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Keywords:

  • blood pressure;
  • clinical trial;
  • hypertension;
  • INTERACT;
  • intracerebral haemorrhage;
  • stroke

Abstract

  1. Top of page
  2. Abstract
  3. Introduction and rationale
  4. Objectives
  5. Methods
  6. References

Rationale: The INTERACT pilot study demonstrated the feasibility of the protocol, safety of early intensive blood pressure lowering and effects on haematoma expansion within 6 h of onset of intracerebral haemorrhage. This article describes the design of the second, main phase, INTERACT2.

Aims: To compare the effects of a management strategy of early intensive blood pressure lowering with a more conservative guideline-based blood pressure management policy in patients with acute intracerebral hemorrhage.

Design: INTERACT2 is a prospective, randomized, open label, assessor-blinded end-point (PROBE). Patients with a systolic blood pressure greater than 150 mmHg and no definite indication for or contraindication to blood pressure-lowering treatment are centrally randomised to either of two treatment groups within 6 h onset of intracerebral haemorrhage. Those allocated to intensive blood pressure lowering will receive primarily intravenous, hypotensive agents to achieve a systolic blood pressure target of <140 mmHg within 1 h of randomisation and to maintain this level for up to 7 days in hospital. The control group will receive blood pressure-lowering treatment to a target systolic blood pressure of <180 mmHg. Both groups are to receive similar acute stroke unit care, therapy and active management. Oral antihypertensive therapy is recommended in patients before hospital discharge with a long-term systolic blood pressure goal of 140 mmHg according to secondary stroke prevention guidelines. A projected 2800 subjects are to be enrolled from approximately 140 centres worldwide to provide 90% power (α 0·05) to detect a 14% difference in the risk of death and dependency between the groups, which equates to one or more cases of a poor outcome prevented in every 15 patients treated.

Study outcomes: The primary outcome is the combined end-point of death and dependency according to the modified Rankin Scale at 90 days. The secondary outcomes are the separate components of the primary end-point in patients treated <4 hours of ICH onset, grades of physical function on the modified Rankin Scale, health-related quality of life on the EuroQoL, recurrent stroke and other vascular events, days of hospitalisation, requirement for permanent residential care and unexpected serious adverse events. The study is registered under NCT00716079, ISRCTN73916115 and ACTRN12608000362392.


Introduction and rationale

  1. Top of page
  2. Abstract
  3. Introduction and rationale
  4. Objectives
  5. Methods
  6. References

Intracerebral haemorrhage (ICH) accounts for approximately 10–15% of all strokes in Western countries (1), however, this figure is at least 20–30% among African, Asian and Latin American populations (2, 3). Despite having high rates and associated mortality and morbidity, a widely available, safe and effective treatment for ICH remains elusive. In particular, early use of the potent haemostatic agent, activated recombinant human factor VII (rFVIIa, NovoSeven®), has failed to show an improvement in clinical outcomes despite its effect in reducing haematoma expansion (4). Furthermore, there is ongoing uncertainty over the role of open surgical evacuation of the haematoma (5), although computerised tomographic (CT)-guided microcatheter removal of superficial haematomas (6) and intraventricular haemorrhage with thrombolysis (7) show considerable promise.

Of the various physiological variables, elevated blood pressure (BP) or ‘hypertension’ is well established as the most important risk factor for both incident and recurrent ICH (8), with BP levels being strongly associated with both incident and recurrent ICH (9). Acute elevation in BP early after the onset of ICH has also been shown to be an important prognostic factor, with poor outcomes likely due to the promotion of haematoma expansion (10–13). Thus, as emphasised in many guidelines such as those of the American Heart Association (14) and of the European Stroke Organization (15), early control of elevated BP has potential beneficial effects in patients with ICH. However, as these recommendations are based mainly on extrapolations from observational data, they represent a low level of evidence. Importantly, there are no definitive trial data to define the effects of early BP lowering, and there is considerable uncertainty over what is the most desirable BP level at which treatment should be commenced, how quickly BP should be lowered and what is the optimal target BP level to reach. A large-scale clinical trial is critical to generating the high-level evidence necessary to inform clinical practice.

