Why Bleeding Matters in ACS

1
Getting in the (Up)Stream of Things
Why Bleeding Matters in ACS Importance of
Multi-specialty ED and IC Therapeutic (EDICT)
Alignment of Upstream Care for ACS Sunil Rao,
MD, FACC Director of Interventional
Cardiology Veterans Administration Medical
Center Assistant Professor Division of
Cardiovascular Medicine Duke University Medical
Center
2
Program Faculty and COI
  COI Disclosures Sunil V. Rao, MD,
FACC Grant/Research Support Cordis, The
Medicines Company Consultant sanofi-aventis,
Bristol-Myers Squibb, The Medicines
Company Speakers Bureau sanofi-aventis,
Bristol-Myers Squibb, Cordis, The Medicines
Company  
3
What Do The Guidelines Mean for ED Physicians and
Cardiologists?

• Acute
• Coronary
• Syndrome

4
What Do The Guidelines Mean for ED Physicians and
Cardiologists?

• Acute
• Controversy
• Syndrome

5
What Do The Guidelines Mean for ED Physicians and
Cardiologists?

• Acute
• Confounded
• Syndrome

NSTE GLs The Writing Committee believes that
inadequate unconfounded, comparative information
is available to recommend a preferred
anticoagulation regimen when an early, invasive
strategy is used for UA/NSTEMI, and physician and
health care system preference, together with
individualized patient application, is advised.
6
What Do The Guidelines Mean for ED Physicians and
Cardiologists?

• Acute
• Contentiousness
• Syndrome

7
What Do The Guidelines Mean for ED Physicians and
Cardiologists?

• Acute
• Collaboration
• Syndrome

8
Opportunities for Collaboration between
Emergency Medicine and Cardiology

• Improve D2R times
• More consistency in anticoagulation and
  antiplatelet therapy in transition from ED to
  cath
• Familiarity and consistency result in fewer
  dosing errors, omissions and delays in therapy
• Improve compliance with evidence-driven best
  practice
• CRUSADE and ACTION indicate better patient
  outcomes new studies suggest further improvement
  is possible

9
ACS Case Presentation

• 77 year old female presents to ED with 2 weeks of
  progressive angina, one episode lasting 90
  minutes
• History of Type 2 DM, HTN, cigarette smoking
• Weight 65 kg
• ECG non-specific, POS TnI 0.79 (ULN 0.5), nl
  CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl
• Given ASA, 300 mg clopidogrel, 5 mg IV
  metoprolol, IV NTG
• Continued chest pain
• Anticoagulation options in the ED?
• Risk stratification strategy?
• Which upstream strategy makes most sense?
• Collaboration with cardiology colleagues?

10
(12 of total, 15 of those undergoing cath)
Surgery
CRUSADE Registry 10/04-9/05 n35,897
No disease
Medical Rx
(52 of total, 63 of those undergoing cath)
Medical Rx (cath)
PCI
(82 of total)
Cath
Patient X
Medical Rx (no cath)
(18 of total)
Medical Rx
Time
ACS Management Pathways
11
Evolving Paradigm for Evaluating ACS Management
Strategies
Composite Adverse Event Endpoints

• Death
• MI
• Urgent TVR

• Major Bleeding
• Minor Bleeding
• Thrombocytopenia

Ischemic Complications
Hemorrhage HIT
Although these complications usually are not seen
in the ED, choices made in the ED influence the
likelihood of these adverse events!
12
Milestones in ACS Management
LMWH
GP IIb/IIIa blockers
Clopidogrel
ICTUS
OASIS-6
TRITON TIMI-38
PRISM-PLUS
ISAR-REACT 2
HORIZONS AMI
CURE
PURSUIT
ACUITY
SYNERGY
ISAR-REACT 3
ESSENCE
1994
1995
1996
1997
1998
1999
2000
2002
2003
2004
2005
2006
2001
2007
2008
Bleeding risk
Adapted from and with the courtesy of Steven
Manoukian, MD.
13
Options for NSTE-ACS Therapy in 2009

• Antiplatelet therapies
• ASA, Clopidogrel
• Glycoprotein IIb/IIIa inhibitors
• Antithrombin therapy
• UFH
• Enoxaparin
• Fondaparinux
• Bivalirudin
• Risk stratification
• Conservative
• Invasive

