Older adults (age ≥75 years) with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) are prevalent among the treated population and are at particularly high risk for recurrent thrombotic events and death (1- 3). Antithrombotic therapy plays an important role in reducing ischemic events in these patients (4- 9), yet paradoxically they are also at relatively higher risk of bleeding with antithrombotic agents and catheter-based interventions (10- 11). Major bleeding compounds adverse outcomes, and independently increases the risk of death and rehospitalization at 30 days and 6 months (12- 15).

Several studies have shown that bivalirudin, a direct thrombin inhibitor, has similar efficacy in reducing ischemic events with a superior bleeding profile compared with standard therapy with a heparin plus glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing elective percutaneous coronary intervention (PCI) or with an initial invasive strategy after moderate- to high-risk NSTE-ACS (16- 20). Based on these studies, bivalirudin has been given a class IB recommendation in the 2007 American College of Cardiology/American Heart Association (ACC/AHA) NSTE-ACS guidelines when an invasive strategy is planned (9). An antithrombotic strategy with relatively lower rates of bleeding and with preserved ischemic efficacy would be particularly desirable for the elderly population, in whom rates of ischemic and bleeding complications are higher than those observed in their younger counterparts.

Therefore, using data from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, we investigated outcomes across age groups (<55, 55 to 64, 65 to 74, and ≥75 years) in moderate- and high-risk NSTE-ACS patients who underwent an early invasive strategy. Outcomes and the number needed to treat (NNT) are shown in those randomized to bivalirudin alone or enoxaparin or unfractionated heparin (UFH) plus GP IIb/IIIa inhibitors overall, among patients receiving a PCI, and in those without excess dosing.

The rationale, design, and primary results of the ACUITY trial have been previously reported (19- 21). The ACUITY trial enrolled NSTE-ACS patients at moderate or high risk for adverse clinical outcomes at 30 days. Patients presenting with ischemic symptoms of at least 10 min duration within the previous 24 h were eligible for enrollment if they met one of the following criteria: new ST-segment depression or transient elevation of at least 1 mm; elevations in the troponin I, troponin T, or creatine kinase-MB levels; known coronary artery disease; or all 4 other variables for predicting Thrombolysis In Myocardial Infarction risk scores for unstable angina (22). Patients were excluded if they had ST-segment elevation or shock, bleeding episodes within the prior 2 weeks, thrombocytopenia, creatinine clearance <30 ml/min, or recent administration of abciximab, warfarin, fondaparinux, fibrinolytic agents, bivalirudin, or 2 or more doses of low molecular weight heparin.

Patients were randomized in an open-label fashion to 1 of the following 3 antithrombotic regimens: a heparin (either enoxaparin or UFH) plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Patients assigned to a GP IIb/IIIa inhibitor arm were further randomized in a 2 × 2 factorial design to either upstream or catheterization laboratory initiation of GP IIb/IIIa inhibitor. Coronary angiography was required per protocol within 72 h of randomization, with subsequent triage to treatment with PCI, coronary artery bypass graft (CABG) surgery, or medical management per physician discretion. Aspirin (300 to 325 mg orally or 250 to 500 mg intravenously) was administered before angiography and daily during the index hospitalization. Dosing and timing of clopidogrel were left to the discretion of the investigators, but 300 mg was required per protocol no later than 2 h after PCI. Clopidogrel 75 mg daily was recommended for 1 year in all patients after PCI and aspirin 75 to 325 mg daily indefinitely.

The ACUITY trial was powered for 3 primary 30-day end points: 1) composite ischemia, defined as death from any cause, nonfatal myocardial infarction (MI), or unplanned revascularization for ischemia; 2) non–CABG-related major bleeding, defined as intracranial, intraocular, or retroperitoneal bleeding, access site hemorrhage requiring intervention, hematoma ≥5 cm diameter, reduction in hemoglobin of ≥4 g/dl without or ≥3 g/dl with an overt bleeding source, reoperation for bleeding, or blood product transfusion; and 3) net adverse clinical outcome (composite ischemia and non-CABG major bleeding outcomes).

The ACUITY trial age-subgroup analysis was pre-specified. All ACUITY trial patients (n = 13,819) were included and stratified into 4 progressively older age groups: <55, 55 to 64, 65 to 74, and ≥75 years. Outcomes are displayed overall (n = 13,819) and among those undergoing PCI (n = 7,789). Sensitivity analyses were also performed after excluding patients with excess dosing of antithrombotic therapies (n = 436). Specifically, patients with creatinine clearance <50 ml/min receiving more than the recommended dose of eptifibatide (n = 415) and those with creatinine clearance <30 ml/min receiving more than the protocol recommended dose of enoxaparin (n = 27) were excluded. Six patients overall received an excess dose of both drugs. In the PCI cohort, there were 281 patients who met the excess dose criteria. Of these patients, 8 received more than the recommended low molecular weight heparin dose, and 274 received more than the recommended eptifibatide dose. Only 1 patient had received an excess dose of both drugs.

