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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Vishnu et al.
World Journal of Pharmacy and Pharmaceutical Sciences
SJIF Impact Factor 6.041
Volume 5, Issue 11, 618-623
Review Article
ISSN 2278 – 4357
TICAGRELOR VERSUS ASPIRIN IN ACUTE STROKE OR
TRANSIENT ISCHEMIC ATTACK: A STUDY.
Sujala Sunil1 , Vishnu Das 2* and Haripriya H.3
1,2,3
Doctor of Pharmacy (Pharm D) Student, Sree Krishna College of Pharmacy and Research
Centre, Trivandrum, 695502.
Article Received on
07 Aug. 2016,
ABSTRACT
Ticagrelor, the newer antiplatelet drug, may be a more effective
Revised on 28 Sept. 2016,
Accepted on 18 Oct. 2016
antiplatelet therapy than aspirin for the prevention of recurrent stroke
DOI: 10.20959/wjpps201611-8025
and cardiovascular events in patients with Transient Ischemic Attack.
Its double-blind, controlled trial in which 13,199 patients with a non-
*Corresponding Author
severe ischemic stroke or high-risk transient ischemic attack who had
Dr. Vishnu Das.
not received intravenous or intraarterial thrombolysis and were not
Doctor of Pharmacy
considered to have had a cardioembolic stroke were randomly assigned
(Pharm D) Student, Sree
with a 1:1 ratio, to receive either ticagrelor or aspirin. The primary end
Krishna College of
point was the time to the occurrence of stroke, myocardial infarction,
Pharmacy and Research
Centre, Trivandrum,
or death within 90 days. During the 90 days of treatment, a primary
end-point event occurred in 442 of 6589 patients (6.7%) treated with
695502.
ticagrelor and 497 of 6610 patients (7.5%) treated with aspirin. The
study concluded that the patients with ticagrelor was not found to be superior to aspirin in
reducing the risk of end points such as stroke, myocardial infarction, or death.
KEYWORDS: Transient Ischemic Attack (TIA), intraartreial, cardioembolic, thrombolysis.
BACKGROUND
The traditional definition of TIA is the one published by the Ad Hoc Committee on
Cerebrovascular Diseases in 1975 defined as “cerebral dysfunction of ischemic nature lasting
no longer than 24 hours with a tendency to recur”. Other published definitions include the
WHO definition as “sudden focal cerebral dysfunction lasting less than 24 hours of presumed
vascular origin confined to the area of brain or eye perfused by a specific artery”.[1] We note
that clinical experience suggests that many minor strokes are casually called Transient
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Ischemic Attack (TIA) because of causing a temporary disruption in the blood supply to part
of the brain. Disruption of the blood supply result in lack of oxygen to the brain. This can
cause sudden symptoms similar to those of a stroke such as speech and visual disturbance and
numbness or weakness in face, arms and legs. Since patients with residual minor symptoms
which are most often ignored diagnostically. The use of acute magnetic resonance imaging
(MRI) with diffusion weighted (DWI) sequences has shown that many patients with a clinical
definition of TIA have small infarcts on imaging. With the recent accumulated data on time
duration of TIA and imaging findings, a new tissue based definition has been proposed by
Albers and TIA working group and defines TIA as “a brief episode of neurological
dysfunction caused by focal brain or retinal ischemia, with clinical symptoms lasting less
than an hour and without neuroimaging evidence of acute infarction”.[2]
Ticagrelor is an oral antiplatelet drug. It binds to the P2Y12 adenosine disphosphate receptor
to reduce platelet activation and aggregation. In contrast to clopidogrel, the action of which is
dependent on variable and genetically determined metabolic activation. But unlike prasugrel
and clopidogrel, ticagrelor binds reversibly, so its inhibitory effect on platelet aggregation is
more quickly reversed. The inhibitory effects of ticagrelor 3 days after discontinuation are
similar to those seen 5 days after stopping clopidogrel. Clopidogrel and prasugrel are
prodrugs, whereas ticagrelor does not need to be metabolised to become biologically active
[3]
Aspirin is a medicine that help to fight coronary heart disease by preventing blood clots. It
thins blood by inhibiting platelet aggregation and preventing blood clot formation in the
arteries those that supply blood to your heart and brain. Thus it prevent heart attack and
stroke.[4]
Transient Ischemic Attack patients are high risk for stoke. Timely investigation and
management of TIAs significantly reduce the chance of stroke. The average risk of stroke
after a TIA is up to 3% in first 2 days, 5% in the first week and up to 12% at 90 days. A
patient 90 day risk can be lowered from 12% to about 2% with timely (<24hour)
investigation and aggressive management. The ABCD2 score with vascular imaging is
available to assess the short term risk after presenting with TIA. The score predicts the risk of
stroke within 2 days after a TIA, but also predicts stroke risk within 90 days.[5]
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SUMMARY
It is a multicentre, randomized, double-blind study were patients enrolled based on National
Institutes of Health Stroke Scale (NIHSS) score of 5 or lower (scores range from 0 to 42, with
higher scores indicating more severe stroke) or high-risk transient ischemic attack (ABCD2
stroke risk score of ≥4 [scores range from 0 to 7 with higher scores indicating higher risk of
stroke] or symptomatic intracranial or extra cranial arterial stenosis) and
have at least 40
years of age, and had undergone a computed tomographic (CT) or magnetic resonance
imaging (MRI) scan before randomization to rule out intracranial bleeding or other conditions
that could account for the neurologic symptoms or contraindicate study treatment.
