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Behshad NaghshtabriziAssociate Professor of Cardiology
Interventional CardiologistFarshchian Heart Center
Hamedan University of Medical Sciences
Why Ticagrelor?
Pivotal Trials of Ticagrelor
Because of reduction in:Mortality
MIStent thrombosis
Without increase in major bleeding
Why Ticagrelor?
PLATO
Study Design
Important Issues
• The benefits with Ticagrelor were seen regardless of whether invasive or
noninvasive management was planned; this issue has not been investigatedwith other P2Y12 inhibitors( Prasugrel only in invasive management)
• Dyspnea occurred more frequently with Ticagrelor than with Clopidogrel.Most episodes lasted less than a week. Discontinuation of the study drugbecause of dyspnea occurred in 0.9% of patients in the Ticagrelor group.
• Holter monitoring detected more ventricular pauses during the first week in theTicagrelor group than in the Clopidogrel group, but such episodes were
infrequent at 30 days and were rarely associated with symptoms.
No change in the overall risk of major bleeding
Result
Continued;
Continued;
Continued;
Continued;
Continued;
Continued;
Conclusions
• Reversible, more intense P2Y12 receptor inhibition for one year with
Ticagrelor in comparison with Clopidogrel in a broad population with ST-
and non-ST-elevation ACS provides:
• Reduction in myocardial infarction and stent thrombosis
• Reduction in cardiovascular and total mortality
• No change in the overall risk of major bleeding
Ticagrelor is more effective than Clopidogrel
for the continuous prevention of ischaemic events, stent thrombosis and
death in the acute and long-term treatment
of patients with ACS
Because its benefits are across the ACS spectrum, irrespective of management
(invasive vs non-invasive)
Why Ticagrelor?
PLATO
Because I can safely switch from Clopidogrel
Why Ticagrelor?
PLATO
Because its benefitaccrues over time (even >12 months)
Why Ticagrelor?
PEGASUS
Study Design
Important Issues• Patients who have had a myocardial infarction are at heightened
risk for recurrent ischemic events, which suggests that thispopulation may derive particular benefit from intensive secondaryprevention.
• A key element in the pathobiology of cardiovascular ischemic events isthe activated platelet.
• Rates of TIMI major bleeding were higher with Ticagrelor (2.60%with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001for each dose vs placebo); the rates of intracranial hemorrhage orfatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%,respectively.
Primary Endpoint
Diabetics vs Nondiabetics
Primary Endpoint
Conclusions• Addition of Ticagrelor at a dose of 90-mg twice daily or 60-mg twice
daily, to low-dose aspirin reduced the risk of CV death, MI, or strokeamong patients who had an MI 1-3 years later.
• A dedicated trial of long-term prevention with Clopidogrel on abackground of Aspirin in a broad population of patients withatherosclerotic disease or risk factors did not show a significant benefit.
• Rates of TIMI major bleeding were higher with Ticagrelor (2.60% with90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 foreach dose vs placebo); the rates of intracranial hemorrhage or fatalbleeding in the three groups were 0.63%, 0.71%, and 0.60%,respectively.
• Within the diabetic subgroup, there was a reduction in cardiovascularand coronary heart disease deaths with Ticagrelor versus placebo.
Because it is being studied across a wide range of patients with atherosclerosis
Why Ticagrelor?
THEMIS
Study Analysis
Primary Composite Endpoint
Primary Safety Outcome
Conclusions• In patients with stable coronary artery disease and diabetes, but
without a prior history of myocardial infarction or stroke,compared with aspirin alone, the combination of Ticagrelor plusAspirin reduced the primary endpoint of CV death, MI, or stroke.
• This benefit was achieved at the expense of increased majorbleeding.
• The incidence of an exploratory composite outcome of irreversibleharm (death from any cause, myocardial infarction, stroke, fatalbleeding, or intracranial hemorrhage) was similar in the Ticagrelorgroup and the placebo group.
Continued;
• In a prespecified exploratory analysis, the number ofevents of the composite of acute limb ischemia ormajor amputation was lower with Ticagrelor thanwith placebo.
• The high NNT and similar NNH currently only supportextended DAPT in diabetic patients having undergonePCI and at high ischaemic risk without high bleedingrisk but overally there was no significantly lowerincidence of the exploratory composite outcome ofefficacy and safety with Ticagrelor than with theplacebo.
THALES
Study Design
Important Issues
• Among patients with an acute ischemic stroke or transient ischemic attack (TIA), the risk of a subsequent ischemic stroke is approximately 5 to 10% in the first few months.
• Clopidogrel requires hepatic conversion to its active form through a pathway that is inefficient in 25% of white and 60% of Asian patients, and efficacy is uncertain in these patients.
• A trial of Ticagrelor alone in patients with acute ischemic stroke or TIA did not show a benefit over Aspirin in preventing subsequent cardiovascular events (stroke, myocardial infarction, or death).
