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Management of Spontaneous Intracerebral Hemorrhage
Management of Spontaneous Intracerebral Hemorrhage

3. Secondary Stroke Prevention in an Individual with Intracerebral Hemorrhage

7th Edition – 2020 UPDATE

Recommendations

This section addresses secondary prevention management issues specific to individuals who have experienced an intracerebral hemorrhage (intraparenchymal and intraventricular hemorrhages) General principles of vascular health and risk reduction that are addressed in the CSBPR Secondary Prevention of Stroke Module may also apply to this population where they are non-specific to stroke type. The topics included here may overlap with the broader prevention module where they may have different levels of evidence available

3.1 Risk Assessment
  1. Persons at risk of stroke and patients who have had an ICH should be assessed for vascular disease risk factors (such as diet, sodium intake, waist-to-hip ratio, sedentary lifestyle, alcohol intake, blood pressure, and smoking) [Evidence Level B].  Please refer to the CSBPR Secondary Prevention of Stroke Module for additional information.
  2. Patients who experience an ICH should be assessed for underlying etiology and risk of recurrence [Evidence Level B].
    1. The assessment of recurrent risk for an ICH should be based on clinical factors (including age, hypertension, ongoing anticoagulation, prior lacunar stroke) and neuroimaging (lobar location of index ICH suggestive of cerebral amyloid angiopathy, presence of associated convexal subarachnoid hemorrhage, and presence and number of cerebral microbleeds and/or cortical superficial siderosis on susceptibility weighted or gradient echo MRI sequences) [Evidence Level B].

Note: Validated risk assessment tools for intracerebral hemorrhage recurrence have not been published.

Clinical Considerations for Section 3.1

  1. In the absence of tissue diagnosis, probable cerebral amyloid angiopathy can be diagnosed in hospital populations based on the modified Boston criteria  as follows:  Age ≥55 years; (and) clinical data and MRI demonstrating multiple macro or microhemorrhages restricted to lobar, cortical, or corticosubcortical regions (cerebellar hemorrhage allowed), or a single lobar, cortical or corticosubcortical macro- or microhemorrhage and cortical superficial siderosis; (and) absence of other cause of hemorrhage or cortical superficial siderosis.
3.2 Lifestyle Management
  1. For individuals with intracerebral hemorrhage, healthcare professionals should recommend increased physical activity, healthy diet, reductions of alcohol consumption, cessation of smoking, and cessation of cocaine/amphetamine use where relevant (Evidence Level C).  Refer to Section 2 CSBPR Secondary Prevention of Stroke Module for recommendations on lifestyle management after stroke.

Clinical Consideration for Section 3.2

  1. There is no evidence to restrict air travel in patients post ICH above and beyond routine limitations following stroke.
3.3 Blood Pressure Management Following Intracerebral Hemorrhage
  1. Long-term, blood pressure should be aggressively monitored, treated and controlled [Evidence level A] to sustain a target blood pressure consistently lower than 130/80 mmHg [Evidence Level B]. 
  2. For specific agents to manage blood pressure, refer to Hypertension Canada’s current blood pressure management guidelines.

Clinical Considerations for Section 3.3

  1. Home blood pressure monitoring devices should be encouraged to achieve blood pressure targets.
3.4 Antithrombotic Therapy Following Intracerebral Hemorrhage
  1. In ICH patients with an indication for anticoagulant treatment, the decision to initiate or resume anticoagulation should be individualized according to the patient’s risk of recurrent hemorrhage and thromboembolism [Evidence Level C]. 
  2. If anticoagulation is deemed necessary and where direct oral anticoagulant (DOAC) treatment is indicated (i.e. atrial fibrillation), DOAC therapy is favored over warfarin. This is based, however, primarily on their reduced rates of ICH in atrial fibrillation randomized trials where ICH patients were excluded [Evidence Level B].
    3. a.
    DOACs should not be used in patients with mechanical heart valves and intracerebral hemorrhage [Evidence Level B].
  3. Where indicated, antiplatelet monotherapy can be considered in patients deemed too high risk for anticoagulation [Evidence Level B].
  4. In patients with an indication for continued antiplatelet treatment, resuming antiplatelet therapy is reasonable [Evidence Level B].
  5. The optimal timing and strategy regarding antithrombotic therapy (antiplatelet or anticoagulant) following an intracerebral hemorrhage is uncertain and should be individualized to the patient [Evidence Level C].

