Antithrombotic Therapies in PPCI - gy-cardio.gr · •Relative performance of bivalirudin and heparin ... •Factors precluding administration of oral A-P therapy ... Reinfarction

Dr Adeel Shahzad

Dr Rod Stables (PI)

Liverpool Heart and Chest Hospital

Liverpool, UK

How Effective are

Antithrombotic Therapies in PPCI

• Anti-thrombotic therapy in PPCI

• Selective (‘bailout’) use of GP IIb/IIIa antagonists (GPI)

• Increasingly the norm in routine practice

• Recommended by international guidelines

• ESC ACCF / AHA

• Anti-thrombotic therapy in PPCI



• Recommended by key guidelines (ESC, ACCF / AHA)

• Bivalirudin + selective (7% - 15%) use of GPI

• Established anti-thrombotic treatment option

• Bleeding is associated with less favourable outcomes

• Increased GPI use - results in increased bleeding

•Observed for both bivalirudin and heparin

• Relative performance of bivalirudin and heparin -

• Cannot be reliably assessed with differential GPI use

• HEAT PPCI

• Bivalirudin + selective GPI v Heparin + selective GPI





• Cannot be assessed reliably with differential GPI use

• HEAT PPCI

• Bivalirudin + ‘bailout’ GPI v Heparin + ‘bailout’ GPI

• Single centre RCT

• Trial recruitment: Feb 2012 - Nov 2013 22 months

• Bivalirudin v Unfractionated Heparin

• STEMI patients

• Randomised at presentation

• Acute phase management with Primary PCI

• Single centre RCT

• Trial recruitment: Feb 2012 - Nov 2013 22 months

• Bivalirudin v Unfractionated Heparin

• STEMI patients

• Randomised at presentation

• Acute phase management with Primary PCI

• Philosophy for clinical teams:

• Assess ‘Every Patient - Every Time’

Inclusion Criterion

• All STEMI patients activating PPCI pathway

Exclusion Criteria

• Active bleeding at presentation

• Factors precluding administration of oral A-P therapy

• Known intolerance / contraindication to trial medication

• Previous enrolment in this trial

• Dual oral anti-platelet therapy pre-procedure

• Heparin: 70 units/kg body weight pre-procedure

• Bivalirudin: Bolus 0.75 mg/kg

Infusion 1.75 mg/kg/hr - procedure duration

• Dual oral anti-platelet therapy pre-procedure

• Heparin: 70 units/kg body weight pre-procedure

• Bivalirudin: Bolus 0.75 mg/kg

Infusion 1.75 mg/kg/hr - procedure duration

• GPI - Abciximab

• Selective (‘bailout’) use in both groups

• ESC guideline indications

At 28 days

Primary Efficacy Outcome Measure

• Major Adverse Cardiac Events (MACE) -

• All-cause mortality

• Cerebrovascular accident (CVA)

• Re-infarction

•Unplanned target lesion revascularisation (TLR)

At 28 days

Primary Efficacy Outcome Measure

• Major Adverse Cardiac Events (MACE)

Primary Safety Outcome Measure

• Major bleeding -

• Type 3-5 bleeding as per BARC definitions

• Data Monitoring and Safety Committee (DMSC)

