7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis : Magdy Selim, MD, PhD : Scott E Kasner, MD, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 07, 2022. INTRODUCTION Spontaneous intracerebral hemorrhage (ICH) is often associated with long-term neurologic symptoms, and patients with ICH have an elevated risk of recurrence. Prevention of recurrent ICH (ie, secondary prevention) may reduce accumulating neurologic disability as well as societal burden of ICH. ICH may be categorized as either spontaneous or traumatic. ICH following traumatic brain injury is reviewed separately. (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology".) This topic will review the epidemiology, secondary prevention, and long-term prognosis in adults with spontaneous ICH. Other aspects of ICH are discussed elsewhere. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) (See "Cerebral amyloid angiopathy".) (See "Hemorrhagic stroke in children".) (See "Stroke in the newborn: Management and prognosis".) RISK OF RECURRENCE https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 1/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Incidence The incidence of recurrent ICH varies from 2 to 7 percent per year, depending on risk factors [1,2]. Patients with a history of ICH have a risk of recurrent ICH that is higher than the risk of recurrence in patients with ischemic stroke [1-3]. In addition, the rate of recurrent ICH was 6.6-fold higher than for a first ICH in a study of patients with prior ischemic stroke [1]. The risk of ICH recurrence may be highest in the first 12 months after the initial ICH but persists for years after the first event, particularly after lobar ICH [4]. The cumulative risk of ICH recurrence varies from 1.3 to 8.9 percent after one year and ranges from 7.4 to 13.7 percent after five years in different populations [2,3,5,6]. Risk factors Initial ICH location and etiology Deep (nonlobar) ICH involving the basal ganglia, thalamus, cerebellum, or brainstem is associated with a lower risk of recurrence than ICH in lobar locations. The annual risk of ICH recurrence after deep ICH is approximately 2 to 3 percent, versus 7 to 14 percent after lobar ICH [2,7-9]. ICH involving deep nuclei is often attributed to hypertensive microvascular disease and lobar ICH is often attributed to cerebral amyloid angiopathy (CAA), but the risk of recurrence appears to be independent of ICH etiology, at least in part. CAA is a major cause of incident and recurrent lobar ICH [10]. A meta-analysis of 10 prospective cohorts of ICH patients found that the annual risk of ICH recurrence after CAA- related ICH was 7.4 percent (95% CI 3.2-12.6), versus 1.1 percent (95% CI 0.5-1.7) for non- CAA-related ICH [11]. (See "Cerebral amyloid angiopathy".) Other secondary causes of ICH, such as brain arteriovenous malformation, moyamoya syndrome, sickle cell disease, and brain tumors are also associated with elevated risks of recurrent ICH based on the nature of the underlying causes and the presence of specific associated high-risk features. These are discussed separately. (See "Brain arteriovenous malformations" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis" and "Prevention of stroke (initial or recurrent) in sickle cell disease" and "Overview of the clinical features and diagnosis of brain tumors in adults".) Other imaging features The presence and number of cerebral microbleeds (CMBs) and/or superficial siderosis on brain magnetic resonance imaging (MRI) identifies patients at high risk for recurrent ICH [11,12]. In one study, the presence of >1 CMB was associated with increased risk of recurrent ICH in patients with CAA-related ICH while a higher threshold, >10 CMBs, identified increased risk of a recurrent event in patients with non- CAA-related ICH [11]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 2/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hyperintensities on diffusion-weighted imaging (DWI) brain MRI sequences found in some patients with ICH may be a marker of severe small-vessel disease associated with the risk of ICH recurrence [13,14]. In one study of 247 patients with ICH, those with DWI hyperintensities had a higher risk of recurrent ICH but not subsequent ischemic stroke at two years [15]. Hypertension Hypertension (HTN) is the most consistent risk factor for ICH recurrence. HTN predisposes to ICH recurrence of both deep and lobar ICH [4]. Inadequate control of HTN is common and increases the risk of recurrent ICH [4,16,17]. In a longitudinal study of 1145 patients with ICH, each 10 mmHg increase in systolic blood pressure was associated with an incremental increase in risk of recurrent lobar ICH (hazard ratio [HR] 1.33, 95% CI 1.02-1.76) and