Patients at high risk of thrombotic events: Duration of antiplatelet therapy

Wael Sumaya MD, MRCP, PhDNIHR Clinical Lecturer in Cardiology

University of Sheffield

Sumaya w, et al. Thrombosis & Haemostasis 2019 2

Valgimigle M, et al. EHJ 2018

However

Is 12 months DAPT enough in all patients?

• 75 year old man admitted via ambulance with anterior STEMI

• Ex-smoker, history of treated hypertension, no DM or CKD

• Treated with aspirin 300mg po in ambulance and loaded with ticagrelor 180mg in cath lab

• Emergency coronary angiography performed via the right radial artery

Case presentation

with permission from Prof Storey

Occluded LAD

Severe circumflex disease

Chronically-occluded right coronary artery

Successful PCI to LAD

• No further chest pain after PCI, mobilising around ward

• Decision to treat residual disease conservatively

• Aspirin, ramipril, atorvastatin, bisoprolol long term

• Ticagrelor 90 mg BD for 12 months

Post-PCI progress

• Required implantable loop recorder 11 months later for investigation of pre-syncopal episodes

• Ticagrelor stopped after 1 year

• Readmitted 2 months later with further STEMI

• Emergency coronary angiography performed via the right radial artery

Subsequently..

with permission from Prof Storey

Very-late stent thrombosis in LAD

Thrombus aspiration then predilated with 2.5x12mm balloon – loss of cardiac output – adrenaline, CPR, Autopulse – PTCA to LAD with 3x20mm balloon gave satisfactory result but failed to recover cardiac output with further inotrope and died

PEGASUS-TIMI 54 study designStable patients >50 years old with history of MI 1–3 years prior + ≥1 additional

atherothrombotic risk factor*N = 21,162

Ticagrelor60 mg BD

Placebo BD

Ticagrelor90 mg BD

Follow-up visits: 4-monthly for first year, then 6-monthlyDuration: Minimum 12 months, up to ~44 months (median 30 months)

Event-driven trial: n ~ 1360 events

Primary efficacy endpoint: CV death, MI or strokePrimary safety endpoint: TIMI major bleeding

Randomized, double-blind

Planned treatment with ASA 75–150 mg + standard background care

*Age ≥65 years, diabetes, second prior MI, multivessel CAD or chronic non-end-stage renal dysfunction

BD, twice daily; CAD, coronary artery disease; TIMI, thrombolysis in myocardial infarction

THE TICAGRELOR 90 MG DOSE IS NOT APPROVED FOR THE MANAGEMENT OF PATIENTS WITH A

HISTORY OF MI (>1 YEAR)

PEGASUS-TIMI 54: Primary endpoint

Bonaca MP et al. N Engl J Med. 2015;372:1791–1800

Ev

en

t ra

te (

%)

Months from randomization

Ticagrelor 60 mg vs placebo

HR 0.84 (95% CI 0.74–0.95) p=0.004

Ticagrelor 90 mg vs placebo

HR 0.85 (95% CI 0.75–0.96) p=0.008

Placebo

Ticagrelor 90 mg bid

Ticagrelor 60 mg bid

9.04% Placebo

7.85% 90 mg bid

7.77% 60 mg bid

0 3 6 9 12 15 18 21 24 27 30 33 360

1

2

3

4

5

6

7

8

9

10

PEGASUS-TIMI 54: Primary endpoint events and individual components of the primary endpoint

Ticagrelor better Placebo better

0.4 0.6 0.8 1 1.25 1.67

Primary – CV death, MI or stroke

(1558 events)

Endpoint3-year KM event rates (%)

HR (95% CI) P valueTicagrelor

60mg bd Placebo

7.77 9.04 0.84 (0.74–0.95) 0.004

2.86 3.39 0.83 (0.68–1.01) 0.07

4.53 5.25 0.84 (0.72–0.98) 0.03*

1.47 1.94 0.75 (0.57–0.98) 0.03*

Ticagrelor 60 mg bid

*Indicates nominal p-value; p<0.026 indicates statistical significance. ** indicates Secondary endpoint; † indicates exploratory endpoint

Adapted from Bonaca MP et al. N Engl J Med. 2015;372:1791–1800.

CV death

(566 events)

**

MI

(898 events)

†

Stroke

(313 events)

†

PEGASUS-TIMI 54: Primary Safety Endpoints

Adapted from Bonaca MP et al. N Engl J Med 2015;372:1791–1800

3-y

ear

KM

event

rate

2.3

1.11.2

0.4

P<0.001

P<0.001

TIMI major bleeding

TIMI minor bleeding

0.70.6 0.6

0.5

0.3 0.3

P=NS P=NS P=NS

Fatal bleeding or ICH

ICH Fatal bleeding

5

4

3

2

1

0

Ticagrelor 60 mg bid

Placebo

Discontinuation of treatment dueto bleeding was more common

with ticagrelor 60 mg compared to ASA therapy alone (6.2% and 1.5%, respectively; p<0.001). The majority of these bleeding events were of lesser

severity (classified as TIMI requiring medical attention), e.g. epistaxis, bruising and

haematomas.

