Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: Design, Methods, and Rationale Authors
Take a Closer Look at Trials
First Online: 28 May 2011 DOI:
Cite this article as: Qureshi, A.I. & Palesch, Y.Y. Neurocrit Care (2011) 15: 559. doi:10.1007/s12028-011-9538-3 Abstract
The December 2003 report from the National Institute of Neurological Disorders and Stroke (NINDS) Workshop on priorities for clinical research in intracerebral hemorrhage (ICH) recommended clinical trials for evaluation of blood pressure management in acute ICH as a leading priority. The Special Writing Group of the Stroke Council of the American Heart Association in 1999 and 2007 emphasized the need for clinical trials to ensure evidence-based treatment of acute hypertensive response in ICH. To address important gaps in knowledge, we conducted a pilot study funded by the NINDS, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) I Trial, during 2004–2008 to determine the appropriate level of systolic blood pressure (SBP) reduction. We now have initiated a multi-center, randomized Phase III trial, the ATACH II Trial, to definitively determine the efficacy of early, intensive, antihypertensive treatment using intravenous (IV) nicardipine initiated within 3 h of onset of ICH and continued for the next 24 h in subjects with spontaneous supratentorial ICH. The primary hypothesis of this large (
N = 1,280), streamlined, and focused trial is that SBP reduction to ≤140 mm Hg reduces the likelihood of death or disability at 3 months after ICH, defined by modified Rankin scale score of 4–6, by at least 10% absolute compared to standard SBP reduction to ≤180 mm Hg. The ATACH II trial is a natural extension of numerous case series, the subsequent ATACH I pilot trial, and a preliminary, randomized, and controlled trial in this patient population funded by the Australian National Health and Medical Research Council. Both trials recently confirmed the safety and tolerability of both the regimen and goals of antihypertensive treatment in acutely hypertensive patients with ICH, as proposed in the present trial. The underlying mechanism for this expected beneficial effect of intensive treatment is presumably mediated through reduction of the rate and magnitude of hematoma expansion observed in approximately 73% of the patients with acute ICH. The Australian trial provided preliminary evidence of attenuation of hematoma expansion with intensive SBP reduction. The ATACH II trial will have important public health implications by providing evidence of, or lack thereof, regarding the efficacy and safety of acute antihypertensive treatment in subjects with ICH. This treatment represents a strategy that can be made widely available without the need for specialized equipment and personnel, and therefore, can make a major impact upon clinical practice for treating patients with ICH. Keywords Intracerebral hemorrhage Clinical trial Randomization Acute hypertensive response Hematoma enlargement
This study was conducted for the ATACH II Investigators.
Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–60.
Qureshi AI, Ezzeddine MA, Nasar A, et al. Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med. 2007;25:32–8.
Broderick JP, Adams HP Jr, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1999;30:905–15.
Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke. 2007;38:2001–23.
Flaherty ML, Woo D, Haverbusch M, et al. Potential applicability of recombinant factor VIIa for intracerebral hemorrhage. Stroke. 2005;36:2660–4.
Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis. 2006;22:294–316.
Sorimachi T, Fujii Y, Morita K, Tanaka R. Rapid administration of antifibrinolytics and strict blood pressure control for intracerebral hemorrhage. Neurosurgery. 2005;57:837–44.
Nishiyama T, Yokoyama T, Matsukawa T, Hanaoka K. Continuous nicardipine infusion to control blood pressure after evacuation of acute cerebral hemorrhage. Can J Anaesth. 2000;47:1196–201.
Ohwaki K, Yano E, Nagashima H, Hirata M, Nakagomi T, Tamura A. Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement. Stroke. 2004;35:1364–7.
Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997;28:1–5.
Mayer SA. Factor seven for acute hemorrhagic stroke (FAST) study. In: 16th European Stroke Conference: Large Clinical Trials 1. Abstract 1 29 May–1 June 2007.
Mayer SA, Davis SM, Begtrup K, et al. Subgroup analysis in the Fast trial: A subset of intracerebral hemorrhage patients that benefit from recombinant activated factor VII. Stroke. 2008;39:528.
Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke. 1996;27:1783–7.
Mayer SA, Sacco RL, Shi T, Mohr JP. Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology. 1994;44:1379–84.
Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality [see comment]. Stroke. 1993;24:987–93.
Qureshi AI, Safdar K, Weil J, et al. Predictors of early deterioration and mortality in black Americans with spontaneous intracerebral hemorrhage. Stroke. 1995;26:1764–7.
Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage [see comment]. Stroke. 2001;32:891–7.
Godoy DA, Pinero G, Di Napoli M. Predicting mortality in spontaneous intracerebral hemorrhage: can modification to original score improve the prediction? Stroke. 2006;37:1038–44.