recurrent deep ICH (HR 1.54, 95% CI 1.03-2.30) [18]. The risks of ICH related to inadequate blood pressure control and management to mitigate these risks are discussed below. (See 'Blood pressure management' below.) Age The risk of ICH recurrence with age is based largely on the association of advancing age with the risk of initial ICH [19]. A meta-analysis of more than 8100 patients with ICH assessed the age-related incidence of ICH over a 28-year period [20]. Using the age group of 45 to 54 years as reference, the incidence ratio increased from 0.10 (95% CI 0.06-0.14) for those under 45 years up to 9.6 (95% CI 6.6-13.9) for patients older than 85 years. These findings are likely true for ICH recurrence as well. Older age is also associated with higher prevalence of CAA and higher use of antithrombotic drugs for accumulating cardiovascular comorbidities. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) Medications Antithrombotic medications (including antiplatelet agents and anticoagulants) and statins may be associated with risk of ICH recurrence. In addition, several other substances including selective serotonin reuptake inhibitors and nonsteroidal anti-inflammatory drugs have been linked to increased risk of bleeding in general, including ICH and ICH recurrence ( table 1). However, studies examining the associations between these drugs and risk of ICH recurrence have yielded inconsistent results [3,18,21,22]. The potential risks of recurrent ICH due to antithrombotic and statin medications are discussed below. (See 'Management of antithrombotic therapy' below and 'Management of statins' below.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 3/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other risk factors Race and ethnicity There are racial and ethnic disparities in the risk of ICH recurrence. Black American, Hispanic American, and Asian American patients with a history of ICH seem to be at higher risk for a recurrent event than White American patients [16,23]. The prevalence of HTN in these groups does not fully account for this elevated risk of ICH. In one study, patients remained at higher risk of ICH recurrence after adjusting for blood pressure measurements and variability [16]. Chronic kidney disease Chronic kidney disease can be a marker of atherosclerotic disease and may further contribute to the risk of ICH through renally mediated impairment of cerebral autoregulation [24]. A large population-based study in Denmark evaluated 15,270 patients with ICH and found that patients with kidney failure at the time of the initial ICH were at higher risk for ICH recurrence (relative risk 1.72, 95% CI 1.34-2.17) [3]. Prior ischemic stroke or ICH The risk of a future ICH is higher in patients with history of prior ICH and those with history of a prior ischemic stroke [1]. Genetic features Certain genetic features associated with CAA are associated with increased risk of ICH recurrence [25]. Patients with ICH who are carriers of apolipoprotein-E (APOE) e2 or e4 genotypes, frequently associated with CAA, are at elevated risk of ICH [9]. Additionally, patients with genetic bleeding disorders also are at risk for ICH. These disorders are discussed separately. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Clinical manifestations and diagnosis of hemophilia" and "Rare inherited coagulation disorders".) FOLLOW-UP NEUROIMAGING All patients whose symptoms unexpectedly fail to improve or worsen during the recovery period require neuroimaging to evaluate for a recurrent hemorrhage. In addition, follow-up imaging studies can help to identify or confirm the cause of the ICH, which in turn determines the risk of recurrence and may help guide preventive measures. For some patients, neuroimaging studies performed during the acute hospitalization identify the etiology such that further imaging studies are not required. For other patients, the initial imaging study does not sufficiently exclude other causes of ICH and follow-up studies are required. When acute https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 4/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate bleeding and surrounding edema from the acute ICH shroud and distort underlying brain structures, delayed imaging performed after bleeding and edema have resolved may identify patients who are at high risk for recurrence due to an underlying structural cause ( algorithm 1). (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Patients with suspected hypertensive ICH Patients with ICH attributed to hypertension (HTN) who continue to improve clinically during recovery may not warrant additional imaging. Clinical and imaging features on head computed tomography (CT) or brain magnetic