Thrombolytic Therapy in Acute Stroke: Outcome, Barriers & How to Overcome

Stroke is the leading cause of disability among adults globally. Despite advances in preventive strategies and initial therapy for stroke, nearly 800,000strokes occur per year in the United States and 87% of all strokes worldwide areischemic in origin.1 As recently as less than 10 years ago, management of acute ischemic stroke consisted of diagnosis, medical support & rehabilitation after acute event. There are now interventions for acute revascularization, either pharmacological or mechanical, that allow blood follow to be restored promptly to the ischemic brain tissue.2,3


Introduction
Stroke is the leading cause of disability among adults globally.Despite advances in preventive strategies and initial therapy for stroke, nearly 800,000strokes occur per year in the United States and 87% of all strokes worldwide areischemic in origin. 1 As recently as less than 10 years ago, management of acute ischemic stroke consisted of diagnosis, medical support & rehabilitation after acute event.There are now interventions for acute revascularization, either pharmacological or mechanical, that allow blood follow to be restored promptly to the ischemic brain tissue. 2,3 is also one of the leading cause of death in our country.But there has been limited progress in management of patientswith stroke in developing countries and data on stroke care inthese countries are sparse. 4,5,6Guidelines are continuouslydeveloped and updated in the developed world but theirpracticality for use in developing regions is unrealistic 6.The number of stroke patients receiving r-tPA in the thirdworld is extremely low .In Stroke thrombolysis is currentlyused in few developing countries like Brazil, Argentina,Senegal, Iran, Pakistan, China, Thailand, and India. 7dly, thrombolysis is still underused in our country.Purpose of this review is to highlight the positive results of thromblytic therapy in acute stroke which willencourage our physician to offer this therapy to an increasing number of stroke patients, and thereby reduce the considerable socioeconomic burden of stroke.

Role of Thrombolytic therapy
Ischemic stroke results from vascular occlusion that reduces cerebral blood flowto the area of brain perfused by the occluded artery.In either thrombotic or embolicstroke, such occlusion is caused by obstruction of the artery by thrombus.If the reduction in blood flow is sufficiently severe, a series of events occurs atthe cellular level that leads to infarction.Tissue plasminogen activator (t-PA) is a serineprotease that acts by enhancing the conversionof inactive plasminogen to active plasmin.Plasminacts on fibrin clots, causing dissolution andlysis.The activity of t-PA is greatly enhanced inthe presence of fibrin, increasing fibrinolysisspecifically at the site of thrombosis 8 .This theoretically result in revascularization of a previously occluded blood vessel well and reversal of brain ischemia.In vivo,t-PA is released by endothelial cells; in contrast,exogenously administered t-PA is derived fromthe application of recombinant DNA technologyand is thus designated recombinant t-PA (rt-PA).Unlike first-generation plasminogen activatorssuch as streptokinase and urokinase, rt-PA is fibrin-selective and preferentially activates fibrinboundplasminogen.

Review Article
Thrombolytic medications in acute stroke became a significant part of stroke treatment after the publications of the National Institute of Neurological Disorders And stroke t-PA Stroke Study Group Trial(NINDS) in 1995.In thisNINDS trial, the rate of a favorable outcome wassignificantly greater with intravenous rt-PA thanwith placebo (odds ratio, 1.7; 95% CI, 1.2 to 2.6;P = 0.008).This benefit was sustained at 6 monthsand at 1 year. 9 the subsequent ECASS III, 821 patients whopresented between 3 and 4.5 hours after the onsetof stroke were randomly assigned to intravenousrt-PA or placebo. 10At 90 days, significantly more patientstreated with rt-PA had favorable outcomes, as com-pared with those given placebo (52.4% vs. 45.2%;oddsratio, 1.34; 95% CI, 1.02 to 1.76; P = 0.04).