-50

-40

-30

-20

-10

0

10

20

30

40

50

PEGASUS-TIMI 54: Estimates of first efficacy and bleeding events prevented and causedTicagrelor 60 mg bd

Rates are annualised from 3-year Kaplan-Meier event rates in the intention-to-treat population.

Bonaca MP et al. N Engl J Med. 2015, Supplementary Appendix

CV death, MI or stroke

TIMI major bleeding

Nu

mb

er

of

ev

en

ts p

er

10

00

0 p

ati

en

ts i

nit

iate

d o

n

tre

atm

en

t fo

r 1

ye

ar

–42

31

0%

2%

4%

6%

8%

10%

12%

0 90 180 270 360 450 540 630 720 810 900 990 1080

HR 0.75

(95% CI 0.61–0.92)

p=0.0064

MACE at 3 years with ticagrelor in patients with P2Y12 inhibitor withdrawal ≤30 days from randomization

CV

D/M

I/s

tro

ke

(%

)

Days from randomization

9.9%

8.0%

Placebo Ticagrelor 60 mg BID

NNT=53

Bonaca M et al. Eur Heart J. 2015 online.*https://www.medicines.org.uk/emc/medicine/23935/SPC/Brilique+90+mg+film+coated+tablets/

PEGASUS-TIMI 54 Sub-analysis:Effect of ticagrelor 60mg bd on STEMI

* Nominal P Value.Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 891)

* Nominal P Value.

0

0

0.5

1.0

1.5

2.0

Days from randomization

ST

EM

I (%

)

90 180 270 360 450 540 630 720 810 900 990 1080

Placebo

Ticagrelor 60 mg bdTicagrelor 60 mg bd

HR 0.62

(95% CI 0.45, 0.86)

P=0.0016*

Adverse events leading to discontinuation

Treatment arm Any AE Bleeding Dyspnoea

Ticagrelor 60

mg bid 16.4% 6.2% 4.6%

Placebo 8.9% 1.5% 0.8%

3 year KM rate (%) – p-value for 60 mg ticagrelor versus placebo <0.001

Bonaca MP et al. N Engl J Med. 2015;372:1791–1800

Efficacy of ticagrelor 60mg + ASA vs ASA alone in patients with multivessel CAD

DEF.ST, definite stent thrombosisBansilal S et al. J Am Coll Cardiol 2018;71:489–496

CV DEATH/MI/STROKE

CORONARY DEATH/MI/DEF.ST

CV DEATH

CORONARY DEATH

MI

STROKE

STENT THROMBOSIS

0.25 0.50 0.75 1.50 3.00

7.80

6.12

2.34

1.39

5.20

1.21

0.66

9.37

7.67

3.18

2.29

6.06

1.76

0.93

TICAGRELOR 60 mg + ASA

ASA alone

0.81 (0.70–0.95)

0.77 (0.65–0.92)

0.76 (0.58–1.01)

0.64 (0.45–0.89)

0.82 (0.68–0.99)

0.70 (0.47–1.02)

0.72 (0.42–1.18)

HR (95% CI)

3-year KM rate

1.0Ticagrelor better Placebo better

• Prior ischaemic stroke

• History of previous intracranial bleed at any time, gastrointestinal (GI) bleed within the past 6 months, or major surgery within 30 days

• Known bleeding diathesis/coagulation disorder

• Requirement for oral anticoagulation

• Severe liver disease

• End-stage renal disease requiring dialysis or likely requirement for dialysis during course of study

• Alcohol or drug abuse

PEGASUS TIMI-54: exclusion criteria related to bleeding risk

Coronary angiography

PCI CABG

Up to 12 months DAPT

Multivessel/extensive CAD with DM, PAD, CKD or recurrent MIs OR very severe multivessel CAD

No

Yes

Prolonged DAPT with aspirin + ticagrelor (downtitrate from 90 mg to 60 mg BD from 1

year post MI)

Indication for oral anticoagulation (e.g. atrial fibrillation) OR high-risk features for life-threatening bleeding: anaemia, history of spontaneous major bleed, bleeding diathesis or thrombocytopenia, severe liver disease, intracranial vascular

abnormality or neoplasm, extreme old age or frailty

History of ischaemic stroke

No

No

Intolerance to ticagrelor(not bleeding related)

Admission with MI and treated with DAPT

No

Yes

Conservative treatment

Yes

Example of decision process for DAPT duration post MI

Adapted from Sumaya W et al. Thromb Haemost 2019

Summary• Ischaemic risk DOES NOT diminish after 12 months following ACS

• Long-term dual aspirin + ticagrelor reduces ischaemic events following MI in patients at high CV risk at the cost of more non-fatal bleeding

• Selecting patients with multivessel disease, either very severe or associated with diabetes, CKD, PAD or recurrent MIs is likely to reduce CV death amongst other ischaemic outcomes

DISCUSSION