Bivalirudin Monotherapy Improves
30-day Clinical Outcomes in
Diabetics with
Acute Coronary Syndrome:
Report from the ACUITY Trial
Frederick Feit, Steven Manoukian, Ramin Ebrahimi, Charles Pollack,
Magnus Ohman, Michael Attubato, Roxana Mehran and Gregg Stone
Bivalirudin Monotherapy Improves 30-day
Clinical Outcomes in Diabetics
with Acute Coronary Syndrome:
Report from the ACUITY Trial
Conflicts:
Shareholder: Johnson and Johnson, Medicines Co.,
Millenium Pharmaceuticals; Consultant: Medicines Co.
ACS in Diabetics:
Metabolic Abnormalities
Increased blood glucose causes coronary
artery inflammation and is prothrombotic
Increased generation of thrombin, CRP,
fibrinogen, von Willebrand factor, factors
VII and VIII, and platelet factor 4
Increased expression of platelet activation
markers including p-selectin, which
mediates platelet-leukocyte interactions
Higher proportion of platelets expressing
GPIIb/IIIa receptors
ACS in Diabetics:
Background
Based on prior data including a meta-
analysis of ACS trials current clinical
guidelines recommend the use of
GPIIb/IIIa inhibitors (GPI) in diabetic
patients with ACS, especially those in
whom PCI is planned1
In the ACUITY Trial 13,819 pts, including
3852 diabetics, with moderate or high risk
ACS, undergoing an early invasive
strategy were randomly assigned to either
the standard of care: Heparin (UFH or
enoxaparin) + GPI; or, Bivalirudin + GPI; or
Bivalirudin with provisional GPI
1. Roffi et al. Circulation. 2001;104:2767-71
ACS in Diabetics: Methods
We compared adverse events:
composite ischemia (death, nonfatal
MI, unplanned ischemia driven
revascularization), major bleeding and
net clinical outcome (composite
ischemia or bleeding) within the first
30 days in diabetic vs. nondiabetic pts
We compared the same 30-day end
points in diabetic pts by treatment
group
ACUITY Design
ACS: Unstable angina or NSTEMI, N=13,819
Chest pain >10’ within 24 hours, plus
Biomarker +, or
Dynamic ECG changes, or
Documented CAD or all other TIMI risk criteria
ASA
Clopidogrel Prior UFH, LMWH (1 dose),
per local practice eptifibatide and tirofiban allowed
Enoxaparin or UFH Bivalirudin Bivalirudin +
+ IIb/IIIa inhibitor + IIb/IIIa inhibitor provisional
Cath within 72 hours IIb/IIIa
PCI, CABG or medical management
30 day endpoints
Death, MI, IUR, ACUITY major bleeding
(net clinical outcome)
Stone et al. Presented 2006; ACC
Study Medications
Anti-thrombin agents (started pre angiography)
UF Heparin Enoxaparin Bivalirudin
U/Kg mg/Kg mg/kg
Bolus 60 1.0 sc bid 0.1 iv
Infusion/h 121 0.25 iv
ACT 0.30 iv bolus2 0.50 bolus iv
PCI
200-250s 0.75 iv bolus3 1.75/h infusion iv4
CABG Per institution Per institution Per institution5
Medical mgt None6 None6 None6
1 Target aPTT 50-75 seconds
2 Iflast enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose
4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if IIb/IIIa inhibitor not used
5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before
6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion
ACS in Diabetics:
Angiographic Triage
Diabetes No Diabetes
(N=3852) (N=9857)
% %
# pts with angiography 98.6 99.3
Triaged procedure results
PCI 55.9 57.1
CABG 14.4 11.1*
Medical management 29.7 31.8
* - p<0.001
ACS in Diabetics:
Baseline Characteristics
Diabetes No Diabetes
P-value
(N=3852) (N=9857)
Age mean, (median, [range], yrs) 63.8 (64.0, [25-92]) 62.1 (62.0, [20-95]) <0.001
Age ≥ 65 yrs 49% 43.4% <0.001
Age ≥ 75 yrs 17.9% 17.6% 0.65
Female 34.9% 28.2% <0.001
Weight 90.8 (88.5, [77-102]) 83.3 (82.0, [72-94]) <0.001
mean, (median, [IQR], kg)
Diabetes – insulin requiring 31.0% -
Hypertension 83.6% 60.5% <0.001
Hyperlipidemia 68.8% 51.3% <0.001
Current smoker 21.4% 32.0% <0.001
Prior MI 36.2% 29.4% <0.001
Prior PCI 46.1% 36.1% <0.001
Prior CABG 23.7% 15.7% <0.001
Creatinine Clearance* 19.8% 18.8% 0.1746
* CrCL <60 mL/min
ACS in Diabetics:
30-Day Outcomes
Diabetes vs. No Diabetes
Diabetes (n=3852) No Diabetes (n=9857)
P = 0.0002 P = 0.0037 P = 0.0002
30 day events (%)
12.8%
10.5%
8.6%
7.2%
5.7%
4.2%
Net clinical outcome Composite ischemia Major bleeding (non-
CABG)
†
Heparin=unfractionated or enoxaparin
