dr adeel shahzad dr rod stables (pi) liverpool heart and chest hospital liverpool, uk h ow e...

HEAT PPCI

Dr Adeel ShahzadDr Rod Stables (PI)

Liverpool Heart and Chest HospitalLiverpool, UK

Heparin versus Bivalirudin in PPCI

How Effective areAntithrombotic Therapies in PPCI

HEAT 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

Background

HEAT PPCI

• Anti-thrombotic therapy in PPCI

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

• Increasingly the norm in routine practice

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

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

• Established anti-thrombotic treatment option

Background

HEAT PPCI

• 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

Background

HEAT PPCI

• 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 assessed reliably with differential GPI use

• HEAT PPCI

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

Background

HEAT PPCI

• 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

Study Description

HEAT PPCI

• 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

Study Description

• Philosophy for clinical teams:

• Assess ‘Every Patient - Every Time’

HEAT PPCI

Inclusion Criterion

• All STEMI patients activating PPCI pathway

Study Population

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

HEAT PPCI

• 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

Study Medication

HEAT PPCI

• 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

Study Medication

• GPI - Abciximab

• Selective (‘bailout’) use in both groups

• ESC guideline indications

HEAT PPCI

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)

Outcome Measures

HEAT PPCI

At 28 days

Primary Efficacy Outcome Measure

• Major Adverse Cardiac Events (MACE)

Outcome Measures

Primary Safety Outcome Measure

• Major bleeding -

• Type 3-5 bleeding as per BARC definitions

HEAT PPCI

• 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

Study Organisation

HEAT PPCI

• 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

Delayed Consent

HEAT PPCI

Results - Population

1917 patients scheduled for emergency angiography

29 (1.5%) already randomised in the trial59 (3.0%) met one or more other exclusion criteria

1829 eligible for recruitment

HEAT PPCI

Results - Population

1917 patients scheduled for emergency angiography

29 (1.5%) already randomised in the trial59 (3.0%) met one or more other exclusion criteria

1829 eligible for recruitment

1829 Randomised

Representative ‘Real-World’ Population

HEAT PPCI

Results - Population

Assigned to Heparin 914 915 Assigned to Bivalirudin

Received allocated Rx 900 Received no study drug 14

Treatment cross-over 0LMWH pre-procedure 3

907 Received allocated Rx7 Received no study drug908 Treatment cross-over 4 LMWH pre-procedure

HEAT PPCI

Results - Population

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 0LMWH pre-procedure 3

907 Received allocated Rx7 Received no study drug908 Treatment cross-over 4 LMWH pre-procedure

HEAT PPCI

Baseline Characteristics

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

HEAT PPCI

Procedural Information

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

HEAT PPCI

PCI Procedural Data

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

HEAT PPCI

Primary Efficacy Outcome

HEAT PPCI

Primary Efficacy Outcome

Bivalirudin Heparinn % % 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

HEAT PPCI

Timing of First MACE Event

Event curve shows first event experienced

HEAT PPCI

MACE Outcome - All Events

Bivalirudin Heparinn % % n

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

HEAT PPCI

MACE Outcome - All Events

Bivalirudin Heparinn % % n

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

HEAT PPCI

MACE Outcome - Hierarchical

Bivalirudin Heparinn % % n

Death 46 5.1 % v 4.3 % 39

CVA 11 1.2% v 0.6% 6

Reinfarction 21 2.3% v 0.8% 7

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

HEAT PPCI

MACE Outcome - Hierarchical

Bivalirudin Heparinn % % n

Death 46 5.1 % v 4.3 % 39

CVA 11 1.2% v 0.6% 6

Reinfarction 21 2.3% v 0.8% 7

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

HEAT PPCI

Stent Thrombosis

Bivalirudin Heparinn % % n

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

HEAT PPCI

Stent Thrombosis

Bivalirudin Heparinn % % n

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

HEAT PPCI

Primary Safety Outcomes

Bivalirudin Heparinn % % n

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

HEAT PPCI

Safety Outcomes

Bivalirudin Heparinn % % n

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

HEAT PPCI

• 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

Study Limitations

HEAT PPCI

• 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

Study Limitations

HEAT PPCI

• A unique study with 100% recruitment of eligible patients

Conclusions

HEAT PPCI

• 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

Conclusions

HEAT PPCI

• 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

Conclusions

HEAT PPCI

• 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

Conclusions

HEAT PPCI

• 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

• Potential for substantial saving in drug costs

Conclusions

HEAT PPCI

Reserve Slides 0

HEAT PPCI

Subgroups – Primary OutcomeSubgroup 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

HEAT PPCI

Subgroups – Primary Outcome

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

HEAT PPCI

Timing of First Major Bleed Event

Event curve shows first major bleed experienced

3

HEAT PPCI

Secondary Outcomes

Bivalirudin Heparin P value

Thrombocytopenia (%) new onset <150 8.3 7.3 0.49

CKMB post procedureMedian (ng/dl) 97 106 0.55

Door-first device time Median (mins) 29 29 0.33

4

HEAT PPCI

LV Function post Index MI Event

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

HEAT PPCI

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

Single-centre Trials ? 6

HEAT PPCI

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

Single-centre Trials ?

No active problems for HEAT PPCI

7

HEAT PPCI

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

Single-centre Trials ? 8

HEAT PPCI

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

Single-centre Trials ?

May affect generalisation to other populations

8

HEAT PPCI

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’

Single-centre Trials ? 9

HEAT PPCI

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’

Single-centre Trials ?

Minimal threat in HEAT PPCI

10

HEAT PPCI

Issues related to clinical performance and outcomes

• 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

Single-centre Trials ? 11

HEAT PPCI

Issues related to clinical performance and outcomes

• 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

Single-centre Trials ?

