COR LOE Recommendations In patients with recently symptomatic extra- cranial vertebral artery stenosis, intensive medical therapy (antiplatelet therapy, lipid lowering, BP control) is recommended to reduce stroke risk.378 In patients with ischemic stroke or TIA and extracranial vertebral artery stenosis who are having symptoms despite optimal medical treatment, the usefulness of stenting is not In patients with ischemic stroke or TIA and extracranial vertebral artery stenosis who are having symptoms despite optimal medical treatment, the usefulness of open surgical procedures, including vertebral endarterec- tomy and vertebral artery transposition, is not well established. Synopsis Extracranial vertebral artery stenosis is thought to account for 10% of posterior circulation strokes. Revas- cularization procedures are not performed often for ver- tebral artery stenosis. Small trials (VAST, VIST) did not show a clear benefit for vertebral artery stenting, and a recent combined analysis also did not demonstrate clear benefit for vertebral artery stenting compared with medical therapy. Recommendation-Specific Supportive Text 1. On the basis of trials of antiplatelet therapy for patients with recent stroke or TIA, antiplatelet ther- apy is recommended for patients with symptomatic vertebral artery stenosis. Similarly, antihypertensive therapy and statins are recommended for patients with symptomatic vertebral artery stenosis. The use of multimodality medical therapy also has been incorporated into clinical trials.378 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 2. In a combined analysis of 3 trials (VAST, VIST, and SAMMPRIS), 244 patients were assigned to either vertebral artery stenting or optimal medical The primary end point for this analysis was fatal or nonfatal strokes. Two of these trials (VAST, VIST) contributed data for patients with extracranial vertebral artery stenosis. During 1036 person-years of follow-up, the HR for stenting compared with medical therapy was 0.63 (95% CI, 0.27 1.46). Thus, no clear benefit has been shown for extracranial vertebral artery stenting. 3. No randomized trials have been performed for sur- gical techniques such as vertebral artery endarter- ectomy or transposition. Case series have been reported, but these typically lack a control group with a consistent medical treatment protocol.379 Thus, the utility of these procedures is not well established. Extracranial Large Artery Atherosclerosis Knowledge Gaps and Future Research Knowledge gaps within this area include the following: Risk-benefit ratio of CEA to modern intensive medi- cal therapy should be assessed. Previous CEA trials were initiated >30 years ago, and clinicians need comparisons of CEA with cur- rently available intensive medical therapy options. As a result of the growing elderly population, more data are needed on the merits of carotid revascular- ization in elderly patients (>80 years of age). Additional information is needed on the mecha- nisms of sex differences in outcomes for patients with symptomatic carotid stenosis. Recent studies have identified that carotid plaques with <50% stenosis but high-risk features may be linked to otherwise cryptogenic ischemic strokes. More information is needed on the frequency and optimal treatment of these nonstenotic plaques with high-risk features. 5.1.3. Aortic Arch Atherosclerosis Recommendations for Aortic Arch Atherosclerosis Referenced studies that support recommendations are summarized in online Data Supplement 29. COR LOE Recommendations In patients with a stroke or TIA and evidence of an aortic arch atheroma, intensive lipid management to an LDL cholesterol target <70 mg/dL is recommended to prevent recur- In patients with a stroke or TIA and evidence of an aortic arch atheroma, antiplatelet therapy is recommended to prevent recurrent Synopsis studies using TEE have identified complex aortic arch plaque to be inde- pendently and strongly associated with ischemic stroke. Prospective studies have found an increased stroke recurrence rate among patients with aortic plaques 4 mm in thickness, particularly with ulceration or mobile or without plaque calcifications.389 There are no strong data from randomized clinical trials or even observational studies that management should be dif- ferent from general secondary prevention recommenda- tions for atherosclerotic stroke. Recommendation-Specific Supportive Text 1. There is evidence that treating patients with ischemic stroke and evidence of atherosclerosis to an LDL tar- get of <70 mg/dL is more effective in stroke preven- tion than less intensive lipid management.210 Detailed guidanceforlipidmanagementbasedonageandvery high-risk status is presented elsewhere in this docu- ment (see Section 4.3, Treatment of Hyperlipidemia for Secondary Prevention of Stroke). Many patients with aortic plaque and ischemic stroke will meet the criteria for very high-risk status because of concomi- tant atherosclerotic conditions and risk factors. In the ARCH study (Aortic Arch Related Cerebral Hazard Trial), the only randomized trial of secondary pre- vention of aortic plaque associated stroke,380 the event rate was only 20% to 30% of the >12% rate expected from observational studies.390 This is likely attributable to the better risk factor management in the trial compared with historical studies. During the trial, mean LDL-C was reduced by 40 mg/dL to 83 to 84 mg/d. It is likely that event rates would be even lower with current, more intensive recommendations for hypertension and cholesterol management. 2. The only randomized trial of this condition, the compared aspirin and clopidogrel with warfarin and was underpowered for the primary end point. Thus, the comparative benefit of these 2 treatments is unknown. However, there were 6 vas- cular deaths (3.4%) in the warfarin arm and none in the dual antiplatelet arm (log-rank test, P=0.013), suggesting no advantage of warfarin over dual anti- platelets. It is not known whether DAPT is prefera- ble to single antiplatelet therapy (SAPT), but recent have suggested that long-term DAPT generally confers increased bleeding risk without a corresponding increased antithrombotic benefit. There is strong evidence that aspirin is effective in the secondary prevention of noncardioembolic stroke or TIA.383,385 Thus, in the absence of compel- ling evidence for an alternative, more effective anti- thrombotic treatment, long-term monotherapy with aspirin is recommended. Minor strokes that meet the inclusion criteria for the POINT study (Platelet- Oriented Inhibition in New TIA and Minor Ischemic Stroke) also should be treated with short-term DAPT with both aspirin and clopidogrel. Knowledge Gaps and Future Research Knowledge gaps within this area include the following: CLINICAL STATEMENTS AND GUIDELINES Kleindorfer For patients with a stroke or TIA and evidence of an aortic arch atheroma, the effectiveness of long-term DAPT with aspirin and clopidogrel compared with aspirin monotherapy therapy to prevent recurrent stroke is unknown. For patients with a stroke or TIA and evidence of an aortic arch atheroma, the effectiveness of anti- coagulation with either warfarin or a direct-acting anticoagulant compared with aspirin monotherapy to prevent recurrent stroke is unknown. For patients with a stroke or TIA and evidence of an aortic arch atheroma, the effectiveness of com- bination antiplatelet and anticoagulation therapy compared with aspirin monotherapy to prevent recurrent stroke is unknown. Optimal treatment strategies depending on plaque morphology and duration of treatment strategies remain unknown. 