Statistical analysis plan for evaluating low- vs. standard-dose alteplase in the ENhanced Control of Hypertension and Thrombolysis strokE stuDy (ENCHANTED)
Craig S Anderson, Mark Woodward, Hisatomi Arima, Xiaoying Chen, Richard I Lindley, Xia Wang, John Chalmers, ENCHANTED Investigators, Craig S Anderson, Mark Woodward, Hisatomi Arima, Xiaoying Chen, Richard I Lindley, Xia Wang, John Chalmers, ENCHANTED Investigators
Abstract
Background: The ENhanced Control of Hypertension And Thrombolysis strokE stuDy trial is a 2 × 2 quasi-factorial active-comparison, prospective, randomized, open, blinded endpoint clinical trial that is evaluating in thrombolysis-eligible acute ischemic stroke patients whether: (1) low-dose (0·6 mg/kg body weight) intravenous alteplase has noninferior efficacy and lower risk of symptomatic intracerebral hemorrhage compared with standard-dose (0·9 mg/kg body weight) intravenous alteplase; and (2) early intensive blood pressure lowering (systolic target 130-140 mmHg) has superior efficacy and lower risk of any intracerebral hemorrhage compared with guideline-recommended blood pressure control (systolic target <180 mmHg).
Objective: To outline in detail the predetermined statistical analysis plan for the 'alteplase dose arm' of the study.
Methods: All data collected by participating researchers will be reviewed and formally assessed. Information pertaining to the baseline characteristics of patients, their process of care, and the delivery of treatments will be classified, and for each item, appropriate descriptive statistical analyses are planned with appropriate comparisons made between randomized groups. For the trial outcomes, the most appropriate statistical comparisons to be made between groups are planned and described.
Results: A statistical analysis plan was developed for the results of the alteplase dose arm of the study that is transparent, available to the public, verifiable, and predetermined before completion of data collection.
Conclusions: We have developed a predetermined statistical analysis plan for the ENhanced Control of Hypertension And Thrombolysis strokE stuDy alteplase dose arm which is to be followed to avoid analysis bias arising from prior knowledge of the study findings.
Trial registration: ClinicalTrials.gov NCT01422616.
Keywords: acute; alteplase; clinical trials; statistical analysis plan; stroke; thrombolysis.
© 2015 The Authors. International Journal of Stroke published by John Wiley & Sons Ltd on behalf of World Stroke Organization.
References
- The National Institute of Disorders and Stroke rt‐PA Stroke Study group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581–1587.
- Emberson J, Lees KR, Lyden P et al Effect of treatment delay, age and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta‐analysis of individual patient data from randomised trials. Lancet 2014; 384:1929–1935.
- Wardlaw JM, Murray V, Berge E et al Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta‐analysis. Lancet 2012; 379:2364–2372.
- Brott TG, Haley EC Jr, Levy DE et al Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992; 23:632–640.
- Haley EC Jr, Levy DE, Brott TG et al Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91–180 minutes from onset. Stroke 1992; 23:641–645.
- Haley EC Jr, Brott TG, Sheppard GL et al Pilot randomized trial of tissue plasminogen activator in acute ischemic stroke: the TPA Bridging Study Group. Stroke 1993; 24:1000–1004.
- Mori E, Yoneda Y, Tabuchi M et al Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology 1992; 42:976–982.
- Yamaguchi T, Kikuchi H, Hayakawa H. Clinical efficacy and safety of intravenous tissue plasminogen activator in acute ischaemic stroke; in Yamaguchi T, Mori E, Minematsu K, del Zoppo GJ. (eds): Thrombolytic Therapy in Acute Ischaemic Stroke III. Tokyo, Springer‐Verlag, 1995:223–229.
- Yamaguchi T, Mori E, Minematsu K et al Alteplase at 0·6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J‐ACT). Stroke 2006; 37:1810–1815.
- Sharma VK, Ng KW, Venketasubramanian N et al Current status of intravenous thrombolysis for acute ischemic stroke in Asia. Int J Stroke 2011; 6:523–530.
- Pandian JD, Srikanth V, Read SJ, Thrift AG. Poverty and stroke in India: a time to act. Stroke 2007; 38:3063–3069.
- Tsai CF, Thomas B, Sudlow CLM. Epidemiology of stroke and its subtypes in Chinese vs white populations: a systematic review. Neurology 2013; 81:264–272.
- Menon BK, Saver JL, Prabhakaran S et al Risk score for intracranial haemorrhage in patients with acute ischemic stroke treated with intravenous tissue‐type plasminogen activator. Stroke 2012; 43:2293–2299.
- Wardlaw JM, Koumellis P, Liu M. Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. Cochrane Database Syst Rev 2013; (5):Art. No.: . doi: .
- 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; 7:391–399.
- Huang Y, Sharma VK, Robinson T et al Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: an international multicenter 2 × 2 quasi‐factorial randomized controlled trial of low‐ vs. standard‐dose rt‐PA and early intensive vs. guideline‐recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment. Int J Stroke 2015; 10:778–788.
- Anderson CS, Heeley E, Huang Y et al Rapid blood pressure lowering in acute intracerebral hemorrhage. N Engl J Med 2013; 368:2355–2365.
- Mulla SM, Scott IA, Jackevicius CA, You JJ, Guyatt GH. How to use a noninferiority trial: users' guides to the medical literature. JAMA 2012; 308:2605–2611.
Source: PubMed