CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 3, April 2013
AFRICA
87
stroke outcome. These include clot busting, clot removal and
prevention of recurrence of stroke.
Clot busting
This is achieved by intravenous or intra-arterial thrombolysis.
Intravenous recombinant tissue plasminogen activa-
tor (IV r-tPA)
IV r-tPA when used within three hours of stroke onset in select
patients with acute ischaemic stroke (AIS) is the only US
Food and Drug Administration (FDA)-approved thrombolytic
treatment for stroke.
7
South African guidelines recommend it
should be administered at a hospital where rapid triage of stroke
patients is possible, with established protocols for the use of
r-tPA and where good post-treatment care is available.
4
In 1995 the landmark NINDS trial randomised 624 patients
with AIS to receive 0.9 mg/kg of IV r-tPA or placebo within
three hours of stroke onset.
8
Three months after treatment, 50%
of patients in the treatment arm had minimal or no disability
compared to 38% of patients in the placebo study arm: a 12%
absolute improvement. Although 6.4% of patients treated with
IV r-tPA developed symptomatic intracerebral haemorrhage
(sICH) compared to 0.6% of patients given placebo, the death
rate in the two treatment groups was similar at three months
(17 vs 20%). This was the first time a treatment for stroke had
improved or reduced disability significantly.
In two other large, randomised, double-blinded phase 3 trials,
the European Cooperative Acute Stroke study (ECASS) and
ECASS-II, IV r-tPA was not more effective than placebo in
improving neurological outcomes 90 days after stroke.
7,9
A dose
of 1.1 mg/kg of IV r-tPA was used in ECASS and a dose of 0.9
mg/kg was used in ECASS II. In both trials, patients were treated
up to six hours after stroke. The ATLANTIS A and ATLANTIS
B trials from North America, both placebo-controlled, double-
blinded, randomised trials, also did not support the use of IV
r-tPA beyond three hours of ischaemic stroke onset.
10,11
Taking into account the findings of all these studies, the
2007 American Heart Association/American Stroke Association
(AHA) guidelines recommended the dosing regimen of 0.9 mg/
kg (maximum 90 mg) for selected patients who may be treated
within three hours of onset of AIS (class I, level of evidence
A).
12
Ten per cent of the dose is given as an initial intravenous
bolus and the rest is infused over one hour provided there are no
contraindications for the treatment.
12
However, this dose is not
universally accepted, with most Japanese studies continuing to
support the use of 0.6 mg/kg.
13
Treatment benefit is time dependent and the number needed
to treat (NNT) to get one more favourable outcome drops from
four during the first 90 minutes to seven at three hours, and
towards 14 between three and 4.5 hours.
14,15
This implies that
there is no potential benefit beyond three hours.
In 2008 the ECASS III trial showed that IV r-tPA administered
within three to 4.5 hours of stroke onset may offer a moderate
benefit when applied to all patients with potentially disabling
deficits.
15
The incidence of intracranial haemorrhage was higher
with IV r-tPA than with placebo in this study [27.0 vs 17.6% for
any intracranial haemorrhage (
p
=
0.001) and 2.4 vs 0.2% for
symptomatic intracranial hemorrhage (
p
=
0.008)], but mortality
did not differ significantly between the two groups.
In the joint-outcome table analysis of the ECASS III trial,
the number needed to treat to benefit (NNTB) was 6.1 and
the number needed to treat to harm (NNTH) was 37.5, which
indicates that for every 100 patients treated in the three- to
4.5-hour window, 16.4 will have a better outcome and 2.7 will
have a worse outcome by
≥
1 level on the modified Rankin score
(mRS) of global disability.
16
In other words, among individuals
matching the ECASS III cohort, as a result of treatment with
IV rTPA in the three- to 4.5-hour window, approximately one in
six patients have a better outcome and one in 35 have a worse
outcome.
Furthermore, in a study determining the NNTH following
IV r-tPA, most patients who experienced sICH after IV r-tPA
therapy had severe baseline insults and were destined for a
poor outcome.
17
In other words, the sICH may have caused
temporary early worsening, but is unlikely to have altered the
final functional outcome. Using a 15-variable prognostic model
derived from the placebo group in NINDS 1 and 2, it was
found that the NNTH ranged from 29.7 to 40.1.
17
This implies
that among individuals matching the NINDS cohort, for every
100 patients treated with IV r-tPA , only one will experience a
severely disabled or fatal final outcome.
Based on these findings, the AHA issued revised guidelines
that expanded the window for IV r-tPA treatment from three to 4.5
hours in eligible patients.
18
In a recent phase 2B trial comparing
the use of alteplase to tenecteplase in eligible patients within six
hours of onset of acute ischaemic stroke, tenecteplace was shown
to be superior in terms of significantly better clinical improvement
and reperfusion.
19
A phase 3 trial is needed to confirm this.
There is no evidence showing benefit with any other intra-
venously administered thrombolytic agents, including strepto-
kinase, reteplase, urokinase, anistreplase and staphylokinase for
use in acute stroke. These should be avoided in routine clinical
practice outside the context of a clinical trial.
4
Studies with
desmoteplase and ancrod, a defibrogenating enzyme derived
from snake venom, are underway.
Risks and benefits of treatment with IV r-tPA for AIS should
be discussed with the patient or family before administration.
12
Written consent has been deemed as not necessary by health
authorities.
12
Adverse events of IV r-tPA include intracranial
haemorrhage, anaphylactic reaction, angio-oedema and
myocardial rupture.
12
In a recent international, multicentre,
randomised, open-treatment trial, assessing the benefits and
harms of IV r-tPA given within six hours of AIS, deterioration
due to swelling of the infarct and sICH in the first seven days
was more significant in those patients who received IV r-tPA
compared to those who did not.
20
Patients receiving IV r-tPA also
had significantly more non-fatal extracranial haemorrhages.
20
Difficulties in administering IV r-tPA within 4.5 hours include
early recognition of signs of stroke by the patient or family
members, early evaluation of the patient by paramedics, rapid
transport of patients to stroke centres, availability of radiological
services, and appropriate evaluation by an experienced clinician
as to the suitability of thrombolytic therapy. Indications and
contraindications for IV r-TPA are described in Table 1.
Intra-arterial (IA) thrombolysis
AHA guidelines recommend that IA thrombolysis can be
considered an option for treatment of AIS due to occlusions of
