ISCHEMIC STROKE / ACUTE THERAPY

Contraindications to intravenous thrombolysis

Created 12/09/2022, last revision 14/09/2022

ESO 2021
AHA-ASA 2019
AHA-ASA
Many of the contraindications listed in the 2016 and 2019 guidelines became relative or obsolete (see comments to IVT)
  • mild nondisabling stroke
  • stroke > 4.5h from onset in unselected patients
    • except for BAO and IVT guided by advanced imaging (see indications for IVT)
  • patients with extensive regions of clear hypoattenuation on CT/DWI (severe stroke) (AHA/ASA 2019 III/A)
    • see comments, IVT can be administered in selected cases
  • severe head trauma < 3 months
  • use of IV alteplase in patients who have had a prior ischemic stroke within 3 mo  (AHA/ASA 2019 III/B-NR)
    • relative contraindication  → see comments
  • recent intracranial or spinal surgery (< 3 months)
  • history of ICH
    • relative contraindication, see comments
  • acute SAH/ICH
  • GI tract tumor with high risk of bleeding / recent GI bleeding (< 3 weeks) – IVT is potentially harmfull
  • coagulopathy
    • platelets count < 100 000/mm3
    • antiplatelet drugs are no contraindication to IVT   (AHA/ASA 2019 I/A  resp. I/B-NR)
  • known or suspected infectious endocarditis   (AHA/ASA 2019 III/C-LD)
  • aortal dissection   (AHA/ASA 2019 III/C-EO)
  • intra-axial brain tumor – IVT is potentially harmfull  (AHA/ASA 2019 III/C-EO)
  • BP > 185/110 mmHg despite intensive parenteral treatment
  • glycemia < 2.7 mmol/l (50 mg/dl) or  > 22 mmol/l (400 mg/dl)
    • relative contraindication, see comments

Other recommendations
(most relative contraindications are discussed in comments to IVT)

