). This early reperfusion success resulted in rates of NIH Stroke Scale (NIHSS) reduction $8 points or NIHSS 0-1 at 3 days in 80% of the EVT group as compared with 37% in the control group (P , 0.001). Functional independence (mRS 0-2) was achieved in 71% in the endovascular arm vs 40% in the t-PA-alone group (P = 0.01) with a number needed to treat of 3. SWIFT-PRIME (31) was similarly stopped prematurely after enrolling 196 patients. Interim analysis showed benefit of endovascular therapy with functional independence Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 MR CLEAN (29) Comparison Intervention Control No. patients (EVT/ control) Selection criteria Age, yr Onset to groin puncture NIHSS ASPECTS criteria Occlusion on CTA/ MRA Additional imaging criteria IAT (urokinase, t-PA, device) + medical management Medical management (±IV t-PA) ESCAPE (18) EXTEND-IA (30) IAT + medical management EVT with Solitaire FR + IV t-PA IV t-PA EVT with Solitaire FR + IV t-PA IV t-PA 35/35 98/98 EVT with Solitaire FR + medical management Medical management (±IV t-PA) 103/103 $18 IV t-PA, ,4.5 h; EVT ,6 h All None ICA, M1, or M2 18-80 ,6 h 18-80* ,8 h 8-29 $6 ICA, M1 $6 $7 or (MRI-DWI $ 6) ICA/M1 233/267 Medical management (±IV t-PA) 165/150 18 ,6 h $18 ,12 h $2 No ICA, M1, M2, A1, A2 All $6 M1 or M2 (±intracranial ICA) None SWIFT-PRIME (31) REVASCAT (32) Primary outcome 90-d mRS‡ Good collaterals on multiphase CTA or small core on CTP 90-d mRS‡ Percent treated with t-PA EVT Percent EVT intervened upon Percent EVT that used retrievable stents Time (mean in minutes) Onset to IV t-PA Onset to groin puncture Results Recanalization (TICI 2b/3), % 87.1 EVT vs 90.6 control 72.7 EVT vs 78.7 control CTP: mismatch .10 mL and ischemic core ,70 mL 1) Reperfusion at 24 h. 2) Neurologic improvement§ 100 both groups 84 92 77 89 95 81.5 86 All All All 85 260 110 185 127 210 110.5 224 118 269 59 72 86 88 66 CT or MRI mismatch† or ASPECTS $ 6 90-d mRS‡ CTP, CTA source, or MRI-DWI required if .4.5 h 90-d mRS‡ 100 both groups 68 EVT vs 77.7 control State-of-the-Art Review 323 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Summary of randomized stroke intervention trials using endovascular thrombectomy MR CLEAN (29) 90-d mRS 0-2, % Adjusted odds ratio, mRS 0-2 (95% CI) NNT for 1 point change in mRS∥ NNT for 1 additional mRS 0-2∥ Complications Mortality Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 Symptomatic ICH, % ESCAPE (18) EXTEND-IA (30) SWIFT-PRIME (31) 32.6 EVT vs 19.1 control 53 EVT vs 29.3 control 71 EVT vs 40 control 1.67 (1.21-2.30) 3.1 (2.0-4.7) 2.0 (1.2-3.8) 60.2 NIR vs 35.5 control 2.75 (1.53-4.95) 2.8 2.6 3-5 REVASCAT (32) 43.7 EVT vs 28.2 control 2.1 (1.1-4.0) 7.0 4.0 3.2 4.0 6.4 No SS difference 7 d: 11.6% EVT vs 12.4% control; 30 d: 18.9% EVT vs 18.4% control 7.7 EVT vs 6.4 control (P = 0.31) EVT superior mortality 90 d: 10.4% EVT vs 19% control (P = 0.04) No SS difference 90 d: 9% EVT vs 20% control (P = 0.18) 3.6 EVT vs 2.7 control (P = 0.75) 0 EVT vs 6 control (P = 0.49) No SS difference 90 d: 9% EVT vs 12% control (P = 0.5) 1 EVT vs 3 control (P = 0.37) No SS difference 90 d: 18.4% EVT vs 15.5% control (P = 0.6) 1.9 EVT vs 1.9 control (P = 1) *Up to 85 if ASPECTS 9-10. † Excluded core size .50 mL, hypoperfusion (Tmax $10 seconds in lesion .100 mL) or mismatch volume of ,15 mL and mismatch ratio #1.8 for first 71 patients; for remaining 125 patients, MRI or CT mismatch or ASPECTS $6. ‡ Improvement in 90-day mRS with blinded shift analysis combining 5 and 6. § Reduction in NIHSS $8 or NIHSS 0, 1 at 3 days. ∥ As compared with t-PA alone. ASPECTS, Alberta Stroke Program Early CT score; CTA, computed tomographic angiography; CTP, computed tomography perfusion; DWI, diffusion-weighted imaging; EVT, endovascular thrombectomy; IAT, intra-arterial therapy; ICA, internal carotid artery; IV, intravenous; mRS, modified Rankin Scale; mRS 0-2, functional