The INTERACT pilot study has established the feasibility and safety of an intensive BP-lowering protocol within 6 h of onset of ICH in 404 patients with coexisting high (150–220 mmHg) systolic BP recruited from sites in Australia, China and Korea (16). Compared with those allocated to a conservative BP protocol, patients in the intensive group achieved 10–13 mmHg lower systolic BP levels and a mean proportional haematoma growth that was 22·6% [95% confidence interval (CI) 0·6–44·5%; P=0·04] less at 24 h. However, this difference failed to reach significance (P=0·06) when baseline imbalances in initial haematoma volume and time from onset to CT were considered, and effects on ‘substantial’ haematoma growth (defined as >33% or >12·5 ml) were similarly borderline significantly lower in the intensive group (36% lower in the intensive group, 95% CI 0–59%, P=0·05) (16). Regarding the potential impact on clinical outcome, the INTERACT pilot study strongly suggests that intensive BP-lowering treatment is not associated with potentially harmful negative side effects. Nonetheless, these results, while promising, are as yet insufficient to advance policy regarding the management of BP in ICH. We aim, therefore, to provide definitive evidence regarding the balance of benefits and the risks of early intensive lowering of BP on major clinical end-points in ICH. Herein, we present the design of the INTERACT2 study.

Objectives

  1. Top of page
  2. Abstract
  3. Introduction and rationale
  4. Objectives
  5. Methods
  6. References

The primary objective is to determine the effects of BP management on all-cause mortality and dependency at 90 days. The key secondary objective is to evaluate the clinical benefit in the subset of patients who receive the treatment <4 h after ICH onset. The other secondary objectives are to determine the effects of the treatment separately on death and dependency, as well as on physical function, health-related quality of life (HRQoL), recurrent stroke and other vascular events, days of hospitalisation and requirements for permanent residential care.

Methods

  1. Top of page
  2. Abstract
  3. Introduction and rationale
  4. Objectives
  5. Methods
  6. References

Design

This INTERACT2 study is a prospective, randomised, open-label, assessor-blinded end-point (PROBE), multicentre, international clinical trial. The study is being conducted in accordance with relevant national and international regulatory and ethical frameworks. All participating hospital sites are to receive approval from the relevant ethics committee or Institutional Review Board before initiation of the study. Written informed consent is obtained from each patient or their legal surrogate in situations where the participants themselves are unable to provide it.

Patient population

Patients aged ≥18 years with CT-confirmed acute spontaneous ICH and at least two systolic BP measurements of ≥150 and ≤220 mmHg recorded ≥2 min apart will be enrolled from over 140 centres worldwide. In addition, it must be possible to commence the randomly assigned BP-lowering treatment within 6 h of ICH onset with admission to a suitable monitoring facility such as a stroke care unit or an intensive care unit over the next 24 h. Exclusion criteria include a clear indication for, or contraindication to, intensive BP lowering; clear evidence that the ICH was secondary to a structural abnormality in the brain or results from thrombolysis treatment; a history of ischaemic stroke within the last 30 days; a score of 3–5 on the Glasgow Coma Scale (GCS, indicating deep coma) (17) or other clinical or radiological reasons to indicate a high likelihood of death within the next 24 h; known dementia; significant prestroke disability or severe concomitant medical illness; and planned early (<6 h) surgical evacuation of the haematoma. In situations where a patient has a systolic BP >220 mmHg at presentation, initial use of agents to lower the BP to that required for inclusion is permitted to allow randomisation into the trial. Table 1 provides a more detailed list of inclusion and exclusion criteria.

