Secondary Stroke Prevention and Management for the Neuro-Ophthalmologist

This article will serve as a comprehensive review of secondary prevention of ischemic stroke and central and branch retinal artery ischemia, which are closely linked pathologically and can be managed similarly to prevent further reoccurrence.

Disease of the Year 2020: Cerebrovascular Disorders Section Editors: Valerie Biousse, MD Koto Ishida, MD Secondary Stroke Prevention and Management for the Neuro-Ophthalmologist Line Abdul Rahman, MD, Ashley M. Wabnitz, MD, Tanya N. Turan, MD, MSCR Background: This article will serve as a comprehensive review of secondary prevention of ischemic stroke and central and branch retinal artery ischemia, which are closely linked pathologically and can be managed similarly to prevent further reoccurrence. Evidence acquisition: We conducted a search in PubMed with a focus on reports involving secondary stroke prevention. Results: This review discusses the etiologies of stroke and addresses the evidence for optimal therapies for secondary stroke prevention. We review recent clinical trials that will serve as an aid to the neuro-ophthalmologist in practice to determine the best next step in management and when to consider further referral to a stroke specialist. Conclusions: The optimal treatment to prevent stroke recurrence is determined by the etiology of stroke. After stroke workup, patients will typically be placed on proper medical therapy for the appropriate duration in addition to counseling on lifestyle modifications to reduce the risk of recurrent strokes. For complex patients, it is reasonable for providers to consider patient referral to stroke specialists for further aid in selection of appropriate medical therapy. Journal of Neuro-Ophthalmology 2020;40:463–471 doi: 10.1097/WNO.0000000000001133 © 2020 by North American Neuro-Ophthalmology Society T his article is a review of secondary prevention of ischemic stroke and central and branch retinal artery ischemia, which are closely linked pathologically and can be Department of Neurology, Medical University of South Carolina, Charleston, South Carolina A. M. Wabnitz receives salary support from the NIH for participation in a blood pressure management study (PACESETTER). T. N. Turan receives salary support from the NIH for participation in a carotid stenosis management study (CREST2) and a stroke trials network (StrokeNet), as well as compensation from Pfizer for serving as a blinded clinical events adjudicator for a diabetes drug trial. The authors report no conflicts of interest. Address correspondence to Line Abdul Rahman, MD, Department of Neurology, 96 Jonathan Lucas Street, Clinical Science Building 301, MSC 606, Medical University of South Carolina, Charleston, SC 29425-8050; E-mail: [e-mail] Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 managed similarly to prevent recurrence. This article will aid the practicing neuro-ophthalmologist in determining the best next step in management and when to consider referral to a stroke specialist. First, the approach to diagnosis and prevention of ischemic stroke will be discussed, followed by evidence for management of modifiable risk factors. GENERAL WORKUP AND APPROACH The optimal treatment to prevent stroke recurrence is determined by the etiology of stroke. Etiology is determined through urgent and detailed workup after an ischemic event and includes vascular imaging of the extracranial and intracranial arteries, structural heart imaging, continuous electrocardiographic monitoring to assess for arrhythmia, and evaluation of modifiable risk factors (e.g., lipid profile, hemoglobin A1c [HbA1c], and blood pressure [BP]). Large Artery Disease Large artery disease includes atherosclerosis and other vasculopathies, such as dissection and vasculitis. Atherosclerotic disease in the large arteries accounts for approximately 15%–20% of all ischemic strokes and is the leading cause of central and branch retinal artery occlusion. Atherosclerosis manifests as stenosis or occlusion on arterial imaging (1) and may result in ischemia if present in the extracranial (internal carotid or vertebral artery) or intracranial (anterior cerebral, middle cerebral, posterior cerebral, internal carotid, basilar, or vertebral) arteries. Extracranial Internal Carotid Artery Stenosis Randomized controlled trials (RCTs) have compared revascularization with medical therapy for symptomatic extracranial carotid disease. Medical therapy includes use of antiplatelet agents, statins, optimized BP control, and smoking cessation therapy. Revascularization techniques studied in RCTs include carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS). 463 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders The North American Symptomatic CEA Trial (NASCET), the European Carotid Surgery Trial (ECST), and the Veterans Administration Cooperative Symptomatic Carotid Stenosis Trial were RCTs that demonstrated the superiority of CEA over medical therapy alone for symptomatic patients with atherosclerotic severe (70%–99%) stenosis (2–4). These trials showed outcomes supporting CEA for severe stenosis with a number needed to treat (NNT) of 6– 9 patients. Based on the NASCET trial, the benefit of CEA is less for symptomatic moderate (50%–69%) stenosis, with an absolute risk reduction (ARR) of 6.5% and NNT of 15, with less benefit in women (5). Factors such as age, sex, medical comorbidities, and surgeon’s perioperative complication rate should be considered when deciding whether to proceed with carotid revascularization (6). Revascularization is not recommended when the degree of stenosis is mild (,50%). Although the NASCET study showed that the risk of cerebral stroke was lower in patients presenting with transient monocular visual loss (TMVL) than in those with a cerebral transient ischemic attack (TIA), patients with definite vascular TMVL and severe carotid stenosis should be considered for CEA similar to those with transient neurologic