Diabetic ACS Patients
Baseline Characteristics by Treatment
Heparin† + Bivalirudin + Bivalirudin
GP IIb/IIIa GP IIb/IIIa alone
(N=1298) (N=1267) (N=1287)
Age
64.0 (65, [25-87]) 63.9 (64, [26-90]) 63.5 (64, [32-92])
mean (median [range], yrs)
Age ≥75 yrs, % 18.4 18.6 16.7
Female, % 35.3 34.5 34.8
Weight mean (median
90.7 (88 [77-102]) 89.7 (87 [77-100]) 91.9 (90 [78-103])
[IQR]) kg
Caucasian, % 84.4 81.5 83.4
Diabetes–Insulin req, % 30.0 31.3 31.7
Hypertension, % 84.4 82.5 83.2
Hyperlipidemia, % 67.8 69.2 69.4
Current smoker, % 20.7 21.2 20.9
Prior MI, % 36.5 32.2 36.6
Prior PCI, % 45.8 42.7 48.0
Prior CABG, % 24.4 21.7 24.9
Prior CVA, % 8.6 7.7 9.0
Creatinine Clearance*, % 21.4 19.1 19.0
†Heparin =
* creatinine clearance <60 mL/min unfractionated or enoxaparin
Diabetic ACS Patients:
30-Day Endpoints by Treatment Group
Heparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa
Heparin+IIb/IIIa (N=1298) Bivalirudin+IIb/IIIa (N=1267)
P = 0.94 P = 0.64 P = 0.43
30 day events (%)
13.7% 13.8%
8.8% 9.3%
7.1%
6.3%
Net clinical outcome Composite ischemia Major bleeding (non-
CABG)
*Heparin = unfractionated or enoxaparin
Diabetic ACS Patients:
30-Day Endpoints
Heparin* + GP IIb/IIIa vs. Bivalirudin alone
Heparin+IIb/IIIa (N=1298) Bivalirudin alone (N=1287)
P = 0.02 P = 0.39 P=0.0002
30 day events (%)
13.7%
10.8%
8.8%
7.8%
7.1%
3.7%
Net clinical outcome Composite ischemia Major bleeding (non-
CABG)
*Heparin = unfractionated or enoxaparin
Diabetic ACS Patients:
Components of Ischemic Endpoint
Heparin* + IIb/IIIa vs. Bivalirudin Alone
Heparin+IIb/IIIa (N= 1298) Bivalirudin alone (N=1287)
P = 0.39 P = 0.32 P= 0.27 P = 0.37
30 day events (%)
8.8%
7.8%
5.6%
4.7%
3.0%
2.1% 2.4%
1.6%
Composite Death Myocardial Unplanned
ischemia infarction revasc for
ischemia
*Heparin=unfractionated or enoxaparin
17
Diabetic ACS Patients:
Myocardial Infarction Classification*
Heparin† + IIb/IIIa vs. Bivalirudin Alone
p = 0.27
30 day events (%)
5.6% 4.7%
Q-wave 1.6%
p = 0.05 Q-wave 0.8%
Non Q-wave Non Q-wave
p = 0.87 3.9%
4.0%
Heparin + IIb/IIIa Bivalirudin alone
(N=1298) (N=1287)
†Heparin=unfractionated or
*CEC-adjudicated enoxaparin
Diabetic ACS Patients:
Bleeding Endpoints 30-days
Heparin† +GP Bivalirudin
p-
IIb/IIIa alone
value
( N=1298) (N=1287)
ACUITY Scale
- Major Bleed, all 14.3% 11.0% 0.012
- Major, non-CABG 7.1% 3.7% 0.0002
- Minor, non-CABG 21.1% 12.3% <0.001
TIMI Scale, non-CABG
- Any 7.5% 3.7% <0.001
- Major 2.4% 0.9% 0.002
- Minor 7.0% 3.6% <0.001
†Heparin=unfractionated or
*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor enoxaparin
Insulin-dependent Diabetic ACS Patients:
30-Day Endpoints by Treatment Group
Heparin† + GP IIb/IIIa vs. Bivalirudin alone
Heparin+IIb/IIIa (N=389) Bivalirudin alone (N=408)
P = 0.23 P = 0.74 P = 0.04
30 day events (%)
15.7%
12.7%
9.8% 9.1%
8.2%
4.7%
Net clinical outcome Composite ischemia Major bleeding (non-
CABG)
†
Heparin=unfractionated or enoxaparin
Diabetic Patients with ACS :
Conclusions
Compared with non-diabetics, diabetic
patients have worse net clinical outcomes
at 30 days (12.8% vs. 10.5%; p=0.0002),
resulting from significantly higher rates of
the composite ischemic end point (8.6%
vs. 7.2%; p=0.0037) and non-CABG major
bleeding (5.7% vs. 4.2%; p=0.0002)
In diabetic patients, compared with the
standard of care, heparin (UFH or
enoxaparin) + GPIIb/IIIa, bivalirudin +
GPIIb/IIIa was not better for protection
from ischemic events or bleeding and
resulted in similar net clinical outcome
Diabetic Patients with ACS:
Conclusions
Compared to those receiving the reference
standard, diabetics receiving bivalirudin
monotherapy, with provisional GPIIb/IIIa in
7.9%, had similar protection from ischemic
events (7.8% vs. 8.8%; p=0.39) and a marked
reduction in major bleeding (3.7% vs. 7.1%;
p=0.0002) with improved net clinical outcome
(10.8% vs. 13.7%; p=0.02)
These 30-day outcomes suggest that
bivalirudin monotherapy is safe and effective
for diabetic patients with ACS, including those
requiring insulin
One-year clinical and economic data will
determine whether this regimen will become
the standard of care for these patients.