Is Bivalirudin Monotherapy Sufficient for Diabetic Patients
with Acute Coronary Syndrome Undergoing PCI?
Frederick Feit, Steven Manoukian, Ramin Ebrahimi, Charles Pollack,Magnus Ohman, Michael Attubato and Gregg Stone
Is Bivalirudin Monotherapy Sufficient for Diabetic Patients
with Acute Coronary Syndrome Undergoing PCI?
Shareholder: Johnson and Johnson, Medicines Co., Millenium Pharmaceuticals; Consultant: Medicines Co.
Conflicts:
PCI for 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
PCI for 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
PCI for 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=13,819Chest pain >10’ within 24 hours, plus
Biomarker +, orDynamic ECG changes, or
Documented CAD or all other TIMI risk criteria
Bivalirudin+ IIb/IIIa inhibitor
Enoxaparin or UFH+ IIb/IIIa inhibitor
Bivalirudin + IIb/IIIai
ASAClopidogrel
per local practice
Cath within 72 hoursPCI, CABG or medical management
30 day endpointsDeath, MI, IUR, ACUITY major bleeding
(net clinical outcome)
Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were
allowed
Stone et al. Presented 2006; ACC
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
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 Medications 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 IIb/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
PCI for ACS in Diabetics: Angiographic Triage
Diabetes(N=3852)
%
No Diabetes(N=9857)
%
# pts with angiography 98.6 99.3
Triaged procedure results
PCI 55.9 57.1
CABG 14.4 11.1*
Medical management 29.8 31.8
* - p<0.001
PCI for ACS in Diabetics: Baseline Characteristics
Diabetes(N=2137)
No Diabetes(N=5604)
P-value
Age mean, (median, [range], yrs) 63.9 (64.0, [25-92]) 62.2 (62.0, [21-95]) <0.001
Age > 75 yrs 19% 17.2% 0.07Female 33.6% 24.4% <0.001Weight mean, (median, [IQR], kg)
91.3 (89.0, [78-102]) 83.9 (82.0, [73-94]) <0.001
Caucasian 84.5% 91.7% <0.001Diabetes – insulin requiring 29.8% -
Hypertension n/N 83.5% 58.7% <0.001
Hyperlipidemia n/N 70.2% 50.8% <0.001Current smoker n/N 22.4% 34.1% <0.001Prior MI n/N 36.0% 28.3% <0.001Prior PCI n/N 48.1% 35.2% <0.001Prior CABG n/N 24.0% 15.1% <0.001Prior CVA n/N 7.6% 5.0% <0.001Creatinine Clearance* n/N 20.7% 17.6% 0.002
* CrCL <60 mL/min
14.9%
9.5%7.5%
5.3%
12.6%
8.5%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
ven
ts (
%)
Diabetes (n=2137) No Diabetes (n=5604)
Diabetes vs. No DiabetesDiabetes vs. No Diabetes
P = 0.008 P = 0.15 P < 0.001
†Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin
PCI for ACS in Diabetics: 30-Day Outcomes
Diabetic ACS Patients Undergoing PCIBaseline Characteristics by Treatment Group
Heparin† +GP IIb/IIIa(N=703)
Bivalirudin + GP IIb/IIIa(N=713)
Bivalirudin alone
(N=721)Age mean (median [range], yrs)
64.6 (66, [25-87]) 63.5 (64, [26-90]) 63.4 (64, [33-92])
Age ≥75 yrs, % 20.2 19.5 17.2Female, % 35.8 32.0 33.0Weight mean (median [IQR]) kg
91.6 (89.9 [78-103])
90.5 (88 [77-100]) 91.7 (89 [78-103])
Caucasian, % 85.1 83.4 85.1Diabetes–Insulin req, % 29.2 29.2 31.1Hypertension, % 85.3 83.1 82.2Hyperlipidemia, % 69.4 71.4 70.0Current smoker, % 22.5 23.0 21.7Prior MI, % 36.1 33.9 38.0Prior PCI, % 47.6 46.8 49.7Prior CABG, % 24.8 22.1 25.0Prior CVA, % 7.1 6.4 9.3Creatinine Clearance*, % 23.3 19.2 19.6
* creatinine clearance <60 mL/min †Heparin = unfractionated or enoxaparin†Heparin = unfractionated or enoxaparin
Diabetic ACS Patients Undergoing PCI: Baseline High Risk Features by Treatment Group
Heparin†
+ GP IIb/IIIa%
Bivalirudin + GP
IIb/IIIa%
Bivalirudin
alone%
Baseline cardiac biomarker
60.9 56.5 60.5
- Troponin 59.5 54.7 58.8
ST-segment ≥1mm
35.4 32.8 32.5
†Heparin = unfractionated or enoxaparin†Heparin = unfractionated or enoxaparin
Diabetic ACS Patients Undergoing PCI: Intervention Type
Heparin† + GP IIb/IIIa( N=692)
Bivalirudin + GP
IIb/IIIa( N=706)
Bivalirudin
alone(N=717)
Drug-Eluting Stent 62.9% 66.0% 62.8%
Non-Drug-Eluting Stent
31.5% 32.0% 33.1%
Thrombectomy 1.3% 1.3% 0.8%
Atherectomy 0.6% 0.7% 1.0%
Cutting Balloon 3.2% 4.0% 2.8%
