Statistical analysis plan for evaluating different intensities of blood pressure control in the ENhanced Control of Hypertension And Thrombolysis strokE stuDy

Abstract

Background

The ENhanced Control of Hypertension And Thrombolysis strokE study (ENCHANTED) trial was initiated as a 2 × 2 partial-factorial active-comparison, prospective, randomized, open, blinded endpoint clinical trial to evaluate in thrombolysis-eligible acute ischemic stroke (AIS) patients whether: (1) Arm A – low-dose (0.6 mg/kg body weight) intravenous (iv) alteplase has noninferior efficacy and lower risk of symptomatic intracerebral hemorrhage (sICH) compared with standard-dose (0.9 mg/kg body weight) iv alteplase; and (2) Arm B – early intensive blood pressure (BP) lowering (systolic target 130–140 mmHg) has superior efficacy and lower risk of ICH compared with guideline-recommended BP control (systolic target <180 mmHg). Arm A was completed in 2016; Arm B is now concluding.

Objective

To outline in detail and make public the predetermined statistical analysis plan (SAP) for the ‘BP control’ arm of this 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 outlined, and for each item, statistically relevant descriptive elements will be described. For the trial outcomes, the most appropriate statistical comparisons to be made between groups are planned and described.

Results

A SAP was developed for the results of the BP control arm of this study that is transparent, available to the public, verifiable, and predetermined before completion of data collection.

Conclusions

We have developed a predetermined SAP for the ENCHANTED BP control arm to be followed to avoid analysis bias arising from prior knowledge of the study findings.

Clinical trial registration

ClinicalTrials.gov (NCT01422616); ISRCTN Register (ISRCTN82387104); Australian New Zealand Clinical Trial Registry (ACTRN12611000236998); EU Clinical Trials Register (2011-005545-12); and Clinical Trials Registry – India (REF/2017/05/014334).

Keywords

Hypertension stroke alteplase thrombolysis clinical trials statistical analysis plan

Get full access to this article

View all access options for this article.

References

Emberson

Lees

Lyden

, 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.

Qureshi

Ezzeddine

Nasar

, et al. Prevalence of elevated blood pressure in 563704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med 2007; 25: 32–38.

Qureshi

. Acute hypertensive response in patients with stroke: pathophysiology and management. Circulation 2008; 118: 176–187.

Tikhonoff

Zhang

Richart

Staessen

. Blood pressure as a prognostic factor after acute stroke. Lancet Neurol 2009; 8: 938–948.

Robinson

Potter

. Blood pressure after stroke. Age Ageing 2004; 33: 6–12.

Geeganage

Bath

. Relationship between therapeutic changes in blood pressure and outcomes in acute stroke: a metaregression. Hypertension 2009; 54: 775–781.

Elewa

Kozak

Johnson

Ergul

Fagan

. Blood pressure lowering after experimental cerebral ischemic provides neurovascular protection. J Hyperten 2007; 25: 855–859.

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.

Powers

Rabinstein

Ackerson

, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association / American Stroke Association. Stroke 2018; 49: e46–e110.

10.

Brott

Kothari

, et al. Hypertension and its treatment in the NINDS rt-PA stroke trial. Stroke 1998; 29: 1504–1509.

11.

Tsivgoulis

Frey

Flaster

, et al. Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke 2009; 40: 3631–3634.

12.

Perini

de Boni

Marcon

Bolgan

Pellizzari

di Dionisio

. Systolic blood pressure contributes to intracerebral haemorrhage after thrombolysis for ischemic stroke. J Neurol Sci 2010; 297: 52–54.

13.

Butcher

Christensen

Parsons

, et al. Postthrombolysis blood pressure elevation is associated with hemorrhagic transformation. Stroke 2010; 41: 72–77.

14.

Wahlgren

Ahmed

Eirksson

, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST). Stroke 2008; 39: 3316–3322.

15.

Ahmed

Wahlgren

Brainin

, et al. Relationship of blood pressure, antihypertensive therapy, and outcome in ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). Stroke 2009; 40: 2442–2449.

16.

Tsivgoulis

Kotsis

Giannopoulos

. Intravenous thrombolysis for acute ischaemic stroke: effective blood pressure control matters. Int J Stroke 2011; 6: 125–127.

17.

Waltimo

Happaniemi

Surakka

, et al. Post-thrombolystic blood pressure and symptomatic intracerebral haemorrhage. Eur J Neurol 2016; 23: 1757–1762.

18.

Mulder

MJHL

Ergezen

Lingsma

, et al. Baseline blood pressure effect on the benefit and safety of intra-arterial treatment in MR CLEAN (multicenter randomized clinical trial of endovascular treatment of acute ischemic stroke in the Netherlands). Stroke 2017; 48: 1869–1876.

19.

Anderson

Robinson

Lindley

, et al. Trial of low-dose versus standard-dose intravenous alteplase in patients with acute ischemic stroke. N Engl J Med 2016; 374: 2313–2323.

20.

Huang

Sharma

Robinson

, 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.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.98 MB