Clinical Consideration for Section 3.4

  1. Consultation with experts in cerebrovascular disease may assist in clinical decision-making regarding antithrombotic therapy following ICH.
  2. Randomized trials are ongoing regarding the net benefit and safety of direct oral anticoagulant (DOAC) therapy and left atrial appendage closure in patients with ICH and atrial fibrillation.  These patients should be assessed by an expert in cerebrovascular diseases if possible, to support decision-making on management.
3.5 Statin Therapy in Intracerebral Hemorrhage
  1. There is no role for statin therapy in the secondary prevention of ICH. Statin therapy should not be initiated for secondary prevention of intracerebral hemorrhage [Evidence Level C].
  2. For intracerebral hemorrhage patients who have a clear concomitant indication for cholesterol lowering treatment, statin therapy should be individualized and should take into account the patient’s overall thrombotic risk as well as the possibility of increased ICH risk with statin therapy [Evidence Level C]. Refer to CSBPR Prevention of Stroke module section 4 on Lipid Management for additional information.

Clinical Considerations for Section 3.5

  1. An ongoing clinical trial (SATURN) addressing this question may potentially inform clinical decision-making for these patients.  Until these results are available, decisions regarding statin therapy should be made based on risk/benefit ratio in consultation with an expert in cerebrovascular disease.
3.6 Functional Assessment
  1. Following an ICH, patients should be assessed for neurological impairments and functional limitations when appropriate (e.g., cognitive evaluation, screening for depression, screening of fitness to drive, need for potential rehabilitation therapy, and assistance with activities of daily living), especially for patients who are not admitted to hospital [Evidence Level C].  Refer to CSBPR Rehabilitation Module Recommendations 5.1 and 5.6 for additional information.
  2. Patients found to have any continued or new neurological impairments and functional limitations should be referred to the appropriate rehabilitation specialist for in-depth assessment and ongoing management [Evidence Level C].
Rationale +-

The incidence of ICH is approximately 20/100,000 in the western populations (van Asch et al. 2010), with a cumulative risk of recurrence of 1% to 7% per year (Poon et al. 2014). The rate of recurrence is less in ICH confined to deep structures (1-2% per annum; deep grey/white matter, brainstem) relative to lobar ICH (5-8% per annum; cortical, corticosubcortical regions).  ICHs carry the highest mortality rate amongst all stroke subtypes, averaging 55% at 1 year, while only 25% of ICH victims resume functional independence. ICH is a major contributor to stroke-related cognitive impairment with 35% of survivors demonstrating progressive cognitive decline (Benedictus et al. 2015). Given their severity, ICH patients add a significant burden to the Canadian Health Care System with a median cost of $10,500, to upwards of $260,000, per hospitalization alone. (Specogna et al. 2014).   

ICH incidence is associated with modifiable lifestyle factors such as alcohol consumption, smoking, unhealthy diet, elevated waist-to-hip ratio and sedentary lifestyle.  ICH recurrence can be considerably reduced by long-term blood pressure reductions (Benavente et al. 2013, Arima et al. 394). The goal is of spontaneous ICH prevention management is to identify and mitigate modifiable risk factors in ICH survivors, to prevent further hemorrhagic events and loss of functional independence.  Many uncertainties persist regarding optimal antithrombotic therapy and lipid lowering therapy in ICH patients who have comorbid vaso-occlusive diseases.

System Implications +-
  1. Education for the public and healthcare providers about the importance of risk factor modification and in particular blood pressure control in the management of ICH patients in order to reduce the risk of recurrent events. Patients and families will also require ongoing education and support related to prevention and management of ICH.
  2. ICH-specific processes and protocols to enable rapid access to expertise for patients with ICH in community healthcare settings and acute healthcare facilities.
  3. Processes that ensure referral of ICH patients to stroke prevention clinics from surgical and other medical subspecialties.
  4. Establishing multidisciplinary pathways for risk-benefit assessment of management decisions in ICH patients who have comorbid vaso-occlusive disease.
Performance Measures +-

System Level

  1. The proportion of ICH patients living independently in the community at 90 days and one year following index ICH.

Clinical Measures

  1. Proportion of people who experienced an initial ICH stroke who then have a recurrent stroke.
  2. Median time between first ICH and recurrent stroke.
  3. Readmission rates to hospital with complications following index ICH (such as venous and systemic thromboembolic events, infections, hydrocephalus, aspiration pneumonia, post-ICH seizures, infection, and low-trauma fracture).

