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Intracerebral haemorrhage: no good treatment but treatment helps
Comment
Intracerebral haemorrhage is a bad disease. It carries a high morbidity and mortality and specific medical and surgical treatments do not change prognosis substantially. When intracerebral haemorrhage is complicated by intraventricular haemorrhage the prognosis is even worse; more than half of patients are estimated to die during the acute phase and most survivors are disabled by the brain injury.1 Because of this sobering background the CLEAR III trial2 was awaited with much interest. In this carefully designed, international, randomised, double-blind, placebo-controlled trial, Daniel Hanley and colleagues tested whether scheduled intraventricular boluses of the thrombolytic drug alteplase (given through clinically indicated ventriculostomy catheters) could improve functional outcomes in patients with intraventricular haemorrhage from intracerebral haemorrhage by accelerating resolution of the intraventricular clot. Enrolled patients had a spontaneous intracerebral haematoma of relatively moderate or small size (<30 mL), which had been stable on serial CT scans, and intraventricular haemorrhage obstructing the third or fourth ventricles. Patients could not be older than 80 years or have previous functional impairment. The trial enrolled 500 patients; follow-up data were available from 246 of 251 participants in the alteplase group and 245 of the 249 participants in the placebo group. The results were neutral: the proportion of patients treated with boluses of alteplase who achieved good functional outcome at 6 months was similar to that of patients who received saline boluses in the control group (48% vs 45%; risk ratio 1·06 [95% CI 0·88–1·28]; p=0·554). Mortality was 11% lower in the alteplase group than in the saline group, but at the expense of an 8% increase in the rate of survivors with severe disability. No differences were noted in the self-reported measure of quality of life between the two groups. Yet, there is a lot to learn from this trial. Patients in both treatment groups did much better than expected. The power analysis, based on previous data, estimated that 22% of the control group would achieve a good functional outcome, but the rate in CLEAR III was 45%.
Mortality, symptomatic rebleeding, and bacterial brain infections were also much lower than anticipated, and greater intraventricular clot removal was associated with improved functional outcomes. Unfortunately, only 30% of patients given alteplase reached the goal of 80% clot reduction, which might be one of the reasons that the treatment was not effective in improving functional outcomes. Yet it is encouraging that the pathophysiological premise of the trial was correct: that effective clearance of intraventricular haemorrhage could improve functional outcomes and mortality.3 There might be much more to learn from information collected during CLEAR III—eg, from detailed analysis of the degree and evolution of hydrocephalus. Some data suggest that the deleterious effects of intraventricular haemorrhage might be caused primarily by the hydrocephalus it produces.4 In fact, characteristic sequelae of chronic hydrocephalus (such as bladder incontinence and abnormal gait) are often encountered after intraventricular haemorrhage from intracerebral haemorrhage.5 Thus it is surprising that the rate of ventriculoperitoneal shunting in CLEAR III was relatively low (18%). My experience in practice has been that residual hydrocephalus after intraventricular haemorrhage is often underdiagnosed and consequently undertreated. Several other randomised controlled trials of promising interventions for intracerebral haemorrhage did not improve clinical outcomes—eg, surgical evacuation by craniotomy6 (even when restricted to superficial haematomas)7 and early administration of recombinant activated factor VII to prevent haematoma expansion.8 Recombinant factor VII achieved its mechanistic goal of reducing haematoma expansion, but without improvements in functional outcomes. The jury is still out regarding intensive blood pressure reduction during the acute stage. INTERACT29 showed modest benefit in functional outcome with more intensive lowering of blood pressure (systolic blood pressure of 140 mm Hg vs 180 mm Hg), but the reasons for this benefit remain unclear because haematoma expansion was not significantly affected. More recently ATACH-210 showed no difference in outcomes between
www.thelancet.com Published online January 9, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30002-8
Javier Larrea/Getty
Intracerebral haemorrhage: no good treatment but treatment helps
Published Online January 9, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30002-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(16)32410-2
1
Comment
the intensive and conservative blood pressure treatment groups. Despite having identical blood pressure targets, actual blood pressures were lower in both arms of ATACH-2 compared with INTERACT2, highlighting the difficulty in reproducing treatment responses across clinical trials of similar design.11 Well-designed neutral trials can teach us a lot. Based on the results of CLEAR III, intraventricular alteplase cannot be recommended at present for the treatment of intraventricular haemorrhage in clinical practice. However, its administration is safe and aggressive clearance of the intraventricular clot, when truly achieved, might improve morbidity and mortality. There is some support for dual simultaneous ventricular drainage catheters for patients with severe intraventricular haemorrhage.12 More selective placement of one or more ventricular drainage catheters, with or without adjunctive thrombolysis, deserves to be investigated. But perhaps most importantly, CLEAR III tells us that aggressive treatment of patients with intraventricular haemorrhage from intracerebral haemorrhage and good premorbid function can achieve better functional recovery than previously thought. We might not have great specific treatments for intracerebral haemorrhage or intraventricular haemorrhage, but doing what we can is still very useful.
