Background
Etiology and risk factors
Initial evaluation and clinical stabilization
Emergency radiologic diagnosis
ICH volume, IVH, and hematoma location
Early neurological deterioration and hematoma expansion
Prediction of hematoma expansion
Clinical severity assessment
Component | Points | Total ICH score | 30-day mortality (%) |
---|---|---|---|
Glasgow Coma Scale | |||
3–4 | 2 | 0 | 0–10 |
5–12 | 1 | ||
13–15 | 0 | ||
Age (years) | |||
≥80 | 1 | 1 | 7–13 |
<80 | 0 | ||
ICH volume (ml) | |||
≥30 | 1 | 2 | 30–44 |
<30 | 0 | ||
Presence of intraventricular hemorrhage | |||
Yes | 1 | 3 | 56–78 |
No | 0 | ||
Infra-tentorial origin of ICH | |||
Yes | 1 | 4 | 70–100 |
No | 0 | ||
Total ICH score | 0–6 | 5–6 | 100 |
Patient disposition
Medical management of ICH
Blood pressure management
INTERACT 2 (n = 2794) | ATACH 2 (n = 1000) | |||
---|---|---|---|---|
Control | Intervention | Control | Intervention | |
Number of enrolled patients | 1430 | 1399 | 500 | 500 |
Treatment target (SBP in mmHg) | <180 | <140 | 140–179 | 110–139 |
Inclusion criteria | GCS > 5 | ICH (volume < 60 cm3), GCS score ≥ 5 | ||
Primary outcome | Death or major disability (mRS = 3–6) at 3 months | Death or disability (mRS = 4–6) at 3 months | ||
Recruitment window | 6 hours | 4.5 hours | ||
Medications used to lower blood pressure | Urapidil: 32.5 % | Nicardipine ± labetalol | ||
Nicardipine or nimodipine: 16.2 % | Intravenous diltiazem or urapidil could be used | |||
Labetalol: 14.4 % | ||||
Nitroglycerin: 14.9 % | ||||
Furosemide: 12.4 % | ||||
Nitroprusside: 12.1 % | ||||
Hydralazine: 5.9 % | ||||
Period of blood pressure intervention | 7 days | 24 hours | ||
Time goal of blood pressure lowering | 1 hour | 2 hours | ||
Mean interval between symptom onset and randomization | 3.7 hours | 3.7 hours | 3.0 hours | 3.0 hours |
Systolic blood pressure at presentation (mmHg) | 179 ± 17 | 179 ± 17 | 201.1 ± 26.9 | 200 ± 27.1 |
Mean systolic blood pressure achieved (mmHg) | 164 within 1 hour | 150 within 1 hour | 141.1 ± 14.8 (2 hours) | 128.9 ± 16 (2 hours) |
153 within 6 hours | 139 within 6 hours | |||
Primary treatment failurea (%) | 66 | 12.2 | ||
Baseline hematoma volume (ml) | 11 | 11 | 10.2 | 10.3 |
Asian (%) | 68.0 | 67.7 | 57.0 | 55.4 |
Death or disability (%)—mRS = 3–6 | 55.6 | 52.0 | 56.1 | 56.2 |
Modified Rankin Scale (%) | ||||
0 | 7.6 | 8.1 | 7.1 | 5.0 |
1 | 18.0 | 21.1 | 19.6 | 19.8 |
2 | 18.8 | 18.7 | 17.3 | 19.1 |
3 | 16.6 | 15.9 | 18.3 | 17.5 |
4 | 19.0 | 18.1 | 26.5 | 26.0 |
5 | 8.0 | 6.0 | 4.2 | 5.8 |
6 | 12.0 | 12.0 | 7.1 | 6.9 |
Anticoagulant-associated ICH
-
Factor Xa inhibitors. These oral anticoagulant agents (e.g., rivaroxaban, apixaban, and edoxaban) act as direct factor Xa inhibitors and prevent factor Xa-dependent conversion of prothrombin to thrombin. Current indications include primary stroke prevention (i.e., in nonvalvular atrial fibrillation), treatment of deep vein thrombosis and pulmonary embolism, and secondary prevention of venous thromboembolism (VTE) [108, 111]. Compared with warfarin, factor Xa inhibitors have shown a lower risk of ICH (Table 3). However, currently there is no specific antidote commercially available for this class of drug, and most information on their reversal is limited to ex-vivo and in-vivo studies on healthy volunteers and animal models of bleeding. Current recommendations suggest immediate discontinuation of the drug followed by the administration of four-factor PCC (50 U/kg) or activated PCC (50 U/kg) in the case of patients presenting within 3–5 terminal half-lives of the drug or in the presence of liver failure. In case of recent ingestion (within 2 hours), 50 g of activated charcoal is recommended [108].
