BRILIQUE® (ticagrelor)

BRILIQUE (ticagrelor) is the only P2Y12 inhibitor licensed in combination with aspirin to protect patients with prior MI and a high risk* of atherothrombotic events against subsequent CV events in both the acute and long-term treatment settings†1

*High risk is defined as ≥1 additional atherothrombotic risk factor (age ≥65 years, >1 prior MI, multivessel coronary artery disease, diabetes requiring medication, chronic non-end-stage renal dysfunction)1

BRILIQUE (ticagrelor) 90mg twice daily  in combination with  acetylsalicylic acid (ASA) is indicated for patients with Acute Coronary Syndromes (ACS) for up to 12 months. BRILIQUE (ticagrelor) 90mg twice daily is not indicated for use in patients beyond 12 months. There are limited data on the efficacy and safety of BRILIQUE (ticagrelor) 60mg beyond 3 years of extended treatment

Clinical Studies

BRILIQUE (ticagrelor) demonstrated acute and long-term CV protection across two large studies: PLATO and PEGASUS-TIMI 54 respectively.4,15

The PLATO study compared BRILIQUE (ticagrelor) (180-mg loading dose, 90mg twice daily thereafter) and clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of thrombotic CV events (CV death, MI, or stroke) in 18,624 patients admitted to hospital with an ACS with or without ST-segment elevation. Patients were treated for at least 6 months and up to 12 months.4

BRILIQUE (ticagrelor) – the only oral antiplatelet with evidence demonstrating a statistically and clinically significant reduction in CV mortality at 12 months compared to clopidogrel in patients with ACS.4,16

The PEGASUS-TIMI 54 study compared BRILIQUE (ticagrelor) (90 mg twice daily or 60 mg twice daily) vs. placebo, each given with low-dose aspirin, for the prevention of thrombotic CV events (CV death, MI, or stroke) in 21,162 patients ≥50 years of age with a history of MI (1 to 3 years prior to randomisation) and at high risk* of another atherothrombotic event.15

*High risk is defined as ≥1 additional atherothrombotic risk factor (age ≥65 years, >1 prior MI, multivessel coronary artery disease, diabetes requiring medication, chronic non-end-stage renal dysfunction)

APOLLO HELICON/HESIOD

Study results

Following an MI, your patients remain at high risk of further CV events for up to 5 years

  • National registry data from Sweden (n=97,254) and Denmark (n=55,747) have shown that ~1 in 5 patients surviving an acute MI experience further CV events during the first year post-discharge17,18
  • Of patients who are event-free at 1 year, up to another 1 in 5 experience an event in the following 3–4 years17,18
Apollo study risk
Apollo study risk

Cumulative risk of MI, ischaemic stroke or CV death during the first year after the index MI and in the subsequent 3 years in the Swedish population. Adapted from reference 17.

CV, cardiovascular; MI, myocardial infarction

Large-scale, real-world retrospective analyses of Swedish and Danish national registry data evaluating CV risk in patients surviving an acute MI during the first year post-event and in subsequent years.17,18

  Sweden (n=97,254) Denmark (n=55,747)
Data Sources

National Inpatient Register

Swedish Prescribed Drug Register

Cause of Death Register

Civil Registrations System

Danish National Patient Registry

Danish Register of Causes of Death

Danish Heart Registry

Danish National Registry of Medicinal Product Statistics

Integrated Database for Labour Market Research

Inclusion criteria

MI population (index MI until day 365) Patients admitted to hospital with a primary diagnosis of acute MI between 01/07/2006 and 30/06/2011, who  were discharged with a diagnosis of acute MI and were alive 7 days after discharge.

Stable post-MI population (day 366 until study end) Patients who survived the first 365 days after the index MI, without a stroke or recurrent MI.

MI population (day 7 after hospital discharge until the primary endpoint, death, emigration or day 365 after discharge)

Patients aged ≥18 years with first recorded primary or secondary diagnosis of index MI between 01/01/2004 and 31/12/2010 and no prior MI admissions in the previous 12 months, who survived the index MI without a stroke or recurrent MI within 7 days of discharge.

