Manuscript
A significant percentage (15-26%) of strokes are preceded by transient
ischemic attacks (TIA) or minor strokes (1). Recurrent strokes following
TIA or minor stroke is highest in the first 48 hours through the first
week (2-6). Early assessment and initiation of preventive treatment at
emergency TIA clinics have shown to reduce the early recurrence of
stroke at 90-days by about 80% in EXPRESS (Effect of urgent treatment
of transient ischemic attack and minor stroke on the early recurrent
stroke) and SOS-TIA studies (7, 8). Therefore, starting secondary
prophylaxis measures as soon as possible is very important.
Aspirin is the most effective treatment and the only antiplatelet
treatment that has evidence to have reduced recurrent disabling ischemic
strokes in patients with noncardioembolic ischemic stroke during the
first 90 days (9-12). Time-course analysis of acute stroke trials had
observed, 60-70% reduction in risk and severity of early recurrent
stroke with early initiation of aspirin following TIA and ischaemic
stroke (13). Furthermore, the benefit of aspirin is highest within the
first 6 weeks and it gradually wains off by 12 weeks and the benefits
become less clear beyond 90 days (13). The benefit of aspirin is more
when initiated following mild to moderate strokes than major stroke
(13). Therefore, early initiation of aspirin, preferably within 24-48
hours had been the guideline for long(14, 15). However, it is also
important to note that
the long-term risk of major bleeding is higher and more sustained in
patients receiving aspirin-based antiplatelet treatment long term
without routine proton pump inhibitor use, and half of the major bleeds
were in patients aged 75 years or older (16).
Dual antiplatelet therapy with aspirin and clopidogrel combination in
acute ischaemic strokes or TIA was studied in two major trials. CHANCE
(Clopidogrel with aspirin in acute minor stroke or transient ischemic
attack) trial studied aspirin vs aspirin and clopidogrel combination
administered within 24 and continued for 21 days following TIA or minor
stroke and demonstrated that aspirin and clopidogrel combination was
more effective in reducing recurrent strokes at 90 days without a
significant increase in bleeding risk (17). But, POINT
(Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke)
Trial observed that early initiation of aspirin and clopidogrel
combination vs aspirin, given for 90 days caused 25% increased risk
reduction of recurrent stroke but at the expense of 0.5% increased risk
of bleeding (18). However, a pooled analysis confirmed that the benefit
of this dual antiplatelet therapy is confined to the first 21 days after
minor ischemic stroke or high-risk TIA (19). Therefore, it is now
recommended in guidelines to treat TIA and minor strokes with dual
antiplatelet therapy (aspirin and clopidogrel) started within 24 hours
after symptom onset and to continue for 21 days in patients presenting
with minor ischemic stroke (NIHSS score ≤3) of noncardioembolic origin
who did not receive IV alteplase (14).
However, clopidogrel is ineffective in patients who are carriers of
CYP2C19 loss-of-function alleles, which is reported to be present in
15-60% of Asians depending on the ethnic group(20). Clopidogrel is a
pro-drug needing activation in the liver whereas the newer P2Y12
receptor blocker; ticagrelor has a direct action and does not need
activation in the liver (21, 22). Ticagrelor is a quick-acting,
predictable (as not dependent on CYP2C19 gene polymorphism) and
reversible platelet inhibitor unlike clopidogrel with an antidote also
being developed in phase II trials(23). Therefore, ticagrelor is being
studied in clinical trials for secondary prevention of TIA and strokes.
SOCRATES (Acute Stroke Or Transient IsChaemic Attack TReated With
Aspirin or Ticagrelor and Patient OutcomES) trial studied aspirin vs
ticagrelor started within 24 hours of the index event. Ticagrelor was
not found to be superior to aspirin in reducing recurrent cardiovascular
events (myocardial infarctions(MI), strokes and death) at 90 days (24)
and therefore, ticagrelor is not recommended over aspirin in the early
management of acute ischaemic strokes in current AHA/ASA guidelines(14).
Even though ticagrelor in SOCRATES trial did not show benefit in
achieving the primary outcome of reducing recurrent MI, stroke or death,
a stratified analysis, showed benefit in the reduction of all
stroke(24). Later in subgroup analyses of SOCRATES trial observed that
ticagrelor was substantially more efficacious In large artery
disease(25) and in patients with a background history of aspirin use
(26).
Dual antiplatelet therapy with aspirin and ticagrelor was compared with
aspirin and clopidogrel in a small, unblinded Chinese study; PRINCE
(Platelet Reactivity in Acute Non-disabling Cerebrovascular Events)
trial and observed that aspirin and ticagrelor combination is superior
in reducing platelet reactivity at 90 days(27). THALES (The Acute STroke
or Transient IscHaemic Attack Treated With TicAgreLor and ASA for
PrEvention of Stroke and Death) trial was studied aspirin vs aspirin and
ticagrelor combination treatment of 30 days in mild to moderate
(NIHSS<5) stroke patients, over 40 years of age started within
24 hours. The results were that the aspirin and ticagrelor combination
was superior to aspirin in reducing stroke or death (1.1%) but at the
expense of increased rate of severe bleeding (0.4%)(24).
Currently, as of emerging strategies, CHANCE-II trial is in progress
comparing dual antiplatelet therapy with aspirin and clopidogrel vs
aspirin and ticagrelor given for 21 days following acute TIA/stroke and
will hopefully bring new recommendations in future (ClinicalTrials.gov
no: NCT04078737).
Therefore, in conclusion, treatment with dual antiplatelet therapy
(aspirin and clopidogrel) started within 24 hours after symptom onset
and continued for 21 days is recommended in patients presenting with TIA
or minor noncardioembolic ischemic stroke (NIHSS score ≤3) who did not
receive IV alteplase, as the current best practice of secondary
prevention.