symptoms (7). The Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) was a RCT that compared CAS with CEA for symptomatic and asymptomatic carotid stenosis (8) and found no difference in recurrent stroke rates between patients treated with CAS and CEA. When analyzing a periprocedural risk, patients who underwent CAS had lower rates of periprocedural myocardial infarctions but higher rates of stroke, compared with patients who underwent CEA. CAS is indicated as an alternative to CEA for symptomatic patients at an average or low risk of complications associated with endovascular intervention (6) as well as stenosis due to radiation therapy, contralateral vocal cord paralysis, previous radical neck surgery, and presence of tracheostomy (9). However, in practice, CAS may be limited to patients who are at a high risk for CEA (e.g., previous carotid procedure, cardiac conditions, etc.) due to restrictions in insurance reimbursement (10). Regarding timing of revascularization, pooled data from the ECST and NASCET showed that for severe carotid stenosis, the ARR for an ipsilateral stroke or any stroke or death within 30 days of trial surgery decreased substantially from 30% when surgery occurred within 2 weeks of the most recent cerebrovascular event to 18% at 2–4 weeks and 11% at 4–12 weeks (11). Therefore, if revascularization is considered, it should be performed within 2 weeks if there is no contraindication (6). This is also true for patients with acute retinal ischemia (7). Transcarotid artery revascularization is a new, hybrid surgical stenting procedure using a flexible sheath that is placed directly into the internal carotid artery connected to a neuroprotection system that reverses blood flow away from the brain. This procedure avoids traversing a poten464 tially atherosclerotic aortic arch as compared to CAS and collects fragments of plaque that may dislodge during the procedure. Although registry data collection is underway, a RCT has not been completed to compare the efficacy of this procedure with CEA or CAS. Intracranial Atherosclerotic Stenosis Intracranial atherosclerotic stenosis (ICAS) is highly prevalent worldwide, with increased rates in Blacks, Hispanics, and Asians. ICAS has a high risk of recurrent stroke (12,13), particularly among those with severe stenosis (70%–99%) and recent TIA or stroke (14). The Warfarin–Aspirin Symptomatic Intracranial Disease study was a RCT that showed aspirin was safer and equally as effective as warfarin at reducing recurrence of stroke over a mean duration of 1.8 years in patients with 50%–99% intracranial stenosis (15), resulting in aspirin becoming the preferred treatment. The Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial aimed to further evaluate the best treatment practices for severe ICAS (16). The SAMMPRIS trial showed that aggressive medical management (AMM) was superior to percutaneous transluminal angioplasty and stenting (PTAS) plus AMM. The substantially lower than a projected risk of the primary end point in the AMM arm of SAMMPRIS has made AMM as used in SAMMPRIS (short-term dual antiplatelet therapy, intensive management of systolic blood pressure and lowdensity lipoprotein (LDL) cholesterol, and a lifestyle program that emphasizes exercise) the standard of care for patients with ICAS (6). Since SAMMPRIS, 2 other RCTs failed to show a benefit of PTAS for stroke prevention in ICAS (17,18). Given that research on the optimal treatment of ICAS is ongoing, we recommend referral of high-risk patients with severe stenosis to a stroke neurologist. Aortic Arch Atheroma Embolism from atherosclerotic disease of the aortic arch may also cause strokes, particularly when the plaque is $4 mm in thickness (19–22). Atheromas can be diagnosed with the use of a transesophageal echocardiogram or with the use of vessel imaging of the aortic arch through computed tomographic angiography. A retrospective study showed that treatment with statins seems to be effective at reducing recurrent strokes in patients with aortic arch atheromas with a relative risk reduction of 59% (23). The Aortic Arch Related Cerebral Hazard trial aimed to assess the use of warfarin vs clopidogrel plus aspirin in patients with aortic arch atheroma; however, it was discontinued early because of low recruitment and results were inconclusive due to low power of the study (24). Post hoc analysis of a large trial of patients with embolic stroke of unknown source found no difference in the recurrent stroke rate among those with aortic arch atheroma randomized to rivaroxaban or aspirin (25). The accompanying meta-analysis Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders of RCTs comparing anticoagulation with antiplatelet agents for secondary stroke prevention in patients with complex aortic arch atherosclerosis did not find a significant difference between the treatments either (25). In most cases, high-dose statins and aspirin are recommended. Other Vasculopathies Nonatherosclerotic vasculopathies (e.g., dissection, vasculitis, and radiation) can also cause ischemic strokes. Dissection of the carotid or vertebral arteries is rare overall but more common in younger stroke patients. Dissection can be spontaneous or induced by trauma. The Cervical Artery Dissection in Stroke Study found no difference in recurrent stroke risk reduction between antiplatelet therapy and anticoagulation in patients with stroke due to dissection, but the potential risk of bleeding with anticoagulation may sway providers toward antiplatelet agents (26). Dissections usually spontaneously heal and an antithrombotic agent should be maintained in patients for at least 3–6 months, if not lifelong, including in patients presenting with an isolated Horner syndrome to prevent subsequent cerebral or ocular arterial ischemic events. Patients with recurrent cerebral ischemic events due to dissection despite medical therapy may be candidates for endovascular therapy under the advisement of a stroke neurologist. CARDIOEMBOLIC