Stable post-MI population (day 366 after hospital discharge until the primary endpoint, death, emigration or study end)

Patients who survived the first 365 days after the index MI, without a stroke or recurrent MI.

Exclusion criteria
Patients who died within 7 days of discharge following the index MI.
Patients who died, or had recurrent MI or stroke, within 7 days of discharge and those with a recent MI history (≤12 months before the index event).
Primary endpoint
Composite endpoint of non-fatal MI, non-fatal stroke or CV death.
Composite endpoint of non-fatal MI, non-fatal stroke or CV death.
Mean follow-up
2.5 years 3.6 years

The risk your patients face may be higher than observed in clinical trials

  • UK electronic health record data (CALIBER) are consistent with the findings from Sweden and Denmark
    • 17.2% of patients surviving an acute MI for ≥1 year had further events over the following 3 years
       
  • In high-risk patients matching the inclusion and exclusion criteria of the PEGASUS-TIMI 54 the risk of further CV events was 18.8%19
    • This compares with a recurrent CV event rate of 9.0% in the placebo arm of the clinical trial15,a
APOLLO CALIBER
APOLLO CALIBER

Cumulative CV risk in the overall population, in high-risk patients matching the PEGASUS-TIMI 54 inclusion and exclusion criteria, and in the placebo arm of the trial. Adapted from references 15 and 19

a  Bleeding (fatal, severe or intracranial) risk was 2.3% in the overall study population and 3.0% in PEGASUS-likepatients, vs 1.06% in the PEGASUS-TIMI 54 placebo arm (TIMI major bleeding).

Comparison of baseline demographics in the CALIBER and PEGASUS-TIMI 54 populations

CALIBER population
CALIBER population

Key baseline characteristics of the CALIBRE and PEGASUS-TIMI 54 populations. Adapted from references 15 and 19.

a Information was available for 94% of patients.
b Multivessel disease was not coded in the CALIBER registry, but it was identified as an important risk factor for further CV events in the Danish registry study.18
c Information was available for 88% of patients.
eGFR, estimated glomerular filtration rate; NA, not available; NSTEMI, non-ST-elevation myocardial infarction;
PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

Study design19

Observational cohort study based on the CALIBER platform with linked electronic health records across primary care (CPRD), ACS registry (MINAP), hospital care (hospital episodes statistics), and cause-specific mortality (Office for National Statistics).

The study included patients admitted to hospital with a primary diagnosis of ACS between April 2005 and March 2010, who survived for at least 1 year after the index MI (n=7,328). A subpopulation of high-risk patients who met the PEGASUS-TIMI 54 trial inclusion (age ≥65,or ≥50 with diabetes, renal disease or a second previous MI) and exclusion criteria was also analysed (n=1,676). Multivessel disease was not coded in the CALIBER registry.

Primary endpoints

  • Composite endpoint of non-fatal MI, non-fatal stroke or CV death
  • Fatal, severe, or intracranial bleeding

Median follow-up

  • 1.5 years

ACS, acute coronary syndrome; CPRD, Clinical Practice Research Datalink; MINAP, Myocardial Ischaemia National Audit Project.

Culprit and non-culprit recurrent ischaemic events in MI patients

The goal of secondary prevention is to reduce the risk of overall coronary disease progression, not just stent-related events22

The risk of recurrent MI is twice as high in non-culprit lesions (NCL) vs culprit lesions (CL)22

SWEDEHEART registry: cumulative proportion with identifiable lesions at recurrent MI

PRECLUDE study
PRECLUDE study

Of the 3464 recurrent MIs, 1566 were indeterminate events and could not be classified as NCL or CL recurrent MIs - because no PCI was performed for the recurrent MI or they were not treated in a SWEDEHEART unit or invasively evaluated.

Treatment with BRILIQUE (ticagrelor) 90mg twice daily is recommended for 12 months in ACS patients.

BRILIQUE (ticagrelor) 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of a least 1 year and a high risk of an atherothrombotic event. There is limited data on the efficacy and safety or ticagrelor beyond 3 years of extended treatment.

This analysis was an observational cohort study using prospectively collected data from SWEDEHEART and the Swedish National Board of Healthcare registries.

