The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial

So no measurement of 100% recovery. Guess it's not important to stroke researchers. Talk to survivors sometime, you'll get an earful. If they haven't been bamboozled by their stroke medical 'professionals' using the tyranny of low expectations to lower their goals for recovery.

The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial

• Prof Lu Ma, MD *
• Xin Hu, MD *
• Lili Song, PhD *
• Xiaoying Chen, PhD *
• Menglu Ouyang, PhD
• Prof Laurent Billot, MRes
• et al.
• Show all authors
• Show footnotes

Open AccessPublished:May 25, 2023DOI:https://doi.org/10.1016/S0140-6736(23)00806-1

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Summary

Background

Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage.

Methods

We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1–7·8 mmol/L in those without diabetes and 7·8–10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed.

Findings

Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76–0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73–0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098).

Interpretation

Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome (Use factual words instead of these weasel words.) for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition.

Funding

Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.

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Introduction

Intracerebral haemorrhage is the most serious and least treatable form of stroke and accounts for approximately 20% of the almost 20 million new strokes that occur globally each year.¹ Most cases of intracerebral haemorrhage occur in low-income and middle-income countries (LMICs), where there is a high prevalence of hypertension, unhealthy diets (eg, a high salt intake), and other risk factors.² Because elevated blood pressure is common after the onset of intracerebral haemorrhage and is strongly associated with a poor outcome, a central component of the management of patients is to provide treatment to lower blood pressure towards a systolic target of 140 mm Hg or less.^3,4,5,6,7 However, inconsistent results across randomised controlled trials^8,9 and little evidence specifically in patients with a large intracerebral haemorrhage or who require neurosurgical intervention¹⁰ has restricted the uptake of this strategy in clinical practice where guidelines generally provide an intermediate strength to their recommendation.^{3, 4, 5, 6, 7} Moreover, the absence of a proven medical or surgical treatment for intracerebral haemorrhage has resulted in an absence of urgency to treat these patients and a low threshold for the withdrawal of active care in these patients,^{11, 12} which contrasts sharply with modern systems of care for patients with acute ischaemic stroke.

Efforts to improve the success of randomised controlled trials in identifying an effective treatment for intracerebral haemorrhage have included the use of clinical and imaging variables to define a potential responder group with a high likelihood of early neurological deterioration from ongoing haemorrhage or haematoma growth.^{13, 14, 15} Another effort has been to extend the assessment of functional outcome beyond the conventional 90 days, because recovery from intracerebral haemorrhage takes longer than from acute ischaemic stroke.¹⁶ Assessing combinations of interventions as part of a multifaceted care bundle might also offer advantages, as shown in an Australian cluster clinical trial where the implementation of a treatment protocol for hyperglycaemia, fever, and dysphagia improved outcome from acute stroke.¹⁷ Further support for this approach was provided by a single-site, so-called before-and-after study in the UK, where the implementation of a quality improvement protocol that included the reversal of anticoagulation, intensive blood pressure lowering, and rapid triage to neurosurgery and critical care was associated with a lower 30-day case fatality after intracerebral haemorrhage.¹⁸ A post-hoc analysis of the second phase of the international Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2)¹⁹ showed that higher scores assigned for any elevation in the baseline of systolic blood pressure, glucose, body temperature, and previous use of anticoagulants in participants independently predicted a poor functional outcome after intracerebral haemorrhage. These issues informed the design of the third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3), with the aim of establishing whether a goal-directed care bundle protocol, comprising early intensive lowering of blood pressure with other management protocols for abnormal physiological variables, improves functional outcome in a broad range of patients with acute spontaneous intracerebral haemorrhage.