  • Wake-Up Stroke (WUS)  –  DWI lesion < 1/3 of MCA territory  + negative FLAIR (DWI/FLAIR mismatch according to  WAKE-UP trial)    (AHA/ASA 2019  IIa/B-R)
  • premorbid disability (including cognitive deficit) – IVT can be considered; consider the premorbid status and quality of life, risk-benefit assessment
  • dural puncture in< 7 days – IVT can be considered (AHA/ASA 2019 IIb/C-EO)
  • IC malformation – the usefulness and risk of IVT is unclear; given the increased risk of bleeding, it may be considered in patients with a severe deficit when the benefit of treatment outweighs its risks
  • acute MI – IVT is not contraindication    (AHA/ASA 2019 IIa/C-EO)
  • periprocedural stroke – IVT can be considered; prefer direct MT if eligible
  • malignancy – patients with survival > 6 months can benefit from IVT without other malignancy-related contraindications (e.g., coagulopathy, recent surgery, etc.)
  • drug-indued stroke – IVT can be administered in the absence of other significant contraindication  (AHA/ASA 2019 IIa/C-LD)
  • ophthalmologic diseases – in patients with a history of hemorrhagic retinopathy or other hemorrhagic ocular events, IVT can be administered, always weighing the benefit versus the risk of complications   (AHA/ASA 2019 IIa/B-NR)
  • sicle cell disease – IVT can be beneficial   (AHA/ASA 2019 IIa/B-NR)
Comments to some contraindications
  • more and more patients, especially in experienced centers, are successfully treated with IVT despite some of the originally published contraindications (off-label thrombolysis)
  • this practice was reflected in the recent guidelines and recommendations, where some contraindications became relative or were abandoned (high age)
    • most of the relative contraindications listed in the ESO guidelines 2021 refer to the 0-4.5h time window (with increasing experience, it can be expected to be officially extended to the 4.5-9h window)
  • typical contraindications that are not respected:
    • high age
    • previous stroke + diabetes
    • 4.5 hour window
    • mild or regressing deficit or, conversely, severe stroke
    • aggressive treatment with parenteral antihypertensives to achieve target BP before initiating IVT
    • use of oral anticoagulants
  • always carefully weigh the risk/benefit
  • low risk of sICH (→ see here for thrombolysis-related ICH classification)
    • according to SITS-ISTR, the risk of parenchymal hematoma was s1.2% in stroke mimics    [Keselman, 2019]
    • according to meta-analyses, the risk of sICH is approx. 0.5%   [Tsivgoulis, 2015]
  • always exclude isodense SDH ⇒ high risk of bleeding complications!!
  • CTA/MRA and CTP/MRP can help detect true stroke
  • seizures belong to common stroke mimics, but can be present in acute stroke patients as well (seizure at stroke onset)
  • evidence of occlusion on CTA or CTP or early signs of ischemia on NCCT may help to confirm the stroke
  • if there is no clear suspicion of mimics or head trauma, then IVT is more likely to be administered (ESO guidelines 2021)
    • particularly in more severe deficits, it is probably a bigger mistake to withhold IVT in a patient with stroke than to thrombolyse mimics. The risk of thrombolysis-related bleeding in seizure is very low (as it is in general for all mimics)   [Polymeris, 2019]
  • according to a meta-analysis of the WAKE-UP, EXTEND, THAWS, and ECASS-4 trials, IVT indicated by advanced imaging is safe and effective [Thomalla, 2020]
  • if the patient is a candidate for both IVT and MT, then IVT is more likely to be administered before MT  (ESO Gidelines 2021 expert consensus)
  • IVT can be administered to WUS patients who have (according to guidelines):
    • DWI/FLAIR mismatch –  DWI lesion < 1/3 of MCA territory + negative FLAIR – corresponds to the WAKE-UP trial  criteria (AHA/ASA 2019 IIa/B-R) (ESO 2021)
    • evidence of penumbra on multimodal CT (criteria used in the EXTEND trial)  (ESO 2021)
  • ESO 2021 guidelines do not recommend IVT in the time window of 4.5-9h from the onset of stroke or in WUS based on NCCT alone
  • this section refers to
    • TIA (NIHSS 0)
    • minor stroke (NIHSS 1-4)
    • rapidly improving stroke – NIHSS improvement of ≥ 4 points
    • special syndromes (hemianopsia, Gerstmann syndrome, posterior circulation stroke, monocular blindness due to CRAO)
  • up to 50% of patients with NIHSS 0-6 will develop an infarction, and 40% have an unfavorable outcome [Strbian, 2013]
  • advanced imaging can help to decide whether to administer tPA
  • it is recommended to thrombolyse patients with:
    • mild disabling deficit (e.g., homonymous hemianopsia, mild aphasia or dysarthria in an actor, mild paresis in a pianist, etc.)  (ESO guidelines 2021) (AHA/ASA 2019 I/B-R)
    • rapidly improving but still disabling deficit
      •  1/3 of patients will progress further and develop a permanent deficit after initial improvement [Smith, 2005]   [Smith, 2011]
      • is the potential benefit of IVT (even mild deficits can be bothersome) and the low risk of ICH
    • mild non-disabling deficit + persistent cerebral artery occlusion (ESO 2021 – expert consensus)
      • neurological deficits may fluctuate; many patients with acute arterial occlusion will eventually progress  if recanalization is not achieved (END – Early Neurological Deterioration)
      • CT perfusion with the RAPID system is a valuable tool for detecting peripheral occlusions
  • if IVT is not indicated due to regression of the deficit, the patient should be closely monitored throughout the whole thrombolytic window
