Thromobolytic Therapy in Acute Stroke

Despite the increased risk of haemorrhage in patients with a massive stroke, fibrinolysis remains indicated whenever other exclusion criteria are absent

"Inclusion and exclusion criteria must be reviewed before administration of thrombolytic therapy" - Dr Charulata Sankhla Neurophysician PD Hinduja Hospital, Mumbai

Ischemic strokes are caused by occlusions of cervico-cerebral blood vessels. Focal brain infarction result due to clots in these arteries. Cerebral angiography performed shortly after the onset of ischemic stroke reveals clots in large cerebral vessels in upto 80 per cent of cases. Thrombolytic agents convert plasminogen to plasmin. Plasmin cleaves fibrin strands in intravascular thrombi, resulting in clotlysis and restoration of blood flow. Worldwide, stroke is the second leading cause of death, responsible for 4.4 million (nine per cent) of the total 50.5 million deaths each year. Globally, stroke death rates vary widely. The highest rates are in Portugal, China, Korea, and most of Eastern Europe and the lowest rates are in Switzerland, Canada, and the United States. ICH is more common and ischemic stroke less common in Asian countries than in the United States. The male-to-female ratio for stroke is about 1.35:1.

Age

The incidence of stroke doubles in every decade after the age of 45 years, rising from 104 every 1, 00,000 per year for adults aged 45-54 years, to 1,113 every 1,00,000 per year for adults aged 75-84 years. Two thirds of strokes occur in persons older than 65 years. No absolute age limits apply to the use of thrombolytic therapy. Other risk factors for ischemic stroke include:

• Hypertension.
• Diabetes.
• Smoking.
• Atrial fibrillation.
• Hypercholesterolemia.
• Coronary artery disease.

Mortality/Morbidity

The three-month mortality rate from ischemic stroke is approximately 12 per cent. However, patients who are candidates for thrombolytic stroke therapy tend to have more severe strokes than the average patient with ischemic stroke. The three-month mortality rate in these more severe patients is approximately 21 per cent, when they do not receive thrombolytic therapy. This death rate is not increased by the use of thrombolytic treatment.

Thrombolytic therapy is of proven and substantial benefit for select patients with acute cerebral ischemia. The evidence base for thrombolysis includes 21 completed randomised controlled clinical trials enrolling 7,152 patients, using various agents, doses, time windows, and intravenous or intra-arterial modes of administration. Data from these trials are congruent in supporting the following conclusions:

• Intravenous fibrinolytic therapy at the cerebral circulation dose within the first three hours of ischemic stroke onset offers substantial net benefits for virtually all patients with potentially disabling deficits.
• Intravenous fibrinolytic therapy at the cerebral circulation dose within 3-4.5 hours offers moderate net benefits when applied to all patients with potentially disabling deficits.
• MRI of the extent of the infarct core (already irreversibly injured tissue) and the penumbra (tissue at risk but still salvageable) can likely increase the therapeutic yield of lytic therapy, especially in the three-to-nine-hour window.
• Intra-arterial fibrinolytic therapy in the three-to-six hour window offers moderate net benefits when applied to all patients with potentially disabling deficits and large artery cerebral thrombotic occlusions.

Intra-Venous V/s Intra Arterial

Intra-Arterial (IA) thrombolysis has also been investigated as a treatment for acute ischemic stroke. Compared with Intra-Venous therapy, IA therapy offers several advantages, including a higher concentration of lytic agent delivered to the clot target, a lower systemic exposure to drug, and higher recanalisation rates. Disadvantages include additional time required to initiate therapy, availability only at specialised centres and mechanical manipulation within potentially injured vessels. Patients must arrive preferably to an institution with a stroke centre. Admission to a skilled care facility (Intensive Care Unit or Acute Stroke Care Unit) that permits close observation, frequent neurological assessments and cardiovascular monitoring is vital.

Who Should Get the Therapy?

Determination of the time of onset of symptoms is critical in deciding eligibility for thrombolytic therapy. On-label treatment must be initiated within three hours of onset of symptoms. Sometimes, the precise onset time cannot be determined with certainty. For example, when a patient awakens with a deficit after a night's sleep or after a nap or is found stricken and unable to communicate the onset time. In these instances, the onset time is taken as the last time the patient was known to be well. Caution should be exercised in patients with neglect syndromes, who may not have observed their onset time reliably.

