Risk Factor Management In patients with a stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, maintenance of SBP below 140 mmHg, high-intensity statin therapy, and at least moderate physical activity are recom- mended to prevent recurrent stroke and Angioplasty and Stenting In patients with severe stenosis (70%-99%) of a major intracranial artery and actively pro- gressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel therapy, achievement of SBP <140 mmHg, and high- intensity statin therapy (so-called medical failures), the usefulness of angio- plasty alone or stent placement to prevent ischemic stroke in the territory of the stenotic artery is unknown.350 352 3: Harm A In patients with stroke or TIA attributable to severe stenosis (70% 99%) of a major intracranial artery, angioplasty and stenting should not be performed as an initial treat- ment, even for patients who were taking an antithrombotic agent at the time of the stroke 3: Harm B-NR In patients with a stroke or TIA attributable to moderate stenosis (50% 69%) of a major intracranial artery, angioplasty or stenting is associated with excess morbidity and mortal- ity compared with medical management Other Procedures Benefit B-R In patients with stroke or TIA attributable to 50% to 99% stenosis or occlusion of a major intracranial artery, extracranial-intracra- nial bypass surgery is not recommended.361 Synopsis ICAS is a common cause of stroke worldwide with a high rate of recurrent stroke.362 Severity of stenosis is a strong predictor of risk of recurrent stroke in the ter- ritory of the stenotic artery, with 1-year rates as high as Therapeutic tri- als have demonstrated that for most patients with ICAS, antithrombotic therapy and vascular risk factor control are effective for stroke prevention. However, there may be a subset of patients (eg, those with low flow or poor collaterals) who have an even higher risk of recurrent stroke despite medical therapy.357,363,364 Current research is focused on identifying characteristics of patients with ICAS at highest risk and studying new therapies for stroke prevention.


However, there may be a subset of patients (eg, those with low flow or poor collaterals) who have an even higher risk of recurrent stroke despite medical therapy.357,363,364 Current research is focused on identifying characteristics of patients with ICAS at highest risk and studying new therapies for stroke prevention. Recommendation-Specific Supportive Text 1. In the WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease), warfarin (target INR, 2 3) compared with aspirin 650 mg twice a day was found to have a higher rate of major hemorrhages (relative difference, 5.1%) and all-cause death (rela- tive difference, 5.4%) but did not prevent more pri- mary end points (stroke, ICH, vascular death) (22% in both arms at a mean follow-up of 1.8 years) or ischemic strokes in the territory of the stenotic artery (2-year rate: 15% for aspirin versus 13% for The optimal dose of aspirin for second- ary prevention in patients with ICAS has not been determined, but doses <1300 mg/d are probably effective given that lower doses of aspirin have been shown to be effective for secondary prevention in trials of heterogeneous causes of stroke and that patients in the medical arm of the SAMMPRIS trial were treated with 325 mg aspirin once daily alone after the first 90 days with favorable results.336 2. Support for the use of short-term combination aspirin and clopidogrel for secondary prevention in patients with severe ICAS comes from post hoc analyses of clinical trials and RCTs studying surro- gate end points for stroke.


Support for the use of short-term combination aspirin and clopidogrel for secondary prevention in patients with severe ICAS comes from post hoc analyses of clinical trials and RCTs studying surro- gate end points for stroke. Patients in the medical arm of SAMMPRIS with severe stenosis received aspirin and clopidogrel for 90 days followed by aspirin alone for the rest of follow-up and had a lower 1-year recurrent stroke rate (12.2%) com- pared with similar patients from WASID on aspi- rin alone (25%).336,337 Subgroup analysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events) reported that patients with ICAS who were randomized to clopidogrel and aspirin for 21 days followed by clopidogrel alone had a lower rate of stroke at 90 days (11.3%) compared with those on aspirin alone (13.6%), although the difference was not statistically significant.338 Patients in the CLAIR trial (Clopidogrel Plus Aspirin for Infarction Reduction) randomized to aspirin and clopidogrel for 7 days had significantly decreased microemboli in the territory of the stenotic ICA or middle cere- bral artery compared with those on aspirin alone and a lower rate of recurrent stroke at day 7 (0% in combination versus 3.8% in aspirin alone), but this difference was not significant.339 In contrast to patients with heterogeneous causes of minor stroke wherein the risk of recurrent stroke plateaus within a few weeks,365 the risk of recurrent stroke from ICAS extends well beyond 30 days.338,353 Data from these studies also suggest that short-term combination aspirin and clopidogrel up to 90 days is safe. 3.


