Women have higher bleeding complication and mortality rates after percutaneous coronary interventions (PCI). The contribution of female gender to bleeding and mortality is poorly understood. We evaluated the effect of gender and bleeding on outcomes of patients treated with bivalirudin during PCI by performing a patient-level pooled analysis of 3 randomized controlled trials (the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events, Acute Catheterization and Urgent Intervention Triage strategY, and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) comparing bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitor (GPI) treatment in patients undergoing PCI. Of 14,784 patients, 7,413 patients received bivalirudin (1,870 women) and 7,371 patients received heparin + GPI (1,910 women). Women had significantly higher 30-day non–coronary artery bypass grafting (CABG)-related major bleeding rates (7.6% vs 3.8%, p <0.0001). After multivariate adjustment, female gender increased the hazard of major bleeding by 80% (hazard ratio 1.80, 95% confidence interval 1.52 to 2.11, p <0.001). Furthermore, women had a higher 1-year mortality rate (3.7% vs 2.7%, p = 0.002) than men; 30-day major bleeding was the strongest independent predictor of 1-year mortality in women (hazard ratio 2.48, 95% confidence interval 1.57 to 3.91, p = 0.001). Bivalirudin therapy in women reduced 30-day non–CABG-related major bleeding (5.6% vs 9.7%, p <0.0001) and 1-year mortality (2.9% vs 4.4%, p = 0.02) compared to standard therapy. In conclusion, in this cohort of patients treated for acute coronary syndrome and ST-segment elevation myocardial infarction, women have a near 2-fold increase in bleeding complications compared to men after PCI. Bleeding complications rather than gender is the strongest independent predictor of 1-year mortality in patients undergoing PCI. Furthermore, we observed a more pronounced clinical benefit in women treated with bivalirudin including a 44% reduction in major bleeding and a significant reduction in mortality rates at 1 year.
In patients undergoing percutaneous coronary intervention (PCI), female gender predicts worse outcomes including increased mortality and bleeding rates. The use of heparin and glycoprotein IIb/IIIa inhibitors (GPI) has been shown to improve patient outcomes after PCI for acute coronary syndrome (ACS). Studies suggest that women derive similar ischemic benefit from the addition of GPI, however, are more likely to suffer from subsequent bleeding complications, which have been associated with increased risk mortality after PCI. Bivalirudin (Angiomax, The Medicines Company), a direct thrombin inhibitor, is an alternative to heparin with GPI anticoagulation therapy for PCI that has been associated with decreased rates of postprocedural major and minor bleeding events after PCI without increasing ischemic events. The benefit of bivalirudin has recently come under scrutiny in a number of studies suggesting no bleeding benefit and possibly increase in ischemic events compared to heparin with selective GPI use. Whether bivalirudin benefits women is relevant in the context of women’s heightened bleeding risk and associated mortality risk with standard heparin + GPI therapy. Thus, we analyzed 3 large-scale randomized controlled trials comparing bivalirudin and heparin + GPI therapy to determine the relative contribution of bleeding and gender on mortality after PCI and the safety and efficacy of bivalirudin across the spectrum of PCI in women.
Methods
The study population is a patient-level pooled analysis of 14,784 patients who underwent PCI from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2), Acute Catheterization and Urgent Intervention Triage strategY (ACUITY), and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trials. The study designs, major inclusion and exclusion criteria, end points, definitions, and results for each individual study have been previously described in detail.
