Article Text

PDF
Review
Medical management of intracerebral haemorrhage
  1. Floris H B M Schreuder1,
  2. Shoichiro Sato2,3,
  3. Catharina J M Klijn1,4,
  4. Craig S Anderson3,5,6,7
  1. 1Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
  2. 2Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
  3. 3Neurological and Mental Health Division, The George Institute for Global Health Australia, Sydney, New South Wales, Australia
  4. 4Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands
  5. 5The George Institute for Global Health China, Peking University Health Science Center, Beijing, China
  6. 6Central Clinical School, University of Sydney, Sydney, Australia
  7. 7Neurology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
  1. Correspondence to Professor Craig Anderson, The George Institute for Global Health, Peking University Health Science Center, Beijing, 100088, PR China; canderson{at}georgeinstitute.org.cn

Abstract

The global burden of intracerebral haemorrhage (ICH) is enormous. Developing evidence-based management strategies for ICH has been hampered by its diverse aetiology, high case fatality and variable cooperative organisation of medical and surgical care. Progress is being made through the conduct of collaborative multicentre studies with the large sample sizes necessary to evaluate therapies with realistically modest treatment effects. This narrative review describes the major consequences of ICH and provides evidence-based recommendations to support decision-making in medical management.

Statistics from Altmetric.com

Introduction

Acute non-traumatic intracerebral haemorrhage (ICH) is not only complex and aetiologically diverse, but also the most serious, least treatable and more variable in incidence and management compared to other stroke subtypes.1 ,2 Although accounting for about one-fifth of the 16.8 million new strokes that occur in the world each year,2 it is more common in developing countries, particularly in Asia,1 ,3 where populations have high prevalence of elevated blood pressure (BP) and less-well-defined predisposing genetic and environmental (eg, high-salt diet) risk factors.4 ,5 Most importantly, its consequence in terms of ‘loss-of-productive-life-years’ is disproportionately greater on a global scale than acute ischaemic stroke, because ICH is serious and tends to affect people at earlier (working) ages.2

Despite improved management of hypertension, there has been no apparent decline in the incidence of ICH, possibly because adherence to antihypertensive therapy remains poor, continued population ageing and increasing use of antithrombotic drugs for various cardiovascular conditions. ICH has a 1 month case death rate of around 40%, and half of the deaths occur in the first few days after onset; an outlook that has similarly remained unchanged in recent decades.1

These gloomy statistics continue to create clinical nihilism in the management of patients with ICH. However, new evidence has emerged supporting the benefits of an active care approach and specific therapies with potential to improve the outcome. The role of decompressive surgery varies around the world depending the availability and organisation of services, and acceptance of the evidence, which has not clearly defined patients with characteristics who have the most to gain from such intervention. The medical management of ICH is, therefore, primarily supportive, directed at providing a systematic clinical assessment that includes ensuring there is no underlying treatable structural lesion; good control of BP and other physiological parameters; management of complications; early rehabilitation to promote recovery; and effective secondary prevention. This narrative review describes the major consequences of ICH and provides expert recommendations that are based on the available evidence to support decision-making in medical management (table 1).

Table 1

Key recommendations for ICH management

Organisation of care

As for acute ischaemic stroke, ICH is a medical emergency that requires rapid assessment after confirmation of the diagnosis on brain imaging, as patients are often unstable and can rapidly deteriorate. Loss of consciousness is a prominent feature of ICH, which complicates the use of scales that assess neurological impairment, such as the National Institutes of Health Stroke Scale. The use of the Glasgow Coma Scale, together with key imaging prognostic features (the site, volume and presence of intraventricular haemorrhage (IVH) extension) of the haematoma in relation to time of presentation,6 is useful in triaging patients. Numerous scales exist for grading the severity of ICH, the ICH Score7 being the most widely known and validated; they all have comparable ‘fair to good’ predictive ability and clinical utility.8

