management of stroke with piracetam
TRANSCRIPT
By,ESENE IGNATIUS ,MDBAKARI TRAORE,MD
EFFECTIVENESS OF PIRACETAM IN THE TREATMENT OF ACUTE CEREBRAL STROKE IN SUB-SAHARAN AFRICA.
Research Protocol
PLAN
• BACKGROUND AND RATIONALE• GOAL • OBJECTIVES• METHODS• ETHICAL CONSIDERATIONS
1.BACKGROUND AND RATIONALE• DEFINITION
A stroke is "neurological deficit of cerebrovascular
cause that persists beyond 24 hours or is interrupted
by death within 24 hours".(WHO,1978)
1.BACKGROUND AND RATIONALE
• EPIDEMIOLOGY
• WORLDWIDE:Ischemic stroke is the 2nd cause of mortality -100 to 200 new cases / 100000 inhabitants occur each year. (Feigin, 2005).
• Developed countries: Cerebral stroke remains the third leading cause of death and the first leading cause of long-term disability in survivors. (LEYS D,1998).
• Africa: 10% global stroke mortality (Connor , 2007 ) and 56 to 83% of these stroke patients die precociously.(SeneDiouf, 2008;Sokrab, 2002).
Cameroon and Burkina Faso: ↗important public health problem ; epidemiologic
transition ↑ communicable diseases ( hypertension and diabetes) which are both
important risk factors for the development of stroke.
1.BACKGROUND AND RATIONALE
80% of strokes 20% of stroke
TWO MAJOR CATEGORIES OF STROKE:
1.BACKGROUND AND RATIONALE
• RISK FACTORS :
Advanced Age,
Hypertension,
Previous Stroke Or Transient Ischemic Attack (TIA),
Diabetes,
High Cholesterol,
Cigarette Smoking And
Atrial Fibrillation. (Donnan, 2008)
1.BACKGROUND AND RATIONALE• AETIOLOGY Depend on the type of stroke:
∆ Thrombotic stroke: Atherosclerosis
∆ Embolic stroke: Fat, Air, Cancer Cells, Bacteria.
∆ Systemic hypoperfusion: Secondary to a cardiopathy
∆ Venous thrombosis: Cerebral venous sinus thrombosis due to
locally increased venous pressure.
∆ Intracerebral hemorrhage: commonly due to hypertension,
trauma, bleeding disorders, and vascular malformations.
1.BACKGROUND AND RATIONALE• PATHOPHYSIOLOGY
Systemic events
Cerebral Hypoperfusion→ Hypoxia → Ischaemia → Infarction
Cerebral events
Ischaemic cascade → Cerebral oedema
PATHOPHYSIOLOGY
Jr cer Bl Flow & Met.2002: 22, 1399–1419;
PATHOPHYSIOLOGY
Marc Fisher,2000
1.BACKGROUND AND RATIONALE• DIAGNOSIS:
CLINICAL BASED ON NEUROLOGIC EXAMINATION.
Neurologic deficit and Cognitive disorder
PARACLINCAL TESTS :
CT scans, MRI scans, Doppler ultrasound, and Arteriography to
determine type and subtype while blood tests together with the
imaging techniques help determine cause.
1.BACKGROUND AND RATIONALE• MANAGEMENT OF STROKE 1
Occurs at stroke or neurologic Unit
Maintenance of body homeostasis is primordial .
Rehabilitative care after intensive care to regain normal life.
Prevention of modifiable risk factors
Disability : 75% of stroke survivors ↙employability, affecting
patients physically, mentally, emotionally, or a combination of the
three.
1.BACKGROUND AND RATIONALE• MANAGEMENT OF STROKE 2
Drugs: neuroprotectors and thrombolytic agents.
There is still no treatment of proven efficacy and wide
applicability for the acute phase of the disease; and various
strategies are currently being considered, both from the point
of view of circulatory impairment (antithrombotics,
thrombolytics, etc) and from the point of view of
neuroprotection of the ischaemic brain (NMDA blocking agents,
sodium channel blockers, etc) (Ricci S, 2009).
1.BACKGROUND AND RATIONALE• PIRACETAM
Piracetam is a cyclic derivative of GABA belonging to the racetams. Its chemical name is 2-oxo-1-pyrrolidine acetamide and is a nootropic drug with neuroprotective properties.