Table 1.   Inclusion and exclusion criteria
Inclusion criteria
 a. Aged 18 years or above.
 b. Acute stroke syndrome due to spontaneous intracerebral haemorrhage (ICH), defined as the sudden occurrence of bleeding into the parenchyma of the brain that may extend into the ventricles and, in rare cases, into the subarachnoid space, confirmed by clinical history and CT scan. [NB: Patients with ICH secondary to medical treatment (e.g. antiplatelet or antithrombotic therapy) are eligible, but ICH secondary to thrombolysis are ineligible].
 c. At least two systolic blood pressure (BP) measurements of ≥150 mmHg and ≤220 mmHg, recorded ≥2 min apart. [NB: Patients with initial systolic BP levels outside this range (e.g. <150 or >220 mmHg) may be randomised should the BP levels fulfil entry criteria on re-checking up to 6 h. Moreover, patients with systolic BP >220 mmHg may receive initial BP lowering and then randomised, provided systolic BP is ≤220 mmHg within 6 h of symptom onset].
 d. Able to commence randomly assigned BP-lowering regimen within 6 h of stroke onset. (NB: If the precise timing of the first symptoms or signs of the qualifying event are unknown, then the time of onset will be taken as the last time at which the patient was known to be well).
 e. Able to be ‘actively’ treated and admitted to a monitored facility, such as an acute stroke unit, high dependency unit or intensive care unit. It is recognised that many ICH patients are designated ‘Not For Resuscitation’ or ‘Do Not Resuscitate’ after appropriate consultation with family members. This in itself is not a contraindication to enrolment in the trial, as long as management is otherwise active.
Exclusion criteria
 a. Known definite contraindication to an intensive BP-lowering regimen (e.g. severe carotid, vertebral or cerebral arterial stenosis, known Moya Moya disease or Takayasu's arteritis, high-grade stenotic valvular heart disease or severe renal failure).
 b. Known definite indication for an intensive BP-lowering regimen that is similar or more intensive than the active treatment arm of this study (e.g. very high systolic BP >220 mmHg, hypertensive encephalopathy or aortic dissection).
 c. Definite evidence that the ICH is secondary to a structural abnormality in the brain (e.g. an AVM, intracranial aneurysm, tumour, trauma or previous cerebral infarction) or previous thrombolysis.
 d. Previous ischaemic stroke within 30 days.
 e. A very high likelihood that the patient will die within the next 24 h on the basis of clinical and/or radiological criteria (e.g. massive haematoma with a mid-line shift of the hemisphere or deep coma on presentation, defined by Glasgow Coma Scale Score of 3–5) (NB: Seizures occur commonly after the onset of ICH, and so a reduction in the level of consciousness that is disproportionate to the size of the haematoma may be secondary to seizure rather than mass effect from the ICH).
 f. Known advanced dementia or significant pre-stroke disability (e.g. modified Rankin Score of 3–5).
 g. Concomitant medical illness that would interfere with outcome assessments and follow-up (e.g. advanced cancer or respiratory disease).
 h. Already booked for surgical evacuation of haematoma.
 i. Previous participation in this trial or current participation in another investigational drug trial.
 j. A high likelihood that the patient will not adhere to the study treatment and follow-up regimen.

Randomisation

Patients are randomised into two treatment arms, stratified according to country, hospital and time since ICH onset (≤4 vs. >4 h) to ensure balance in key prognostic factors. Randomisation is implemented by internet access to a 24-h password-protected website operated from The George Institute for International Health in Sydney, Australia. In China, investigators have the option of using a customised 24-h digital Interactive Voice Response System that connects to the website to allow patients to be randomised at sites where rapid access to the internet may not be possible.

Treatments

Figure 1 outlines the study protocol. A key principle is the rapid initiation of the randomised treatment. Investigators should aim to achieve a ‘door-to-needle’ time of 60 min, which allows time to confirm eligibility, obtain informed consent, record several key clinical baseline parameters and identify the randomised assignment. For patients allocated to the intensive group, the goal is to achieve a target systolic BP of <140 mmHg within 1 h of randomisation and subsequently to maintain this level for the next 7 days, or until hospital discharge should this occur earlier. At each site, a standardised, stepped, intravenous BP-lowering protocol, based on available medications (e.g. urapidil, labetolol, hydralazine, metoprolol and nicardipine), is established in advance. In most cases, the treatment will be titrated by repeat intravenous boluses (or maintenance infusion) of hypotensive agent(s) in a monitored facility. Co-administration of oral antihypertensive agent(s) is to be commenced as soon as practical. A systolic BP of 130 mmHg is considered the threshold level for the cessation of intravenous treatment to avoid possible risk from low BP. In most cases, intravenous agents are likely to be required for up to several hours but the timing of the switch to oral antihypertensive agents is at the discretion of the responsible investigator on the basis of BP control and the broader status of the patient. For patients allocated to the standard treatment group, BP-lowering treatment is at the discretion of the responsible physician, with the recommended threshold for commencing treatment being a systolic BP level of 180 mmHg in line with American Heart Association (14) and European Stroke Organization (15) guidelines. Treatment modalities for BP lowering in the standard care group are unlimited and once again at the discretion of the responsible physician until the recommended target systolic BP of <180 mmHg is achieved. In both groups, patients who have been taking oral antihypertensive therapy before randomisation are permitted to continue their usual medication if possible. The introduction (or re-commencement) of such treatment is recommended in all patients before hospital discharge, with a systolic BP goal of 140 mmHg as recommended for appropriate secondary prevention. In all other respects, patients in both treatment groups are to receive standard best practice care for acute stroke.