As it is often difficult to reliably predict the outcome of patients at the time they present with ICH, and evidence indicates that the premature use of ‘do-not-resuscitate’ or ‘withdrawal of care’ orders independently predicts mortality,9 ,10 initiation of an active management plan is recommended unless there are particular clinical (eg, massive ICH with deep coma), comorbid (eg, advanced dementia or malignancy) or social (eg, advanced directives) circumstances. This also allows time for a patient's condition to stabilise, potential complicating factors (eg, seizures and dehydration) to resolve and for counselling family members in the context of their cultural, religious and personal beliefs. Active care includes monitoring and timely intervention for neurological deterioration and adverse events, and this is ideally organised in an intensive care or high dependency unit, which provide high nurse:patient ratio of care and expertise. Well organised acute stroke unit care benefits ICH patients (number needed to treat (NNT) 18)11 by directing effective management according to the type and severity of neurological impairment.

Non-contrast brain CT is the most appropriate initial investigation to confirm the presence of ICH, but it is less useful in establishing any underlying structural cause. A secondary cause of an ICH should be suspected if it has an atypical deep or lobar location with a disproportionate amount of subarachnoid haemorrhage or perihaematomal oedema, and in younger patients without a history of hypertension or illicit drug use as predisposing factors. Recent attention has focused on particular features of morphology of the haematoma (eg, swirl, irregularity and fluid level) and the ‘spot-sign’ (ie, extravasation of contrast on CT producing a spot or blush within or at the edge of the haematoma) that signify ongoing bleeding, greater haematoma growth and poor outcome.12 While the former features are simple to apply in routine practice, the utility of the spot-sign appears limited outside of well-resourced specialist centres.

CT or MRI angiography is the next step towards a diagnosis of any underlying vascular anomaly,13 such as intracranial aneurysm, arteriovenous malformation (AVM), dural arteriovenous fistula, cavernoma and cerebral venous sinus thrombosis. This can be organised at the time of presentation or in the early follow-up period, depending of clinical features, available resources and organisation of services. However, a small vascular anomaly may be missed in patients with large haematomas (figure 1).

Figure 1

Example of an intracerebral haemorrhage.

A previously well, 48-year-old woman presented with sudden left hemiparesis during fitness exercise. CT showed right frontal lobar haemorrhage, volume 12 mL (image A). Early CT angiography and MRI with venous contrast excluded any vascular anomalies and cortical vein or cerebral venous sinus thrombosis. Digital subtraction angiography 1 month later showed a small AVM in the right precentral gyrus, with an identified small irregular vessel fed by a distal branch of the right middle cerebral artery (arrow, image B) without a clear nidus. During the capillary phase, premature venous drainage to the superior sagittal sinus and Sylvian vein (arrowheads, image C) was observed. Subsequent surgical resection of the AVM was undertaken.

Thus, where there is a high suspicion of an underlying vascular anomaly with negative imaging findings in the acute phase, patients should be re-examined 1–3 months after ICH, when the haematoma has been resorbed. The relevance of cerebral microbleeds detected on MRI in guiding treatment options is currently unknown. Conventional cerebral angiography is usually required in cases where there is a high likelihood of a vascular anomaly and interventional treatment is being considered.13

Although early mobilisation is likely beneficial for patients, care should be taken in the early mobilisation of patients where potential resultant adverse impact on BP variability and orthostatic hypotension may have harmful effects.14

Recommendations: After confirmation of ICH by a non-contrast brain CT, patients should be admitted to a designated stroke unit with an active treatment plan. Diagnosis of ICH should trigger additional cerebrovascular imaging to exclude underlying vascular anomalies.