-
Direct thrombin inhibitor reversal. Available direct thrombin inhibitors include competitive direct thrombin inhibitor (e.g., oral dabigatran), reversible direct thrombin inhibitors (argatroban and bivalirudin, both intravenous only), and irreversible direct thrombin inhibitors (e.g., desirudin SC and lepirudin IV). Their main current indications include primary stroke prevention in patients with non-valvular AF, treatment of VTE, and management of heparin-induced thrombocytopenia [108]. Data on the incidence and outcomes of direct thrombin inhibitor-related ICH is scant. Dabigatran seems to be associated with an ICH rate of 0.2–0.3 %/year, which is lower compared with warfarin [108]. Recently, a dabigatran-specific monoclonal antibody, idarucizumab (Praxbind®), has been approved for clinical use. The use of idarucizumab in dabigatran reversal was demonstrated in an interim analysis of the Reversal Effects of Idarucizumab on Active Dabigatran Study (the RE-VERSE AD study) [112]. The report included 90 patients (one-third with ICH) with uncontrolled or life-threatening bleeding, or requiring emergency surgical procedures (<8 hours) [112]. Patients received 5 g of idarucizumab divided in two doses of 2.5 g at 15-minute intervals. Idarucizumab reversed anticoagulation in 90 % of patients within 10–30 minutes of drug infusion, as assessed by the dilute thrombin time (TT) and ecarin clotting time (ECT). Therefore, for patients with dabigatran-related ICH, emergency treatment should include discontinuation of the drug, followed by two doses of 2.5 g idarucizumab IV at 15-minute intervals, if the last dose of dabigatran was ingested within 3–5 half-lives or if renal failure is present. In the occurrence of dabigatran intoxication or renal failure, the use of hemodialysis can be considered. If idarucizumab is not available, or if the ICH is related to other direct thrombin inhibitors, emergency treatment should include discontinuation of the drug followed by the administration of activated PCC (50 U/kg) or a four-factor PCC (50 U/kg), if the last dose of drug was ingested within 3–5 terminal half-lives. If the drug was taken more than 3–5 half-lives before presentation, reversal in not indicated. In the case of recent ingestion (within 2 hours), 50 g of activated charcoal is recommended. The use of rFVIIa or FFP in direct thrombin inhibitor-related intracranial hemorrhage is not recommended.
Drug | Target | Elimination and half-life (hours) | Rate of ICH | Monitoring coagulation tests | Antidote and reversal | Possible intervention | Guidelines |
---|---|---|---|---|---|---|---|
Vitamin K antagonist | |||||||
Warfarin | Factors II, VII, IX, X; proteins C, S | Hepatic metabolism | 0.3–1.1 % [90] | Good linear correlation PT/INR | Vitamin K | Not dialyzable | Withhold VKA + intravenous vitamin K + replace vitamin K–dependent factors (three- or four-factor PCC IV or FFP if PCCs are not available), and correct the INR (keep INR < 1.4) (Class I; Level of Evidence C) [9] |
92 % renal elimination | Vitamin K 10 mg IV associated with 4-FPCC 20 IU/kg (or FFP = 10–15 ml/kg, if PCC is not available) | PCCs might be considered over FFP (Class IIb; Level of Evidence B) [9] | |||||
20–60 | Goal: INR < 1.4 [90] | rFVIIa is not recommended for VKA reversal in ICH (Class III; Level of Evidence C) [9] | |||||
Unfractionated heparin, LMWHs, and heparinoids | |||||||
UFH | Binds and activates antithrombin (which blocks coagulation factors Xa and IIa). By inactivating thrombin, heparin prevents fibrin formation | Renal | Good linear correlation aPTT | Protamine sulfate 1 mg of protamine per 100 units of UFH infused over the preceding 3 hours | Not dialyzable | Protamine sulfate—1 mg for every 100 units of heparin given in the previous 2–3 hours with a maximum single dose of 50 mg (Strong recommendation, moderate quality evidence) [90] | |
0.5–2.5 (dose dependent) | If aPTT is still elevated, repeat administration of protamine at a dose of 0.5 mg protamine per 100 units of UFH (Conditional recommendation, low quality of evidence) [90] | ||||||
Reversal of prophylactic SC heparin only if aPTT is significantly prolonged (Good Practice statement) [90] | |||||||
