Antihypertensive Treatment of Acute Cerebral Hemorrhage-II

The primary outcome was death or disability, defined by modified Rankin scale (mRS) of 4-6 at 90 days following treatment. The modified Rankin Scale score ranges from 0, indicating no symptoms, to 6, indicating death. A score of 4 indicates moderately severe disability including the inability to walk or attend to one's own bodily needs. A score of 5 indicates severe disability; bedridden, incontinent, and requiring constant nursing care. To score a 3 or lower on the mRS, a person must at least be able to walk without the assistance of another person. We chose the mRS because of its high inter-observer reliability, superiority to other indices, and consistency with previous trials in patients with ICH. Reliability was further increased by use of a structured interview template and by requiring mRS assessors to pass a certification test. Persons conducting the 90-day mRS assessment were to be unaware of the treatment arm or clinical course of the patients they assessed.

Time frame: 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization

Population: All subjects were analyzed for known death at any time following randomization. Patients surviving through 90 days (± 14 days per protocol window; data used up to ± 30 days) were assessed for disability using the mRS. Patients not completing the 90-day visit within 30 days of due date aren't included in the death \& disability participant counts.

Hematoma expansion as determined by serial CT scans: Hematoma expansion was defined as an increase in the volume of intraparenchymal hemorrhage of 33% or greater as measured by a central imaging analyst who was was unaware of the treatment assignments, clinical findings, and time points of image acquisition. The area of the hematoma was delineated by image analysis software with the use of density thresholds on each slice, followed by manual correction. To ensure accuracy and consistency of the readings, images were coded randomly and independently of subject numbers and manual correction was also done without awareness of treatment assignments, clinical findings, or time points of image acquisition. This data point is defined as being present (hematoma expansion of 33% or more was calculated between the baseline scan hematoma volume and the 24 +/- 6 hours hematoma volume measures at data analysis), meaning that hematoma expansion as defined must have occurred or it was not counted.

Time frame: From the baseline head CT to the 24 +/- 6 hours from randomization head CT

Population: Participants with readable head CTs at baseline and 24 +/- 6 hours from randomization (submitted before data lock) were analyzed. Hematoma expansion was only recorded as present if ≥ 33% volume increase was calculated. Scans done outside of time window + margin, submitted after data lock, or not readable in standard DICOM format could not be used.

Standardized scales developed by the EuroQol Research Foundation were used as a secondary outcome measure in addition to the mRS scale score. The EQ-5D is a simple, standardized non-disease-specific instrument for describing and valuating health-related quality of life. The EQ-5D-3L questionnaire consists of 5 questions in 5 different domains and allows for responses from 1 (the best outcome) to 3 (the worst outcome) in each of five categories (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Total scores range from 5 to 15, with lower scores indicating better quality of life and a higher score indicating a worse quality of life. A second component of EuroQol outcome measurements is a printed 20 cm visual analogue scale (EQ VAS) that appears somewhat like a thermometer, on which a score from 0 (worst imaginable health state or death) to 100 (best imaginable health state) is marked by the patient (or, when necessary, their proxy) with the scale in view.

Time frame: 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization

Population: All available valid data were analyzed. Outcomes collected outside of 90 ± 30 days weren't considered valid. EQ-5D data were missing for 28 patients in the intensive group \& for 27 in the standard group. EQ VAS data were missing for 144 patients in the intensive group and for 146 in the standard group.

The complete count of all subjects who experienced any serious adverse events throughout their participation in the trial was included in this tabulation. Adverse events (AEs) and serious adverse events (SAEs) were assessed by the site investigators for all patients. Potential relatedness to the study treatment was a required reporting element for all adverse events but was not considered in this count. Terminology from the Medical Dictionary for Regulatory Activities (MedDRA) and severity criteria from the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03) were used as a basis for reporting adverse events. Serious adverse events are defined as being fatal, life-threatening, resulting in hospitalization or prolonged hospitalization, resulting in disability or congenital anomaly, or requiring intervention to prevent permanent impairment or damage and were required to be reported promptly. An Independent Oversight Committee (IOC) reviewed and adjudicated adverse event data.

Time frame: From randomization through the 90 day visit (90 ± 14 days per protocol window; up to ± 30 days data is used) or until known death, withdrawal, or loss to follow-up.

Population: Patients may have experienced more than one adverse event. This measure is designed to show the total count of any patients who experienced any type of serious adverse event, whether it was felt to be related to the study treatment or not, throughout the duration of their participation in the study.

Hypotension (abnormally low blood pressure) was the most likely adverse event that could be associated with the study treatment, and is the primary basis (risk) on which neurological deterioration or other untoward effects of the study treatment could occur. It is therefore examined as a numerically-measured occurrence in addition to monitoring patients closely for neurological deterioration or other symptoms. Hypotension, when named as an adverse event, was defined as the syndrome of low blood pressure with SBP \< 85 mmHg. Instances of hypotension were to be avoided through close monitoring, and administration of fluid bolus for SBP \< 110 mmHg. If hypotension did occur, it was to be reversed as quickly as possible through discontinuation of intravenous nicardipine and intravenous fluid administration, which can be accomplished readily in a variety of settings where patients with intracerebral hemorrhage are routinely housed during early hospitalization.

Time frame: From randomization through 72 hours from randomization

Population: Blood pressure including the potential for hypotension was monitored according to intensive care unit standards for ICH patients during early hospitalization. Blood pressure was monitored more closely during the 24-hour study period and at times when nicardipine (or other/secondary IV antihypertensive medications) were being titrated.

Neurologic deterioration was measured using two scales. The Glasgow Coma Scale (GCS) score measures of level of consciousness in eye, motor, and verbal components. At least one point is given in each category. The scale ranges from 3 to 15, with 3 indicating deep unconsciousness and 15 indicating consciousness is not impaired. The National Institutes of Health Stroke Scale (NIHSS) quantifies neurologic deficits in 11 categories. Level of consciousness, horizontal eye movement, visual fields, facial palsy, movement in each limb, sensation, language & speech, and extinction or inattention on one side of the body are tested. Scores range from 0 to 42, with 0 indicating normal function and higher scores indicating greater deficit severity. Neurological status was checked per ICU standards through 24 hours, recommended as hourly GCS and full assessment every 2 hours. NIHSS assessment at baseline and 24 +/- 3 hours was pre-specified. Assessments were added for suspected neurological change.

Time frame: From randomization through the 24-hour treatment period

Population: All subjects were assessed for neurological status regularly. Grid-estimated verbal scoring based on eye and motor scores was used for intubated patients so that GCS scores could be compared over time and was consistent across patients.

Adverse events (AEs) and serious adverse events (SAEs) were assessed by the site investigators for all patients, including for their potential relatedness to the study treatment. An Independent Oversight Committee (IOC) reviewed and adjudicated all adverse event data. The 72-hours-from-randomization time window was considered the most likely time frame during which treatment-related adverse events or serious adverse events would be observed. Terminology from the Medical Dictionary for Regulatory Activities (MedDRA) and severity criteria from the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03) were used as a basis for reporting adverse events. Serious adverse events are defined as being fatal, life-threatening, resulting in hospitalization or prolonged hospitalization, resulting in disability or congenital anomaly, or requiring intervention to prevent permanent impairment or damage and were required to be reported promptly.

Time frame: From randomization through 72 hours (3 days)

Population: Relatedness is defined by the terms unrelated, unlikely, possibly, probably, or definitely related to the study treatment. Results are entered as the count of participants experiencing any serious adverse event within 72 hours of randomization that was determined by the site investigator to possibly or more have relationship to the study treatment.