History-1964:Piracetam was first created in Belgium by UCB
Early 1970s :approved in Europe after several clinical trials Currently it sold in over 100 countries outside the US for treating several health conditions (dementia, dyslexia, stroke, vertigo, and sickle-cell anemia )under the name Nootropil.
In the US it is sold as a dietary supplement.
1.BACKGROUND AND RATIONALE• PIRACETAM:MECHANISM OF ACTION
Exact mechanism of action unknown, & different effects have been described:
Neuroprotective effect :Restorationof neurotransmission, improvement of metabolism which is evident in the presence of hypoxia (Giurgea 1970; Schaffler 1988)
Antithrombotic effect :Improvement of microcirculation,decrease of platelet aggregation.(Herrschaft 1978;Moriau 1993).
PIRACETAM:MECHANISM OF ACTION
Marc Fisher,2000
1.BACKGROUND AND RATIONALE
PIRACETAM: Presentation:Injectable. Ampoule of 5 ml contains 1 g Piracetam (200 mg/ml).
Film-coated tablets of400 mg .
Dosage:3 - 12 grams daily .
Contraindicationo Severe Renal Impairment o Hepatic Impairment And o Age <16 Years. o Cerebral Hemorrhage o hypersensitivity to piracetam, other pyrrolidone derivatives or any of the
excipients.o First trimester for pregnant women
1.BACKGROUND AND RATIONALE
• PIRACETAM:EFFECTSPositive
Ameliorate cognitive function;language inaphasic stroke patients (Greener 2001)
The drug has been reconsidered for acute stroke treatment as well (Noble 1996).
Side Effects
Are few, usually mild and transient but usually well tolerated? Symptoms of
general excitability (anxiety, insomnia, irritability, headache, agitation,
nervousness and tremor) are occasional reported (Hakkrainen, 1978).
1.BACKGROUND AND RATIONALE RATIONALE
Cerebral stroke is a grave condition (third leading cause of death in
developed countries, and the first leading cause of long-term disability in
survivors) necessitating not only an emergency treatment to prevent
neurologic complications and death but a continuation therapy to halt and
revert the consequences of the brain damage. Piracetam has been a
molecule used for this purpose owning to its purported neuroprotective
effect but its effectiveness has not been proven. A number of randomized
controlled trials have preformed but none has provided conclusive evidence
of the effect of piracetam for acute stroke patients thus recommending
further large scale or multicenter trials for the extensive testing of the
effectiveness (Ricci, 2009).
1.BACKGROUND AND RATIONALE RATIONALE
Despite its uncertain effectiveness, benefits and high cost for the patient, it is
routinely and indiscriminately prescribed by practitioners in many developing
countries Cameroon and Burkina Faso inclusive .It is on this grounds that we
intend to carry out our multicenter randomized controlled trial to ascertain
the effectiveness so as to provide a more rational treatment for the cerebral
stroke.
Among patients with acute ischemic stoke, can piracetam given within 48
hours of the onset of stroke reduce the risk of precocious death or yield a
better outcome in terms of recovery from neurologic deficit within a month
of treatment and follow up?
2. GOAL
◊To assess the Effectiveness and the Safety of piracetam in
acute stroke patients admitted in the two university teaching
hospitals of Burkina Faso and Cameroon, in Sub-Saharan
Africa, during a period of two years, from January 2010 to
December 2011.
2. OBJECTIVES
To determine in patients with cerebral stroke:
The short term effectiveness of piracetam(Onset to 1 month)
The safety of piracetam particularly for patients with hemorrhagic stroke
Early benefits of piracetam (post stroke recuperation of neurologic function).
4. METHODOLOGY
STUDY DESIGN
• Multicenter randomized triple-blind clinical trial comparing piracetam and placebo
in the treatment of acute cerebral stroke.
STUDY SETTING
Two Stroke Units in the Capital cities of Cameroon and Burkina Faso:
• University hospitals Yalgado Ouedraogo at Ouagadougou in Burkina Faso
• University hospital of Yaoundé, in Cameroon
STUDY PERIOD
• January 2010 to December 2011
4. METHODOLOGYSTUDY POPULATION (PARTICIPANTS):
• All adult patients with CT scan confirmed stroke reporting at the Ouagadougou and
Yaoundé Stroke Units within 24-48H after the onset of cerebral stroke
necessitating medical treatment only.
Exclusion criteria
Ø Cerebral stroke >48 H after onset of symptoms related to the current episode.