resonance imaging (MRI) suggestive of hemorrhage related to HTN or other atherosclerotic risk factors associated with deep penetrating vasculopathy include: Hematoma or cerebral microbleeds (CMBs) in basal ganglia or thalamus, cerebellar nuclei, or brainstem ( image 1) Known history or new diagnosis of HTN No prior ICH (unless in setting of uncontrolled HTN) No atypical clinical or neuroimaging features ( table 2) Patient age 65 years Clinically stable patients who meet most or all of the criteria listed above likely do not require a follow-up imaging study. For patients with only some of these features, we suggest repeating a brain MRI with gadolinium contrast in 12 to 16 weeks after the ICH to assess for alternative secondary causes. Additional associated imaging features found in some patients with a hypertensive ICH include evidence of prior chronic ischemic stroke attributed to small vessel (penetrating artery) and CMBs located in the basal ganglia or thalamus evident on T2*-weighted brain MRI sequences. Patients with suspected CAA-related ICH Some patients with ICH attributed to cerebral amyloid angiopathy (CAA) whose symptoms continue to improve during recovery may not require additional imaging in the ambulatory setting. Imaging features on brain MRI suggestive of ICH related to CAA include lobar location and evidence of lobar CMBs or cortical superficial siderosis in an older patient ( image 1 and image 2). The approach to confirming that diagnosis is discussed separately. (See "Cerebral amyloid angiopathy", section on 'Diagnostic approach'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 5/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other patients We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause but not identified or excluded during the acute hospitalization ( table 2). Clinical features that raise suspicion for an underlying cause of ICH include: Age <65 years No history or new diagnosis of HTN History of protracted new-onset headaches History of new-onset neurologic symptoms preceding ICH Thunderclap headache at onset of hemorrhage History of prior ICH (unless attributed to uncontrolled HTN or CAA) Imaging features of the hemorrhage on imaging (head CT or brain MRI) raising suspicion for other secondary causes of ICH (such as a vascular lesion, primary or metastatic brain tumor, cerebral venous thrombosis, or hemorrhagic transformation of ischemic infarct) include: Early perihematomal edema out of proportion to the size of the ICH ( image 3) Hemorrhage appears to be in arterial vascular territory suggesting primary ischemic infarction ( image 4) Enhancement of intracranial vessels around ICH ( image 5) Multifocal hemorrhage ( image 6) Isolated intraventricular hemorrhage ( image 7) Specific underlying etiologies of nontraumatic ICH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Specific etiologies'.) We prefer brain MRI with gadolinium for most patients who undergo post-acute testing to identify underlying cause of ICH. MRI should include T2*-weighted (gradient echo [GRE] or susceptibility-weighted imaging [SWI]) sequences. In an observational study in 400 patients with spontaneous ICH, MRI performed within 30 days improved diagnostic accuracy regarding ICH etiology over CT, changing the diagnostic impression in approximately 14 percent and management in 20 percent of cases [26]. These findings were confirmed in a subsequent study of 123 patients where MRI was most useful for establishing the diagnosis of ICH secondary to cerebral venous sinus thrombosis, hemorrhagic transformation of an ischemic infarct, neoplasms, and vascular malformations [27]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 6/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients who are unable to undergo MRI, head CT with contrast is a reasonable but less sensitive alternative. When an underlying vascular cause is suspected, additional noninvasive vascular imaging with CT or MR angiogram should be performed. Digital subtraction angiography (DSA) is performed when CT or MR angiography is inconclusive or is negative and clinical suspicion for an underlying vascular lesion remains high ( image 5) [28,29]. In addition, we generally obtain DSA to evaluate for a vascular lesion such as an arteriovenous malformation. CT or MR venography is performed for suspected venous lesions, such as cerebral venous thrombosis. (See "Brain arteriovenous malformations" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) The optimal time to obtain follow-up imaging depends on the indication and the clinical recovery of the patient. For patients who did not undergo evaluation during the acute hospitalization for potential underlying secondary causes of the ICH, we