Reversal of Antithrombotic Agents in ICH

Antithrombotic Reversal agent
VKA INR ≥ 1.4: Vitamin K 10 mg IV + KCentra OR FFP 10-15 ml/Kg IV if not available
FXa inhibitors 50 g activated charcoal if within 2 + KCentra 50 units/kg IV
DTI Dabigatran reversal:

50 g activated charcoal within 2 h + idarucizumab 5 g IV

HD or repeat idarucizumab for refractory bleeding

Other DTIs: KCentra 50 units/kg IV

UFH Protamine 1 mg IV q 100 U heparin for the past 2–3 h

(up to 50 mg in a single dose)

LMWH Enoxaparin:

Within 8h: Protamine 1 mg IV per 1 mg enoxaparin (up to 50 mg in single dose)

Within 8–12 h: Protamine 0.5 mg IV per 1 mg enoxaparin (up to 50 mg in single dose)

>12 h: minimial utility

Dalteparin, Nadroparin and Tinzaparin:

Within 3–5 half-lives: Protamine 1 mg IV per 100 anti-Xa units (up to 50 mg in single dose)

OR rFVIIa 90 mcg/kg IV if protamine contraindicated

Danaparoid rFVIIa 90 mcg/kg IV
Pentasaccharides Activated PCC (FEIBA) 20 units/kg IV or rFVIIa 90 mcg/kg IV
tPA Cryoprecipitate 10 units IV OR

Antifibrinolytics (TXA 10–15 mg/kg IV over 20 min or aminocaproic acid 4–5 g IV) if cryoprecipitate contraindicated

Antiplatelet agents DDAVP 0.4 mcg/kg IV × 1

If neurosurgical intervention: Platelet transfusion (one apheresis unit)

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Warfarin Reversal:

Reference:

Frontera, Jennifer A. et al. “Guideline For Reversal Of Antithrombotics In Intracranial Hemorrhage”. Neurocritical Care 24.1 (2015): 6-46.

ENLS 2017 Pharmacotherapy.  Neurocritical Care Journal.

Burns, J., Fisher, J. and Cervantes-Arslanian, A. (2018). Recent Advances in the Acute Management of Intracerebral Hemorrhage. Neurosurgery Clinics of North America, 29(2), pp.263-272.

FXa and “Universal” Reversal Agent Drug Targets

TWO REVERSAL AGENTS IN DEVELOPMENT:
  • Andexanet alfa = recombinant modified FXa decoy molecule
    • see previous blog
  • Ciraparantag = reverse many anticoagulants including the FXa inhibitors
    • developed by Perosphere
    • formerly known as “aripazine” or “PER977”
    • di-arginine piperazine
    • small (512 Da) synthetic molecule
    • binds to UFH, LMWH, fondaparinux, DOACs
    • inactivates anticoagulants via noncovalent hydrogen binding, blocks binding to target sites of FIIa and FXa
FXa and “Universal” Reversal Agent Drug Targets:
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Reference:

Milling, Truman J. and Scott Kaatz. “Preclinical And Clinical Data For Factor Xa And “Universal” Reversal Agents”. The American Journal of Emergency Medicine 34.11 (2016): 39-45.

PATCH Trial

Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH)

Research Question:  Will platelet transfusion compared to standard of care reduce death or dependence in patients who present with ICH who took antiplatelet drugs within 7 days?

NOTES:

  • multicenter, open-label, randomized trial
  • 60 hospitals in Netherlands, UK and france
  • Inclusion: supratentorial ICH, antiplatelets for 7 days, GCS at least 8
  • standard of care vs standard of care + platelet transfusion within 90 minutes of CT scan
  • primary outcome: shift towards death or dependence on mRS at 3 months

Results:

  • 190 participants (97 treatment, 93% standard of care)
  • death or dependence at 3 months:  adjusted OR 2.05 95% CI 1.18-3.56; p=0.0114
  • serious adverse event:  42% vs 29%
  • deaths during hospital stay:  29% vs 24%

 

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Subgroup analysis:

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Reference:

Baharoglu, M Irem et al. “Platelet Transfusion Versus Standard Care After Acute Stroke Due To Spontaneous Cerebral Haemorrhage Associated With Antiplatelet Therapy (PATCH): A Randomised, Open-Label, Phase 3 Trial”. The Lancet 387.10038 (2016): 2605-2613.

