From Nature Reviews Neurology

Advances in the Management of Intracerebral Hemorrhage

Opeolu Adeoye, MD; Joseph P. Broderick, MD Authors and Disclosures CME Released: 09/28/2010; Valid for credit through 09/28/2011

CME

Abstract and Introduction Natural History Clinical Trials Conclusions Key Points
References

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Abstract and Introduction

Abstract

Intracerebral hemorrhage (ICH) is a major public-health problem worldwide. No proven treatments are available for this condition, which is associated with high rates of morbidity and mortality. Only 20% of individuals who survive ICH are independent at 6 months. Hypertension, cerebral amyloid angiopathy (CAA) and anticoagulation are known to be associated with such hemorrhages. No effective preventive therapies exist specifically for CAA-related ICH. The incidence of hypertension-related ICH might be decreasing in some populations with improvements in the treatment of hypertension; however, the incidence of anticoagulantrelated ICH is increasing, as the use of anticoagulants rises. Many questions remain unanswered regarding the clinical management of ICH, although in the past 10 years completed medical and surgical clinical trials examining hemostatic therapy, blood pressure control and/or hematoma evacuationhave refined our understanding of the goals of such management. Ongoing clinical trials, which have built on the lessons of past studies, hold promise for the development of effective, scientifically proven treatments for ICH. In this Review, we discuss clinical trials for ICH that have been completed in the past 10 years, the contributions of these studies to the clinical management of ICH, and the ongoing trials that might further improve clinical care.
Introduction

Spontaneous nontraumatic intracerebral hemorrhage (ICH) occurs in 2 million people worldwide every year [1-4] and represents a major global public-health problem. ICH is associated with a 30 day mortality rate of 32-50%, [2,5,6] and 6 month functional independence is only achieved in 20% of individuals who survive such hemorrhages.[6] ICH represents 10-15% of all strokes that occur in the US, Europe and Australia, and 20-30% of all strokes that occur in Asian countries.[7] In the US alone, ICH accounts for US$12.7 billion of the US$74 billion in direct costs related to stroke care annually. [8,9] The most important risk factor for ICH is age. Each advancing decade from 50 years of age is associated with a twofold increase in ICH incidence. The most notable modifiable risk factor for ICH is hypertension, which is present in 50-70% of patients who develop such hemorrhages. [10] Hypertension is primarily associated with ICH that occurs in deep cerebral and brainstem locations and, to a lesser extent, lobar locations, [11] and confers a higher risk of ICH in younger individuals (aged 45 years) than in older people (aged >45 years). [12] Evidence indicates that the incidence of ICH might have decreased in some populations with improvements in hypertension control.[13,14] In a study of cardiovascular disease in three cohorts of Japanese people from 1961, 1974 and 1988, the incidence of ICH in men but not in women was found to have declined (by 61%) from the first to the second cohort, although from the second to third cohorts the incidence remained stable in both sexes.[13] In a Chinese study conducted from 1991-2000, the incidence of ICH decreased by 12.0% per year in Beijing, 4.4% per year in Shanghai and 7.7% per year in Changsha. [14]

Anticoagulant-related ICH is associated with a higher mortality rate and a more-prolonged period of continued bleeding than non-anticoagulant-related ICH,[15-17] and has risen in incidence over the past decade.[18] Indeed, a study conducted in the Greater Cincinnati region of the US found that the annual incidence of anticoagulantrelated ICH per 100,000 people increased significantly ( P <0.001) from 0.8 (95% CI 0.3-1.3) in 1988, to 1.9 (95% CI 1.1-2.7) in 1993-1994, and to 4.4 (95% CI 3.2-5.5) in 1999. Since warfarin distribution in the US quadrupled on a per capita basis from 1988-1999, the investigators who conducted this study suggested that most of the increase in anticoagulant-related ICH could be attributed to the increase in use of this agent. [18] Cerebral amyloid angiopathy (CAA) has emerged as an increasingly important cause of ICH, particularly in the elderly.[19] CAA-related ICH rarely occurs in people aged <60 years but markedly increases in incidence thereafter, and is nearly always associated with a lobar location of the hemorrhage. [19] No specific preventive therapies exist for CAA-related ICH, although evidence suggests that control of hypertension might reduce the risk of such hemorrhages.[20] To date, no medical or surgical clinical trials have unequivocally demonstrated improvements in functional outcome after ICH. Thus, this condition remains a challenging clinical and public-health problem. In this Review, we discuss the natural history of acute ICH, clinical trials for this condition that were completed and/ or initiated in the past 10 years, and prospective novel therapies and future clinical trials that might improve functional outcomes and reduce the overall societal burden of ICH.

