SwitchSwitch

SwitchSwitch

Safety and Efficacy of Crossover (Switch) from UFH/Enox to

Bivalirudin: Results from ACUITY

Safety and Efficacy of Crossover (Switch) from UFH/Enox to

Bivalirudin: Results from ACUITY

Dr. Harvey White

Green Lane Cardiovascular Service

Auckland City Hospital, Auckland, NZ

Dr. Harvey White

Green Lane Cardiovascular Service

Auckland City Hospital, Auckland, NZ

DisclosureDisclosure

Research Grants : Alexion Fournier Laboratories Sanofi Aventis

Johnson & Johnson Eli Lilly Proctor & Gamble Merck Sharpe & Dohme Schering Plough Roche The Medicines Company Glaxo Smith Kline Pfizer Neuren Pharmaceuticals NIH

Consultant: Sanofi Aventis The Medicines Company

BackgroundBackground ACS patients

87% of patients receive either UFH or Enox within 24 hours after admission1

72% of patients in Synergy and 50 % of patients in OASIS- 5 received prior antithrombin2,3

Published studies and perceptions Patients in Synergy who crossed over between UFH

and Enox had an increase in bleeding complications2

This activity occurred at various times through the study period: at times in response to clinical or clinician perception

Consistent therapy is better4

ACS patients 87% of patients receive either UFH or Enox within 24

hours after admission1

72% of patients in Synergy and 50 % of patients in OASIS- 5 received prior antithrombin2,3

Published studies and perceptions Patients in Synergy who crossed over between UFH

and Enox had an increase in bleeding complications2

This activity occurred at various times through the study period: at times in response to clinical or clinician perception

Consistent therapy is better4

1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al,NEJM 2006; 4 Cohen et al, JACC 2006;

Scope of AnalysisScope of Analysis This analysis will address the question of

the safety and efficacy of switching from indirect thrombin inhibition (UFH or Enox) to direct thrombin inhibition (bivalirudin) A protocol-driven activity of the ACUITY study

at the time of randomization

This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or Enox) to direct thrombin inhibition (bivalirudin) A protocol-driven activity of the ACUITY study

at the time of randomization

ACUITY: Primary resultsACUITY: Primary results

Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

7.3%5.7%

11.7%

7.7%

11.8%

5.3%

3.0%

10.1%

7.8%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.011 PSup = 0.32

PNI <0.001PSup <0.001

*Heparin=unfractionated or enoxaparin

UF Heparin Enoxaparin BivalirudinU/Kg mg/Kg mg/kg

Bolus 60 1.0 sc bid 0.1 iv

Infusion/h 121 0.25 iv

PCIACT

200-250s

0.30 iv bolus2

0.75 iv bolus3

0.50 bolus iv

1.75/h infusion iv4

CABG Per institution Per institution Per institution5

Medical mgt None6 None6 None6

Study MedicationsStudy Medications Anti-thrombin agents (started pre angiography) Anti-thrombin agents (started pre angiography)

1 Target aPTT 50-75 seconds2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

Prior treatmentPrior treatment ACUITY Protocol requirements

Patients on an antithrombin (either UFH or Enox) prior to randomization:

Continued the same treatment if randomized into Heparin(s) + GP IIb/IIIa arm

Switched to bivalirudin if randomized to one of the bivalirudin arms

Following results of Synergy UFH was allowed in the trial Sites prospectively determined the preferred anti-

thrombin strategy of either UFH or Enox Switch between UFH and Enox was not permitted

ACUITY Protocol requirements Patients on an antithrombin (either UFH or Enox) prior

to randomization: Continued the same treatment if randomized into Heparin(s)

+ GP IIb/IIIa arm Switched to bivalirudin if randomized to one of the bivalirudin

arms

Following results of Synergy UFH was allowed in the trial Sites prospectively determined the preferred anti-

thrombin strategy of either UFH or Enox Switch between UFH and Enox was not permitted

Current AnalysisCurrent Analysis

Hypothesis Bivalirudin improves bleeding outcomes while

preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation.

Is it better to switch to bivalirudin or remain on consistent therapy?

Hypothesis Bivalirudin improves bleeding outcomes while

preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation.

Is it better to switch to bivalirudin or remain on consistent therapy?

