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Safety and Efficacy of Bivalirudin in patients undergoing PCI: The impact of duration of infusion in ACUITY trial

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Title: Safety and Efficacy of Bivalirudin in patients undergoing PCI: The impact of duration of infusion in ACUITY trial


1
Safety and Efficacy of Bivalirudin in patients
undergoing PCI The impact of duration of
infusion in ACUITY trial
Duration
  • Dr. David Cox
  • Lehigh Valley Hospital
  • Allentown, PA

Duration
2
Presenter Disclosure
  • Consultant, lecture fees from The
    Medicines Company

3
Bivalirudin as an Alternative to UFH/LMWH
  • Advantages of the direct thrombin inhibitor
    bivalirudin
  • No requirement for anti-thrombin III
  • Effective on clot-bound thrombin
  • Inhibits thrombin-mediated platelet activation
  • No interactions with PF-4
  • Plasma half-life 25 minutes
  • No requirement for anticoagulant monitoring
  • Clinical results with bivalirudin in PCI
  • Similar protection from ischemic events as UFH
    GP IIb/IIIa inhibitors, with markedly reduced
    bleeding1

REPLACE 2. Lincoff AM et al. JAMA
2003289853-863
4
Study Design
  • Moderate-high risk unstable angina or NSTEMI
    undergoing an invasive strategy (N 13,819)

Moderate- high risk ACS
Aspirin in all Clopidogrel dosing and timing per
local practice
Stratified by pre-angiography thienopyridine use
or administration
ACUITY Design. Stone GW et al. AHJ 200414876475
5
Major Entry Criteria
  • Moderate-high risk unstable angina or NSTEMI

Inclusion Criteria
Age 18 years Chest pain 10 within 24h At least one of New ST depression or transient ST elevation 1 mm Troponin I, T, or CKMB? Documented CAD All other 4 TIMI risk criteria Age 65 years Aspirin within 7 days 2 angina episodes w/i 24h 3 cardiac risk factors Written informed consent
Exclusion Criteria
No angiography within 72h Acute STEMI or shock Bleeding diathesis or major bleed within 2 weeks Platelet count 100,000/mm3 INR gt1.5 control CrCl 30 ml/min Abcx or 2 prior LMWH doses Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed Allergy to drugs, contrast
ACUITY Design. Stone GW et al. AHJ 200414876475
6
Primary Endpoints (30 day)
  • Net Clinical Outcome
  • Death, MI, unplanned revascularization for
    ischemia or non-CABG major bleeding
  • Composite Ischemic
  • Death, MI or unplanned revascularization for
    ischemia
  • Non-CABG Major Bleeding Endpoint
  • Intracranial, intraocular, or retroperitoneal
    bleeding
  • Access site bleed requiring intervention/surgery
  • Hematoma 5 cm
  • Hgb ?4g/dL w/o overt source
  • Hgb ?3g/dL with an overt source
  • Reoperation for bleeding
  • Any blood transfusion

7
ACUITY Primary Results (ITT)
  • Heparin IIb/IIIa vs. Bivalirudin IIb/IIIa
    vs. Bivalirudin Alone

Heparinunfractionated or enoxaparin
8
ACUITY Major Bleeding Endpoints
  • Heparin IIb/IIIa vs. Bivalirudin IIb/IIIa
    vs. Bivalirudin Alone

PSup0.38
PSuplt0.001
PSup0.31
PSup0.001
All Major Bleeding (All, including CABG)
Major Bleeding (Non-CABG related)
Heparinunfractionated or enoxaparin
9
Median Time Intervals PCI patients
Time in hours(interquartile range) Heparin IIb/IIIa N 2561 Bivalirudin IIb/IIIa N 2609 Bivalirudin alone N 2619
Admission to start of first PCI 19.7 6.3-30.5 19.3 6.3-29.2 19.6 6.3-30.7
Randomization to first PCI 4.92 2.0 21.2 4.92 2.0 20.6 5.08 2.1-21.5
Antithrombinstudy drug to PCI 4.05 1.4-18.7 3.85 1.2-18.7 3.98 1.4-19.7
Duration of PCI (min) 25 16-41 25 15-40 25 15-42
10
Current Analysis Objective and Methods
  • Objective
  • Examine the utility of bivalirudin monotheraphy
    as the antithrombotic regimen in patients with
    delay to PCI.
  • Methods
  • Comparison of 30-day event rates for net clinical
    outcomes, ischemia and bleeding in patients
    undergoing PCI within 24 hours from randomization
    versus gt 24 hours.