Patients in the medical arm of SAMMPRIS with severe stenosis received aspirin and clopidogrel for 90 days followed by aspirin alone for the rest of follow-up and had a lower 1-year recurrent stroke rate (12.2%) com- pared with similar patients from WASID on aspi- rin alone (25%).336,337 Subgroup analysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events) reported that patients with ICAS who were randomized to clopidogrel and aspirin for 21 days followed by clopidogrel alone had a lower rate of stroke at 90 days (11.3%) compared with those on aspirin alone (13.6%), although the difference was not statistically significant.338 Patients in the CLAIR trial (Clopidogrel Plus Aspirin for Infarction Reduction) randomized to aspirin and clopidogrel for 7 days had significantly decreased microemboli in the territory of the stenotic ICA or middle cere- bral artery compared with those on aspirin alone and a lower rate of recurrent stroke at day 7 (0% in combination versus 3.8% in aspirin alone), but this difference was not significant.339 In contrast to patients with heterogeneous causes of minor stroke wherein the risk of recurrent stroke plateaus within a few weeks,365 the risk of recurrent stroke from ICAS extends well beyond 30 days.338,353 Data from these studies also suggest that short-term combination aspirin and clopidogrel up to 90 days is safe. 3. Data from the THALES trial (Acute Stroke or Transient Ischaemic Attack Treated With Recommendations for Intracranial Large Artery Atherosclerosis (Continued) COR LOE Recommendations Antithrombotic Therapy (Continued) CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Ticagrelor and ASA for Prevention of Stroke and Death; discussed in more detail in Section 5.19, Use of Antithrombotic Medications in Secondary Stroke Prevention) also inform recommenda- tions for short-term treatment with combination ticagrelor and aspirin in patients with atheroscle- rosis ipsilateral to the ischemic territory, including ICAS.


Data from the THALES trial (Acute Stroke or Transient Ischaemic Attack Treated With Recommendations for Intracranial Large Artery Atherosclerosis (Continued) COR LOE Recommendations Antithrombotic Therapy (Continued) CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Ticagrelor and ASA for Prevention of Stroke and Death; discussed in more detail in Section 5.19, Use of Antithrombotic Medications in Secondary Stroke Prevention) also inform recommenda- tions for short-term treatment with combination ticagrelor and aspirin in patients with atheroscle- rosis ipsilateral to the ischemic territory, including ICAS. In this prespecified subgroup analysis,340 risk of recurrent stroke or death at 30 days among patients with 30% intracranial stenosis ipsilateral to the ischemic event was 9.9% in the ticagrelor 90 mg twice a day plus aspirin 100 mg once a day group versus 15.2% in the aspirin 100 mg alone group (HR, 0.66 [95% CI, 0.47 0.93]; P=0.016). In contrast to the THALES patients without atherosclerosis, bleeding events among the ipsilateral atherosclerosis subgroup treated with ticagrelor and aspirin were not significantly higher than in those taking aspirin alone. Of note, THALES required loading doses of both ticagre- lor and aspirin. Also of note, in this analysis, ICAS was not required to be related to the index isch- emic event, so some patients may not have had symptomatic ICAS. Given the lack of comparative data between various dual-antiplatelet regimens in ICAS, the choice of adding ticagrelor or clopido- grel to aspirin should be based on patient factors such as medication adherence (eg, relative cost and dose frequency), but the role of genetic stud- ies or platelet function testing remains unclear. 4. Several RCTs have studied the efficacy of cilo- stazol 200 mg/d combined with other antiplate- let agents in patients with symptomatic ICAS.


