Journal review of THALES trial published by NEJM on July 2020

1. Presented by:- Dr. Diptiman Behera
Preceptor:- Asst. Prof. Dr. Amita Kerketta
Department of General Medicine
S.C.B.M.C.H

2. STROKE
• Defined by the WHO as
– a clinical syndrome of rapidly developing clinical signs of
focal or global disturbance of cerebral function
– lasting more than 24 hours or leading to death with no
apparent cause other than a vascular origin
• TIA [Transient Ischemic Attack]
– Abrupt onset of neurological deficit, attributable to focal
vascular flow cessation to brain tissue for few minutes
– Where all the neurological signs and symptoms resolve
within 24 hours without evidence of brain infarction on
imaging

3. STROKE OR TIA
Ischemic Stroke or TIA
Globally - 68%
USA - 87%
Hemorrhage
Globally - 32%
USA - 10% ~ ICH
3% ~ SAH
In INDIA, the cumulative incidence of stroke range from 105 to
152/100,000 persons per year, and the crude prevalence of stroke ranged
from 44.29 to 559/100,000 persons in different parts of the country during
the past decade.
Sureshkumar Kamalakannan, Aashrai S. V. Gudlavalleti, Venkata S. Murthy Gudlavalleti, Shifalika Goenka,
Hannah Kuper, Incidence & prevalence of stroke in India: A systematic review
Indian J Med Res. 2017 Aug; 146(2): 175–185

4. for Ischemic Stroke

5. Ischemic
Stroke • (1) medical support,
• (2) IV thrombolysis,
• (3) endovascular
revascularization,
• (4) antithrombotic
treatment,
• (5) neuroprotection, and
• (6) stroke centers and
rehabilitation
Treatments
designed to
reverse or lessen
the amount of
tissue infarction
and improve
clinical outcome
fall within six
categories:
[Smith Wade S., Johnston S. Claiborne, Hemphill J. Claude, Ischemic Stroke: Primary and Secondary Prevention
of Stroke and TIA, Chapter 420, HARRISON Principles of Internal Medicine 20th ed, Vol. 2.Pg 3080]

6. Antithrombotic Treatment
Platelet Inhibition
Platelet antiaggregation agents can
prevent atherothrombotic events by
inhibiting the formation of intraarterial
platelet aggregates
Aspirin is the only antiplatelet agent that
has been proven to be effective for the
acute treatment of ischemic stroke.
[International Stroke Trial (IST) and the Chinese Acute
Stroke Trial (CAST)]
Aspirin, clopidogrel, and the combination
of aspirin plus extended-release
dipyridamole are the antiplatelet agents
most commonly used for secondary
prevention
Anticoagulation
For Cardioembolic
Stroke Prevention
No benefit of
anticoagulation in
the primary
treatment
of
atherothrombotic
cerebral ischemia

7. When to start antiplatelet therapy
• If not undergoing intravenous thrombolysis
– As soon as possible after the ischemic event
• With Aspirin alone for higher severity ischemic stroke
( NIHSS Score > 5 )
• With DAPT using aspirin and clopidogrel for minor
ischemic stroke
( NIHSS score ≤ 5 )
© 2020 UpToDate, Inc. and/or its affiliates

8. What is NIHSS Score ?
Orientation questions (2)
Level of
Consciousness
Response to commands (2)

9. (RANGE 0 to 42)

11. BACKGROUND
• Trials have evaluated the use of clopidogrel and aspirin
to prevent stroke after an ischemic stroke or TIA.
• In a previous trial, ticagrelor was found to be not better
than aspirin in preventing vascular events or death
after a stroke or TIA. [Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor
versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med. 2016;375(1):35-43]
[SOCRATES Trial]
• The effect of the combination of ticagrelor and aspirin
on prevention of stroke had not been well studied

12. • An exploratory analysis of subgroup of
patients in that SOCRATES trial, who had
received aspirin within 7 days, before
randomization and treatment with ticagrelor,
showed that they had reduced risk of major
vascular events.
– [Wong KSL, Amarenco P, Albers GW, et al. Efficacy and safety of ticagrelor in relation
to aspirin use within the week before randomization in the SOCRATES Trial. Stroke
2018; 49: 1678-85.]

13. Why Ticagrelor over Clopidogrel for DAPT
• Clopidogrel requires hepatic conversion to its active form
through a pathway that is inefficient in 25% of white and
60% of Asian patients due to genetic loss-of-function
(LoF SNPs) variants of CYP2C19 (Genetic polymorphism)
[Pan Y, Chen W, Xu Y, et al. Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient
ischemic attack: a systematic review and meta-analysis. Circulation 2017; 135: 21-33]
• Ticagrelor is a direct-acting antiplatelet agent that is not
dependent on metabolic activation, reversibly binds and
inhibits the P2Y12 receptor on platelets.