Current AnalysisCurrent Analysis

Methods Patients on prior antithrombin

Consistent: No switching from pre-randomization anti-thrombin to randomized therapy:

Enox →Enox or UFH → UFH

Switch: Single switch to bivalirudin determined by randomization code

from Enox → bivalirudin or UFH →bivalirudin

Event rates at 30-days Net Clinical Outcome Ischemic Composite Major Bleeding

Methods Patients on prior antithrombin

Consistent: No switching from pre-randomization anti-thrombin to randomized therapy:

Enox →Enox or UFH → UFH

Switch: Single switch to bivalirudin determined by randomization code

from Enox → bivalirudin or UFH →bivalirudin

Event rates at 30-days Net Clinical Outcome Ischemic Composite Major Bleeding

ACUITY Primary Endpoints at 30 daysACUITY Primary Endpoints at 30 days

Net Clinical Endpoint Composite ischemic and non-CABG major bleeding endpoints

Ischemic Endpoint Death, MI, or unplanned revascularization

Non-CABG Major Bleeding Endpoint Intracranial, intraocular, or retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source Blood transfusion

Net Clinical Endpoint Composite ischemic and non-CABG major bleeding endpoints

Ischemic Endpoint Death, MI, or unplanned revascularization

Non-CABG Major Bleeding Endpoint Intracranial, intraocular, or retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source Blood transfusion

Consort DiagramConsort Diagram

ACUITYACUITYN = 13819

Arm AArm AHeparins + IIb/IIIa

N = 4603

Arm CArm CBivalirudinN = 4612

Arm BArm BBivalirudin + GP IIb/IIIa

N = 4604

Consort DiagramConsort Diagram

ACUITYACUITYN = 13819

Arm AArm AHeparins + IIb/IIIa

N = 4603

Arm CArm CBivalirudinN = 4612

Consort DiagramConsort Diagram

ACUITYACUITY13819

Arm A: CONSISTENTArm A: CONSISTENTHeparins + IIb/IIIa

N = 2223

Arm C: SWITCHArm C: SWITCHBivalirudinN = 2237

Pts on Prior ATN = 6606 ╪

•╪ excludes Arm B and pts. with multiple crossovers, missing data

Consort DiagramConsort Diagram

ACUITYACUITY13819

CONSISTENTCONSISTENTUFH/EnoxN = 2223

SWITCHSWITCHBivalirudin*

N = 2237

UFH→UFHN = 1294

Enox→EnoxN = 929

UFH→BivN = 1313

Enox→BivN = 857

Pts on Prior ATN = 6606 ╪

• * Includes 67 pts. who had UFH and Enox • ╪ excludes Arm B and pts. with multiple crossovers, missing data

Baseline Characteristics Consistent UFH/Enox vs. Switch to Biv

Baseline Characteristics Consistent UFH/Enox vs. Switch to Biv

* creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes

ConsistentUFH/EnoxN = 2223

SwitchBivalirudinN = 2237

P-value

Age (median [range], yrs) 63 [23, 91] 62 [20, 92] 0.02Male (%) 71.6 70.0 NS

Weight (median [IQR], kg) 83 [73, 96] 84 [73, 96] NS

Diabetes(%) 27.6 25.0 0.05Hypertension (%) 64.5 63.8 NSHyperlipidemia (%) 54.6 54.0 NSCurrent smoker (%) 29.5 30.7 NSPrior MI (%) 31.0 30.4 NSPrior PCI (%) 36.8 36.8 NSPrior CABG (%) 18.4 18.1 NSThienopyridine exposure 63.8 66.1 NSRenal insufficiency* (%) 19.6 17.4 NSHigh Risk* (%) 77.6 74.6 0.02Troponin + (%) 65.4 63.6 NS

11.9%

7.3%5.8%

6.9%

9.1%

2.8%

Net Clinical Outcome Ischemic composite Major bleeding

30

da

y e

ve

nts

(%

)

Consistent UFH/Enox (N = 2223 )

Switch to Bivalirudin (N= 2237)

Comparing Consistent therapy on UFH/Enoxvs. Switch Bivalirudin Alone

Comparing Consistent therapy on UFH/Enoxvs. Switch Bivalirudin Alone

Consistent vs. SwitchConsistent vs. Switch

P=0.002

0.77 [0.63 – 0.91]

P=0.601

0.95 [0.76 – 1.17]

P<0.001

0.47 [0.35 – 0.64]

0 1 2

0.83 (0.67-1.02)

OR (95% CI)Odds ratio±95% CI

Switch to Bivalirudin alone betterSwitch to Bivalirudin alone better Consistent UFH/Enox betterConsistent UFH/Enox better

Major Bleeding

Ischemia

Net Clinical Outcome

1.10 (0.86-1.41)

0.47 (0.34-0.65)

P-value

0.073

0.464

<0.001

* Comparing consistent Hep/Enox vs Switch Bivalirudin* Comparing consistent Hep/Enox vs Switch Bivalirudin