Control of BP and other physiological variables

Hypertension

Elevated BP or hypertension, defined by systolic BP ≥140 mm Hg, is very common after ICH and independently predicts haematoma growth, perihaematomal oedema and subsequent neurological worsening and poor outcome, including death and disability.15 The association between elevated BP at ICH presentation and haematoma expansion is strongest for systolic BP >175 mm Hg.16 There has been long-standing concern that early lowering of BP after ICH can cause cerebral ischaemia by reducing cerebral perfusion pressure, particularly if there is altered cerebral autoregulation from long-standing hypertension or from brain injury. However, advanced imaging has not been able to show any significant relationship between BP lowering and perihaematomal cerebral blood flow in patients with acute ICH.17 The main phase, Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2)18 evaluated the effect of target-driven, early intensive BP lowering treatment (systolic BP <140 mm Hg within 1 hour and continued for 7 days) compared to contemporaneous standard management (systolic BP of <180 mm Hg) in 2839 ICH patients who presented within 6 hours of onset with elevated systolic BP (150–220 mm Hg). The frequency of the primary outcome, death or disability (modified Rankin scale (mRS) score of 3–6) was 52% in the intensive and 56% standard BP lowering groups (OR 0.87, 95% CI 0.75 to 1.01; p=0.06; NNT 28). Moreover, analyses on the pre-specified key secondary outcome, an ordinal shift analysis of the full range of score on the mRS, showed that the intensive BP lowering group had significantly better functional recovery at 90 days (OR for greater disability 0.87, 95% CI 0.77 to 1.00; p=0.04). Although a nested imaging substudy demonstrated only a modest and non-significant trend towards a reduction in haematoma growth over 24 hours from intensive BP lowering, the effect on this most plausible mechanistic surrogate end point became significant in a meta-analysis of four randomised controlled trials that included INTERACT2.19

The more recent, second Antihypertensive Treatment for Acute Cerebral Hemorrhage (ATACH-II) study20 compared ‘very early’ (<4.5 hours of onset) and ‘very rapid and intensive’ (systolic BP <140 mm Hg with intravenous nicardipine for 24 hours) BP lowering with standard BP management (systolic BP of 140–180 mm Hg). Death or disability (mRS score 4–6; the primary outcome) at 90 days was 38.7% in the very intensive and 37.7% in the standard BP lowering groups (adjusted relative risk (RR) 1.04, 95% CI 0.85 to 1.27; p=0.72). While there was no overall significant difference in treatment related serious adverse events within 72 hours, significantly more renal adverse events emerged over the initial 7 days (9.0% vs 4.0%; p=0.002) and borderline more serious adverse events during 90 days in the very intensive group (adjusted RR 1.30, 95% CI 1.00 to 1.69; p=0.05). Interestingly, the percentage of patients with haematoma growth (defined as >33% increase in ICH volume over the initial 24 hours) was 18.9% in the very intensive group and 24.4% in the standard treatment group (adjusted RR 0.78, 95% CI 0.58 to 1.03; p=0.08).

The discrepancy in results between INTERACT2 and ATACH-II may temper enthusiasm for early BP lowering in ICH, but there are important differences between the two trials. To begin with, all patients enrolled in ATACH-II had elevated systolic BP of >180 mm Hg at presentation (mean 200 mm Hg) for which most received initial treatment, while only approximately half of INTERACT2 participants had this same level of systolic BP at the time of randomisation. Furthermore, INTERACT2 participants received a wide variety of intravenous and oral BP-lowering agents (eg, α-adrenergic antagonist (urapidil), calcium-channel blocker (nicardipine or nimodipine), combined α blocker and β blocker (labetalol), nitroglycerin, diuretics (furosemide), nitroprusside, hydralazine, and others) based on cost and local availability, according to pre-specified protocols; whereas most ATACH-II participants were administered intravenous nicardipine. Another difference is that the achieved mean minimum systolic BP of patients in the intensive treatment group in ATACH-II was <130 mm Hg (129 mm Hg at 0–2 hours and 122 mm Hg at 2–24-hours), due to the protocol-defined level of BP-lowering intensity and the BP level for cessation of intravenous BP being lower in ATACH-II (<110 mm Hg) than in INTERACT2 (<130 mm Hg). A subanalysis of INTERACT2 showed that achieved post randomisation mean systolic BP of 130–139 mm Hg during the initial 24 hours was associated with the best outcome for ICH patients; but a modest increase in poor outcome was suggested for levels <130 mm Hg.21 These differences would imply that very rapid and intensive BP lowering to treatment targets <130 mm Hg in patients with very high BP could refute any potential treatment benefit. With these differences in mind, and since ATACH-II and INTERACT2 included predominantly ICH of mild-moderate severity, individual patient data meta-analyses of these and other trials could provide further valuable information regarding BP control (eg, regimens, starting and stopping limits for BP treatment) and in subgroups (eg, large haematoma, pre- and postdecompressive surgery) of ICH patients.22

