Controlling Hypertension After Severe Cerebrovascular Event (CHASE): study protocol for a randomized controlled trial

The study aims at assessing the effect of individualized BP-lowering regimens vs guideline-recommended BP-lowering regimens on mortality and morbidity in patients with acute severe stroke.

This study has a multicenter, randomized, controlled, single-blind design. Patients will be randomized to two different arms: (1) intervention group (individualized BP lowering), with an individualized target for BP lowering during the first week of hospitalization; and (2) control group (guideline-recommended BP lowering), with a fixed target recommended by the guideline for BP lowering during the first week of hospitalization. The participants are blind to the grouping results; the researchers are informed of the grouping results because they have to follow a specified strategy of BP management. Figure 1 shows a flowchart of the study design. Recommendations for Interventional Trials (SPIRIT) Figure are outlined in Additional file 1.

This is a Chinese multicenter trial involving 18 tertiary and district general hospitals in Shaanxi province, an administrative region with a population of 38 million located at the very center of China. The study will be conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki. The study has been approved by the ethics committees of Xijing hospital (KY20162085-2).

All CHASE investigators are required to be trained in the protocol, Good Clinical Practice, and use of the Glasgow Coma Scale (GCS), National Institute of Health stroke scale (NIHSS), Barthel index, and modified Rankin Scale (mRS) if they had no recent certifications.

The study will include patients with acute severe stroke who have elevated BP on admission. In order to be eligible for inclusion in the study, the patients have to comply with the following criteria: (1) age ≥ 18 years; (2) the randomly assigned BP-lowering regimen is able to be commenced within 72 h after the onset of stroke (ischemic or hemorrhagic), confirmed by a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain (if the precise timing of the onset of symptoms or signs of the qualifying event is unknown, then the time of onset will be taken as the last time the patient was known to be well); (3) GCS on admission ≤ 12 or NIHSS on admission ≥ 11; (4) there are at least two SBP measurements of ≥ 150 and ≤ 210 mmHg, recorded ≥ 5 min apart (patients with an initial SBP < 150 mmHg may be randomized when the SBP fulfils entry criteria on rechecking up to 72 h after the onset of stroke); and (5) written informed consent is able to be obtained directly from the patient or an appropriate surrogate, based on local ethics committee recommendations.

Exclusion criteria are: (1) patients who have received thrombolytic therapy, embolectomy, or decompressive craniectomy for the current stroke; (2) patients with subarachnoid hemorrhage; (3) known definite contraindication to acute BP lowering (e.g. known severe carotid, vertebral, or cerebral arterial stenosis, Moyamoya disease or Takayasu’s arteritis, high grade stenotic valvular heart disease); (4) secondary to a structural abnormality in the brain (e.g. an arteriovenous malformation, intracranial aneurysm, tumor, or trauma); (5) unstable vital signs and requiring the use of vasoactive agents; (6) known existing dementia or pre-stroke disability (e.g. score 3–5 on the modified Rankin scale); (7) concomitant medical illness that would interfere with the outcome assessments and/or follow-up (advanced cancer; severe pulmonary dysfunction [forced expiratory volume in 1 s < 50%]; severe cardiac dysfunction [ejection fraction ≤ 50%]; severe hepatic failure [Child-Pugh score ≥ 7]; severe renal failure [glomerular filtration rate ≤ 30 mL/min or serum creatinine ≥ 4 mg/dL]); (8) patients who are currently participating in other investigational trials; and (9) patients who are considered to have a high likelihood of not adhering to the study treatment or the follow-up regimen.

A secure website (http://​traillogin.​applinzi.​com) will be used to perform the centralized randomization (computerized random numbers). Patients will be randomized into one of the two intervention arms (1:1).

In patients who are assigned to receive individualized regimen to lower BP (individualized BP-lowering group), antihypertensive treatments are to be initiated to reduce SBP to a range of 130–180 mmHg and by 10–15% from the admission level within 2 h after randomization. SBP in the individualized BP-lowering group is to be maintained around the target level for one week with or without the use of hypertensive agents. In participants who were assigned to receive guideline-recommended treatment [13, 14] (guideline-recommended BP-lowering group), antihypertensive agents are to be administered if the SBP was > 200 mmHg in acute ischemic stroke (AIS) or the SBP was > 180 mmHg in intracerebral hemorrhage (ICH). The goal is to maintain the SBP < 200 mmHg in ischemic stroke and < 180 mmHg in ICH for one week with or without the use of hypertensive agents. Table 1 presents the detailed management of BP in the first week after randomization.