Enoxaparin | LMWH Binds and activates antithrombin (which blocks coagulation factors Xa and IIa) | 40 % renal | 0.2–0.5 % [98] Enoxaparin 1 mg/kg BID; bridging warfarin with target INR 2–3 | Anti-factor Xa | Protamine sulfate partially reverses (60 %) LMWH effect. One mg protamine for every 1 mg enoxaparin | Not dialyzable | Strong recommendation, moderate quality evidence [90] |
4.5 hours | Protamine sulfate 1 mg per 1 mg of enoxaparin (maximum single dose of 50 mg—if enoxaparin was given within 8 hours) | ||||||
Protamine sulfate 0.5 mg of protamine per 1 mg of enoxaparin (if enoxaparin was given within 8–12 hours) | |||||||
After 12 hours, protamine is not needed | |||||||
Dalteparin | LMWH Binds and activates antithrombin (which blocks coagulation factors Xa and IIa) | Renal | Not established | Anti-factor Xa | Protamine sulfate partially reverses (60 %) LMWH effect. One mg protamine for every 100 anti-Xa IU dalteparin | Not dialyzable | Protamine sulfate 1 mg per 100 IU of dalteparin administered in the past 3–5 half-lives (maximum 50 mg) (Strong recommendation, moderate quality evidence) [90] |
2.5 hours | |||||||
3.7–7.7 hours with RF | |||||||
Nadroparin | LMWH Binds and activates antithrombin (which blocks coagulation factors Xa and IIa) | Renal | Not established | Anti-factor Xa | Protamine sulfate partially reverses (60 %) LMWH effect. One mg protamine for every 100 anti-Xa IU nadroparin | Not dialyzable | Protamine sulfate 1 mg per 100 IU of nadroparin administered in the past 3–5 half-lives (maximum 50 mg) (Strong recommendation, moderate quality evidence) [90] |
3.5 hours | |||||||
Pentasaccharides | |||||||
Fondaparinux (Aristra®) | Binds with antithrombin and potentiates inhibition of free factor Xa, preventing formation of the prothrombinase complex | 50–77 % renal | Not established | Anti-factor Xa | None | Activated PCC (FEIBA 20 units/kg) | aPCC 20 IU/kg (Conditional recommendation, low-quality evidence) [90] |
17–21 hours | Dialyzable (clearance increased by 20 %) | rFVIIa (90 μg/kg) if aPCC is not available (Conditional recommendation, low-quality evidence) [90] | |||||
Prolonged in older patients and in RF | Protamine sulfate is not recommended (Strong recommendation, low-quality evidence) [90] | ||||||
Direct thrombin (factor IIa) inhibitors | |||||||
Argatroban (Acova®) | Competitive direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation | No renal excretion 0.75 hours (prolonged in hepatic dysfunction) | Not established | aPTT, ACT | None | Activated PCC (FEIBA 50–80 units/kg) Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid) Hemodialysis (approximately 20 % over 4 hours) | aPCC (50 units/kg) or four-factor PCC (50 units/kg) (Conditional recommendation, low-quality evidence) [90] rFVIIa or FFP are not recommended in direct thrombin inhibitor-related ICH (Strong recommendation, low-quality evidence) [90] |
Bivalirudin | Reversible direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation | 20 % renal | 0.1 % [151] | ECT (PT, aPTT, ACT has nonlinear prolongation) | None | Activated PCC (FEIBA 50–80 units/kg) | |
0.5 (prolonged in renal impairment) | Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid) | aPCC (50 units/kg) or four-factor PCC (50 units/kg) (Conditional recommendation, low-quality evidence) | |||||
GFR 30–59, 34 minutes | Hemodialysis (approximately 25 % over 4 hours) | rFVIIa or FFP are not recommended in direct thrombin inhibitor-related ICH (Strong recommendation, low-quality evidence) | |||||
GFR 10–29, 57 minutes | |||||||
Dabigatran (Pradaxa®) | Reversible direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation | >80 % renal | 0.30 % (150 mg) [98] | Modified TT/ECT/prolongs PT linearly with increasing serum levels, while aPTT is affected in a nonlinear way | Idarucizumab or Praxbind® (humanized antibody fragment against dabigatran), in two doses of 2.5 g IV 15 minutes apart | Activated PCC (FEIBA 50–80 units/kg) | Idarucizumab 5 g IV in two divided doses if dabigatran was administered within 3–5 half-lives and no RF (Strong recommendation, moderate quality of evidence) or in the presence of RF leading to continued drug exposure beyond the normal 3–5 half-lives (Strong recommendation, moderate quality of evidence) |
12–17 hours | 0.23 % (110mg) [98] | Activated charcoal if last dose was taken < 2 hours Hemodialysis (approximately 57 % over 4 hours) Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid) | Hemodialysis if idarucizumab is not available (Conditional recommendation, low-quality data) | ||||