Hyperglycaemia

Early (enteral) feeding (ie, within 48 hours) should be considered in ICH patients as it is associated with reduced risk of pneumonia and improved survival.23 High blood glucose in the acute phase of ICH shows a continuous relation with early deterioration, poor functional outcome and higher mortality regardless of diabetic status.24 However, the UK Glucose Insulin in Stroke Trial (GIST-UK)25 showed no benefit for the use of standard glucose–potassium–insulin therapy during the initial 24 hours on mortality in 933 patients with stroke (including 12% with ICH) when it was stopped early due to slow enrolment. Although underpowered, a possible explanation for this finding is that hyperglycaemia is a hyperacute stress reaction, merely reflecting stroke severity. A meta-analysis of eight randomised controlled trials suggests similar magnitude of benefits of stroke unit care, including management of hyperglycaemia for ICH and acute ischaemic stroke,11 while the Quality in Acute Stroke Care (QASC) study, a cluster randomised trial, showed improved functional outcome from a multidisciplinary intervention involving early control of fever, hyperglycaemia and swallowing in patients with stroke (including 5% of ICH).26 Yet, there is uncertainty over the optimal glucose level and controlling methods specifically in patients with ICH. At this stage, intensive insulin treatment in patients with moderate to high levels of hyperglycaemia with attention to avoiding hypoglycaemia seem reasonable.27

Fever

Fever, often defined as a temperature of >38°C, is relatively common and an independent prognostic factor of poor outcome after acute ICH.28 Although often related to sepsis, fever can also relate to an inflammatory reaction around the haematoma, as well as associated IVH or subarachnoid extension of the ICH.29 Animal studies suggest that induced hypothermia mitigates perihaematomal oedema by reducing several mediators of secondary brain injury, such as thrombin and the proinflammatory cytokines;30 preliminary clinical studies further support this action on perihaematomal oedema,31 an independent prognostic factor in ICH.32 It seems reasonable, therefore, that early treatment of fever should be safe and provide benefits to patients, but the results of several ongoing phase II trials, such as the Targeted Temperature Management after Intracerebral Hemorrhage (TTM-ICH)33 and Paracetamol (Acetaminophen) In Stroke 2 (PAIS 2)34 are awaited (table 2).

Table 2

Ongoing clinical trials on medical management of ICH

Recommendations: Patients with ICH and a systolic BP >160 mm Hg should receive urgent BP lowering therapy. The approach should allow safe and easy titration of dose, but no advice can be made on a preferred antihypertensive agent. The optimal systolic BP target level appears to be 130–139 mm Hg in the first 24 hours and continued during the next several days. ICH patients with moderate to severe hyperglycaemia should be treated with insulin. Early enteral feeding and rapid treatment of fever should be considered.