14
Antiplatelet Tx 2007

• ICS with recurrent ischemia on ASA, clopidogrel,
  and anticoag add IIb/IIIa upstream
• EIS it is reasonable to give both clopidogrel
  and IIb/IIIa upstream
• EIS can omit IIb/IIIa if bivalirudin is
  anticoagulant at least 300mg clopidogrel given
  gt 6h prior to cath

15
New Guidance on Thienopyridines

• Clopidogrel 75mg/d should be added to ASA in
  STEMI patients if lysed or if not reperfused
• If lt 75y/o and lysed or if not reperfused, add
  oral load of 300mg clopidogrel
• In PPCI, give 600mg clopidogrel as soon as
  possible

Antman et al, 2007 Focused Update to 2004 ACC/AHA
STEMI GLs King et al, 2008 Focused Update to 2005
ACC/AHA/SCAI PCI GLs
16
Balancing Ischemic Events and Bleeding Risk
Risk of events
Risk of bleeding
Hemostasis
Thrombosis
Two sides of the same coin
17
CRUSADE In-Hospital Outcomes 2006
Death 3.6
(Re)-Infarction 1.8
CHF 6.6
Cardiogenic Shock 2.2
Stroke 0.7
RBC Transfusion 9.1
Excluding CABG-related transfusions CRUSADE
DATA January 1, 2006 December 31, 2006 (n
29,825)
18
ACS-related Bleeding Relevant Questionsfor the
Emergency Medicine Specialist

• Who bleeds? Can we risk stratify?
• Should bleeding risk affect upstream
  antithrombotic care? If so, how?
• Is bleeding bad or a necessary evil?
• Can blood transfusion correct risks associated
  with bleeding?
• Does bleeding affect resource use?
• What options do we have to balance efficacy
  (reduced risk for ischemic outcomes) and safety
  (reduced bleeding)?

19
Bleeding in ACSIdentification

• Questions to be answered
• Who bleeds?
• What risk factors are predictive of bleeding?
• How should initial choices for upstream care be
  influenced by bleeding risk?

20
Predictors of Major Bleeding in ACS

• Older Age
• Female Gender
• Renal Failure
• History of Bleeding
• Right Heart Catheterization
• GPIIb-IIIa Antagonists

Independent predictors of major bleeding in
marker- positive acute coronary syndromes
Moscucci, GRACE Registry, Eur Heart J. 2003
Oct24(20)1815-23.
21
Predictors of Major Bleeding
Results The ACUITY Trial PCI Population
P-value
RR (95 CI)
Risk ratio 95 CI
Age gt75 (vs. 55-75)
Anemia
CrCl lt60mL/min
Diabetes
Female gender
High-risk (ST / biomarkers)
Hypertension
No prior PCI
Prior antithrombotic therapy
Heparin(s) GPI (vs. Bivalirudin)
1.56 (1.19-2.04) 0.0009
1.89 (1.48-2.41) lt0.0001
1.68 (1.29-2.18) lt0.0001
1.30 (1.03-1.63) 0.0248
2.08 (1.68-2.57) lt0.0001
1.42 (1.06-1.90) 0.0178
1.33 (1.03-1.70) 0.0287
1.47 (1.15-1.88) 0.0019
1.23 (0.98-1.55) 0.0768
2.08 (1.56-2.76) lt0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006
Manoukian, Feit, Mehran et al., JACC 2007
49(12) 1362-68.
22
Predictors of Transfusion
Results The ACUITY Trial
P-value
RR (95 CI)
Risk ratio 95 CI
Age gt75 (vs. 55-75)
Anemia
CrCl lt60mL/min
Diabetes
Female gender
High-risk (ST / biomarkers)
Hypertension
Heparin(s) GPI (vs. Bivalirudin)
1.420 (1.055-1.910) 0.0060
3.764 (2.919-4.855) lt0.0001
2.097 (1.568-2.803) lt0.0001
1.560 (1.209-2.014) 0.0060
2.233 (1.739-2.867) lt0.0001
1.754 (1.297-2.372) 0.0003
1.457 (1.051-2.020) 0.0241
1.728 (1.256-2.379) 0.0007
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
23
Bleeding Predictors Conclusions

