BLEEDING AND ACUTE CORONARY SYNDROMESCardiac Catherization Conference

Syed Raza MDCardiology Fellow

VCU Medical Center06/02/2011

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

24000 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

ACUITY

> 13000 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

ACUITY

Independent predictors of mortality

ACUITY

CRUSADE

(Circulation. 2009;119:1873-1882.)

CRUSADE

> 89000 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;119:1873-1882

CRUSADE

CRUSADE

Very low 20 or less Low 21-30 Moderate 31-40 High 41-50 Very high > 50

CRUSADE

CRUSADE

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;114:774-782

Pooled analysis of > 34000 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;114:774-782

6 month mortality

Eikelboom et al Circulation. 2006;114:774-782

Dose relation

Eikelboom et al Circulation. 2006;114:774-782

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;114:774-782

If bleeding kills…..

Can blood transfusion save lives?

Transfusion > Mortality

24000 pts with ACS analyzed from GUSTO IIb, PURSUIT and PRAGON.

10% underwent transfusion.

Transfusion was associated with HR of 3.94 [CI 3.26-4.75] for death.

Predicted probability of 30 day death was higher with transfusion at nadir HCT > 25%.

Rao et al. JAMA. 2004;292:1555-1562

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;358:1229-39.

Possible mechanisms linking bleeding with increased mortality

Strategies to reduce bleeding

Assess bleeding risk

Lower risk drugs

Use of radial site for catherization

`

About 17000 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

Integer risk score

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

high

CRUSADE BLEEDING SCOREwww.crusadebleedingscore.org

Very low 20 or less Low 21-30 Moderate 31-40 High 41-50 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;468-476

OASIS-5

OASIS-5

Jolly et al. JACC 2009;54;468-476

OASIS-5

Jolly et al. JACC 2009;54;468-476

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;468-476

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-AMI

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.