Review of major drugs used for the management of acute stroke and the place of neuroprotective agents

1. Dr. Samiran Adhikari, MD

2. • Kashmir (1986) - 244North
• Kolkata (1998-99) - 334East
• Mumbai (1985) - 424West
• Vellore (1969-71) – 84South
Banerjee TK and Das SK. Neurology Asia 2006;11:1-4.

3.  Limited data
available
 Only 13.5% of all deaths in
India were medically
certified in 1994
 1.2% of the total deaths in
the country
 in the oldest group stroke
contributed 2.4% of all
deaths Banerjee TK et al. Neuroepidemiology 2001;20:201-7.
Anand Ket al. Neuroepidemiology 2001;20:208-11.

4. N Engl J Med 2007;357:572-9.
Ischemic Penumbra Infarct Core
Progression over Time of the Infarct Core, with Irreversible
Damage at the Expense of the Ischemic Penumbra

5. STROKE
Management
SECONDARY
PREVENTIONPRIMARY
PREVENTION
ACUTE
CARE
COMPREHENSIVE
REHABILITATION

6. Acute stroke:
What do we have in
store?
Another
patient
suffers a
stroke every
2nd sec
Leading
cause of
adult
disability
Vast
majority
(85%) due
to an Acute
Ischemic
Stroke
Few
treatment
options
A massive disease
burden with few
treatment options
Disease
Drugs

7. Thrombolytics
Antiplatelet
Agents
Anticoagulants
Vasodilators
Surgical
Interventions
Neuroprotective
Agents

8. STRENGTH
 Approved by US FDA
WEAKNESS
 Negative results of some
trials
 Symptomatic brain
hemorrhage- 6.4 % of
the patients
Stroke 2007;38;1655-1711

9.  t-PA is contraindicated in hemorrhagic
stroke

10.  Short therapeutic window or
reperfusion window is a serious
limitation and implementation of
intravenous therapy may not always be
easy and safe
t-PA is effective
if treatment is
initiated within 3
hours

11. Antiplatelet Agents
 The oral administration of aspirin
(initial dose is 325 mg) within 24
to 48 hours after stroke onset is
recommended for treatment of
most patients
The
administration of
clopidogrel
alone or in
combination with
aspirin is not
recommended
for the treatment
of acute
ischemic stroke
Stroke 2007;38;1655-1711

12.  The results of the recent trials show that early
administration of either heparin or a LMW
heparin/danaparoid is associated with an
increased risk of bleeding complications.
 Initiation of anticoagulant therapy within 24
hours of treatment with intravenously
administered rtPA is not recommended
Stroke 2007;38;1655-1711

13. Vasodilators in
Acute Ischemic
Stroke
 The administration of
medications such as
pentoxifylline is not
recommended for treatment
of patients with acute
ischemic stroke
The trial by Huber
et al in 1993
included 30 patients
after pentoxifylline
treatment and found
no difference in late
case fatality
Stroke 2007;38;1655-1711

14. Surgical
Interventions: CEA
 Data on the safety and
effectiveness of carotid
endarterectomy and other
operations for treatment of
patients with acute ischemic
stroke are not sufficient to
permit a recommendation
increase the
development of
brain edema
lead to
hemorrhagic
transformation
Stroke 2007;38;1655-1711

15. Structural lesion
Impairment of function (‘penumbra’)
Hours
Days and weeks
Minutes
Preventing the
progression of Ischemic
stroke - the goal of
neuroprotection
PENUMBRA
PENUMBRA
NEURON
CORE
NEURON
CLOT
CORE
The ischemic
penumbra is considered
to be the area of constrained
blood flow with partially
preserved

16.  Although piracetam may be
effective in some patients
with ischemic stroke, there
may be a trend for increased
risk of death among patients
treated with piracetam
 NXY 059 – unfulfilled
promise
 Data are not
sufficiently
clear to draw
a conclusion
about the
utility of
Piracetam
1. Cerebrovasc Dis. 2001;11(suppl 1):60 –70.
2. Cochrane Database Syst Rev. 2002;(4):CD000419.
3. Stroke 2007;38;1655-1711

17. SAINT I - PROMISE
 1699 subjects
 The administration of NXY-059 within six
hours after the onset of acute ischemic
stroke significantly improved the primary
outcome (reduced disability at 90 days)
 Additional research is needed to confirm
SAINT II – PROBLEM
 3195 patients
 NXY-059 is safe but ineffective for
the treatment of acute ischemic stroke
within 6 hours after the onset of
symptoms
Shuaib A et al. N Engl J Med 2007;357:562-71.Kennedy R et al. N Engl J Med 2006;354:588-600.

18.  Meta analysis reported that patients
with moderate to severe stroke
might be helped if citicoline was
started within 24 hours of onset
of symptoms1
 Clinical trials found that
edaravone might improve
outcomes2,3
 Seizes the
moment of
neuroprotect
ive window
before it slips
away
√ 1. Stroke. 2002;33:2850 –2857
2. Stroke 2007;38;1655-1711
3. Cerebrovasc Dis. 2003;15:222–2

19. Questions