Patients
were not eligible for participation if other specific antiplatelet therapy or anticoagulation
therapy was planned or if carotid, cerebrovascular, or coronary revascularization was planned
that would require halting study treatment within 7 days after randomization. Patients were
also not eligible if they had hypersensitivity to ticagrelor or aspirin; had a history of atrial
fibrillation, ventricular aneurysm, or suspicion of cardioembolic cause for transient ischemic
attack
or stroke; underwent intravenous or intraarterial thrombolysis or mechanical
thrombectomy within 24 hours before randomization; were in need of therapy with strong
cytochrome P-450 3A (CYP3A) inhibitors or CYP3A substrates with narrow therapeutic
indexes; required treatment with no steroidal anti-inflammatory drugs for more than 7
consecutive days; had a known bleeding diathesis or coagulation disorder; had a history of
symptomatic non traumatic intracerebral hemorrhage at any time, gastrointestinal bleed
within the past 6 months, or major surgery within 30 days; had severe liver disease; had renal
failure requiring dialysis; were pregnant or lactating; or could not understand or comply with
study procedures or follow-up.
Eligible patients were randomly assigned in a 1:1 ratio into two treatment groups. The
loading and maintenance doses of ticagrelor were selected on the basis of data from previous
phase 2–3 clinical studies. First group received either ticagrelor (a loading dose of 180 mg
given as two 90-mg tablets followed by 90 mg twice daily given orally together and daily
doses of aspirin placebo) and the second receive aspirin (a loading dose of 300 mg given as
three 100-mg tablets followed by 100 mg daily given orally and twice-daily doses of
ticagrelor placebo). It has given for the 90-day treatment period. At the end of 90 days of
study treatment, patients were treated at the discretion of the investigator and followed for an
additional 30 days.
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Overall, 13,307 patients were enrolled, and 13,199 patients underwent randomization. A total
of 494 patients (3.7%) presented with ischemic stroke within 4.5 hours after symptom onset,
of whom 128 (1.0% of the total patient population) had an NIHSS score higher than 3.Two
patients were lost to follow-up, and we were unable to determine the vital status of 7 others
after they withdrew their consent. Event statuses for components of the primary end point
were ascertained for 98.5% of the potential patient follow-up time.
The occurrence of any event for a given end point was compared with the use of the Cox
proportional hazards model. Interactions between treatment assignment and prespecified
subgroups were evaluated by including terms for treatment, subgroup, and treatment-bysubgroup interaction in the Cox model. Interaction terms with a P value of less than 0.05
were considered to be statistically significant.
A primary composite end-point such as stoke, myocardial infraction and death are occurred in
442 of the 6589 patients (6.7%) in the ticagrelor group and in 497 of the 6610 patients (7.5%)
in the aspirin group.
The main secondary end point, ischemic stroke, myocardial infraction
and cardiovascular death occurred in 423 patients (6.4%) in the ticagrelor group and 475
patients (7.2%) in the aspirin group.
A primary safety end-point event (PLATO-defined major bleeding) occurred in 31 patients
(0.5%) in the ticagrelor group and 38 patients (0.6%) in the aspirin group (hazard ratio, 0.83;
95% CI, 0.52 to 1.34). Intracranial haemorrhage occurred in 12 patients (0.2%) in the
ticagrelor group and in 18 patients (0.3%) in the aspirin group. Fatal bleeding occurred in 9
patients (0.1%) in the ticagrelor group and in 4 patients (0.1%) in the aspirin group.
Similarly, there were no significant differences in the other major safety outcomes. Dyspnoea
was more common in the ticagrelor group than in the aspirin group (6.2% vs. 1.4%).
