Table 4 Evidence-based summary

Rapid Blood Pressure Reduction in Acute Intracerebral Hemorrhage [152]

Prospective randomized, single-center study

Primary outcome: clinical deterioration (NIHSS drop ≥ 2 points) within the first 48 hours. Hematoma enlargement at 24 hours was a secondary endpoint

Eligible patients: acute spontaneous supra-tentorial ICH within 8 hours of symptom onset

Exclusion criteria: history of head trauma; coma with signs of herniation; coagulopathy; MAP < 110 mmHg at presentation; secondary ICH; surgical hematoma evacuation

Blood pressure targets: standard treatment (MAP = 110–130 mmHg) vs aggressive BP treatment (MAP < 110 mmHg)

Maximum interval from symptom onset to treatment: 8 hours

Duration of treatment: 48 hours

Drugs used:

– Initially, intermittent labetalol infusions (10–20 mg)

– If target blood pressure was not achieved, a continuous infusion of nicardipine (5–15 mg/hour) was started

– More severe cases were treated with intravenous nicardipine from the onset (i.e., initial dose, 5 mg/hour followed by titration and increases of 2.5 mg/hour every 5–15 minutes, and no bolus)

– Most severe cases of hypertension were treated with sodium nitroprusside infusion at 0.3 μg/kg/minute IV infusion and titrated every few minutes to desired effect

21 patients in each group

Treatment was started on average 3.2 ± 2.2 hours after symptom onset

Target blood pressure was achieved within 87.1 ± 59.6 minutes in the standard group and 163.5 ± 163.8 minutes in the aggressive BP treatment group

No significant differences in early neurological deterioration, hematoma and edema growth, and clinical outcome at 90 days (mRS)

INTERACT trial [76]

Open-label, multicenter, blinded outcome, randomized trial; 44 hospital sites in Australia, China, and South Korea

Primary outcome: proportional change in hematoma volume at 24 hours

Eligible patients: spontaneous ICH and elevated BP (≥2 measurements of 150–220 mmHg, recorded ≥ 2 minutes apart)

Exclusion criteria: SBP > 220 mmHg or hypertensive encephalopathy; severe cerebral artery stenosis or renal failure; secondary ICH or the use of a thrombolytic agent; ischemic stroke within 30 days; GCS 3–5; significant prestroke disability or medical illness; or early planned decompressive neurosurgical intervention

Blood pressure targets: early intensive BP-lowering strategy (target SBP = 140 mmHg within 1 hour) vs standard approach (target SBP =180 mmHg)

Maximum interval from symptom onset to treatment: 6 hours

Duration of treatment: 7 days

Drugs used: treatment conducted with locally available intravenous or oral BP-lowering agent, each included (treatment group): furosemide (35 %), urapidil (47 %), phentolamine (16 %), glycerol trinitrate (10 %), labetalol (6 %), nicardipine (5 %), hydralazine (3 %), metoprolol (1 %), nitrate patch (3 %). It also included some oral agents

203 patients randomized to intensive BP management vs 201 to standard guidelines-based management

Trend toward lower hematoma growth at 24 hours in the intensive treatment group (difference 22.6 %, 95 % CI 0.6–44.5 %, p = 0.04; absolute difference in volume 1.7 ml, 95 % CI 0.5–3.9 ml, p = 0.13)

No excess of neurological deterioration, other clinical outcomes, or adverse events

ATACH I trial [154]

Phase I, dose-escalation, multicenter prospective study

Eligible patients: spontaneous ICH with admission SBP ≥ 170 mmHg on two repeat measurements at least 5 minutes apart. Symptom onset < 6 hours at the time to evaluation and initiation of treatment with IV nicardipine

Primary outcomes: (1) Feasibility end point: SBP reduction and maintenance in the respective target range achieved (treatment success) or not (failure); (2) Safety end points: (a) neurologic deterioration (defined by a decline in the GCS score 2 or increase in NIHSS score 4 points not explained by use of sedatives or hypnotics) within 24 hours from treatment initiation; (b) serious adverse events within 72 hours

Blood pressure targets:

– Tier 1: SBP ≥ 170 and < 200 mmHg

– Tier 2: SBP ≥ 140 and < 170 mmHg

– Tier 3: SBP ≥ 110 and < 140 mmHg

Maximum interval from symptom onset to treatment: 6 hours

Duration of treatment: 18–24 hours

Drugs used: intravenous nicardipine infusion, initiated at 5 mg/hour, and then increased by 2.5 mg every 15 minutes as needed, up to a maximum of 15 mg/hour. Once the target SBP was achieved, the infusion rate was decreased by 1–3 mg/hour. If the SBP dropped below the specified levels, infusion was reduced by 2.5 mg/hour every 15 minutes until the drug was stopped