Management of common complications

Seizures

The frequency of early seizures (within 7 days of ICH onset) varies considerably (1–14%) across studies, and is even higher if subclinical seizure activity is considered; these rates are greater than those for acute ischaemic stroke.35–40 Early seizures are thought to arise from acute disruption of brain integrity and biochemical disturbances (eg, release of excitatory neurotransmitters, direct toxic effects of blood degradation products), and cortical involvement appears to be a key risk factor.37 ,41 Prolonged or single severe seizures should be treated with benzodiazepines or a loading dose of an antiepileptic drug. In patients with otherwise unexplained altered mental status, a trial of antiepilepsy drug treatment should be considered; the use of continuous EEG monitoring to determine subclinical seizures is possible but is often complicated by the use of sedation, brain injury and recording interference.40 ,42 Early seizures do not appear to influence prognosis with respect to mortality or functional outcome, but may increase the risk of long-term recurrent seizures.37 ,43

Late seizures (beyond 7 days of ICH onset) occur in 1–10% of patients and are thought to result from gliotic scarring and neuronal reorganisation.36 The risk of late seizures can be estimated using the CAVE score,44 which provides one point for each of the four factors—cortical (C) involvement, young age ((A) <65 years), haematoma volume (V) >10 mL and early seizures (E)—with the risk of late seizures increasing from 0.6% for a score of 0% to 46.2% for a score of 4. Late seizures are associated with poor long-term functional outcome and have a high rate of recurrence.37 Antiepilepsy drugs are recommended in guidelines of the American Heart Association (AHA)/American Stroke Association (ASA)27 and European Stroke Organisation.45

Primary prevention of seizures after ICH by means of prophylactic use of antiepileptic drugs is a still a matter of debate and is not recommended by current guidelines.27 ,45 In a small placebo-controlled trial of sodium valproate in 72 patients for 1 month, the active group had a lower risk of early seizures and better functional outcomes at 12 months, despite similar rates of seizures between the groups.46 Sodium valproate should be used cautiously in patients with ICH as it can occasionally cause coagulopathy.47 ,48 The results of a large clinical trial investigating the effect of 7-day prophylaxis with sodium valproate on early and late seizures up to 12 months are expected shortly (http://www.chictr.org.cn; ChiCTR-PRC-11001294; table 2).49

Venous thromboembolism

Venous thromboembolism (VTE) occurs in up to one-fifth of patients with ICH, most often asymptomatic or as deep vein thrombosis (DVT),50–52 which can lead to life-threatening pulmonary embolism (PE) in 1–2%.53 Preventive measures for VTE can consist of low-dose anticoagulation with (unfractionated or low-molecular-weight) heparin, graduated compression stockings, and intermittent pneumatic compression. A meta-analysis of four small studies (all with methodological shortcomings) showed that heparin was associated with a significant reduction in PE (RR 0.37, 95% CI 0.17 to 0.80; NNT 86) and trend towards lower mortality (RR 0.76, 95% CI 0.57 to 1.03), and importantly without any significant increase in haematoma enlargement (RR 1.42, 95% CI 0.57 to 3.53).54 However, post hoc propensity-score matched analysis of the INTERACT2 study indicates that heparin-treated ICH patients were more likely to have death or major disability at follow-up (OR 2.06, 95% CI 1.53 to 2.77; number needed to harm (NNH) 6) compared to other patients.55 The 2015 AHA/ASA guideline recommends initiation of heparin after 1–4 days of ICH in those patients with persistent immobility and where there is radiological confirmation of stable haematoma size.27 Graduated compression stockings should be avoided as they are ineffective and lead to complications.50 ,51 A large clinical trial has demonstrated that intermittent pneumatic compression decreases the risk of VTE in ICH patients (OR 0.36, 95% CI 0.17 to 0.75; NNT 10).52

Inferior vena cava filter can be considered as an alternative to systemic full-dose therapeutic anticoagulation, taking into account the patient's individual risks of VTE (ie, risk factors for VTE, clinical condition), potential for haematoma enlargement (time from ICH onset, size and stability of haematoma, and lobar vs deep location), and the potential harms of interventions.27 ,56

