Clinical stroke

trials in an overview
Dr Melvin George

Introduction
v Stroke remains a leading cause of death and disability worldwide. v Recombinant tissue plasminogen activator (rtPA) - in acute ischemic stroke has improved the clinical outcome of patients who present early after onset of symptoms.

Clinical trials in stroke

Acute ischemic stroke trials Acute hemorragic stroke trials Stroke Prevention trials Stroke rehabilitation trials

Acute ischemic stroke trials

A randomized controlled trial of antiplatelet therapy in combination with rt-PA thrombolysis in ischemic stroke: rationale and design of the ARTIS-Trial

Hypotheses:
Immeditate addition of antiplatelet therapy to rt-PA in acute ischemic stroke improves outcome by enhancing clot lysis and preventing re-occlusion after initial recanalisation.

Primary objective

To investigate whether the addition of aspirin to standard rt-PA thrombolysis reduces poor outcome in acute ischemic stroke.

v Poor outcome is defined as death or dependency assessed by the modified Rankin Scale ( mRS , score 3 - 6 ) at 3 months follow - up .

Rankin score
v Most widely used clinical outcome measure for stroke clinical trials. v v It was originally introduced in 1957 by Rankin

Modified Rankin Score (mRS)

Score Description 0 1 2 3 4 5 6 No symptoms at all
No significant disability despite symptoms ; able to carry out all usual duties and activities Slight disability ; unable to carry out all previous activities , but able to look after own affairs without assistance Moderate disability ; requiring some help , but able to walk without assistance Moderately severe disability ; unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability ; bedridden , incontinent and requiring constant nursing care and attention

Dead

Inclusion criteria
1 . Age 18 - 80 years 2 . Patients with acute ischemic stroke

3.

Exclu sion cr it e r ia
1. known antiplatelet therapy in the previous 5 days ( in case of uncertainty the patient may be included ); 2 . known thrombocytopenia 3 . known contra - indications to acetylsalicylic acid treatment ; 4 . known anticogualant therapy in the previous 5

Recommendations for rtPA

q Diagnosis of ischemic stroke causing measurable neurological deficit q Neurological signs should not be clearing spontaneously q Neurological signs should not be minor and isolated q Symptoms not suggestive of intracerebral haemorrhage

Recommendations for rtPA

q Onset of symptoms <3 hours before beginning treatment q No head trauma or prior stroke in previous 3 months q No MI in the previous 3 months q No GI or UT haemorrhage in the previous 21 days q No major surgery in previous 3 months q

Recommendations for rtPA

q No evidence of active bleeding q Not taking anticoagulant q If on heparin, aPTT must be in normal range q Blood glucose >50 mg/dl q Platelet count >100 000 mm3

Recommendations for rtPA

q CT does not show multilobar infarction (hypodensity greater than one third of cerebral hemisphere) q No seizure with residual neurologic deficit q Blood pressure not elevated (systolic> 185 mm Hg and diastolic >110 mm Hg) q The patient or family members understand the potential risks and benefits from treatment. q

Randomization
Randomisation procedure will be computer - and web based , using permuted blocks . Randomisation will be stratified by

centre , age ( 60 years , > 60 years ), gender time between symptom onset and time of rt - PA bolus (< 2 hours , 2 - 3 hours , > 3 hours ).

 Aspirin

will be administered within 1.5 hours after the rt-PA bolus. and treating physician are not blinded for treatment allocation. Aspirin intravenously?

Patient Why

Treatment of acute ischemic stroke

Infuse 0 . 9 mg / kg ( maximum dose 90 mg ) over 60 minutes with 10 % of the dose given as a bolus over 1 minute . Admit the patient to an intensive care or stroke unit for monitoring . Perform neurological assessments every 15 minutes during the infusion and every 30 minutes thereafter for the next 6 hours , then hourly until 24 hours after treatment . If the patient develops severe headache , acute hypertension , nausea , or vomiting , discontinue the infusion ( if rtPA is being administered ) and

 Measure blood pressure every 15 minutes for the first 2 hours and subsequently every 30 minutes for the next 6 hours , then hourly until 24 hours after treatment . Increase the frequency of blood pressure measurements if a systolic blood pressure is > 180 mm Hg or if a diastolic blood pressure is > 105 mm Hg ; administer antihypertensive medications to maintain blood pressure at or below these levels Delay placement of nasogastric tubes , indwelling bladder catheters , or intra - arterial pressure catheters . Obtain a follow - up CT scan at 24 h before starting anticoagulants or antiplatelet agents .

Treatment of acute ischemic stroke

Blood pressure should not be lowered with medication prior to rt-PA treatment.

Rescue therapy
If during rt-PA administration, SBP > 180 mmHg or DBP > 105 mmHg, administer 10 mg labetalol iv in 1-2 minutes. Repeat every 10-20 minutes until blood pressure is below 180 mmHg systolic or below 105 mmHg diastolic.

Rescue therapy
150

mg labetalol is the maximum dose in 24 hours. During this treatment blood pressure should be measured every 15 minutes. If the blood pressure does not respond to labetalol, iv nitroprusside 0.5-10 g/kg/minute should be added, with continuous blood pressure monitoring.

 All

medication used before the stroke may be continued, except anticoagulants.