11
Baseline Characteristics Patients undergoing PCI
gt 24 hours after randomization
Heparin IIb/IIIa(N484) Bivalirudin alone(N511) P-value
Age (median range, yrs) 65 31, 91 64 34, 92 0.60
Male () 73.6 73.6 0.99
Weight (median IQR, kg) 83 73, 94 82 72, 94 0.82
Diabetes() 28.1 27.2 0.83
Hypertension () 64.7 60.9 0.38
Hyperlipidemia () 55.7 47.9 0.05
Current smoker () 30.4 30.3 0.30
Prior MI () 28.9 29.7 0.75
Prior PCI () 34.1 33.1 0.93
Prior CABG () 18.8 20.0 0.56
Thienopyridine exposure 80.5 79.6 0.71
Renal insufficiency () 21.7 19.8 0.47
High Risk () 78.0 81.1 0.23
creatinine clearance lt60 mL/min
Elevated cardiac markers and/or ST changes
12
Procedural characteristics Patients undergoing
PCI gt 24 hours after randomization
Heparin IIb/IIIa (N484) Bivalirudin alone (N511) P- value
PCI immediately after angiography () 78.7 80.2 0.554
Attempted vessels per patient ()
1 82.6 82.8 0.96
2 14.9 15.3 0.86
gt3 2.3 1.8 0.56
Target Vessel
LAD () 41.4 45.1 0.250
RCA () 37.4 32.0 0.074
13
Baseline ComparisonsTime to PCI lt24 hours vs. gt
24 hours
lt 24 hours(N6321) gt 24 hours(N1453) P-value
Age (median range, yrs) 62 21, 95 64 31, 92 lt0.001
Male () 73.1 73.4 0.789
Weight (median IQR, kg) 84 74, 96 82 72, 93 lt0.001
Diabetes() 27.7 27.2 0.700
Hypertension () 66.3 61.9 0.001
Hyperlipidemia () 57.0 52.4 0.002
Current smoker () 31.0 30.5 0.695
Prior MI () 30.4 30.6 0.895
Prior PCI () 39.9 33.4 lt0.001
Prior CABG () 17.1 19.2 0.063
Renal insufficiency () 17.9 20.7 0.013
Thienopyridine exposure 65.5 80.5 lt0.001
High Risk () 75.3 80.4 lt0.001
creatinine clearance lt60 mL/min
Elevated cardiac markers and/or ST changes
14
Primary Endpoint Measures by Duration
  • Heparin IIb/IIIa vs. Bivalirudin Alone

1.08(0.88-1.33)
0.57(0.43-0.75)
0.90(0.77-1.07)
1.05(0.72-1.52)
0.37(0.22-0.65)
0.77(0.57-1.04)
Time to PCI lt 24 hrs
Time to PCI gt 24 hrs
Results persist after adjusting for differences
in baseline characteristics
15
Primary Endpoint Measures by Duration Ischemia
and Bleeding
  • Heparin IIb/IIIa vs. Bivalirudin Alone

1.08 (0.88-1.33)
0.57 (0.43-1.75)
1.05(0.72-1.52)
0.37 (0.22-0.65)
Time to PCI lt 24 hrs
Time to PCI gt 24 hrs
Results persist after adjusting for differences
in baseline characteristics
16
Non-CABG Bleeding Patients undergoing PCI gt24
hours of medical therapy
  • Heparin IIb/IIIa vs. Bivalirudin Alone

Plt 0.001
P0.008
Plt0.001
P0.06
Heparinunfractionated or enoxaparin
17
Primary Endpoint Measures by DurationIschemia
and Bleeding in HIGH Risk PCI
  • Heparin IIb/IIIa vs. Bivalirudin Alone

1.08 (0.86-1.37)
0.59 (0.43-0.80)
1.10 (0.73-1.66)
0.45 (0.26-0.79)
Time to PCI lt 24 hrs
Time to PCI gt 24 hrs
  • High Risk elevated cardiac markers and/or ST
    changes
  • Results persist after adjusting for differences
    in baseline characteristics

18
PCI
  • Results adjusted for baseline characteristics

Time to PCI 24h
Time to PCI gt24h
Odds ratio 95 CI
Odds ratio 95 CI
RR (95 CI)
RR (95 CI)
Ischemia
Ischemia
1.14 (0.92-1.41)
0.98 (0.67-1.43)
Bleeding
Bleeding
0.59 (0.45-0.76)
0.34 (0.21-0.55)
Net ClinicalOutcome
Net ClinicalOutcome
0.90 (0.75-1.09)
0.66 (0.49-0.89)
Bivalirudin alone better
Heparin IIb/IIIa better
Bivalirudin alone better
Heparin IIb/IIIa better
19
High-Risk PCI
  • Results adjusted for baseline characteristics

Time to PCI 24h
Time to PCI gt24h
Odds ratio 95 CI
Odds ratio 95 CI
RR (95 CI)
RR (95 CI)
Ischemia
Ischemia
1.13 (0.89-1.43)
0.99 (0.66-1.48)
Bleeding
Bleeding
0.61 (0.46-0.82)
0.41 (0.26-0.67)
Net ClinicalOutcome
Net ClinicalOutcome
0.95 (0.79-1.14)
0.73 (0.53-1.01)
Bivalirudin alone better
Heparin IIb/IIIa better
Bivalirudin alone better
Heparin IIb/IIIa better
20
Conclusions
  • Delay greater than 24 hours in time to PCI in ACS
    patients may be associated with increased
    ischemia and bleeding compared to rapid
    intervention.
  • Bleeding complications are not increased when
    using bivalirudin alone.
  • Compared with Heparin/Enoxaparin with IIb/IIIa
    inhibitor, bivalirudin monotherapy significantly
    reduces major bleeding while providing similar
    ischemic protection regardless of time to PCI.

21
Limitations
  • Unblinded non-randomized subgroup analysis
  • Time to intervention may have been influenced by
    factors not collected in the study
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