Natural History
Clinically, patients with ICH present with a focal neurological deficit that might be associated with headache, nausea, vomiting or other symptoms. After the initial presentation, early (within hours) neurological deterioration can occur. Historically, the 'hemorrhage' in ICH was thought to be a static process, and the observed neurological deterioration was believed to result from cerebral edema. [21] A sentinel prospective study demonstrated, however, that early neurological deterioration in ICH was due to ongoing bleeding and hematoma expansion (Figure 1).[22] In this study, which involved 103 patients with ICH who presented within 3 h of symptom onset, head CT scans were obtained at presentation (baseline), 1 h later, and then at 20 h. 26% of patients had a significant increase in hematoma volume (defined as a >33% increase in volume) within 1 h of the baseline CT, and an additional 12% of patients exhibited further hematoma expansion at 20 h. Hematoma expansion was associated with neurological deterioration, as measured by the Glasgow Coma Scale (GCS) and the NIH Stroke Scale.[22] Subsequently, other large prospective studies have confirmed the early dynamic changes observed in hemorrhages in patients with ICH ( Table 1 ).[23-25] Figure 1. Hematoma Expansion Revealed by CT. Head CT scans were obtained from a 63 yearold woman who presented within 3 h of the onset of stroke symptoms. a | The scan taken on the patient's arrival at the hospital showed a right basal ganglion intracerebral hemorrhage. b | As a result of a deterioration in the neurological status of the patient, a second scan was obtained 4 h after the initial CT. In this image hematoma expansion can be observed.
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In addition to the volume of the parenchymal hematoma, the presence and expansion of intraventricular hemorrhage (IVH) are powerful and independent predictors of ultimate outcomes in cases of ICH. IVH occurs in 45% of patients with spontaneous ICH,[26] and contributes to early neurological deterioration and poor functional outcomes.[27,28] In a secondary analysis of data from a prospective study of 1,033 patients with ICH, the presence of IVH was associated with a lower probability of favorable outcomes than was an absence of IVH (15% versus 31%, P <0.00001).[27] Another study showed that a >2 ml increase in IVH volume in the first 24 h from baseline was associated with an odds ratio (OR) of a poor outcome of 4.21 (95% CI 1.06-16.63, P = 0.0405).[28] Thus, hematoma expansion in the brain parenchyma or into the ventricular system might have dire consequences for patient outcomes. In addition to the influence of IVH, early deterioration in ICH might also be affected by cerebral edema. In a prospective observational cohort of 142 patients with ICH, baseline and 24 h absolute and relative (to the hematoma volume) edema volumes were measured.[29] Baseline relative edema volume was found to be the strongest predictor of outcome, with a large relative volume being associated with lower odds of a poor 3 month

functional outcome than a small baseline relative volume. By contrast, patients with a low level of baseline edema were more likely to develop increases in edema volume during the subsequent 24 h than individuals with a high level of baseline edema.[29] Another prospective study (INTERACT) of 270 patients with ICH that described the evolution of perihematomal edema in the first 72 h after ICH (baseline, 24 h and 72 h CT scans were reviewed) reported different results.[30] In this study, baseline perihematomal edema volume was highly correlated with baseline hematoma volume (coefficient of determination 0.45). In multivariate analysis, both absolute (OR 1.85, 95% CI 1.30-2.65, P = 0.001) and relative (OR 1.48, 95% CI 1.13-1.94, P = 0.004) increases in perihematomal edema volume were associated with death or dependency at 90 days before adjustment for baseline hematoma volume. Once this adjustment had been made, however, neither the absolute nor the relative increases in perihematomal edema were associated with the 90 day outcomes. The investigators concluded that the degree and growth of perihematomal edema were strongly related to the volume of the underlying hematoma, and that these factors did not seem to have an independent effect on ICH outcome.[30] Given the variability in the results described above, the contribution of early changes in edema to overall ICH-related morbidity remains unclear. Delayed edema can occur 3 days to 2 weeks after ictus in ICH. Zazulia et al. studied the progression of mass effect or the increase in midline shift during hospitalization in 76 patients with supratentorial ICH. [31] Early development of mass effect (within 48 h of symptom onset) occurred in 13% of cases and was associated with hematoma expansion, while delayed mass effect (9-21 days after ictus) was thought to be independently related to edema and occurred in 9% of cases.[31] Sansing and colleagues studied 80 patients with supratentorial ICH. Peak edema volume was found to occur 56 days after ICH onset.[32] In this study, edema growth was correlated with platelet counts, and the investigators suggested that interactions between activated platelets and thrombin might contribute to edema development.
[32]

Delayed mass effect is thought to be induced by red blood cell lysis and hemoglobin-induced neurotoxicity. Slow thrombin release over time has also been suggested as the basis for delayed edema. [33] No established means exists for predicting hematoma expansion, early edema or delayed edema in patients with ICH; however, the results of published and ongoing clinical trials suggest that targeted therapy to improve outcomes in such patients might become available in the near future.

Clinical Trials
Therapy for ICH can be described as medical or surgical. To date, data from one large surgical [34] and five large medical[23-25,35,36] interventional clinical trials for ICH have been published ( Table 2 ). None of these trials has shown a definite functional benefit from the tested therapy; however, refinements to research questions and improvements in patient selection for the studied interventions in ongoing and future clinical trials should lead to effective therapies for ICH.
Medical Management Trials

Hemostatic Therapy. To date, only two large prospective interventional studies targeting hematoma expansion in ICH by administration of recombinant factor VIIa (rFVIIa) have been published. [24,25] In the phase IIb study, 399 patients with ICH, who were diagnosed by CT within 3 h of symptom onset, were randomized to receive placebo (n = 96) or 40 g/kg (n = 108), 80 g/kg (n = 92) or 160 g/kg (n = 103) rFVIIa within 1 h after the baseline scan.[25] The primary outcome measure was the percentage change in ICH volume at 24 h. The mean increase in ICH volume was 29% in the placebo group and 16%, 14%, and 11% in the groups receiving 40 g/kg, 80 g/kg, and 160 g/kg rFVIIa, respectively (a comparison of all three rFVIIa groups combined with the placebo group revealed a significant difference in volume; P = 0.01). ICH volume expansion was reduced by 3.3 ml, 4.5 ml and 5.8 ml in the 40 g/kg, 80 g/kg and 160 g/kg rFVIIa treatment groups, respectively, compared with the placebo group ( P = 0.01 for all three rFVIIa groups combined compared with placebo). The study was underpowered to detect differences in mortality rates or functional outcomes; however, mortality and severe disability rates (defined as a modified Rankin Scale [mRS] score of 4-6) were significantly higher in the placebo group than in all rFVIIa treatment groups combined (P = 0.004). The investigators who conducted this study concluded, therefore, that in patients with ICH, rFVIIa treatment within 4 h of symptom onset leads to reductions in hematoma expansion and mortality rate and to improvements in functional outcomes.[25]