14. {carboxylesterase-1 }
PLATELET
{carboxylic acid metabolite}

15. Clopidogrel resistance in Indian
Patients

16. Patel Samir, Arya Vandana, Saraf Amrita, Bhargava Manorama & Agrawal C.S., Aspirin and Clopidogrel
Resistance in Indian Patients with Ischemic Stroke and its Associations with Gene Polymorphisms: A
Pilot Study. Annals of Indian Academy of Neurology., June 2019, Vol 22, Issue 2. 147-152.
In 65 stroke patients studied, 15.4% were resistant and 49.2% were semi-
responder to clopidogrel on platelet aggregation analysis.
Measured platelet aggregation on Light
Transmission Platelet Aggregometry

17. Among 200 INDIAN patients with MI, About 68% were sensitive to clopidogrel, and
32% were resistant.
Pareed Sadath A, Vijayaraghavan G, Kartha C C, Manoj M T, Antiplatelet drug
resistance in Indians, Annals of Clinical Cardiology, 2020 Volume: 2, Issue No.1,
Page: 36-41,.

18. • Ticagrelor is superior to clopidogrel in inhibiting
platelet reactivity (HPR) (indicates persistent
response of the P2Y12 receptor to ADP) measured
by the PL platelet function analyzer among
patients with acute minor stroke or TIA.
• [Yang Y, Chen W, Pan Y, Yan H, Meng X, Liu L, Wang Y and Wang Y; Ticagrelor Is Superior to
Clopidogrel in Inhibiting Platelet Reactivity in Patients With Minor Stroke or TIA. Front. Neurol.
2020, 11:534]

19. METHOD
• TRIAL DESIGN
– International multicenter, randomized, double-blind,
placebo-controlled, parallel-group trial
– conducted at 414 sites in 28 countries
– randomized within 24 h of symptom onset
– 30 days of treatment with ticagrelor or placebo on top of
standard-of-care therapy with aspirin and
– followed up for 30 days for efficacy and 60 days for safety
• The first patient was recruited on 22 January 2018.

20. • The sponsor, AstraZeneca, provided the trial
drug (ticagrelor) and placebo, monitored the
trial, and analyzed the data with the
oversight of the executive committee.
• All the authors vouch for the accuracy and
completeness of the data, for the adherence
of the trial to the trial protocol and statistical
analysis plan, and for full reporting of
adverse events.

21. PATIENTS
Inclusion Criteria
• ≥ 40 years of age
• mild-to-moderate acute
noncardioembolic ischemic
stroke ( NIHSS Score ≤ 5)
• High risk TIA (ABCD2 ≥ 6)
• Symptomatic intracranial or
extracranial arterial
stenosis(≥ 50% narrowing in
the diameter of the lumen
of an artery that could
account for TIA)
Exclusion Criteria
• If opting i.v. or intraarterial
thrombolysis
• If there was planned use of
anticoagulant or specific
antiplatelet therapy other than
aspirin
• Hypersensitivity to Ticagrelor or
Aspirin
• Cardioembolic cause of stroke
or TIA; Atrial Fib.
• Bleeding diathesis/ coagulation
disorder
• H/of ICH, GI bleeding within last
6 months or major surgery in
last 30 days

23. • Most patients (91%) presented with ischemic
stroke and 9% presented with TIA.
• The mean age of the patients was 65 years, and
39% were women.
• 13% of the patients were taking aspirin before
the initial index stroke or TIA.
• During the treatment period, 74% of the patients
received an antihypertensive agent, 83% received
a statin, and 28% received a glucose-lowering
agent.

25. Primary Outcome
• Composite of Stroke or Death
in a time-to-first event analysis
• Stroke included ischemic or
hemorrhagic (ICH, IVH, SAH)
• Death included all causes of
death
Secondary Outcome
• First, time from randomization to
first subsequent ischemic stroke
will be assessed,
• and then overall disability will be
measured by modified Rankin
Scale (mRS) score >1 at the end of
treatment (3rd Visit)
OUTCOMES

27. • The main safety outcomes are: First bleeding
event and is categorized based on criteria from
the Global Utilization of Streptokinase and
tissue-type plasminogen activator for Occluded
Coronary Arteries (GUSTO) trial

28. Severe bleeding (according to the GUSTO criteria)
was fatal bleeding or intracranial or other bleeding
that caused hemodynamic compromise for which
intervention was warranted (blood or fluid
replacement, vasopressor or inotropic support or
surgical intervention)
– Intracranial bleeding, including hemorrhagic
stroke and symptomatic hemorrhagic
transformation, was also reported as a severe
bleeding event

29. • Asymptomatic hemorrhagic transformations
of brain infarctions and microhemorrhages
<10mm evident only on MRI were excluded
from fulfilling intracranial hemorrhage criteria.