The selection of antihypertensive agents is based on the local availability; no specific agent is stipulated (both intravenous and oral agents can be used). Patients who take antihypertensive agents before stroke continue to take the same antihypertensive medication (same drug with same dosage). The rest of the medical care for stroke is based on the guideline [15, 16]. The management of BP after the first week of hospitalization adheres to the guideline as well.

Table 2 presents all the variables measured at each time point of the study. At the time point of baseline screening, demographics, subtypes of stroke, medical history (e.g. AIS, ICH, coronary event, diabetes mellitus, and hypertension), physical examination, clinical scores (NIHSS, GCS, Barthel index, mRS), and vital signs are recorded. On day 1 and day 7, routine laboratory tests for stroke patients are assessed, including blood routine, liver and renal function test, serum lipid, fasting glucose, urine routine, and electrocardiography. Co-morbidities on the day of screening and hospital discharge are recorded. Clinical scores on day 7, the day of hospital discharge, and day 90 are collected. During the whole hospitalization, BP, vital signs, and adverse events (AEs) are monitored, and concomitant treatments are documented.

An automatic BP cuff on the unaffected arm (right arm is chosen when both sides are affected or unaffected) is used to monitor the BP (SBP, diastolic BP, and mean arterial pressure). During the first 24 h after randomization, BP is recorded every 2 h. On days 2 and 3, BP is recorded every 4 h. During days 4–7, BP is recorded every 8 h. On the day of hospital discharge, BP at 08:00 is recorded. Three measurements of BP are required for each time point and the average is recorded.

The following procedures to minimize bias and ensure data quality and protocol standardization are required: (1) a training session will be held for research coordinators from all the participating centers before the commencement of CHASE study; (2) the principal investigator in each research site takes charge of quality control by supervising the conduct of the trial in accordance with the prespecified protocol, applicable guidelines, and regulations; (3) all participating sites will have monitoring visits via video conferencing after every ten patients are randomized, to verify consent, eligibility criteria, anomalous data, and reported serious AEs; (4) the Shaanxi Cerebrovascular Disease Clinical Research Center (SCRC) will prepare monthly reports on recruitment, randomization, data completeness, and protocol adherence. Case report forms and informed consent forms will be securely stored in a locked cabinet in a secure office with limited access. All digital data will be password-protected and stored in a firewall-protected secure environment. The trial sponsor has access to the final trial dataset.

The primary outcome measurement is the proportion of participants with a poor outcome at day 90 of enrollment. Poor outcome is defined as major disability (mRS ≥ 3, unable to live independently) or all-cause death. The proportion of participants with a poor outcome at hospital discharge is the key secondary outcome. Other secondary outcomes are the disability (evaluated by NIHSS, GCS, and Barthel index) at hospital discharge and the ability of activities of daily living at day 90 of enrollment evaluated by Barthel index. Outcomes are assessed independently by trained research assistants who are blind to the grouping results and clinical data. The 90-day outcomes are evaluated via telephone interviews at day 90 of enrollment (a delay of up to three days is acceptable). In cases when the patient is incapable to complete the interview, the first choice for a proxy is the spouse/live-in companion.

The sample size was set at 500 to provide at least 80% power to detect a 6% absolute risk reduction in the primary outcome for patients in the individualized BP-lowering group compared to those in the guideline-recommended control group, using a two-sided significance test with 5% type I error. The following assumptions were made: a primary outcome of 60% in the control group will be reduced to 54% in the individualized group; and there will be 10% non-adherence to the treatment protocol and 5% overall loss to follow-up. The 60% incidence of unfavorable 90-day outcome is extrapolated from one Chinese study on severe stroke (NIHSS > 10) in 2013 [17]. The 10% non-adherence rate and the absolute risk reduction in primary outcome are extrapolated from the INTERACT1&2 studies which were designed to compare the effects of two different BP-lowering strategies in acute stroke patients [8, 18].

Protocol amendments will be agreed upon with the CHASE Study Group, Sponsor and Funding Body before submission for ethical approval. Following ethical approval, protocol modifications will be communicated with relevant parties such as the trial investigators, the trial registry, and, if required, trial participants.

The results of this trial will be disseminated to a wide clinical audience (patients, health professionals, policy makers, and the general public) through publication in a high-impact international scientific journal.

The CHASE study trial was conceived and designed in 2016. At the time this manuscript was submitted, full approval by the Medical Ethics Committee has been obtained for all centers and recruitment was started. The patients’ follow-up is currently ongoing.