In the FAST trial, a phase III efficacy and safety study of rFVIIa for acute ICH, 841 patients with such hemorrhages were randomly assigned to receive placebo ( n = 268), 20 g/kg rFVIIa (n = 276) or 80 g/kg rFVIIa (n = 297) within 4 h of symptom onset.[24] The primary end point of this trial was rate of poor outcome, which was defined as death or severe disability (according to the mRS) 90 days after the stroke. The phase IIb trial initially excluded patients with symptomatic thrombotic or vaso-occlusive disease (that is, angina, claudication, deep vein thrombosis, or cerebral or myocardial infarction) within 30 days before ICH onset. Midway through the trial, however, patients with any history of thrombotic or vaso-occlusive disease were excluded.[25] By contrast, the FAST trial allowed participation of patients with a history of vaso-occlusive disease but excluded individuals with symptoms within 30 days of ICH.[24] Treatment with 80 g/kg rFVIIa led to a significant reduction in hematoma expansion at 24 h (11% increase in volume with 80 g/kg rFVIIa versus 26% with placebo, P <0.001), and a nonsignificant decrease in hematoma expansion was observed in patients who received 20 g/kg rFVIIa (18% versus 26% in placebo, P = 0.09). No differences in functional outcomes were observed, however, among the three treatment groups (rate of poor clinical outcomes was 24% in the placebo group, 26% in the 20 g/kg rFVIIa group and 29% in the 80 g/kg rFVIIa group). [24] The posited explanations for the discrepant results between the phase IIb and phase III trials included randomization imbalances (a higher rate of IVH was present in patients treated with rFVIIa than occurred in patients receiving placebo in the FAST study), an increase in arterial thromboembolic events in patients receiving rFVIIa, inclusion of very elderly patients (aged >80 years) and patients with very large (>60 ml) ICHs, and better than expected outcomes in the placebo arm of the FAST trial. [24] A subgroup analysis of the FAST trial suggested that patients aged 70 years who had an ICH <60 ml and an IVH <5 ml, and arrived within 2.5 h of symptom onset, might benefit from rFVIIa.[37] Nevertheless, in contrast to the 5% absolute increase in arterial thromboembolic events initially reported in both rFVIIa trials, a follow-up study found a 19% absolute increase in arterial thrombotic events with such therapy. [38] Accurate prediction of the probability of hematoma expansion before administration of hemostatic therapy is, therefore, important for harnessing the potential benefits of limiting hematoma expansion while avoiding the potential thromboembolic complications associated with rFVIIa therapy. The appearance of contrast extravasation on CT angiography (the 'spot sign') early after symptom onset represents a promising tool for the prediction of hematoma expansion in ICH (Figure 1). In two case series, patients with a spot sign had a greater risk of hematoma expansion than patients without extravasation. [39,40] Wada et al. prospectively studied 39 patients with ICH by CT angiography within 3 h of symptom onset. Hematoma expansion occurred in 11 patients (28%), and 13 patients (33%) had the spot sign. In multiple regression analysis, the spot sign independently predicted hematoma expansion ( P = 0.0003).[40] Goldstein et al. retrospectively reviewed images from 104 patients with ICH who underwent CT angiography. Contrast extravasation was present in 56% of patients, and was associated with an increased risk of hematoma expansion compared with the absence of such signs (22% versus 2%, P = 0.003).[39] Taken together, these studies suggest that the spot sign has a sensitivity of 91-93% and a specificity of 50-89% for the prediction of hematoma expansion. Follow-up studies have found, however, that spot sign mimics can confound interpretation of CT angiography in ICH.[41] Thus, the role of the spot sign in the clinical care of patients with ICH requires further study. The STOP-IT study is an ongoing two-arm prospective study of patients with ICH who present within 6 h of symptom onset. The first arm is a randomized, double-blind, placebo-controlled trial comparing rFVIIa with placebo for treatment of patients who have acute ICH and a spot sign on CT angiography. The second arm is a prospective observational study of hematoma expansion among patients without a spot sign. The STOP-IT study will, therefore, determine the predictive value of the spot sign for ICH growth, and the capability of CT angiography to guide administration of hemostatic therapy in the acute clinical setting. The trial should be completed in the next 3-5 years. Another 'imaging' modality that has been proposed for monitoring hematoma expansion is transcranial duplex sonography (TDS). In a small prospective study, 34 patients with supratentorial ICH presenting <3 h after symptom onset were evaluated by CT and TDS at baseline and 6 h later. [42] The data generated from TDS were shown to correlate with the results of CT in terms of total hematoma volume (coefficient of correlation 0.82, P = 0.001).[42] Further studies are warranted to establish the utility of TDS for monitoring hematoma expansion after ICH. To our knowledge, only one published study has explored blood biomarkers for the prediction of hematoma expansion in ICH. In this multicenter prospective study, blood samples were obtained from 183 ICH patients within 12 h of symptom onset, and the concentrations of interleukin 6 (IL-6), tumor necrosis factor (TNF), matrix

