China Antihypertensive Trial in Acute Ischemic Stroke II
China Antihypertensive Trial in Acute Ischemic Stroke II
The investigators propose to conduct a multicenter randomized trial to test the primary
 hypothesis of whether early antihypertensive treatment starting between the first 24-48 hours
 after the onset of an acute ischemic stroke will reduce the risk of composite case-fatality
 and major disability (modified Rankin Scale score ≥3) at three months compared to delayed
 antihypertensive treatment (starting on day 8 after stroke onset). In the proposed China
 Antihypertensive Trial in Acute Ischemic Stroke II (CATIS-2), the investigators will recruit
 4,776 patients from 100 hospitals within the China-US Collaborative Stroke Clinical Trial
 Network. Eligibility criteria for the trial participants include age ≥40 years, acute
 ischemic stroke confirmed by CT/MRI, symptom onset between 24-48 hours, and average systolic
 blood pressure (BP) between 140-200 mmHg at randomization. Patients with extracranial or
 intracranial artery stenosis (≥70%) in both sides or the affected side, NIH Stroke Scale
 score of ≥21, Glasgow Coma Scale score <8, preceding moderate or severe dependency (modified
 Rankin scale score 3-5), revascularization, intravenous thrombolytic therapy or mechanical
 thrombectomy will be excluded. All eligible patients will discontinue their home
 antihypertensive medications. Patients admitted within 24 hours of symptom onset will require
 a reevaluation prior to randomization at 24 hours after stroke onset. After randomization,
 patients in the early treatment group will immediately receive antihypertensive treatment
 aimed at lowering average systolic BP by 10-20% within the first 24 hours and achieving an
 average BP <140/90 mmHg within five days. Patients in the delayed treatment group will
 discontinue antihypertensive medications for the first seven days. After seven days, both
 groups will receive antihypertensive treatment with a BP goal of <140/90 mmHg. The primary
 study endpoint is a composite outcome of death and major disability at three months. The
 major secondary endpoint will be the first recurrent stroke (hemorrhagic or ischemic) over
 three-month follow-up after randomization. Other secondary endpoints include ordered 7-level
 categorical score of the modified Rankin Scale, all-cause mortality, major vascular events,
 cognitive impairment, and health-related quality of life at three months. The proposed study
 provides 85% statistical power to detect a 15% reduction in the composite outcome of death
 and major disability over three months at a significance level of 0.05 for a two-sided test.
 Based on experience from our previous trials, we assumed a 25% event rate of the primary
 study endpoint and potential loss to follow-up of 5% over three months. The CATIS-2 trial
 will provide important information for the development of clinical guidelines in the early
 management of BP among patients with acute ischemic stroke for reducing mortality and major
 disability.
Stroke is the leading cause of death in China and the second leading cause of death in the
 world. In addition, stroke is the leading cause of long-term disability worldwide and a major
 financial burden to society. It is estimated that there are probably more than 3 million new
 strokes every year in China. In 2013, more than 1.9 million Chinese adults died from stroke,
 which represented an increase of 47.7% from 1.3 million in 1990.

 Elevated blood pressure (BP) is common in the acute phase of ischemic stroke, occurring in
 ≥75% of all patients. The early BP increase following ischemic stroke often reflects
 uncontrolled chronic hypertension. In addition, the potential causes of this transient rise
 include disturbed cerebral autoregulation, damage or compression of brain regions that
 regulate BP, neuroendocrine disturbance, and non-specific mechanisms such as headache, urine
 retention, and psychological stress. Several clinical trials have tested the effects of
 immediate BP lowering on adverse clinical outcomes in patients with acute ischemic stroke and
 showed a neutral effect on death or dependency. The China Antihypertensive Trial in Acute
 Ischemic Stroke (CATIS) suggested a beneficial effect of BP lowering on death or major
 disability (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.55-0.96, p=0.03) and
 recurrent stroke (OR 0.25, 95% CI 0.08-0.74, p=0.01) among patients with acute ischemic
 stroke who received antihypertensive treatment between 24-48 hours in a subgroup analysis.
 There are important knowledge gaps in BP management in acute ischemic stroke, such as when is
 the optimal time for initiation of antihypertensive treatment.