Several RCTs have studied the efficacy of cilo- stazol 200 mg/d combined with other antiplate- let agents in patients with symptomatic ICAS. The TOSS-1 and TOSS-2 trials (Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis) found that cilostazol (200 mg/d) plus aspirin was as safe as aspirin alone or clopidogrel plus aspirin but was no better for stroke prevention in patients The CATHARSIS trial (Cilostazol- Aspirin Therapy Against Recurrent Stroke With Intracranial Artery Stenosis) reported that the combination of cilostazol and aspirin was superior to aspirin for the prevention of the combined sec- ondary end point of all vascular events and new but had no impact on ICAS progression.343 Subgroup analysis of the CSPS trial reported that patients with ICAS who were randomized to cilostazol plus either aspirin or clopidogrel (dual group) had a lower rate of stroke compared with those on aspirin or clopidogrel alone (4% versus Of note, these trials were conducted in a primarily Asian population, the dose of aspirin when used in com- bination with cilostazol did not exceed 150 mg/d, and many were unblinded. 5. Antithrombotic agents that have been specifically studied in RCTs of patients with ICAS include war- farin, aspirin, cilostazol, and the combination of clopidogrel plus aspirin or cilostazol. 6.


Antithrombotic agents that have been specifically studied in RCTs of patients with ICAS include war- farin, aspirin, cilostazol, and the combination of clopidogrel plus aspirin or cilostazol. 6. Post hoc analyses from WASID (N=567), the med- ical arm of SAMMPRIS (n=227), and the CICAS registry (Chinese Intracranial Atherosclerosis; N=2426) showed that achievement of a mean SBP <140 mmHg during follow-up in patients with ICAS was associated with a lower risk of stroke and vascular events, even in patients with or those treated early Although most patients with ICAS probably benefit from lower BP, some small stud- ies suggest that patients with documented hemo- or those treated to SBP <120 mmHg early after stroke348 may not benefit, and the lower threshold associated with increased stroke risk is not known. High-intensity statin use is supported by an RCT in patients with ICAS that showed that high-intensity statins lowered the rate of cerebrovascular events349 and by general recommendations (see Section 4.3, Treatment of Hyperlipidemia for Secondary Prevention of Stroke). An optimum target LDL for patients with ICAS has not been determined, but WASID and SAMMPRIS post hoc analyses show lower LDLs are associated with lower vascular event rates in patients with ICAS,110,337 and a recent RCT dem- onstrated benefit of an LDL target <70 mg/dL in patients with stroke and atherosclerosis.210 Moderate physical activity at least 3 to 5 times per week was the factor most strongly associated with lower risk of recurrent stroke and vascular events in a post hoc analysis of SAMMPRIS medically 7. Two uncontrolled multicenter registries reported outcomes after percutaneous transluminal angio- plasty and stenting (PTAS) in patients with ICAS who have progressive symptoms or failed medical therapy (ie, had a recurrent stroke or TIA despite treatment with antithrombotic medications or risk factor control).


Two uncontrolled multicenter registries reported outcomes after percutaneous transluminal angio- plasty and stenting (PTAS) in patients with ICAS who have progressive symptoms or failed medical therapy (ie, had a recurrent stroke or TIA despite treatment with antithrombotic medications or risk factor control). The WEAVE prospective registry (Wingspan Stent System Post Market Surveillance) reported a periprocedural complication rate of 2.6% in 152 patients who met the specific US Food and Drug Administration Humanitarian Device Exemption criteria for Wingspan stent use, but outcomes beyond 72 hours after the procedure have not been published.350 However, the stroke or death rate was 23.9% in the 46 patients treated off- label, many of whom had not failed medical therapy or were treated less than a week from symptom A retrospective registry of 101 patients with ICAS receiving stenting or balloon angioplasty, which included both patients who failed medical CLINICAL STATEMENTS AND GUIDELINES Kleindorfer therapy and those with progressive stroke symp- toms, reported a 90-day ischemic stroke rate of Post hoc analysis of SAMMPRIS patients who had a prior stroke or TIA while on antithrombotic therapy (n=284) showed that medical therapy was supe- rior to PTAS for the prevention of the primary end point in this subgroup (15% for aggressive medical management versus 24% for PTAS; P=0.043).352 Given the lack of efficacy data, PTAS is considered investigational in this population. 8. Three RCTs have compared PTAS with medi- cal therapy for stroke prevention in patients with recent stroke or TIA attributable to 70% to 99% stenosis. The SAMMPRIS trial (N=451) used the Wingspan stenting system; the VISSIT trial (Vitesse Intracranial Stent Study for Ischemic Stroke Therapy; N=112) used the Pharos system; and a single-center RCT in China (N=70) allowed either Wingspan or Coroflex stenting systems.