Elevated intracranial pressure

Management of raised intracranial pressure (ICP) in ICH is based on the experience of managing patients with traumatic brain injury. If ICP approaches mean arterial pressure (MAP), cerebral perfusion becomes compromised, leading to secondary ischaemic injury.57 In particular, younger patients and those with large volume haematomas, extensive perihaematoma oedema, IVH and emerging concurrent hydrocephalus are at high risk of raised ICP.58 The AHA/ASA guideline suggests a stepwise approach, with considering less invasive methods first and, if unsuccessful, initiating of more invasive measures.27 Patients with (suspected) elevated ICP should have the head of the bed elevated to 30° and a neutral head position to ensure optimal jugular venous drainage. The use of analgesia or sedation to reduce ICP has not been clearly defined. Additionally, BP should theoretically be controlled to ensure cerebral perfusion pressure of 50–70 mm Hg, but in the absence of any clear alternative data, those provided by INTERACT2 (aim for a systolic target <140 mm Hg) seems reasonable. Clear treatment thresholds for ICP have not been identified, but one study showed that an ICP >30 mm Hg is associated with poor outcome.59 Osmolar therapy (eg, mannitol) is commonly applied to patients with raised ICP, particularly in Asia, but a Cochrane review60 and post hoc propensity-score matched analysis of the INTERACT2 study have shown no benefit of such treatment.61

Other therapeutic options for raised ICP are limited. Intravenous glycerol has shown no clear effect.62 A new phase III clinical trial of dexamethasone will start soon (Klijn, personal communication) as previous studies have showed no benefit due to being under powered and with other methodological shortcomings.63 Other approaches to decrease ICP (ie, hypertonic saline, neuromuscular blockage, forced hyperventilation, therapeutic hypothermia and barbiturate coma) have not been studied systematically. The effect of surgical treatment, including cerebrospinal fluid drainage through an external ventricular drain, hemicraniectomy and evacuation of the haematoma, are beyond the scope of this review.

Recommendations: Patients with ICH with prolonged or severe seizures should be treated. Prophylactic use of antiepileptic drugs should be avoided. Intermittent pneumatic compression or prophylactic dose heparin/heparinoid therapy should be used to prevent VTE in all immobile patients. Raised ICP should be treated with non-invasive methods before invasive monitoring and decompressive surgery is considered.

Corrective therapy for antithrombotic associated ICH

Haemostatic therapy

Early haemostatic therapy may benefit ICH patients, as 20–40% of haematomas expand from active bleeding, and that this predicts poor outcome.64 In one of the largest clinical trials showed that recombinant tissue factor VII (rFVIIa) could restrict haematoma growth but this failed to improve clinical outcome and increased risks of arterial thromboembolic events.65 Two ongoing phase-II trials (NCT00810888 and NCT01359202; table 2) are evaluating rFVIIa in highly selected patients with increased risk of haematoma enlargement on the basis of a CT angiography-identified spot-sign. Tranexamic acid, which showed positive results in patients with trauma, is also being investigated in a phase II study (NCT01702636; table 2) of spot-sign-positive patients, and in a large phase III trial (ISRCTN93732214; table 2) with a broad range of patients.66

Platelet transfusion

Antiplatelet therapy-associated ICH was shown in a review of 25 published and unpublished cohort studies to increase the risk of death but not of worse functional outcome.67 In patients who experience an ICH while on an antiplatelet agent, a platelet transfusion is often used to replace non-functional thrombocytes to reduce the risk of further haemorrhage and improve outcome if decompressive surgery is planned. However, the recent PlAtelet Transfusion in Cerebral Haemorrhage (PATCH) trial showed that platelet transfusion was associated with an increased risk of poor outcome after ICH (OR 2.05, 95% CI 1.18 to 3.56; NNH 7),68 and results of a second trial of platelet transfusion (NCT00699621; table 2) are expected shortly.