The study population consisted of 44,332 out of 108,615 patients hospitalised for STEMI or NSTEMI who had a culprit lesion identified at baseline by coronary angiography (between 1 July 2006 and 29 November 2014). During follow-up (median 3.2 years) re-MI occurred in 3,464 patients. Of those patients, the infarct originated from a ‘non-culprit’ lesion in 1,243 patients, from a ‘culprit’ lesion in 655 patients and 1,566 re-MIs could not be classified as ‘non-culprit’ or ‘culprit’.

Medications at hospital discharge for the index MI: ASA 95.8%; clopidogrel 69.6%; ticagrelor 23.5%; prasugrel 2.4%.

 

ASA, acetylsalicylic acid

PLATO

BRILIQUE (ticagrelor) 90mg significantly reduced CV events vs. clopidogrel4

Briligue (ticagrelor) 90 mg twice daily with low dose ASA (75-100mg daily) demonstrated a significant reduction in the risk of CV events compared to clopidogrel with ASA in ACS patients.

Time to first occurrence of primary efficacy endpoint: Composite of death from vascular causes, MI or stroke at 12 months4

Primary efficacy endpoint: CV death, MI or stroke at 12 months
Primary efficacy endpoint: CV death, MI or stroke at 12 months

No. at Risk

  Month 0 Month 2
Month 4
Month 6
Month 8
Month 10
Month 12
Ticagrelor 9333 8628 8460 8219 6743 5161 4147
Clopidogrel 9291 8521 8362 8124 6650 5096 4047

Analysis at 30 days is an exploratory endpoint

Risk (KM estimate) of CV death, non-fatal MI or non-fatal stroke (primary endpoint) in patients with ACS treated with Brilique (ticagrelor) over 12 months. All patients were on background low-dose asprin (75-100 md/day). Adapted from Wallentin et al. 2009

More than half of the absolute risk reduction with BRILIQUE (ticagrelor) occurred after 30 days treatment, and continued to diverge from that of clopidogrel over 12 months of continuous therapy.4

BRILIQUE (ticagrelor) 90mg significantly reduced CV mortality vs. clopidogrel4

Briligue (ticagrelor) 90 mg twice daily with low dose ASA (75-100mg daily) significantly reduced the risk of death from vascular causes alone vs. clopidogrel with ASA4

Secondary efficacy endpoint: Death from vascular causes alone at 12 months4

Secondary efficacy endpoint CV mortality at 12 months
Secondary efficacy endpoint CV mortality at 12 months

Adapted from Wallentin et al 2009

No. at Risk

  Month 0 Month 2
Month 4
Month 6
Month 8
Month 10
Month 12
Ticagrelor 9333 8924 8822 8626 7119 5482 4419
Clopidogrel 9291 8865 8780 8589 7079 5441 4364

PLATO bleeding rates

There was no significant difference in total major and fatal bleeding despite improved efficacy vs. clopidogrel4

Non-CABG related major bleeding was higher with BRILIQUE (ticagrelor) than with clopidogrel (PLATO criteria: 4.5% vs 3.8%, p=0.03)4

In PLATO4, there was no increase in either PLATO defined or TIMI defined major bleeding with ticagrelor vs clopidogrel (PLATO major bleeding: HR 1.04, P=0.43; TIMI major bleeding: HR 1.03, P=0.57). There was also no increase in fatal bleeding (HR 0.87, P=0.66) or intracranial bleeding (HR 1.87, P=0.06). However, there was an increase in fatal intracranial bleeding (ticagrelor 11/9235 (0.1%), clopidogrel 1/9186 (0.01%), P=0.02). Non-CABG related major bleeding was increased (PLATO definition: HR 1.19, P=0.03; TIMI definition: HR 1.25, P=0.03). PLATO minor & minimal bleeding were also increased in patients treated with ticagrelor vs clopidogrel: PLATO minor bleeding 4.8% vs 3.8%; PLATO minimal bleeding 17.2% vs clopidogrel 10.6%44.