Patient-Oriented Outcomes

  1. Self-reported quality of life following ICH using a validated measurement tool.
  2. Functional ability (mRS score) at 90 days and one year following ICH.
Implementation Resources and Knowledge Transfer Tools +-

Health Care Provider Information

Information for People with Stroke, their Families and Caregivers

Summary of the Evidence +-

Evidence Table and Reference List

Lifestyle

Certain lifestyle risk factors may increase the risk of ICH to a greater extent compared with ischemic stroke. Smoking, a sedentary lifestyle and excessive alcohol consumption are of particular concern. In the second phase of the INTERSTROKE study (O’Donnell et al. 2016), the risk of ICH was increased to a greater degree compared with ischemic stroke among persons who consumed higher amounts of alcohol, defined as >14 drinks/week in women or >21 drinks/ week in men, and in those who did not engage in at least four hours of moderate or strenuous leisure activity, weekly. In phase one of the INTERSTROKE study, (O’Donnell et al. 2010) consuming >30 drinks/month or binge drinking was associated with an increased risk of hemorrhagic stroke compared with never/former drinkers. The risk of hemorrhagic stroke was higher than ischemic stroke. Zang et al. (2014) reported that while low-to-moderate alcohol intake was not associated with hemorrhagic stroke risk, an intake of ≥45 g/day was associated with increased risk was, in a systematic review that included the results of 27 prospective studies.

Blood Pressure

In terms of treatment for secondary prevention, long-term intensive blood pressuring lowering to <130/80 mmHg, was shown to be safe and reduce the risk of future ICH (63% RRR) in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial (Benavente et al. 2013). This finding was among patients with lacunar stroke, who share a prevalent underlying pathophysiology (arteriolosclerosis or hypertensive arteriopathy) with ICH. Moreover, a mean blood pressure reduction of 9/4 mmHg in participants within PROGRESS trial reduced the risk of cerebral amyloid angiopathy-related ICH by 77% and hypertensive arteriopathy-related ICH by 46% (Arima et al. 2010).

Statin Use

Administration of statins, used for the prevention of ischemic strokes, has been associated with an increased risk of ICH.  In the Stroke Prevention by Aggressive Reduction in Cholesterol (SPARCL) trial (Amarenco et al. 2006), 4,732 patients with a previous stroke were randomly assigned to receive either 80 mg/day atorvastatin or matching placebo for an average of 4.9 years. While the risk of ischemic stroke was reduced significantly for patients in the statin group, the risk of ICH was increased significantly (55 vs. 33, HR=1.66 95% CI 1.08-2.55, p=0.020).  Independent risk factors for ICH included treatment with atorvastatin (HR=1.69, 95% CI 1.10-2.60, p=0.02), male gender, previous ICH and stage 2 hypertension (Goldstein et al. 2008).  Pooling the results from two secondary prevention trials (SPARCL and the Heart Protection Study-including patients with prior cardiovascular disease), Amarenco & Labreuche (2009) reported that statin therapy was associated with a significantly increased risk of ICH (RR=1.73, 95% CI 1.19-2.50). However, when analyzed separately, statin use was not associated with an increased risk of ICH in subgroup analysis of primary prevention studies (n=9, RR=0.81, 95% CI 0.60-1.08). Ziff et al. (2019) included the results of 51 studies examining the use of statin therapy in patients with previous ischemic or hemorrhagic stroke. Among patients with previous ICH (n=15 studies), statins did not significantly increase the risk of recurrent ICH (RR=1.04, 95% CI 0.86 to 1.25), while the risks of all-cause mortality and poor functional outcome were reduced significantly with statin therapy (RR=0.49, 95% CI 0.36-0.67 and RR=0.71, 95% CI 0.67-0.75). McKinney & Kostis (2012) included 31 RCTs (n=182,803 patients) in a meta-analysis examining the use of statins (high vs. low-dose statins, n=6 and any statin vs. control or usual care, n=25 trials) for stroke prevention with a mean duration of follow-up of 46 months. Using the results from all trials, any statin use was not associated with a significantly increased risk of ICH (0.39% vs. 0.35%, OR=1.08, 95% CI 0.88-1.32, p=0.47).  In subgroup analysis of primary and secondary prevention trials, the risks of ICH were also not significantly increased with statin use (OR=0.86, 95% CI 0.75-1.23, p=0.77 and OR=1.26, 95% CI 0.91-1.73, p=0.54, respectively). The ongoing SATURN trial is assessing the effect of statin continuation compared with discontinuation on recurrent ICH rates following lobar ICH.