16.6 hours in mild RF | ICH distribution: 46 % intraparenchymal, 45 % SDH, and 8 % SAH [90] | ||||||
18.7 hours in moderate RF | |||||||
27.5 hours in severe RF | |||||||
34.1 hours in patients on hemodialysis | |||||||
Desirudin | Irreversible direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation | 40–50 % renal 2 hours (12 hours with renal impairment) | Not established | aPTT | None | Dialyzable | aPCC (50 units/kg) or four-factor PCC (50 units/kg) (Conditional recommendation, low-quality evidence) [90] rFVIIa or FFP are not recommended in direct thrombin inhibitor-related ICH (Strong recommendation, low-quality evidence) [90] |
Direct factor Xa inhibitors | |||||||
Apixaban (Eliquis®) | Prevents factor Xa-mediated conversion of prothrombin to thrombin | Mainly fecal 27 % renal 8–14 hours | Apixaban 5 mg twice daily 0.33 %/year [98] | Anti-factor Xa There are scant data regarding the effect of apixaban on traditional coagulation tests | Currently, there is no FDA-approved specific antidote for this class of anticoagulants Antidotes under investigation: – Aripazine (PER977—synthetic small molecule) – Andexanet (PRT064445—recombinant modified factor Xa protein) | Unactivated four-factor PCC (50 units/kg). If not available, a three-factor PCC can be used. Activated charcoal if last dose was taken < 2 hours Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid) Minimal removal with dialysis (decreased by 14 % over 4 hours) | Activated charcoal (50 g) within 2 hours of ingestion (Conditional recommendation, very low-quality evidence) [90] aPCC (50 units/kg) or Four-factor PCC (50 U/kg) or activated PCC (50 U/kg) if ICH happened within 3–5 half-lives of drug or if liver failure (Conditional recommendation, low-quality evidence) [90] Four-factor PCC or activated PCC over rFVIIa (Conditional recommendation, low-quality evidence) [90] |
Rivaroxaban (Xarelto®) | Prevents factor Xa-mediated conversion of prothrombin to thrombin | 66 % renal 28 % fecal 7 to 11 hours | Rivaroxaban 20 mg daily - < 0.5 % /year | Anti-factor Xa Rivaroxaban levels linearly increase PT and aPTT levels | Currently, there is no FDA-approved specific antidote for this class of anticoagulants Antidotes under investigation: – Aripazine (PER977—synthetic small molecule) – Andexanet (PRT064445—recombinant modified factor Xa protein) | Unactivated four-factor PCC (50 units/kg). If not available, a three-factor PCC can be used. Activated charcoal if last dose was taken < 2 hours Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid) Not dialyzable (rivaroxaban is highly protein bound) | Activated charcoal (50 g) within 2 hours of ingestion (Conditional recommendation, very low-quality evidence) [90] Four-factor PCC (50 U/kg) or activated PCC (50 U/kg) if ICH happened within 3–5 half-lives of drug or if liver failure (Conditional recommendation, low-quality evidence) [90] Four-factor PCC or activated PCC over rFVIIa (Conditional recommendation, low-quality evidence) [90] |
Edoxaban | Prevents factor Xa-mediated conversion of prothrombin to thrombin | 50 % renal 10–14 hours | Edoxaban 60 mg daily compared with warfarin (HR 0.54, 95 % CI 0.38–0.77) [90] | There are scant data regarding the effect of edoxaban on traditional coagulation tests | Currently, there is no FDA-approved specific antidote for this class of anticoagulants Antidotes under investigation: – Aripazine (PER977—synthetic small molecule) – Andexanet (PRT064445—recombinant modified factor Xa protein) | Unactivated four-factor PCC (50 units/kg). If not available, a three-factor PCC can be used. Activated charcoal if last dose was taken < 2 hours Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid) Not dialyzable (edoxaban is highly protein bound) | Activated charcoal (50 g) within 2 hours of ingestion (Conditional recommendation, very low-quality evidence) [90] Four-factor PCC (50 U/kg) or activated PCC (50 U/kg) if ICH happened within 3–5 half-lives of drug or if liver failure (Conditional recommendation, low-quality evidence) [90] Four-factor PCC or activated PCC over rFVIIa (Conditional recommendation, low-quality evidence) [90] |
Antiplatelets | |||||||