independence; NIHSS, NIH Stroke Scale; NIR, neurointervention; NNT, number needed to treat; SS, statistically significant. State-of-the-Art Review 324 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) State-of-the-Art Review FIG. 3. Functional outcome of patients with ischemic stroke by trials of endovascular thrombectomy (EVT). Left axis, rates of independent functional outcome at 90 days after treatment. Right axis, adjusted odds ratio for 90-day modified Rankin Scale (mRS) 0-2. Data row, number needed to treat (NNT) with EVT for one additional independent functional outcome, mRS 0-2 (33). achieved in 60% vs 35% of the medical control arm (P = 0.001) with a number needed to treat of 4. Not all patients had perfusion imaging after the protocol changed to include selection based on Alberta Stroke Program Early CT score (ASPECTS) of $6. ASPECTS is a 10-point CT grading system with a point subtracted for evidence of ischemic changes by territory that was also used for selection in ESCAPE and REVASCAT. The majority of SWIFT-PRIME patients, 161 in total, did have penumbral imaging with exclusion for large core (.50 mL), severe hypoperfusion (Tmax $ 10 seconds in lesion .100 mL), or mismatch volume of ,15 mL and mismatch ratio #1.8. REVASCAT (32) enrolled 206 consecutive patients over 2 years. Acute stroke patients who could be treated within 8 hours of symptom onset were randomized to medical therapy (IV t-PA) vs medical plus endovascular therapy. Thrombectomy resulted in reduction of disability adjusted OR of 1.7 for improvement of mRS by 1 point (95% CI, 1.05-2.8) and led to higher rates of functional independence at 90 days, 43.7% vs 28.2%, adjusted OR, 2.1 (95% CI, 1.1-4.0). REVASCAT enrolled nearly all eligible patients, missing only a small number at its sites. Taken together, these trials provide Level I evidence demonstrating benefit of EVT with current stent retriever devices in select patients. The 2015 guidelines by the American Heart Association/American Stroke Association (AHA/ASA) suggest the use of these techniques within 6 hours of onset in select acute stroke patients receiving IV t-PA with confirmed large vessel anterior circulation occlusions (38). Active EVT trials evaluating expansion of these guidelines including extended time windows, more definitive patient selection based on advanced imaging techniques, and use of EVT in patients who have not received IV t-PA are ongoing. Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 Notably, patients with strokes affecting the central retinal and ophthalmic arteries as well as those referable to the posterior circulation were excluded from the above EVT trials. IV and intra-arterial t-PA have been evaluated for CRAO with mixed results. A retrospective case-control study of 42 consecutive patients, half treated with IA tPA up to 15 hours from onset and the remaining with medical therapy, found visual acuity improvement in 76% of the IA-treated patients compared with 33% in the medically treated group (P = 0.012) (39). However, the EAGLE trial, a prospective randomized clinical trial of 84 patients with CRAO within 20 hours of onset, did not find a clinical difference between IA thrombolysis and standard therapy (60% vs 57.1%) and reported a higher rate of adverse events in the IA group (37% vs 4.3%) (40). Inclusion of patients up to 20 hours after symptom onset may have contributed to these disappointing results. Evidence of infarct is seen within 90 minutes of CRAO, and animal models suggest partial recovery if recanalization is established within 240 minutes (41). Smaller trials report recovery only in patients treated within 6 hours (42), although fewer than 20% of patients present within that time frame (43). For basilar occlusions, recanalization is associated with superior outcomes, but optimal patient selection and specific treatment method are uncertain because these patients are typically excluded from randomized trials. A meta-analysis of 2,056 patients with acute basilar occlusions treated before 2013 showed that recanalization (by IV t-PA or EVT) reduces risk of death and disability by 1.5 times. No large difference in outcome was noted by method, IV t-PA vs EVT, but study of IV t-PA was limited to 4 trials vs 41 for EVT (44). The prospective registry Basilar Artery International Cooperation Study employed older generation devices and did not demonstrate superiority of EVT compared with IV t-PA (45). 