 

Bleeding definitions in the PLATO study

  PLATO4 TIMI15
Major

Life-threatening

  • Fatal, intracranial or pericardial with tamponade
  • Hypovolaemic shock or severe hypotension requiring pressors or surgery
  • Decrease in haemoglobin >5 g/dL or transfusions of ≥4 units for bleeding

Other

  • Significantly disabling (e.g. intraocular)
  • Decrease in haemoglobin of 3–5 g/dL or transfusion of 2–3 units for bleeding
  • Clinically overt (including imaging) bleeding or documented symptomatic intracranial haemorrhage
  • Decrease in haemoglobin ≥5 g/dL
Minor
  • Requires medical intervention to treat or stop bleeding
  • Clinically overt (including imaging) bleeding
  • Decrease in haemoglobin ≥3 and <5 g/dL
Minimal
  • All other bleeding events not requiring intervention or treatment
  • Clinically overt (including imaging) bleeding
  • Decrease in haemoglobin <3 g/dL

Primary (PLATO-defined major bleeding) and secondary safety endpoints4

PLATO Bleeding Rates
PLATO Bleeding Rates

* Secondary safety endpoints of the trial

a  Fatal intracranial bleeding occurred in 0.1% (11/9,235) patients in the BRILIQUE (ticagrelor) group and 0.01% (1/9186) patients in the clopidogrel group (p=0.02).24

Study design

The PLATO study was a large, multicentre, double-blind, randomised trial.4

Patient were randomised 1:1 to either BRILIUQE 90mg or clopidogrel, plus low-dose ASA
Patient were randomised 1:1 to either BRILIUQE 90mg or clopidogrel, plus low-dose ASA

aSTEMI patients for primary PCI were randomised, however, they may not have received PCI
bA loading dose of 300mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300mg allowed at the discretion of the investigator
cThe PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients.

PRACTICAL study

Study results

Real-world outcomes for BRILIQUE (ticagrelor) 90 mg twice daily in ACS patients support the results of randomised trials

  • In a prospective cohort study in Sweden (n=45,073), outcomes with BRILIQUE vs clopidogrel were comparable with PLATO results25, 26
    • Risk of MI, stroke or all-cause death over 12 months (sensitivity analysis):a 5.6% vs 16.8% (ARR=11.2%, adjusted HR=0.85)
    • Readmissions due to bleeding over 24 months: 5.5% vs 5.2% (adjusted HR=1.20)
  • In PLATO, the risk of MI, stroke or all-cause death over 12 months was 10.2% with BRILIQUE vs 12.3% with clopidogrel (HR=0.84, p<0.001)4
Real world outcomes
Real world outcomes

Unadjusted cumulative incidence of MI, stroke or all-cause death (KM estimate) in real-world patients discharged on DAPT with asprin and either BRILIQUE (ticagrelor) or clopidogrel following an MI. Adapted from Sahlen et al 2016 .

Brilique 90 mg twice daily is licensed for 12 months in ACS patients.1 90.9% of patients prescribed BRILIQUE had an intended treatment duration of ≤12 months, vs 75.5% for clopidogrel.25

Study design25

Prospective cohort study in 45,073 ACS patients enrolled into the Swedish Web system for Enhancement and Development of Evidence-based care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) between 1 January 2010 and 31 December 2013.

Inclusion criteria

  • Cardiac biomarker-verified acute MI (ICD code I21)
  • Age ≥18 years
  • Discharged on DAPT with aspirin (almost exclusively 75 mg daily) and BRILIQUE (n=11,954) or clopidogrel (n=33,119)

Exclusion criteria

  • Previous admission for MI Treatment with oral anticoagulant
  • Revascularisation by CABG during the index hospitalisation

Primary endpoint

  • Time from discharge to the first occurrence of a combination of death, readmission for MI or stroke over 24 months
  • The primary bleeding outcome was time from discharge to hospitalisation with bleeding over 24 months
  • A sensitivity analysis was performed at 12 months

Secondary endpoints

  • Time from discharge to each of the individual components of the primary endpoint
  • The secondary bleeding outcome was the probability of PCI-related in-hospital bleeding, defined as any of the following: puncture site haematoma or pseudoaneurysm, drop in haemoglobin or requirement for prolonged compression, transfusion or surgical intervention

ICD, International Statistical Classification of Diseases and Related Health Problems.