obtain early imaging in four weeks to identify potential underlying structural sources amenable to early treatment. For other patients with a suspected secondary cause where the acute evaluation did not identify or exclude an underlying source, we obtain imaging after six to eight weeks to allow for better visualization of underlying brain tissue after some resorption of the hematoma. For patients without worrisome clinical or imaging features of the ICH for whom the acute evaluation for underlying causes did not identify the etiology, repeat imaging is indicated to exclude underlying structural sources. For these patients, we typically delay repeat imaging for 12 to 16 weeks after the ICH to promote optimal visualization of underlying brain tissue and reduce the risk of identifying confounding abnormal imaging findings that may be attributed to healing of the ICH in the late subacute time period. BLOOD PRESSURE MANAGEMENT Blood pressure (BP) control is an important aspect of reducing the risk of recurrent ICH. Hypertension (HTN) is one of the single most important modifiable risk factors for initial ICH and ICH recurrence. (See 'Risk factors' above.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 7/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Small improvements in BP control help to reduce the risk of ICH. The relationship between BP control and ICH recurrence has been studied somewhat indirectly in patients with either ischemic stroke or ICH. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, patients with prior stroke (hemorrhage or infarction) were randomly assigned to an angiotensin-converting enzyme inhibitor (perindopril) with or without a diuretic (indapamide) versus placebo. A modest BP reduction rate by 9/4 mmHg in patients assigned to active treatment reduced the risk of ICH from 2.4 to 1.2 percent, corresponding to a 50 percent relative risk reduction (95% CI 26-67 percent) [30]. The relative risk reduction for recurrent stroke was 49 percent (95% CI 18-68 percent) among patients whose qualifying event was ICH [30-32]. Blood pressure goals We suggest aiming for BP <130/80 mmHg as a long-term target to reduce the risk of recurrence after ICH ( table 3) [33]. The risk of ICH is reduced with each incremental reduction in BP, but the benefit may be greatest for patients whose BP reaches intensive BP-lowering targets [18,31]. The benefit for intensive BP reduction has not been demonstrated specifically for ICH recurrence; however, indirect evidence from patients with other cerebrovascular conditions suggests a likely benefit. In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, 3020 patients with prior ischemic stroke were assigned either to a systolic BP target of 130 to 149 mmHg or <130 mmHg [34]. During a mean follow-up of 3.7 years, there were fewer ICH events in those assigned to the intensive BP target (6 versus 16), corresponding to a lower rate of ICH at 0.1 percent per patient-year in the intensive group compared with 0.3 percent per patient-year in the higher target. A more intensive BP target was assessed in the Recurrent Stroke Prevention Clinical Outcome (RESPECT) trial, in which 1266 patients with ischemic stroke were randomly assigned to intensive BP control (<120/80 mmHg) or to standard treatment (<140/90 mmHg) [35]. There was a trend toward fewer strokes in patients assigned to the intensive group; however, limitations in this study prevent firm conclusions. The actual mean BP achieved in the intensive group was 127/77, not very different from 133/78 mmHg in the standard group. The trial was stopped early with relatively few (12) ICH events, most in the standard treatment group (11 versus 1). In a meta-analysis of these studies along with two additional trials in patients after ischemic stroke, more intensive BP lowering (variably defined) was associated with a reduced risk of ICH (relative risk [RR] 0.25, 95% CI 0.07-0.90) [35]. Blood pressure lowering has additional benefits in reducing the risk of other vascular events including ischemic stroke, although in the population of patients with prior ICH, the absolute benefits in this regard are likely to be small [35]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 8/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate When to begin antihypertensive therapy The approach to BP control after ICH is stepwise. However, high quality data to specify when to safely implement BP control after ICH are lacking. In the acute (typically hospital) setting, initial steps to control the BP are begun immediately to prevent hematoma expansion. The benefit of acute control of elevated blood pressure must be balanced against the competing risk of cerebral or other organ hypoperfusion. Initial target systolic blood pressure is 140 to 160 mmHg for most patients. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) Further reductions in BP toward normotension are made in a stepwise fashion. For most patients, we aim to achieve the BP target of <130/80 mmHg within 10 to 14 days after the onset of ICH. We also advise close outpatient monitoring to ensure that BP control is maintained. Selection of antihypertensive agent For patients without a clinical indication for a specific agent, we typically start an angiotensin-converting enzyme (ACE) inhibitor. For those unable to tolerate or who prefer an agent other than an ACE inhibitor, we offer an angiotensin receptor blocker, thiazide diuretic, or calcium channel blocker, based on analyses of risk reduction in patients with atherosclerotic disease [36,37]. The choice of agent should be guided by efficacy in achieving target BP. Clinical indications to guide individualized medication selection are discussed elsewhere ( table 4). (See "Choice of drug therapy in primary (essential) hypertension".) The use of combination antihypertensive regimen (ie, multiple antihypertensive drugs, instead of a single drug) may decrease the risk of adverse effects and improves tolerability and compliance [38]. (See "Choice of drug therapy in primary (essential) hypertension".) Education of patients and their caregivers about target BP and their engagement in self- monitoring at home and communications with their medical providers are also key to achieve better BP control and to improve adherence to therapy [39]. Lifestyle modifications and management of obstructive sleep apnea and obesity are fundamental components of BP management. (See 'Lifestyle modifications' below.) MANAGEMENT OF ANTITHROMBOTIC THERAPY Many patients with ICH have comorbid cardiovascular conditions and may have indications for antiplatelet or oral anticoagulant agents. Whether to resume or discontinue these medications after ICH requires weighing the competing risks of thromboembolic events versus ICH recurrence. In the absence of high-quality trial data, observational reports and expert opinion guide risk/benefit assessment and decision-making. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 9/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy Antiplatelet therapy is typically withheld in the acute setting to mitigate the risk of hemorrhage expansion. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) We suggest resuming antiplatelet therapy after ICH for most patients who have a specific indication for such therapy. However, it is important to balance individual risks and benefits. Patients with established atherosclerotic disease We resume antiplatelet therapy for most patients with nonlobar ICH and those with lobar ICH attributed to cerebral amyloid angiopathy (CAA) who have established atherosclerotic disease, in agreement with guidelines from the American Heart Association (AHA) [33]. Such indications may include prior cardiovascular disease, ischemic stroke, or peripheral arterial disease. These indications are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The risks and benefits of resuming antiplatelet medications for patients with CAA are discussed in detail separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) If lobar ICH was attributed to an alternative source, we base decisions on resuming antiplatelet therapy on the individual risks associated with the underlying etiology. We prefer low-dose aspirin (81 mg per day), typically starting a few days after ICH, if neuroimaging confirms stability. Low-dose aspirin has been most studied in relationship to ICH recurrence. Some [4,40-42] but not all [43] small studies have reported no difference in the rates of ICH recurrence among patients with ICH who continued aspirin and those who discontinued it. In the Restart or Stop Antithrombotics Randomized Trial (RESTART), 537 patients who developed ICH while taking antithrombotic therapy were assigned either to continue or discontinue antiplatelet therapy [44]. Most patients (88 percent) were taking antithrombotic therapy for secondary prevention of atherosclerotic disease; 25 percent had atrial fibrillation, either as a comorbid condition or as their primary indication. After a median two years of follow-up, the risk of recurrent ICH was similar (nonsignificantly lower) in patients who continued versus discontinued antiplatelet therapy (4 versus 9 percent; adjusted hazard ratio [aHR] 0.51, 95% CI 0.25-1.03), while rates of major occlusive and thromboembolic events were higher and were similar among treatment groups (15 versus 14 percent; aHR 1.02, 95% CI 0.65-1.60). These findings were sustained in an extended follow-up