The SAMMPRIS trial (N=451) used the Wingspan stenting system; the VISSIT trial (Vitesse Intracranial Stent Study for Ischemic Stroke Therapy; N=112) used the Pharos system; and a single-center RCT in China (N=70) allowed either Wingspan or Coroflex stenting systems. Medical therapy was similar in the 3 RCTs and consisted of risk factor management and combination aspirin and clopidogrel for 90 days and then aspirin alone. All 3 RCTs showed a higher 30-day rate of cere- brovascular events or death in the PTAS group than the medical group and no benefit of PTAS beyond the periprocedural period.353 355 Post hoc analyses of SAMMPRIS baseline characteristics failed to demonstrate any subgroup of patients who ben- efited from PTAS but did identify some possible high-risk features for future study.356,357 Two other RCTs (VAST [Vertebral Artery Stenting Trial] and VIST [Vertebral Artery Ischemic Stenting Trial]) that randomized patients with intracranial and extracra- nial posterior circulation stenosis to PTAS or medi- cal therapy reported no significant benefit of PTAS among the patients with ICAS.358,359 9. No RCTs have directly compared PTAS with med- ical therapy in patients with symptomatic 50% to 69% stenosis. However, the low rate of stroke on medical therapy in patients with 50% to 69% high periprocedural risk, which does not vary by degree of stenosis,368 and lack of demonstrated benefit of PTAS in well-designed RCTs performed in a higher-risk population do not support the use of PTAS. 10.


However, the low rate of stroke on medical therapy in patients with 50% to 69% high periprocedural risk, which does not vary by degree of stenosis,368 and lack of demonstrated benefit of PTAS in well-designed RCTs performed in a higher-risk population do not support the use of PTAS. 10. A large multicenter RCT comparing extracranial- intracranial arterial bypass with medical therapy in 1377 patients with recent minor stroke or TIA included patients with 70% intracranial middle cerebral artery (n=109) or ICA (n=149) stenosis and found higher rates of stroke in patients with ICAS treated with extracranial-intracranial arterial bypass than in those in the medical group.361 Knowledge Gaps and Future Research Despite numerous advances in ICAS treatment over the past several decades, the recurrent stroke risk remains high. Further investigation into the following should be prioritized: Studying new therapies in well-designed clinical trials, including novel antithrombotic regimens (eg, direct thrombin inhibitors), improved endovascular treatments (eg, submaximal balloon angioplasty), indirect bypass, and ischemic preconditioning. Determining the interaction between hemodynamic function or collateral flow and treatments (eg, BP management and endovascular therapy). Developing and using surrogate markers of stroke risk (eg, plaque characteristics) or high-risk prognostic fea- tures (eg, diabetes) that may lead to new therapies or improve patient selection for future therapeutic trials. Genetic variants that relate to ICAS (eg, ring finger protein 213) and whether such variants affect the rate of stroke recurrence or treatment responses. 5.1.2. Extracranial Large Artery Atherosclerosis 5.1.2.1. Extracranial Carotid Stenosis Recommendations for Extracranial Carotid Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28.