5.2. Moyamoya Disease Recommendations for Moyamoya Disease Referenced studies that support recommendations are summarized in online Data Supplement 30. COR LOE Recommendations In patients with moyamoya disease and a history of ischemic stroke or TIA, surgi- cal revascularization with direct or indirect extracranial-intracranial bypass can be beneficial for the prevention of ischemic stroke In patients with moyamoya disease and a his- tory of ischemic stroke or TIA, the use of anti- platelet therapy, typically aspirin monotherapy, for the prevention of ischemic stroke or TIA may be reasonable.393,394,397 401 Synopsis Moyamoya disease is an idiopathic rare steno-occlusive disease of the arteries of the circle of Willis, typically anterior circulation, with abnormal collateral development in lenticulostriate arteries, resulting in the characteristic angiographic puff of smoke appearance. Moyamoya disease may be more common in individuals of Asian descent, but non-Asian people can be affected.402 404 Moyamoya disease has a bimodal distribution, with a peak in childhood (more ischemic) and adulthood (isch- emic and hemorrhagic), and can be asymptomatic.404 Although a causal relationship is not well established, similar vascular changes also may be seen in association with prior radiation exposure, Down syndrome, sickle cell disease, neurofibromatosis, and atherosclerosis. This sit- uation is often referred to as moyamoya syndrome. Treat- ment focuses on preventing progression and reducing the risk of ischemic or hemorrhagic stroke. One prospec- tive RCT (JAM trial [Japan Adult Moyamoya]) examined the efficacy of surgical revascularization for preventing hemorrhagic stroke, but there are no similar prospective RCTs for ischemic stroke prevention.405 No prospective RCTs have studied medical management of either symp- tomatic or asymptomatic moyamoya disease. Although multiple case series and meta-analyses of varying sizes and quality exist, many include both patients with moy- amoya disease and those with moyamoya syndrome, as well as pediatric and adult patients. Few address second- ary prevention of ischemic stroke specifically or issues of ethnic/geographic variability in general. Selection bias and publication bias are significant concerns. The resulting low-quality evidence related to the second- ary prevention of ischemic stroke precludes any strong recommendations. Recommendation-Specific Supportive Text 1. Within the realm of surgery, there is considerable controversy as to what constitutes the best sur- gical option, direct superficial temporal artery to middle cerebral artery bypass or an indirect bypass procedure such as encephaloduroarteriosynangio- sis or encephalomyosynagiosis. The differences in surgical technique even within the broad catego- ries of direct and indirect bypass, the frequent use of combined procedures, and the heterogeneity of the patient population make it difficult to draw robust conclusions about the superiority of one procedure over another. Again, there are no pro- spective RCTs to inform recommendations in this area. Although several meta-analyses and case series favor direct over indirect bypass,391 395 all but 1 of these studies combined both hemorrhagic and ischemic patients. A propensity score matched analysis on 220 adult patients with ischemic-type moyamoya disease showed that direct bypass was superior to indirect bypass for the prevention of In this series, however, the pri- mary end point of recurrent stroke was defined as both ischemic and hemorrhagic events. In contrast, and a retrospective mul- reported no difference between direct and indirect modalities. 2. Although traditionally thought to result from poor perfusion, there is some evidence that many instances of ischemia in moyamoya disease actu- ally result from thromboembolic phenomenon.406 In a propensity score matched analysis, Onozuka found that prehospital antiplatelet use was significantly associated with good functional sta- tus on hospital admission for patients with non- hemorrhagic moyamoya disease in Japan. Several meta-analyses and case series have compared antiplatelet therapy with surgical bypass or obser- vation alone with mixed results.393,397 399 Although some found a benefit or no difference with anti- others found surgery to However, many studies include patients with both ischemic and hemorrhagic CLINICAL STATEMENTS AND GUIDELINES Kleindorfer moyamoya disease, and conclusions are often based on subgroup analyses. Antiplatelet therapy may also be of benefit in conjunction with surgi- An international survey of perceived experts in the treatment of moyamoya disease reported that the majority of non-Asian respondents recommended antiplatelet therapy, in contrast to their Asian counterparts, perhaps reflecting a difference in the typical pattern of dis- ease seen in the 2 geographic regions.407 Knowledge Gaps and Future Research Significant knowledge gaps exist in our understand- ing of moyamoya disease. No prospective RCT exists comparing medical management with surgical interven- tion for either the primary or secondary prevention of ischemic events in patients with moyamoya disease. Similarly, there are no prospective RCTs comparing the efficacy of the most common surgical revascular- ization procedures used for the prevention of ischemic events in this patient population. Numerous obstacles to the performance of such trials exist, including a lack of equipoise among many treating neurologists and neurosurgeons, particularly for symptomatic patients. Consideration should therefore also be given to com- prehensive, adjudicated long-term registries as an alternative means of investigation. Future investigations should have the following aims: To better understand the natural history of moy- amoya disease, including ethnic and geographic variability. To examine the efficacy of medical management options, including antiplatelet therapy and antico- agulation, with or without surgical intervention for ischemic moyamoya disease. To determine the most effective surgical interven- tion for moyamoya disease. To establish the optimal timing for surgical interven- tion after an acute clinical event in a patient with moyamoya disease. 5.3. Ischemic Stroke Caused by Small Vessel Disease Recommendation for Small Vessel Stroke Referenced studies that support the recommendation are summarized in online Data Supplement 31. COR LOE Recommendation In patients with ischemic stroke related to small vessel disease, the usefulness of cilostazol for secondary stroke prevention is Synopsis Cerebral small vessel disease represents a common pathogenetic mechanism for ischemic stroke, accounting This ischemic stroke sub- type is characterized by subcortical infarcts of <15 mm in diameter or lacunes in patients often presenting with lacunar stroke syndromes.38 Hypertension and diabe- tes are the most commonly recognized risk factors for small vessel disease.38,412 Although the risk of mortality is lower after small vessel stroke compared with other stroke types, the 1-year recurrence risk is estimated at Furthermore, small vessel disease and lacunar strokes are a leading cause of vascular dementia and vascular cognitive impairment.414,415 Prior investigative studies have assessed the impact of BP control and antiplatelet therapy on stroke recurrence after stroke related to small vessel disease.382,408,416,417 These studies support the general guidance for the use of antiplatelet therapy and BP recommendations refer- enced in relevant sections of this report. More research is needed to develop and test disease-specific treatments for secondary stroke prevention after small vessel stroke. We focus here on clinical ischemic stroke related to small vessel disease, not on silent small vessel disease, which was reviewed in a 2017 scientific statement.418 Recommendation-Specific Supportive Text 1. Cilostazol has been studied as an alternative to aspirin therapy for ischemic stroke related to small vessel disease. In the CSPS trial (Cilostazol for Prevention of Secondary Stroke), cilostazol was compared with placebo in 1095 Japanese patients with noncardioembolic ischemic stroke There was a sig- nificant reduction in the risk of recurrent stroke in the cilostazol treatment group and in partici- pants with lacunar stroke in the subgroup analy- sis. Cilostazol was compared with aspirin for the prevention of ischemic stroke in the CSPS II trial, which enrolled 2575 Japanese participants, 64% of whom had small vessel stroke as the qualify- Cilostazol was associated with a significantly reduced risk of first occurrence of ischemic or hemorrhagic stroke in the cilostazol group compared with the aspirin group. There were significantly fewer hemorrhagic events in the cilostazol group. There was a nonsignificant reduction in recurrent stroke risk in participants with small vessel stroke in the subgroup analysis. There were more reported side effects, includ- ing headache, dizziness, palpitations, diarrhea, tachycardia, and constipation, in the cilostazol group. These findings have not yet been dupli- cated, and the inclusion of a single ethnic group may limit generalizability. Knowledge Gaps and Future Research The role of cilostazol in secondary prevention after stroke related to small vessel disease. Targeted strategies for secondary prevention after small vessel stroke that also reduce the risk of vas- cular dementia. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 5.4.1. Atrial Fibrillation Recommendations for AF Referenced studies that support recommendations are summarized in online Data Supplement 32. COR LOE Recommendations In patients with nonvalvular AF and stroke or TIA, oral anticoagulation (eg, apixaban, dabi- gatran, edoxaban, rivaroxaban, or warfarin) is recommended to reduce the risk of recurrent In patients with AF and stroke or TIA, oral anticoagulation is indicated to reduce the risk of recurrent stroke regardless of whether the AF pattern is paroxysmal, persistent, or In patients with stroke or TIA and AF who do not have moderate to severe mitral stenosis or a mechanical heart valve, apixaban, dabi- gatran, edoxaban, or rivaroxaban is recom- mended in preference to warfarin to reduce the risk of recurrent stroke.419 426 In patients with atrial flutter and stroke or TIA, anticoagulant therapy similar to that in AF is indicated to reduce the risk of recurrent In patients with AF and stroke or TIA, without moderate to severe mitral stenosis or a mechanical heart valve, who are unable to maintain a therapeutic INR level with warfa- rin, use of dabigatran, rivaroxaban, apixaban, or edoxaban is recommended to reduce the risk of recurrent stroke. In patients with stroke at high risk of hemor- rhagic conversion in the setting of AF, it is reasonable to delay initiation of oral antico- agulation beyond 14 days to reduce the risk In patients with TIA in the setting of nonvalvu- lar AF, it is reasonable to initiate anticoagu- lation immediately after the index event to reduce the risk of recurrent stroke. In patients with stroke or TIA in the setting of nonvalvular AF who have contraindications for lifelong anticoagulation but can tolerate at least 45 days, it may be reasonable to consider percutaneous closure of the left atrial appendage with the Watchman device to reduce the chance of recurrent stroke and In patients with stroke at low risk for hemor- rhagic conversion in the setting of AF, it may be reasonable to initiate anticoagulation 2 to 14 days after the index event to reduce the risk of recurrent stroke.428,429,437 In patients with AF and stroke or TIA who have end-stage renal disease or are on dialysis, it may be reasonable to use warfarin or apixaban (dose adjusted if indicated) for anticoagulation to reduce the chance of Synopsis AF is an important cause of cardioembolic stroke, and the initial clinical presentation of AF is often stroke or TIA. In patients with ischemic stroke or TIA, a diagnosis of AF allows the reduction of recurrent events by treat- ment with long-term oral anticoagulation. The left atrial appendage is thought to be the main source of cardio- embolism in AF. In a series of patients with stroke and AF evaluated by echocardiography, 90% of identified thrombus was seen in the left atrial appendage.432 Anti- coagulation decreases thrombus formation systemically, including the left atrium, and reduces the risk of stroke or systemic embolism in AF, but at the cost of increased bleeding. Four approved direct-acting oral anticoagu- lants (DOACs) have been studied in large randomized trials and shown to clinically reduce the risk of throm- botic stroke with less bleeding risk compared with vita- min K antagonists (VKAs). Patients with stroke or TIA represent a higher-risk population for recurrent stroke events than the overall population studied in the largest randomized trials. Moreover, when considering use of the -VASc risk calculators,420,439,440 the presence of stroke or TIA places a patient in a category in which anticoagulation is recommended regardless of other risk factors. Recommendation-Specific Supportive Text 1. The risk of thromboembolism from AF is reduced by anticoagulation. VKA with warfarin reduced the primary event rate in the randomized SPAF trial (Stroke Prevention in Atrial Fibrillation Study) by 67% (7.4% to 2.3%) and was superior to treat- ment with aspirin alone, which reduced the primary event rate by 42%.419 Subsequent studies using risk characterization scores have further supported the effectiveness of VKAs in reducing stroke risk Furthermore, in all scoring systems of stroke risk in AF, prior stroke or TIA alone places a patient in a risk category in which anticoagulation is recommended. Four DOACs apixaban, dabigatran, edoxaban, and rivaroxaban have been studied in 4 large randomized trials against VKA with consistent evidence of noninferior reduction in thromboem- bolic risk and reduced bleeding risk.423 426 All trials of DOACs specifically excluded patients with val- vular AF; however, up to 20% of patients in these trials had some degree of valvular heart disease (VHD). This discrepancy has led to some confu- sion in practice, which was clarified in the 2019 AHA/ACC/Heart Rhythm Society guideline on the management of AF.32 DOACs should not be used in patients with moderately severe or greater mitral stenosis or a mechanical heart valve. 2. AF is the most common arrhythmia in the adult pop- ulation and can be categorized by the proportion of time a given patient spends in AF as paroxys- mal, persistent, or permanent. Even brief subclini- cal episodes of AF are associated with increased risk of stroke.427 Anticoagulation is recommended for patients with stroke or TIA regardless of the CLINICAL STATEMENTS AND GUIDELINES Kleindorfer amount of time spent in AF. There is no established lower limit of embolism risk from time spent in AF; furthermore, patients with AF tend to progress to greater proportions of time spent in arrhythmia over time. Moreover, up to 28% of patients are found to have AF with prolonged monitoring after stroke. Patients with a remote history of a discrete AF episode (eg, postoperative or thyrotoxicosis) represent a group at increased risk for arrhythmia but the objective risk of recur- rence is poorly defined. 3. All 4 randomized trials of DOACs demonstrated advantages to stroke risk reduction with the DOAC compared with a VKA with similar or improved stroke rates associated with similar or less bleed- ing. In the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy), at 2 years, high-dose dabigatran was associated with lower stroke (1.11% versus 1.69%) and similar bleeding (3.11% versus 3.36%) rates compared with war- In ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), rivaroxa- ban was noninferior to warfarin with similar rates of stroke or systemic embolism (2.1 vs 2.4 per 100 patient-years) and major bleeding (5.6% versus The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) of 18201 patients demon- strated that apixaban was superior to warfarin at 1.8 years with fewer strokes or systemic embo- lisms (1.27% versus 1.60%) and less bleeding The ENGAGE AF-TIMI 48 trial (Global Study to Assess the Safety and Effectiveness of Edoxaban [DU-176b] vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation) showed similar rates of stroke or systemic embolism with less bleeding in 21105 patients comparing 2 doses of edoxaban with war- A meta-analysis combining the data from all 4 trials found an overall 19% reduction in stroke or systemic embolism driven by a 51% reduction in hemorrhagic stroke and a 10% overall reduction in The improved safety profile of DOACs in the context of noninferior thromboembolic risk leads to the recommendation to consider prefer- ential use of a DOAC over a VKA. 4. Compared with AF, atrial flutter is a more organized macro-reentrant arrhythmia often involving the tri- cuspid isthmus. Atrial flutter is less common than AF overall; however, patients with atrial flutter are at increased risk for developing AF, and the risk of stroke associated with atrial flutter is similar to that associated with AF.28 In a single-center series of 1121 patients referred for atrial flutter ablation and followed up for 2.1 2.7 years, 31.7% had AF before ablation and 23.2% of patients experienced AF after ablation for atrial flutter.446 5. Therapy with VKA has a narrow therapeutic win- dow. Patients who do not maintain an INR in the therapeutic range are at increased risk for both bleeding and thrombotic events. Time in thera- peutic range is an important metric indicating the overall time spent by a patient with an INR in the therapeutic range; time with subtherapeutic INRs confers greater risk of embolic events, whereas time spent with supratherapeutic INR confers risk of major bleeding. In the ACTIVE W trial (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events), patients random- ized to warfarin who did not maintain >60% time in therapeutic range did not derive net benefit from A meta-analysis of data from the 4 seminal trials of DOACs confirmed this finding, observing substantially greater benefit of DOACs compared with VKAs when the center- based time in therapeutic range was <66% (31% versus 7% improvement in major bleeding).445 For patients who have documented suboptimal time in therapeutic range with VKA in the setting of AF and prior stroke or TIA, it is recommended to use a DOAC preferentially. 6. Patients with stroke or TIA in the setting of AF are at increased risk of recurrent ischemic stroke and at risk for ICH. Recurrent ischemic stroke risk is 0.5% per day to 1.3% per day in the first 14 days, whereas the rate of symptomatic hemorrhagic transformation after stroke ranges substantially, depending on the use of thrombolytics, with rates of 6% to 21% and 1% to 7% in the thrombolytic and placebo arms, respectively, across multiple tri- als of thrombolytic therapy.428,448 Anticoagulation reduces the risk of recurrent ischemic stroke but increases the risk of cerebral hemorrhage dur- ing the acute poststroke phase.429,449 Patients with larger cerebral infarcts are at greater risk for hemorrhagic transformation and worse bleeding with early initiation of anticoagulation430 ; thus, it is reasonable to delay initiation of oral anticoagula- tion for 14 days after stroke onset in that setting. Although there is no uniformly accepted definition of a large cerebral infarction, accepted defini- tions have included National Institutes of Health Stroke Scale (NIHSS) score >15450 and lesions involving complete arterial territory or >1 arterial Moreover, patients with early signs of hemorrhage on neuroimaging are at highest risk of further intracerebral bleeding and should delay initiation of oral anticoagulation to allow healing of the blood brain barrier.451 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 7. Patients who have a TIA rather than stroke in the setting of AF are at relatively low risk for intra- cranial hemorrhage but remain at increased risk for recurrent stroke. The balance of bleeding risk versus benefit of stroke risk reduction from oral anticoagulation favors earlier initiation in the set- ting of TIA when no cerebral infarction is present. The relative safety of earlier anticoagulation in TIA is in contrast to the recommended delay with stroke (particularly large stroke), in which cerebral infarction can disrupt the blood brain barrier and increases the risk of hemorrhage with initiation of anticoagulation. 8. In patients with stroke in the setting of nonvalvular AF, the left atrial appendage is the location of identi- fied thrombus 90% of the time.432 This observation gave rise to the concept of left atrial appendage closure to reduce the risk of stroke from AF. The Watchman device is a plug-style device placed in the ostium of the left atrial appendage to occlude it and prevent thromboembolism. It was studied in the randomized PROTECT AF trial (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) and PREVAIL trial (Prospective Randomised Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy), as well as the nonrandomized CAP (Continued Access Registry), demonstrating non- significant numerically greater thrombotic risk with the device but lower bleeding risk and over- all net benefit.433 436 The Watchman device is the only currently available device with US Food and Drug Administration approval for left atrial append- age closure. Other devices to close the left atrial appendage are under investigation. Current prac- tice based on clinical trial design involves short- term (1.5 months) use of oral anticoagulation after Watchman device placement to reduce the risk of device-related thrombus followed by 4.5 months of DAPT. In patients at high bleeding risk from oral anticoagulation, left atrial appendage closure can reduce the long-term risk of bleeding with an isch- emic stroke risk comparable to that of anticoagula- tion with VKA. 9. Cerebral infarction weakens the blood brain bar- rier, increasing the risk of spontaneous hemor- rhage after acute ischemic stroke, yet patients with stroke or TIA in the setting of AF are at increased risk of recurrent stroke.428 Anticoagulation reduces the risk of recurrent embolism but increases the risk of cerebral hemorrhage during the acute post- The optimal timing of initiating oral anticoagulation should be individualized for each patient s risk of hemorrhage versus recurrent embolism. Although the annualized risk of recurrent stroke can be significant, the daily risk of embolism from AF is generally small. For example, a patient with a 6% risk of stroke over 1 year would have a daily risk of 0.016% and a risk of 0.23% over 14 days. Nevertheless, an analysis of the VISTA cohort study (Virtual International Stroke Trials Archive) of 1644 patients found fewer recurrent strokes with initiation of VKA 2 to 3 days after stroke compared with >3 days without increased risk of symptom- In patients with larger cerebral infarcts, evidence of hemorrhage on neuroimaging, NIHSS score >9, or other features that place them at increased risk of hemorrhagic conversion after acute stroke, the balance of risk and benefit favors waiting for healing and reduced bleeding risk.429 10. Patients with renal failure on dialysis are at increased risk for both bleeding and thrombotic events. All DOAC medications are renally cleared, increasing the risk for drug accumulation, supra- therapeutic drug levels, and bleeding events in patients with renal failure. Although overall data are limited in this population, a large retrospective study matched 2351 patients with AF on dialysis who took apixaban against 23172 taking warfarin and found a 28% lower rate of bleeding events in those taking apixaban.438 This finding supports the use of apixaban as an alternative choice for antico- agulation in patients with AF on dialysis. Knowledge Gaps and Future Research Optimal management strategies to reduce the risk of recurrent stroke in patients with AF have improved sub- stantially with support from large trial data; however, knowledge gaps remain, including: The minimal duration of AF that engenders signifi- cant stroke risk and benefit of oral anticoagulation beyond the bleeding risk remains unknown. Multiple studies reflecting the increased use of monitoring technologies are ongoing. The safety of discontinuing oral anticoagulation after surgical appendage closure remains uncertain. Small series of surgical technologies have demon- strated technical success, but the relevance to clini- cal need for oral anticoagulation remains unknown. Multiple transcatheter approaches to left atrial appendage closure are under investigation and will provide additional options for stroke risk reduction while minimizing risk of bleeding with long-term anticoagulation. For patients who have had AF followed by success- ful ablation, the need for continued anticoagulation is uncertain and continues to be studied. Patients with limited postoperative AF are at increased risk of recurrence; however, further research is needed to identify which patients would benefit from long-term anticoagulation. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer The safety of oral anticoagulation in the setting of cerebral amyloid angiopathy and in the presence of microhemorrhages remains unclear and merits fur- ther study. The efficacy of left atrial appendage closure com- pared with DOACs is unknown. The DOAC efficacy in morbidly obese patients is unknown. 5.4.2. Valvular Disease Recommendations for Valvular Disease Referenced studies that support recommendations are summarized in online Data Supplements 33 and 34. COR LOE Recommendations In patients with ischemic stroke or TIA and valvular AF (moderate to severe mitral steno- sis or any mechanical heart valve), warfarin is recommended to reduce the risk of recurrent stroke or TIA.452 457 In patients with a mechanical mitral valve and a history of ischemic stroke or TIA before valve replacement, aspirin (75 100 mg/d) is recom- mended in addition to warfarin with an INR target of 3.0 (range, 2.5 3.5) to reduce the risk of thrombosis and recurrent stroke or TIA.458,459 In patients with ischemic stroke or TIA and native aortic or nonrheumatic mitral valve disease (eg, mitral annular calcification or mitral valve prolapse) who do not have AF or another indication for anticoagulation, anti- platelet therapy is recommended to reduce the risk of recurrent stroke or TIA. In patients with a bioprosthetic aortic or mitral valve, a history of ischemic stroke or TIA before valve replacement, and no other indication for anticoagulation therapy beyond 3 to 6 months from the valve placement, long-term therapy with aspirin is recommended in preference to long-term anticoagulation to reduce the risk of recur- rent stroke or TIA. In patients with ischemic stroke or TIA and IE who present with recurrent emboli and persistent vegetations despite appropri- ate antibiotic therapy, early surgery (during initial hospitalization before completion of a full therapeutic course of antibiotics) is reasonable to reduce the risk of recurrent embolism if there is no evidence of intracra- nial hemorrhage or extensive neurological In patients with history of ischemic stroke or TIA and a mechanical aortic valve, anti- coagulation with higher-intensity warfarin to achieve an INR of 3.0 (range, 2.5 3.5) or the addition of aspirin (75 100 mg/d) can be beneficial to reduce the risk of thromboem- bolic events. In patients with ischemic stroke or TIA and native left-sided valve endocarditis who exhibit mobile vegetations >10 mm in length, early surgery (during initial hospitalization before completion of a full therapeutic course of anti- biotics) may be considered to reduce the risk of recurrent embolism if there is no evidence of intracranial hemorrhage or extensive neurologi- In patients with ischemic stroke or TIA and IE, early valve surgery (during initial hospital- ization before completion of a full therapeutic course of antibiotics) may be considered in patients with an indication for surgery who have no evidence of intracranial hemorrhage or extensive neurological damage.466,467 In patients with IE and major ischemic stroke, delaying valve surgery for at least 4 weeks may be considered for patients with IE and major ischemic stroke or intracranial hemorrhage if the patient is hemodynamically 3: Harm B-R In patients with ischemic stroke or TIA and mechanical heart valves, treatment with dabigatran causes harm.*457 *A similar recommendation in another guideline is worded slightly differently; however, the process used to reach consensus was the same in both cases. Synopsis In patients with VHD (except moderate to severe mitral stenosis or a mechanical heart valve), ischemic stroke or TIA, and AF, DOACs (dabigatran, rivaroxaban, apixa- ban, and edoxaban) are recommended over warfarin In patients with valvular AF (ie, moderate to severe mitral stenosis or a mechanical heart valve), warfarin is recommended.32,458,464,469 472 Antiplatelet therapy continues to be recommended over warfarin in patients with VHD other than rheumatic mitral disease and ischemic stroke or TIA.9 For patients with prosthetic heart valves, the choice of type of antithrombotic therapy after ischemic stroke or TIA is influenced by the type of valve (bioprosthetic versus mechanical), the timing of the embolic event, prior documented compliance to anti- thrombotic therapy, and assessment of the function of the prosthetic valve.9,33 Indications and timing for surgical interventions in patients with IE and stroke or TIA depend on multiple factors, including recurrent events while on antibiotic therapy, size of the vegetation, and presence of associated intracranial hemorrhage.33,460,464 467 summarizes the recommended antithrombotic regimen in patients with history of ischemic stroke or TIA and dif- ferent VHD conditions. Recommendation-Specific Supportive Text 1. AF is highly prevalent in patients with VHD and represents one of the most important risk fac- tors for ischemic stroke and TIA. In patients with prior ischemic stroke or TIA and associated AF, the distinction between valvular and nonvalvular AF is crucial because it has important implications in the selection of the optimal oral anticoagula- Valvular AF refers to AF in the context of moderate to severe mitral stenosis or in the presence of any mechanical heart valve.32 It is important to highlight that the term nonvalvular AF does not imply the absence of VHD but only Recommendations for Valvular Disease Continued COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Kleindorfer the absence of moderate to severe mitral stenosis or mechanical heart valves (ie, AF in the setting of bioprosthetic valves, mild mitral stenosis, and any native aortic, pulmonary, or tricuspid valve dis- ease is still considered nonvalvular).32 According to the results of subgroup analyses of RCTs testing DOACs to prevent thromboembolic complications in patients with AF and meta-analyses of random- in patients with VHD except mod- erate to severe mitral stenosis or a mechanical heart valve, ischemic stroke or TIA, and AF, DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) are recommended over warfarin therapy. anticoagulation with warfarin is recommended with an INR target of 3.0 (range, 2.5 3.5).33,473 The inci- dence of thromboembolism is higher in patients with mechanical prostheses in the mitral compared with the aortic position, and the rate of thrombo- embolism is lower in patients with a higher INR goal. In the GELIA study (German Experience With Low Intensity Anticoagulation) of patients with a mechanical mitral prosthesis, a lower INR (2.0 3.5) was associated with lower survival rates than a higher target INR range (2.5 4.5).458 Although routine addition of aspirin to warfarin therapy in patients with mechanical valves is not recom- mended, patients with a history of ischemic stroke or TIA before the mechanical valve surgery repre- sent a group with an inherently higher thrombo- embolic risk in whom the protection from recurrent thromboembolic events associated with the com- bination of aspirin and warfarin therapy may out- weigh the competing bleeding risk.459 3. In the absence of AF, observational studies have reported conflicting results with regard to the asso- ciation between nonrheumatic mitral valve disease or native aortic disease and increased risk of throm- An early case-con- trol study reported that mitral valve prolapse was associated with an increased risk for ischemic More recent studies have not confirmed Observational studies have consistently shown that the risk for stroke in people with mitral valve prolapse is low (<1% At least 4 population-based cohort studies have evaluated the association between mitral annular calcification and stroke.478,479,484,485 Figure 3. Recommended antithrombotic regimen in patients with history of ischemic stroke or transient ischemic attack (TIA) and different valvular heart disease conditions. Colors correspond to Class of Recommendation in Table 3. Abx indicates antibiotics; AF, atrial fibrillation; AV, aortic valve; AVD, aortic valve disease; DOAC, direct oral anticoagulant; MAC, mitral annular calcification; MS, mitral stenosis; MV, mitral valve; MVD, mitral valve disease; MVP, mitral valve prolapse; and VHD, valvular heart disease. *Definition of valvular AF. Includes MAC and MVP. Rheumatic and nonrheumatic AVD. Increase the target international normalized ratio by 0.5, depending on bleeding risk. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer The cumulative evidence does not support a causal association between mitral annular calcification and increased risk of thromboembolism. Similarly, there is no conclusive evidence supporting a causal association between native aortic valve disease and increased risk of stroke or TIA.478,479 Additional distinct valvular lesions such as Libman-Sacks or bicuspid aortic valves487 have been associated with increased risk of thromboembolism, although no properly designed trial has addressed the optimal therapeutic strategy to prevent ischemic stroke or TIA in these specific conditions. Therefore, no spe- cific management recommendations can be made for these conditions. 4. In patients undergoing bioprosthetic mitral or aor- tic valve replacement surgery, oral anticoagulation with warfarin to achieve a target INR of 2.5 (range, 2.0 3.0) is reasonable for at least 3 months and for as long as 6 months after surgery in patients at low risk of bleeding.33 This recommendation is based on the results of observational studies that have reported an increased risk of ischemic stroke early after surgery.488 490 After 3 to 6 months after surgery, long-term therapy with only aspirin 75 to 100 mg daily is recommended.473,491 493 Patients with a history of ischemic stroke or TIA (before the bioprosthetic valve surgery) who are already receiving antiplatelet therapy and have no indica- tion for anticoagulation therapy should continue to be managed with antiplatelet therapy alone after the bioprosthetic valve insertion. 5. In patients with mechanical prosthetic heart valves, effective antithrombotic therapy requires continu- ous effective warfarin anticoagulation with an INR in the target range.33 ACC/AHA guidance on the selection of the most appropriate antithrombotic regimen in patients with mechanical heart valves has been published in separate guidelines.33 Anticoagulation with warfarin to achieve an INR of 2.5 is typically recommended for patients with a mechanical bileaflet or current-generation single- tilting-disk aortic valve replacement and no risk factors for thromboembolism.458,469,472,473 However, patients with an aortic mechanical prosthesis who have a history of ischemic stroke or TIA are at higher risk of thromboembolic complications, and it is recommended to maintain the INR at a higher target of 3.0 (range, 2.5 3.5) or to add aspirin 75 6. Neurological complications are the most frequent and severe extracardiac complications of IE, with an estimated incidence of up to 20% to 40% and a significant impact on mortality.460 462 Ischemic cerebrovascular events represent the most com- mon neurological complication of IE. Risk factors for ischemic stroke or TIA include vegetation size and mobility, infection with Staphylococcus aureus, and involvement of the mitral valve.460 Timely and appropriate institution of antibiotic therapy is the first-line therapy for patients with IE and embolic stroke or TIA. ACC/AHA guid- ance on the management of patients with IE has been published in separate guidelines.33,463 In patients with IE and recurrent embolic stroke or TIA despite antibiotic therapy, an early consid- eration for surgery (during the index hospitaliza- tion and before completion of a full therapeutic course of antibiotics) is reasonable if there is no evidence of intracranial hemorrhage or extensive 7. Vegetation size represents an important risk fac- tor for systemic embolization in patients with In a multicenter prospective study includ- ing 384 consecutive patients with IE who under- went TEE, embolic complications occurred in 131 cases (34.1%). Of these, 28 patients (7.3%) had an embolic event after the institution of adequate antibiotic therapy. Vegetation length was larger in patients with new embolic events (after initiation of antibiotic therapy) than in those without (median, 15.5 mm versus 9 mm, respectively; P<0.001). A vegetation length threshold of 10 mm was iden- tified as having the highest predictive value for embolic events while on adequate antibiotic ther- In a small randomized trial including 76 patients with left-sided IE, severe mitral valve or aortic disease, and large vegetations (>10 mm), early surgery (within 48 hours of randomization) was associated with a significant reduction of the composite end point of in-hospital death or embolic with conventional treatment.464 8. Decisions on the optimal timing of surgical inter- vention in patients with IE after an acute stroke should balance the benefits associated with sur- gical correction of the IE lesion with the risk of worsening of the neurological insult attributable to ICH (typically caused by hemorrhagic conversion of ischemic lesions, mycotic aneurysms, or septic necrotic arteritis), hypotension, and further intraop- In patients with IE who have had an acute stroke without extensive neurologi- cal damage and no intracranial hemorrhage, data suggest that early surgery (with no delay) may be associated with better outcomes.33,466,467 An early Japanese retrospective study including 181 of 244 patients with cerebral complications reported a correlation between the time delay to surgery and More recently, a prospective cohort study evaluated the relationship between the tim- ing of surgery after a stroke and in-hospital and CLINICAL STATEMENTS AND GUIDELINES Kleindorfer A total of 198 patients with IE who underwent valve replacement surgery after a stroke were analyzed. Of these, 58 patients (29.3%) underwent early surgical treatment and 140 (70.7%) had late surgical treatment. After adjustment for other risk factors, early surgery was not associated with increased in-hospital or 1-year 9. Hemorrhagic complications of IE are multifactorial and can result from hemorrhagic conversions of ischemic lesions, rupture of mycotic aneurysms, or septic necrotic arteritis.460,468 Patients with hemor- rhagic stroke and IE have high surgical risk for at least 4 weeks after the event. One observational study showed a substantial difference in mortality rates when patients who underwent surgery within 4 weeks of a hemorrhagic stroke were compared with those whose surgery was delayed until after the rate of new hemorrhagic events after surgery was 50% in patients who underwent surgery within the first 2 weeks, 33% in patients who underwent surgery in the third week, and 20% in patients who underwent surgery at least 21 days after the neu- 10. A phase II randomized trial comparing dabigatran and warfarin in patients with mechanical heart valves (RE-ALIGN [Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement]) was stopped prematurely after enrollment of 252 patients because of an excess of thromboembolic and bleeding events in the dab- At this point, there is no published randomized study evaluating the safety and effi- cacy of other DOACs in patients with mechanical heart valves, and warfarin remains the only recom- mended oral anticoagulant in these patients. Knowledge Gaps and Future Research Rheumatic mitral valve disease often results in left atrial structural changes and adverse remodeling, which predisposes to thromboembolic complica- tions also when in sinus rhythm, a condition that has been defined as atrial cardiomyopathy.496,497 In patients with ischemic stroke or TIA who have rheumatic mitral valve disease without AF and no other likely cause for their symptoms (eg, carotid stenosis), the role of oral anticoagulation has not been adequately