• Older age, chronic kidney disease, female gender
  are consistently associated with bleeding and
  blood transfusion
• Analysis of large randomized trials have also
  identified novel risk factors for bleeding such
  as diabetes and anemia
• These risk factors can readily be identified
  during the ED evaluation of a patient with ACS

24
Bleeding in ACS Consequences

• Questions to be answered
• Is bleeding bad or a necessary evil?
• What is the relationship between bleeding and
  patient outcomes in ACS?
• What initial choices can the ED physician make
  that are compatible with guidelines and that will
  reduce bleeding?

25
Major Bleeding PredictsMortality in ACS
24,045 ACS patients in the GRACE registry,
in-hospital death

Plt0.001
Patients ()
Overall Unstable NSTEMI
STEMI ACS Angina
Moscucci M et al. Eur Heart J 2003241815-23.
26
Bleeding and Outcomes in ACS
Kaplan Meier Curves for 30-Day Death, Stratified
by Bleed Severity N26,452 ACS patients from
GUSTO IIb, PARAGON A, PARAGON B, PURSUIT
log rank p-value for all four categories
lt0.0001 log-rank p-value for no bleeding vs. mild
bleeding 0.02 log-rank p-value for mild vs.
moderate bleeding lt0.0001 log-rank p-value for
moderate vs. severe lt0.001
Rao SV, et al. Am J Cardiol. 2005 Nov
196(9)1200-6. Epub 2005 Sep 12.
27
Bleeding and Outcomes in NSTE-ACS
26,452 patients from PURSUIT, PARAGON A, PARAGON
B, GUSTO IIb NST
Bleeding severity and adjusted hazard of death
Bleeding Severity 30d Death 30d Death/MI 6 mo. Death
Mild 1.6 1.3 1.4
Moderate 2.7 3.3 2.1
Severe 10.6 5.6 7.5
plt0.0001
Bleeding as a time-dependent covariate
Rao SV, et al. Am J Cardiol. 2005 Nov
196(9)1200-6. Epub 2005 Sep 12.
28
Impact of MI and Major Bleeding (non-CABG) in the
First 30 Days on Risk of Death Over 1 Year
ACUITY
1 yearEstimate
30
28.9
25
20
Mortality ()
15
12.5
10
8.6
5
3.4
0
0
30
60
90
120
150
180
210
240
270
300
330
360
390
Days from Randomization
Stone GW, et al. JAMA 2007 2982497-2506
29
Impact of MI and Major Bleeding (non-CABG) in the
First 30 Days on Risk of Death Over 1 Year
ACUITY TRIALCox model adjusted for baseline
predictors Bleeding and MI as time updated
covariates
P-value
Deaths (n/)
HR 95 CI
HR (CI)
Day 0 2 after MI 12.6 (7.8-20.4) 12.6 (7.8-20.4) 29 (37.6) lt0.0001 lt0.0001
Day 3 7 after MI 5.3 (2.7-10.4) 5.3 (2.7-10.4) 11 (14.3) lt0.0001 lt0.0001
Day 8 35 after MI 1.6 (0.8-3.1) 1.6 (0.8-3.1) 12 (15.6) 0.18 0.18
Day gt 35 after MI 1.2 (0.8-1.9) 1.2 (0.8-1.9) 25 (32.5) 0.34 0.34

Day 0 2 after Major Bleed 3.0 (1.6-5.6) 3.0 (1.6-5.6) 12 (12.9) 0.0009 0.0009
Day 3 7 after Major Bleed 4.0 (2.1-7.5) 4.0 (2.1-7.5) 15 (16.1) lt0.0001 lt0.0001
Day 8 35 after Major Bleed 4.5 (2.8-7.4) 4.5 (2.8-7.4) 25 (26.9) lt0.0001 lt0.0001
Day gt 35 after Major Bleed 2.2 (1.5-3.2) 2.2 (1.5-3.2) 41 (44.1) lt0.0001 lt0.0001

