International Care Bundle Evaluation in Cerebral Hemorrhage Research

Official title

International Care Bundle Evaluation in Cerebral Hemorrhage Research - a Batched Parallel Cluster-randomized Trial With a Baseline Period

Overview

Spontaneous intracerebral haemorrhage (ICH) accounts for approximately 10-15% of all strokes but stands for 50% of stroke-related morbidity and mortality. Approximately half of all patients with ICH have a decreased level of consciousness at hospital admission. Despite this, intensive care and neurosurgical interventions are uncommon. A study conducted in low- and middle-income countries has demonstrated a beneficial effect of a treatment package consisting of early intensive blood pressure lowering, as well as the treatment of pyrexia and elevated blood glucose levels. The I-CATCHER team is now planning to conduct a similar study in Sweden and Australia, as well as in other high-income countries. The study has a clear focus on implementation, aiming to improve treatment and prognosis for patients with ICH within a few years. The purpose of I-CATCHER is to investigate whether a structured treatment package (Care Bundle) improves 3-month prognosis in patients with spontaneous ICH compared to standard care.

Detailed description

Spontaneous intracerebral hemorrhage (ICH) accounts for 10 to 15% of all strokes in high-income countries (HIC), and nearly twice this number in low-income to upper-middle-income countries (LMIC) (29.5%). It is the most devastating type of stroke given the high one-month case fatality of approximately 30-40%, and only 12-39% suffer persistent disability.

Despite several advances in the management of acute ischemic stroke supported by numerous randomized controlled trials (RCT), progress in establishing novel interventions to improve outcomes for ICH has been slow. Still today, the diagnosis of ICH evokes pessimism among treating physicians, and patients may be withheld guideline adherent treatment for this reason. This nihilistic approach is presumably due to an over-estimation of poor outcome, often influenced by the neurologically devastating features commonly present at ICH admission. Additionally, the scarcity of RCTs providing strong evidence for treatment recommendations may contribute to a more reluctant approach in the acute setting of ICH, particularly when presenting with debilitating symptoms.

The third INTEnsive care bundle with BP reduction in acute cerebral hemorrhage trial (INTERACT3) was recently published in 2023. This trial employed a stepped wedge cluster RCT design to evaluate the implementation of a Care Bundle protocol. This comprehensive protocol included early intensive BP lowering (EIBPL), management of pyrexia and hyperglycemia, and the early reversal of OAC treatment. The design of this trial drew inspiration from a post-hoc analysis of the INTERACT2 study that showed that the scoring of abnormal baseline variables, interventions included in the future INTERACT3 Care Bundle, independently predicted a poor functional outcome following ICH. The implementation of the time sensitive bundle of care in INTERACT3 resulted in an improved functional outcome at 6 months following ICH. However, as the trial included patients predominantly from LMIC, further studies are warranted to determine if these results are applicable to HIC with a more applicable Care Bundle for these populations. An earlier intervention study from the United Kingdom, published in 2019, studied a similar 'quality improvement' acute Care Bundle. This Care Bundle aimed to improve the speed of treatment delivery, access to acute care, and decrease case fatality following ICH. Despite certain limitations, including a non-randomized design, this study demonstrated significantly lower mortality rates in patients receiving the Care Bundle versus the pre-implementation standard of care.

I-CATCHER is an international, multicenter, batched, parallel, cluster, randomized clinical trial (RCT) to assess a multifaceted package of protocols in a broad range of patients with acute ICH. In each batch, hospitals will be randomized into two groups according to the timing of the intervention (Care Bundle) over 3 phases (phase 1: usual care, phase 2: randomized evaluation - to intervention or usual care, phase 3: post-implementation follow-up - all hospitals implement the intervention). This design will capture consecutive patients with ICH and allow continued intervention in perpetuity as more hospitals join. Compared to a conventional stepped-wedge cluster RCT, the intervention effect in this design is less likely to be confounded by background temporal trends as only baseline and parallel comparison data (first 2 periods in bold black frame) are used to determine the effectiveness of the Care Bundle. All hospitals will be exposed to the Care Bundle which allows assessment of sustainability and integration of the intervention into routine practice. Each batch period is 18 months (6 months per phase); whole study will be rolled out in 2.5 years.

