Bleeding Events Are Predictors of Mortality in PCI

• There is a step-wise increase in short- and long-term mortality with increasing bleeding severity^1,2
• Even mild bleeding has been associated with a statistically significant increase in the adjusted hazard for death and death or MI²
• Access-site hematoma requiring a blood transfusion leads to increased mortality^1,3
• Major bleeding is associated with^4-6

  — Age >75 years — Use of heparin — Female gender — Renal insufficiency — Longer procedure — More provisional GP IIb/IIIa use — Anemia — Complicated lesions — Longer hospital stay

Patients who experience a major hemorrhage are more likely to die within 30 days

In REPLACE-2, patients who had a major hemorrhage were 30 times more likely to die within 30 days than those who did not have a major bleeding complication (10/195 [5.2%] vs 9/5007 [0.2%], P <.001).^4,5 Multivariate analysis identified major hemorrhage as the third strongest predictor of 1-year mortality (OR, 3.53; 95% CI 1.91-6.53,
P <.0001) after renal function and congestive heart failure.⁴

Impact of In-Hospital Major Bleeding on Early and Late Mortality in REPLACE-2 (pooled analysis)

Both Major and Minor Bleeding Events Increase the Risk of Mortality in PCI

• In a retrospective analysis of 10,974 patients undergoing PCI from 1991-2000, Kinnaird et al reported TIMI major bleeding as an independent risk factor for in-hospital mortality (OR 3.5; 95% CI 1.9-6.7; P = .0001)¹
• Patients who experienced major bleeding had significantly (P <.001) higher rates of death (7.5% vs. 0.6%), Q-wave MI (1.2% vs. 0.2%), non–Q-wave MI (30.7% vs 11.8%) and repeat lesion revascularization (1.9% vs 0.3%) compared to patients with no bleeding complications
• Even TIMI minor bleeding significantly increased the risk of death vs patients without bleeding (1.8% vs 0.6%, P <.001)
• At 1 year, mortality rates were 17.2%, 9.1%, and 5.5% for patients with major, minor, and no bleeding, respectively

Treatment With Heparin Is the Most Important Risk Factor for Bleeding

• Based on data from a multivariate logistic regression analysis, treatment with heparin plus GP IIb/IIIa is the most important risk variable for major hemorrhage after accounting for the independent effects of all other covariables
• These data further support the conclusion that Angiomax® (bivalirudin) with or without “provisional” GP IIb/IIIa has a better safety profile than heparin or heparin plus GP IIb/IIIa at similar or superior levels of anticoagulant effect
• The multivariate logistic regression model was developed to identify patient and treatment variables that were able to predict the risk of major hemorrhage in association with treatment. A comprehensive list of potential risk variables was considered, which included almost all candidate predictors of major hemorrhage cited in the literature. Among the risk variables, randomization to treatment with heparin plus GP IIb/IIIa was one of the most important independent predictors of risk of major hemorrhage (odds ratio 1.8;
  P<.0002).^4,7 Other independent covariables predicting risk of major hemorrhage were:
  • Creatinine clearance
  • Age >75 years
  • Female gender
  • LMWH treatment in prior 48 hours

The intensity of anticoagulation as measured by ACT levels was not found to be predictive of risk of major hemorrhage in any univariate or multivariate analysis performed. These data are consistent with published reports that have shown age, female gender, and renal function to be important predictors of risk of hemorrhage in PCI.

Consistent with REPLACE-2, treatment with heparin is one of the most important risk factors for bleeding in BAT. In a multivariate logistic regression analysis to identify patient and treatment variables that were able to predict the risk of major hemorrhage, randomization to treatment with heparin was the most important independent predictor of risk of major hemorrhage (odds ratio 2.9; 95% CI: 2.2–3.8, for risk of major hemorrhage adjusted for covariables).^8,9

• Age >70 years (odds ratio 2.1; 95% CI: 1.6–2.7)
• Female gender (odds ratio 2.3; 95% CI: 1.8–2.9)
• Small body surface area (odds ratio 1.5; 95% CI: 1.2–2.0)
• Prior heparin within 1 hour of angioplasty (odds ratio 1.4; 95% CI: 1.1–1.9)

The intensity of anticoagulation as measured by ACT levels was not found to be predictive of risk of major hemorrhage in any univariate or multivariate analysis performed.

Safety Considerations

ANGIOMAX with provisional use of glycoprotein IIb/IIIa inhibitor is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), and in patients with or at risk for heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI. ANGIOMAX is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin. ANGIOMAX is contraindicated in patients with active major bleeding or hypersensitivity to ANGIOMAX or its components. The most common (10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache, and hypotension. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of ANGIOMAX administration. Please see complete prescribing information.