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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.
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).
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.
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.