anticoagulation is after 10 weeks [51]. The risk of ischemic stroke was lowest and the risk of recurrent hemorrhage was highest within the first five weeks after the initial hemorrhage, suggesting anticoagulation may be delayed during this time interval. Mechanical prosthetic heart valves Resumption of warfarin is recommended for most patients with mechanical prosthetic valves who develop ICH while taking warfarin because the ongoing risk of thromboembolic events is higher than the risk of recurrent ICH, regardless of hemorrhage etiology. In a meta-analysis of more than 13,000 patients with mechanical heart valves, the incidence of major embolism was four times higher among those not on antithrombotic therapy versus those taking warfarin (4 versus 1 per 100 patient-years) [52]. A https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 12/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prosthesis in the mitral position increased the thromboembolic risk almost twice as compared with the aortic position. (See "Antithrombotic therapy for mechanical heart valves".) CAA-related ICH Many patients with lobar ICH do not resume anticoagulation because of the associated risk of recurrent ICH attributed to CAA outside a compelling indication such as a mechanical heart valve. The specific risks of future ICH for individual patients with CAA should be weighed against the benefits of resuming anticoagulation. These risks and benefits of anticoagulation for patients with CAA are discussed separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) Atrial fibrillation In the absence of high-quality trial data, the decision to resume or withhold anticoagulation in patients with ICH and atrial fibrillation requires balancing future hemorrhagic and thromboembolic risks at an individual level. For many patients with atrial fibrillation, ischemic stroke is more common than recurrent ICH and the risk-benefit analysis favors resuming anticoagulation after ICH [6]. In a 2017 meta- analysis of eight studies including 5306 patients with anticoagulation-associated ICH, restarting anticoagulation after ICH was associated with a lower risk of thromboembolic complications and no excess risk of ICH recurrence [53]. Most patients resumed warfarin and atrial fibrillation was the most common indication for restarting anticoagulation. Resumption of oral anticoagulation was also associated with reduced risk of all-cause stroke and mortality at 12 months in an analysis of 1012 patients with warfarin-associated lobar and nonlobar ICH [54]. Another meta- analysis of 50,470 patients with spontaneous or anticoagulation-associated intracranial hemorrhage and atrial fibrillation also found that resuming anticoagulation was associated with lower risk of subsequent thromboembolism without excess risk of recurrent intracranial hemorrhage [55]. However, interpretation of these meta-analyses is limited by heterogeneity of included studies, their retrospective and observational nature, and inherent selection, indication, and prescription biases. Estimating bleeding and thromboembolic risks Several clinical prediction scores have been developed to help quantify individual risks of future bleeding and thromboembolism. The CHADS2 or CHA2DS2-VASc scores to assess thromboembolic risks are used widely ( table 5 and algorithm 2). Other scores have been developed to help estimate bleeding risk. Among these, the HAS-BLED score incorporates clinical risk factors associated with bleeding to help to assess initial hemorrhagic risk (scored 1 to 9) in patients with atrial fibrillation ( table 6) [56]. However, its generalizability is limited by the small number of patients with risks who scored 5 to 9 and may also be restricted to the assessment of initial ICH risk among patients taking warfarin. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 13/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Additionally, subjective clinical assessment of bleeding risk may have a similar predictive accuracy to bleeding scores [57]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) As examples: For a typical patient with nonlobar ICH attributed to HTN without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may resume anticoagulation once HTN is controlled. For a typical patient with lobar ICH attributed to CAA without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may pursue alternatives to anticoagulation. For a typical patient with non-lobar ICH of undetermined source who has atrial fibrillation a CHA2DS2-VASc score 2, we would exclude underlying sources prior to considering resuming anticoagulation. One study using a decision-analysis model to compare warfarin resumption versus discontinuation after ICH found that resumption improves quality-adjusted life (QoL) expectancy