Contraindications to intravenous thrombolysis

• 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)

→ see separate chapter

• 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