The main end points of this study include protocol-defined major bleeding at 30 days and mortality at 12 months. Other reported 30-day protocol-defined individual end points (myocardial infarction, ischemia-driven revascularization) were similar between trials justifying pool ability of these outcomes. The 30-day composite major adverse cardiac event (MACE) end points were different between the trials: REPLACE-2 and ACUITY defined MACE as a composite of death, myocardial infarction (MI), and revascularization for ischemia, whereas HORIZONS-AMI defined MACE as the composite of death, MI, and revascularization for ischemia and stroke. All 3 trials studied major bleeding which included intracranial or intraocular hemorrhage, a decrease in the hemoglobin level of ≥4 g/dl without an overt bleeding source or ≥3 g/dl with an overt bleeding source. In addition, the REPLACE-2 major bleeding definition also included retroperitoneal bleeds and transfusions requiring ≥2 units of packed red blood cells or whole blood. HORIZONS-AMI and ACUITY included access site bleeding requiring intervention or a hematoma that was ≥5 cm in diameter; blood transfusions, and reoperation for bleeding in their major bleeding definitions. Thrombolysis In Myocardial Infarction major and minor bleeding was assessed in all 3 trials. Major end points were adjudicated by blinded independent core laboratories or by clinical-event adjudication committees.
This is a post hoc patient-level pooled analysis with complete baseline and clinical outcome data on each individual patient from each individual study. Categorical variables were compared with the Cochran–Mantel–Haenszel test stratified by study. Continuous variables are presented as means ± 1SD and were compared using the Wilcoxon 2-sample test. All p values are 2 sided. Major bleeding in this analysis was a combination of each study’s protocol-defined major bleeding variable. Multivariate analyses of predictors of 30-day major bleeding and 1-year death were performed using stepwise Cox regression with entry/stay criteria of 0.2/0.1. Variables chosen for initial entry in the model included age >65 years, gender, hypertension, diabetes, creatinine clearance, current smoking, anemia, previous myocardial infarction, previous CABG, previous PCI, baseline platelets, baseline white blood cells, presentation with ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) with biomarker elevation, and randomization to heparin + GPI or bivalirudin. Interaction testing was performed to assess the interaction between gender and treatment effect on 30-day major bleeding and 1-year mortality. Consistency of results across the 3 trials was tested using the Breslow–Day heterogeneity test with a threshold of significance of 0.05 to define heterogeneity.
Results
Of the 14,784 randomized patients, 7,413 were assigned to bivalirudin treatment (including 1,870 women [25.2%]) and 7,371 were assigned to standard heparin and GPI (including 1,910 women [25.9%]). Differences in baseline demographics according to gender and treatment randomization are detailed in Table 1 . Compared to men, women were older, had more diabetes, hypertension, renal impairment, and previous CVA, but fewer were smokers, had previous percutaneous transluminal coronary angiography, CABG, or MI. Previous aspirin use was higher among women, whereas previous heparin use was higher in men.
