1. Outcomes in Elderly Patients Undergoing PCI Treated with Bivalirudin Monotherapy versus Glycoprotein IIb/IIIa Inhibitors with Heparin or LMWH: Results from the Randomized ACUITY Trial
Karen P. Alexander, E. Magnus Ohman, Michel E. Bertrand, Frederic Feit, Charles V. Pollack Jr, James Hoekstra, Bernard J. Gersh, Harvey D. White, Gregg W. Stone for the ACUITY Investigators

2. Disclosures
Research Funding (Minor): Schering Plough, BMS, Amgen, CV Therapeutics
Speakers Bureau: Pfizer

3. Background
Elderly patients presenting with NSTE ACS are at high risk for recurrent ischemic events
Use of antithrombotic therapy and an early invasive strategy are beneficial
Elderly patients are at high risk for bleeding with antithrombotic therapy and catheter interventions
Major bleeding is associated with adverse outcomes
Therapy for NSTEACS has become multi-tiered, particularly in pts undergoing PCI
The elderly with NSTE ACS experience a high incidence of recurrent ischemic events and death. The use of antithrombotic therapy and an early invasive strategy both reduce the risk of recurrent events. However, elderly are also at particular risk from bleeding complications related to antithrombotic therapy and catheter interventions. As new therapeutic agents continue to be added to the list of beneficial therapies, the ideal combination of these agents remains debated. There is continued need for optimizing the therapeutic regimen to minimize treatment associated risks.

4. Bivalirudin
Bivalirudin is a direct thrombin inhibitor with certain advantages
Circulating and clot bound thrombin, no requirement for AT III, may reduce thrombin mediated platelet activity
Clearance by proteolysis, with minor renal contribution
Short half life, no required monitoring
Studied in trials which enrolled PCI pts with various comparison groups *
Similar protection from ischemic events
Superior bleeding profile compared to standard combination therapy
* Replace-2, Protect TIMI 30, ACUITY, BAT

5. ACUITY Trial
Moderate-high risk NSTE ACS undergoing invasive care (13, 819 patients, 448 centers,17 countries)
Inclusion Criteria
Exclusion Criteria
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
No angiography within 72h
Acute STEMI or shock
Bleeding diathesis or major bleed within 2 weeks
Platelet count ≤100,000/mm3
INR >1.5 control
CrCl ≤30 ml/min
Abcx or ≥2 prior LMWH doses
Prior UFH, LMWH (1 dose), eptifibatide and tirofiban OK
ACUITY enrolled moderate risk ACS pts undergoing invasive care to evaluate a number of antithrombotic strategies in this population.
ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

6. ACUITY Design –Randomization
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)
UFH or Enoxaparin
Routine upstream GPI in all pts
GPI started in CCL for PCI only
Medical
management
PCI
CABG R2
Moderate-
high risk
ACS
Bivalirudin
Routine upstream GPI in all pts
Angiography within 72h R1
GPI started in CCL for PCI only
ACUITY had two randomization points. The first randomization was to one of three treatment arms, and the second randomization was within the combined hep or bival with GPI treatment arms to either upstream or cardiac cath lab initiation of the GPI. In this trial, approximately 7% of patients with Bivalirudin monotherapy also received “Bail Out” GPI inhibitors. The use of oral antiplatelet agents was high among all three treatment arms; use of ASA occurred in over 98%; use of clopidogrel either prior to enrollment, or prior to intervention occurred in approximately 85%.
Aspirin in all
Clopidogrel
dosing and timing
per local practice*
Bivalirudin
Alone
*Stratified by pre-angiography thienopyridine use or administration
ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

7. ACUITY Primary Endpoint 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

8. ACUITY Primary Results by Treatment
Heparin + GP IIb/IIIa
(4603)
Bivalirudin + GP IIb/IIIa
(4604)
Bivalirudin alone
(4612)
Endpoint
Rate
P Value
Net clinical outcome
11.7%
11.8%
<0.001 NI
10.1%
Sup
Ischemic events
7.3%
7.7%
0.007 NI
7.8%
0.011 NI
Major bleeding
5.7%
5.3%
3.0%
<0.001 Sup
NI = non-inferiority; Sup = superiority
Dr. Gregg Stone, ACC 2006 Presentation

9. Purpose
To compare age subgroup results with Bivalirudin monotherapy, heparin/GPI and Bival/GPI in PCI patients in ACUITY
Ischemic Endpoints
Major and Minor Bleeding
Describe differences across age
In terms of absolute risk reduction
Among those with preserved renal function

10. Baseline Characteristics by Age Subgroups PCI Cohort n=7,789; 56%
< ≥75
N (%) 2,052 (26.3) 2,240 (28.8) 2,121 (27.2) 1,376 (17.7)
Age (yrs) 48.0 ± ± ± ±3.5
Weight (kg) 92.1 ± ± ± ±14.1
Female (%)
HTN DM
CVA
Renal Insuff
EF <30%
Continuous Variables as Means ± SD

11. Cardiac Markers and Creatinine Clearance PCI Cohort n=7,789; 56%
< ≥75
N (%) 2,052 (26.2) 2,240 (28.8) 2,121 (27.2) 1,376 (17.7)
Hgb (mg/dl) 14.6 ± ± ± ±1.6
Troponin I (>ULN)
CrCl (ml/min) 127 ± ± ±36 59 ±36
CrCl ≥ 90 (%)
CrCl (%)
CrCl (%)
CrCl <30 (%)
Continuous Variables as Means ± SD