Permanent discontinuation of study treatment occurred in 17.5% of patients in the ticagrelor
group, versus 14.7%of patients in the aspirin group. Dyspnoea and bleeding events were the
most frequent factors accounting for the difference, with rates of discontinuation due to
dyspnoea in the ticagrelor and aspirin groups of 1.4% and 0.3%, respectively, and rates of
discontinuation due to any bleeding of 1.3% and 0.6%. A net clinical outcome, defined as a
composite of stroke, myocardial infarction, death, or life threatening bleeding, occurred in
6.9% of patients in the ticagrelor group and 7.7% of patients in the aspirin group.
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CONCLUSION
In conclusion, in this trial involving patients with acute ischemic stroke or transient ischemic
attack, ticagrelor was not found to be superior to aspirin in reducing the risk of the composite
end point of stroke, myocardial infarction, or death. It only just shows a moderate reduction
in the primary and secondary endpoints. In this study the enrolment of not based on their co
morbid conditions nor by ABCD2 or NHSS score. By dividing the patients with that
parameters so that only we can assess and compare the efficacy and safety of drug accurately.
Because of lack of larger difference in the result which require further studies to agree with
the result.
RELEVANCE OF THE STUDY
Each year, approximately 200 000 to 500 000 patients are diagnosed by a physician as having
experienced a Transient Ischemic Attack (TIA) in the United States. An additional 300,000 to
700,000 individuals experience neurological symptoms suggestive of a TIA but never seek
medical attention for their symptoms. The clinical syndrome of TIA designates that the
abnormality in the cardiovascular system leading to compromised blood flow to the brain is
unstable and, if not properly treated, may also cause a debilitating ischemic stroke.
Approximately one in 10 patients with TIA experiences a stroke in the next 3 months; this
risk may be greater depending upon stroke mechanism. TIA can be imminent; the risk is
highest within hours of TIA and declines steadily within the ensuing days, weeks, and
months; nearly half of strokes occurring within the next 30 days occur within the first 24
hours after TIA. It is estimated that 12% to 30% of patients report a history of TIA soon
before their stroke and approximately a quarter of them occur during the hours before the
stroke. TIA constitutes a true medical emergency. Early initiation of preventive treatment for
TIA (for instance within 24 hours instead of 20 days) can reduce the 90-day risk of stroke by
approximately 80%. While rapid and accurate diagnosis and urgent initiation of treatment are
key to the management of TIA. So it is critical to accurately identify patients who are most
likely to benefit from further diagnostic investigations and rapid treatment.
Aspirin is the most commonly used drug for the treatment of Transient Ischemic Attack for
centuries. For the prevention of disease and further episodes, patient would need to take the
drug along their life time. Because of the long term treatment which produce a large no of
adverse
effects
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angioedema,
bronchospasm,
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hepatotoxicity
and
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complication of the drug with other co morbid conditions such as asthma, chronic liver
disease which limits the use of the drug. So that finding an alternative is very necessary.
Ticagrelor which is a newer hope for this. It is a potent antiplatelet and is direct-acting agent
that reversibly binds and inhibits the P2Y12 receptor on platelets. The large no of adverse
effects of the drug that limit its use. So proper assessment of safety and efficacy ticagrelor
over aspirin is inevitable for making the use of the drug beyond aspirin.
The purpose of the review is to compare the safety and efficacy of the newer drug, ticagrelor
over aspirin, the most commonly prescribed drug for TIA either as prophylaxis and as
treatment.
REFERENCE
1. Sylaja NP, Hill DM. Transient Ischemic Attacks- definition, risk prediction and urgent
management. Neurology India., Jun 2009; 57(3): 252-56.
2. Sorensen GA, Ay H. Transient Ischemic Attack Definition, Diagnosis, and Risk
Stratification. Neuroimaging clinical and anatomy. NIH Public Access., May 2011; 21(2):
303-13.
3. Ticagrelor
(Brilinta).
[Serial
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Dec
2011.Available
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http://www.npsradar.org.au/ Ticagrelor (Brilinta) for acute coronary syndrome.
4. London B. Aspirin. Journal of the American heart foundation [serial from internet].
Available from: http://www.ahajournals.org/Aspirin.
5. BCGuidelines.ca: Stroke and Transient Ischemic Attack – Acute and Long-Term
Management:
Appendix
C
[serial
from
internet].
2015.
Available
from:
http://www2.gov.bc.ca/gov/content/health/ Stroke and Transient Ischemic Attack- Acute
and Long Term Management: Appendix C.
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