| Total | p Value ∗ | Heparin + GPI Women | Bivalirudin Women | p Value | Heparin + GPI Men | Bivalirudin Men | p Value | ||
|---|---|---|---|---|---|---|---|---|---|
| Women | Men | ||||||||
| N † | 3780 | 11004 | – | 1910 | 1870 | – | 5461 | 5543 | – |
| Age (Mean in y ± SD) | 65.6±11.5 | 61.1±11.0 | <0.0001 | 65.9 ± 11.6 | 65.2 ± 11.5 | 0.03 | 61.1±11.0 | 61.1±11.0 | 0.87 |
| Diabetes mellitus | 30.0% | 22.9% | <0.0001 | 29.8% | 30.2% | 0.77 | 22.6% | 23.1% | 0.54 |
| Hypertension | 72.0% | 60.2% | <0.0001 | 71.1% | 70.9% | 0.12 | 60.9% | 59.5% | 0.15 |
| Smoking within 30d | 28.5% | 34.1% | <0.0001 | 28.3% | 28.6% | 0.81 | 33.4% | 34.8% | 0.15 |
| Prior percutaneous transluminal coronary angiography | 28.6% | 31.1% | 0.003 | 27.9% | 29.3% | 0.36 | 31.4% | 30.9% | 0.60 |
| Prior coronary artery bypass graft | 10.5% | 15.7% | <0.0001 | 10.8% | 10.2% | 0.59 | 15.5% | 15.8% | 0.71 |
| Prior myocardial infarction | 22.8% | 30.3% | <0.0001 | 23.1% | 22.5% | 0.64 | 30.0% | 30.6% | 0.51 |
| Prior cerebral vascular accident | 5.3% | 3.6% | <0.0001 | 5.4% | 5.3% | 0.88 | 3.0% | 4.1% | 0.008 |
| Prior aspirin | 82.6% | 80.5% | 0.006 | 82.2% | 82.9% | 0.60 | 80.5% | 80.5% | 0.96 |
| Prior clopidogrel | 59.0% | 58.9% | 0.91 | 58.7% | 59.4% | 0.69 | 58.5% | 59.3% | 0.40 |
| Prior heparin | 34.5% | 37.7% | 0.0004 | 36.0% | 32.9% | 0.046 | 39.1% | 36.3% | 0.002 |
| Baseline Hgb (mean in mg/dl ± SD) | 13.0±1.5 | 14.4±1.5 | <0.0001 | 13.0±1.4 | 13.0±1.5 | 0.19 | 14.3±1.5 | 14.4±1.5 | 0.48 |
| Baseline CrCl <60mL/min | 30.4% | 12.2% | <0.0001 | 31.7% | 29.0% | 0.07 | 12.3% | 12.1% | 0.74 |
| Coronary artery stenosis location | |||||||||
| Number of lesions | 3639 | 10627 | – | 1836 | 1803 | – | 5259 | 5368 | – |
| Left anterior descending | 45.5% | 42.8% | 0.006 | 45.9% | 45.1% | 0.64 | 42.9% | 42.8% | 0.85 |
| Left circumflex | 26.3% | 30.6% | <0.0001 | 25.6% | 27.1% | 0.12 | 30.0% | 31.1% | 0.22 |
| Right | 40.0% | 39.2% | 0.38 | 40.6% | 19.4% | 0.48 | 38.8% | 39.5% | 0.45 |
| Left main | 1.2% | 1.3% | 0.84 | 1.2% | 1.2% | 0.95 | 1.2% | 1.3% | 0.84 |
∗ p Values were from post-hoc analysis, unadjusted for multiple comparison and for descriptive purpose only.
Clinical characteristics were well matched by gender subgroups. However, women treated with heparin + GPI were older and had higher rates of previous heparin use than women treated with bivalirudin. In men, those treated with bivalirudin had increased rates of previous CVA and lower rates of previous heparin use.
Although women had similar rates of composite ischemic events at 30 days compared to men, bleeding events were more common in women ( Table 2 ). In addition to women’s near 2-fold increased rates of protocol-defined non–CABG-related major and minor bleeding complications, women also had more frequent access site and retroperitoneal bleeding leading to increased rates of blood transfusions and hemoglobin drops ≥3 g/dl. By multivariate analysis, female gender and age, current smoking, anemia, decreased creatinine clearance, NSTEMI presentation, and STEMI presentation were independent predictors of non–CABG-related major bleeding ( Figure 1 ). Bivalirudin, in contrast, was the only independent predictor of decreased major bleeding in our model.