Aspirin | Irreversible COX-1 and 2 enzyme inhibitor (inhibits thromboxane A2) | 5.6–35.6 % renal 0.3 hours | It is unclear if antiplatelet therapy increases the incidence of ICH | Light Transmission Platelet Aggregation with or without Secretion | None The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | Dialyzable DDAVP 0.4 μg/kg | DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90] Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90] Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90] DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90] |
Clopidogrel | Irreversible inhibition of P2Y12 ADP receptor | 50 % renal 46 % fecal 6–8 hours | It is unclear if anti platelet therapy increases the incidence of ICH | Light Transmission Platelet Aggregation with or without Secretion | None The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | Not dialyzable DDAVP 0.4 μg/kg | DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90] Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90] Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90] DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90] |
Prasugrel | Irreversible inhibition of P2Y12 ADP receptor | 68 % renal 27 % fecal 2–15 hours | It is unclear if anti platelet therapy increases the incidence of ICH | Light Transmission Platelet Aggregation with or without Secretion | None The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | Not dialyzable DDAVP 0.4 μg/kg | DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90] Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90] Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90] DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90] |
Ticlopidine | Irreversible inhibition of P2Y12 ADP receptor | 60 % renal 23 % fecal 12 hours (increases with RF to 4–5 days after repeated doses) | It is unclear if anti platelet therapy increases the incidence of ICH | Light Transmission Platelet Aggregation with or without Secretion | None The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | Not dialyzable DDAVP 0.4 μg/kg | DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90] Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90] Platelet transfusion for patients who will undergo a neurosurgical. procedure (Conditional recommendation, moderate quality of evidence) [90] DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90] |
Dipyridamole | Reversible adenosine reuptake inhibitor | Fecal 10 hours | It is unclear if anti platelet therapy increases the incidence of ICH | Light Transmission Platelet Aggregation with or without Secretion | None The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | Not dialyzable DDAVP 0.4 μg/kg | DDAVP 0.4 mcg/kg IV (Conditional recommendation, low-quality evidence) [90] Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90] Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90] DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90] |
Ticagrelor | Reversible inhibition of P2Y12 ADP receptor | 26 % renal 58 % fecal 7 hours (metabolite = 9 hours) | It is unclear if anti platelet therapy increases the incidence of ICH | Light Transmission Platelet Aggregation with or without Secretion | None The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | Not dialyzable DDAVP 0.4 μg/kg | DDAVP 0.4 mcg/kg IV (Conditional recommendation, low-quality evidence) [90] Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90] Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90] DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90] |
Cilostazol | Reversible phosphodiesterase III inhibitor, increases cAMP, inhibits ADP-induced platelet aggregation, and causes vasodilation | 74 % renal 20 % fecal 10 hours | It is unclear if anti platelet therapy increases the incidence of ICH | Light Transmission Platelet Aggregation with or without Secretion | None The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | Not dialyzable DDAVP 0.4 μg/kg The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain | DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90] Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90] Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90] DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90] |
Study | Design | Intervention | Results |
---|---|---|---|
Blood pressure management | |||
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) |
Hemostasis | |||
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 |
Surgical treatment | |||
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 |