325 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review DIAGNOSIS OF PAROXYSMAL ATRIAL FIBRILLATION IN CRYPTOGENIC STROKE Cryptogenic strokes account for 20%-40% of ischemic strokes, amounting to approximately 200,000 strokes annually in the United States. Cryptogenic strokes are not attributed to known high-risk mechanisms including cardioembolism, large artery atherosclerosis, or small vessel disease after extensive clinical evaluation. The ability to better define the etiology of cryptogenic stroke has profound implications, as most patients are treated with antiplatelet therapy which may be insufficient for those with an underlying cardioembolic mechanism like AF. Occult AF is suspected to account for a substantial portion of cryptogenic strokes. AF affects 5.2 million people in the United States, with prevalence expected to double by 2030 related to population aging (46). When untreated, AF increases stroke risk by nearly 5-fold (47). Evidence suggests that 25%-40% of patients with cryptogenic stroke have paroxysmal AF, thought to have similar stroke risk as permanent AF (48). Previous guidelines recommended at least 24 hours of telemetry monitoring after an ischemic stroke, but short-term cardiac monitoring is relatively insensitive for the detection of paroxysmal AF. Two recent randomized controlled trials published in 2014 provide support for prolonged cardiac monitoring in detection of occult AF. The EMBRACE (49) trial randomized 572 patients aged 55 years or older without known AF, who had cryptogenic stroke or TIA within the previous 6 months to undergo additional noninvasive ambulatory electrocardiogram monitoring with either a 30-day event-triggered recorder or a conventional 24-hour monitor. AF lasting $30 seconds was detected in 45 of 280 patients (16.1%) in the intervention group, as compared with 9 of 277 (3.2%) in the conventional group, an absolute difference of 12.9% (95% CI, 8.0-17.6) and number needed to screen of 8. By 90 days, anticoagulant therapy had been prescribed for more patients in the intervention group, 18.6%, than the conventionally monitored group, 11.1%. The CRYSTAL-AF (50) study was a prospective, multicenter randomized controlled trial to assess whether longterm monitoring was more effective than conventional follow-up for detecting AF in patients with cryptogenic stroke. A total of 441 patients older than 40 years of age with cryptogenic stroke or TIA within 90 days without history of AF were randomized to continuous implantable loop recorder vs intermittent EKGs. Stroke was classified as cryptogenic if the following tests did not reveal a clear cause for stroke: 12-lead EKG, 24 hours or more of telemetry, transesophageal echocardiography, screening for thrombophilic states (in patients ,55 years of age), and MRA, CTA, or catheter angiography of the head and neck. By 6 months, the rate of AF detection was 8.9% (n = 19) in the implantable loop recorder group vs 1.4% in control groups (hazard ratio [HR], 6.4; 95% CI, 1.9-21.7). By 12 months, AF was 326 detected in 12.4% of the implantable loop recorder group vs 2% of the control group (HR, 7.3; 95% CI, 2.6-20.8). In patients in whom AF was detected by 1 year, 97% were receiving anticoagulation. The median time from randomization to detection of AF was 84 days in the implantable loop recorder group. Of 208 implantable loop recorders inserted, only 