PEGASUS-TIMI 54 study

Long-term treatment with BRILIQUE (ticagrelor) 60 mg reduces the risk of a further CV event vs placebo

In the PEGASUS-TIMI 54, BRILIQUE (ticagrelor) 60 mg twice daily significantly reduced the rate of CV death, MI, or stroke (primary endpoint) over 3 years vs placebo.15

BRILIQUE 60mg significantly reduced CV events vs placebo: 7.77 vs. 9.04% (p=0.004)
BRILIQUE 60mg significantly reduced CV events vs placebo: 7.77 vs. 9.04% (p=0.004)

95 % CI: 0.74-0.95. Adapted from Bonaca et al 2015

Risk of CV death, MI, or stroke (KM estimate) with BRILIQUE (ticagrelor) and placebo in patients who had an index MI 1-3 years before randomisation. All patients were on background low-dose asprin (75-150 mg/day). 

The effect of BRILIQUE (ticagrelor) 60 mg twice daily was directionally consistent on all components of the primary endpoint15

Contributions to the composite primary endpoint
Contributions to the composite primary endpoint

Adapted from Bonaca et al 2015

HR and cumulative rates (KM estimate) for the primary endpoint and each of its components in patients treated with BRILIQUE (ticagrelor) and placebo.

CV death, MI and stroke were secondary endpoints in the statistical analysis plan. CV death failed to meet statistical significance (p=0.07), MI and stroke are therefore exploratory endpoints.

CI confidence interval
ARR absolute risk reduction
RRR relative risk reduction
HR hazard ratio
KM Kaplan-Meier
 

PEGASUS-TIMI 54 bleeding rates

BRILIQUE (ticagrelor) 60 mg twice daily is associated with an increased risk of TIMI major and minor bleeding vs placebo.

In PEGASUS-TIMI 54, TIMI major and minor bleedings were more frequent with BRILIQUE vs placebo15

  • There were no significant differences in the rates of  fatal bleeding or non-fatal ICH (Intracranial haemorrhage)

Bleeding events leading to treatment discontinuation were more frequent with BRILIQUE vs placebo (6.2% vs 1.5%, p<0.001)15

  • These occurred early during treatment and were mostly non-major27
Bleeding rates for BRILIQUE 60mg compared with placebo
Bleeding rates for BRILIQUE 60mg compared with placebo

Bleeding rates (KM estimate) with BRILIQUE (ticagrelor) and placebo in PEGASUS-TIMI54. All patients were on background low-dose asprin (75-150 mg/day).15

TIMI, Thrombolysis in Myocardial Infarction
ICH, intracranial haemorrhage

Discontinuation of treatment due to bleeding was more common with BRILIQUE (ticagrelor) 60mg twice daily compared with ASA therapy alone (6.2% and 1.5%, respectively; p<0.001). The majority of these bleedings were of less severity (classified as TIMI requiring medical attention), e.g. epistaxis, bruising and haematomas.1

PEGASUS-TIMI 54 study: bleeding definitions28

Major bleed:

  1. Any intracranial bleeding, OR
  2. Clinically overt signs of haemorrhage associated with a drop in haemoglobin (Hgb) of ≥5 g/dL  (or, when haemoglobin is not available, a fall in haematocrit of ≥15%), OR
  3. Fatal bleeding (a bleeding event that directly led to death within 7 days)

Minor bleed:

  • Any clinically overt sign of haemorrhage (including imaging) that is associated with a fall in Hgb of 3 to <5g/dL (or, when haemoglobin is not available, a fall in haematocrit of 9 to <15%)
  • Transfusions were accounted for by adjusting Hgb measurements for any packed red blood cells (PRBCs) or whole blood given between baseline and post-transfusion measurements. A transfusion of one unit of blood was assumed to result in an increase of 1gm/dL in Hgb

Medical attention:

Any overt sign of haemorrhage that meets one of the following criteria and that does not meet criteria for a major or minor bleeding event

  • Requiring intervention: defined as medical practitioner-guided medical or surgical treatment to stop or treat bleeding including temporarily or permanently discontinuing or changing the dose of a medication or study drug
  • Leading to hospitalisation: defined as leading to or prolonging hospitalisation
  • Prompting evaluation: defined as leading to unscheduled contact with a healthcare professional and diagnostic testing (laboratory or imaging)