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Hansen BM, Morgan TC, Betz JF, et al. Intraventricular extension of supratentorial intracerebral hemorrhage: the Modified Graeb Scale improves outcome prediction in Lund Stroke Register. Neuroepidemiology 2016; 46: 43–50. Hanley DF, Lane K, McBee N, et al, for the CLEAR III trial investigators. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet 2017; published online Jan 9. http://dx.doi.org/10.1016/S0140-6736(16)32410-2. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke 2009; 40: 1533–38. Mahta A, Katz PM, Kamel H, Azizi SA. Intracerebral hemorrhage with intraventricular extension and no hydrocephalus may not increase mortality or severe disability. J Clin Neurosci 2016; 30: 56–59. Woo D, Kruger AJ, Sekar P, et al. Incontinence and gait disturbance after intraventricular extension of intracerebral hemorrhage. Neurology 2016; 86: 905–11. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 2005; 365: 387–97. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013; 382: 397–408. Mayer SA, Brun NC, Begtrup K, et al; FAST Trial Investigators. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358: 2127–37. Anderson CS, Heeley E, Huang Y, et al. for the INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368: 2355–65. Qureshi AI, Palesch YY, Barsan WG, for the ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016; 375: 1033–43. Prasad V, Vandross A, Toomey C, et al. A decade of reversal: an analysis of 146 contradicted medical practices. Mayo Clin Proc 2013; 88: 790–98. Hinson HE, Melnychuk E, Muschelli J, Hanley DF, Awad IA, Ziai WC. Drainage efficiency with dual versus single catheters in severe intraventricular haemorrhage. Neurocrit Care 2012; 16: 399–405.
Alejandro A Rabinstein Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA [email protected] I declare no competing interests.
2
www.thelancet.com Published online January 9, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30002-8
Intracerebral haemorrhage is a bad disease. It carries a high morbidity and mortality and specific medical and surgical treatments do not change prognosis substantially. When intracerebral haemorrhage is complicated by intraventricular haemorrhage the prognosis is even worse; more than half of patients are estimated to die during the acute phase and most survivors are disabled by the brain injury.1 Because of this sobering background the CLEAR III trial2 was awaited with much interest. In this carefully designed, international, randomised, double-blind, placebo-controlled trial, Daniel Hanley and colleagues tested whether scheduled intraventricular boluses of the thrombolytic drug alteplase (given through clinically indicated ventriculostomy catheters) could improve functional outcomes in patients with intraventricular haemorrhage from intracerebral haemorrhage by accelerating resolution of the intraventricular clot. Enrolled patients had a spontaneous intracerebral haematoma of relatively moderate or small size (<30 mL), which had been stable on serial CT scans, and intraventricular haemorrhage obstructing the third or fourth ventricles. Patients could not be older than 80 years or have previous functional impairment. The trial enrolled 500 patients; follow-up data were available from 246 of 251 participants in the alteplase group and 245 of the 249 participants in the placebo group. The results were neutral: the proportion of patients treated with boluses of alteplase who achieved good functional outcome at 6 months was similar to that of patients who received saline boluses in the control group (48% vs 45%; risk ratio 1·06 [95% CI 0·88–1·28]; p=0·554). Mortality was 11% lower in the alteplase group than in the saline group, but at the expense of an 8% increase in the rate of survivors with severe disability. No differences were noted in the self-reported measure of quality of life between the two groups. Yet, there is a lot to learn from this trial. Patients in both treatment groups did much better than expected. The power analysis, based on previous data, estimated that 22% of the control group would achieve a good functional outcome, but the rate in CLEAR III was 45%.