Counts and percentages for demographic characteristics, medical history, procedures, and concomitant medications are shown by age group. The mean, median, and standard deviation are provided for continuous variables. Baseline characteristics were compared across age groups using the nonparametric Kruskal-Wallis test for continuous variables and Mantel-Haenszel chi-square test for categorical variables. All event rates are percentages of patients who experienced the outcome. Statistical comparisons of these event rates across age groups were performed using Mantel-Haenszel chi-square tests.

The primary outcomes in those randomized to bivalirudin or a heparin plus a GP IIb/IIIa inhibitor are shown by age overall and in the subgroup undergoing PCI. The differences between these arms in terms of NNT to prevent 1 major bleeding event are also shown. The NNT is derived by dividing the absolute event rate difference between the heparin plus GP IIb/IIIa inhibitor arm (event rate A) and the bivalirudin alone arm (event rate B) into the number 1 (1/[event rate A − event rate B]).

The SAS statistical software package (SAS Institute Inc., Cary, North Carolina) was used for all analyses. A p value of 0.05 was used to declare statistical significance, bearing in mind the exploratory nature of these analyses.

Of the 13,819 patients enrolled in the ACUITY trial, 3,655 (26.4%) were <55 years of age, 3,940 (28.5%) were between 55 and 64 years of age, 3,783 (27.4%) were between 65 and 74 years of age, and 2,441 (17.7%) were ≥75 years of age. The median age in each age category was 49.0, 60.0, 69.0, and 79.0 years, respectively. Older patients comprised a sicker group who were more often female, weighed less, and had more hypertension, prior cerebral vascular disease, renal insufficiency (creatinine clearance <50 ml/min), and prior CABG (Table 1). They also had slightly lower baseline hematocrit and platelet counts (Table 1). Older patients had longer hospital stays, but a similar prevalence of left ventricular dysfunction (ejection fraction <30%). Procedural characteristics were similar across the age subgroups (Table 2).

Ischemic events increase with age (Table 3). The rates of composite ischemia in the age groups overall were 5.7%, 7.3%, 8.0%, and 10.7%, for age <55, 55 to 64, 65 to 74, and ≥75 years, respectively. Mortality and composite ischemic outcomes at 30 days were not statistically different in patients randomized to bivalirudin alone or randomized to heparin with GP IIb/IIIa inhibitors across all age categories. Particularly, for patients older than 75 years of age the rates of composite ischemic outcomes, death, MI, and unplanned revascularization at 30 days for the 2 different antithrombotic strategies (bivalirudin alone vs. heparin with GP IIb/IIIa inhibitors) were 11.7% versus 9.6% (p = 0.17), 4.2% versus 3.0% (p = 0.20), 7.4% versus 5.8% (p = 0.19), and 2.2% versus 2.4% (p = 0.74), respectively. Similar results were observed for the components of the ischemic end point in the other age categories, and among the PCI subgroup (Table 4). For patients >75 years old in this last subgroup, the rates of composite ischemic outcomes, death, MI, and unplanned revascularization at 30 days for the 2 different antithrombotic strategies (bivalirudin alone vs. heparin with GP IIb/IIIa inhibitors) were 12.2% versus 11.0% (p = 0.57), 3.2% versus 2.6% (p = 0.64), 8.1% versus 6.6% (p = 0.37), and 3.2% versus 3.5% (p = 0.77), respectively. For all the 30-day ischemic outcomes, the interaction between age and treatment was not statistically significant. The overall 1-year mortality and composite ischemic outcomes across all age categories were not statistically different between those patients randomized to bivalirudin alone and those randomized to heparin plus GP IIb/IIIa inhibitors (Table 3).

Major bleeding events increase with age (Table 3). The rates of major bleeding in the age groups overall were 3.4%, 3.8%, 4.7%, and 9.1%, for ages <55, 55 to 64, 65 to 74, and ≥75 years, respectively. Bivalirudin was associated with less major and minor bleeding in comparison to heparin with GP IIb/IIIa inhibitors regardless of age. Similar results were observed for the components of major bleeding, and among the PCI subgroup (Table 4). The rates of major bleeding in those patients who underwent PCI in the age groups were 3.4%, 5.1%, 5.5%, and 11.8%, for ages <55, 55 to 64, 65 to 74, and ≥75 years, respectively. Using the Thrombolysis In Myocardial Infarction bleeding classification, bivalirudin was also significantly associated with less major and minor bleeding in comparison to heparin and GP IIb/IIIa inhibitors among patients older than 75 years of age overall and among the PCI population (Table 4).