Clinical Use of Fibrinolytic Therapy
Intravenous administration of t-PA within 3 hoursafter the onset of stroke increases the probability of a favorable outcome.Recommended protocolsfor selecting patients for treatment with intravenousrt-PA are adapted from the inclusionand exclusion criteria from the NINDSrt-PA trial .On the basis of results of ECASS III, 10 some stroke centers now treat patients who presentfrom 3 to 4.5 hours after stroke onset; however, at present, the FDA has approved only rt-PAtreatment delivered within 3 hours after strokeonset.
When a patient is evaluated for any thrombolytic therapy,it is vital to evaluate the patient as soon as practicable.In Acute setting patient should receive as quickly as possible: • Triage to emergency room • Airway, Breathing , Circulation & finger stick test to exclude hypoglycaemia • CT scan of Head to exclude haemorrhage& to look for early signs of infarct.
• Blood Test: Complete blood count,complete metabolic panel and coagulation profile to rule out thrombocytopenia,liver failure and recent use of anticoagulsnts.
• ECG • Evaluation of blood pressure with control using labetatol or nicarsdipine if systolic blood presssure is 180 or greater.
• Nerological evaluation that includes -Time of Onset (time the patient was last seen as normal, not time the family thinks stroke occured) -NIH stroke scale: Many protocols exclude patients who have mild deficits, since their prognosis for recovery is good without thrombolytic therapy.However, treatment should be initiated on the basis of the assessmentof adisabling deficit rather than on a defined lower limit for the NIHSSscore.For example, isolated aphasia or hemianopia is a disabling deficit despite an NIHSS score of 2 or 3.

Inclusion criteria Exclusion criteria
• Diagnosis of ischemic stroke causing • Head trauma or prior stroke within the previous 3 month measurable neurologic deficit.
• Symptoms suggestive of subarachnoid hemorrhage • Onset of symptoms <3 hr before start of treatment • Arterial puncture at no compressible site within the previous 7 days (or, in selected cases,<4.5hr) • History of intracranial hemorrhage The FDA-approved dose of intravenous rt-PA is0.9 mg per kilogram of body weight, with a maximumdose of 90 mg.A bolus of 10% of the doseis given over a period of 1 minute, with the remainderinfused over a period of 60 minutes.Weightshould be determined as reliably as is possible.

Management of post-fibrinolytic period
For the first 24 hours after treatment, patientsreceiving rt-PA should be closely monitored in aspecialized unit so that the patient can be evaluated frequentlyby the nursing staff.Blood pressure shouldbe checked every 15 minutes for the first 2 hours,every 30 minutes for the next 6 hours, and thenevery hour for 16 hours.Antihypertensive therapywith labetalol or, if necessary, intravenous nicardipineshould be administered to maintain blood pressure at a level below 180 mm Hg systolic and105 mm Hg diastolic. 13,14Neurologic examinationwith the use of the NIHSS should be performedevery 15 minutes for the first 2 hours,every 30 minutes for the next 6 hours, and thenevery hour for 16 hours.If a change in neurologicstatus is noted, the rt-PA infusion should be discontinuedand a CT scan obtained.No anticoagulantor antiplatelet therapy should be given for thefirst 24 hours after treatment with intravenousrt-PA.If a CT scan at 24 hours shows no evidenceof hemorrhage, antithrombotic therapy directed atsecondary stroke prevention and tailored to thepresumed cause of the stroke should be started.