 The investigators propose to conduct a multicenter randomized controlled trial to test the
 primary hypothesis of whether early antihypertensive treatment starting between the first
 24-48 hours after the onset of an acute ischemic stroke will reduce the risk of composite
 case-fatality and major disability (modified Rankin scale score ≥3) at three months compared
 to delayed antihypertensive treatment (starting on day 8 after stroke onset). Patients with
 acute ischemic stroke will be randomly assigned within the first 24-48 hours after stroke
 onset to the early and delayed treatment groups. Patients in the early treatment group will
 immediately receive antihypertensive treatment aimed at lowering average systolic BP by
 10-20% (with a mean reduction of 15%) within the first 24 hours, achieving an average
 systolic/diastolic BP <140/90 mmHg within five days, and maintaining this level afterward.
 Patients in the delayed treatment group will discontinue antihypertensive medications for the
 first seven days. After then, both groups will receive antihypertensive treatment with an
 average systolic/diastolic BP goal of <140/90 mmHg. The primary study endpoint will be a
 composite outcome of death and major disability (modified Rankin Scale score ≥3) at three
 months after randomization. The major secondary endpoint will be the first recurrent stroke
 (hemorrhagic or ischemic) within three months. Other secondary endpoints include ordered
 7-level categorical score of the modified Rankin Scale, all-cause mortality, major vascular
 events, cognitive impairment, and health-related quality of life at three months.

 In the proposed China Antihypertensive Trial in Acute Ischemic Stroke II (CATIS-2), the
 investigators will recruit 4,776 patients (2,388 for each group) from 100 hospitals within
 the China Stroke Clinical Research Network. Eligibility criteria for the trial participants
 include age ≥40 years, acute ischemic stroke confirmed by computed tomography (CT) or
 magnetic resonance imaging (MRI), symptom onset between 24-48 hours, and an average systolic
 BP between 140-200 mmHg. The proposed study provides 85% statistical power to detect a 15%
 reduction in the primary study endpoint at three months at a significance level of 0.05 for a
 two-sided test. Based on experience from our previous CATIS trial, we assumed an event rate
 of 25% for the primary study outcome and potential loss to follow-up of 5% over three months.
 To achieve the CATIS-2 study objectives, we plan to:

 1. Recruit and randomize 4,776 eligible patients (2,388 for each group) to the early
 antihypertensive treatment group or the delayed antihypertensive treatment group
 according to the study eligibility criteria;

 2. Achieve and maintain target treatment goals for BP in the randomization groups;

 3. Follow a study-wide strategy to encourage a standard of care based on clinical
 guidelines for the treatment of acute ischemic stroke other than BP for all
 participants;

 4. Obtain follow-up data on clinical endpoints, neurological and functional status,
 cognitive function, and Health related-quality of life (HRQoL) for each participant
 according to the study protocol; and

 5. Estimate the effect of early antihypertensive treatment vs. delayed treatment on the
 primary and secondary endpoints according to intention-to-treat analysis and conduct
 predefined subgroup analyses.

 The CATIS-2 study will provide important information for the development of clinical
 guidelines in the early management of BP among patients with acute ischemic stroke for
 reducing mortality and major disability.
Inclusion Criteria:

 -  Men and women aged ≥40 years

 -  Acute ischemic stroke confirmed by computed tomography (CT) or magnetic resonance
 imaging (MRI) of the head

 -  Stroke onset within 24-48 hours*

 -  Systolic blood pressure between 140-200 mmHg and diastolic blood pressure between
 80-120 mmHg

 Exclusion Criteria:

 -  Hemorrhagic stroke confirmed by CT or MRI of the head

 -  CT or MRI-diagnosed vascular malformation, tumor, abscess, or other major non-ischemic
 brain disease (e.g., multiple sclerosis)

 -  Extracranial or intracranial artery stenosis (≥70%) in both sides or the affected side
 based on imagine study

 -  Stroke caused by arteritis, migraine, vasospasm, or substance abuse

 -  Severe stroke (NIHSS score of ≥21)

 -  Coma (Glasgow Coma Scale [GCS] score <8)

 -  Preceding moderate or severe dependency (modified Rankin scale [mRS] score 3-5)

 -  Planned or probable revascularization (any angioplasty or vascular surgery) within 3
 months after screening

 -  Intravenous thrombolytic therapy (such as intravenous rtPA) or mechanical thrombectomy

 -  Severe heart failure (NY Heart Association class III and IV) or left ventricular
 ejection fraction <35%

 -  Myocardial infarction or unstable angina within past 3 months

 -  History of atrial fibrillation.

 -  History of aortic dissection

 -  History of all-cause dementia

 -  Difficult-to-control hypertension (systolic blood pressure ≥170 mmHg despite use of ≥4
 antihypertensive medications for ≥6 months)

 -  Acute renal failure or dialysis or estimated glomerular filtration rate (eGFR) <20
 ml/min/1.73 m2

 -  Any clinical conditions judged by the clinic team to likely limit the adherence to
 study procedures

 -  Inability to understand and/or follow research procedures due to mental, cognitive, or
 emotional disorders

 -  Unable to participate in the follow-up examination (e.g., cannot travel to the
 participating hospital)

 -  Participation in another clinical trial within 30 days

 -  Pregnant, currently trying to become pregnant, or of child-bearing potential and not
 using birth control

 -  Failure to obtain informed consent from a participant