60 patients enrolled (Tier 1 = 18; Tier 2 = 20; Tier 3 = 22)

Nine patients in Tier 3 had treatment failure

Seven patients had neurologic deterioration (one, two, and four in Tiers 1, 2, and 3, respectively)

One subject in Tier 2 and three in Tier 3 had serious adverse events; however, the safety-stopping rule was not activated in any of the tiers

These results confirmed the feasibility and safety of early rapid lowering of BP in ICH and formed the based for the larger randomized ATACH II trial

ICH ADAPT study [74]

Multicenter, prospective, randomized, open-label, with blinded evaluation study. A block randomization design (six patients/block), stratified by onset to treatment time (≤6 and 6–24 hours)

Eligible patients: spontaneous ICH diagnosed <24 hours after onset and SBP >150 mmHg

Exclusion criteria: Secondary ICH (e.g., vascular malformation), planned surgical resection, or contraindications to CT perfusion (CTP; e.g., contrast allergy or renal impairment)

Primary end-point: difference in perihematoma relative cerebral blood flow (CBF) between treatment groups as assessed by CT perfusion imaging 2 hours post randomization

Blood pressure targets: SBP target <150 mmHg vs <180 mmHg to be achieved within 1 hour of randomization

Drugs used: labetalol test dose: 10 mg bolus over 1 minute. If SBP > target (150 or 180 mmHg) and heart rate (HR) > 55 bpm, the bolus was repeated (10 mg bolus in 5 minutes). 10–20 mg IV push every 5 minutes until SBP < target or HR < 55. Labetalol maximum 300 mg/24 hours

Hydralazine was used only if SBP persistently > target, or if HR was below 55

Enalapril was used in the SBP < 150 mmHg target group. It was considered in patients with labile BP, who required repeated doses of labetalol and/or hydralazine. 1.25 mg IV every 6 hours PRN

75 patients enrolled

Focal decreases in CBF and cerebral blood volume within the perihematoma region evident in all patients.

After adjustment for baseline intraparenchymal hematoma volume and time to randomization, perihematoma relative CBF not significantly lower in patients randomized to SBP < 150 mmHg (p = 0.18; absolute difference 0.03, 95 % CI –0.018 to 0.078)

INTERACT2 trial [71]

International, multicenter, prospective, randomized, open-treatment, blinded end-point trial

Eligible patients: spontaneous ICH and elevated BP (at least two SBP measurements of ≥150 and ≤220 mmHg, recorded 2 or more minutes apart)

Exclusion criteria: structural cerebral cause for the intracerebral hemorrhage; GCS 3–5; massive hematoma with a poor prognosis; or early planned surgery to evacuate the hematoma

Primary outcome: death or major disability (mRS3–6 at 90 days)

Blood pressure targets: intensive treatment (SBP <140 mmHg within 1 hour) vs guideline-recommended treatment (SBP <180 mmHg)

Maximum interval from symptom onset to treatment: 6 hours

Duration of treatment: 7 days

Drugs used: treatment conducted with locally available intravenous BP-lowering agent, each included (treatment group): alpha-adrenergic antagonist (i.e., urapidil, 32.5 %), calcium-channel blocker (nicardipine or nimodipine, 16.2 %), combined alpha- and beta-blocker (labetalol, 14.4 %), nitroglycerin (14.9 %), furosemide (12.4 %), nitroprusside (12.1 %), hydralazine (5.9 %)

2839 patients enrolled at 144 hospitals in 21 countries (n = 1403 early intensive treatment; n = 1436 guideline-recommended treatment)

No statistically significant difference between two groups in the rates of death or severe disability (52 % vs 55.6 %; OR with intensive treatment 0.87, 95 % CI 0.75–1.01, p = 0.06)

A pre-specified ordinal analysis of the mRS score showed significantly lower scores with intensive treatment (OR for greater disability 0.87, 95 % CI 0.77–1.00, p = 0.04)

ATACH 2 [77]

International, multicenter, randomized, open label trial

Eligible patients: ICH (volume, <60 cm³) and GCS ≥ 5

Exclusion criteria: structural cerebral cause for the intracerebral hemorrhage; GCS 3–4; massive hematoma with a poor prognosis; or early planned surgery to evacuate the hematoma

Primary outcome: death or major disability (mRS 4–6 at 3 months)