  • a mild non-disabling deficit should not be thrombolyzed (ESO guidelines 2021) (AHA/ASA 2019 III/B-R)
    • see results of the PRISMS trial (2018)
  • “severe stroke” criteria:
    • NIHSS > 25
    • presence of early signs of ischemia > 1/3 of the MCA territory
    • ASPECTS < 7
  • it seems that even in this group of patients there may be a benefit of IVT and there may not be a higher risk of bleeding
    • a joint analysis of the ECASS, NINDS and Atlantis trials showed a benefit of IVT, but with an increased risk of poor outcome
    • benefit of IVT was demonstrated in patients with NIHSS > 22 [Frank, 2013]
  • in patients with clinically severe stroke of <4.5 h duration, IVT is recommended
  • for patients with severe stroke (defined by the extent of early ischemic changes on CT) of <4.5 h duration,  IVT should be considered in selected cases (ESO 2021)
  • if bleeding risk is further increased (extensive leukoencephalopathy, known microbleeds, etc.) consider direct MT (dMT)
  • previous ICH
    • patients with previous ICH were excluded from thrombolytic trials, and IVT is generally not recommended for them; we only have data from case series and small non-randomized cohorts where no exaggerated increase in ICH was observed [Zhao, 2019]
    • the risk of sICH depends on the etiology of the bleeding
      • amyloid angiopathy or untreated vascular malformation pose a high risk
      • relatively low risk is present in patients with hypertonic bleeding > 12 months ago
    • the decision on IVT is individual (ESO guidelines 2021 – expert consensus)  (ESO guidelines 2021 – expert consensus)
      • administration of IVT may be recommended if a long time has elapsed since the hemorrhage, for non-recent subcortical ICH, for bleeding from a secured source, for bleeding caused by the anticoagulant agent overdose, etc.
  • cerebral microbleeds (CMBs)
    • there is an increased risk of bleeding with CMBs > 10 (OR 13 !) ⇒ it is recommended not to administer IVT ( (ESO guidelines 2021)   [Zand, 2017]   [Fiehler, 2007]
    • for patients with unknown cerebral microbleed burden or known to be low (e.g., <10), IVT is suggested (ESO guidelines 2021)
      • probability of finding > 10 CMBs is approx. 0.6-2.7% – MRI screening to assess cerebral microbleed burden before making a treatment decision regarding IVT is not recommended
  • TIA
    • data only from case reports and small series of patients
    • patients with a previous TIA (<1 month) appear not to be at higher risk of bleeding complications or worse outcome after IVT  [De Leciñena, 2012]
    • IVT seems safe even in patients with very recent TIA [Tsivgoulis, 2014]
  • recent stroke
    • IVT can be administered in selected cases (e.g., lacunar infarction, infarction occurring > 1 month ago with good recovery) (ESO guidelines 2021)
    • according to a meta-analysis of 900 patients, a higher incidence of sICH or worse outcome was not found [Tsivgoulis, 2019]
    • a higher risk is seen in recent stroke (highest risk is present in stroke within 14 days); the location and extent of ischemia and the etiology of the previous stroke should also be considered (higher risk of sICH in cardioembolization) [Tan, 2014]
    • IVT appears safe in asymptomatic infarction detected on DWI [Stösser, 2020]
  • for patients with an initial BP of >185/110 mmHg, which has subsequently been lowered (with/without the help of antihypertensive drugs) to <185 and <110 mm Hg, IVT is recommended (ESO guidelines 2021)
    • a subanalysis of the IST-3 trial and other smaller studies have not shown a higher risk of bleeding in patients treated aggressively for hypertension [Martin-Schild, 2008]
    • strict BP control is required for 24 h after thrombolysis
    • another analysis showed a higher incidence of sICH in patients with BP > 185/110; however they had a better clinical outcome (mRS) compared to controls [Frank, 2013]
  • for patients with persistently increased BP >185/110 mmHg even after blood pressure lowering treatment, intravenous thrombolysis is suggested  (ESO guidelines 2021)
  • originally, IVT was contraindicated in hypoglycemia  (< 2.7 mmol/l / 50 mg/dl) or hyperglycemia ( > 22 mmol/l / 400 mg/dl)
    • hypoglycemia, in particular, can lead to “stroke mimics”
    • hyperglycemia is associated with worse outcome and ↑  risk of sICH
  • according to expert recommendations:
    • contraindications do not apply in case of proven stroke  (CT/CTA/CTP or MRI)
    • IVT is suggested in the presence of glycemia > 22 mmol/l (400 mg/dl) even without evidence of arterial occlusion (ESO guidelines 2021)
    • if hypoglycemia is corrected and deficit persists, then IVT can be given (administration of IVT in patients with stroke mimics is relatively safe)
  • IVT should not prevent the administration of insulin therapy in acute stroke patients with high blood glucose levels
  • IVT is not suggested if the platelet count is < 100 000 /mm3 (ESO guidelines 2021)
  • IVT can be considered (off-label) at platelet counts of 70,000-100,000 /mm3   [Tsivgoulis, 2021]
  • if the platelet count is unknown and there is no reason to expect abnormal values, IVT can be started while waiting for lab tests results (ESO guidelines 2021)
  • DAPT is associated with only a modest increase in ICH and does not worsen outcome  [Malhotra, 2020]
    • mortality 17.9% vs. 16.6%, sICH 2.9% v.s. 1.5% (according to SITS-MOST criteria)  [Tsivgoulis, 2018]
  • IVT is not contraindicated in patient with single or dual antiplatelet agents (AHA/ASA 2019 I/B-NR)   (ESO guidelines 2021)