Minimal bleed: Any overt bleeding event that does not meet the preceding criteria

*High risk is defined as ≥1 additional atherothrombotic risk factor (age ≥65 years, >1 prior MI, multivessel coronary artery disease, diabetes requiring medication, chronic non-end-stage renal dysfunction)

Study design

PEGASUS-TIMI 54 is the first prospective, randomised, controlled clinical trial robustly powered to assess the benefit of long-term dual anti-platelet therapy in post-MI patients at high risk* of atherothrombotic events.15

 

 

The PEGASUS-TIMI 54 study included a high risk population15
High risk patients in the Brilique (ticagrelor) 60mg indication
High risk patients in the Brilique (ticagrelor) 60mg indication

a  Estimated creatinine clearance <60 mL/min.
b  Based on an interim snapshot of the data, after completion of enrollment but during ongoing trial and data cleaning9

Randomisation and study treatment

PEGASUS-TIMI 54 was a randomised, double-blind, placebo-controlled clinical trial.15

Patient were randomised 1:1:1 to BRILIQUE (two different doses) and placebo, plus low-dose aspirin
Patient were randomised 1:1:1 to BRILIQUE (two different doses) and placebo, plus low-dose aspirin

*High risk is defined as ≥1 additional atherothrombotic risk factor (age ≥65 years, >1 prior MI, multivessel coronary artery disease, diabetes requiring medication, chronic non-end-stage renal dysfunction)1

There are limited data on the efficacy and safety of BRILIQUE (ticagrelor) 60mg beyond 3 years of extended treatment

There are limited data on the efficacy and safety of BRILIQUE 60mg beyond 3 years of extended treatment

PEGASUS-TIMI 54 study: EU label population

From PEGASUS-TIMI 54 to the EU Label: Refining the patient population

The PEGASUS trial included patients who were at between one and three years post MI.  The licence for the 60mg dose of ticagrelor states that patients must be within 2 years post MI or within 12 months of P2Y12 inhibitor withdrawal. 

Therefore, the EMA proposed that AstraZeneca conduct a post-hoc analysis of the patient population within the PEGASUS trial that met our licensed indication.  This data is the “EU label analysis”.

Peagsus EU Label
Peagsus EU Label

a BRILIQUE 60mg and placebo groups
EMA, European Medicines Agency

Time from index MI

The benefit of BRILIQUE (ticagrelor) 60mg twice daily appeared more marked if treatment was started <2 years after the index MI28

HR and cumulative rates (KM estimate) of the primary endpoint and TIMI major bleeding with BRILIQUE vs placebo by time to index MI in PEGASUS-TIMI-54 (prespecified subgroup analysis). Adapted from reference 28.

P2Y12 inhibitor withdrawal

The benefit of BRILIQUE vs placebo was more marked in patients continuing on or restarting P2Y12 inhibitor treatment after a short interruption30

Primary efficacy endpoint

P2Y12 Inhibitor Withdrawal
P2Y12 Inhibitor Withdrawal

Adapted from Bonaca MP et al. 2016 and Bonaca MP et al. 2016 (supplementary information). 

HR and cumulative rates (KM estimate) of the primary endpoint with BRILIQUE vs placebo by time from P2Y12 inhibitor withdrawal at randomisation in PEGASUS-TIMI-54 (prespecified subgroup analysis). P-value for interaction pooled across both doses is <0.001.

Bleeding risk was higher with BRILIQUE 60mg vs placebo

  • TIMI major bleeding, interruption ≤30 days: HR=3.3, p=0.0001; >30 days and ≤1 year: HR=2.94, p=0.0002; >1 year: HR=2.1, p=0.037

PEGASUS-TIMI 54 study: EU Label subgroup summary

The risk benefit profile of Brilique (ticagrelor) 60mg vs placebo in teh EU label is consistent with the overrall PEGASUS TIMI 54 population.15,32

EU Label summary
EU Label summary

Summary of efficacy and safety outcomes with BRILIQUE and placebo in the overall and EU label populations from PEGASUS-TIMI 54.