Blood pressure targets: intensive treatment (SBP 110–139 mmHg within 2 hours) vs SBP between 140 and 179 mmHg)

Maximum interval from symptoms onset to treatment: 4.5 hours

Duration of treatment: 24 hours

Drugs used: nicardipine IV, started at a dose of 5 mg per hour, and increased by 2.5 mg per hour every 15 minutes (maximum dose of 15 mg per hour). Intravenous labetalol was added as second-line agent, if the systolic blood pressure target was not reached

1000 patients enrolled at 110 sites in six countries (n = 500 intensive treatment; n = 500 standard treatment)

No statistically significant difference in the rates of death or disability (38.7 vs 37.7 %; intensive vs standard treatment, respectively)

Relative risk, 1.04; 95 % CI 0.85–1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage

The rate of renal adverse events within 7 days was significantly higher in the intensive treatment group (9.0 % vs 4.0 %, p = 0.002)

Intensive blood pressure reduction in acute intracerebral hemorrhage: a meta-analysis [155]

Systematic review and meta-analysis according to PRISMA guidelines. Included available randomized controlled trials that randomized patients with acute ICH to either intensive or guideline BP-reduction protocols at the time of publication

Included four studies:

– Rapid Blood Pressure Reduction in Acute Intracerebral Hemorrhage [152]

– INTERACT [76]

– ICH ADAPT [74]

– INTERACT2 [71]

3315 patients

Death rates were similar between the groups (OR 5 1.01, 95 % CI 0.83–1.23, p ≤ 0.914)

Intensive BP-lowering treatment tended to be associated with lower 3-month death or dependency (mRS grades 3–6) compared with guideline treatment (OR 5 0.87, 95 % CI 0.76–1.01, p = 0.062)

No evidence of heterogeneity between estimates (I ² ≤ 0 %, p ≤ 0.723), or publication bias in the funnel plots (p ≤ 0.993, Egger statistical test), was detected

Intensive BP reduction was also associated with a greater attenuation of absolute hematoma growth at 24 hours (standardized mean difference ± SE: –0.110 ± 0.053, p = 0.038)

FAST trial [153]

Multicenter, randomized, double blinded, placebo-controlled trial

Eligible patients: spontaneous ICH within 3 hours of symptom onset

Exclusion criteria: GCS ≤ 5; secondary ICH; known use of anticoagulant therapy, thrombocytopenia, or coagulopathy; acute sepsis; crush injury; disseminated intravascular coagulation; pregnancy; previous disability; known recent thromboembolic disease

Primary outcome: death or severe disability (mRS 5–6 at 90 days)

Patients randomized to single intravenous dose of rFVIIa (20 or 80 μg/kg) or placebo within 4 hours from stroke

841 patients (n = 268, placebo; n = 276, rFVII 20 μg/kg; n = 297, rFVII 80 μg/kg)

80 μg/kg of rFVIIa associated with significant reduction in ICH expansion (mean estimated increase in volume of ICH: 26 % placebo; 18 % 20 μg/kg; 11 % 80 μg/kg)

Despite the reduction in bleeding, no significant difference in the proportion of patients with poor outcome (24 % placebo; 26 % 20 μg/kg; 29 % 80 μg/kg)

More arterial thromboembolic events in the group receiving rFVII 80 μg/kg versus placebo (9 % vs 4 %, p = 0.04)

A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia [131]

Systematic review and meta-analysis

Included five studies (one included traumatic ICH patients):

– Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage

– Recombinant activated factor VII for acute intracerebral hemorrhage

– Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial

– Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a dose-escalation clinical trial

– Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage

rFVIIa reduced the change in ICH volume

There was no significant difference in mortality, mRS score or extended Glasgow Outcome Scale (GOS-E) score in patients treated with rFVIIa or placebo

There was a significant increase in arterial thromboembolic adverse events in patients treated with rFVIIa

There was an increase in deep vein thrombosis in patients with spontaneous ICH and traumatic ICH

PATCH trial [107]

Multicenter, randomized, open-label, masked end-point, parallel-group, phase 3 trial; 60 hospitals (36 Netherlands, 13 UK, 11 France)

Eligible patients: nontraumatic supra-tentorial ICH; GCS 8–15; antiplatelet therapy for at least 7 days preceding ICH; pre-ICH mRS 0–1

Exclusion criteria: epidural or subdural hematoma; underlying aneurysm or arteriovenous malformation; planned surgical evacuation of ICH within 24 hours of admission; IVH more than sedimentation in the posterior horns of the lateral ventricles; previous adverse reaction to platelet transfusion; vitamin k antagonist use or knows coagulopathy; thrombocytopenia (<100,000 cells/ml)