Ischemic strokes secondary to embolism from the heart are termed cardioembolic (1). Patients should undergo transthoracic echocardiograms and continuous heart rhythm monitoring to evaluate for a cardioembolic source, including atrial fibrillation (AF), atrial cardiopathy, heart failure, and a patent foramen ovale (PFO). Other cardioembolic causes of stroke, such as left atrial appendage thrombus or endocarditis, may only be seen using advanced cardiac imaging with transesophageal echo, cardiac MRI, or cardiac computed tomography. Therefore, advanced cardiac imaging should be considered in patients for whom there is a high suspicion for a cardioembolic source but no cause identified (27). Atrial Fibrillation AF is the most common cardioembolic cause of stroke, particularly for older patients. AF is usually asymptomatic and can go undetected and therefore the stroke risk could be underestimated (28). In a large meta-analysis, newly diagnosed AF was detected in approximately 24% of patients with stroke (29). About 10% of patients with acute cerebrovascular events will have new AF detected during their hospitalization (30) and another 11% who undergo 30 days of continuous electrocardiographic monitoring will have AF (31). Therefore, for patients with cryptogenic cerebrovascular events, rhythm monitoring for at least 30 days is recommended (6). Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 If AF is detected in a patient with a cerebrovascular event, oral anticoagulation (OAC) is recommended, unless contraindicated. Early initiation of OAC for preventing early recurrence of stroke should be balanced with a risk of hemorrhagic transformation. Initiation of OAC within 2 weeks of stroke is recommended, except in patients with large infarcts or other risk factors for hemorrhage, such as uncontrolled hypertension or hemorrhagic transformation on initial imaging (32). Patients with TIA due to AF and no other confounding factors may be started on OAC immediately. Multiple clinical trials have demonstrated the superior therapeutic effect of warfarin compared with placebo in the prevention of thromboembolic events among patients with nonvalvular AF (33). Both factor Xa inhibitors (rivaroxaban, apixaban, and endoxaban) and direct thrombin inhibitors (dabigatran) have been evaluated and found to be equally or more effective than warfarin for stroke prevention (34–36) and are indicated for stroke prevention in patients with nonvalvular AF (6). Selection of anticoagulation should be based on individualized risk factors (e.g., cost, renal function, etc.). For patients with contraindications to long-term OAC, referrals to a stroke neurologist are recommended to discuss percutaneous closure of the left atrial appendage with the WATCHMAN device (37). The same recommendation can be made for patients with ocular ischemia and AF, although no RTC has specifically addressed this issue (38). Atrial Cardiopathy New evidence suggests that some cryptogenic strokes may arise from atrial cardiopathy in the absence of AF (39,40) due to atrial derangements resulting in left atrial thromboembolism, not the dysrhythmia itself. Markers of atrial dysfunction, such as an increased left atrial size on an echocardiogram and serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), have been associated with ischemic cardioembolic stroke (41). The ongoing AtRial Cardiopathy and Antithrombic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial is a multicenter RCT that compares apixaban with aspirin for stroke prevention in patients who have evidence of atrial cardiopathy and recent cryptogenic stroke. Other Cardioembolic Cardiomyopathy also increases the risk of stroke. The Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found that among patients with a left ventricle ejection fraction of #35% (42), warfarin reduced the risk of ischemic stroke compared with aspirin. However, warfarin did not decrease the combined primary end point (stroke and death) and increased bleeding, raising uncertainty about its overall benefit. Left ventricle thrombus, another cardioembolic source, can occur in the setting of anteroapical wall motion abnormalities, low ejection 465 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders fraction, or after a large myocardial infarction (usually within 1–2 weeks but up to 3 months) (43). Warfarin is recommended for patients with left ventricle thrombus (6) because newer anticoagulants (e.g., Xa inhibitors) are not well studied outside of AF. A PFO is associated with an increased risk of stroke related to possible paradoxical embolism, particularly in younger patients. Although PFO closure for stroke prevention has historically been a topic of debate, recent RCTs showed benefit in a select subset of stroke patients with moderate or large right-to-left shunts and otherwise unexplained stroke (44–49). The risk of paradoxical embolism (RoPE) score is an assessment tool to determine probability that a PFO may be responsible for stroke of unknown cause (50). However, the management of PFO-related stroke is complex and must involve both a stroke neurologist and cardiologist (51). SMALL VESSEL DISEASE Small artery (e.g., lenticulostriate or pontine perforator) occlusions aka “lacunar infarcts” account for about 30% of strokes and are strongly associated with diabetes and hypertension (1). Lacunar infarct diagnosis requires radiological imaging showing a subcortical lesion (e.g., basal ganglia, brainstem, etc.) of ,1.5-cm diameter associated with a small vessel syndrome (e.g., ataxic hemiparesis, etc.). Patients with lacunar infarcts are treated with antiplatelet agents for secondary stroke prevention and counseled on risk factor management. OTHERS Patients who have undergone extensive workup with unclear etiology of stroke are classified as cryptogenic. Patients with cryptogenic stroke should undergo prolonged cardiac rhythm monitoring to further exclude AF. All cryptogenic patients should be prescribed long-term antiplatelet