Distal Protection 1.7% 2.4% 1.1%
Brachytherapy 0.0% 0.1% 0.3%
All comparisons p= NS †Heparin = unfractionated or enoxaparin†Heparin = unfractionated or enoxaparin
Diabetic ACS Patients Undergoing PCI: GP IIb/IIIa Inhibitor Administration
Heparin + IIb/IIIa(N=703)
Bivalirudin + IIb/IIIa(N=713)
Bivalirudin
alone(N=721)
GPI inhibitor during PCI 96.3% 97.1% 7.9%
- Eptifibatide 63.9% 67.0% 3.7%
- Tirofiban 16.2% 16.0% 0.4%
- Abciximab 16.2% 14.0% 3.7%
Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints by Treatment Group
15.2%
9.5%8.5%
10.7%
17.4%
9.5%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
ven
ts (
%)
Heparin+IIb/IIIa (N=703) Bivalirudin+IIb/IIIa (N=713)
Heparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIaHeparin* + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa
*Heparin = unfractionated or enoxaparin*Heparin = unfractionated or enoxaparin
P = 0.51 P = 0.48P = 0.27
Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints
15.2%
9.5%8.5%
4.6%
12.1%
8.3%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
ven
ts (
%)
Heparin+IIb/IIIa (N=703) Bivalirudin alone (N=721)
Heparin* + GP IIb/IIIa vs. Bivalirudin aloneHeparin* + GP IIb/IIIa vs. Bivalirudin alone
*Heparin = unfractionated or enoxaparin*Heparin = unfractionated or enoxaparin
P = 0.08 P = 0.42 P = 0.003
22
Diabetic ACS Patients Undergoing PCI: Components of Ischemic Endpoint
9.5%
1.3%
6.3%
3.6% 3.9%
0.7%
8.3%
5.5%
Compositeischemia
Death Myocardialinfarction
Unplannedrevasc forischemia
30
da
y e
ve
nts
(%
)
Heparin+IIb/IIIa (N= 703) Bivalirudin alone (N=721)
Heparin* + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin Alone
PSup = 0.42 PSup = 0.26 PSup = 0.57 PSup = 0.74
*Heparin=unfractionated or enoxaparin*Heparin=unfractionated or enoxaparin
30 d
ay e
ven
ts (
%)
Diabetic ACS Patients Undergoing PCI: Myocardial Infarction Classification*
6.3% 5.6%
Heparin† + IIb/IIIa vs. Bivalirudin AloneHeparin† + IIb/IIIa vs. Bivalirudin Alone
*CEC-adjudicated*CEC-adjudicated †Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin
Heparin + IIb/IIIa
Q-wave 1.7%
(N=703)Bivalirudin alone
(N=721)
Non Q-wave
4.9%
Q-wave 0.7%
Non Q-wave
4.6%
p = 0.57
p = 0.08
p = 0.79
Diabetic ACS Patients Undergoing PCI: Bleeding Endpoints 30-days
Heparin† +GP IIb/IIIa
( N=703)
Bivalirudin alone
(N=721)
p-value
ACUITY Scale
- Major Bleed, all 9.2% 5.3% 0.004
- Major, non-CABG 8.5% 4.6% 0.003
- Minor, non-CABG 24% 14.1% <0.001
TIMI Scale
- Any 8.7% 4.3% <0.001
- Major 3.1% 0.7% <0.001
- Minor 8.4% 4.0% <0.001
*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor †Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin
Insulin-dependent Diabetic ACS Patients Undergoing PCI: 30-Day Endpoints by Treatment Group
17.6%
9.3%11.2%
5.8%
11.6%
7.1%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
ven
ts (
%)
Heparin+IIb/IIIa (N=205) Bivalirudin alone (N=224)
Heparin† + GP IIb/IIIa vs. Bivalirudin aloneHeparin† + GP IIb/IIIa vs. Bivalirudin alone
P = 0.08 P = 0.42 P = 0.04
†Heparin=unfractionated or enoxaparin†Heparin=unfractionated or enoxaparin
Diabetic Patients with ACS Undergoing PCI: Conclusions
Compared with non-diabetics, diabetic patients have worse net clinical outcomes at 30 days (14.9% vs. 12.6%; p=0.008), resulting from similar rates of the composite ischemic end point (9.5% vs. 8.5%; p=0.15) and a significantly higher rate of major bleeding (7.5% vs. 5.3%; p=0.008)
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 Undergoing PCI: 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 (8.3% vs. 9.5%; p=0.42) and a marked reduction in major bleeding (4.6% vs. 8.5%; p=0.003) with a trend towards improved net clinical outcome (12.1% vs. 15.2%; p=0.08)
These 30-day outcomes suggest that bivalirudin monotherapy is safe and effective for diabetic patients with ACS undergoing PCI, including those requiring insulin
One-year clinical and economic data will determine whether this regimen will become the standard of care for these patients.