Primary outcome: difference in functional outcome at 3 months after randomization scored with mRS

Platelet transfusion (leukocyte-depleted, either buffycoat derived or collected by apheresis) to be initiated within 6 hours of symptom onset and 90 minutes of brain imaging

– COX inhibitor, with or without adenosine-reuptake inhibitor: 1 platelet concentrate (equivalent to 5 donor units)

– ADP receptor inhibitor, with or without another antiplatelet drug: 2 platelet concentrates

190 participants at 41 different sites enrolled between February 2009 and October 2015 (97 patients assigned to receive standard care with platelet transfusion and 93 assigned to standard care without transfusion)

4 patients assigned to platelet transfusion did not receive it; 2 participants assigned to standard care alone received platelet transfusion

Primary outcome: higher odds of a shift towards death or dependence at 3 months in the platelet transfusion group (adjusted common OR 2.05, 95 % CI 1.18–3.56, p = 0.0114)

Secondary analysis: more patients in the platelet transfusion group with mRS 4–6 than those in standard care group

In-hospital mortality: 24 (25 %) patients assigned to platelet transfusion; 15 (16 %) patients assigned to standard care alone

Pre-specified subgroup analyses (type of anti-platelet therapy; country; hematoma volume): no significant interaction

Serious adverse events: 40 (42 %) patients in platelet transfusion group; 28 (29 %) patients in standard care group

STICH [114]

International, multicenter, prospective, randomized trial

Eligible patients: spontaneous supra-tentorial ICH within 72 hours; uncertainty about the benefits of either treatment according to responsible neurosurgeon

Exclusion criteria: secondary ICH; cerebellar hemorrhage or extension of a supra-tentorial hemorrhage into the brainstem; severe pre-existing physical or mental disability or severe comorbidities; surgery not undertaken within 24 hours of randomization

Primary outcome: death or disability using the extended Glasgow Outcome Scale 6 months after ictus

Patients randomized to early surgery (hematoma evacuated within 24 hours of randomization by the method of choice of the responsible neurosurgeon, combined with the best medical treatment) or to initial conservative management (best medical treatment; later surgical evacuation allowed in case of neurological deterioration)

1033 patients from 83 centers in 27 countries (n = 503 early surgery; n = 530 initial conservative treatment)

Of the 468 patients randomized to early surgery analyzed at 6 months, 122 (26 %) had a favorable outcome compared with 118 (24 %) of 496 patients randomized to initial conservative treatment (OR 0.89, 95 % CI 0.66–1.19, p = 0.414; absolute benefit 2.3 %; relative benefit 10 %)

26 % of patients initially randomized to conservative treatment underwent surgery after an initial period of observation

Subgroup analysis of patients with lobar ICH within 1 cm of the cortical surface who underwent surgery had a statistically significant increase in good outcomes compared with similar subjects in the medical arm (8 % absolute increase, p = 0.02)

STICH II [115]

International, multicenter, prospective, randomized, parallel group, pragmatic trial

Eligible patients: spontaneous lobar ICH, ≤1 cm from the cortical surface of the brain, volume between 10 and 100 ml; within 48 hours of onset of ictus; best GCS motor score ≥ 5 and best GCS eye score ≥ 2

Exclusion criteria: secondary ICH; involvement of basal ganglia, thalamic, cerebellar, or brainstem regions; presence of IVH; severe pre-existing physical or mental disability or severe comorbidities

Primary outcome: prognosis-based favorable or unfavorable outcome dichotomized from the Extended Glasgow Outcome Scale at 6 months after randomization

Patients randomized to early surgery (evacuation of hematoma within 12 hours of randomization) or initial conservative treatment (delayed evacuation permitted if judged clinically appropriate)

601 patients from 78 centers in 27 countries (n = 307 early surgery; n = 294 initial conservative treatment)

Median time to craniotomy: 26 hours after stroke onset

No difference in the primary outcome (absolute difference 3.7 %, 95 % CI –4.3 to 11.6 %; OR 0.86, 95 % CI 0.62–1.20, p = 0.37)

In the subgroup of patients with a poor expected prognosis at enrollment (lower GCS, greater age, and larger ICH volume), early surgical intervention was associated with more favorable outcome (OR 0.49, 95 % CI 0.26–0.92, p = 0.02)

No advantage for surgery in the good prognosis group (OR 1.2, 95 % CI 0.75–1.68, p = 0.57)

Among patients in the initial conservative treatment group, 21 % had surgery