Reversal of anticoagulation

Vitamin K antagonists, mainly warfarin, have a 7–10-fold increased risk of ICH,69 and the resulting haematoma has a larger volume, a greater and more protracted expansion, and results in a higher case death (up to 50%) than for other types of ICH.70 ,71 Thus, rapid replenishment (avoiding delays for coagulation test results72) of the vitamin K-dependent coagulation factors (II, VII, IX and X) is considered essential to reverse the anticoagulant effects, but the benefit of this approach has never been demonstrated. The rapid reversal international normalised ratio (INR) to <1.3, achieved within 4 hours, was associated with a low rate of haematoma expansion in a large German retrospective cohort study.73 Other treatment options include the use of fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC). Advantages of PCC include the small infusion volume (lower risk of congestive heart failure) and rapid infusion speed enabling rapid reversal, whereas FFP requires thawing before infusion (as it is kept frozen), thus delaying INR normalisation. Moreover, 30 mg/kg 4-factor PCC has been shown superior over 20 mL/kg FFP in reversing anticoagulation within 3 hours after the start of treatment (OR 30.6, 95% CI 4.7 to 197.9) with higher odds of significant haematoma expansion in the FFP group (OR 3.8%, 95% CI 1.1 to 16.0).74 A large multinational pooled analysis of 16 stroke centres suggests that the combination of FFP and PCC might further improve the outcome compared to PCC alone.75 Besides repletion of coagulation factors, 5–10 mg of vitamin K should also be administered intravenously to restore the production of vitamin K-dependent coagulation factors.27 INR should be checked at regular intervals because of the long half-life of warfarin.

Reversal strategies for new oral anticoagulants

Direct acting, new oral anticoagulants (DOACs, apixaban, dabigatran, edoxaban and rivaroxaban) have been associated with lower rates of ICH in comparison to warfarin.76 The enthusiasm for DOACs was initially tempered by the fear that they would be associated with larger haematomas and worse outcome due to their lack of an antidote, but this has not been corroborated by recent reports.77–79 Emergency reversal of DOACs in case of bleeding complications is largely expert-based and includes the intravenous administration of 30–50 U/kg 4-factor PCC, 90 U/kg activated 4-factor PCC (FEIBA) and/or 90 µg/kg rFVIIa.80 Based on in vitro studies and animal experiments, it has been suggested that FEIBA or rFVIIa may be more potent to reverse dabigatran, whereas other PCCs may be better for the Factor-Xa inhibitors. If ICH occurs within 2–3 hours after the last dose, administration of activated charcoal (all DOACs) or haemodialysis (in case of dabigatran) may be considered. Administration of vitamin K is not useful.81 Recently, preliminary data of a phase-II trial testing a single dose of 5 mg idarucizumab intravenously as an antidote for dabigatran showed a complete, immediate and sustained reversal of the anticoagulation effect in the majority of patients, of whom 18 had ICH.82 Although efficacy on clinical outcome remains to be proved, the antidote has been approved by a number of drug regulatory authorities.83 Antidotes for Factor-Xa inhibitors (andexanet α and arapazine/ciraparantag (PER977)) are currently being tested in phase-II and phase III trials for the reversal of apixaban, edoxaban and rivaroxaban.84 ,85

Recommendations: Haemostatic agents or platelet transfusion should be avoided in anticoagulation-free ICH patients. Patients with vitamin K-associated ICH should receive urgent reversal therapy combining PCC and intravenous vitamin K. In case of DOAC use, consideration should be given for urgent reversal therapy with selective antidotes where available.