in some patients. For patients with lobar ICH, warfarin discontinuation improves QoL expectancy by 1.9 years and is therefore preferred unless the rate of ICH recurrence is estimated to be <1.4 percent per year [58]. By contrast, for patients with deep ICH, resumption of warfarin may be preferred if the rate of recurrent ICH is low (eg, <1.6 percent per year) and the rate of ischemic stroke is high (eg, >7 percent per year). This analysis was limited to patients taking warfarin. Therapeutic options Therapeutic options for patients with ICH and atrial fibrillation include: Resumption of anticoagulation For patients with ICH who have atrial fibrillation, anticoagulation may be resumed when the associated risk of thromboembolism is higher than the future hemorrhagic risk. (See 'Estimating bleeding and thromboembolic risks' above.) For long-term anticoagulation, options include a direct oral anticoagulant (DOAC) or a vitamin K antagonist, such as warfarin. For most patients with atrial fibrillation who develop ICH while on an oral anticoagulant and in whom oral anticoagulation is resumed, we suggest a DOAC over warfarin because of a favorable hemorrhagic risk profile. For select patients, warfarin may be preferred for specific indications, described immediately below. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 14/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Direct oral anticoagulants DOACs are at least as effective as warfarin for prevention of thromboembolic events in patients with atrial fibrillation [59]. Because they are associated with a lower risk for ICH, they are an appealing option to help reduce the risk of recurrent ICH [60]. In a study of patients with atrial fibrillation or venous thromboembolism resuming anticoagulation, there was a trend toward fewer ICH recurrences in those taking a DOAC [61]. The incidence rate of recurrent ICH was 2.5 per 100 patient-years with warfarin and 1.3 per 100-patient years with a DOAC (risk ratio 1.9, 95% CI 0.6-7.4) [61]. There were too few recurrent events to assess a difference among specific DOACs. Warfarin Much of the experience with resumption of anticoagulation has been from patients taking warfarin [48,50,51]. Warfarin may be chosen based on cost or availability and is indicated for patients with specific indications, including some patients with atrial fibrillation associated with valvular heart disease and those with mechanical prosthetic heart valves. (See 'Mechanical prosthetic heart valves' above and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Patients with valvular heart disease'.) Warfarin may be preferred by patients previously taking the medication whose international normalized ratio (INR) is well-controlled. Additionally, warfarin may be preferred for other patients, including some with bodyweight <60 kg or age 80 years, and those unable to take a DOAC (eg, drug interaction, creatinine clearance <30 mL/minute). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Settings in which a heparin or vitamin K antagonist may be preferable'.) Left atrial appendage occlusion Percutaneous left atrial appendage occlusion (LAAO) may be a viable treatment option for patients with ICH and nonvalvular atrial fibrillation who are at high risk for recurrent ICH and thromboembolic events and in whom resumption of oral anticoagulation is not resumed or contraindicated [33]. In a meta- analysis of trials comparing LAAO closure with oral anticoagulation, the rates of both systemic embolism and major bleeding were similar after a mean follow-up of 39 months [62]. The risk of ICH was lower for patients assigned to LAAO (0.5 versus 2.4 percent; relative risk 0.22, 95% CI 0.02-0.58). In the Amplatzer Cardiac Plug multicenter registry, the subsequent annual major bleeding rate was 0.7 percent, corresponding to a relative risk reduction of 89 percent in patients with prior intracranial hemorrhage compared with those with other indications for LAAO [63,64]. LAAO is discussed in further detail separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 15/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy For patients with ICH and atrial fibrillation in whom anticoagulation is not resumed, antiplatelet therapy is used as an alternative. Because the benefit of aspirin to prevent thromboembolism in this population has not been established, we reserve antiplatelet therapy for patients with other indications. (See 'Antiplatelet therapy' above.) Other patients Anticoagulation may be used for patients with selected indications associated with a very high risk of thromboembolism and inadequate alternative choices. In these circumstances, risks and benefits should be discussed with patients and decisions should be individualized based on risk analysis and patient