why ticagrelor?

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?

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;

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?

Because I can safely switch from Clopidogrel

Why Ticagrelor?

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

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

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.

why ticagrelor?

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