therapy for stroke prevention. Rare causes of stroke include hypercoagulable states, such as inherited thrombophilia, antiphospholipid antibody syndrome, or presence of malignancy. Hypercoagulable testing is not routinely recommended but should be pursued in younger patients with an unknown cause of stroke. Anticoagulation is considered in some stroke patients who are found to be hypercoaguable in consultation with a hematologist (6). MEDICAL MANAGEMENT After stroke workup, patients should be placed on appropriate medical therapy and counselled on lifestyle modification to reduce recurrent stroke. Complex patients should be referred to a stroke neurologist for further guidance on appropriate medical therapy. Antiplatelets are the first line for stroke prevention in patients without a cardioembolic source. The use of anticoagulation is currently limited to those indications previously described. 466 Antiplatelet Stroke risk reduction from aspirin is approximately 15% (52). Aspirin monotherapy (doses of 50–325 mg/d) is recommended for secondary stroke prevention (6), but the optimal dose in this range is debated. Weight-based dosing is supported by a recent pooled analysis of more than 100,000 clinical trial participants that reported patients weighing .70 kg did not benefit from aspirin doses ,100 mg/day for prevention of vascular events, including stroke (53). Given that many stroke patients are overweight or obese, the use of higher doses of aspirin (325 mg/day) may be a more effective approach for stroke prevention in these patients. Clopidogrel was compared with aspirin in the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, which showed the combined outcome (ischemic stroke, myocardial infarction, and vascular death) was significantly lower with clopidogrel but no significant difference for stroke prevention (54). Clopidogrel is a reasonable, safe alternative to aspirin (6) but may have reduced efficacy in patients with genetic polymorphisms that interfere with its metabolism (55). Short-term dual antiplatelet therapy can be appropriate in certain stroke subgroups, but long-term dual antiplatelet therapy is not recommended (56). Two large RCTs compared short-term dual antiplatelet therapy with clopidogrel and aspirin with aspirin monotherapy in patients with minor stroke or high-risk TIA, the Clopidogrel in High-risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial (POINT) (57,58). The dual antiplatelet therapy group in both trials showed a lower rate of major ischemic events but a higher rate of hemorrhage compared with the monotherapy group. A meta-analysis of these 2 trials showed the benefit of dual antiplatelet therapy occurs predominantly within the first 21 days with no substantial benefit afterward and an increased risk of bleeding (59). As a result, dual antiplatelet therapy is recommended for up to 21 days in qualifying patients. These trials excluded patients with isolated visual symptoms in the study protocol, thus the treatment strategy for acute with acute central and branch retinal artery occlusion and TMVL is unclear. The Acute Stroke or TIA Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial is a recent study that evaluated the use of dual antiplatelet therapy with ticagrelor and aspirin for 30 days compared with aspirin alone in patients with mild-to-moderate stroke or TIA (60). Patients on combination of ticagrelor and aspirin vs aspirin alone had a lower rate of stroke, a higher rate of severe hemorrhage, and similar disability rates to aspirin. In addition to patients with minor stroke or TIA, the use of dual antiplatelet therapy in patients with severe ICAS is also recommended up to 90 days (based on SAMMPRIS (61)), but the optimal duration is unknown. Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders MODIFIABLE RISK FACTORS The Global Burden of Disease study showed that 91% of stroke risk could be attributed to modifiable risk factors, such as hypertension, hyperglycemia, hyperlipidemia, and obesity (62). While before 2008, the recurrent stroke rate in the United States seemed to be declining because of improvements in risk factor management (63), the decline has stopped or reversed in some regions and ethnic groups since 2013 (64). Hypertension Hypertension is the most common modifiable risk factor for stroke (65) and the population attributable risk of stroke is 50% in some racial and ethnic groups (66,67). The 2017 AHA Hypertension Clinical Practice Guideline recommends intensive BP, targeting ,130/80 mm Hg for recurrent stroke prevention in most patients based on analyses of previous trials (68). In 2019, the Recurrent Stroke Prevention Clinical Outcome Study (RESPECTS) showed a tendency toward lower recurrent stroke rates in the intensive BP management group (,120/80) compared with the standard group (,140/90) (69). The concurrent meta-analysis including 3 other RCTs (70–72) showed that intensive BP treatment was more effective at preventing recurrent stroke than standard BP targets (69). Several other meta-analyses have shown similar benefit for more intensive BP targets in stroke patients (73,74). Several categories of BP-lowering medications are available, and specific patient characteristics (e.g., cardiac disease, diabetes mellitus, etc.) should be considered when choosing a regimen. For secondary stroke prevention, evidence supports the use of thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers (74–77), but other guideline-based therapies including calcium-channel blockers may be considered (6,78). Hyperlipidemia Hyperlipidemia treatment is a critical aspect of stroke prevention, with lifestyle interventions and statins as the cornerstone of therapy for patients with atherosclerotic vascular disease, including stroke (79). The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial showed that among patients with stroke or TIA and LDL 100–190 mg/dL, randomization to atorvastatin 80 mg conferred an ARR of 2.2% for recurrent stroke vs placebo (80). A