Ø Past medical history of episode of stroke
Ø Cerebrovascular accident associated to other co-morbidities
Ø Patients with untestable GCS
Ø Wish not to join the study
4. METHODOLOGY• PROCEDURESelection and Randomization
• The two principal investigators will independently select and randomize
participants at the trial centers using a random sequence of allocation generated
using computer software based on tables of random digits.
• Allocation rule defined at the start of study and respected throughout the studyIntervention
Two groups of patients:
Treatment group will receive piracetam, intravenously (800 mg of piracetam two
times per day) and, orally as soon as possible (the same dosage)
Control group will receive the placebo following same protocol as for treatment
group. The blinding will be triple for the clinicians ,the patients and the statisticians
4. METHODOLOGY• PROCEDURESample size requirements
• Assume α= 5% (probability to be wrong)
• and a statistical power (1-β )= 80%;
• a one month stroke mortality rate of of 33.6 % (Rosman,1986) ;
• Previous studies claim a reduction in mortality of piracetam to 20%
• STATCAL calculations n = Total (2 centers):500 (250 cases for same controls).
• Succintly: Center 1 (Yaounde): Total 250 subjects →Cases= 125 for 125 controls
Center 2 (Ouagadougou): Total 250 subjects→ Cases= 125 for 125 controls
• All the patients meeting the criteria of inclusion who give formal consent will be included
• Assumptions:20% loss to follow-up; total patient compliance
5. OUTCOME
• Our main outcomes of interest will be death from all causes and poor outcome (that is, dead, neurologic deficit) at the end of the acute phase (one month).
• *First 72H: Mortality from any cause within the first 72H following start of treatment.
• *One week-end 4 weeks: Mortality rate and Functional status using the WFNS Score WFNS SCORE• World Federation of Neurologic Surgeons (WFNS) Score, which was first reported in 1988 and
is based on the GCS (which is in worldwide used by both nurses and physicians). • WFNS Score: I-V;
score= I representing a neurologically normal individual, and score of V representing a severely damaged/moribund patient.
EYE OPENING BEST VERBAL RESPONSE BEST MOTOR RESPONSE
4=Spontaneous 5=Oriented 6=Obeys3=To speech 4=Confused 5=Localizes2=To pain 3=Inappropriate Words 4=Withdraws1=None 2=Incomprensible 3=Abnormal Flexion
(decortications)1=None 2=Extension (decelerations)99=Untestable 1=None
GLASGOW COMA SCALE
WFNS SCORE
Total GCS ∑subcategory scoresMax = 15 (4 + 6 + 5). Min=3 (1+1+1)
The WFNS Score combines GCS & neurologic deficit.
5. OUTCOME
WFNS SCORE GCS* NEUROLOGIC DEFICIT
I 15 No motor deficit
II 13-14 No motor deficit
III 13-14 Any motor deficit or aphasia
IV 7-12 With/without motor deficit
V 3-6 With/without motor deficit
99 UNTESTABLE Not testable
6. DATA COLLECTION AND ANALYSIS
The collection of the data will envisage avoiding or minimizing
any bias. Other concerns will be related to the summary of
the characteristics of the treatment group and the control
group, the specification of the primary and the secondary
data analyses for the physicians and the nurses involved in the
study, any subgroup analyses, the selection of the analytic
methods, the decision about how to handle missing data in
the analysis, how to interpret the results for “their
importance”
7. ETHICAL CONSIDERATIONS
• Permission from the Committee of Ethics of the Ministry of Health
• Formal consent from the participants or their close relative sought for their
participation to the study.
• The Respect of their confidentiality as well as the warranty of their anonymity
during the data collection and analysis proceeding, and also at the publications of
the results of the study.
8. TRIAL MANAGEMENT
The trial management is a relevant issue and will envisage in this study :
Strick monitoring and the follow- up of the patients involved ,
The measurements of the outcomes,
The handling of the loss to follow up,
Check for adverse effects
as well as the respect of patients’ privacy.
SUMMARIZE
• PROBLEM/PATIENTS: Effectiveness of Piracetam/ Cerebral Stroke patients
• INTERVENTION:Treatment with Piracetam
• COMPARISON:Placebo
• OUTCOME:Death,Neurologic Deficit
• STUDY:Multicenter Triple-Blinded Randomized Clinical Trial
Cameroon &Burkina Faso
• THANK YOU FOR YOUR KIND ATTENTION