investigated. Patients with a bioprosthetic aortic or mitral valve are typically managed with antiplatelet therapy. If an ischemic stroke or TIA occurs in these patients despite adequate antiplatelet, the benefit of switch- ing to oral anticoagulation with warfarin or a DOAC is unknown and warrants further investigation. In patients with IE, small observational series sug- gest a role for routine neurovascular imaging studies (CT or MRA) to screen for mycotic aneurysms, which can potentially influence the treatment plan.498,499 Further larger studies are needed to determine whether routine neurovascular imaging to screen for mycotic aneurysms in IE improves outcomes. Patients with transcatheter aortic valve replacement and transcatheter mitral valve replacement represent a growing population.500,501 Antiplatelet therapy is the standard antithrombotic regimen after transcatheter aortic valve replacement,33 whereas a combination of oral anticoagulation and antiplatelet therapy has been used with transcatheter mitral valve replace- ment, although with scant supporting evidence.501 At the present time, DOACs are not routinely used in transcatheter aortic valve replacement,502,503 and additional studies are needed to further evaluate the potential benefit of DOACs therapy to prevent isch- emic stroke or TIA in this population. Furthermore, the optimal antithrombotic regimen for patients with a transcatheter aortic valve replacement who have a TIA or ischemic stroke despite adequate antiplatelet therapy is still undefined. 5.4.3. LV Thrombus Recommendations for LV Thrombus Referenced studies that support recommendations are summarized in online Data Supplement 35. COR LOE Recommendations In patients with stroke or TIA and LV thrombus, anticoagulation with therapeutic warfarin for at least 3 months is recommended to reduce the risk of recurrent stroke.504 508 In patients with stroke or TIA in the setting of acute MI, it is reasonable to perform advanced cardiac imaging (eg, contrasted echocar- diogram or cardiac MRI) to assess for the presence of LV thrombus. In patients with stroke or TIA and new LV thrombus (<3 months), the safety of antico- agulation with a direct oral anticoagulant to reduce risk of recurrent stroke is uncertain.509 In patients with stroke or TIA in the setting of acute anterior MI with reduced ejection fraction (EF; <50%) but no evidence of LV thrombus, empirical anticoagulation for at least 3 months might be considered to reduce the risk of recurrent cardioembolic stroke. Synopsis Decreased contractility in the LV, particularly at the LV apex, creates the possibility of blood pooling and subse- quent coagulation and thrombus formation. Thrombus in the LV is then at risk of systemic embolization. Although LV thrombus can form anytime blood stasis occurs, patients with acute MI, who have had acute vessel clo- sure with associated loss of myocardial contractility, are at risk of forming LV thrombus. Patients with anterior MI and reduced EF are a subgroup shown to be at particular risk CLINICAL STATEMENTS AND GUIDELINES Kleindorfer for LV thrombus formation. The associated risk of stroke or systemic embolism in the presence of LV thrombus is reduced by use of systemic anticoagulation. Over time, thrombus in the LV matures and becomes incorporated into the wall of the akinetic segment, and the risk of embolism is reduced. The exact time for each thrombus to mature to this point is unknown, but the risk of sys- temic embolism or stroke is reduced after 3 months. In the context of secondary stroke prevention, detection of LV thrombus is an important determinant of stroke type and appropriate therapy. Standard transthoracic echocar- diography is relatively insensitive for the detection of LV thrombus. Both contrast echocardiography with the use of a microbubble contrast agent and cardiac MRI are superior imaging modalities for detecting LV thrombus compared with standard transthoracic echocardiography. Recommendation-Specific Supportive Text 1. Patients with stroke or TIA in the context of LV thrombus should be anticoagulated until the thrombus has matured and the risk of further embolism has waned, 3 months. The bulk of evi- dence has used VKA for oral anticoagulation with a goal INR of 2.0 to 3.0. A large cohort study of 2160 patients from 1979 to 1998 noted that the risk of stroke after MI was dramatically higher in the first month after infarct and remained elevated for years afterward.510 In the percutaneous coro- nary angiography era, a multicenter study of 753 patients with ST-segment elevation MI identified LV thrombus in 3.5% and 7.1% of patients after ante- rior ST-segment elevation MI using cardiac MRI, although mural thrombus has been noted in as many as 26% of those studied in other series.504,505 In a meta-analysis of 8 studies encompassing 856 patients, Vaitkus and Barnathan506 noted an increased risk of stroke or systemic embolism in the presence of LV thrombus demonstrated on echocardiogram with an OR of 5.45. Moreover, the risk of embolism was substantially reduced in the presence of oral anticoagulation with a VKA with an OR of 0.14. A smaller single-center ret- rospective study of 33 patients with LV thrombus on cardiac MRI compared with 66 matched con- trols observed a short-term risk of stroke of 9.1%; another study of LV thrombus noted stroke or systemic embolism in 7.7% of patients with docu- Finally, a larger, more het- erogeneous single-center study of 155 patients with LV thrombus found on cardiac MRI compared with 400 matched patients over 3.3 years found an annualized rate of stroke or systemic embolism of 3.7% versus 0.8% in those without LV throm- bus, suggesting that an increased risk of embo- lism may persist.508 It is unclear whether events in the cohort with LV thrombus were caused by the thrombus or the LV thrombus was a marker of a higher-risk population. 2. Both administration of microbubble contrast with transthoracic echocardiography and cardiac MRI have been shown to be superior to echocardiog- raphy without contrast for the detection of LV thrombus. Both modalities also increase the defi- nition of MI size where larger areas of infarction increase the risk of thrombus formation. In a study of 210 patients with cardiac MRI and echocar- diography after ST-segment elevation MI, cardiac MRI detected LV thrombus in 12.3% of patients, and echocardiography detected LV thrombus Another single-center study of 201 patients with ST-segment elevation MI also noted lower rates of LV thrombus detection using echo- cardiography (35%) and contrast echocardiogra- phy (64%) compared with cardiac MRI.511 Overall, detection of LV thrombus is increased by admin- istration of microbubble contrast, and cardiac MRI has the highest demonstrated sensitivity.512 Tailoring imaging strategy on the basis of patient risk may optimize diagnostic yield. 3. In a pooled meta-analysis of studies of mural throm- bus after anterior MI, use of oral anticoagulation with VKA reduced the risk of stroke by 86% and resulted in resolution of LV thrombus in 68%.506 Anticoagulation with DOACs has been shown to be as effective as VKA for the prevention of stroke in AF and for the treatment of deep vein thrombosis and pulmonary embolism with a lower risk of bleed- ing and with greater convenience, driving interest in use for LV thrombus. A single-center retrospective study of anticoagulation with a DOAC in 52 patients for the treatment of LV thrombus found resolution of the thrombus in 86% of patients on follow-up echo- cardiography, but the study was too small to address embolic event rates.509 A larger retrospective analy- sis of 514 patients with identified LV thrombi from 3 centers and a median follow-up of 351 days com- pared 300 patients who received warfarin with 185 patients treated with DOAC and noted a higher rate of stroke or systemic embolism in the DOAC group (HR, 2.71 versus warfarin), although this difference was noted beyond the currently recommended duration of therapy for LV thrombi.513 4. Patients with reduced LV systolic function (LV EF <50%) in the setting of acute anterior