Blood Pressure Goals in Neurocritical Care

Subarachnoid Hemorrhage (Take home:  target SBP <140mm Hg)

Optimal blood pressure target unknown.  2012 American Stroke Association guidelines suggests that a systolic BP goal <160mm Hg is reasonable.  Avoid nitroprusside or NTG (increases cerebral blood volume / ICP). Use labetalol, nicardipine, enalapril.

Lowering BP decreases risk of rebleeding in unsecured aneurysm, but may increase risk of infarction.  CPP = MAP – ICP.  Increased ICP necessitates an elevated MAP to keep CPP.  CPP threshold may be 70mm Hg.

In the absence of ICP measurement, clinical findings (i.e. alertness) may guide therapy, Uptodate recommends keep SBP <140mm Hg in these instances.

Traumatic Brain Injury (Take home:  target CPP 50-70mm Hg)

Cerebral autoregulation is disrupted in about a third of patients with severe TBI, these patients are described as “pressure-passive.”  In these patients, rise in MAP leads to elevated ICP due to increased cerebral blood volume, while drops in MAP may be associated with hypoperfusion and ischemia.

Bedside measurement of cerebral blood flow is not easily obtained.  CPP = MAP – ICP, is a surrogate measure.  Low MAP, high ICP or low CPP are associated with secondary brain injury and worse outcomes.

Old strategy to induce hypertension to CPP >70mm Hg (using saline boluses or vasopressors) does not improve outcome, and increases risks of other complications s.a. ARDS.  2007 Guidelines from BTF recommend CPP target of 60 mm Hg, avoid <50 and >70 mm Hg.  In children, lower thresholds are recommended (40-65 mm Hg).  Target ICP first before MAP.

Post-neurosurgical Procedure

[coming soon]  Our practice is to keep SBP within 100-150mm Hg during the immediate post-operative period.

Cerebrovascular Accident (Take home:  tPA <185/110 then <180/105; no tPA treat if >220/120)

After stroke, CPP distal to obstructed vessel is low and distal vessels are dilated.  Blood flow depends on systemic blood pressure.  Elevated BP is necessary to maintain perfusion in ischemic penumbra.  BP rises spontaneously after stroke, this is transient and BP falls by as much as 20/10 within 10 days.

Analysis from International Stroke Trial showed a U-shaped relationship between SBP and outcomes.  SBP >200mm Hg is associated with risk of recurrent stroke while SBP <120mm Hg was associated with excess number of deaths from coronary heart disease.

Lowering BP within 24 hours of acute stroke has been associated with clinical deterioration.  Some may even benefit from pharmacologic increases in BP (studies show improvement in aphasia or perfusion imaging). [Induced HTN currently not recommended except in the setting of a clinical trial.]  Severe increase in BP can also cause hypertensive encephalopathy.

No good RCTs to guide BP management in hyperacute phase (<12hours) of stroke.

Ultra-acute treatment: ongoing RIGHT-2 Trial is assessing safety and efficacy of transdermal NTG [8]

For patients eligible for tPA:  Blood pressure goal  ≤185/110 mmHg is recommended prior to starting lytic therapy.  Maintain BP ≤180/105 mmHg x 24 hours after tPA.

*Ongoing ENCHANTED trial is assessing effects of early intensive BP lowering post-tPA.  Results expected in early 2019.[8]

For patients not treated with tPA:  most guidelines recommend no treatment for BP unless hypertension is extreme (SBP >220mm Hg or diastolic >120m Hg) or patient has active ischemic coronary disease, heart failure, aortic dissection, hypertensive encephalopathy, acute renal failure, or pre-eclampsia / eclampsia.  If so, lower BP by ~15% during first 24 hours.

Restart antihypertensive medications ~24 hours after stroke in patients with pre-existing HTN who are neurologically stable.  Patients with large artery stenosis may require a slower reduction in BP (over 7-10 days after stroke)

Guidelines suggest IV labetalol and nicardipine as first-line antihypertensives.