Secondary prevention in ICH survivors

Patients who survive ICH are at high risk for new vascular events. The annual risk of recurrent ICH lies between 1.3% and 7.4%, but it is higher in lobar compared to non-lobar ICH. The 5-year survival rate is 29% (95% CI 26% to 33%).86 Effective long-term BP lowering is the single most significant intervention for the secondary prevention of serious vascular events after ICH,87 yet the optimal magnitude of BP drop or regimens to achieve BP control are uncertain. Poor BP control increases the risk of recurrent ICH regardless of subtype (ie, lobar vs non-lobar).88 ,89 A single-centre study involving 1145 ICH patients with a median follow-up of 37 months showed that the risk of ICH recurrence gradually increases from mean systolic BP of 110–119 mm Hg and mean diastolic BP of 70–79 mm Hg, for lobar and non-lobar ICH. The risk of recurrence steeply increases with BP above 140/90 mm Hg.89 In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, of 660 participants with a history of ICH at baseline, a massive 49% (95% CI 20% to 67%) relative risk reduction was observed on recurrent stroke; and there was a near-continuous relationship between lower BP and lower risk.90 Similar effects of BP lowering for the prevention of ICH were also seen in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial,91 where there was 63% relative risk reduction on ICH but insignificant reductions in recurrent total and ischaemic strokes. These data suggest that much stricter BP control than is currently recommended in guidelines could provide larger benefits in terms of prevention of recurrent major cardiovascular events. However, it is recognised that intensive long-term BP control is often difficult to achieve in clinical practice and there are ongoing concerns that the potential harms (eg, falls, fatigue, renal failure) out way any benefits. Most patients with hypertension require two or more antihypertensive agents to achieve adequate BP control,92 but multiple tablets negatively impact on adherence and attendance to scheduled visits. Electronic reminders and simpler, more tolerable treatment regimens could achieve better BP control from improved adherence in this high-risk patient group. The ongoing Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT, NCT02699645; table 2), a double-blind, placebo-controlled trial, has been initiated to determine the effectiveness of more intensive chronic BP lowering using a fixed low-dose combination of BP lowering agents (telmisartan, amlodipine and indapamide—Triple Pill strategy) on top of standard of care, on recurrent stroke in 4200 patients with ICH.

Some other important questions for ICH survivors that remain unanswered are whether to resume oral anticoagulant or antiplatelet therapy (which will be studied in the APACHE-AF (NCT02565693) and RESTART trials (ISRCTN71907627); table 2), whether lipid lowering therapy is beneficial or harmful, and if the intensity of secondary prevention should differ between patients with lobar and non-lobar ICH.

Recommendation: Patients who survive an ICH should have strict BP-lowering therapy.

Summary

ICH is a major health burden, particularly in developing countries where there is much hypertension. Apart from early control of elevated BP and possibly hyperglycaemia, there are no proven medical therapeutic options. Management is based on well-organised active care with close neurological monitoring by trained staff, and early detection and management of complications. This is largely based on empirical guidelines in the absence of clinical end point, randomised controlled trials. Once patients are stable, early rehabilitation is likely to reduce the risk of further complications and promote recovery and return to usual activities. Good long-term control of BP is the single most important strategy to reduce the likelihood of recurrent ICH and other serious cardiovascular events.

References

View Abstract

Footnotes

  • Contributors CSA outlined the review process and contributed particular sections. FHBMS and SS wrote first drafts of particular sections. CJMK wrote particular sections. All authors made comments on the final manuscript and approved submission.

  • Funding CJMK is supported by a clinical established investigator grant of the Dutch Heart Foundation (grant number 2012 T077), and an Aspasia grant from The Netherlands Organisation for Health Research and Development, ZonMw (015008048). CSA holds a Senior Principle Research Fellowship of the National Health and Medical Research Council (NHMRC) of Australia.

  • Competing interests SS reports receiving speaker fees from Otsuka Pharmaceutical and Boehringer Ingelheim. CJMK reports receiving speaker fees from Boehringer Ingelheim and Penumbra, which were paid to the hospital research fund and not to a personal account; and has been site Principal Investigator for a Pfizer-sponsored clinical stroke trial. CSA reports receiving travel reimbursement and speaker fees from Boehringer Ingelheim and Takeda, and Advisory Board sitting fees from AstraZeneca and Medtronic.

  • Provenance and peer review Commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.