12. Combined Ischemic Endpoint PCI Cohort by Age Groups
12.3
12.2
11.0
9.3
9.0
8.6
8.6
8.3
8.2
7.0
7.1
6.5
There were no significant differences in the occurrence of the combined ischemic endpoint, or its components, in any of the 4 age groups. This is consistent with the results of the overall ACUITY trial which demonstrated noninferiority for bivalirudin.
N=2052
N=2240
N=2121
N=1376
Patient Age
P for all comparisons = NS

13. Major Bleeding Endpoint PCI Cohort
4.3
4.2
1.7
5.7
6.6
3.0
6.7
5.5
12.3
16.5
6.1
Patient Age
N=1376
N=2121
N=2240
N=2052
P=0.006
P=0.001
P=NS
P<0.001
P=0.007
P=0.010
P=0.033
The rate of major bleeding increases significantly with age. However, across all age groups, there was a significantly lower rate of major bleeding with bivalirudin monotherapy. Among those age >75, the rate of major bleeding was 11% overall, 16.5% with bivalirudin with GPI, but just 6.1% with bival alone.
Excluding CABG-related bleeding

14. Implication for Number Needed to Treat (NNT) Given the Absolute Risk Reduction (ARR) in Major Bleeding with Bivalirudin vs. Heparin/GPI 40 38 37 16
While the relative risk reduction in bleeding was similar across age with bivalirudin, there was a greater absolute risk reduction seen in the older patient subgroups. The impact of absolute risk reduction is also shown by the calculation of the NNT to prevent one event. Specifically, while an ARR of 2.5% corresponds to a NNT of 40, an ARR of over 6% in the elderly (age >75) corresponds to a NNT of 16 with bivalirudin to prevent one major bleeding event.
Patient Age

15. Minor Bleeding PCI Cohort** ** ** **
35.5 ** **
33.2 *
28.9
28.6
28.8 **
24.7
22.5
19.5
20.6
14.3
14.4
12.5
The rate of minor bleeding also increases significantly with age. Across all age groups, there was a significantly lower, and nearly half, the rate of minor bleeding with bivalirudin monotherapy compared to the other treatment arms.
N=2052
N=2240
N=2121
N=1376
Patient Age
*P<0.001; ** P<0.0001
Excluding CABG-related bleeding

16. Implication for NNT given the ARR in Minor Bleeding with Bivalirudin vs. Heparin/GPI
Major Bleeding Rate with Heparin/GPI 14 10 8 7
When the ARR in minor bleeding, which is between 10 and 15% for bival vs. heparin/GPI, is applied across age groups, the NNT with bival is in the single digits above age 65 years.
Patient Age

17. Limiting Cohort to CrCl >50cc/min addressing the question of renal dosing
93%
92%
85.5%
62%
By limiting the population to those with CrCl above 50, we can eliminate the question of dose adjustment for the GP IIb/IIIa inhibitors as a contributor to the bleeding rates observed in those two arms. The ACUITY population had an exclusion for pts with crcl <30, and the average renal function was >60 mg/dL in each age group, so this additional cut made little difference in the size of the groups <75. However, 40% of pts over age 75 were excluded from this comparison.
Patient Age

18. Combined Ischemic Endpoints PCI Cohort with CrCl >50 cc/min
12.3
P=0.04
10.4
9.6
9.3
8.7
8.5
7.8
8.0
8.0
7.4
6.7
6.6
Again, no significant differences across age subgroups were noted in ischemic endpoints in the three treatment arms.
N=1909
N=2063
N=1813
N=849
Patient Age
All other P = NS

19. Non-CABG Major Bleeding Endpoint PCI Cohort with CrCl >50 cc/min
12.7
9.6
P=0.008
=0.049
P=0.002
P=0.021
6.3
P=NS
5.9
P=0.012
5.7
5.0
4.5
4.1
4.3
3.5
And similar significantly lower bleeding was noted in the bival monotherapy arms.
2.8
1.9
N=1909
N=2063
N=1813
N=849
Patient Age
Patient Age

20. Implication for NNT Given ARR in Major Bleeding with Bivalirudin vs
Implication for NNT Given ARR in Major Bleeding with Bivalirudin vs. Heparin/GPI PCI Cohort with CrCl >50 cc/min 42 45 34
Major Bleeding Rate with Heparin/GPI 20
The rate of major bleeding in the hep/GPI arm is lower among the subset with crcl >50 as shown in the bars, with a 9.6% occurrence in the elderly age >75. However, the relationship between absolute risk and the NNT is similar with a NNT of 19 with Bivalirudin alone versus Hep and GPI to prevent one major bleed. This is compared with a NNT of 12 in all patients over age 75.
Patient Age

21. Conclusions Ischemic and hemorrhagic events increase with age
Across all age groups, bivalirudin is associated with significantly less major and minor bleeding and similar ischemic outcomes
Even among those with preserved renal function
ARR for major bleeding was greatest in the elderly (age >75)
NNT of 16 to prevent one major bleed
NNT of 8 to prevent one minor bleed
Dose all agents carefully, fewer agents may be better
The antithrombotic analogy to “start low, go slow” when initiating drugs in the elderly, may well be “Dose carefully, fewer agents may be better.”