values. Such indications may include: Cancer-related thrombophilia with high risk of or prior venous thromboembolism (see "Risk and prevention of venous thromboembolism in adults with cancer") Hypercoagulable (acquired or inherited) conditions (see "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors") Venous thromboembolism with high risk of recurrence (see "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation") Other forms of cardiovascular disease (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Antithrombotic therapy in patients with heart failure") Other temporary high-risk indications for anticoagulation (see "Atrial fibrillation: Left atrial appendage occlusion", section on 'Postprocedure management' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" and "Left ventricular thrombus after acute myocardial infarction") Alternatives to intravenous thrombolytic therapy We do not routinely offer intravenous thrombolytic therapy to patients with ICH who develop conditions such as ischemic stroke, myocardial infarction, or pulmonary embolism, consistent with AHA guideline recommendations [65]. Endovascular and mechanical thrombectomy procedures may be an option for such patients. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) MANAGEMENT OF STATINS https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 16/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate The decision to resume statins (hydroxymethylglutaryl [HMG] CoA reductase inhibitors) for patients with ICH requires balancing the benefits of therapy with the potential hemorrhagic risks. We suggest resuming statins in most patients with ICH who have a strong indication for therapy. This includes patients with diabetes and coronary artery disease and those with recent myocardial infarction or baseline severe atherosclerotic arterial disease. We discontinue statins for patients with ICH with less compelling indications such as isolated dyslipidemia and for those with multiple (recurrent) lobar ICHs who are at high risk for ICH recurrence [66]. For patients with ICH who resume statins, we avoid high doses and prefer hydrophilic statins (eg, pravastatin or rosuvastatin). For patients who discontinue statins after ICH, we use the indication for therapy to help select an alternative medication. (See "Statins: Actions, side effects, and administration" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management".) Statins appear to increase the propensity for ICH by inhibiting platelets, decreasing thrombus formation, and enhancing fibrinolysis [67,68]. In addition, hyperlipidemia appears to be protective against ICH. In a case-control study including 3492 patients with ICH, a reduced risk of ICH was associated with each increase in serum cholesterol by 5 mg/dL (odds ratio 0.87, 95% CI 0.86-0.88) [69]. Additionally, lower levels of low-density lipoprotein cholesterol are also associated with increased risk for ICH [70,71]. The contribution of statin drugs to the risk of initial ICH is supported by trials and several observational studies [69,72,73]. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, patients with prior transient ischemic attack or ischemic stroke assigned to atorvastatin had fewer major cardiovascular events than those assigned to placebo (3.5 percent absolute risk reduction) [74]. However, the incidence rate of ICH was significantly higher in patients who received atorvastatin 80 mg daily (2.3 versus 1.4 percent; risk ratio [RR] 1.68, 95% CI 1.09-2.5). However, data on the risk of recurrent ICH are less certain [75,76]. Outcomes associated with statin use were evaluated in a 2018 systematic review of 15 studies that included more than 50,000 patients with prior ICH [25]. Among studies reporting ICH recurrence, the risk associated with statin use was similar to controls (RR 1.04, 95% CI 0.86-1.25). However, statin use was associated with improved functional outcome and reduced mortality in patients with prior ICH. These findings may reflect variability of individual risk related to several factors including statin dose or formulation, prescription bias, the burden of atherosclerotic disease, and the cause of the prior ICH. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 17/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Effect of statin dose Statin dose may modify the risk of hemorrhagic complications such as ICH [77]. A meta-analysis of seven randomized controlled trials found that higher doses of statins were associated with increased risk for ICH compared with placebo (RR 1.53, 95% CI 1.16-2.01) [78]. However, a large 10-year nationwide cohort study from Taiwan found no association between statin dose and risk of recurrent ICH [79]. Effect of statin formulation Statins with lipophilic solubility (atorvastatin, lovastatin, simvastatin, cerivastatin, and fluvastatin) have a greater ability to penetrate across blood- brain barrier and have been associated with increased odds of recurrent ICH compared with hydrophilic statins [79]. Cause of incident ICH Some cohorts suggest the hemorrhagic risk with statin use is associated with patients with lobar ICH [80-82]. The protective effect of hyperlipidemia also appears to be higher for patients with lobar versus nonlobar ICH [69]. LIFESTYLE MODIFICATIONS We advise lifestyle modifications based on their association as risk factors of stroke, including ICH [33]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) These include: Regular physical activity (see "The benefits and risks of aerobic exercise") Maintenance of healthy body weight (see "Obesity in adults: Overview of management") Healthy diet (see "Healthy diet in adults") Cessation of smoking and excessive alcohol use (see "Cardiovascular risk of smoking and benefits of smoking cessation") Avoidance of sympathomimetic medications (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors') LONG-TERM PROGNOSIS Prognosis after ICH involves both initial prognosis and long-term prognosis. The clinical and imaging determinants of initial prognosis occur within the acute hospitalization and recovery periods, typically comprising the first 180 days after ICH. Long-term prognosis focuses on sequelae of ICH, which persist beyond 180 days. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 18/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Acute prognosis in ICH is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Early prognosis'.) Functional recovery The rate of recovery after ICH may be highest in the first few weeks to months. In one study, recovery was greatest within the first 30 days after ICH [83]. However, recovery after ICH is often delayed and can be slow; many patients report functional improvements for 6 to 12 months [84,85]. In a post-hoc analysis of individual patient data from two clinical trials of patients with intracerebral or intraventricular hemorrhage, poor functional outcome at 30 days was reported in 715 of 999 patients (72 percent) [86]. By one year, 308 of these patients (46 percent) had achieved good functional outcome, including 30 percent who were functionally independent. Older age, larger hemorrhage volumes, and baseline conditions such as diabetes mellitus and severe leukoaraiosis on imaging were associated with poor one- year outcomes. In addition, common complications of acute ICH were also predictors of poor outcome at one year including sepsis, new ischemic stroke, prolonged mechanical ventilation, hydrocephalus, and the need for gastrostomy feeding tube. Aggressive acute treatment to prevent these acute complications may help avoid premature withdrawal of support and improve long-term outcomes. Early rehabilitation and sustained support are recommended to maximize functional recovery [83,87,88]. Educating patients and caregivers regarding secondary prevention strategies and addressing lifestyle changes, depression, and caregiver burden is an important part of post-ICH rehabilitation program. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Initial aggressive care'.) The main clinical determinants associated with reduced functional recovery after ICH include increasing age, baseline comorbidities, and severity of ICH as assessed by Glasgow Coma Scale score at presentation. Key imaging determinants include ICH volume, the presence of intraventricular hemorrhage, and specific ICH locations (including brainstem, posterior limb of internal capsule, or thalamus) [89,90]. Functional outcome may be assessed using varying performance thresholds or clinical scoring tools. The modified Rankin Scale (mRS) is frequently used ( table 7). In several trials, patients with ICH achieving a score of 0 to 3 have been described as having a good functional outcome; poor outcome included those scoring 4 to 6. In a retrospective study of 1499 patients, 51 percent of patients with a first ICH had good functional recovery after 90 days, compared with 31 percent of patients after recurrent ICH [91]. A decline in long-term functional status has been observed among patients after ICH. In a single-center observational study of 560 patients, 23 percent of those with a good functional outcome at six months had declined over a median nine-year follow-up [92]. Advanced age, https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 19/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate higher initial ICH volume, lower six-month functional status, and new diagnoses of dementia or stroke during follow-up were predictors of functional decline. Cognitive impairment Cognitive impairment is frequent among patients after ICH [93,94]. A