Extracranial Carotid Stenosis Recommendations for Extracranial Carotid Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28. COR LOE Recommendations In patients with a TIA or nondisabling ischemic stroke within the past 6 months and ipsilateral severe (70% 99%) carotid artery stenosis, carotid endarterectomy (CEA) is recommended to reduce the risk of future stroke, provided that perioperative morbidity and mortality risk is estimated to be <6%.369 In patients with ischemic stroke or TIA and symptomatic extracranial carotid stenosis who are scheduled for carotid artery stent- ing (CAS) or CEA, procedures should be performed by operators with established periprocedural stroke and mortality rates of <6% to reduce the risk of surgical adverse In patients with carotid artery stenosis and a TIA or stroke, intensive medical therapy, with antiplatelet therapy, lipid-lowering therapy, and treatment of hypertension, is recom- mended to reduce stroke risk.210 In patients with recent TIA or ischemic stroke and ipsilateral moderate (50% 69%) carotid steno- sis as documented by catheter-based imaging or noninvasive imaging, CEA is recommended to reduce the risk of future stroke, depending on patient-specific factors such as age, sex, and comorbidities, if the perioperative morbidity and mortality risk is estimated to be <6%.369 In patients 70 years of age with stroke or TIA in whom carotid revascularization is being considered, it is reasonable to select CEA over CAS to reduce the periprocedural stroke rate.371 In patients in whom revascularization is planned within 1 week of the index stroke, it is reasonable to choose CEA over CAS to reduce the periprocedural stroke rate.372 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer In patients with TIA or nondisabling stroke, when revascularization is indicated, it is reasonable to perform the procedure within 2 weeks of the index event rather than delay surgery to increase the likelihood of stroke- In patients with symptomatic severe stenosis ( 70%) in whom anatomic or medical condi- tions are present that increase the risk for surgery (such as radiation-induced stenosis or restenosis after CEA) it is reasonable to choose CAS to reduce the periprocedural In symptomatic patients at average or low risk of complications associated with endovascular intervention, when the ICA stenosis is 70% by noninvasive imaging or >50% by catheter-based imaging and the anticipated rate of periprocedural stroke or death is <6%, CAS may be considered as an alternative to CEA for stroke preven- tion, particularly in patients with significant cardiovascular comorbidities predispos- ing to cardiovascular complications with In patients with a recent stroke or TIA (past 6 months), the usefulness of transcarotid artery revascularization (TCAR) for prevention of recurrent stroke and TIA is uncertain.376 Benefit A In patients with recent TIA or ischemic stroke and when the degree of stenosis is <50%, revascularization with CEA or CAS to reduce the risk of future stroke is not recom- Benefit A In patients with a recent (within 120 days) TIA or ischemic stroke ipsilateral to atherosclerotic stenosis or occlusion of the middle cerebral or carotid artery, extracranial- intracranial bypass surgery is not recom- Synopsis Previous randomized clinical trials have compared CEA with best medical therapy in patients with a recent stroke or TIA.


A combined analysis of these trials found the greatest benefit for CEA was in severe (70% 99%) ICA stenosis with recent symptoms. Post hoc analysis of these original trials found a greater benefit of CEA when the surgery was done in patients who were enrolled within 2 weeks of their last ischemic event. These trials were initiated >30 years ago, and current optimal medi- cal therapy was not used in these trials. There is a paucity of data on CEA compared with current optimal medical therapy in patients with symptomatic carotid stenosis. CEA also has been compared with CAS. Across several trials, CAS was associated with a higher periprocedural stroke rate, but similar results have been seen with CEA and CAS beyond the immediate periprocedural period. Extracranial-to-intracranial bypass for internal carotid occlusion has not been demonstrated to reduce the risk of recurrent stroke. Recommendation-Specific Supportive Text 1. A combined analysis by Rothwell et al369 of the original CEA trials (NASCET [North American Symptomatic Carotid Endarterectomy Trial], ECST [European Carotid Surgery Trial], and VA [Veterans Affairs Trial 309]) found robust benefit for CEA in patients with severe (70% 99%) ICA stenosis (16.0% absolute benefit over 5 years). In these studies, patients were typically >40 years of age and of either sex. The NASCET method of stenosis measurement was used in the combined analysis of the 3 trials. In the original trials (NASCET and ECST), angiography was used for stenosis mea- surements, but more recent trials (CREST [Carotid Revascularization Endarterectomy versus Stenting Trial]) and routine clinical practice typically use noninvasive imaging, with angiography used for cases with discrepant or ambiguous results from noninvasive tests. 2. Surgical results and statistical modeling from clini- cal trials such as NASCET and CREST support this threshold for perioperative outcomes.24 3.


Surgical results and statistical modeling from clini- cal trials such as NASCET and CREST support this threshold for perioperative outcomes.24 3. On the basis of trials of antiplatelet therapy for patients with recent stroke or TIA, antiplatelet therapy is recommended for patients with symp- tomatic carotid stenosis. Similarly, antihyperten- sive therapy and statins are recommended for patients with symptomatic carotid stenosis. A recent trial of 2 different lipid targets for patients with a recent stroke or TIA found that an LDL tar- get of <70 mg/dL was associated with a reduced vascular event rate compared with a target of 90 This trial included patients with symptomatic carotid stenosis. The use of multi- modality medical therapy also has been incorpo- rated into clinical trials.18 4. The analysis by Rothwell et al369 found mild ben- efit in patients with 50% to 69% ICA stenosis (4.6% over 5 years). In the NASCET analysis of this stenosis range, there was no clear benefit of CEA seen in women and in patients with retinal ischemic events. In the combined analysis of symp- tomatic CEA trials, the number needed to treat to prevent 1 stroke was higher in women compared with men (36 versus 9). Life expectancy also should be considered when treatment decisions are made because CEA has delayed benefit. 5. Several variables have been analyzed in relation to CEA and CAS outcomes. The Carotid Stenting Trialists Collaboration analyzed outcomes in 4754 patients from 4 clinical trials.371 Within 120 days of study entry, HRs were calculated according to 5-year age intervals to compare CAS with CEA. In the group 65 to 69 years of age, the HR was 1.61 (95% CI, 0.90 2.88).