| Total | p Value ∗ | Heparin + GPI Women | Bivalirudin Women | p Value | Heparin + GPI Men | Bivalirudin Men | p Value | ||
|---|---|---|---|---|---|---|---|---|---|
| Women | Men | ||||||||
| N † | 3780 | 11004 | – | 1910 | 1870 | – | 5461 | 5543 | – |
| Net adverse clinical events | 13.8% | 9.9% | <0.0001 | 15.1% | 12.4% | 0.01 | 10.6% | 9.1% | 0.01 |
| Bleeding end points | |||||||||
| Protocol | |||||||||
| Non-coronary artery bypass graft major bleeding | 7.6% | 3.8% | <0.0001 | 9.7% | 5.6% | <0.0001 | 5.0% | 2.7% | <0.0001 |
| Non-coronary artery bypass graft minor bleeding | 23.5% | 18.7% | <0.0001 | 7.3% | 4.0% | <0.0001 | 24.2% | 13.3% | <0.0001 |
| TIMI classification | |||||||||
| Major bleeding | 2.0% | 1.3% | 0.001 | 2.9% | 1.1% | <0.0001 | 1.6% | 1.0% | 0.004 |
| Minor bleeding | 5.6% | 3.1% | <0.0001 | 7.3% | 4.0% | <0.0001 | 4.1% | 2.1% | <0.0001 |
| Major or minor bleeding | 6.7% | 4.1% | <0.0001 | 8.7% | 4.7% | <0.0001 | 5.2% | 2.9% | <0.0001 |
| Access site hemorrhage | 0.6% | 0.1% | <0.0001 | 0.8% | 0.4% | 0.15 | 0.1% | 0.1% | 0.19 |
| Hemoglobin drop >3g/dl with overt bleed | 3.1% | 1.5% | <0.0001 | 4.6% | 1.7% | <0.0001 | 1.9% | 1.0% | <0.0001 |
| Retroperitoneal bleeding | 0.9% | 0.3% | <0.0001 | 1.4% | 0.4% | 0.002 | 0.3% | 0.2% | 0.12 |
| Blood transfusion | 4.6% | 1.5% | <0.0001 | 5.6% | 3.5% | 0.002 | 1.9% | 1.0% | <0.0001 |
| Composite ischemic events | 7.6% | 7.0% | 0.35 | 7.5% | 7.6% | 0.91 | 6.8% | 7.3% | 0.38 |
| Death | 1.3% | 1.0% | 0.06 | 1.6% | 1.1% | 0.15 | 1.1% | 0.9% | 0.34 |
| Myocardial infarction | 5.4% | 5.2% | 0.74 | 5.2% | 5.6% | 0.62 | 4.8% | 5.5% | 0.86 |
| Q-wave myocardial infarction | 0.8% | 0.9% | 0.72 | 0.7% | 0.9% | 0.54 | 0.9% | 0.9% | 0.75 |
| Non-Q wave myocardial infarction | 4.6% | 4.3% | 0.66 | 4.5% | 4.7% | 0.79 | 4.0% | 4.6% | 0.10 |
| Target vessel revascularization | 1.3% | 1.7% | 0.12 | 0.9% | 1.7% | 0.046 | 1.8% | 1.6% | 0.37 |
| 1-year Death | 3.7% | 2.7% | 0.002 | 4.4% | 2.9% | 0.02 | 2.9% | 2.6% | 0.33 |
∗ p Values were from post-hoc analysis, unadjusted for multiple comparisons and for descriptive purpose only.
At 1 year, women had higher mortality rates than men; however, paradoxically, female gender was an independent predictor of lower 1-year mortality (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.55 to 0.90, p = 0.004) in multivariate analyses once 30-day major bleeding complications were adjusted for (HR 3.63, 95% CI 2.77 to 4.75, p <0.0001). Therefore, when controlling for differences in co-morbidities, bleeding is the great differentiator in women, which tilts the balance from excess mortality to lower mortality if bleeding can be controlled or reduced.
Gender subgroup analyses of clinical outcomes are detailed in Table 2 . Bivalirudin resulted in similar reductions in the rates of 30-day major bleeding complications in both men (HR 0.53, 95% CI 0.44 to 0.65, p <0.001) and women (HR 0.56, 95% CI 0.44 to 0.72, p <0.001). There was no significant gender–treatment interaction for non-CABG major bleeding at 30 days (p ≥0.86) confirming a similar benefit of bivalirudin in both men and women. In addition, women treated with bivalirudin had lower retroperitoneal bleeding, hemoglobin drops ≥3 g/dl with overt bleeding, and blood transfusion rates than women treated with heparin + GPI.
At 1 year, women treated with bivalirudin had a significant decrease in mortality compared to women treated with heparin + GPI (HR 0.66, 95% CI 0.47 to 0.93, p = 0.02; Figure 2 ). In contrast, a mortality benefit was not seen in men treated with bivalirudin compared to men treated with heparin + GPI (HR 0.90, 95% CI 0.71 to 1.12, p = 0.33; Figure 2 ). However, the sex–treatment interaction for 1-year death (p ≥0.15) was not significant suggesting similar mortality benefit of bivalirudin across gender, albeit more pronounced in women.
