Heparin Drip for DCI prevention in Aneurysmal SAH?

Interesting article from Journal of Neurointerventional Surgery looking at use of heparin after endovascular treatment of cerebral aneurysms.  The study was retrospective, included ~400 patients (~200 given heparin post-coiling and ~200 matched controls), and collected data on incidence of vasospasm, DCI, and functional outcome.

Results of the study is shown in the graph below:


Rate of severe vasospasm was shown to be significantly reduced in the heparin group (14.2 vs 25.4% p=0.005).  The study concluded that patients who received continuous heparin after endovascular coiling of cerebral aneurysms have a reduced rate of severe vasospasm.


Mechanism of Action

How does heparin prevent DCI? (theoretically)  The article explains that heparin prevents secondary injury in SAH through its anti-inflammatory effects.  Heparin is the highest negatively charged biological molecule existing.  Due to the negative charges, it can bind to positively charged proteins and surfaces, including growth factors, cytokines and chemokines – thereby reducing inflammation.  It can also bind oxyhemoglobin and block free radical activity.  It can also antagonize endothelin, reducing endothelin-related vasoconstriction.



The study has several limitations – including the retrospective and single-center nature of the study design, and the potential for selection bias – even with case matching.  This study adds more evidence (albeit weak) to the argument that heparin infusions may help prevent secondary brain injury in patients with aneurysmal SAH who undergo endovascular coiling.


Heparin would be a potential “4th H,” adding to the 3 H’s historically used in the vasospasm prevention – i.e. hypervolemia, hemodilution, hypertension.  As with the previous H’s, randomized controlled studies will need to be performed to prove this theory.  The first 3 Hs have largely been debunked, and instead, the current standard of care is to keep patients with subarachnoid hemorrhage euvolemic, and induce hypertension only in the setting of vasospasm and/or delayed cerebral ischemia.  Therefore, as with the first 3 Hs, until more evidence surfaces, the use of continuous heparin cannot be recommended in this setting.




Bruder, Markus et al. “Effect Of Heparin On Secondary Brain Injury In Patients With Subarachnoid Hemorrhage: An Additional ‘H’ Therapy In Vasospasm Treatment”. Journal of NeuroInterventional Surgery (2017): neurintsurg-2016-012925.




Acute hypertension after ICH is associated with larger hematoma volumes and worse outcomes. Three recent RCTs investigated if control of acute hypertension (aggressive versus moderate) would lead to decreased hematoma expansion, lower mortality and improved functional outcomes.

INTERACT Phase 2 – neutral results

INTERACT Phase 3 – equivocal; no difference in mRS but possible shift in favor of intensive group.

ATACH 2 – more definitively negative results; no benefit of Brensilver antihypertensive treatment, higher rate of renal adverse events within 7d of randomization

TAKE HOME: SBP control to 120-140mm Hg does not lead to improved outcomes compared with 140-160mm Hg, may be associated with increased risk of acute renal dysfunction.


Comparison of the 3 major RCTs on BP reduction in ICH:




Majidi, Shahram, Jose I. Suarez, and Adnan I. Qureshi. “Management Of Acute Hypertensive Response In Intracerebral Hemorrhage Patients After ATACH-2 Trial”. Neurocritical Care (2016).

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.


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?


  • 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


  • 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%





Subgroup analysis:




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.


NEJM has been parceling out the results of the ANNEXA studies like the Harry Potter movie series.  I can’t wait for the final verdict on Xa-inhibitor reversals and the subgroup analysis on intracranial bleeds.  But for now, here is the study methodology:


  • bolus over 15-30 minutes + 2-hour infusion
  • For Apixaban or Rivaroxaban >7h before
    • 400mg bolus, 480mg infusion
  • For Enoxaparin, Edoxaban, Rivaroxaban <7h before or unknown time
    • 800mg bolus, 960mg infusion


Anti–Factor Xa Activity and Percent Change from Baseline in Patients Receiving Rivaroxaban and Apixaban (Efficacy Population).




Subgroup Analysis:




Connolly, Stuart J. et al. “Andexanet Alfa For Acute Major Bleeding Associated With Factor Xa Inhibitors”. New England Journal of Medicine (2016).

The AKIKI Trial

Aside from the fact that this trial has a really cool acronym, I thought this trial deserved a blog because the results are practice-changing (or practice-confirming if you’re already practicing the delayed strategy.)  Published ahead of print in NEJM.

Artificial Kidney Initiation in Kidney Injury trial (AKIKI)

Compared two groups:

  • early initiation of renal-replacement therapy (early-strategy group)
  • delayed initiation of renal-replacement therapy (delayed-strategy group)

Primary outcome:

  • overall survival


Secondary outcomes:

  • receipt of renal-replacement therapy at least once with the delayed strategy
  • renal-replacement therapy–free days
  • dialysis catheter–free days
  • mechanical ventilation–free days
  • vasopressor therapy–free days
  • Sepsis-related Organ Failure Assessment (SOFA) score at day 3 and day 7
  • vital status at day 28
  • length of stay in the intensive care unit and in the hospital
  • proportion of patients with treatment limitations (i.e., withholding or withdrawal of treatment)
  • nosocomial infections
  • complications potentially related to acute kidney injury or renal-replacement therapy


Results of the study:

  • 5528 patients eligible
  • 620 patients underwent randomization
    • 312 were assigned to the early-strategy group
    • 308 were assigned to the delayed-strategy group
  • early-strategy group underwent first renal-replacement therapy session within a median of 2 hours after randomization and within a median of 4.3 hours after documentation of stage 3 acute kidney injury and of the fulfillment of other inclusion criteria
  • 157 patients (51%) received renal-replacement therapy in the delayed-strategy group within a median of 57 hours after randomization, median interval between the occurrence of at least one criterion mandating renal-replacement therapy and its initiation was 4.7 hours
    • 49% in delayed-strategy group did not receive RRT
  • rate of catheter-related bloodstream infections was higher in early-strategy group
  • diuresis occurred earlier in the delayed strategy group
  • No difference in mortality, delayed strategy averted the need for RRT in an appreciable number of patients.



Take-home points:

  • do not interpret study as “wait and see” approach is safe for all patients
  • careful surveillance is mandatory when deciding to delay RRT in patients with severe AKI



Gaudry, Stéphane et al. “Initiation Strategies For Renal-Replacement Therapy In The Intensive Care Unit”. New England Journal of Medicine (2016): n. pag. Web. 19 May 2016.