*UK National Clinical Guidelines for stroke advocate only restarting preexisting antihypertensive therapy when patients are medically stable and can swallow their medication safely. [8]

Blood Pressure s/p thrombectomy:  optimal BP range not well defined; keep SBP 150-180mm Hg prior to reperfusion (to maintain adequate collateral flow while occluded);  keep SBP <140mm Hg once recanalized.

Blood Pressure s/p thrombectomy and s/p tPA:  keep SBP <=180/105 x 24h

BEST TRIAL (2019) – BP after Endovacular Therapy for Ischemic Stroke [9]; study validates that a peak SBP of 158 mm Hg during 1st 24h post-EVT best dichotomies good versus bad outcomes in EVT-treated patients.

Malignant MCA Infarction:  IV antihypertensive therapy recommended if SBP >220mm Hg or DBP >120mm Hg in trials demonstrating benefit with DHC (DECIMAL / HAMLET) [8]

 

Intracerebral Hemorrhage

Elevations in BP may cause hemorrhage to expand, but increased MAP may be necessary to maintain cerebral perfusion.  INTERACT2 trial compared intensive BP lowering (<140mm Hg within 1 hour) vs traditional management (<180mm Hg) in patients with acute ICH (within 6 hours).  Intensive BP lowering improved modified Rankin scores, with similar adverse events.  INTERACT study suggested that more aggressive BP lowering is associated iwth reduced hematoma growth.  ATACH II is in progress.

  • SBP >200 or MAP >150aggressively reduce BP   [aggressive lowering is safe based on INTERACT2]
  • SBP >180 or MAP >130 + high ICP – insert ICP bolt, keep CPP 61-80 mm Hg
  • SBP >180 or MAP >130 + no ICP issues – reduce BP modestly (MAP 110 or BP 160/90)

Useful IV antihypertensives include: labetalol, nicardipine, esmolol, enalapril, hydralazine, nitroprusside, and nitroglycerin.

The results of INTERACT2 trial was published in NEJM (June, 2013).  In this trial, early intensive lowering of BP compared with a more conservative BP control did not result in reduced rates of death or major disability.  However, there were significantly better functional outcomes among patients assigned to intensive treatment, as well as better physical and psychological well-being. [5]

(ENLS 2017) AHA/ASA Guidelines and European Stroke Organization recommend target BP of <140mm Hg

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INTERACT studies equivocal, but recent ATACH2 shows more definitely negative results. Aggressive control of BP does not result in improved functional outcome or decreased hematoma expansion. Consider SBP control to 140-160mm Hg instead of 120-140mm Hg. [7]

Spinal Surgery

[coming soon]  Some neurosurgeons routinely keep MAP goals >85 mm Hg in spinal surgeries where perfusion of the spinal cord is critical.  Evidence for this practice is lacking, whereas the harms from induced hypertension and prolonged ICU stay is real.

References

[1] Uptodate.  “Treatment of Aneurysmal Subarachnoid Hemorrhage.”  Accessed 07/07/2016.

[2] Uptodate.  “Initial assessment and management of acute stroke.”  Accessed 07/07/2016.

[3] Uptodate.  “Management of acute severe traumatic brain injury.”  Accessed 07/07/2016.

[4] Uptodate.  “Spontaneous intracerebral hemorrhage: Treatment and prognosis.”  Accessed 07/07/2016.

[5] Anderson, Craig S. et al. “Rapid Blood-Pressure Lowering In Patients With Acute Intracerebral Hemorrhage”. New England Journal of Medicine 368.25 (2013): 2355-2365.

[6] ENLS 2017 (ICH)

[7] Burns, J., Fisher, J. and Cervantes-Arslanian, A. (2018). Recent Advances in the Acute Management of Intracerebral Hemorrhage. Neurosurgery Clinics of North America, 29(2), pp.263-272.

[8] Appiah, K., Minhas, J. and Robinson, T. (2017). Managing high blood pressure during acute ischemic stroke and intracerebral hemorrhage. Current Opinion in Neurology, p.1.

[9] Mistry EA et al, Stroke. 2019 Oct 7:STROKEAHA119026889. doi: 10.1161/STROKEAHA.119.026889. [Epub ahead of print] Blood Pressure after Endovascular Therapy for Ischemic Stroke (BEST): A Multicenter Prospective Cohort Study.