metalloproteinase-9 (MMP-9), and cellular fibronectin (cFN) were determined. [43] CT scans were performed at baseline and at 48 6 h, and 54 patients (29.5%) were found to exhibit hematoma expansion. A cFN concentration >6 g/ml (OR 92, 95% CI 22-381, P <0.0001) and an IL-6 level >24 pg/ml (OR 16, 95% CI 2.3119, P = 0.005) were independently associated with hematoma expansion in the logistic regression analysis. These findings are yet to be independently validated. In addition to the markers examined in the study described above, glial fibrillary acidic protein, activated protein C-protein C inhibitor complex, and a panel of markers, including S100, MMP-9, D-dimer and brain natriuretic peptide, might have diagnostic utility in the differentiation of ICH from ischemic stroke. [44-46] Confirmation of these findings and exploration of the capacity of these markers to predict hematoma expansion are warranted. Anticoagulant-related ICH. In anticoagulant-related ICH, rapid correction of the underlying coagulopathy is the goal of therapy. A retrospective study of 69 patients with anticoagulant-related ICH found that the median time from symptom onset to first dose of fresh frozen plasma (FFP) had been shorter in patients who showed successful normalization of their international normalized ratio (INR) at 24 h than in individuals whose INR failed to normalize (90 min versus 210 min, P = 0.02). Moreover, this study found that every 30 min of delay in FFP administration was associated with a 20% decrease in probability of INR normalization within 24 h (OR 0.8, 95% CI 0.63-0.99).[47] The slow correction of coagulopathy with administration of FFP and vitamin K in patients with anticoagulantrelated ICH has led to an interest in alternative agentssuch as prothrombin complex concentrates (PCCs), factor IX complex concentrate and rFVIIato achieve this objective. PCCs contain high levels of factors II, VII and X, while factor IX complex concentrate contains factors II, VII, IX and X. These preparations require much smaller infusion volumes than FFP, and they correct coagulopathy more rapidly. [48,49] The INCH trial is an ongoing, multicenter, prospective randomized trial examining the use of PCCs and FFP in patients with anticoagulant-related ICH.[50] Two small studies have shown that rFVIIa can normalize the INR rapidly but requires co-administration with full doses of FFP and vitamin K, as the former has a short half-life (2.6 h) and lacks other relevant clotting factors. [51,52] Given the potential thrombotic complications with rFVIIa therapy and the limited available data, this agent is not currently recommended for routine use in cases of anticoagulant-related ICH. Blood Pressure Management. Markedly elevated blood pressure in patients who experience acute ICH has been associated with poor out-comes,[53,54] as has a rapid reduction in blood pressure in the first 24 h from symptom onset.[55] Thus, optimal blood pressure management in ICH requires a controlled, modest reduction in blood pressure levels for patients with hypertension. To date, INTERACT has been the largest study of blood pressure reduction in ICH.[23] Patients with ICH were eligible to participate in INTERACT if they were diagnosed by CT within 6 h of symptom onset and had a systolic blood pressure of 150-220 mmHg. Individuals meeting these criteria were randomly assigned to receive intensive blood pressure management (n = 203) to lower systolic blood pressure to 140 mmHg, or standard guideline-based management (n = 201) to achieve a systolic blood pressure of 180 mmHg. The primary efficacy end point was the proportional change in hematoma volume at 24 h. [23] At 1 h postrandomization, mean systolic blood pressure was 153 mmHg in the intensively managed group and 167 mmHg in the guideline-managed group (P <0.0001). From 1 h to 24 h, the systolic blood pressure was 146 mmHg in the intensive group and 157 mmHg in the guideline group (P <0.0001). Mean hematoma expansion was markedly higher (P = 0.04) in the guideline group (36.3% hematoma expansion) than in the intensive group (13.7% hematoma expansion) at 24 h. After adjustment for baseline ICH volume and for time from onset to CT, the median hematoma expansion was 16.2% in the guideline group and 6.2% in the intensive group, although this difference did not quite reach significance (P = 0.06). No difference in 90 day functional outcomes was observed between the two treatment groups (median mRS score 2 in both groups, P = 0.66). Risk of serious adverse events was not altered by intensive blood pressure reduction. [23] INTERACT2, a phase III trial, is ongoing and aims to confirm these findings and to determine whether intensive blood pressure reduction in ICH is associated with improvements in functional outcomes in treated patients. The ATACH trial was an open-label pilot study designed to evaluate the feasibility and safety of three escalating levels of antihypertensive treatment in hypertensive patients with ICH. [56] Individuals with ICH and systolic blood pressure 170 mmHg who presented within 6 h of symptom onset were eligible for enrollment in this study. Intravenous nicardipine was infused to achieve a target systolic blood pressure of 170-200 mmHg in the first cohort of patients (n = 18), 140-170 mmHg in the second cohort (n = 20), and 110-140 mmHg in the third cohort (n = 22). The primary outcomes were feasibility of treatment, neurological deterioration within 24 h

