BLEEDING AND ACUTE CORONARY SYNDROMES Cardiac Catherization Conference Syed Raza MD Cardiology Fellow VCU Medical Center 06/02/2011

Outline:  Introduction- Classification of bleeding scales  Risk factors  Prognostic implications  Strategies to reduce bleeding  Conclusion

Bleeding and ACS  In patients with acute coronary syndromes, early treatment with anti-thrombotic medications and catheter based interventions reduced ischemic events but at an increased risk of bleeding.  The reported incidence of bleeding after treatment for ACS ranges from 1% to 10% and depends on a number of factors.  Bleeding is strongly associated with adverse outcomes in patients with ACS. 2/3rd of patients bleed at access site.  Bleeding has been classified by different investigators using different scales.

Bleeding Scales- Why?  Bleeding scale = Common language  Consistent reporting of bleeding events across different populations, regions and trials.  Facilitate comparisons across different regions and populations, treatment strategies and different data sets.

Popular Bleeding Scales  GUSTO  TIMI  ACUITY  REPLACE-2

GUSTO Severe or life-threatening: Intracranial or bleeding that causes hemodynamic compromise and requires intervention. Moderate: Bleeding that requires blood transfusion but does not result in hemodynamic compromise. Mild: Bleeding that does not meet criteria for either severe or moderate bleeding.

TIMI Major:  Intracranial or ≥ 5 g/dl decrease in the hemoglobin concentration or ≥ 15% decrease in HCT. Minor:  Observed blood loss with ≥ 3 g/dl decrease in the Hgb concentration or ≥ 10% decrease in HCT Minimal:  All other bleeding

ACUITY Major:  Intracranial or intraocular bleeding  Access site bleeding requiring intervention  Hematoma ≥ 5 cm in diameter  Drop in Hgb ≥ 4 g/dl without overt source of bleeding or ≥ 3 g/dl with an overt source  Bleeding requiring reoperation or transfusion Minor:  All other bleeding

Case 1  70 y o F with CAD s/p PCI with DES to LAD 6 months ago  On aspirin 81 mg po daily and plavix 75 mg po daily  Fell and brought to ED  Head CT shows a 2 x 3 cm frontal intraparenchymal hemorrhage  How do you classify her bleeding? GUSTO = Major TIMI = Major ACUITY = Major

Case 2  58 y o male with NSTEMI received DES to LAD  On ASA 325 mg po daily and plavix 75 mg po daily  Bivalirudin given during PCI  Had hemetemesis with Hgb drop from 13 g/dl to 10.5 g/dl (2.5 g/dl drop). Vitals remained stable.  Received 1 unit of PRBCs  EGD- non-bleeding ulcer= PPI Rx  How do you classify his bleeding? GUSTO = Moderate TIMI = Minimal ACUITY = Major

Bleeding Classifications  Clinical elements  Laboratory values  Response to bleeding  Optimal scale should probably have all the above elements

Risk Factors Associated with Bleeding  Older age  Female sex  Renal failure  History of bleeding  Use of GP IIb/IIIa use

Risk Factors For Bleeding- Evidence  GRACE  ACUITY  CRUSADE

Risk Factors For Bleeding

GRACE  patients with ACS were studied.  Risk factors for bleeding were identified using logistic regression analysis.  Major bleeding was defined as life-threatening bleeding requiring transfusion of ≥ 2 units of PRBCs, or HCT decrease of 10% or hemorrhagic/subdural hematoma.  Major bleeding occurred in 3.9% overall patients and:  4.8 % with STEMI  4.7% with NSTEMI  2.3% with unstable angina

GRACE

Bleeding = Mortality GRACE Registry Data

ACUITY

 > patients with ACS were randomized to:  Heparin plus GPI  Bivalirudin plus GPI  Bivalirudin alone  3 primary outcomes (30 days):  Composite ischemia  Major bleeding  Net clinical outcome

ACUITY Independent Predictors of Major Bleeding

ACUITY

Independent predictors of mortality

ACUITY

CRUSADE (Circulation. 2009;119: )

CRUSADE  > patients with NSTEMI were studied.  Developed and validated a model that identified 8 independent predictors of in-hospital mortality.  Bleeding score (1-100) was created by assigning weighted integers that corresponded to the coefficient of each variable.  Rate of major bleeding increased by bleeding risk quintiles. Circulation. 2009;119:

CRUSADE

 Very low 20 or less  Low  Moderate  High  Very high > 50

CRUSADE

Euro Heart Survey-ACS Data (STEMI) Gitt et al. JACC 2010;55;A101.E945

Euro Heart Survey-ACS Data (NSTEMI) Gitt et al. JACC 2010;55;A115.E1073

Bleeding Mortality BLEEDING = MORTALITY BLEEDING = HIGH RISK PATIENTS = MORTALITY

BLEEDING=MORTALITY Eikelboom et al Circulation. 2006;114:

 Pooled analysis of > patients from OASIS, OASIS-2 and CURE trial.  Major bleeding defined as that requiring > 2 units of PRBCs or life-threatening >intracranial, Hgb drop of atleast 5 g/dl, requiring surgical intervention. All other was minor.  Primary outcome was death during the first 30 days.  Also examined were the association between bleeding and outcomes in subgroups and dose relation between bleeding and death.