• All key clinical events adjudicated

• Clinical Events Committee

• Blinded to the treatment allocation

• Use of a delayed consent strategy

• Full UK ethical approval

• Patients randomised and treated without discussion

• Subsequent informed consent in recovery phase

• Additional national approval -

•Use of data from patients who died before consent

1917 patients scheduled for emergency angiography

29 (1.5%) already randomised in the trial

59 (3.0%) met one or more other exclusion criteria

1829 eligible for recruitment

1917 patients scheduled for emergency angiography

29 (1.5%) already randomised in the trial

59 (3.0%) met one or more other exclusion criteria

1829 eligible for recruitment

1829 Randomised

Representative ‘Real-World’ Population

Assigned to Heparin 914 915 Assigned to Bivalirudin

Received allocated Rx 900

Received no study drug 14

Treatment cross-over 0

LMWH pre-procedure 3

907 Received allocated Rx

7 Received no study drug

1 Treatment cross-over

4 LMWH pre-procedure

Assigned to Heparin 914

Included in analysis 907

915 Assigned to Bivalirudin

905 Included in analysis

Consent not available in surviving patients

Consent not available in surviving patients

7 10

Received allocated Rx 900

Received no study drug 14

Treatment cross-over 0

LMWH pre-procedure 3

907 Received allocated Rx

7 Received no study drug

1 Treatment cross-over

4 LMWH pre-procedure

Characteristic Bivalirudin Heparin

Median age (years) 62.9 63.6

Female sex (%) 28.5 26.9

Caucasian race (%) 95.8 95.9

Diabetes mellitus (%) 12.6 15.1

Previous MI (%) 13.5 10.3

eGFR (ml/min/1.73m2) 80.0 80.0

Haemoglobin (g/dl) 13.6 13.7

Characteristic Bivalirudin (%) Heparin (%)

P2Y12 use - Any 99.6 99.5

- Clopidogrel 11.8 10.0

- Prasugrel 27.3 27.6

- Ticagrelor 61.2 62.7

GPI use 13.5 15.5

Radial arterial access 80.3 82.0

PCI performed 83.0 81.6

Characteristic Bivalirudin (%) Heparin (%)

Thrombectomy 59.1 57.6

Single vessel Tx 93.2 90.3

Any stent implant 92.8 92.2

DES implantation 79.8 79.9

TIMI III flow - post PCI 93.3 92.7

Bivalirudin Heparin n % % n

MACE 79 8.7 % v 5.7 % 52

Absolute risk increase = 3.0% (95% CI 0.6, 5.4)

Relative risk = 1.52 (95% CI 1.1 – 2.1) P=0.01

Event curve shows first event experienced


Death 46 5.1 % v 4.3 % 39

CVA 15 1.6% v 1.2% 11

Reinfarction 24 2.7% v 0.9% 8

TLR 24 2.7% v 0.7% 6

Any MACE 79 8.7 % v 5.7 % 52


Death 46 5.1 % v 4.3 % 39

CVA 15 1.6% v 1.2% 11


TLR 24 2.7% v 0.7% 6

Any MACE 79 8.7 % v 5.7 % 52


Death 46 5.1 % v 4.3 % 39

CVA 11 1.2% v 0.6% 6


TLR 1 0.1% v 0% 0

Any MACE 79 8.7 % v 5.7 % 52

Censored by the most significant event - in order displayed


Death 46 5.1 % v 4.3 % 39

CVA 11 1.2% v 0.6% 6


TLR 1 0.1% v 0% 0

Any MACE 79 8.7 % v 5.7 % 52

Censored by the most significant event - in order displayed


All Events 24 3.4 % v 0.9 % 6

Relative risk = 3.91 (95% CI 1.6 - 9.5) P=0.001

ARC definite or probable stent thrombosis events


Definite 23 3.3 % v 0.7 % 5

Probable 1 0.1 % v 0.1 % 1

Acute 20 2.9 % v 0.9 % 6

Subacute 4 0.6% v 0% 0

ARC definite or probable stent thrombosis events


Major Bleed 32 3.5 % v 3.1 % 28

Relative risk = 1.15 (95% CI 0.7 - 1.9) P=0.59

Major Bleed BARC grade 3-5


Minor Bleed 83 9.2 % v 10.8 % 98

Major or Minor 113 12.5 % v 13.5 % 122

Minor Bleed P=0.25 Major or Minor P=0.54

Major Bleed BARC grade 3-5 Minor Bleed BARC grade 2

• Single centre

• Potential impact minimised by:

•Meticulous trial conduct

•Unselected representative population

• Study treatments are iv drugs (no ‘skill’ component)

• Multiple operators

•Outcomes as expected by national norms

• Single centre

• Open label

• Potential impact minimised by:

• Complete follow-up - No ‘lost’ cases

•Outcome measures were overt clinical events

• Most MI events involved angiographic imaging

• Independent blinded adjudication

•Open label used in HORIZONS and EUROMAX

• A unique study with 100% recruitment of eligible patients


Use of heparin rather than bivalirudin

• Reduced rate of major adverse events (NNT = 33)

• Fewer stent thromboses and reinfarction events





• Consistent effect across pre-specified subgroups






• No increase in bleeding complications






• No increase in bleeding complications

• Potential for substantial saving in drug costs

0

Subgroup Relative Risk (95% CI)P Value for

interaction

All patients 1.52 (1.09, 2.13)

Arterial access site 0.87

Radial 1.58 (1.01, 2.48)

Femoral 1.45 (0.70, 2.98)

Diabetes 0.35

Yes 2.22 (1.04, 4.76)

No 1.54 (1.04, 2.28)

Age 0.11

≥75 1.09 (0.68, 1.77)

<75 1.97 (1.23, 3.16)

Favours Bivalirudin Favours Heparin

1

Subgroup Relative Risk (95% CI)P Value for

interaction

P2Y12 agent used 0.78

Clopidogrel 1.34 (0.54, 3.31)

Prasugrel 1.91 (0.87, 4.21)

Ticagrelor 1.41 (0.93, 2.14)

Left Ventricular Function Impaired 0.67

Yes 1.28 (0.84, 1.95)

No 1.63 (0.64, 4.16)

PCI attempted 0.88

Yes 1.55 (1.06, 2.28)

No 1.45 (0.71, 2.96)

Favours Bivalirudin Favours Heparin

2

Event curve shows first major bleed experienced

3

Bivalirudin Heparin P value

Thrombocytopenia (%) new onset <150

8.3 7.3 0.49

CKMB post procedure Median (ng/dl)

97 106 0.55

Door-first device time Median (mins)

29 29 0.33

4

Bivalirudin Heparin P value

Normal (EF >54%) 45.4% 43.9% 0.53

Mild (EF 45-54%) 25.2% 26.2% 0.65

Moderate (EF 36-44%) 20.1% 19.8% 0.88

Severe (EF <36%) 9.3% 10.1% 0.60

5

Common assumptions - based on historic connotations

• Smaller studies - often underpowered

• Potential subversion of randomisation

• Less robust trial procedures and documentation

• No adjudication of adverse events

6

Common assumptions - based on historic connotations

• Smaller studies - often underpowered

• Potential subversion of randomisation

• Less robust trial procedures and documentation

• No adjudication of adverse events

No active problems for HEAT PPCI

7

Issues related to the patient population

• Unselected: External referral to trial centre

• Near universal inclusion in trial

• Patients typical for UK population

• Predominantly Caucasian race

May affect generalisation to other populations

8

Issues related to clinical performance and outcomes

In HEAT PPCI -

• Randomised treatments are routine iv medications

• Established and standardised approach to

• Purchase and storage

• Administration and dosing

• Outcomes are not affected by practice pattern or ‘skill’

9


In HEAT PPCI -

• Randomised treatments are routine iv medications

• Established and standardised approach to

• Purchase and storage

• Administration and dosing

• Outcomes are not affected by practice pattern or ‘skill’

Minimal threat in HEAT PPCI

10


• Treatments administered in setting of a PPCI procedure

• Procedures performed by 14 different cardiologists

• Operator and institution outcomes as expected

•Match national and international norms for PPCI

11


• Treatments administered in setting of a PPCI procedure

• Procedures performed by 14 different cardiologists

• Operator and institution outcomes as expected

•Match national and international norms for PPCI

Minimal threat in HEAT PPCI

12

Registry and Trial PPCI Outcomes

Mortality (%)