of treatment, and serious adverse events within 72 h of therapy. No significant adverse events above the prespecified safety stopping points were observed, [56] and a follow-up phase III trial is in the planning stages. Neuroprotective Therapies. As discussed above, secondary injury in ICH can result from cerebral edema, slow thrombin release, red blood cell lysis and/or hemoglobin-induced neurotoxicity. The multitude of processes that occur after ICH have been collectively termed 'neurohemoinflammation'. [33] The pursuit of targeting these processes as a means of improving ICH outcomes has generated notable clinical interest, and the results of two large trials of putative neuroprotective drugs in ICH have been published. [35,36] In the GAIN International and GAIN Americas trials, patients with either ischemic stroke or ICH were randomly assigned to receive gavestinel, a glycinesite antagonist of the N-methyl- D-aspartate (NMDA) receptor, or placebo within 6 h of symptom onset. The trials' outcomes were death or one of the three following levels of functional ability, as measured by the Barthel Index (BI): functionally independent (BI score 95-100), assisted independence (BI score 60-90) or functionally dependent (BI score 0-55). An analysis of the 571 patients with ICH included in the two trials revealed no significant difference (P = 0.09) in the trichotomized BI scores at 3 months between patients receiving gavestinel and patients receiving placebo. [36] The CHANT trial explored the safety and efficacy of NXY-059 (disufenton sodium), a free radical-trapping agent, in patients with ICH who presented within 6 h of symptom onset. [35] Overall, the drug had a good safety and tolerability profile, with no adverse effects observed. However, the OR for an improvement in the 3 month mRS score in the NXY-059 group was 1.01 (95% CI 0.75-1.35). Given the absence of evidence for efficacy, the investigators concluded there was "no suggestion that NXY-059 benefits ICH patients". [35] In addition to the studies described above, two smaller clinical trials have investigated citicoline-an intermediate compound in the synthetic pathway of structural phospholipidsas a putative neuroprotective agent in ICH. [57,58] A randomized study of 32 patients with supratentorial ICH found that muscular strength was improved in patients receiving intravenous citicoline administered twice daily for 14 days (n = 16) compared with individuals who received placebo (n = 16).[57] The scale used to determine muscle strength was not validated; thus, interpretation of the findings from this study is difficult. In a randomized pilot study designed to test the safety and efficacy of citicoline in human ICH, 1 g of oral or intravenous citicoline or placebo was administered twice daily for 2 weeks to patients with ICH who presented within 6 h of symptom onset. [58] In total, 19 patients received placebo and 19 patients received citicoline (either orally or intravenously). At 3 months, only one patient in the placebo group was rated as functionally independent (mRS 2), whereas 5 patients in the citicoline group were deemed independent (OR 5.38, 95% CI 0.55-52). No differences were observed in adverse events between the two treatment groups. The investigators concluded that citicoline was safe to use in humans and showed a positive trend towards efficacy for ICH. [58] Overall, insufficient data are currently available to recommend citicoline for clinical use. To date, no neuroprotective therapy has been shown to be effective in ICH. Several promising agents, however, are progressing to or have entered early-phase human ICH trials ( Table 3 ).
Surgical Management Trials