5 (2.4%) were removed because of infection or inflammation at the insertion site. A meta-analysis on detection of AF in cryptogenic stroke pooling data from 1,770 patients concluded that prolonged (.30 days) outpatient monitoring is superior to routine follow-up and that implantable loop recorder is superior to wearable devices. Overall detection of AF with prolonged outpatient monitoring was 17.6% (95% CI, 12.5-22.7). There was significantly higher detection with implantable loop recorder in 23.3% (95% CI, 13.8-32.3) compared with wearable devices in 13.6% (95% CI, 7.9-19.3) (51). The comparatively lower rates of detection overall reported in CRYSTAL-AF may have been because of inclusion of younger patients (.40 years) and comprehensive workup performed for the diagnosis of cryptogenic stroke. In patients with cryptogenic stroke with unrevealing comprehensive workup and no contraindications to anticoagulation, AHA/ASA guidelines recommend prolonged rhythm monitoring (w30 days) for the detection of AF within 6 months of stroke (Class IIa, Level of Evidence C) (52). Since the publication of these guidelines in 2014, data from EMBRACE and CRYSTAL-AF have provided further evidence that even longer term monitoring further increases AF detection in high-risk patients. New implantable loop recorder devices may be most appropriate for higher risk patients. In patients who undergo implantation of a cardiac device and have at least one stroke risk factor (congestive heart failure [CHF], hypertension, age 65+, diabetes, previous stroke/TIA) with a history of thromboembolic events, occult AF has an incidence of 28% at 1 year (53). Although prolonged monitoring has improved detection of AF, trials have yet to demonstrate improved clinical outcomes. STROKE PREVENTION IN ATRIAL FIBRILLATION: NEW ANTICOAGULANTS Warfarin had been the mainstay of treatment in NV-AF, reducing the risk of stroke by two-thirds and death by 25% compared with placebo (54) and demonstrating clear superiority to aspirin in this setting (55). Warfarin has a narrow therapeutic range, multiple food and drug interactions, and requires international normalized ratio (INR) monitoring. In the United States, 4 novel anticoagulants have been approved for stroke prevention in NV-AF: dabigatran (2010), rivaroxaban (2011), apixaban (2012), and edoxaban (2014) (Table 2, Fig. 4). Compared with warfarin, these agents offer advantages of stable dosing, rapid onset and offset, few interactions with food or other medications, and lack of monitoring requirement. However, Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 RELY (56) Drug Mechanism 1/2 life, h Renal excretion, % Trial design Intervention Control Patients Population Women, % Age .75 yr, % Median follow-up, yr TTR warfarin group, % Efficacy results, RR (95% CI) Stroke, embolic event (primary endpoint) Ischemic stroke Hemorrhagic stroke Safety results, RR (95% CI) ICH, RR (95% CI) GI bleeding, RR (95% CI) ROCKET-AF (57) ARISTOTLE (58) ENGAGE-AF (59) Dabigatran Direct thrombin inhibitor 14-17 .80 Rivaroxaban Xa inhibitor 7-11 25 Apixaban Xa inhibitor 8-14 Edoxaban Xa inhibitor 10-14 50 150 mg dabigatran twice a day or 110 mg dabigatran twice a day Dose-adjusted warfarin 18,113 NV-AF + CHADS $1 37 39 2.0 67 150 mg superior, 110 mg noninferior 150 mg: 0.66 (0.53-0.82), 110 mg: 0.91 (0.74-1.11) 150 mg: 0.76 (0.60-0.98), 110 mg: 1.11 (0.89-1.40) 150 mg: 0.26 (0.14-0.49), 110 mg: 0.31 (0.17-0.56) 150 mg noninferior, 110 mg superior 150 mg: 0.94 (0.81-1.07), 110 mg: 0.8 (0.69-0.93) 150 mg: 0.40 (0.27-0.60), 110 mg: 0.31 (0.20-0.47) 150 mg: 1.50 (1.19-1.89), 110 mg: 1.10 (0.86-1.41) 20 mg rivaroxaban OD 5 mg apixaban twice a day 60 mg edoxaban OD or 30 mg edoxaban OD Dose-adjusted warfarin 14,264 NV-AF + CHADS $2 40 43 1.9 58 noninferior Dose-adjusted warfarin 18,201 NV-AF + CHADS $1 36 31 1.8 66 superior Dose-adjusted warfarin 56,346 NV-AF + CHADS $2 