This design involves implementation of an intervention package applied to all patients with ICH as part of routine care. Patients are only excluded if they refuse to have details of their management included and/or participate in follow-up procedures.

Study site inclusion criteria: Organized systems of acute stroke care; no established comprehensive protocols for the management of ICH; suitable location, infrastructure and willingness to participate in clinical research; suitable numbers of ICH patients (at least 30 per year).

Patient inclusion criteria: Adults (≥18 years) with spontaneous ICH confirmed by imaging and admitted hospital within 24 hours of the onset of symptoms.

Interventions

• Other Reversal of Oral anticoagulation within 30 minutes
  In situations of either an elevated INR with the use of warfarin - treatment with either 3- or 4-factor prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) within 30 minutes of ICH diagnosis on NCCT to reach and maintain an INR target \<1.3; or where there has been recent use (\<48 hours) of a direct oral anticoagulant (DOAC), use of an appropriate reversal agent within 30 minutes, where available, and according to local approvals.
• Other Early intensive blood pressure lowering
  A systolic blood pressure (BP) target of 130-140 mmHg within 30 minutes of ICH diagnosis on NCCT is strived for, and to maintain this BP level for the first 7 days (for patients presenting with blood pressure \<200 mmHg). If blood pressure ≥200 and \<220, a target BP of 160 mmHg should be targeted at 30 minutes, and 130-140 mmHg should be achieved in 60 minutes. If BP ≥220, target BP of 160 mmHg and should be achieved in 60 minutes.
• Other Treatment of pyrexia
  To achieve a body temperature target \<37.5 °C within the first 24h following ICH diagnosis on NCCT
• Other Hyperglycemia treatment
  To maintain a blood glucose level 7-10 mmol/L within the first 24h following ICH diagnosis on NCCT
• Other Do-not-resuscitate (DNR) or withdrawal of care
  Refrain from the use of DNR or withdrawal of care orders for 48 hours
• Other Referral to Intensive Care
  Immediate (\<30 min) referral to intensive care if airway, breathing and/or circulation are compromized
• Other Referral to Neurosurgery
  Immediate (\<30 min) referral to neurosurgery if any of the following criteria are fulfilled: * Large and/or rapidly evolving supratentorial ICH (\>20 ml volume) * Any intraventricular extension * Posterior fossa bleed, irrespective of volume * Suspicion of a vascular malformation, independent of volume or location * Reduction in reaction to sensory stimulation or drowsiness
• Diagnostic test Repeat brain imaging
  Repeat 6-12-hour brain imaging with the physicians choice of modality, preferably computed tomography (CT), if clinical deterioration or the patient received OAC reversal treatment
• Other Standard care
  For patients in the usual-care group, decisions about the location of care delivery, investigations, monitoring, and all treatments are made by the treating clinical team. Data will be collected regarding the management of patients, including insertion of invasive monitoring devices, intravenous fluid resuscitation, BP lowering, vasoactive support, glycemic control, mechanical ventilation, neurosurgery, and other supportive therapy.

Primary outcome measures

• Evaluation of functional outcome based on the Utility Weighted modified Rankin Scale score [Time frame: 180±30 days]

Secondary outcome measures (4)

• Ordinal shift analysis of mRS [Time frame: 180 days±30 days]
• Assessment of health-related quality of life (HRQoL) [Time frame: 180 days±30 days]
• Poor outcome defined as mRS 3-6 [Time frame: 180 days±30 days]
• Separate outcomes for death and disability [Time frame: 180 days±30 days]

Eligibility criteria

Inclusion criteria

• Adults (age ≥18 years)
• Non-contrast computerized tomography (NCCT) imaging-verified diagnosis of spontaneous intracerebral haemorrhage
• ≤24 hours from symptom onset or presumed symptom onset (last seen well)

Exclusion criteria

• Previous care limitation
• End-stage comorbidity with short life-expectancy (<6 m; e.g. terminal cancer)
• ICH caused by brain tumor or cerebral venous thrombosis
• Clinical signs of brain herniation at first presentation (unresponsive patient with bilaterally fixed, maximally dilated pupils)
• Pregnant women beyond 22 weeks gestation may only be included after thorough discussion with an obstetrician to determine risks vs benefit.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Sweden · 38 centers