MI are at the greatest risk of developing LV thrombus.514 The observed rate of LV thrombus in anterior MI was 24% in 1 series by cardiac MRI.505 The risk of stroke among patients with defined LV throm- bus has been reported to be as high as 9% to Therefore, for patients who have stroke or TIA in the context of anterior MI with reduced EF (ie, the cardiac population at the highest risk for CLINICAL STATEMENTS AND GUIDELINES Kleindorfer developing thrombus), one might consider empiri- cal anticoagulation even in the absence of demon- strated thrombus. Knowledge Gaps and Future Research Ventricular thrombus complicating insults to LV function can present a challenge to the care team. Our under- standing is based on aging data and small case series, leaving gaps in our knowledge and opportunities for future research in diagnosis, prognosis, and therapy. Often, the initial manifestation of LV thrombus is stroke. Identifying patients at highest risk of devel- oping LV thrombus before it forms may prevent stroke. Advanced imaging methods offer the prom- ise of identifying features of ventricular remodeling or dysfunction through strain patterns, blood vec- tor mapping, and hematologic assays that point to patients who are at highest risk and would benefit from prophylactic anticoagulation. Furthermore, the optimal timing and frequency of screening for LV thrombus remain poorly characterized and would benefit from longitudinal study. The optimal duration of anticoagulation in the set- ting of thrombus remains elusive. Natural history studies with serial advanced imaging could better determine LV thrombus embolic risk and the need for anticoagulation. Recommendations for Cardiomyopathy Referenced studies that support recommendations are summarized in online Data Supplements 36 and 37. COR LOE Recommendations In patients with ischemic stroke or TIA and left atrial or left atrial appendage thrombus in the setting of ischemic, nonischemic, or restrictive cardiomyopathy and LV dysfunction, antico- agulant therapy with warfarin is recommended for at least 3 months to reduce the risk of recurrent stroke or TIA. In patients with ischemic stroke or TIA in the setting of a mechanical assist device, treatment with warfarin and aspirin can be beneficial to reduce the risk of recurrent stroke or TIA.516 523 In patients with ischemic stroke or TIA in the setting of LV noncompaction, treatment with warfarin can be beneficial to reduce the risk of recurrent stroke or TIA. In patients with ischemic stroke or TIA in sinus rhythm with ischemic or nonischemic cardio- myopathy and reduced EF without evidence of left atrial or LV thrombus, the effectiveness of anticoagulation compared with antiplatelet therapy is uncertain, and the choice should be 3: Harm B-R In patients with stroke or TIA and LV assist devices (LVADs), treatment with dabigatran instead of warfarin for the primary or second- ary prevention of ischemic stroke or TIA Synopsis Compared with the general population without cardio- myopathy, patients with cardiomyopathy and impaired LV EF have a higher incidence of thromboembolism. In patients with cardiomyopathy, ischemic stroke, or TIA in sinus rhythm who have intracardiac thrombus dem- onstrated by echocardiography or another imaging anticoagulant therapy with a warfarin is recommended for 3 months (Figure 4). Patients with noncompaction cardiomyopathy represent a peculiar subgroup at higher risk of thromboembolic complica- In patients with ischemic stroke or TIA in the setting of LV noncompaction, treatment with war- farin therapy can be beneficial. The effectiveness of oral anticoagulation compared with antiplatelet therapy in patients with cardiomyopathy and reduced EF and ischemic stroke or TIA in sinus rhythm with no evidence of left atrial or LV thrombus is uncertain, and the choice should be individualized, taking into account the bleed- ing risk and estimated risk of recurrent thromboembo- Patients with LVADs have a high prevalence of neurological complications (thromboembolic/hemor- rhagic). Warfarin together with aspirin is the standard antithrombotic regimen to minimize the risk of LVAD and to prevent recurrent ischemic stroke or TIA. At this point, the use of DOACs in patients with LVAD should be avoided.529 Recommendation-Specific Supportive Text 1. The prevalence of intracardiac thrombosis in patients with cardiomyopathy has not been con- clusively determined, and it varies between differ- ent underlying causes. In a retrospective database including 86374 patients, 62 cases (0.7%) of LV thrombosis were identified. The majority of patients (81%) had ischemic cardiomyopathy, and the remaining had a nonischemic type.537 Oral antico- agulation with warfarin has been used in patients with intracardiac thrombus, and the efficacy has been documented in several observational stud- A duration of therapy <3 months has been associated with a higher recurrence rate.539 The evidence for the use of DOACs in patients with intracardiac thrombus is limited largely to isolated case reports and small case series.529,540 546 It is also important to note that DOACs have not been studied specifically to prevent thromboembolism in patients with documented LV or left atrial throm- bus. In addition, uncertainty about the optimal dos- ing of DOACs and the long-term safety remains. Therefore, at the present time, warfarin should be preferred to DOACs in patients with ischemic, non- ischemic, or restrictive cardiomyopathy; ischemic stroke or TIA in sinus rhythm; and documented left atrial or LV thrombus. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 2. Thromboembolic complications represent a major therapeutic challenge in the LVAD population and can occur at any point after LVAD implantation, including the immediate postoperative period and the long-term follow-up.516 519 The pathophysiology associated with ischemic stroke in the LVAD popula- tion is complex, and the postulated underlying mech- anisms are different for early versus late strokes. In the immediate postoperative period, several surgical factors have been reported to possibly increase the risk. These factors include duration of cardiopul- monary bypass and the need for other associated surgeries (eg, coronary artery bypass surgery, valve Pump thrombosis, reduced pump speeds, venous thromboembolism, uncontrolled hypertension, and systemic infections have been associated with late strokes.518,519,521,522 A subopti- mal anticoagulation regimen, which includes either supratherapeutic or subtherapeutic INR and no aspi- rin use, has also been associated with increased risk of ischemic strokes. The use of DAPT compared with acetylsalicylic acid alone in addition to warfarin does not appear to affect the rates of ischemic stroke.523 Therefore, at the present time, the combination of warfarin and aspirin is the preferred regimen in pre- venting recurrent ischemic stroke. 3. LV noncompaction is a rare primary cardiomyopa- thy possibly caused by an arrest of normal embryo- genesis of the endocardium and mesocardium that leads to the formation of prominent trabeculations and deep intertrabecular recesses within the LV wall communicating with the cavity. The inferior and lat- eral walls of the LV from the midcavity to the apex are most commonly involved by this process.547 Among cohorts of patients with cardiac disease, the esti- mated prevalence of LV noncompaction varies from 0.9% by echocardiographic criteria to 9.8% with car- diac magnetic resonance criteria.548 LV noncompac- tion has a broad spectrum of clinical manifestations, ranging from asymptomatic state to severe heart failure, ventricular arrhythmias, and thromboembolic The risk of thromboembolism in LV noncompaction cardiomyopathy has been evaluated in several case series, which have reported an up to 24% risk of cerebral embolism at follow-up.534,549 This increased risk has been theorized to result from blood stasis within the prominent LV trabecula- tions and intertrabecular recesses.533 535 Given the shared pathophysiological basis with LV endocavi- tary thrombus, we make this recommendation. 4. 