Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction by Dr. Vaibhav Yawalkar MD, DM Cardiology

1. Ticagrelor vs Clopidogrel After Fibrinolytic Therapy
in Patients With ST-Elevation Myocardial Infarction
TREAT - A Randomized Clinical Trial
JAMA Cardiology March 11, 2018
Dr. Vaibhav Yawalkar
MD, DM Cardiology

2. IMPORTANCE
The bleeding safety of ticagrelor in patients with ST-
elevation myocardial infarction treated with
fibrinolytic therapy remains uncertain.
OBJECTIVE
To evaluate the short-term safety of ticagrelor when
compared with clopidogrel in patients with ST-
elevation myocardial infarction treated with
fibrinolytic therapy.

3. DESIGN
A multicenter, randomized, open-label with blinded end point
adjudication trial evaluating non-inferiority of intervention
Enrolled 3799 patients (younger than 75 years) with STEMI
who received fibrinolytic therapy
Place of study: 152 sites from 10 countries
Duration: November 2015 through November 2017
Follow up: 7th day, 30th day, 6 months and 12 months
Prespecified upper boundary for noninferiority, was an
absolute difference of not more than 1.0% for bleeding
episodes

4. Argentina (06 sites)
Australia (10 sites)
Brazil (25 sites)
New Zealand (07 sites)
Peru (05 sites)
Canada (17 sites)
China (47 sites)
Colombia (02 sites)
Russia (20 sites)
Ukraine (13 sites)
3,799 Patients from 10 Countries
341
27
863
34
55
161
82
293
694
1249

5. Inclusion Criteria
• Age 18 – 75 years
• STEMI presenting < 24h after symptom onset
• Received fibrinolytic therapy
Exclusion Criteria
• Contraindication to clopidogrel, ticagrelor or fibrinolysis
• Use of oral anticoagulant therapy
• Increased risk of bradycardia (not further defined)
• Concomitant use of a strong CYP3A4 inhibitor/inducer
• Dialysis-dependent
• Clinically-important anemia or thrombocytopenia, or active
bleeding (therefore excluding those who bled early with the
initial fibrinolytic + antiplatelet regimen)

6. Randomization
Patients were randomly assigned, in a 1:1 ratio to receive
• Ticagrelor with a loading dose of 180 mg
or
• Clopidogrel (with a loading dose of 300 to 600 mg)
As early as possible after Fibrinolysis and not more than
24 hours after fibrinolysis

7. Randomization
 If randomized to ticagrelor, the trial loading dose (180 mg)
was recommended.
 If randomized to clopidogrel, the patients could receive an
additional 300 mg of clopidogrel at the discretion of the
investigator if undergoing PCI (as 90% patients had already
received loading dose of Clopidogrel after diagnosis of
STEMI) else was directly started on maintenance
Clopidogrel dose.
 The randomized maintenance therapy for Ticagrelor was 90
mg twice daily and for clopidogrel was 75 mg once daily.

8.  All patients received Acetylsalicylic acid (ASA), 75 to 100 mg
daily, during all the follow-up unless intolerant. For patients not
previously receiving ASA, a loading dose of 162 mg to 325 mg
was given.
 Clopidogrel dose administered before randomization:
> 300 mg (3%)
= 300 mg (87%)
none or < 300 mg (10%)
 Fibrinolytic selection:
TNK ~40%
Alteplase ~20%
Reteplase 17%
other 23%

9.  Median interval from symptom onset to fibrinolytic
administration = 2.6 hours
 Median interval from fibrinolytic administration to
randomization = 11.4 hours
 PCI during hospitalization was done in 56%, drug-
eluting stent implanted in 34%, no changes in
maintenance dose of either Ticagrelor or Clopidogrel
were made post PCI

10. Outcome Parameters
Safety outcomes
Primary:
Major bleeding, according to the Thrombolysis in
Myocardial Infarction (TIMI) definition
Secondary:
Major or minor bleeding according to the PLATO
and the Bleeding Academic Research Consortium
(BARC) definitions
Clinically relevant non-major bleeding or minor
bleeding according to the TIMI definition