 

  • intra-axial tumors remain contraindication to IVT due to a high risk of sICH
  • patients with extra-axial tumors (typically meningiomas) can be treated with IVT after an individual assessment of risk-benefit
  • optimally, perform MRI to detect microbleeds in the tumor and assess the extent of any collateral edema
  • renal failure is generally not a contraindication to IVT
  • severe CKD (<30 mL/min per 1.73 m2) is associated with higher mortality and worse outcome, but not with the increase of sICH; it may be a consequence of comorbidities, not IVT itself
  • avoid IVT in case of unfavorable risk-benefit ratio (e.g., minor stroke + poorly controlled hypertension or multiple relative CIs)
  • APTT must be normal
  • IVT appears to be safe for saccular aneurysms, including larger ones (> 10 mm) [Virta, 2021]
  • IVT can be administered in unruptured aneurysms (without specifying the size)  (ESO guidelines 2021)
  • AVMs, cavernomas and DAVFs should be treated individually – there are few data available
  • according to older European recommendations, the interval between IVT a surgery should be 3 months, according to AHA/ASA 14 days, new ESO guidelines 2021 claim 14 days
  • IVT may be safely administered in postoperative patients as off-label procedure, evaluate the risk–benefit according to the nature of the surgery and the compressibility of the surgical area
  • in a cohort of patients thrombolysed after previous surgical procedures including major procedures, the risk of bleeding was 7%, of which 3% were major, the risk was higher with recent procedures (< 10 days, OR 10) [Voelkel, 2017]
  • a relative contraindication
  • according to available data, it is better not to administer IVT for recent GIT bleeding (< 3 weeks) and severe craniocerebral injury in < 3 months (consider the type and extent of the injury and CT findings)
  • recent extracranial trauma (< 14d) – IVT can be considered (AHA/ASA 2019)
  • isolated extracranial carotid dissection – IVT recommended (ESO guidelines 2021)
  • aortic arch dissection – absolute contraindication to IVT! (ESO guidelines 2021)
  • intracranial dissection – IVT should be avoided  (ESO guidelines 2021 – expert consensus)
  • even extensive leukoencephalopathy is not a clear contraindication to IVT (ESO guidelines 2021)

→ quantification of white matter lesions (FAZEKAS)

  • acute myocardial infarction (MI) (< 6h) is not a contraindication to IVT (standard tPA dose 0.9 mg/kg)
  • subacute MI (> 6h – 7 days) with ST elevation – no IVT is suggested (ESO guidelines 2021)
  • subacute MI (>1 week and < 3 months) was the official contraindication to IVT (↑ risk of hemopericardium and tamponade); however, according to AHA/ASA guidelines 2018 and ESO guidelines 2021, IVT can be given in non-STEMI and considered in STEMI of inferior wall, right heart and left anterior wall   (ESO guidelines 2021)
    • most complications are present in recent  STEMI  ( < 1 week from onset)
    • the extent of myocardial infarction and available TTE findings should be taken into account
  • infectious endocarditis – for patients with a clear or suspected diagnosis of infective endocarditis, IVT is not suggested (ESO guidelines 2021)
  • pericarditis – IVT can be considered for severe stroke; the benefit in mild stroke is unclear; consult a cardiologist
  • intracardiac thrombus – IVT should be considered for severe stroke; the benefit in mild stroke is unclear
  • myxoma and fibroelastoma  – IVT should be considered for severe stroke; the benefit in mild stroke is unclear
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