image

Figure 1.  Flow diagram of the INTERACT2 study.

Download figure to PowerPoint

Outcomes

Table 2 outlines the schedule of assessments. Vital signs are to be measured according to a standard protocol, with BP recorded with the patient supine ideally using the same automated device throughout the trial. Assessments including the GCS and the National Institutes of Health Stroke Scale (NIHSS) (18) are performed on enrolment, at 24 and 72 h, and at 7 days, after randomisation. Patients are followed by in-person or a telephone interview at 28 and 90 days for vital status and the assessment of several functional outcome parameters.

Table 2.   Schedule of evaluations
 Before randomisationDay
  • *

    In the first 600 patients (approximately 300 Chinese and 300 non-Chinese) who have agreed to provide a second CT scan at 24 ± 3 h, according to a standardised protocol.

  • BP and HR are recorded every 15 min during the first hour, hourly till 6 h and 6 hourly till 24 h. At any point where intravenous bolus drugs are administered, BP and HR should be recorded 5 and 15 min later.

  • a

    Consent may be obtained after randomisation;

  • b

    b or the day of discharge if before day 7;

  • c

    c information collected at a face-to-face consultation or through a telephone interview.

  • BP, blood pressure; HR, heart rate; GCS, Glasgow Coma Scale; NIHSS, National Institute of Health Stroke Scale; HRQoL, health-related quality of life; mRS, modified Rankin Scale.

Evaluation 17b28c90c
EligibilityX    
CT scanXX*   
Fever to be recordedX X  
BP/HRX BP × 2X 15 min × 1 h hourly × 2–6 h 6 hourly × 6–24 h   
ConsentaX    
Clinical history and prior medicationsX    
Physical exam with GCS/NIHSSXXX  
Functional assessment with mRS  XXX
HRQoL assessment with EQ5D   XX
Standard care and routine blood testsXX   
BP-lowering treatment XXXX
Standard stroke care XXXX
Hospitalised or not XXXX
Contact details for follow-up XX  

The effect of early intensive BP lowering in acute ICH will be tested using the primary composite outcome of death or dependency at 90 days. Dependency will be defined by a score of 3–5 on the modified Rankin Scale (mRS) (19). The secondary outcomes include the separate outcomes of mortality and dependency, level of disability on the mRS, HRQoL using the EuroQoL for the calculation of an overall health utility score (EQ5D) (20); recurrent stroke as confirmed by neuroimaging (or necropsy) after 24 h of the initial ICH and other major cardiovascular events (acute myocardial infarction or sudden death); need for permanent residential care; and the duration of initial hospitalisation. At each site, an investigator who is blind to the acute treatment of each patient is required to undertake the outcome assessments.

Data and safety monitoring

An independent data and safety monitoring board (DSMB) consisting of clinicians and biostatisticians will monitor the safety and progress of the trial. The DSMB will review all unblinded data including the BP separation (between the two groups), dropout and event rates in the study at twice-yearly intervals. Two interim efficacy analyses detailed in a Statistics Analysis Plan are planned after approximately 30 and 60% of the patients have been followed up at 90 days; differences of more than 3 SD are considered as providing clear evidence of an effect.

Quality assurance

Independent experienced neurologists will review and adjudicate all deaths and major vascular events. Regionally based clinical research monitors will perform on-line and on-site data verification. The initial monitoring visit will take place after the first few patients are randomised at a site. Thereafter, sites will be monitored at least annually during the course of the trial. All CT imaging data will be sent to the International Coordinating Centre (ICC) for analysis using MIStar software, version 3·2 (Apollo Medical Imaging Technology, Melbourne, Vic., Australia) (21). A responsible administrative research officer ensures that the information is de-identified before experienced analysis scientists review the CT scans for measurement of haematoma volumes and other parameters. These analyses will include regular quality checks.

Sample size

The proposed sample size is 2800, which will provide at least 90% power (α 0·05) to detect a 14% relative risk reduction in the primary outcome with the active intervention compared with the standard treatment. This assumes that the proportional rate of the primary outcome will be reduced from 50% in the control group to 43% in the active group, and that nonadherence to the active treatment arm (dropout) and loss to follow-up will be similar to the pilot phase at 10% and 3%, respectively, figures based on the pilot phase. The 14% relative risk reduction is also based on the pilot phase findings where a 10–14 mmHg difference in systolic BP between randomised groups in the first 24 h of treatment resulted in a 1·7 ml absolute difference in haematoma growth (16). A meta-analysis of the rFVIIa trials (22) indicates that a 1 ml growth in haematoma is associated with a 7% relative increase in the risk of death or worsening of disability (1 point increase on mRS) at 90 days. Thus, a difference in haematoma growth of 2 ml (0–6 h) from BP lowering should result in at least a 14% (7% absolute) relative reduction in poor outcome from ICH. A beneficial effect of early treatment on the primary outcome would equate to one or more cases of death or dependency prevented among approximately every 15 patients treated.

A post hoc analysis of the pilot phase suggests that the treatment effect may be larger in those patients randomised <4 h of ICH onset as the absolute difference in haematoma growth was 3·4 ml between groups. This would equate to a 21% (10% absolute) relative reduction in the avoidance of a poor outcome in ICH. If the sample size is balanced with regard to patients being randomised into the 0–4- and the 4–6-h time epochs, there will be 90% power to detect a relative risk reduction of 20% in those patients treated <4 h of onset.

Statistical analysis

The intention-to-treat principle will be applied to the analysis. All analyses will be conducted with patients allocated to the group to which they were assigned at randomisation. Baseline and demographic characteristics will also be summarised by treatment group. The primary and secondary end-point of death and disability will be analysed by means of a χ2-test as will the categorical secondary outcomes. Fisher's test might be used for smaller numbers.

The primary analysis will be unadjusted. The effect of treatment on any time-to-event type of outcome will be in principle tested by means of a log-rank test. This includes time to recurrent stroke and time to first event. For patients who are ‘lost to final follow-up’, all information collected from randomisation to the time of the last contact will be included in these analyses. Continuous end-points such as the HRQoL EQ5D at 28 or 90 days will all be summarised by means (SD) or medians (IQR). The effect of treatment will preferably be tested by a Wilcoxon's test, based on the assumption that the data will be skewed as in the pilot phase. If the data distribution is not unacceptably skewed, mixed models will be used to describe the health utility score over time and assess the effect of BP-lowering therapy. No adjustment for multiplicity is planned as a small number of prespecified efficacy outcomes are investigated.

Descriptive statistics will be provided for safety data. The number of patients reporting any serious adverse event (SAE), the occurrence of specific SAEs and discontinuation due to SAEs will be tabulated using the Medical Dictionary for Regulatory Authorities (MedDRA) terminology. The effect of treatment on the number of patients experiencing at least one SAE will be tested using a χ2-test.

Heterogeneity of the treatment effect on the primary end-point of death and disability will be assessed for seven subgroups by addition of an interaction term to the models. Subgroups will be age at randomisation (<65 vs. ≥65 years), time from ICH to treatment (<4 vs. ≥4 h), history of hypertension, systolic BP and diastolic BP (above vs. below the overall mean in both cases), ethnicity and NIHSS at baseline (above vs. below the overall median). Adjusted analyses will be performed to determine the robustness of the findings. The exact list of all analyses to be performed will be specified a priori in the full Statistical Analysis Plan.

Data management

The study database uses electronic Case Reports Forms (CRF) in both English and Chinese that have been especially developed by The George Institute for International Health. The system allows for a web-based data entry and management. The data are captured and entered at each participating hospital site using an electronic signature (unique user and password). All changes made following the electronic signing have an electronic audit trail with a signature and date. The International and Regional Coordinating Centre (RCC) staff have access to online reports on overall study status, subject visit calendar, CRF completion status and SAE reports to assist with monitoring the quality of the data.

Study organisation and funding

The management of INTERACT2 includes an ICC based at the George Institute for International Health of the University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia. The study is overseen by an International Executive (Steering) Committee comprised of experts in the fields of stroke, hypertension, neurology, geriatrics, cardiovascular epidemiology and clinical trials. The ICC currently communicates with three RCCs: The George Institute India in Hyderabad (India), The George Institute China in Beijing (China) and the Clinical Research Unit of Lariboisière Hospital in Paris (France). The ICC and RCCs will communicate with approximately 140 participating hospitals in Africa, Australia, China, several European countries, India, Pakistan, several South American countries and the United States. The study is supported by a Project (512402) and Programme (571281) Grants from the National Health and Medical Research Council (NHMRC) of Australia.

Summary

INTERACT has been designed to provide a definitive answer to the management of BP in patients with ICH, a topic of ongoing clinical uncertainty in stroke medicine and of direct relevance to clinical practice. The study will test the physiologic principle of BP lowering rather than the effect of one specific antihypertensive drug. The expected size of absolute benefit being assessed is considered clinically valuable in other areas of neurology and is comparable to the magnitude of benefit seen with calcium channel blockers in subarachnoid haemorrhage and use of acute stroke unit care. Should the trial demonstrate the effectiveness of routinely available, low-cost, BP lowering early after the onset of ICH, the strategy could be widely adopted so that many tens of thousands of patients could stand to benefit each year, with associated major health gains, particularly in low-income and developing countries with high rates of the disease. The enrolment of patients into INTERACT2 began in October 2008. As of mid-January 2010, 820 patients have been randomised. Results are expected in 2012.

Study organization

Executive committee: Craig Anderson (Principal Investigator), John Chalmers (Chair), Stephen Davis, Yining Huang, Richard Lindley, Lewis Morgenstern, Bruce Neal, Mark Parsons, Christian Stapf, Christophe Tzourio and Jiguang Wang.

China steering committee: Yining Huang, Jiguang Wang, Liying Cui, Shengdi Chen, Zhenguo Liu, Chuanzhen Lu, Qidong Yang, En Xu, Jingfen Zhang, Chaodong Zhang, Shizheng Wu and Xining Yan Chen

European advisory board: Austria – Ronny Beer, Erich Schmutzhard; Belgium – Patricia Redondo; Finland – Markku Kaste, Lauri Soinne, Turgut Tatlisumak; France – Christian Stapf, Christophe Tzourio, Eric Vicaut; Germany – Katja Wartenberg; Italy – Stefano Ricci; Netherlands – Karin Klijn; Portugal – José Ferro; Spain – Angel Chamorro; Switzerland – Marcel Arnold, Urs Fischer.

Operations committee: Emma Heeley, Candice Delcourt, Hisatomi Arima and Zahava Wolfowicz.

Regional coordinators: Africa – Albertino Damasceno; Americas – Alejandro Rabinstein; Argentina – Conrado J. Estol, Andres Moles, Adelaida Ruiz, Mariana Zimmermann; Brazil – Gisele Silva; Chile – Pablo Lavados; China – Jian Sun, Aiwu Song, Nan Li, Li'e Zhang, Chen Xiaoying, Ying Shu; France – Sofiane Kabla, Cecile Dert; India – Subash Kaul, Hemalata Boyini and Shilpa Singh.

DSMB members: John Simes (Chair), Marie-Germaine Bousser, Graeme Hankey, Konrad Jamrozik, Claiborne Johnston and Li Shunwei.

Statisticians: Laurent Billot, Stephane Heritier and Qiang Li.

References

  1. Top of page
  2. Abstract
  3. Introduction and rationale
  4. Objectives
  5. Methods
  6. References
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