Nilsson OG, Lindgren A, Brandt L, Saveland H. Prediction of death in patients with primary intracerebral hemorrhage: a prospective study of a defined population. J Neurosurg. 2002;97:531–6.
Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med. 2000;28:1556–64.
European Stroke Initiative Writing C, Writing Committee for the EEC, Katse M, et al. Recommendations for the management of intracranial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis. 2006;22:294–316.
St Louis EK, Wijdicks EF, Li H. Predicting neurologic deterioration in patients with cerebellar hematomas. Neurology. 1998;51:1364–9.
Sumer MM, Acikgoz B, Akpinar G. External ventricular drainage for acute obstructive hydrocephalus developing following spontaneous intracerebral haemorrhages. Neurol Sci. 2002;23:29–33.
Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage [see comment]. Crit Care Med. 1999;27:617–21.
Bhattathiri PS, Gregson B, Prasad KSM, Mendelow AD, Investigators S. Intraventricular hemorrhage and hydrocephalus after spontaneous intracerebral hemorrhage: results from the STICH trial. Acta Neurochir Suppl. 2006;96:65–8.
Steiner T, Diringer MN, Schneider D, et al. Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII. Neurosurgery. 2006;59:767–73. discussion 773–764.
Lisk DR, Pasteur W, Rhoades H, Putnam RD, Grotta JC. Early presentation of hemispheric intracerebral hemorrhage: prediction of outcome and guidelines for treatment allocation. Neurology. 1994;44:133–9.
PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–41.
Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359:1225–37.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National High Blood Pressure Education Program 2004;
. Accessed April 2011.
Qureshi AI, Hutson AD, Harbaugh RE, et al. Methods and design considerations for randomized clinical trials evaluating surgical or endovascular treatments for cerebrovascular diseases. Neurosurgery. 2004;54:248–64. discussion 264–7.
Day SJ, Altman DG. Statistics notes: blinding in clinical trials and other studies. BMJ. 2000;321:504.
Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what [see comment]. Lancet. 2002;359:696–700.
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604–7.
Wilson JT, Hareendran A, Grant M, et al. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. Stroke. 2002;33:2243–6.
Choi SC, Clifton GL, Marmarou A, Miller ER. Misclassification and treatment effect on primary outcome measures in clinical trials of severe neurotrauma. J Neurotrauma. 2002;19:17–22.
Mayer SA. Recombinant activated factor VII for acute intracerebral hemorrhage. Stroke. 2007;38:763–7.
Group TE. EuroQol—a new facility for the measurement of health-related quality of life. Health Policy. 1990;16:99–208.
Segal ME, Schall RR. Determining functional/health status and its relation to disability in stroke survivors. Stroke. 1994;25:2391–7.
Dorman PJ, Waddell F, Slattery J, Dennis M, Sandercock P. Is the EuroQol a valid measure of health-related quality of life after stroke? Stroke. 1997;28:1876–82.
Dorman P, Slattery J, Farrell B, Dennis M, Sandercock P. Qualitative comparison of the reliability of health status assessments with the EuroQol and SF-36 questionnaires after stroke. United Kingdom Collaborators in the International Stroke Trial. Stroke. 1998;29:63–8.
Pickard AS, Johnson JA, Feeny DH, Shuaib A, Carriere KC, Nasser AM. Agreement between patient and proxy assessments of health-related quality of life after stroke using the EQ-5D and Health Utilities Index. Stroke. 2004;35:607–12.
Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT Trial. Stroke. 2007;38:2262–9.
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.
Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:2127–37.
Narayan RK, Michel ME, Ansell B, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–57.
Qureshi AI, Suri MFK, Nasar A, et al. Changes in cost and outcome among US patients with stroke hospitalized in 1990 to 1991 and those hospitalized in 2000 to 2001. Stroke. 2007;38:2180–4.
Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175–81.
Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777–85.
Anderson CS, Huang Y, Wang JG, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7:391–9.
Kraemer HC, Mintz J, Noda A, Tinklenberg J, Yesavage JA. Caution regarding the use of pilot studies to guide power calculations for study proposals. Arch Gen Psychiatry. 2006;63:484–9.
Arnold DM, Burns KE, Adhikari NK, Kho ME, Meade MO, Cook DJ. The design and interpretation of pilot trials in clinical research in critical care. Crit Care Med. 2009;37:S69–74.
Adams HP Jr. Trials of trials in acute ischemic stroke. The Humana lecture. Stroke. 1993;24:1410–5.
Bolland K, Sooriyarachchi MR, Whitehead J. Sample size review in a head injury trial with ordered categorical responses. Stat Med. 1998;17:2835–47.
Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006;5:603–12.
Saver JL. Novel end point analytic techniques and interpreting shifts across the entire range of outcome scales in acute stroke trials. Stroke. 2007;38:3055–62.