30 day mortality Eikelboom et al Circulation. 2006;114:

6 month mortality Eikelboom et al Circulation. 2006;114:

Dose relation Eikelboom et al Circulation. 2006;114:

Conclusions :  Increase in mortality among patients who develop major bleeding remains evident after adjustment for baseline characteristics.  Mortality is greatest in first 30 days and is markedly reduced if patients survive at least 30 days after a major bleed.  There appears to be a strong, consistent, temporal and dose related association between major bleeding and death. Eikelboom et al Circulation. 2006;114:

If bleeding kills….. Can blood transfusion save lives?

Transfusion > Mortality  pts with ACS analyzed from GUSTO IIb, PURSUIT and PRAGON.  10% underwent transfusion.  Transfusion was associated with HR of 3.94 [CI ] for death.  Predicted probability of 30 day death was higher with transfusion at nadir HCT > 25%. Rao et al. JAMA. 2004;292:

Transfusion > Mortality Doyle et al J Am Coll Cardiol 2009;53:2019–27

Older blood > higher mortality  Red cell transfusion in post-CABG and valve pts was studied.  3000 pts were given old blood (> 2 weeks) and 3000 pts were given new blood (< 2 weeks).  At 1 year, mortality was significantly less in pts given new blood (7.4% vs 11%, p < 0.001). Koch et al. N Engl J Med 2008;358:

Possible mechanisms linking bleeding with increased mortality

Strategies to reduce bleeding  Assess bleeding risk  Lower risk drugs  Use of radial site for catherization

`  About patients in ACUITY and HORIZON-AMI trial were studied  Independent predictors of non-CABG related bleeding within 30 days were evaluated  Integer risk score for major bleeding within 30 days was developed

Predictors of major bleeding

Integer risk score

 < 10 = Low risk  10-14= Moderate  15-19= High  20 or more= Very high

CRUSADE BLEEDING SCORE  Very low 20 or less  Low  Moderate  High  Very high > 50

Drugs with lower bleeding risk  Fondaparinux – OASIS-5  Bivalirudin – HORIZON-AMI

 20, 000 patients randomized to enaxaparin or fondaparinux.  Thienopyridines and GP IIa/IIIb use at discretion of physician.  Outcomes measured: Efficacy, safety and net clinical outcome of fondaparinux versus enoxaparin in patients with NSTE-ACS treated with 1) GP IIb/IIIa 2) Thienopyridines Jolly et al. JACC 2009;54;

OASIS-5

Jolly et al. JACC 2009;54;

OASIS-5 Jolly et al. JACC 2009;54;

OASIS-5 : Conclusions  Ischemic events were similar between the groups.  Major bleeding was reduced by 40% in fondaparinux group compared with enoxaparin.  Fondaparinux improved net clinical outcome. Jolly et al. JACC 2009;54;

 STEMI patients were randomized to receive either bivalirudin or heparin plus a GP IIa/IIIb.  Patients were followed for 1 year.  2 primary endpoints:  Major Bleeding  NACE (Major bleeding + MACE- death, re-infarction, TVR or CVA) Mehran et al. Lancet 2009; 374: 1149–59

HORIZON-AMI Mehran et al. Lancet 2009; 374: 1149–59

HORIZON-AM I

HORIZON-AMI : Conclusions  In STEMI patients undergoing primary PCI, anticoagulation with bivalirudin reduced net adverse clinical events and major bleeding at 1 year compared with heparin plus GP IIb/IIIa.  The rate of MACE was similar.  Cardiac mortality and all-cause mortality at 1 year was lower in bivalirudin group.

Jolly et al. Am Heart J 2009;157:132-40

Conclusions:  A strong association exists between bleeding and higher mortality in patients with acute coronary syndromes.  Key to improved patient outcomes:  Identify patients at high risk of bleeding.  Institute strategies to lower bleeding while still yielding a net clinical benefit for patients.

QUESTIONS AND ANSWERS Thank you.