• Höglandssjukhuset i Eksjö — Eksjö
• Sahlgrenska Universitetssjukhuset — Gothenburg
• Östra Sjukhuset — Gothenburg
• Hässleholms Sjukhus — Hässleholm
• Helsingborgs Lasarett — Helsingborg
• Karolinska Universitetssjukhuset Huddinge — Huddinge
• Länssjukhuset Ryhov — Jönköping
• Länssjukhuset Kalmar — Kalmar
• … and 30 more centers

Italy · 5 centers

• Avezzano Ospedale SS. Filippo e Nicola — Avezzano
• Citta di Castello Ospedale Città di Castello — Città di Castello
• Gubbio Ospedale di Gubbio e Gualdo Tadino — Gubbio
• Azienda Ospedaliera Santa Maria della Misericordia Perugia — Perugia
• Roma Policlinico Gemelli — Roma

Australia · 3 centers

• Royal Adelaide Hospital — Adelaide
• Monash Medical Centre — Clayton
• The George Institute for Global Health — Sydney

Canada · 3 centers

• Health Sciences North/Health Sciences North Research Institute — Greater Sudbury
• Hamilton General Hospital — Hamilton
• Ottawa Hospital Research Institute — Ottawa

Malaysia · 2 centers

• National University of Malaysia Hospital — Kuala Lumpur
• Universiti Putra Malaysia Hospital — Serdang

United States · 1 center

• The University of Oklahoma Health — Oklahoma City

Hong Kong · 1 center

• Hong Kong University Hospital — Hong Kong

Iceland · 1 center

• Landspitali University Hospital — Reykjavik

Publications

• GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021 Oct;20(10):795-820. doi: 10.1016/S1474-4422(21)00252-0. Epub 2021 Sep 3. PMID 34487721
• Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001 May 10;344(19):1450-60. doi: 10.1056/NEJM200105103441907. No abstract available. PMID 11346811
• van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010 Feb;9(2):167-76. doi: 10.1016/S1474-4422(09)70340-0. Epub 2010 Jan 5. PMID 20056489
• Parry-Jones AR, Sammut-Powell C, Paroutoglou K, Birleson E, Rowland J, Lee S, Cecchini L, Massyn M, Emsley R, Bray B, Patel H. An Intracerebral Hemorrhage Care Bundle Is Associated with Lower Case Fatality. Ann Neurol. 2019 Oct;86(4):495-503. doi: 10.1002/ana.25546. Epub 2019 Aug 16. PMID 31291031
• Hemphill JC 3rd, Newman J, Zhao S, Johnston SC. Hospital usage of early do-not-resuscitate orders and outcome after intracerebral hemorrhage. Stroke. 2004 May;35(5):1130-4. doi: 10.1161/01.STR.0000125858.71051.ca. Epub 2004 Mar 25. PMID 15044768
• Becker KJ, Baxter AB, Cohen WA, Bybee HM, Tirschwell DL, Newell DW, Winn HR, Longstreth WT Jr. Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies. Neurology. 2001 Mar 27;56(6):766-72. doi: 10.1212/wnl.56.6.766. PMID 11274312
• Zahuranec DB, Brown DL, Lisabeth LD, Gonzales NR, Longwell PJ, Smith MA, Garcia NM, Morgenstern LB. Early care limitations independently predict mortality after intracerebral hemorrhage. Neurology. 2007 May 15;68(20):1651-7. doi: 10.1212/01.wnl.0000261906.93238.72. PMID 17502545
• Song L, Hu X, Ma L, Chen X, Ouyang M, Billot L, Li Q, Munoz-Venturelli P, Abanto C, Pontes-Neto OM, Antonio A, Wasay M, Silva A, Thang NH, Pandian JD, Wahab KW, You C, Anderson CS; INTERACT3 investigators. INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial. Trials. 2021 PMID 34930428

Identifiers

NCT: NCT06429332 · 2024-02523-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