30. STATISTICAL ANALYSIS

32. • A primary-outcome event occurred in 303
patients in the ticagrelor–aspirin group (5.5%)
and in 362 patients in the aspirin group (6.6%)
(hazard ratio, 0.83; 95% confidence interval [CI],
0.71 to 0.96; P = 0.02)
• The first secondary outcome, subsequent
ischemic stroke, occurred in 276 patients in the
ticagrelor–aspirin group (5.0%) and in 345
patients in the aspirin group (6.3%) (hazard
ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004)

33. • The other secondary outcome of overall disability
(score >1 on the modified Rankin scale) occurred
in 23.8% of the patients in the ticagrelor–aspirin
group and in 24.1% of the patients in the aspirin
group (odds ratio, 0.98; 95% CI, 0.89 to 1.07; P =
0.61).
• Thus, the incidence of overall disability (modified
Rankin scale score >1) did not differ significantly
between the two treatment groups

34. PRIMARY OUTCOME

35. SAFETY OUTCOME

36. DISCUSSION
• The risk of recurrent stroke and other vascular
events is high in the first few weeks after
index minor ischaemic stroke and high risk
transient ischaemic attack (5-11.7%).
• Aspirin is the only antiplatelet agent with a
class 1 recommendation in international
guidelines and the only antiplatelet therapy
that has been shown to reduce disabling
strokes. [Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early
management of patients with acute ischemic stroke: a guideline for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke 2018; 49: e46–e110]

37. Why use Dual Antiplatelet Therapy?
• Several randomized controlled trials such as
the CHANCE and POINT trials, proved that the
addition of clopidogrel to aspirin significantly
decreased neurologic deterioration in patients
with acute non-cardioembolic ischemic
strokes.
– Platelet-Oriented Inhibition in New TIA and minor ischemic stroke Trial
(POINT)
– Clopidogrel in High-Risk Patients with Acute Nondisabling
Cerebrovascular Events Trial (CHANCE)

38. Risk of stroke recurrence -

39. • Following the encouraging results of these
trials of DAPT, many guideline-forming bodies
recommended short term use of DAPT
containing Clopidogrel and Aspirin in the
acute setting of non-cardiogenic minor
ischemic stroke and high risk TIA

41. • Studies have shown that patients who are
carriers of the cytochrome P450 (CYP)
CYP2C19*2 and *3 loss-of-function alleles do
not benefit from dual antiplatelet therapy
(aspirin combined with clopidogrel)
• Ticagrelor takes the upper hand regardless of
the CYP2C19 genotype.

42. Conclusion of THALES Trial
BENEFITS
• Lower risk of stroke or
death (Primary Outcome)
• Decreased incidence of the
secondary outcome of
subsequent ischemic stroke
• Better anti-platelet agent
than Clopidogrel
LIMITATIONS
• Incidence of overall
disability, didn’t differ
significantly between the
two treatment groups
• Ticagrelor–aspirin was
associated with higher risks
of severe hemorrhage and
cerebral hemorrhage than
aspirin alone

43. BIBLIOGRAPHY

44. I. Johnston S. Claiborne, M.D., Ph.D., et al, THALES Investigators, Ticagrelor and Aspirin or Aspirin Alone
in Acute Ischemic Stroke or TIA, N Engl J Med July 2020; 383:207-217
II. Smith Wade S., Johnston S. Claiborne, Hemphill J. Claude, Ischemic Stroke: Primary and Secondary
Prevention of Stroke and TIA, Chapter 420, HARRISON Principles of Internal Medicine 20th ed, Vol. 2.
III. Johnston SC, Amarenco P, Denison H, et al. The Acute Stroke or Transient Ischemic Attack Treated with
Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial: Rationale and design. Int J
Stroke. 2019;14(7):745-751.
IV. Cucchiara Brett L, MD., Messé Steven R, MD., Kasner Scott E, MD., Dashe John F, MD, PhD., Antiplatelet
therapy for the secondary prevention of ischemic stroke, In: UpToDate, Post, TW (Ed),
UpToDate, Waltham, MA, 2020.
V. Tantry Udaya S, PHD., Hennekens Charles H, MD., DrPH., Zehnder James L, MD., Gurbel Paul A, MD.,
Clopidogrel resistance and clopidogrel treatment failure, In: UpToDate, Post, TW (Ed),
UpToDate, Waltham, MA, 2019.
VI. Chugh C. Acute Ischemic Stroke: Management Approach. Indian J Crit Care Med 2019;23(Suppl
2):S140–S146.
VII. Wang Yongjun, Johnston S Claiborne, Bath Philip M, Grotta James C, Pan Yuesong, Amarenco Pierre et
al. Acute dual antiplatelet therapy for minor ischaemic stroke or transient ischaemic attack,
BMJ 2019; 364 :l895
VIII. Nakajima Steven H., Pharm.D., BCCCP; and Chester Katleen Wyatt, Pharm.D., BCCCP, BCGP: Acute Ischemic
Stroke, Critical and Urgent Care, PSAP 2020 Book 1, Pg 7-32

45. Thank You