Minimal threat in HEAT PPCI

12

HEAT PPCI

Mortality Outcomes in PPCI

Registry and TrialPPCI 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

HEAT PPCI

• Comprehensive follow-up

•No ‘lost’ cases

Open Label Design ? 14

HEAT PPCI

• Comprehensive follow-up

• All primary efficacy and safety outcome measures -

•Overt clinical events with robust documentation

•MI events substantiated by imaging in almost all cases

Open Label Design ? 15

HEAT PPCI

• Comprehensive follow-up

• All primary efficacy and safety outcome measures

•Overt clinical events with robust documentation

•MI events substantiated by imaging in almost all cases

• Independent adjudication of events

• Blinded to patient identity and treatment allocation

Open Label Design ? 16

HEAT PPCI

• Comprehensive follow-up

• All primary efficacy and safety outcome measures

•Overt clinical events with robust documentation

•MI events substantiated by imaging in almost all cases

• Independent adjudication of events

• Open label norm - used in HORIZONS EUROMAX

Open Label Design ? 17

HEAT PPCI

• 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

Power Calculation 18

HEAT PPCI

• Assuming no observed treatment difference

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

• Event rate difference = 0%

• Calculate 95% CI for the rate difference

Power Calculation

0%+2.4

%-2.4%

19

HEAT PPCI

• 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

Power Calculation

2.5%

+2.3%

-2.3%

20

HEAT PPCI

Conventional Superiority - Tx A

0%

1%

2%

3%

4%

4%

3%

2%

1%

Event Rate Difference

Favours Treatment A Favours Treatment B

2.5%

+2.3%

-2.3%

21

HEAT PPCI

Conventional Superiority - Tx B

0%

1%

2%

3%

4%

4%

3%

2%

1%

Event Rate Difference

Favours Treatment A Favours Treatment B

2.5%

+2.3%

-2.3%

22

HEAT PPCI

Pre-specified Equivalence Zone

0%

1%

2%

3%

4%

4%

3%

2%

1%

Event Rate Difference

Favours Treatment A Favours Treatment B

Point estimate lies in zone ± 0.5% from zero difference

25

HEAT PPCI

Equivalence - Examples

0%

1%

2%

3%

4%

4%

3%

2%

1%

Event Rate Difference

Favours Treatment A Favours Treatment B

0.4%

+2.4%

-2.4%

0.4%

+2.4%

-2.4%

26

HEAT PPCI

Non-Inferiority - Example for Tx A

0%

1%

2%

3%

4%

4%

3%

2%

1%

Event Rate Difference

Favours Treatment A Favours Treatment B

Point estimate better than (-0.5%)

23

HEAT PPCI

Non-Inferiority - Example for Tx A

0%

1%

2%

3%

4%

4%

3%

2%

1%

Event Rate Difference

Favours Treatment A Favours Treatment B

Point estimate better than (-0.5%)

1%+2.4

%-2.4%

24

HEAT PPCI

• Anti-thrombotic therapy in PPCI for STEMI

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

• Increasingly the norm in routine practice

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

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

• Established anti-thrombotic treatment option

Background

HEAT PPCI

• Bivalirudin and heparin -

• Appear to have similar anti-ischaemic efficacy

• Similar impact on MACE events

Background

HEAT PPCI

Bivalirudin v Heparin

HAS REPLACE REPLACE 2

ISAR REACT 4 ACUITY ISAR REACT 3

HORIZONS ISAR REACT 3A EUROMAX

No difference in ischaemic outcomes

HEAT PPCI

• Bivalirudin and heparin - similar impact on MACE events

• Use of GPI agents causes increased bleeding

•When used with heparin

Background

HEAT PPCI

Heparin - Differential GPI use

Heparin Heparin

EPIC Placebo GPI Universal

RESTORE Placebo GPI Universal

PRISM Plus Placebo GPI Universal

CAPTURE Placebo GPI Universal

↑ bleeding with ↑ GPI use

HEAT PPCI

• Bivalirudin and heparin - similar impact on MACE events

• Use of GPI agents causes increased bleeding

•When used with heparin

•When used with bivalirudin

Background

HEAT PPCI

Bivalirudin - Differential GPI use

Bivalirudin Bivalirudin

GPI Bailout GPI Universal

ACUITY 9 % 97 %

↑ bleeding with ↑ GPI use

HEAT PPCI

• Bivalirudin and heparin - similar impact on MACE events

• Use of GPI agents causes increased bleeding

• With similar GPI use -

• Bivalirudin and heparin have similar bleeding rates

Background

HEAT PPCI

Both Drugs with Similar GPI use

Bivalirudin Heparin

GPI Universal GPI Universal

ACUITY 97 % 97 %

REPLACE 72 % 71 %

No differences in bleeding

HEAT PPCI

• Bivalirudin and heparin - similar impact on MACE events

• Use of GPI agents causes increased bleeding

• With similar GPI use -

• Bivalirudin and heparin have similar bleeding rates

• With differential GPI use -

• Bivalirudin and heparin have different bleeding rates

Background

HEAT PPCI

Both Drugs with Differential GPI use

Bivalirudin Heparin

GPI Bailout GPI Universal

ACUITY 9 % 97 %

ISAR REACT 4 0 % 100 %

HORIZONS 7 % 98 %

EUROMAX 9 % 70 %

↑ bleeding with ↑ GPI use

HEAT PPCI

• 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 assessed reliably with differential GPI use

• HEAT PPCI

• Bivalirudin + selective GPI v Heparin + selective GPI

Background