ISCHEMIC STROKE / ACUTE THERAPY
Contraindications to intravenous thrombolysis
Created 12/09/2022, last revision 02/01/2023
ESO 2021
- new recommendations have been incorporated into the chapter Intravenous thrombolysis (IVT) and further into the tab “Comments to some contraindications“
- see the full ESO guidelines 2021 here
AHA-ASA 2019

Many of the contraindications listed in the 2016 and 2019 guidelines have become relative or obsolete (see comments on IVT)
- mild non-disabling stroke
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stroke > 4.5 hours from the onset in unselected patients
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except for BAO and IVT guided by advanced imaging (see indications for IVT and comments on IVT contraindications)
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- patients with extensive regions of clear hypoattenuation on CT/DWI (severe stroke) (AHA/ASA 2019 III/A)
- see comments, IVT may be used in selected cases
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severe head trauma < 3 months
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use of IV alteplase in patients who have had a prior ischemic stroke within 3 months (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 a high bleeding risk / recent GI bleeding (< 3 weeks) – IVT is potentially harmful
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coagulopathy
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platelets count < 100 000/mm3
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antiplatelet therapy is not a contraindication to IVT (AHA/ASA 2019 I/A resp. I/B-NR)
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known or suspected infective endocarditis (AHA/ASA 2019 III/C-LD)
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aortic dissection (AHA/ASA 2019 III/C-EO)
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intra-axial brain tumor – IVT is potentially harmful (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 the comments on IVT)
- Wake-Up Stroke (WUS) – DWI lesion < 1/3 of MCA territory + negative FLAIR (DWI/FLAIR mismatch according to the WAKE-UP trial) (AHA/ASA 2019 IIa/B-R)
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pre-morbid disability (including cognitive deficit) – IVT can be considered after evaluation of the premorbid status, quality of life, and risk-benefit ratio
- dural puncture in < 7 days – IVT may be considered (AHA/ASA 2019 IIb/C-EO)
- IC malformation – the benefit and risk of IVT is unclear; given the increased risk of bleeding, it may be considered in patients with a severe deficit if the benefits of treatment outweigh the risks
- acute MI – IVT is not contraindicated (AHA/ASA 2019 IIa/C-EO)
- periprocedural stroke – IVT may be considered; prefer direct MT if eligible
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malignancy – patients with survival > 6 months may benefit from IVT in the absence of other malignancy-related contraindications (e.g., coagulopathy, recent surgery, etc.)
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drug-indued stroke – IVT may be administered in the absence of other significant contraindications (AHA/ASA 2019 IIa/C-LD)
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ophthalmologic diseases – in patients with a history of hemorrhagic retinopathy or other hemorrhagic ocular events, IVT can be administered; always weigh the benefits against the risk of complications (AHA/ASA 2019 IIa/B-NR)
- sickle cell disease – IVT may 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 (e.g., 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 in selected patients)
- typical contraindications that are not respected:
- high age
- history of a previous stroke AND 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):
- 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
- amyloid angiopathy or untreated vascular malformation pose a high risk
- 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)
- 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
- most complications are present in recent STEMI ( < 1 week from onset)
- 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
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intracardiac thrombus – IVT should be considered for severe stroke; the benefit in mild stroke is unclear
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myxoma and fibroelastoma – IVT should be considered for severe stroke; the benefit in mild stroke is unclear
Menstruation
Gravidity
Intravenous thrombolysis (IVT)
- due to its large molecule size, tPA does not cross the placental barrier; there is no evidence of teratogenicity
- there are concerns about placental abruption, intrauterine hemorrhage, preterm delivery, or fetal death
- there are no data from RCTs (pregnancy was an exclusion criterion)
- most case reports and small series are from patients who received thrombolysis for non-stroke diagnoses than stroke (PE, valvular thrombosis, DVT, stroke, myocardial infarction)
- in 8 published cases of IVT, only 1 case of uterine bleeding occurred
- according to a published cohort of 28 patients, the risk of TL-related abortion was 8%, and the maternal risk of IVT did not differ from that of non-pregnant patients [Leonhardt, 2006]
- case reports of successful IVT for stroke in late pregnancy have also been published [Wiese, 2006] [Daprich, 2006]
- all recommendations are based on expert consensus (ESO guidelines 2022)
- IVT may be considered on an individual basis for moderate and especially severe stroke when the expected benefit of IVT outweighs the risk of uterine bleeding (ESO guidelines 2022 – expert consensus) (AHA/ASA 2019 IIb/C-LD)
- factors favoring IVT:
- severe, debilitating deficit
- likely benefit of IVT
- MR DWI/PWI mismatch and small lesion on DWI
- likely peripheral occlusion – from M2 distally
- if MT is available and LVO is involved, direct MT is preferable to bridging therapy
- stroke occurring shortly after delivery
- the safety and efficacy of IVT shortly after delivery (<10 days) are not established (AHA/ASA 2019 IIb/C-LD)
- if the stroke occurs > 10 days after delivery, IVT may be given after individual consideration (ESO guidelines 2022 – expert consensus)
if MT is available and there is a presumption of increased bleeding risk, dMT is preferred (ESO guidelines 2022 – expert consensus)
Mechanical recanalization
- there is a relatively limited experience with MT in pregnant women; no RCTs are available
- direct MT may be preferable to bridging therapy for LVO during pregnancy and shortly after delivery
- fetal shielding with lead vests is required
IVT in children
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