11. Outcome Parameters
Secondary Efficacy outcomes
 The composite outcome of death from vascular causes,
MI, or stroke (similar to the PLATO primary outcome)
 Same composite outcome with the addition of recurrent
ischemia, TIA or other arterial thrombotic events
 Individual components of the composite outcome
 All-cause mortality at 30 days

12. TIMI Definition of Bleeding (Non-CABG related )
Major
• Any intracranial bleeding (excluding microhemorrhages
< 10 mm evident only on gradient echo MRI)
• Clinically overt signs of hemorrhage associated with a drop in hemoglobin of
>5 g/dL
• Fatal bleeding (bleeding that directly results in death within 7 days)
Minor
• Clinically overt (including imaging), resulting in hemoglobin drop of 3 to < 5
g/dL
Requiring medical attention
Any overt sign of hemorrhage that meets one of the following criteria and does not
meet criteria for a major or minor bleeding event
• Requiring intervention (medical or surgical)
• Leading to or prolonging hospitalization
• Prompting evaluation (leading to an unscheduled visit to a healthcare
professional and diagnostic testing, either laboratory or imaging)
Minimal
• Any overt bleeding event that does not meet the criteria above

13.  The mean (SD) age was 58.0 (9.5) years
 77.1% were men
 46.3% were current smokers
 8.6% had a history of MI.
 99.9% of the patients received fibrinolytic agent, of whom
75.9% received a fibrin specific agent
 The 2 treatment groups were well balanced as
demonstrated by the baseline characteristics
Baseline characteristics

18. Results: (At 30 days)
Bleeding
 The primary outcome (TIMI major bleeding up to 30 days)
occurred in
14 of 1913 patients (0.73%) in the ticagrelor group and
13 of 1886 patients (0.69%) in the clopidogrel group
(absolute difference,0.04%; 95%CI,- 0.49% to 0.58%;
P < .001 for noninferiority)
 Major bleeding as assessed by the PLATO criteria and
BARC types 3 to 5 bleeding occurred in
23 of 1913 patients (1.20%) in the ticagrelor group and
26 of 1886 patients (1.38%) in the clopidogrel group
(absolute difference, -0.18%; 95% CI, -0.89% to 0.54%;
P = .001 for noninferiority)

19.  The rates of fatal bleeding (0.16 % vs 0.11%; P = .67) and
intracranial bleeding (0.42% vs 0.37%; P = .82) were similar
between the ticagrelor and the clopidogrel groups,
respectively.
 Minor and minimal bleeding, as well as total bleeding, were
more common with ticagrelor than with clopidogrel,
irrespective of the classification used
Results: (At 30 days)
Bleeding

20.  In patients who received study drugs within 4 hours after
initiation of fibrinolytic therapy, the TIMI major bleeding
events rates in both groups were more compared to those
who received drugs after 4 hours.
< 4 hours : 1.5% vs 1.2%
4 – 8 hours: 0.8% vs 1.2%
8 - 16hours: 0.5% vs 0.3%
16+ hours: 0.5% vs 0.2%
(Ticagrelor vs Clopidogrel)
Results: (At 30 days)
Bleeding

24. Results: (At 30 days)
Efficacy
 The composite outcome of death from vascular causes, MI,
or stroke occurred in
76 patients (4.0%) treated with ticagrelor and in
82 patients (4.3%) receiving clopidogrel
(hazard ratio, 0.91; 95%CI, 0.67- 1.25; P = 0.57).
 The rates of individual outcomes of MI, stroke, and other
arterial thrombotic events were similar in the ticagrelor and
clopidogrel groups.

25. Results: (At 30 days)
Other adverse Events
 Discontinuation of the study drug owing to serious adverse
events was similar between ticagrelor and clopidogrel
groups (0.40% vs 0.40%; P = .99).
 Dyspnea was more common in the ticagrelor group than in
the clopidogrel group [13.9%] vs [7.6%] respectively
 Few patients discontinued the study drug because of
dyspnea (19 of 1913 patients [1.0%] in the ticagrelor group
and none in the clopidogrel group).
 The frequencies of serious adverse events were similar
between groups.