systematic review reported that the prevalence of cognitive impairment ranged between 14 and 88 percent after ICH [95]. Predictive factors were previous stroke, ICH volume and location, and markers of cerebral amyloid angiopathy. Cognitive deficits after ICH were common across multiple domains. The most frequently impaired domains were naming, processing speed, executive functioning, memory, visuospatial abilities, and attention. Long-term mortality In population-based cohorts of patients hospitalized after ICH the 10- year survival rate ranged from 18 to 25 percent [5,96]. Life expectancy among patients after ICH was decreased compared with age- and sex-matched controls in the general population [97-99]. In a cohort of 219 patients with ICH, the major cause of death within five years was cardiovascular disease, largely due to recurrent ICH and its sequelae (10 percent) irrespective of ICH location [5]. The risk of death was similar in patients with lobar versus nonlobar ICH and higher in patients with anticoagulation-associated ICH. A retrospective multicenter 10-year study of 1499 patients with ICH reported recurrent ICH in 9.5 percent of patients and found that 30-day mortality was similar (approximately 14 percent) after first and recurrent ICH [91]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 20/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hemorrhagic stroke (The Basics)") Beyond the Basics topic (see "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Risk factors for recurrent ICH Several risk factors have been implicated in the risk of recurrent intracerebral hemorrhage (ICH). These include the location and etiology of the initial ICH, hypertension, older age, several medications ( table 1), race/ethnicity, chronic kidney disease, prior stroke, and specific genetic features. (See 'Risk of recurrence' above.) Follow-up imaging to evaluate for underlying causes We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause ( algorithm 1 and table 2). For most patients, we prefer brain magnetic resonance imaging (MRI) with gadolinium to evaluate for an underlying cause. (See 'Follow-up neuroimaging' above.) Blood pressure management Blood pressure control is an important feature of secondary prevention for all patients with ICH. We suggest a long-term target <130/80 mmHg to lower the risk of ICH recurrence (Grade 2B). (See 'Blood pressure management' above.) Management of antiplatelet therapy We suggest resuming antiplatelet therapy for most patients with ICH who have a specific indication for such therapy (Grade 2C). For patients with ICH in whom antiplatelet therapy is being resumed, we typically start aspirin within a few days after the ICH has stabilized. (See 'Antiplatelet therapy' above.) Management of anticoagulation We balance the risks of recurrent ICH and thromboembolism to help make decisions about resuming anticoagulation for each patient ( algorithm 2). (See 'Anticoagulation' above.) Early resumption of anticoagulation may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve). For most other patients who resume anticoagulation, we generally suggest waiting for at least four weeks after onset of the ICH to restart the anticoagulant (Grade 2C). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 21/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients with atrial fibrillation, prediction models such as the HAS-BLED score may be used to help assess bleeding risk ( table 6) and CHADS2 or CHA2DS2-VASc scores used to help assess thromboembolic risks ( table 5). For many patients with atrial fibrillation, the risk-benefit analysis favors resuming anticoagulation after ICH. For most patients with atrial fibrillation who develop ICH while on warfarin and in whom oral anticoagulation is resumed, we suggest a direct oral anticoagulant (DOAC) over warfarin (Grade 2B). DOACs generally have a lower risk of bleeding, including ICH, than warfarin. Warfarin may be selected for patients with valvular atrial fibrillation, a mechanical heart valve, or an inability to take a DOAC. Management of statins We suggest resuming statins for most patients with lobar and nonlobar ICH who have atherosclerotic disease (Grade 2C). We discontinue statins for most patients with multiple (recurrent) lobar ICHs. (See 'Management of statins' above.) Long-term prognosis The rate of recovery after ICH may be highest in the first few months. However, the greatest extent of recovery may not be evident until 6 to 12 months after ICH. (See 'Functional recovery' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Arima H, Tzourio C, Butcher K, et al. Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial. Stroke 2006; 37:1497. 2. Poon MT, Fonville AF, Al-Shahi Salman R. 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