Mortality, symptomatic rebleeding, and bacterial brain infections were also much lower than anticipated, and greater intraventricular clot removal was associated with improved functional outcomes. Unfortunately, only 30% of patients given alteplase reached the goal of 80% clot reduction, which might be one of the reasons that the treatment was not effective in improving functional outcomes. Yet it is encouraging that the pathophysiological premise of the trial was correct: that effective clearance of intraventricular haemorrhage could improve functional outcomes and mortality.3 There might be much more to learn from information collected during CLEAR III—eg, from detailed analysis of the degree and evolution of hydrocephalus. Some data suggest that the deleterious effects of intraventricular haemorrhage might be caused primarily by the hydrocephalus it produces.4 In fact, characteristic sequelae of chronic hydrocephalus (such as bladder incontinence and abnormal gait) are often encountered after intraventricular haemorrhage from intracerebral haemorrhage.5 Thus it is surprising that the rate of ventriculoperitoneal shunting in CLEAR III was relatively low (18%). My experience in practice has been that residual hydrocephalus after intraventricular haemorrhage is often underdiagnosed and consequently undertreated. Several other randomised controlled trials of promising interventions for intracerebral haemorrhage did not improve clinical outcomes—eg, surgical evacuation by craniotomy6 (even when restricted to superficial haematomas)7 and early administration of recombinant activated factor VII to prevent haematoma expansion.8 Recombinant factor VII achieved its mechanistic goal of reducing haematoma expansion, but without improvements in functional outcomes. The jury is still out regarding intensive blood pressure reduction during the acute stage. INTERACT29 showed modest benefit in functional outcome with more intensive lowering of blood pressure (systolic blood pressure of 140 mm Hg vs 180 mm Hg), but the reasons for this benefit remain unclear because haematoma expansion was not significantly affected. More recently ATACH-210 showed no difference in outcomes between
www.thelancet.com Published online January 9, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30002-8
Javier Larrea/Getty
Intracerebral haemorrhage: no good treatment but treatment helps
Published Online January 9, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30002-8 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(16)32410-2
1
Comment
the intensive and conservative blood pressure treatment groups. Despite having identical blood pressure targets, actual blood pressures were lower in both arms of ATACH-2 compared with INTERACT2, highlighting the difficulty in reproducing treatment responses across clinical trials of similar design.11 Well-designed neutral trials can teach us a lot. Based on the results of CLEAR III, intraventricular alteplase cannot be recommended at present for the treatment of intraventricular haemorrhage in clinical practice. However, its administration is safe and aggressive clearance of the intraventricular clot, when truly achieved, might improve morbidity and mortality. There is some support for dual simultaneous ventricular drainage catheters for patients with severe intraventricular haemorrhage.12 More selective placement of one or more ventricular drainage catheters, with or without adjunctive thrombolysis, deserves to be investigated. But perhaps most importantly, CLEAR III tells us that aggressive treatment of patients with intraventricular haemorrhage from intracerebral haemorrhage and good premorbid function can achieve better functional recovery than previously thought. We might not have great specific treatments for intracerebral haemorrhage or intraventricular haemorrhage, but doing what we can is still very useful.
1
2
3 4
5
6
7
8
9
10
11 12
Hansen BM, Morgan TC, Betz JF, et al. Intraventricular extension of supratentorial intracerebral hemorrhage: the Modified Graeb Scale improves outcome prediction in Lund Stroke Register. Neuroepidemiology 2016; 46: 43–50. Hanley DF, Lane K, McBee N, et al, for the CLEAR III trial investigators. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet 2017; published online Jan 9. http://dx.doi.org/10.1016/S0140-6736(16)32410-2. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke 2009; 40: 1533–38. Mahta A, Katz PM, Kamel H, Azizi SA. Intracerebral hemorrhage with intraventricular extension and no hydrocephalus may not increase mortality or severe disability. J Clin Neurosci 2016; 30: 56–59. Woo D, Kruger AJ, Sekar P, et al. Incontinence and gait disturbance after intraventricular extension of intracerebral hemorrhage. Neurology 2016; 86: 905–11. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 2005; 365: 387–97. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013; 382: 397–408. Mayer SA, Brun NC, Begtrup K, et al; FAST Trial Investigators. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358: 2127–37. Anderson CS, Heeley E, Huang Y, et al. for the INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368: 2355–65. Qureshi AI, Palesch YY, Barsan WG, for the ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016; 375: 1033–43. Prasad V, Vandross A, Toomey C, et al. A decade of reversal: an analysis of 146 contradicted medical practices. Mayo Clin Proc 2013; 88: 790–98. Hinson HE, Melnychuk E, Muschelli J, Hanley DF, Awad IA, Ziai WC. Drainage efficiency with dual versus single catheters in severe intraventricular haemorrhage. Neurocrit Care 2012; 16: 399–405.
Alejandro A Rabinstein Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA [email protected] I declare no competing interests.
2
www.thelancet.com Published online January 9, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30002-8