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