38 40 2.8 65 60 mg superior, 30 mg noninferior 0.88 (0.75-1.03) 0.80 (0.67-0.95) 0.91 (0.73-1.13) 0.92 (0.75-1.14) 0.58 (0.37-0.92) 0.51 (0.35-0.75) Noninferior Superior 60 mg: 0.79 (0.63-0.99), 30 mg: 1.07 (0.87-1.31) 60 mg: 1.0 (0.83-1.19), 30 mg: 1.41 (1.19-1.67) 60 mg: 0.54 (0.38-0.77), 30 mg: 0.33 (0.22-0.50) 60 mg superior, 30 mg superior 1.03 (0.89-1.18) 0.70 (0.61-0.81) 0.66 (0.47-0.92) 0.42 (0.31-0.59) 1.46 (1.19-1.78) 0.88 (0.68-1.14) 60 mg: 0.80 (0.71-0.91), 30 mg: 0.47 (0.41-0.55) 60 mg: 0.47 (0.34-0.63), 30 mg: 0.30 (0.21-0.43) 60 mg: 1.23 (1.02-1.50), 30 mg: 0.67 (0.53-0.83) CHADS, congestive heart failure history; GI, gastrointestinal; NV-AF, nonvalvular atrial fibrillation; OD, once a day; RR, relative risk; TTR, percent time in therapeutic international normalized ratio (INR) range. State-of-the-Art Review Major bleed, RR (95% CI) 327 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Summary of ischemic stroke trial using novel anticoagulants State-of-the-Art Review FIG. 4. Forrest plot of novel anticoagulant trial results. A. Relative risk (RR) of stroke or systemic events with 95% CI. B. Meta-analysis of data from RELY (56), ROCKET-AF (57), ARISTOTLE (58), and ENGAGE-AF (59) for RR of outcome with 95% CI (60). NOAC, novel anticoagulant. there have been concerns about the lack of monitoring parameters and reversal agents. RELY (56) compared warfarin and dabigatran, a direct thrombin inhibitor, for the prevention of stroke and systemic embolism in patients with NV-AF. RELY randomized 18,113 patients to blinded doses of dabigatran or adjusted dose warfarin. Dabigatran (150 mg) was superior to warfarin in stroke and systemic embolism prevention (relative risk [RR], 0.66; 95% CI, 0.53-0.82), with similar rates of major hemorrhage. The efficacy for 110 mg of dabigatran was noninferior (RR, 0.91; 95% CI, 0.74- 1.11), but with significantly lower rates of bleeding than warfarin. Notably, only the 150 mg is approved for use in the United States, with a 75 mg renal dose which was not studied in the trial. ROCKET-AF (57) randomized AF patients to receive rivaroxaban or dose-adjusted warfarin. Inclusion criteria included 2 or more stroke risk factors and documented AF within 6 months. Rivaroxaban was similar to warfarin in the prevention of stroke and systemic embolism with reduction in rates of major bleeding, including intracranial hemorrhage. In ARISTOTLE (58), apixaban was demonstrated to be superior to warfarin in efficacy and safety for the prevention of stroke or systemic embolism in patients with NV-AF and at least one risk factor for stroke. The rate of primary outcome stroke or systemic embolism was reduced by 21% in the apixaban group compared with the warfarin group, with 31% less major bleeding and 11% fewer deaths from any cause. The rate of hemorrhagic stroke in the apixaban group was about half that in the warfarin group. Superiority of 328 apixaban in AF was consistent independent of risk of stroke or bleeding based on CHADS score for stroke risk (CHF = 1, hypertension = 1, age .75 = 1, diabetes mellitus = 1, history of stroke = 2) and HAS-BLED score for bleeding risk (hypertension = 1, renal disease = 1, history of stroke = 1, labile INR = 1, age .65 = 1, aspirin use = 1, alcohol use = 1), with perhaps the greatest benefit in patients at higher risk of bleeding. Apixaban is the only novel anticoagulant that was not associated with a significant increase in gastrointestinal (GI) bleeding risk at recommended dosages. In ENGAGE-AF (59), both low 30 mg and high 60 mg dosages of edoxaban were noninferior to warfarin in the prevention of stroke and systemic embolism and were associated with significantly lower rates of major bleeding, death, or intracranial hemorrhage. Although 60 mg of edoxaban was superior overall in stroke and systemic embolism (HR, 0.79; 95% CI, 0.63-0.99), for patients with normal renal function (CrCl . 