Consistent vs. SwitchAll Patients - Adjusted

Consistent vs. SwitchAll Patients - Adjusted

Consistent vs. SwitchHigh Risk - Unadjusted

Consistent vs. SwitchHigh Risk - Unadjusted

Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin

Consistent

UFH/Enox

N = 1654

Switch

Bivalirudin

N = 1623

RR

Net Clinical Outcome

13.1% 10.6% 0.81 [0.67-0.98]

Ischemia 8.0% 7.8% 0.97 [0.76-1.22]

Major Bleeding 6.6% 3.5% 0.52 [0.38-0.72]

0 1 2

0.86 (0.68-1.07)

OR (95% CI)Odds ratio±95% CI

Switch to Bivalirudin alone betterSwitch to Bivalirudin alone better Consistent UFH/Enox betterConsistent UFH/Enox better

Major Bleeding

Ischemia

Net Clinical Outcome

1.11 (0.85-1.46)

0.51 (0.36-0.72)

P-value

0.177

0.445

<0.001

Consistent vs. SwitchHigh Risk - Adjusted

Consistent vs. SwitchHigh Risk - Adjusted

Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin

Consistent vs. SwitchPatients undergoing PCI - Unadjusted

Consistent vs. SwitchPatients undergoing PCI - Unadjusted

Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin

Consistent

UFH/Enox

N = 1293

Switch

Bivalirudin

N = 1390

RR

Net Clinical Outcome

13.3% 11.8% 0.89 [0.73 -1.08]

Ischemia 8.1% 9.0% 1.06 [0.81 -1.40]

Major Bleeding 6.9% 3.5% 0.50 [0.36-0.71]

11.2%

7.0%

5.2%6.4%

9.1%

2.8%

Net Clinical Outcome Ischemic composite Major bleeding

30

da

y e

ve

nts

(%

)

Consistent Enox (N = 929 )

Switch from Enox to Bivalirudin (N= 857)

Comparing Consistent therapy on Enox vs. Switch from Enox to Bivalirudin Alone

Comparing Consistent therapy on Enox vs. Switch from Enox to Bivalirudin Alone

Consistent vs. SwitchConsistent vs. Switch

P=0.145

0.81 [0.61 – 1.07]

P=0.626

0.92 [0.65 – 1.30]

P=0.013

0.54 [0.34 – 0.88]

12.4%

7.6%6.3%

7.4%

9.4%

2.8%

Net Clinical Outcome Ischemic composite Major bleeding

30

da

y e

ve

nts

(%

)

UFH+ GP IIb/IIIa (N = 1294 )

UFH to Bivalirudin (N= 1313)

Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone

Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone

Consistent vs. SwitchConsistent vs. Switch

P=0.012

0.75[0.60 – 0.94]

P=0.857

0.98[0.74 – 1.28]

P<0.001

0.44[0.30 – 0.65]

0 1 2

0.89 (0.64-1.23)

OR (95% CI)Odds ratio±95% CI

Switch to Bivalirudinalone better

Switch to Bivalirudinalone better

Consistent Enoxbetter

Consistent Enoxbetter

MajorBleeding

Ischemia

Net ClinicalOutcome

1.07 (0.72-1.59)

0.55 (0.32-0.95)

P-value

0.472

0.732

0.032

0 1 2

0.78 (0.59-1.03)

OR (95% CI)Odds ratio±95% CI

Switch to Bivalirudinalone better

Switch to Bivalirudinalone better

Consistent UFHbetter

Consistent UFHbetter

MajorBleeding

Ischemia

Net ClinicalOutcome

1.18 (0.86-1.63)

0.40 (0.26-0.61)

P-value

0.081

0.312

<0.001

Consistent vs. SwitchAdjusted

Consistent vs. SwitchAdjusted

Comparing Consistent UFH/Enox vs Switch to BivalirudinComparing Consistent UFH/Enox vs Switch to Bivalirudin

Consistent Enox vs. bivalirudin Consistent UFH vs. bivalirudin

LimitationsLimitations Post-hoc subgroup analysis

Pre-randomization use of anti-thrombin was not stratified

Timing and dose of last UFH and Enox was not collected in the CRF

Post-hoc subgroup analysis

Pre-randomization use of anti-thrombin was not stratified

Timing and dose of last UFH and Enox was not collected in the CRF

ConclusionsConclusions Switching to bivalirudin is safe

Switching from any heparin (either enoxaparin or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events.

Furthermore Switch to bivalirudin provides patients the

50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin.

Switching to bivalirudin is safe Switching from any heparin (either enoxaparin

or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events.

Furthermore Switch to bivalirudin provides patients the

50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin.