An appraisal of the POINT trial (dual antiplatelets in stroke)

2. Background
• The risk of ischemic stroke ranges from 3 to 15% in the 90 days after a minor
ischemic stroke or a transient ischemic attack (TIA).
• Risk is particularly high in the first few days after TIA, with the onequarter to one-half
of the strokes that occur within 3 months of the onset of the TIA occur within the first
2 days
• Aspirin has been shown to reduce the risk of recurrent stroke by approximately 20%.
• CHANCE trial, which was initiated after the POINT trial and was completed before the
termination of the POINT trial, showed a 32% lower risk of stroke recurrence among
Chinese patients who were treated within 24 hours after a minor ischemic stroke or
TIA with a combination of clopidogrel and aspirin

3. Platelet-Oriented Inhibition in New TIA and minor ischemic
stroke (POINT) Trial
Primary null hypothesis
In patients with TIA or minor ischemic stroke treated with aspirin
50-325 mg/day,
there is no difference in the event-free survival at 90 days in those
treated with clopidogrel (600 mg loading dose then 75 mg/day) as
compared to placebo

4. Methods
• Prospective, randomized, double-blind, multicenter trial
• May 28, 2010 to December 19, 2017
• 269 sites in 10 countries in North America, Europe, Australia, and
New Zealand
• Patients 18 years of age or older with high-risk TIA ( ABCD2 score
>4) or minor ischemic stroke (with NIHSS <3) who can be
randomized within 12 hours of time last known free of new
ischemic symptoms

5. Methods
• Sponsored by the National Institute of Neurological Disorders
and Stroke (NINDS).
• Sanofi provided the clopidogrel and matching placebo for 75%
of the patients enrolled in the trial
• An independent data and safety monitoring board : monthly
assessments of safety and study conduct and oversight of the
interim analyses.

6. Inclusion criteria
1. Neurologic deficit (based on history or exam) attributed to focal
brain ischemia and EITHER:
a. High risk TIA: Complete resolution of the deficit at the time of
randomization AND ABCD2 score >4 OR
b. Minor ischemic stroke: residual deficit with NIHSS <3 at the time
of randomization
2. Ability to randomize within 12 hours of time last known free of new
ischemic symptoms.

7. Inclusion criteria
3. Head CT or MRI ruling out hemorrhage or other pathology, such as
vascular malformation, tumor, or abscess, that could explain
symptoms or contraindicate therapy.
4. Ability to tolerate aspirin at a dose of 50-325 mg/day.

8. • Age <18 years.
• TIA symptoms limited to isolated numbness, isolated visual
changes, or isolated dizziness/vertigo.
• In the judgment of treating physician, a candidate for thrombolysis,
endarterectomy or endovascular intervention, unless the subject
declines intervention at the time of evaluation for eligibility.
• Clear indication for anticoagulation (e.g., warfarin, heparin)
anticipated during the study period (atrial fibrillation, mechanical
heart valve, deep venous thrombosis,pulmonary embolism,
antiphospholipid antibody syndrome, hypercoagulable state)
Exclusion criteria

9. • Receipt of any intravenous or intra-arterial thrombolysis within
1week prior to index event.
• Gastrointestinal bleed or major surgery within 3 months prior to
index event.
• History of nontraumatic intracranial hemorrhage.
• Qualifying ischemic event induced by angiography or surgery.
• Severe non-cardiovascular comorbidity with life expectancy
<3months
Exclusion criteria

10. • Contraindication to clopidogrel or aspirin:
:Known allergy
:Severe renal (serum creatinine >2 mg/dL ) or hepatic insufficiency
:Hemostatic disorder or systemic bleeding in the past 3 months
:Current thrombocytopenia or neutropenia/granulocytopenia
:History of drug-induced hematologic or hepatic abnormalities
• Anticipated requirement for long-term (>7 day) non-study
antiplatelet drugs or NSAIDs affecting platelet function
• Not willing or able to discontinue prohibited concomitant
medications.
• Inability to swallow medications.
Exclusion criteria

11. • At risk for pregnancy: premenopausal or post menopausal woman
within 12 months of last menses without a negative pregnancy test
or not committing to adequate birth control
• Signed and dated informed consent not obtained from patient.
• Other neurological conditions that would complicate assessment of
outcomes during follow-up.
• Ongoing treatment in another study of an investigational therapy
that may potentially interact with study drug, or treatment in such
a study within the last 7 days.
Exclusion criteria

12. • Patients were randomly assigned in a 1:1 ratio to receive either
clopidogrel plus aspirin or placebo plus aspirin
• Stratification according to trial site
• Randomization takes place centrally and electronically via the
WebDCU™ clinical trials management system housed at the POINT
Statistics and Data Coordinating Center at the Medical University of
South Carolina (MUSC)
Randomization

13. St
Study Flowchart

14. Schedule of Assessments
MEASUREMENTS BASELINE PHONE F/U
Day 7
PHONE F/U
Day 30
Day 90/ Event
Visit
ABCD2 Score 
mRS 
NIHSS  
Index symptoms
Medical History

Head CT/MR Scan
Carotid Imaging
 
Stroke free/QVSFS
Questionnaire
  

15. Outcomes
Primary efficacy outcome
• Risk of a composite of new ischemic vascular events: ischemic
stroke, myocardial infarction, or death from ischemic vascular
causes upto 90 days
Secondary efficacy outcome
• Ischemic stroke
• Myocardial infarction
• Death from ischemic vascular causes
• Ischemic or hemorrhagic stroke
• Composite of ischemic stroke, myocardial infarction, death from
ischemic vascular causes, or major hemorrhage

16. Safety end points
Primary safety end point
• Risk of major hemorrhage, which was defined as :
:Symptomatic intracranial hemorrhage
:Intraocular bleeding causing vision loss
:Transfusion of 2 or more units of red cells or an equivalent
amount of whole blood
:Need for hospitalization or prolongation of an existing
hospitalization , or
:Death due to hemorrhage.

17. Sample-size calculation
• A sample of 4150 patients would provide the trial with 90%
power to detect a RRR of 23 %with a two-sided @ of 0.05 on the
basis of an event rate of 15% in the aspirin-only group and takes
into account 12% crossovers, and 2% losses to follow-up.
• As primary endpoint event rate in the trial was low , sample size
was increased to 5,840 participants and the statistical power was
reduced from 90% to 80%.

18. Trial discontinuation
• In December 2017, the prespecified boundary for a safety signal of
major hemorrhage was exceeded and a planned analysis
determined that a treatment effect had crossed the significance
boundary for efficacy.
• At the time that the trial was halted, 4881 patients had been
enrolled, which represented 83.6% of the anticipated number of
patients

20. Characteristics at Baseline

21. Characteristics at Baseline

22. Characteristics at Baseline

23. Results

24. Results

25. Efficacy and Safety Stratified by time period

28. Conclusion
• Patients from diverse countries with minor ischemic stroke or
high-risk TIA, those who received a combination of clopidogrel
and aspirin had a lower risk of a composite of ischemic stroke,
myocardial infarction, or death from ischemic vascular causes but
had a higher risk of major hemorrhage than patients who
received aspirin alone during the 90-day trial period

29. Critical Appraisal

30. Validity assessment
• Did the study ask a clearly-focused question?
• Yes
P: Patients with TIA or minor stroke treated with Aspirin
I: Clopidogrel
C: Placebo
O: New ischemic vascular events

31. • Was there a control group?
• Yes
• Were the patients randomised?
• Yes. Web based system.
• Was the randomisation concealed?
• Yes
• Are the prognostic factors comparable between two groups?
• Yes
Validity Assessment

32. • Was there any Co-intervention bias?
• No. All enrolled patients were provided standard treatment
• Was there any crossover/contamination?
• Not mentioned
• Was the compliance adequate?
• No . 29.6% patients in clopidogrel/aspirin group and 27.5% patients
in aspirin group discontinued medication
• Was the analysis based on Intention to treat principle?
• Yes
Validity Assessment

33. • Was the Follow up complete/ Adequate?
• 3.8% patients in intervention arm and 4.3% patients in control
arm were lost to follow up.
98.0% patients had been followed up for atleast 7 days, and
93.4% had completed the 90-day trial visit or had died.
• Was outcome measured by blinded assessors?
• Nature of outcome ( stroke, mortality) cannot be influenced by
unblinded assessors but study was double-blinded
Validity Assessment

34. Result assessment
• Did the new treatment make any difference?
• Yes. 25% Relative risk reduction for Ischemic/Hemorrhagic
stroke vs Aspirin alone with NNT of 62.5
Risk of Major hemorrhage : 1 person per 200 treated
• Is the observed difference real or by chance?
• Real / P value: 0.02 (CI 0.59 - 0.95) for the primary outcome

35. Applicability
• Were the study patients similar to patients in our practice?
• Yes /apart from ethnicity
• Were all patient important outcomes considered?
• Yes
• Are the study results applicable in our practice?
• Yes / With caveats
: Dual therapy should be confined to first 3 weeks
: Exclude patients at increased risk of bleeding

36. Thank you

38. As Treated Analysis