Density and Shape of ICH

Can hematoma shape or heterogeneity of hematoma density predict ICH growth?

A 2009 study published in stroke presented a new scale for categorizing ICH based on the shape and homogeneity of the intracerebral hematoma.  The study applied this novel 5-point categorical scale to randomly baseline CT images of ICH. Density and shape were defined as either homogeneous/regular (Category 1 to 2) or heterogeneous/irregular (Category 3 to 5).  The density and shape was then correlated to the risk of hematoma expansion.

Rationale:

A hematoma arising from a solitary focus will have a more regular shape, and a more homogeneous density of blood. Hemorrhage arising from multiple foci will have an irregular shape.  Heterogeneous CT density may reflect either 1.) active hemorrhage, 2.) more variable hemorrhagic time course, 3.) multifocality or multiple bleeding vessels.  Density of blood on CT in ICH is related to 1. age of blood, 2. time course, 3. number of foci of hemorrhage and 4. hematocrit.

In relation to time course:  liquid blood from active hemorrhage hypoattenuates on CT scans relative to surrounding brain or associated organized hyperattenuating thrombus.  As clot retracts, hypoattenuating serum is released.  As thrombi progressively liquefy into breakdown products, sites of hemorrhage become less dense on CT. Hypoattenuating edematous changes in perihematoma region evolve (in part) due to RBC hemolysate products such as thrombin and iron with associated BBB disruption.

 

Categorical Scales for shape (left) and density (right) of ICHF1.large

 

The 2 scales ranged from Category 1 (most regular shape and most homogeneous density) to Category 5 (most irregular shape and most heterogeneous density). Each progressive category added an extra lesion edge irregularity on the shape scale or degree of density variation on the density scale.

In cases of “satellite” bleeds, progressive irregularity and heterogeneity features could be joined or separate from the principal hemorrhage. Hematomas with more numerous lesion edge irregularities or more heterogeneous density than represented on the scale were assigned the maximum rating.

The study concluded that larger ICHs were significantly more irregular in shape, heterogenous in density and had greater growth.  Density heterogeneity independently predicted ICH growth.  Irregular shape was not identified as an independent ICH growth predictor.

 

References

Barras, C. D. et al. “Density And Shape As CT Predictors Of Intracerebral Hemorrhage Growth”. Stroke40.4 (2009): 1325-1331. Web.

 

SMASH U Classification of ICH

A simple and practical clinical classification for the etiology of intracerebral hemorrhage from Helsinki University Central Hospital.

SMASH U stands for:

  • (S) structural vascular lesions – including cavernomas and AVMs – 5%
  • (M) medication – 14%
  • (A) amyloid angiopathy – 20%
  • (S) systemic disease (liver cirrhosis, thrombocytopenia, others) – 5%
  • (H) hypertension – 35%
  • (U) undetermined – 21%

*patients with structural lesions have smallest hemorrhages and best prognosis; anticoagulation-related ICH were largest and most often fatal.

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REFERENCE:  

Stroke. 2012 Oct;43(10):2592-7. Epub 2012 Aug 2.  SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage.  Meretoja A., et al.

Spot Sign Score in ICH

What is a “spot sign”?

  • presence of contrast extravasation into an intracerebral hematoma at the time of CTA
  • SIGNIFICANCE:  indicates active hemorrhage
  • IMPLICATION:  associated with increased risk of hematoma expansion and mortality

Note:  increase of hematoma volume >33% or >12.5 mL is considered a hematoma expansion [but varies among studies].