at a median time of three years (interquartile range two to five years) [45]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 10/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hemorrhagic and thromboembolic outcomes were similar among patients who continued versus those who discontinued antiplatelet therapy, and the rate of recurrent ICH remained lower than the rate of major vascular events (9 versus 30 percent). Primary prevention of atherosclerotic disease For patients with ICH without established atherosclerotic disease, we consider individual risk factors to weigh overall benefits of antiplatelet therapy against the risk of hemorrhage. As examples, we typically would resume aspirin for patients with ICH and hypertension (HTN), hyperlipidemia, and diabetes mellitus or those with carotid atherosclerotic disease. For such patients, ICH may be a marker of atherosclerotic risk. In a Danish cohort study, patients with prior ICH had a higher risk of subsequent cardiovascular events than age- and sex-matched controls, including ischemic stroke (1.5 versus 0.6 per 100 person-years) and major adverse cardiovascular events (4.2 versus 1.4 per 100 person-years) [46]. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".) For most of these patients in whom antiplatelet therapy is resumed, we prefer low-dose aspirin and restart such therapy several days after the ICH has stabilized. For patients with lobar ICH and suspected CAA without high risk of ischemic stroke or cardiovascular events, we avoid antiplatelet therapy. (See "Cerebral amyloid angiopathy".) Patients with intravascular stents Patients with symptomatic atherosclerotic disease who have undergone intravascular stent placement are typically prescribed antiplatelet therapy for several months to prevent vascular occlusion from thrombosis at the site of the stent. We typically resume these medications in patients with ICH because of the thrombotic risks related to their discontinuation and typically start within a few days after ICH if neuroimaging confirms stability. Whenever feasible, we prefer single antiplatelet therapy over dual antiplatelet therapy. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting" and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.) Patients taking nonsteroidal antiinflammatory drugs We prefer nonacetylated salicylates (eg, magnesium salicylate) over other nonsteroidal antiinflammatory medications with antithrombotic properties that impair platelet function. Anticoagulation Anticoagulation is typically withheld, and the effects are reversed acutely for patients with ICH, to reduce the risks of hemorrhagic expansion and associated morbidity. (See https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 11/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) Many patients with ICH benefit from resuming anticoagulation when the thromboembolic risk is higher than the risk of recurrent ICH. However, it is important to balance individual risks and benefits. Individualize decision to resume or discontinue We balance the risks of recurrent ICH with the risk of thromboembolism to help make decisions about resuming anticoagulation for individual patients ( algorithm 2). Only limited observational data and expert opinion are available to support clinical decisions regarding resuming or withholding anticoagulation [47-50]. These decisions should be made along with the patient after weighing the individualized risks, benefits, and exploring alternative options whenever possible. Timing of resumption The optimal time for restarting oral anticoagulation after ICH has not been established and may depend on the underlying indication for anticoagulation. Early resumption of anticoagulation within several days after stabilization of the ICH may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve) [33]. (See 'Mechanical prosthetic heart valves' below.) For most other patients who resume anticoagulation, we generally suggest delaying restarting oral anticoagulants for four to eight weeks after onset of the ICH, in agreement with AHA guidelines [33]. We use hemorrhage size and thromboembolic risks to guide the specific timing of resumption for an individual patient. In one study of 177 patients with intracranial hemorrhage and an indication for anticoagulation, the combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a nadir when warfarin was resumed after 10 weeks, suggesting that the optimal timing for resumption of oral 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 7/6/23, 12:54 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 7/6/23, 12:54 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 7/6/23, 12:54 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