Barrier of thrombilytic therapy
Prehospital Barriers : One of the most important prehospital barriers of thrombolysistherapy in the developing world is nonrecognitionof stroke warning signs by patients at risk, families, thegeneral public and even health workers in some places 15 .There is poor recognition of stroke symptoms in developingcountries 16 .The people at the highest risk have the lowestknowledge regarding vascular disease including limitationsto ascertain mild and transient symptoms as stroke 17 .In summary following three types of prehospital barrier is identified in different studies: • The patient or family did not recognise symptoms of stroke or seekurgent help: Several studies identified this as a barrier [18][19][20][21][22][23] .The commonest factors associated with it were: (i) patientliving alone 24 , (ii) symptomsnot recognised or not interpreted as stroke (iii) lack of bystander witness when stroke symptomsoccurred (iv) patient or family not seekingmedical help at all (v) patient or family having nosense of urgency to seek help when symptoms started (vi) stroke symptoms started at home and (vii) patient refused to go to hospital .
6][27][28] These studies foundthat ambulance transfer was associated with a shorter delayto arrival at hospital, whereas first contacting a general practitioner(GP) increased the delay.
• Paramedical staff did not triage stroke as an emergency: Wefound seven studies that evaluated delays from calling theemergency services to the time of ambulance arrival, and from ambulance arrival at the patient to reaching the hospital 29 .These studies found that stroke was often not regarded as an emergency by the paramedicalstaff, leading to slower ambulance transfer.
In -Hospital barrier: • Emergency department did not triage stroke as an emergency:several studies have found that examined delay from stroke onset(or arrival at hospital) to first medical assessment, neurologistsassessment, or alerting the acute stroke team [21][22][23] .The median delay from arrival at hospital to first medicalassessment varied considerably, ranging from 20 minutesto 4 hours 30 .
• Delay in neuroimaging: Delays occurred in: requesting the scan,transporting the patient to the radiology department, carrying out the scan, and reporting the scan by a neuroradiologist • Ineffcient process of in-hospital emergency department: Reported reasons for delay in wardtransfer included beds being unavailable and delay in obtaininga porter to transport the patient .
• Diffculties in obtaining informed consent for thrombolysis: Inthe acute phase, many stroke patients have language impairmentor reduced consciousness, which makes it diffcult to get their consent for treatment.Two studies identified thisbarrier.In one study, 10% of patients did not receive the treatment because they refused consent whereas only0.4% of patients refused in another study ' • Physicians' uncertainty in administering rt-PA: In the USA,where rt-PA is licensed, one study in 1998 found that only16% of neurologists had ever administered the treatment.In this review, one study showed that some physicianswere reluctant to administer rt-PA because of conflicting trial results and difficulty in starting treatment within3 hours of stroke onset .
• Other identified barriers: Five studies reported other barriers:(a) delays in retrieving old medical records, performingphlebotomy, and acquiring the drug from pharmacy (b) delays in transferring the patient from another hospital.
Stroke patient is a great burden for a family as well as for the country because of huge cost of treatment and rehabilitation.So, if we give quick recovery of the patient it is beneficial for his family and the country.For this purpose we should try to overcome the barriers of treatment .
Measures to overcomethese in-hospital barriers could include, e.g.training ofemergency department staff to triage stroke as an emergency,improving access to CT scanning and training ofdoctors in administering thrombolysis.

Conclusion
Treatment with intravenous rt-PA can be given any acute ischemic stroke patients whomeet the stated inclusion criteria, including presentationwithin 3 hours after the onset of stroke, and who do not meet any of the stated exclusion criteria.28,67.Both American Heart association and the European Stroke organization have recently updated their guidelines to extend the treatment window to 4.5 hours.So in conclusion intravenous rt-Pa is a reasonable treatment option when used in tertiary care hospital and is administered according to the guideline established by the NINDS study.Commonest reasons for being ineligible The proportions of patientswho were forthrombolysis using rt-PA, ineligible for these reasons(% range) • Delay to treatment >3 hours, or onsettime unknown 22-94 • CT scan shows haemorrhage or signsof extensive infarction 10-22 • Clinical signs of stroke too mild or resolving rapidly.9-19 • Medical contraindications to rt-PA 6-10 • Refusal to consent to treatment 0.4-10 14. Adams HP Jr, del Zoppo G, AlbertsMJ, et al.Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists.Stroke 2007;38:1655-711.[Errata,Stroke 2007;38(6):e38, 38(9):e96.]