28. Discussion
 In this trial of patients younger than 75 years with STEMI
who received fibrinolytic therapy as their initial reperfusion
strategy, delayed administration of ticagrelor was noninferior
to clopidogrel with respect to major bleeding (according to
the TIMI, PLATO, and BARC classifications) at 30 days.
 “Delayed” here meaning that, Ticagrelor was not used as
primary antiplatelet to be given after diagnosis of STEMI,
rather was given soon after & within 24 hours of fibrinolysis.
Clopidogrel was the primary antiplatelet received by 90% of
patients.
 The rates of fatal and intracranial bleeding were similar
between the Ticagrelor and Clopidogrel groups.

29. Discussion
 In contrast the rates of minor, minimal , and total bleeding
events were numerically higher with ticagrelor than with
clopidogrel.
 Because most of the included patients were pretreated with
clopidogrel, these findings reflect mostly the noninferiority of
switching from clopidogrel to ticagrelor in patients already
treated with clopidogrel.

30. Other Trials
 A trial by Dehghani et al compared ticagrelor with clopidogrel
in 144 patients undergoing early PCI post-reperfusion with
tenectaplase.
 All patients received clopidogrel pre randomization, and the
median time of thrombolytic administration to randomization
(and initiation of ticagrelor vs clopidogrel) was about 6 hours.
 The BARC types 3 to 5 bleeding rates at 30 days were 1.3%
in both the ticagrelor and clopidogrel groups at 30 days,
which are similar to the rates observed in TREAT for the
same outcome

31. Other Trials
 The Sampling P2Y12 Receptor Inhibition With Prasugrel and
Ticagrelor in Patients Submitted to Thrombolysis (SAMPA)
trial compared ticagrelor and prasugrel in patients with
STEMI post-fibrinolytic therapy.
 Similar to TREAT, all patients also received clopidogrel pre-
randomization, and the median time to randomization after
thrombolytic therapy was 12.2 hours.
 No major bleeding events were observed within 30 days

32. Limitations
 Comparisons of safety event rates between TREAT and
other large-scale ticagrelor trials in patients with acute
coronary syndromes are limited owing to differences in study
designs, populations, and follow-up.
 Noninferiority margin of 1% could be quite wide and
reflective of the modest sample size.
 Owing to the low number of events, statistical power to
assess superiority is limited; thus, these findings must be
interpreted as exploratory.

33. Limitations
 The median time of thrombolytic administration to
randomization was about 11 hours, which is beyond the half-
life of fibrin-specific fibrinolytics. Thus, it is likely that patients
who had early bleeding events associated with fibrinolytic
therapy were excluded.
 Trial does not address treatment of patients older than 75
years, who were excluded.
 The crucial question that needs to be addressed—
concomitant use of ticagrelor with lytic therapy for acute
revascularization— remains unanswered in this trial.

34. Conclusions
 Given that patients who received fibrinolytic therapy in the
previous 24 hours were excluded from the PLATO trial and
STEMI guidelines recommend that ticagrelor should only be
initiated after 48 hours after fibrinolysis, this trial adds new
safety information for Ticagrelor for early use after
fibrinolysis.
 In patients younger than 75 years with STEMI, delayed
administration of ticagrelor after fibrinolytic therapy was
noninferior to clopidogrel for TIMI major bleeding at 30 days.
However, minor bleeding was increased with ticagrelor, and
there was no benefit on efficacy outcomes.

35. Bottom line:
 In patients < 75 years who received fibrinolytic therapy
plus a loading dose of clopidogrel for STEMI & already
not actively bleeding from this, switching to ticagrelor with
a loading dose 8 - 24hours after administration of the
fibrinolytic agent does not appear to increase the risk of
major, fatal or intracranial bleeding at 30 days versus
continuing with clopidogrel.
 Follow-up in TREAT is ongoing; 12-month outcomes as
well as meta-analysis with PLATO STEMI subgroup will
likely be reported in 2019.