Antithrombotics

The decision whether to resume antithrombotic therapy for patients following an ICH can be challenging due to the increased risk of recurrence. This risk must be balanced with the prevention of a future ischemic event, particularly for patients with nonvalvular atrial fibrillation. While the issue remains unresolved and is best approached on an individual basis, the evidence from recent studies suggest that the benefits may outweigh the risks. The RESTART trial (2019), randomized 537 participants with spontaneous ICH, to receive antiplatelet therapy (either aspirin, clopidogrel, and/or dipyridamole) or to avoid antithrombotic therapy. Antiplatelet therapy did not increase the risk of recurrent ICH (aHR 0.51 [95% CI 0.25-1.03, p=0.06), and was associated with a 35% (p=0.025) relative risk reduction in the secondary composite outcome of non-fatal myocardial infarction, non-fatal stroke and vascular death.  Further reassurance is provided in the RESTART MRI subgroup analyses that did not demonstrate any treatment modification according to ICH location, or the presence and burden of MRI markers of cerebral small vessel disease, including cerebral microbleeds and cortical superficial siderosis (Al-Shahi Salman et al. 2019). Ottosen et al. (2016) included 6,369 patients presenting with first-ever spontaneous, non-traumatic ICH, who survived for the first 30 days. During a median of 2.3 years of follow-up, post-discharge use of oral antithrombotics (including oral anticoagulants and antiplatelets), which was initiated most frequently within 3-6 months of stroke, was associated with a significantly reduced risk of death (HR=0.59, 95% CI 0.43-0.82) and thromboembolic events (HR=0.58, 95% CI 0.35-0.97), with no increased risk of major bleeding (HR=0.65, 95% CI 0.41-1.02) or recurrent ICH (HR=0.90, 95% CI 0.44-1.82). Kuramatsu et al. (2015) compared ICH recurrence of 719 patients who restarted oral anticoagulation (OAC) therapy with vitamin K antagonists, with patients who did not restart OACs following oral anticoagulant-related ICH. The risk of ischemic complication was significantly higher for patients who did not resume OACs (15.0 vs. 5.2%, p<0.01), while the risk of hemorrhagic complications was not (8.1 vs. 6.6%, p=0.48). Nielsen et al. (2015) included 1,752 patients with nonvalvular atrial fibrillation who were subsequently admitted to hospital with an intracranial hemorrhage, who survived for the first 6 weeks and had been receiving anticoagulation therapy for at least 6 months prior to the event. The combined risk of ischemic stroke/systemic embolism and all-cause mortality was significantly reduced compared with patients who did not resume oral anticoagulation therapy (HR=0.55, 95% CI 0.39-0.78), without a significant risk of recurrent ICH or extracranial bleeding. Pooling the results from these 3 studies and 5 others, Murthy et al. (2017) reported there was no significantly increased risk of recurrent ICH after resumption of anticoagulation therapy (RR=1.01, 95% CI 0.58-1.77) while the risk of stroke or MI was significantly lower (RR=0.34, 95% CI 0.25-0.45).  Similar net benefit seems to generalize to higher risk patients with lobar ICH, and may generalize to those with cerebral amyloid angiopathy.  However, confounding by indication limits the interpretation of these observational studies.  In the Canadian-led NASPAF-ICH trial presented at the 2020 International Stroke Conference there was only one primary outcome of recurrent ICH and/or ischemic stroke amongst 30 participants with atrial fibrillation and previous ICH randomized (2:1) to standard dosing non-vitamin K antagonist oral anticoagulant (NOAC) therapy or aspirin 81 mg daily over mean follow-up of 1.53 years (SD 0.54). This event was an ischemic stroke occurring in a patient with temporary discontinuation of assigned aspirin therapy due to a major genitourinary hemorrhage. There was no recurrent ICH in either arm of the study. All participants had close home blood pressure monitoring to ensure target <130/80 mm Hg. These preliminary results are being investigated further in ongoing randomized trials.

Stroke Resources
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