SPARCL post hoc analysis showed that LDL-C ,70 mg/dL was associated with a 28% relative risk reduction of stroke (81). Similarly, in a recent RCT of patients with stroke or TIA who had atherosclerotic disease, patients randomized to a target LDL of ,70 mg/dL had a lower risk of recurrent events than those with a target of 90–100 mg/dL (82). Diabetes Mellitus Diabetes Mellitus (DM) is an independent risk factor for stroke recurrence as shown in a meta-analysis of 18 studies Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 involving 43,899 participants with previous stroke (83). All patients with stroke or TIA should be screened for DM, usually with HbA1C (6). Patients should undergo DM selfmanagement education and lifestyle modification. Metformin can be initiated and repeat HbA1C is recommended after 3 months of treatment. The current recommended American Diabetes Association target HbA1C is #7% for most patients with DM (84) but may be individualized based on other factors. The Insulin Resistance Intervention After Stroke trial showed stroke and TIA patients with insulin resistance randomized to pioglitazone had lower rates of recurrent stroke (85) but also had higher rates of adverse events (e.g., weight gain, edema, bone fractures, etc.) compared with the placebo group, limiting its use in practice. Sleep Apnea Obstructive sleep apnea (OSA) is associated with a stroke risk (86) and may be more prevalent after stroke (87). The diagnosis of OSA is made using the apnea–hypopnea index, which describes the number of air flow reductions per hour observed during sleep. The American Academy of Sleep Medicine’s Adult OSA Task Force recommend stroke patients with symptoms of OSA should receive polysomnography (88). Treatment with continuous positive airway pressure should be considered in conjunction with a sleep specialist for patients with stroke and OSA. The ongoing NIH-funded Sleep for Stroke Management and Recovery Trial (Sleep SMART) is assessing whether treatment of OSA with positive airway pressure shortly after stroke or TIA reduces recurrence of stroke and improves outcomes. Sedentary Lifestyle Systematic reviews and meta analyses have shown that physical activity is effective for primary prevention of stroke and mortality (89,90), but evidence for the benefit of physical activity for secondary stroke prevention is limited to patients with ICAS (91). The 2018 Physical Activity Guideline recommends at least 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity aerobic activity and muscle-strengthening activities at least 2 days per week (92,93). However, physical activity may be challenging for stroke survivors because of disabilities such as hemiparesis or spasticity, resulting in high rates of sedentary lifestyle (94). Stroke patients who are willing and able to start activity may be referred to a comprehensive, behaviorally oriented program (6). For those with disabilities, it is reasonable to have supervision by physical therapy or cardiac rehabilitation. CONCLUSION Completing a thorough stroke workup is essential in identifying stroke etiology (large artery atherosclerosis, cardioembolic, small vessel disease, cryptogenic, or others) 467 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders to offer the best, personalized secondary prevention approach for patients. After stroke workup, patients should receive medical therapy for the appropriate duration in combination with lifestyle modification to optimally reduce the risk of recurrent strokes. The combination of aspirin and dietary modification, exercise, statin use, and antihypertensive therapy leads to an estimated 80% relative risk reduction of recurrent stroke (95). Unfortunately, despite the recognized effectiveness of these measures for secondary stroke prevention, up to 70% of patients with coronary artery disease and cerebrovascular disease are undermanaged when it comes to an optimal control of risk factors, with particularly a poor control of individual risk factors among patients with cerebrovascular disease (96–98). Although secondary prevention is not as well studied for ocular ischemia, patients with acute central and branch retinal artery occlusion and TMVL should also be managed with antithrombotic medications and risk factor controls (7). For complex patients, providers should refer to stroke specialists for further aid in selection of appropriate medical therapy. REFERENCES 1. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE III. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41. 2. Barnett HJM, Taylor DW, Haynes RB, Sackett DL, Peerless SJ, Ferguson GG, Fox AJ, Rankin RN, Hachinski VC, Wiebers DO, Eliasziw M. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–453. 3. European Carotid Surgery Trialists Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. European Carotid Surgery Trialists’ Collaborative Group. Lancet. 1991;337:1235–1243. 4. Mayberg MR, Wilson SE, Yatsu F, Weiss DG, Messina L, Hershey LA, Colling C, Eskridge J, Deykin D, Winn HR. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veterans Affairs Cooperative Studies Program 309 Trialist Group. JAMA. 1991;266:3289– 3294. 5. Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE, Spence JD. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 1998;339:1415–1425. 6. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC, Kasner SE, Kittner SJ, Mitchell PH, Rich MW, Richardson D, Schwamm LH, Wilson JA. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2014;45:2160–2236. 7. Biousse V, Nahab F, Newman NJ. Management of acute retinal ischemia: follow the guidelines! Ophthalmology. 2018;125:1597–1607. 8. Brott TG, Hobson RW, Howard G, Roubin GS, Clark WM, Brooks W, Mackey A, Hill MD, Leimgruber PP, Sheffet AJ, Howard VJ, Moore WS, Voeks JH, Hopkins LN, Cutlip DE, Cohen DJ, Popma JJ, Ferguson RD, Cohen SN, Blackshear JL, Silver FL, Mohr JP, Lal BK, Meschia JF. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363:11–23. 