HORIZONS (30d) 2.6 %

EUROMAX (30d) 3.0 %

US CathPCI 2011 (In-Hosp) 5.7 %

UK BCIS 2012 (30d) 6.4 %

HEAT PPCI (28d) 4.7 %

13

• Comprehensive follow-up

•No ‘lost’ cases

14


• All primary efficacy and safety outcome measures -

•Overt clinical events with robust documentation

•MI events substantiated by imaging in almost all cases

15


• All primary efficacy and safety outcome measures



• Independent adjudication of events

• Blinded to patient identity and treatment allocation

16


• All primary efficacy and safety outcome measures



• Independent adjudication of events

• Open label norm - used in HORIZONS EUROMAX

17

• Estimated MACE rate = 7.5%

• Sample size 1800 patients

• Two-sided testing

• Allows superiority testing in favour of either agent

• Pre-specified boundaries for

•Non-Inferiority Equivalence

• Calculations based on absolute event rate difference

18

• Assuming no observed treatment difference

‘Treatment A’ 7.5% = 7.5% ‘Treatment B’

• Event rate difference = 0%

• Calculate 95% CI for the rate difference

0% +2.4% -2.4%

19

• Assuming an observed treatment difference

‘Treatment A’ 5.5% = 8.0% ‘Treatment B’

• Event rate difference = 2.5%

• Calculate 95% CI for the rate difference

2.5% +2.3% -2.3%

20

0% 1% 2% 3% 4% 4% 3% 2% 1%

Event Rate Difference

Favours Treatment A Favours Treatment B

+2.3% -2.3%

2.5%

21

0% 1% 2% 3% 4% 4% 3% 2% 1%



22

2.5% +2.3% -2.3%

0% 1% 2% 3% 4% 4% 3% 2% 1%



Point estimate better than (-0.5%)

23

0% 1% 2% 3% 4% 4% 3% 2% 1%



Point estimate better than (-0.5%)

1% +2.4% -2.4%

24

0% 1% 2% 3% 4% 4% 3% 2% 1%



Point estimate lies in zone ± 0.5% from zero difference

25

0% 1% 2% 3% 4% 4% 3% 2% 1%



0.4% +2.4% -2.4%

0.4% +2.4% -2.4%

26

• Anti-thrombotic therapy in PPCI for STEMI



• Recommended by key guidelines (ESC, ACCF / AHA)

• Bivalirudin + selective (7% - 15%) use of GPI

• Established anti-thrombotic treatment option

• Bivalirudin and heparin -

• Appear to have similar anti-ischaemic efficacy

• Similar impact on MACE events

HAS REPLACE REPLACE 2

ISAR REACT 4 ACUITY ISAR REACT 3

HORIZONS ISAR REACT 3A EUROMAX

No difference in ischaemic outcomes

• Bivalirudin and heparin - similar impact on MACE events

• Use of GPI agents causes increased bleeding

•When used with heparin

Heparin Heparin

EPIC Placebo GPI Universal

RESTORE Placebo GPI Universal

PRISM Plus Placebo GPI Universal

CAPTURE Placebo GPI Universal

↑ bleeding with ↑ GPI use



•When used with heparin

•When used with bivalirudin

Bivalirudin Bivalirudin

GPI Bailout GPI Universal

ACUITY 9 % 97 %




• With similar GPI use -

• Bivalirudin and heparin have similar bleeding rates

Bivalirudin Heparin

GPI Universal GPI Universal

ACUITY 97 % 97 %

REPLACE 72 % 71 %

No differences in bleeding



• With similar GPI use -

• Bivalirudin and heparin have similar bleeding rates

• With differential GPI use -

• Bivalirudin and heparin have different bleeding rates

Bivalirudin Heparin

GPI Bailout GPI Universal

ACUITY 9 % 97 %

ISAR REACT 4 0 % 100 %

HORIZONS 7 % 98 %

EUROMAX 9 % 70 %






• Cannot be assessed reliably with differential GPI use

• HEAT PPCI

• Bivalirudin + selective GPI v Heparin + selective GPI

Documents

Antithrombotic Therapies in PPCI - gy-cardio.gr · •Relative performance of bivalirudin and heparin ... •Factors precluding administration of oral A-P therapy ... Reinfarction