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Early vs Delayed Spot Sign:

  1. Early spot sign
    1. detected by first-pass CTA
    2. acquired within 30 seconds after contrast injection [arterial phase]
  2. Delayed spot sign
    1. detected by second-pass CTA or post-contrast CT or CTP
    2. performed between 40 seconds to 3 minutes after contrast injection and assess spot sign during venous phase
    3. may help detect spot sign with increased time interval during which contrast is circulating and permating into the hematoma

CRITERIA FOR SPOT SIGN

Spot sign can be defined according to this criteria:

  1. serpiginous or spot-like appearance within the margin of a parenchymal hematoma without connection to an outside vessel
  2. contrast density >1.5 mm in diameter
  3. contrast density (Hounsfield units, HU) >2x background hematoma
  4. no hyperdensity at the corresponding location on non-contrast CT

 

Another criteria is listed in the Table below:

Spot Sign Criteria

 

The Spot Sign Score can be calculated as follows:

Spot Sign Score

 

INTERPRETATION:

A.  mRS by 3-month follow up by spot sign score:

mRS

B. In-hospital mortality and overall outcome by spot sign score

mortality

PREDICT STUDY [Predicting Hematoma Growth and Outcome in ICH Using Contrast Bolus CT] for spot-positive patients, sensitivity for expansion was only 51%.  Are there other radiologic clues to risk of hematoma expansion in ICH?  (1) margin irregularity, (2) density heterogeneity, (3) fluid levels

  • Fluid-blood levels (or blood sedimentation level) observed in anticoagulant-associated ICH
  • shape and density variation of the hematoma [irregular margins / heterogeneous density associated with expansion]
Recent study showed that overall, overall, spot sign was the most reliable and predictive measure for expansion, although noncontrast markers performed reasonably well. Therefore, in scenarios where spot sign cannot be evaluated, other radiologic criteria may be able to predict expansion, but with less sensitivity.

LIMITING HEMATOMA EXPANSION:

  • Mechanism of hematoma expansion is unclear:
    • dysregulation of hemostasis via inflammatory cascade activation and matrix metalloproteinase overexpreesion
    • breakdown of BBB
    • sudden increase in ICP leading to local tissue distortion and disruption
    • vasculr engorgement due to reduced venous outflow

Can hematoma expansion be restricted?

  • few clinical trials on restricting hematoma expansion
  • Options:
    • hemostatic therapy
    • cautious lowering of high BP
      • INTERACT [Intensive BP Reduction in Acute ICH Trial] and ATACH [Antihypertensive Treatment of Acute ICH] trials:  SBP reduction might restrict hematoma expansion in hyperactue phase
    • quick reversal of prior anticoagulation
      • use of rFVIIa limits hematoma expansion in non-coagulopathic ICH but there was an increase in thromboembolic risk with no clear clinical benefit in unselected patients
    • surgical evacuation
      • many clinical trials have failed to show an outcome benefit of surgery over conservative treatment
      • STICH:  no overall benefit of early surgical clot evacuation, although subgroup analysis show potential benefit in lobar ICH within 1 cm of cortical surface
      • AHA/ASA indications for surgical intervention:
        • for most patients with ICH, the usefulness of surgery is uncertain
        • cerebellar hemorrhage who are deteriorating neurologically or who have brainstem compression and/ or hydrocephalus from ventricular obstruction should undergo surgical removal of the hemorrhage as soon as possible
        • lobar clots >30 mL and within 1 cm of the surface, evacuation of supratentorial ICH by standard craniotomy might be considered
        • effectiveness of minimally invasive clot evacuation utilizing either stereotactic or endoscopic aspiration with or without thrombolytic usage is uncertain and is considered investigational

 

 

 

References

Blacquiere, Dylan et al. “Intracerebral Hematoma Morphologic Appearance On Noncontrast Computed Tomography Predicts Significant Hematoma Expansion”. Stroke 46.11 (2015): 3111-3116. Web.

Delgado Almandoz, J. E. et al. “The Spot Sign Score In Primary Intracerebral Hemorrhage Identifies Patients At Highest Risk Of In-Hospital Mortality And Poor Outcome Among Survivors”. Stroke41.1 (2009): 54-60. Web.

Du, Fei-Zhou et al. “The Accuracy Of Spot Sign In Predicting Hematoma Expansion After Intracerebral Hemorrhage: A Systematic Review And Meta-Analysis”. PLoS ONE 9.12 (2014): e115777. Web.

Han, Ju-Hee et al. “The Spot Sign Predicts Hematoma Expansion, Outcome, And Mortality In Patients With Primary Intracerebral Hemorrhage”. J Korean Neurosurg Soc 56.4 (2014): 303. Web.