To be considered for thrombolytic therapy, a patient must have more than a minimal neurological deficit. Patients with only minimal weakness, isolated ataxia, isolated sensory deficit, or isolated dysarthria are generally not lytic candidates.

Absolute Contraindications

• History or evidence of intracranial haemorrhage.
• Clinical presentation suggestive of subarachnoid haemorrhage.
• Known arteriovenous malformation.
• Systolic Blood Pressure (SBP) >185 mm Hg or Diastolic Blood Pressure (DBP). >110 mm Hg despite repeated measurements and treatment.
• Seizure with postictal residual neurologic impairment.
• Platelet count <100,000/mm3.
• Prothrombin time (PT) >15 or INR >1.7
• Active internal bleeding or acute trauma (fracture).
• Head trauma or stroke in the previous three months
• Arterial puncture at a noncompressible site within one week.

No adjunctive therapies should be given with thrombolytic therapy for the management of acute ischemic stroke. Anti-coagulants and anti-platelet agents may increase the risk of bleeding complications and are not recommended within 24 hours of alteplase administration.

Despite the increased risk of haemorrhage in patients with a massive stroke, fibrinolysis remains indicated whenever other exclusion criteria are absent, because the potential benefit is tremendous in this population of patients, who almost always have a dismal outcome if therapy is withheld. Inclusion and exclusion criteria must be reviewed before administration of thrombolytic therapy. Be aware of subarachnoid haemorrhages that present early without CT scan findings.

Thrombolytic Agents

Tissue Plasminogen Activator (TPA) is a naturally occurring fibrinolytic agent found in vascular endothelial cells and is involved in the balance between thrombolysis and thrombogenesis. It exhibits significant fibrin specificity and affinity. At the site of the thrombus, the binding of TPA and plasminogen to the fibrin surface induces a conformational change facilitating the conversion of plasminogen to plasmin and plasmin dissolvs the clot. Fibrinolytics, sometimes referred to as plasminogen activators, are divided into two categories. Fibrin-specific agents such as alteplase, reteplase, and tenecteplase produce limited plasminogen conversion in the absence of fibrin, whereas non-fibrin-specific agents such as streptokinase catalyse systemic fibrinolysis. Streptokinase is indicated for the treatment of acute myocardial infarction, acute massive pulmonary embolism, deep vein thrombosis, arterial thrombosis and occluded arteriovenous cannulae. Streptokinase is not widely used in the United States, but continues to be used elsewhere because of its lower cost.

Alteplase is the only current lytic agent US Food and Drug Administration (FDA) approved for AMI, acute ischemic stroke, massive pulmonary embolism and occluded central venous access devices. New agents and new dosing regimen are under constant investigation. A choice of lytic agents must be based upon the results of ongoing clinical trials and upon the clinician's experience. The most appropriate agent and regimen for each clinical situation will change over time and may differ from patient to patient.

Management of Stroke in Children

There is no data concerning the use of r-TPA for the treatment of acute ischemic stroke in neonates, infants or children. People younger than 18 years were not enrolled in the recent trials. Thrombolytic drugs have been given to children with other thromboembolic diseases, including arterial thrombosis, right atrial and caval thrombosis, pulmonary embolism, thrombosis of a Blalock-Taussig shunt, thrombosed dialysis shunts and cerebral venous thrombosis. One study suggests that a dose of 0.5 mg/ kg should be used in children.

The safety and efficacy of the use of r-TPA in neonates, infants and children with acute ischemic stroke requires further study. The risk of bleeding may be particularly high in neonates because plasminogen concentrations are often low, hemostatic and fibrinolytic mechanisms are not fully developed, and the cerebral vasculature is still changing.

If, recognising that risk benefit has not been established, r-TPA is to be given to a paediatric patient, the same guidelines as in adults should be followed (Grade C recommendation). This medication should be administered only with caution in a highly individualised manner to paediatric patients with acute ischemic stroke. Because of the potential high risk of haemorrhage, neonates and infants should be treated only in very exceptional circumstances.

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