468 9. Hobson RW, Mackey WC, Ascher E, Murad MH, Calligaro KD, Comerota AJ, Montori VM, Eskandari MK, Massop DW, Bush RL, Lal BK, Perler BA. Management of atherosclerotic carotid artery disease: clinical practice guidelines of the Society for Vascular Surgery. J Vasc Surg. 2008;48:480–486. 10. Decision Memo for Carotid Artery Stenting (CAG-00085R). Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/medicare-coveragedatabase/details/nca-decision-memo.aspx?NCAId=157. Accessed May 30, 2020. 11. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet. 2004;363:915–924. 12. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke. 2008;39:2396–2399. 13. Chimowitz MI. Endovascular treatment for acute ischemic stroke—still unproven. N Engl J Med. 2013;368:952–955. 14. Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Benesch CG, Sila CA, Jovin TG, Romano JG, Cloft HJ. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation. 2006;113:555–563. 15. Chimowitz MI, Kokkinos J, Strong J, Brown MB, Levine SR, Silliman S, Pessin MS, Weichel E, Sila CA, Furlan AJ. The warfarin-aspirin symptomatic intracranial disease study. Neurology. 1995;45:1488–1493. 16. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS, Lutsep HL, Barnwell SL, Waters MF, Hoh BL, Hourihane JM, Levy EI, Alexandrov AV, Harrigan MR, Chiu D, Klucznik RP, Clark JM, McDougall CG, Johnson MD, Pride GL Jr, Torbey MT, Zaidat OO, Rumboldt Z, Cloft HJ. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993–1003. 17. Miao Z, Jiang L, Wu H, Bao Y, Jiao L, Li S, Wu J, Hua Y, Li Y, Zhu J, Zhu F, Liu X, Ling F. Randomized controlled trial of symptomatic middle cerebral artery stenosis. Stroke. 2012;43:3284–3290. 18. Zaidat OO, Fitzsimmons BF, Woodward BK, Wang Z, KillerOberpfalzer M, Wakhloo A, Gupta R, Kirshner H, Megerian JT, Lesko J, Pitzer P, Ramos J, Castonguay AC, Barnwell S, Smith WS, Gress DR. Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial. JAMA. 2015;313:1240–1248. 19. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med. 1996;334:1216–1221. 20. Amarenco P, Duyckaerts C, Tzourio C, Hénin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med. 1992;326:221–225. 21. Di Tullio MR, Sacco RL, Gersony D, Nayak H, Weslow RG, Kargman DE, Homma S. Aortic atheromas and acute ischemic stroke: a transesophageal echocardiographic study in an ethnically mixed population. Neurology. 1996;46:1560–1566. 22. Jones EF, Kalman JM, Calafiore P, Tonkin AM, Donnan GA. Proximal aortic atheroma. An independent risk factor for cerebral ischemia. Stroke. 1995;26:218–224. 23. Tunick PA, Nayar AC, Goodkin GM, Mirchandani S, Francescone S, Rosenzweig BP, Freedberg RS, Katz ES, Applebaum RM, Kronzon I. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol. 2002;90:1320–1325. 24. Amarenco P, Davis S, Jones EF, Cohen AA, Heiss WD, Kaste M, Laouénan C, Young D, Macleod M, Donnan GA. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke. 2014;45:1248–1257. 25. Ntaios G, Pearce LA, Meseguer E, Endres M, Amarenco P, Ozturk S, Lang W, Bornstein NM, Molina CA, Pagola J, Mundl H, Berkowitz SD, Liu YY, Sen S, Connolly SJ, Hart RG. Aortic arch atherosclerosis in patients with embolic stroke of Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. undetermined source: an exploratory analsysis of the NAVIGATE ESUS trial. Stroke. 2019;50:3184–3190. CADISS Trial Investigtors. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol. 2015;14:361– 367. Camen S, Haeusler KG, Schnabel RB. Cardiac imaging after ischemic stroke or transient ischemic attack. Curr Neurol Neurosci Rep. 2020;20:36-. Elijovich L, Josephson SA, Fung GL, Smith WS. Intermittent atrial fibrillation may account for a large proportion of otherwise cryptogenic stroke: a study of 30-day cardiac event monitors. J Stroke Cerebrovasc Dis. 2009;18:185–189. Sposato LA, Cipriano LE, Saposnik G, Ruiz Vargas E, Riccio PM, Hachinski V. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and metaanalysis. Lancet Neurol. 2015;14:377–387. Rizos T, Guntner J, Jenetzky E, Marquardt L, Reichardt C, Becker R, Reinhardt R, Hepp T, Kirchhof P, Aleynichenko E, Ringleb P, Hacke W, Veltkamp R. Continuous stroke unit electrocardiographic monitoring versus 24-hour Holter electrocardiography for detection of paroxysmal atrial fibrillation after stroke. Stroke. 2012;43:2689–2694. Flint AC, Banki NM, Ren X, Rao VA, Go AS. 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;43:2788–2790. Lansberg MG, O’Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE, Sonnenberg FA, Schulman S, Vandvik PO, Spencer FA, Alonso-Coello P, Guyatt GH, Akl EA. Antithrombotic and thrombolytic therapy for ischemic stroke: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141:e601S–e36S. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–867. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139– 1151. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American college of cardiology/American heart association Task Force on clinical practice guidelines and the heart rhythm society in collaboration with the society of thoracic surgeons. Circulation. 2019;140:e125–e51. Zarkali A, Cheng SF, Dados A, Simister R, Chandratheva A. Atrial fibrillation: an underestimated cause of ischemic monocular visual loss? J Stroke Cerebrovasc Dis. 2019;28:1495–1499. Kamel H, Healey JS. Cardioembolic stroke. Circ Res. 2017;120:514–526. Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 40. Kamel H, Okin PM, Elkind MS, Iadecola C. Atrial fibrillation and mechanisms of stroke: time for a new model. Stroke. 2016;47:895–900. 41. Kamel H, Bartz TM, Elkind MSV, Okin PM, Thacker EL, Patton KK, Stein PK, deFilippi CR, Gottesman RF, Heckbert SR, Kronmal RA, Soliman EZ, Longstreth WT. Atrial cardiopathy and the risk of ischemic stroke in the CHS (cardiovascular health study). Stroke. 2018;49:980–986. 42. Homma S, Thompson JLP, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, Ammon SE, Graham S, Sacco RL, Mann DL, Mohr JP, Massie BM, Labovitz AJ, Anker SD, Lok DJ, Ponikowski P, Estol CJ, Lip GYH, Di Tullio MR, Sanford AR, Mejia V, Gabriel AP, del Valle ML, Buchsbaum R. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med. 2012;366:1859–1869. 43. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, Alonso-Coello P, Akl EA, Lansberg MG, Guyatt GH, Spencer FA. Primary and secondary prevention of cardiovascular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141:e637S–e68S. 44. Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, Felberg R, Herrmann H, Kar S, Landzberg M, Raizner A, Wechsler L. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366:991–999. 45. Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D, Dudek D, Andersen G, Ibrahim R, Schuler G, Walton AS, Wahl A, Windecker S, Jüni P. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368:1083–1091. 46. Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA, Marks DS, Tirschwell DL. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368:1092–1100. 47. Søndergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, Settergren M, Sjöstrand C, Roine RO, Hildick-Smith D, Spence JD, Thomassen L. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377:1033–1042. 48. Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, Arquizan C, Béjot Y, Vuillier F, Detante O, Guidoux C, Canaple S, Vaduva C, Dequatre-Ponchelle N, Sibon I, Garnier P, Ferrier A, Timsit S, Robinet-Borgomano E, Sablot D, Lacour JC, Zuber M, Favrole P, Pinel JF, Apoil M, Reiner P, Lefebvre C, Guérin P, Piot C, Rossi R, Dubois-Randé JL, Eicher JC, Meneveau N, Lusson JR, Bertrand B, Schleich JM, Godart F, Thambo JB, Leborgne L, Michel P, Pierard L, Turc G, Barthelet M, Charles-Nelson A, Weimar C, Moulin T, Juliard JM, Chatellier G. Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke. N Engl J Med. 2017;377:1011– 1021. 49. Lee PH, Song JK, Kim JS, Heo R, Lee S, Kim DH, Song JM, Kang DH, Kwon SU, Kang DW, Lee D, Kwon HS, Yun SC, Sun BJ, Park JH, Lee JH, Jeong HS, Song HJ, Kim J, Park SJ. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO trial. J Am Coll Cardiol. 2018;71:2335–2342. 50. Kent DM, Thaler DE. The Risk of Paradoxical Embolism (RoPE) Study: developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke. Trials. 2011;12:185. 51. Stone DK, Buchwald N, Wilson CA. Updates in the management of cryptogenic stroke and patent foramen ovale. J Neuroophthalmol. 2020;40:60–66. 52. Johnson ES, Lanes SF, Wentworth CE III, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the doseresponse effect of aspirin on stroke. Arch Intern Med. 1999;159:1248–1253. 53. Rothwell PM, Cook NR, Gaziano JM, Price JF, Belch JFF, Roncaglioni MC, Morimoto T, Mehta Z. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018;392:387–399. 469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders 54. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329–1339. 55. FDA Drug Safety Communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. Available at: https://www.fda.gov/drugs/postmarketdrug-safety-information-patients-and-providers/fda-drug-safetycommunication-reduced-effectiveness-plavix-clopidogrelpatients-who-are-poor. Accessed July 28, 2020. 56. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebocontrolled trial. Lancet. 2004;364:331–337. 57. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. 58. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215–225. 59. Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao X, Meurer WJ, Liu L, Dietrich D, Wang Y, Johnston SC. Outcomes associated with clopidogrel-aspirin use in minor stroke or transient ischemic attack: a pooled analysis of clopidogrel in high-risk patients with acute non-disabling cerebrovascular events (CHANCE) and platelet-oriented inhibition in new TIA and minor ischemic stroke (point) trials. JAMA Neurol. 2019;76:1466–1473. 60. Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med. 2020;383:207–217. 61. Chaturvedi S, Turan TN, Lynn MJ, Derdeyn CP, Fiorella D, Janis LS, Chimowitz MI, Investigators ST. Do patient characteristics explain the differences in outcome between medically treated patients in SAMMPRIS and WASID? Stroke. 2015;46:2562– 2567. 62. Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh S, Mensah GA, Norrving B, Shiue I, Ng M, Estep K, Cercy K, Murray CJL, Forouzanfar MH. Global burden of diseases I, risk factors S, stroke experts writing G. Global burden of stroke and risk factors in 188 countries, during 1990–2013: a systematic analysis for the global burden of disease study 2013. Lancet Neurol. 2016;15:913–924. 63. Fang MC, Coca Perraillon M, Ghosh K, Cutler DM, Rosen AB. Trends in stroke rates, risk, and outcomes in the United States, 1988 to 2008. Am J Med. 2014;127:608–615. 64. Yang Q, Tong X, Schieb L, Vaughan A, Gillespie C, Wiltz J, King SC, Odom E, Merritt R, Hong Y, George MG. Vital signs: recent trends in stroke death rates—United States, 2000–2015. MMWR Morb Mortal Wkly Rep. 2017;66:933–939. 65. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387:957– 967. 66. Clark D III, Colantonio LD, Min YI, Hall ME, Zhao H, Mentz RJ, Shimbo D, Ogedegbe G, Howard G, Levitan EB, Jones DW, Correa A, Muntner P. Population-attributable risk for cardiovascular disease associated with hypertension in black adults. JAMA Cardiol. 2019:1–9. 67. Willey JZ, Moon YP, Kahn E, Rodriguez CJ, Rundek T, Cheung K, Sacco RL, Elkind MSV. Population attributable risks of hypertension and diabetes for cardiovascular disease and stroke in the northern Manhattan study. J Am Heart Assoc. 2014;3:e001106–e. 68. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith 470 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e127–e248. Kitagawa K, Yamamoto Y, Arima H, Maeda T, Sunami N, Kanzawa T, Eguchi K, Kamiyama K, Minematsu K, Ueda S, Rakugi H, Ohya Y, Kohro T, Yonemoto K, Okada Y, Higaki J, Tanahashi N, Kimura G, Umemura S, Matsumoto M, Shimamoto K, Ito S, Saruta T, Shimada K. Effect of standard vs intensive blood pressure control on the risk of recurrent stroke: a randomized clinical trial and meta-analysis. JAMA Neurol. 2019;76:1309–1318. Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382:507–515. Mant J, McManus RJ, Roalfe A, Fletcher K, Taylor CJ, Martin U, Virdee S, Greenfield S, Hobbs FDR. Different systolic blood pressure targets for people with history of stroke or transient ischaemic attack: PAST-BP (Prevention after Stroke—blood Pressure) randomised controlled trial. BMJ. 2016;352:i708. Bath PM, Scutt P, Blackburn DJ, Ankolekar S, Krishnan K, Ballard C, Burns A, Mant J, Passmore P, Pocock S, Reckless J, Sprigg N, Stewart R, Wardlaw JM, Ford GA. Intensive versus guideline blood pressure and lipid lowering in patients with previous stroke: main results from the pilot ’prevention of decline in cognition after stroke trial’ (PODCAST) randomised controlled trial. PLoS One. 2017;12:e0164608. Katsanos AH, Filippatou A, Manios E, Deftereos S, Parissis J, Frogoudaki A, Vrettou A-R, Ikonomidis I, Pikilidou M, Kargiotis O, Voumvourakis K, Alexandrov AW, Alexandrov AV, Tsivgoulis G. Blood pressure reduction and secondary stroke prevention: a systematic review and metaregression analysis of randomized clinical trials. Hypertension. 2017;69:171–179. Zonneveld TP, Richard E, Vergouwen MD, Nederkoorn PJ, de Haan R, Roos YB, Kruyt ND. Blood pressure-lowering treatment for preventing recurrent stroke, major vascular events, and dementia in patients with a history of stroke or transient ischaemic attack. Cochrane Database Syst Rev. 2018;7:Cd007858. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–1041. PATS Collaborating Group. Post-stroke antihypertensive treatment study. A preliminary result. Chin Med J (Engl). 1995;108:710–717. Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events. Stroke. 2003;34:2741–2748. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Himmelfarb CD, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/ AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American college of cardiology/American heart association Task Force on clinical practice guidelines. Hypertension. 2018;71:1269–1324. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, Ferranti Sd, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American college of Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders 80. 81. 82. 83. 84. 85. 86. 87. 88. cardiology/American heart association Task Force on clinical practice guidelines. Circulation. 2019;139:e1082–e143. Amarenco PB J, Callahan A III, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–559. Amarenco P, Goldstein LB, Szarek M, Sillesen H, Rudolph AE, Callahan A III, Hennerici M, Simunovic L, Zivin JA, Welch KM. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2007;38:3198–3204. Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Béjot Y, Cabrejo L, Cha J-K, Ducrocq G, Giroud M, Guidoux C, Hobeanu C, Kim YJ, Lapergue B, Lavallée PC, Lee BC, Lee KB, Leys D, Mahagne MH, Meseguer E, Nighoghossian N, Pico F, Samson Y, Sibon I, Steg PG, Sung SM, Touboul PJ, Touzé E, Varenne O, Vicaut É, Yelles N, Bruckert E. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2019;382:9–19. Shou J, Zhou L, Zhu S, Zhang X. Diabetes is an independent risk factor for stroke recurrence in stroke patients: a metaanalysis. J Stroke Cerebrovasc Dis. 2015;24:1961–1968. Chamberlain JJ, Rhinehart AS, Shaefer CF Jr, Neuman A. Diagnosis and management of diabetes: synopsis of the 2016 American diabetes association standards of medical care in diabetes. Ann Intern Med. 2016;164:542–552. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O’Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321–1331. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D’Agostino RB, Newman AB, Lebowitz MD, Pickering TG. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA. 2000;283:1829–1836. Hermann DM, Bassetti CL. Role of sleep-disordered breathing and sleep-wake disturbances for stroke and stroke recovery. Neurology. 2016;87:1407–1416. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, Weinstein MD. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5:263–276. Abdul Rahman et al: J Neuro-Ophthalmol 2020; 40: 463-471 89. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke. 2003;34:2475–2481. 90. Wendel-Vos GC, Schuit AJ, Feskens EJ, Boshuizen HC, Verschuren WM, Saris WH, Kromhout D. Physical activity and stroke. A meta-analysis of observational data. Int J Epidemiol. 2004;33:787–798. 91. Turan TN, Nizam A, Lynn MJ, Egan BM, Le NA, Lopes-Virella MF, Hermayer KL, Harrell J, Derdeyn CP, Fiorella D, Janis LS, Lane B, Montgomery J, Chimowitz MI. Relationship between risk factor control and vascular events in the SAMMPRIS trial. Neurology. 2017;88:379–385. 92. Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, George SM, Olson RD. The physical activity guidelines for Americans. JAMA. 2018;320:2020–2028. 93. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, LloydJones D, McEvoy JW, Michos ED, Miedema MD, Munoz D, Smith SC Jr, Virani SS, Williams KA Sr, Yeboah J, Ziaeian B. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;140:e596– e646. 94. Billinger SA, Arena R, Bernhardt J, Eng JJ, Franklin BA, Johnson CM, MacKay-Lyons M, Macko RF, Mead GE, Roth EJ, Shaughnessy M, Tang A. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2532–2553. 95. Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke. 2007;38:1881–1885. 96. Saposnik G, Goodman SG, Leiter LA, Yan RT, Fitchett DH, Bayer NH, Casanova A, Langer A, Yan AT. Applying the evidence: do patients with stroke, coronary artery disease, or both achieve similar treatment goals? Stroke. 2009;40:1417– 1424. 97. Alvarez-Sabin J, Quintana M, Hernandez-Presa MA, Alvarez C, Chaves J, Ribo M. Therapeutic interventions and success in risk factor control for secondary prevention of stroke. J Stroke Cerebrovasc Dis. 2009;18:460–465. 98. Brenner DA, Zweifler RM, Gomez CR, Kissela BM, Levine D, Howard G, Coull B, Howard VJ. Awareness, treatment, and control of vascular risk factors among stroke survivors. J Stroke Cerebrovasc Dis. 2010;19:311–320. 471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.