95), 60 mg of edoxaban had higher risk of stroke than warfarin (HR, 1.41; 95% CI, 0.97-2.05). As part of its label, edoxaban is not recommended in patients with normal kidney function. Both 60 and 30 mg doses are approved in the United States. Among the novel anticoagulants, there is similar efficacy and safety. A 2014 meta-analysis of all 4 trials assessing 42,411 patients who received novel anticoagulants and 29,272 who received warfarin reported significant reduction in the risk of stroke or systemic embolism by 19% in those receiving one of the novel anticoagulants as compared with warfarin (RR, 0.81; 95% CI, 0.73-0.91) (60). The benefit was mainly driven by a large reduction in the risk of hemorrhagic stroke, which was reduced by half (RR, 0.49; 95% CI, Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review 0.38-0.64). This analysis included only the higher dose data for RELY and ENGAGE-AF (150 mg dabigatran and 60 mg edoxaban). The novel anticoagulants were similar to warfarin in the prevention of ischemic stroke and myocardial infarction. Overall, they were associated with reduction in hemorrhagic stroke and intracranial hemorrhage and demonstrated a more favorable safety profile compared with warfarin; however, they were associated with an increase in GI bleeding. As a group, novel anticoagulants were also associated with a reduction in all-cause mortality. The benefit of novel anticoagulants in reducing stroke or systemic embolic events was consistent across all subgroups, including stratification by age, sex, existing diabetes, previous stroke, renal function, and CHADS2 score, a measure of stroke risk in NV-AF based on risk factors (C = CHF, H = hypertension, A = age more than 75 years, D = diabetes, S = previous stroke or TIA). The lower dose regimens, 110 mg of dabigatran and 30 mg of edoxaban, had similar efficacy to warfarin for preventing all-cause stroke, but the 30-mg edoxaban was associated with higher rates of ischemic stroke (HR, 1.31; 1.19-1.67; P , 0.001). Criticism of the novel anticoagulants has focused on the lack of clinically available accurate monitoring parameters as well as specific antidotes to reverse anticoagulant effect. However, this is changing with the advent of reversal agents. The antidotes Idarucizumab (Praxbind), a monoclonal antibody that reverses thrombin inhibitor dabigatran, and Andexanet alfa, which binds the Xa inhibitors, are FDA approved with breakthrough designation (61). In addition to similar efficacy in stroke prevention and favorable bleeding profiles compared with warfarin, the novel anticoagulants offer convenience of use. CONCLUSIONS For patients with ischemia affecting the visual system, early diagnosis and triage to emergent care is crucial given the options for acute treatment now available including IV t-PA and endovascular therapy and subacutely carotid endarterectomy or carotid artery stenting for atherosclerotic disease of the ICA. Given the high recurrence rates of stroke after initial presentation, comprehensive diagnostic evaluation including long-term monitoring for AF in addition to efficacious and convenient therapies including the novel anticoagulants will improve secondary prevention. A key theme in both diagnosis and treatment is individualized risk assessment and optimizing patient selection for targeted therapies. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: B. Chancellor, K. Ishida; b. Acquisition of data: B. Chancellor, K. Ishida; c. Analysis and interpretation of data: B. Chancellor, K. Ishida. Category 2: a. Drafting the manuscript: B. Chancellor, K. Ishida; b. Revising it for intellectual content: B. Chancellor, K. Ishida. Category 3: a. Final approval of the completed manuscript: B. Chancellor, K. Ishida. Chancellor and Ishida: J Neuro-Ophthalmol 2017; 37: 320-331 REFERENCES 1. Lovett JK, Coull AJ, Rothwell PM. 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