RELATIVE CONTRAINDICATIONS FOR THROMBOLYSIS-Are they

real contraindications?DR SUDHIR KUMAR MD DM

CONSULTANT NEUROLOGISTAPOLLO HOSPITALS, HYDERABAD

THROMBOLYSIS IN AIS• Thrombolysis in acute ischemic stroke with

tissue plasminogen activator has been approved for two decades,

• Still, only 10-15% of eligible patients are able to receive this treatment,

• There are several factors responsible for low thrombolysis rates,

• Relative contraindications account for a good proportion of “denial of thrombolysis”.

ABSOLUTE CONTRAINDICATIONS (1)

• Presence of intracerebral hemorrhage on brain scan,• Systolic BP>185 mmHg, or Diastolic BP>110 mmHg,

despite treatment with antihypertensive medications,• Serious head trauma or stroke within the previous

three months,• Platelet count<1,00,000• Current use of anticoagulant, with INR>1.7• Patients on therapeutic dose of LMWH, within the

previous 24 hours.

ABSOLUTE CONTRAINDICATIONS (2)

• Patients on direct thrombin inhibitors (dabigatran)

• Patients on factor Xa inhibitors (apixaban, rivaroxaban)

• Involvement of more than one-third of hemisphere on CT/MRI scan

RELATIVE CONTRAINDICATIONS

• Advanced age• Mild or improving stroke symptoms• Severe stroke and coma,• Recent major surgery,• Arterial puncture of noncompressible vessel,• Recent genitourinary or gastrointestinal hemorrhage,• Seizure at onset,• Recent MI,• CNS structural lesions,• Dementia

ADVANCED AGE• Advanced age is not a contraindication as per

AHA guidelines,• However, alteplase drug insert lists that rt-PA

risks may be increased in people above 75,• IST-3 and SITS-international stroke thrombolysis

registry have shown that rt-PA is safe in people above 80; and functional outcome is better in those thrombolysed

• In summary, evidence does not support excluding patients older than 80 from receiving rt-PA.

THROMBOLYSIS BEYOND 4.5 HOURS

• IV thrombolysis is not recommended beyond 4.5 hours stroke onset,

• However, several small and large studies have shown benefit in selected cases,

• MR perfusion/CT perfusion may be done to select cases with salvageable brain tissue and IV rt-PA may be administered in them.

MILD OR IMPROVING STROKE SYMPTOMS (1)

• FDA label does not recommend using rt-PA for minor stroke symptoms,

• 20-30% of patients with minor or improving stroke symptoms when thrombolysis is being considered can have substantial disability at 3 months

• NIHSS 0-4 is considered as mild stroke, however, one can have major disability within this score too- severe monoparesis, gait imbalance, aphasia, visual deficits.

MILD OR IMPROVING STROKE SYMPTOMS (2)

• Patients with mild neurological symptoms may have proximal vessel occlusion, and they have higher risk of deterioration and disability later,

• Patients with early improvement may also have higher chances of neurological decline later,

• AHA guidelines: Thrombolysis may be considered in patients with mild stroke deficits or those with rapidly improving symptoms (Class IIb, level of evidence C)

SEVERE STROKE AND COMA(1)

• FDA package insert: Higher risk of ICH in patients with severe stroke (NIHSS>20 or 25)

• IV thrombolysis is beneficial in patients with severe stroke, and these patients may derive maximum benefit

• NINDS: Improved outcomes in patients with NIHSS>20• IST-3: Greater benefits with IV rt-PA in patients with

NIHSS>25• VISTA: Greater odds of better functional outcome in

those with NIHSS>22

SEVERE STROKE AND COMA(2)

• Coma was excluded in NINDS trial, so as to exclude stroke mimickers,

• However, coma can be a presentation of basilar artery thrombosis, where thrombolysis is useful,

• Current AHA guidelines do not mention severe stroke (or coma) as a relative contraindication for IV thrombolysis within 3 hours; however, cautions against treating patients with NIHSS>25 after 3 hours.

HYPOGLYCEMIA OR HYPERGLYCEMIA

• Hypoglycemia (<50) or hyperglycemia (>400) are relative contraindications,

• Hypoglycemia can cause focal neurological deficits (stroke mimic) and can also cause MRI changes,

• IV rt-PA may be administered after lack of improvement with IV dextrose,

• Blood sugars may be brought down with insulin, and rt-PA administered once RBS<400 mg%

RECENT MAJOR SURGERY

• Drug insert lists recent surgery as a warning, not an absolute contraindication,

• AHA guidelines also lists this as a relative contraindication, but it is not listed as a contraindication in European Stroke Initiative Recommendations,

• Potential risk of bleeding at operative site; and risks of systemic hemorrhage

• IV rt-PA can be given in selected cases; however; if bleeding risk is high, endovascular therapy may be preferred.

ARTERIAL PUNCTURE OF A NONCOMPRESSIBLE VESSEL

• Arterial puncture within 7 days is listed as a warning in drug package insert, and a relative contraindication in AHA guidelines,

• Generally, this group of patients are critically ill, with jugular or subclavian catheters, with poor functional status; therefore, less likely to benefit from thrombolysis,

• There is no data to oppose or support this.

RECENT GI OR GU BLEED

• 2013 AHA guidelines state recent GI/GU bleeding within 21 days as a relative contraindication to IV rt-PA (active bleeding is an absolute contraindication)

• 21 days has been arbitrarily chosen and is over-cautious.

• In selected cases, IV rt-PA may be considered.• If bleeding risks are higher, intra-arterial

thrombolysis may be preferred.

SEIZURE AT ONSET• Seizure at onset with post-ictal neurological deficits is

considered a relative contraindication as per AHA guidelines

• Purpose is to exclude Todd’s paresis (a stroke mimic)• However, seizures can occur in “real” strokes too,• Moreover, thrombolysis in a stroke mimic is safe and risk

of symptomatic ICH is low,• Only 2 patients out of 300 thrombolysed patients with

seizure at onset had ICH,• As per a recent survey, 91% of stroke neurologists would

administer rt-PA in a patient with seizure at onset.

RECENT MYOCARDIAL INFARCTION

• Recent MI during 3 months prior to stroke is a relative contraindication as per AHA guidelines, but it is not a contraindication as per European guidelines or according to the drug label.

• Possible risks include myocardial wall rupture, hemorrhagic conversion of post-MI pericarditis and systemic embolization of ventricular thrombi.

• Myocardial fibrosis and scarring are complete by 7th week; and hence, it has been suggested to reduce the relative contraindication period to 7 weeks (from current 3 months)

CNS STRUCTURAL LESIONS

• Presence of intracranial neoplasm, AVM or aneurysm is a contraindication as per AHA guidelines and drug label,

• Few case reports reported “successful” thrombolysis with rt-PA; especially if tumor was small and extra-axial

• Published data also supports safety of thrombolysis in patients with small, incidental, unruptured intracranial aneurysm.

DEMENTIA

• Dementia was not listed as a contraindication in most thrombolysis trials, and is not a contraindication as per recent guidelines too,

• Still, presence of dementia leads to under-utilization of thrombolysis

• This could be because of fear of increased bleeding, or lesser expectation of good functional outcome,

• Published data shows that the risk of ICH is not increased due to dementia.

• IV rt-PA can be given in carefully selected cases.

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