CV death, MI, stroke and all cause morality were secondary endpoints in the statistical analysis plan. CV death failed to meet statistical significance (p=0.07). All cause morality also failed to meet statistical significance (p=0.14), MI and stroke are therefore exploratory endpoints.

a  p values should be considered exploratory and of nominal significance.
b Only the primary endpoint was statistically significant; all other endpoints should be considered exploratory.
There are limited data on the efficacy and safety of BRILIQUE 60 mg beyond 3 years of extended treatment.

PEGASUS-TIMI 54 study: Landmark analysis33

Prespecified subgroup analysis of PEGASUS-TIMI 54 investigating the pattern of ischaemic risk and the consistency of the efficacy and safety of BRILIQUE over time.

  • Landmark analyses were performed at yearly intervals from randomisation in patients who were alive and event-free at the start of the landmark period
  • Additional sensitivity analyses explored efficacy over time in patients stratified based on the time from qualifying MI to randomisation and the timing of discontinuation of P2Y12 inhibitor therapy before randomisation

Prolonged treatment with Brilique (ticagrelor) 60 mg twice daily + ASA vs placebo + ASA provides consistent benefits over 3 yearsa

A landmark analysis of PEGASUS-TIMI 54 evaluated the pattern of ischaemic risk over time33

The efficacy of Brilique (ticagrelor) 60 mg twice daily with low dose ASA (75-100mg daily) was similar over each sequential year of follow-up33

PEGASUS Landmark efficacy
PEGASUS Landmark efficacy

Risk (KM estimate) of CV death, MI, or stroke (primary endpoint) in patients from the PEGASUS-TIMI 54 trial, analysed year by year. Adapted from Bonaca et al 2017 

a There are limited data on the efficacy and safety of BRILIQUE 60 mg beyond 3 years of extended treatment.

PEGASUS-TIMI 54 study: Landmark analysis - Safety33

The risk of bleeding with Brilique (ticagrelor) 60 mg twice daily with low dose ASA (75-100mg daily) vs placebo with low dose ASA is constant after the first year

  • There was no significant increase in fatal bleeding or ICH vs placebo at any point
PEGASUS Landmark safety
PEGASUS Landmark safety

TIMI major bleeding in the PEGASUS-TIMI 54 trial analysed year by year. Only patients who were alive and event-free at the start of each time period were included (on-treatment analysis).

Safety analyses by definition are in patients still on study drugs and therefore, select for a cohort who has tolerated therapy. Thus, the trend for a diminished bleeding risk over time likely reflects selection of patients who have maintained therapy without intolerable bleeding. 

CPRD adherence data

Study results

Medically managed ACS patients are at highest risk of subsequent events34 and show the lowest persistence with treatment34

  • Medically managed MI patients are at greater risk of a subsequent CV event vs invasively managed patients,18,35 and tend to be older and undertreated, with a greater comorbidity burden18
  • To promote adherence in these patients, it is essential to initiate medication before discharge,18 provide education about their condition and treatment, and complete regular monitoring36
CPRD Data
CPRD Data

Analysis of patient persistencea on BRILIQUE (ticagrelor) 90 mg over 15 months in ACS patients in primary care. Data from the CPRD database. The x-axis begins at month 1 as only primary care prescriptions are included (assuming 1-month hospital supply on discharge)34

 Persistence to treatment is defined as time from initiation to discontinuation of therapy in primary care (first ticagrelor prescription date, to last prescription date plus duration supplied on last prescription).34
ACS, acute coronary syndrome; CABG, Coronary Artery Bypass Grafting; CPRD, Clinical Practice Research Datalink; PCI, Percutaneous coronary intervention.

CPRD ticagrelor outcomes study design34

Analysis of prescription data from English GP practices within CPRD that are linked to Hospital Episode Statistics data, including patients with a first primary care BRILIQUE prescription issued between December 2010 and March 2015. A 1-month prescription of BRILIQUE from the hospital at discharge was assumed.

Inclusion criteria

  • ≥12 months of patient history in the database before the first prescription
  • ACS event in the 3 months prior to inclusion
  • Alive and registered with the practice 11 months after inclusion

Exclusion criteria

  • Primary care prescription for clopidogrel or prasugrel between the ACS event and inclusion