Endpoints
• Primary endpoint:Time to the first occurrence of any event in the composite of stroke (ischemic or hemorrhagic) and death
• Secondary endpoints:
Time to the first occurrence of any ischemic stroke
• Safety endpoint:Time to first severe bleeding event (GUSTO definition)
• Exploratory endpoint:Disabling stroke (stroke event with mRS>1 at 30 days)
THALES
THALES
Conclusions• Among patients with mild-to moderate ischemic stroke or high-risk TIA who
received a combination of Ticagrelor and Aspirin, the risk of stroke or death(the composite primary outcome) was lower than that among patients whoreceived aspirin alone.
• The incidence of overall disability was similar in the two groups.
• The risk of severe hemorrhage was higher among patients who receivedTicagrelor–Aspirin than among those who received aspirin alone.
• Given the THALES results, targeting patients with atherosclerotic stenosis fordual therapy with Ticagrelor and Aspirin could yield a clinically meaningfulrelative and absolute risk reduction of stroke and death as compared to Aspirinalone with a number needed to treat of 92 and a number needed to harm of263.
SHORTER DURATION OF DAPT (THREE MONTHS)
Why Ticagrelor?
TWILIGHT
Study Design
Important Issues
• Key exclusion criteria included presentation with ST-segment elevation
myocardial infarction, cardiogenic shock, ongoing long-term treatment
with oral anticoagulants, or contraindication to Aspirin or Ticagrelor. Two
previous studies showed that among patients who had undergone PCI
and were at relatively low risk for ischemic events, Clopidogrel
monotherapy after 1 to 3 months of DAPT was associated with a
significantly lower incidence of bleeding than Clopidogrel plus aspirin,
without an apparent difference in ischemic risk.
• The SMART-DATE trial, which only included ACS patients, and use Clopidogrel in the majority of the DAPT, did show a higher risk of MI with 6 months DAPT as compared to 12 months.
Study Endpoint
• Primary Endpoint (Bleeding): Superiority Hypothesis
BARC 2, 3 or 5 bleeding between 0 - 12 months after randomization
• Key Secondary Endpoint (Ischemic): Non-inferiority Hypothesis
Non-fatal MI, stroke or all-cause death between 0 - 12 months after randomization
Primary Endpoint
BARC 2, 3 or 5 Bleeding ITT Cohort
Key Secondary Endpoint: Death, MI or Stroke
PP Cohort
Conclusion;
• The antithrombotic potency of Ticagrelor alone seems to be comparable to that of Ticagrelor and Aspirin with respect to ex vivo blood thrombogenicity.
• Although previously considered relatively benign, post-PCI bleeding has been shown to be associated with asubstantial and durable risk of death, approximating oreven exceeding that associated with myocardialinfarction.
Continued;
• In high-risk patients who underwent PCI and were treated with
Ticagrelor and Aspirin for 3 months without any major adverse
(bleeding or ischemic) events, an antiplatelet strategy of
continuing Ticagrelor monotherapy resulted in:
• Substantially less bleeding than Ticagrelor plus Aspirin
• Without increasing ischemic events over a period of 1 year
• In fact, even complete omission of Aspirin after PCI is now a topic of investigation.
TICO-STEMI
OUTCOME
OUTCOME
Conclusions
Ticagrelor monotherapy after just 3 months of dual antiplatelet
therapy (DAPT) in patients with STEMI treated with DES
proved a wining strategy in TICO-STEMI, a major randomized
trial.
Important Issues The future of antithrombotic therapy lies in an individualized
duration and composition based on risk stratification.
A pooled meta-analysis showed that extended DAPT reduced
ischaemic events with no effect on bleeding in patients with a
high DAPT score, and conversely increased bleeding without
an ischaemic benefit was seen in patients with a low DAPT
score who received extended DAPT.
Continued; There is some evidence supporting genotype guided P2Y12
inhibition, but still insufficiently for its routine adoption in
clinical practice.
Interestingly, the recently proposed ABCD-GENE score
integrates four clinical factors (age, body mass index, chronic
kidney disease, and diabetes mellitus) and CYP2C19
genotype. The ABCD-GENE score identifies patients with
HPR on Clopidogrel and those who are subsequently at
increased risk for death, MI, or stroke.
Important Issues
Compared with Clopidogrel, Ticagrelor appears to rapidly reduce the prevalence of inflammatory reactions and stabilize the functions of vascular endothelium to improve the stability of atherosclerotic plaque and decrease the occurrence rate of thrombosis as well as ischemic outcome events without any obvious increase in the risk of bleeding in patients with acute STEMI receiving urgent PCI.
Platelet inhibition at 1-year was higher in the Ticagrelor group, without an accompanying increase in bleedings. Endothelial function improved over time in Ticagrelor patients, while it did not change in the Prasugrel group.
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