Simvastatin dipyridamole

OUTCOME MEASURES
The

primary endpoint is poor functional health at 3 months defined as dependency or death (mRS 3 - 6).

Modified Rankin Score (mRS)

Score Description 0 1 2 3 4 5 6 No symptoms at all
No significant disability despite symptoms ; able to carry out all usual duties and activities Slight disability ; unable to carry out all previous activities , but able to look after own affairs without assistance Moderate disability ; requiring some help , but able to walk without assistance Moderately severe disability ; unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability ; bedridden , incontinent and requiring constant nursing care and attention

Dead

v Primary outcome will be assessed by a blind research nurse from the clinical trial office of the coordinating centre , who will score the mRS by telephone using a structured interview .

v To increase the inter - observer reliability the number of research nurses will be limited to a maximum of three .

Secondary outcome measures

v Complications within 48 hours after randomisation including the occurrence of SICH and serious systemic bleeding.

v SICH is defined as
CT-documented haemorrhage

Clinical deterioration leading to 4 or more points increase on the National Institute of Health Stroke Scale (NIHSS) as compared to the best score on the NIHSS since admission.

What is the NIHSS?

Secondary outcome measures

neurological symptoms quantified by the NIHSS 7 10 days after randomisation or at discharge if the patient is discharged within 7 days;

survival at 3 months; disability at 3 months assessed by the AMC Linear Disablility Scale

functional health at 3 months non-dichotomized (ordinal mRS);

causes of poor outcome

Data collection
Age, sex, ethnicity, medical history, pre-stroke medication, pre-stroke mRS, blood pressure, Glasgow Coma Scale (GCS), National Institutes of Health Stroke Scale (NIHSS), time of symptom onset,

v Baseline CT-scans will be collected from participating centres and assessed blindly centrally at the coordinating centre by an independent blinded neuro-radiologist. v

 At follow-up, neurological deficits are assessed by the NIHSS at 7-10 days.

SAE
Clinical deterioration, defined as a 4 or more points increase on the NIHSS, will be followed by CT-scan and registration as (serious) adverse events including possible cause by each participating site.

 All adverse event reported by the subjects or observed by the treating physicians will be recorded. In case of serious adverse events (SAE), the principal investigator will be notified by email or telephone within 24 hours. The principal investigator subsequently reports SAE to the Data Safety Monitoring Board (DSMB).

DSMB
safety surveillances

recommend the Steering Committee to terminate the trial if clear evidence of harm.

unblinded interim analysis on the primary outcome to assess the strength of the efficacy data

Decisions
Possible decisions:
Continue with trial as planned Stop: safety problem Stop: efficacy established Stop: new knowledge (usually from other trials suggesting risks) Stop: futile. Trial unlikely to show a result Modify trial design

Haemorragic stroke trial

To evaluate the safety and effectiveness of lowering blood pressure using nicardipine in persons with acute hypertension associated with intracerebral hemorrhage.

Inclusion criteria
Age older than 18 years. Onset of new neurological signs of a stroke within 12 hours of the time to evaluation AND initiation of treatment with intravenous nicardipine. Clinical signs consistent with the diagnosis of stroke, including impairment of language, motor function, cognition, and/or gaze, vision, or neglect.

Inclusion criteria

The total GCS score is greater than 8 at the time of enrollment . CT scan demonstrates intraparenchymal hematoma with manual hematoma volume measurement less than 60 cc . ICH is supratentorial and is located in lobar , basal ganglionic , or thalamic based on the initial CT scan appearance . Admission systolic blood pressure greater than 170 mm Hg on two repeat measurements at least 5 minutes apart . Evidence of chronic hypertension . Subject is not considered a surgical candidate by the

AVERT A Very Early Rehabilitation Trial

 To

determine if very early mobilization (VEM) of stroke patients in addition to standard care compared to standard care (SC) alone is more effective in lowering mortality, disability, and severity of complications at 3 months and at improving quality of life at 12 months.

 Primary

Outcome:

Modified Rankin Score at 3 months.

Secondary

outcome

barthel.pdf

ARISTOTLE
APIXABAN FOR THE PREVENTION OF STROKE IN SUBJECTS WITH ATRIAL FIBRILLATION

Is apixaban , an investigational anticoagulant is as effective as standard therapy ( warfarin ) in preventing stroke and systemic embolism in subjects with atrial fibrillation and risk factors for stroke?

Inclusion Criteria
Males and females 18 yrs with AF one or more of the following risk

factors for stroke:

Age 75, previous stroke, TIA or Systemic Embolism, symptomatic congestive heart failure or left ventricular dysfunction with LVEF 40%, diabetes mellitus or hypertension requiring pharmacological treatment.

Primary Outcome : Confirmed stroke or systemic embolism . ( time to first occurrence )

Secondary Outcome : Confirmed ischemic stroke , hemorrhagic stroke , systemic embolism , all cause death . ( time to first occurrence )

 Death - primary outcome in some stroke trials . Problems

Avoiding dependency is more important to stroke patients than dying . Death is inefficient statistically - only a minority of patients in most trials

Conclusion
Numerous

trials in acute stroke have been performed advances made

Few

Sound

knowledge of methodology of trials can supplement the scientific progress in basic research.

Thank you.