Cerebellar ICH. The discussion below focuses largely on supratentorial ICH. Nevertheless, cerebellar ICH comprises 6-10% of all cases of ICH.[59-62] Hematoma evacuation in cerebellar ICH can be life saving and is a class I recommendation in patients who are deteriorating neurologically, or who have brainstem compression and/or hydrocephalus from ventricular obstruction due to cerebellar hemorrhage. [2,63] Thus, when feasible and necessary, emergent surgery should be performed promptly in cases of such ICH. Craniotomy. Surgical treatment options for ICH include standard craniotomy for clot evacuation and/or decompression, and minimally invasive endoscopic clot evacuation, with or without thrombolysis. Craniotomy for clot evacuation is the most extensively studied surgical treatment option for ICH. The data generated from the STICH trial represent the best available evidence to inform the surgical management of ICH. [34] In this study, 1,033 patients with ICH were randomly assigned to surgery or medical management within 96 h of symptom onset. Of note, patients were only allocated to one of these treatment groups after the investigators had determined that they were not candidates for urgent neurosurgery. Hemorrhage evacuation occurred within 24 h of randomization. The primary outcome measure was the Glasgow Outcome Scale score at 6 months. In the STICH study, no overall benefitin terms of the percentage of patients with favorable outcomeswas seen from early surgery over initial medical treatment (26% versus 24% had favorable outcomes, P = 0.41). A preplanned subgroup analysis, however, showed that patients with a hematoma within 1 cm of the cortical surface who were treated with surgery showed a trend towards better outcomes than in patients treated

medically (P = 0.07).[34] The STICH II trial is underway and aims to determine whether carefully selected patients might benefit from surgery over medical management. Minimally Invasive Endoscopic Procedures. To date, the largest study of minimally invasive clot evacuation in ICH involved the random assignment of 377 patients with basal ganglion ICH (hemorrhage volumes of 25-40 ml) to receive minimally invasive craniopuncture therapy (n = 195) or medical control treatment (n = 182).[64] Patients in the craniopuncture arm were treated with clot aspiration and urokinase (10,00050,000 IU). The primary outcomes of the trial were death or dependency at 90 days (the latter was measured by the mRS and the BI). At 90 days, no significant difference was apparent in the mortality rates of the two groups (6.7% in the craniopuncture group versus 8.8% in the medically treated group, P = 0.44). The patients in the medical treatment group were, however, significantly less likely than the individuals who underwent clot evacuation to be functionally independent at 90 days (63.0% versus 40.9% had an mRS score 3-6, P <0.01). The researchers concluded that minimally invasive craniosurgery was safe and might improve independent survival in ICH.[64] A confirmatory phase III trial is under way. In a single-center trial, 100 patients with ICH were randomly assigned to burr hole and continuous lavage of the hematoma cavity or medical therapy within 48 h of symptom onset. [65] In this study, the surgical group had a significantly lower mortality rate than the medically treated group (42% versus 70%, P = 0.01). A multicenter randomized controlled trial of 71 patients with ICH, each of whom had a GCS score 5 or clots 10 ml in volume, examined stereotactic infusion of urokinase infusion within 72 h of symptom onset. [66] Urokinase (5,000 IU) was infused every 6 h over a period of 48 h, and the primary outcomes in this study were death and functional disability at 6 months. The median reduction in volume of ICH from baseline was 40% in the surgical group and 18% in the medical group, while rebleeding occurred in 35% of patients in the former group and 17% of patients in the latter treatment group. In the logistic regression analysis, a nonsignificant reduction was noted in mortality at 180 days in the urokinase group (OR 0.23, 95% CI 0.05-1.20, P = 0.08).[66] Stereotactic administration of recombinant tissue plasminogen activator (rtPA) into the hematoma cavity of parenchymal ICH has also been studied.[67] After CT-guided placement of a catheter via a burr hole, 28 patients with ICH received 1 mg of rtPA infusion into the clot cavity every 8 h over a period of 48 h. In these patients, the ICH volume was reduced by 77 6 ml (13%) on final CT scans compared with baseline CT scans (P <0.0002). No episodes of symptomatic hematoma expansion occurred, although one patient had asymptomatic bleeding along the catheter tract.[67] The MISTIE study is an ongoing, multicenter, randomized clinical trial that is testing whether early minimally invasive surgery plus administration of rtPA is a safe treatment for ICH and, by comparison with medically treated patients, leads to a reduction in clot size. [68] The study began in 2006 and is expected to reach completion in 2013. Interest has been expressed in the use of thrombolytic therapy in conjunction with ventriculostomy in cases of IVH. In the open-label CLEAR-IVH trial, 52 patients with IVH were treated prospectively with intraventricular rtPA. The 30 day mortality rate in this study was 17%, and symptomatic bleeding occurred in 4% of treated individuals.[69] In a small randomized trial, patients with IVH who had undergone ventriculostomy received intraventricular injections of normal saline solution (5 patients) or urokinase (25,000 IU; 7 patients) at 12 h intervals. Clot resolution occurred at a faster rate in the urokinase-treated group than in the saline-treated group (P = 0.02).[70] The CLEAR III study is an international, multicenter, double-blind, randomized phase III trial comparing the use of ventriculostomy plus rtPA with ventriculostomy plus placebo for the treatment of IVH. The primary aim is to determine whether the former improves mRS scores at 6 months, and enrollment is expected to be completed in 2012.

Conclusions
The clinical trials discussed above have broadly been described as medical or surgical. Medical trials in the acute phase of ICH are aimed mainly at attenuation of hematoma expansion (hemostasis), while surgical trials require cessation of bleeding before evacuation of a stable hematoma. Evacuation of the hematoma might decrease mass effect, and reduce neurotoxicity resulting from red blood cell lysis and delayed thrombin release, but the trauma associated with surgery or rebleeding due to surgery can worsen outcomes. These contrasting effects might account for the equivocal findings in trials of surgery for ICH to date.

Both medical and surgical trials require consistently excellent neurocritical care of enrolled patients, if such studies are to be successful in testing the efficacy of a given approach to treatment. If CT angiography or biomarkers are proven to predict hematoma expansion accurately, patients who are destined to have ongoing bleeding might be considered for appropriate medical therapies, while individuals who are unlikely to have hematoma expansion might be operated on more quickly than would otherwise be the case. An early time to surgery has been associated with not only an improvement in mortality rate in patients with ICH, but also an increase in the risk of bleeding.[71,72] The accurate identification of the 60% of patients with ICH who will not have marked hematoma expansion in the first few hours after symptom onset might allow selected individuals to undergo early evacuation of the hematoma by surgical techniques that minimize brain injury. Combination therapies such as early administration of hemostatic agents followed by surgical evacuation could also be pursued if early accurate stratification of patients can be achieved. A scientifically proven and effective treatment for ICH remains elusive; however, trials in the past 10 years have led to improvements in our understanding of the goals of clinical care for the various subpopulations of patients who develop this condition. Careful selection of patients for enrollment in ongoing trials should lead to proven therapies for ICH in the coming years.

Key Points Globally, 2 million people every year develop intracerebral hemorrhage (ICH), which is associated
with high morbidity and mortality rates and has no effective treatment Medical trials conducted for acute ICH in the past decade have included trials of hemostasis with recombinant factor VIIa and trials of blood pressure control Surgical trials for ICH of the past 10 years have included studies of craniotomy with clot evacuation, and minimally invasive clot aspiration with or without thrombolysis Data generated from medical and surgical trials have led to improvements in our understanding of the strategies to undertake for effective clinical management of ICH Ongoing trials show promise for the development of a therapy that improves ICH outcomes

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