0.5 1 2 4 8 16
Stone, ACC 2007
30
In-Hospital Bleeding and Discharge
TherapiesN2498 pts in PREMIER Registry
Discharge 1 Month 6 Months 1 Year Discharge 1
Month 6 Months 1 Year Discharge 1 Month 6
Months 1 Year
Aspirin
Thienopyridine
Beta-Blocker
0 0.5 1.0 1.5
Less likely
More likely
Wang TY, et.al. Circulation (in press)
31
Bleeding and Outcomes Conclusions

• Bleeding is associated with adverse short- and
  long-term outcomes among patients with ACS and
  those undergoing PCI
• Mortality rates are higher among those who bleed
• MI rates are higher among those who bleed
• The risk is at least similar to that conferred by
  MI (maybe higher)
• The risk is persistent out to 1 year while the
  risk from recurrent ischemia appears limited to
  30 days
• Decisions made in the ED may affect subsequent
  bleeding risk, and in turn, evidence-based
  therapy and clinical outcomes

32
Bleeding in ACS
Question To Be Answered Can blood
transfusioncorrect adverse outcomes associate
with bleeding?
33
Transfusion in ACS
N24,111
30-Day Survival By Transfusion Group
Rao SV, et. al., JAMA 200429215551562.
34
Cox Model for 30-day Death
PRBC Transfusion Among NSTE ACS Patients
N24,111
Adjusted for transfusion propensity Adjusted for
baseline characteristics Adjusted for baseline
characteristics, bleeding propensity, transfusion
propensity, and nadir HCT
3.77 (3.13, 4.52
3.54 (2.96, 4.23)
3.94 (3.26, 4.75)
-4.0 1.0
10.0
Transfusion as a time-dependent covariate
Rao SV, et. al., JAMA 200429215551562.
35
Adjusted Risk of In-Hospital Outcomes By
Transfusion Status
N74,271 ACS patients from CRUSADE
Death
Death or Re-MI
1.0
2.0
Non-CABG patients only
Yang X, J Am Coll Cardiol 20054614905.
36
Transfusion, Ischemic Endpoints,and Mortality in
ACUITY Trial
Results The ACUITY Trial (N13,819)
Plt0.0001 for all
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
37
Transfusion Post PCI REPLACE 2 One Year
Mortality
Increased 1-year mortality in transfused
patients Adjusted Odds Ratio 4.26 (2.258.08)
Plt0.0001
Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA,
Feit F, Lincoff AM. CRT 2005. Abstract.
38
Blood Transfusion Conclusions

• Blood transfusion is independently associated
  with death and re-MI
• Transfusion does not correct the adverse impact
  bleeding and is not an insurance policy for
  choices made in the ED
• Blood transfusion is best avoided in ACS patients
  whenever possible
• Decisions regarding bleeding risk should be part
  of ED decision-making process

39
Bleeding in ACS

• Question To Be Answered
• Does bleeding impact resource use?

40
Bleeding and Resource Use Predictors of Total
Costs
Moderate/severe bleed Per patient cost -
530 Transfusion - 2,080, P lt 0.01 Per patient
cost - 287
N1235 pts from GUSTO IIb
Model C-index0.87 Adjusted for patient
characteristics
Rao SV, et. al. AHJ 2008.
41
Bleeding and Costs Conclusions

• The available costs data clearly show that a
  balance must be struck between ischemia reduction
  and bleeding
• Both ischemic complications and bleeding are
  associated with increased costs such that any
  cost savings realized by reducing one is offset
  by cost increases associated with the other
• Although these costs are not realized in the ED,
  the choices made there impact costs downstream

42
Risk versus Benefit
Thrombosis
Bleeding
43
Case Presentation

• Decision made to pursue rapid invasive risk
  stratification
• High-risk features
• Elevated troponin
• Ongoing chest pain despitemedical therapy
• Antithrombin therapy choices
• Risk for bleeding
• Age, Female sex, renalinsufficiency, anemia
• Bivalirudin bolus and gtt initiated
• Angiography

44
Addressing the Challenges of Selecting an
Anticoagulation Strategy
Age
Renal function
Bleeding Risk
Cost
Ease of use
Ischemic Risk
PCI vs CABG vs Med Rx
Time to cath
45
The Mandate to Cooperate and Collaborate