Saver JL, Gornbein J. Treatment effects for which shift or binary analyses are advantageous in acute stroke trials. Neurology. 2009;72:1310–5.
Brant R. Assessing proportionality in the proportional odds model for ordinal logistic regression. Biometrics. 1990;46:1171–8.
Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6:215–22.
Lai SM, Duncan PW. Stroke recovery profile and the Modified Rankin assessment. Neuroepidemiology. 2001;20:26–30.
Feinstein AR, Landis JR. The role of prognostic stratification in preventing the bias permitted by random allocation of treatment. J Chronic Dis. 1976;29:277–84.
Lipchik GL, Nicholson RA, Penzien DB. Allocation of patients to conditions in headache clinical trials: randomization, stratification, and treatment matching [see comment]. Headache. 2005;45:419–28.
Kernan WN, Viscoli CM, Makuch RW, Brass LM, Horwitz RI. Stratified randomization for clinical trials [see comment]. J Clin Epidemiol. 1999;52:19–26.
Beach ML, Meier P. Choosing covariates in the analysis of clinical trials. Control Clin Trials. 1989;10:161S–75S.
McHugh R, Matts J. Post-stratification in the randomized clinical trial. Biometrics. 1983;39:217–25.
Rectenwald JE, Upchurch GR Jr. Impact of outcomes research on the management of vascular surgery patients. J Vasc Surg. 2007;45(Suppl A):A131–40.
Lipscomb J, Donaldson MS, Hiatt RA. Cancer outcomes research and the arenas of application. J Natl Cancer Inst. 2004;Monographs:1–7.
Anonymous. Priorities for clinical research in intracerebral hemorrhage: report from a National Institute of Neurological Disorders and Stroke workshop. Stroke. 2005;36:e23–41.
Krumholz HM, Brindis RG, Brush JE, et al. Standards for statistical models used for public reporting of health outcomes: an American Heart Association Scientific Statement from the Quality of Care and Outcomes Research Interdisciplinary Writing Group: cosponsored by the Council on Epidemiology and Prevention and the Stroke Council. Endorsed by the American College of Cardiology Foundation. Circulation. 2006;113:456–62.
Taylor SM, Robison JG, Langan EM 3rd, Crane MM. The pitfalls of establishing a statewide vascular registry: the South Carolina experience. Am Surg. 1999;65:513–8. discussion 518-519.
Isenberg SF. Community-based outcomes research: the project solo experience. Laryngoscope. 2000;110:21–3.
Qureshi AI, Suri MFK, Nasar A, et al. Thrombolysis for ischemic stroke in the United States: data from National Hospital Discharge Survey 1999–2001. Neurosurgery. 2005;57:647–54. discussion 647-654.
Qureshi AI, Kirmani JF, Sayed MA, et al. Time to hospital arrival, use of thrombolytics, and in-hospital outcomes in ischemic stroke. Neurology. 2005;64:2115–20.
Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM, Cleveland Clinic Health System Stroke Quality Improvement T. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke. 2003;34:799–800.
Anonymous. Comparison of patients with intracerebral hemorrhage treated within and outside clinical trials: A report of the antihypertensive treatment of acute cerebral hemorrhage investigators. In: American Academy of Neurology 59th Annual Meeting 2007. Boston. 2007.
Qureshi AI. Antihypertensive treatment of acute cerebral hemorrhage (ATACH): rationale and design. Neurocrit Care. 2007;6:56–66.
Morgan T, Awad I, Keyl P, Lane K, Hanley D. Preliminary report of the clot lysis evaluating accelerated resolution of intraventricular hemorrhage (CLEAR-IVH) clinical trial. Acta Neurochir Suppl. 2008;105:217–20.
Haley EC Jr, Thompson JL, Levin B, et al. Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies. Stroke. 2005;36:1006–10.
del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism [see comment]. Stroke. 1998;29:4–11.
Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism [see comment]. JAMA. 1999;282:2003–11.
Investigators IMSS. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study [see comment]. Stroke. 2004;35:904–11.
Investigators IIT. The Interventional Management of Stroke (IMS) II Study. Stroke. 2007;38:2127–35.
Adams HP Jr, Effron MB, Torner J, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: abciximab in emergency treatment of stroke trial (AbESTT-II). Stroke. 2008;39:87–99.
Qureshi AI, Palesch YY, Martin R, Novitzke J, Cruz-Flores S, Ehtisham A, Ezzeddine MA, Goldstein JN, Hussein HM, Suri MF, Tariq N, Antihypertensive Treatment of Acute Cerebral Hemorrhage Study Investigators. Effect of systolic blood pressure reduction on hematoma expansion, perihematomal edema, and 3-month outcome among patients with intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral hemorrhage study. Arch Neurol. 2010;67:570–6.
© Springer Science+Business Media, LLC 2011