In the group 65 to 69 years of age, the HR was 1.61 (95% CI, 0.90 2.88). In the group 70 to 74 years of age, the Recommendations for Extracranial Carotid Stenosis (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Kleindorfer HR comparing CAS to CEA was 2.09 (95% CI, 1.32 3.32). This supports the recommendation for consid- ering patient age in the selection of the procedure. 6. In addition, CEA is associated with a reduced complication rate relative to CAS in patients who undergo the procedure within 1 week of a stroke or TIA. The Carotid Stenosis Trialists Collaboration evaluated 4138 patients randomly assigned to CEA or CAS.372 In patients who received the proce- dure within 1 week of the last symptomatic event, the stroke/death rate was 8.3% with CAS versus 1.3% with CEA (RR, 6.7; P=0.002). This supports a preference for CEA in patients who undergo early revascularization. 7. Post hoc analysis of these trials found a greater ben- efit of CEA when the surgery was done in patients who were enrolled within 2 weeks of their last non- disabling ischemic event.373 Therefore, if the patient is suitable for operation, early CEA is preferred. 8. In the SAPPHIRE trial (Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy), patients with high anatomic or phys- iologic risk for CEA were assigned to CEA or CAS.374 The primary end point was stroke, MI, or death within 30 days or ipsilateral stroke up to 12 months. Among symptomatic patients, the primary end point occurred in 16.8% of patients undergoing CAS and 16.5% of patients undergoing CEA (P=0.95). However, the trial was not powered to evaluate only the symptom- atic group of patients. This study supports the option of CAS in patients at elevated surgical risk. 9.


This study supports the option of CAS in patients at elevated surgical risk. 9. In the CREST multicenter randomized clinical trial, CEA and CAS were directly compared in both symp- tomatic and asymptomatic patients. Among the 1321 symptomatic patients, over the 4-year study period, the primary end point (periprocedural stroke, death, or MI, plus later ipsilateral stroke) occurred in 8.6% of patients undergoing CAS and 8.4% of patients Both surgeons and intervention- alists were required to be credentialed for the study, and a periprocedural stroke/death rate of <6% (or lower) has been suggested in earlier statements. 10. TCAR is a relatively new endovascular technique that has several unique features. The interventional specialist directly accesses the common carotid artery, and flow reversal is provided to have blood drain to the femoral vein. A stent is placed at the site of ICA stenosis with no need to traverse the aortic arch. TCAR results have been analyzed in registries only thus far. A propensity score matched analysis compared TCAR with transfemoral CAS. Among 3286 patient pairs, approximately half of the patients were symptomatic. In symptomatic patients, TCAR, relative to transfemoral CAS, was associated with a lower rate of in-hospital stroke/death (2.1% versus 4.2%), stroke (2.0% versus 3.1%), and death TCAR has not been evalu- ated in randomized trials thus far and has not been compared with CEA or intensive medical therapy. 11. The combined analysis by Rothwell et al369 of CEA in patients with recent stroke or TIA found no ben- efit in patients with <50% ICA stenosis. 12.


The combined analysis by Rothwell et al369 of CEA in patients with recent stroke or TIA found no ben- efit in patients with <50% ICA stenosis. 12. In COSS (Carotid Occlusion Surgery Study), 195 subjects with recently symptomatic carotid occlu- sion and increased oxygen extraction fraction measured by positron emission tomography were assigned to bypass surgery or medical therapy.377 The primary end point was stroke/death within 30 days and ipsilateral stroke up to 2 years. The pri- mary end point occurred in 21.0% of the surgery group and 22.7% of the medically treated patients (P=0.78). This supports the recommendation against bypass surgery for patients with recently symptomatic carotid occlusion. 5.1.2.2. Extracranial Vertebral Artery Stenosis Recommendations for Extracranial Vertebral Artery Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28. 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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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 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.


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).


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.


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.


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.


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 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.


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.


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.


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 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 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.


*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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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 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.


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.