The rates of major bleeding in patients after excluding those with excess dosing was 2.7%, 3.6%, 4.5%, and 8.2%, in the age groups, respectively. Among these patients, the rates of major bleeding were significantly lower in those treated with bivalirudin alone when compared with those treated with heparin plus GP IIb/IIIa inhibitors. Similar results in rates of major bleeding were observed in patients without excess dosing who underwent PCI: 3.4%, 4.9%, 5.2%, and 10.5%, by age group, respectively.

The NNT in each age category given the absolute risk reduction in major bleeding with bivalirudin alone versus heparin plus GP IIb/IIIa inhibitors for overall and PCI groups are shown in (Figure 1)A and (Figure 1)B, respectively. Because the absolute risk reduction for major bleeding was greater in those patients age ≥75 years, the NNT was much smaller (23 to prevent 1 bleed) in this age category when compared with patients <55 years old (NNT of 67 to prevent 1 bleed). For the PCI cohort, the absolute risk reduction for major bleeding was even greater in the elderly (age ≥75 years), and the NNT to prevent 1 major bleed was just 16 (Figure 1B), similarly lower than among younger patients (age <55 years) at 38.

A validation analysis was performed to show the NNT in each age category given the absolute risk reduction in major bleeding with bivalirudin alone versus heparin plus GP IIb/IIIa inhibitors among patients without excess dosing. These results are shown overall and for the PCI subgroup in (Figure 2)A and B. The absolute risk reduction for major bleeding was still greater in those age ≥75 years treated with bivalirudin alone, and the NNT was smaller (24) to prevent 1 bleed) in this age category when compared with patients <55 years old (NNT of 67). For the PCI cohort, the NNT to prevent 1 major bleed in the elderly (age ≥75 years) was 15 (Figure 2B), similarly lower than among younger patients (age <55 years) at 38.

The 30-day and 1-year mortality rates among those who did and did not experience a non-CABG major bleeding event are shown by age in (Figure 3). Patients who experienced a non-CABG major bleed had significantly higher 30-day mortality rates when compared with those who did not (Figure 3A). This was consistent across all 4 age categories. Similar patterns were observed for 1-year mortality rates across age (Figure 3B).

This analysis confirms no significant differences in efficacy but superior safety among patients randomized to a strategy of bivalirudin alone compared with a strategy of heparin plus a GP IIb/IIIa inhibitor across patient age. Furthermore, it emphasizes that the absolute reduction in bleeding events is most pronounced in the oldest patient subgroup (age ≥75 years), which then translates into the lowest NNT in this age range. Among the oldest subgroup of patients, the NNT with bivalirudin to prevent 1 major bleed overall and among those managed with PCI was 23 and 16, respectively. This observation also persists in a subgroup in which patients who received excess dosing of antithrombotic therapies were eliminated. Thus, the lower rate of bleeding with bivalirudin alone reflects persisting differences between these strategies, and seems to be most relevant for the oldest patients in whom standard pharmacotherapy advice has always been “start low, go slow.”

Aging is associated with an altered hemostatic state with a tendency toward increased bleeding in response to antithrombotic agents (23). Hemostatic changes with aging include increased anticoagulant proteins, clotting factors, and plasma viscosity. Aging also leads to diminished vascular response to injury because of impaired endothelial cell regeneration capacity (24). At the same time, there is a decrease of regulatory proteins of endothelial cell origin such as nitric oxide, nitric oxide synthase, and prostacyclin, and a decrease in fibrinolytic capacity with age (25- 26). Older adults undergoing catheter-based interventions are at additional risk for bleeding because of the temporary loss of vascular integrity. Moreover, these age-related changes in the thrombotic milieu and capacity for vascular repair may lead to different efficacy and safety of antithrombotic strategies in older adults. In our study older adults had a lower median weight and similar rates of aspirin and thienopyridine use compared with younger patients. Recently it was shown that a higher body mass index is associated with lower level of platelet inhibition (27). Therefore, a probable lower body mass index among the elderly patients may have contributed to more platelet inhibition and played a role in the higher bleeding rates among older adults.

In the ACUITY trial, approximately 18% of the patients were older than age 75 years, of whom 98% received a cardiac catheterization and 56% were treated with a PCI. These numbers differ in terms of prevalence and invasive care patterns from those observed in registries. In the GRACE (Global Registry of Acute Coronary Events) trial, approximately 25.7% of the patients were over 75 years of age, of whom 60% received a cardiac catheterization and 38% were treated with a PCI (28). Similarly, in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative, 35.5% of patients were older than 75 years of age, of whom 64% received a cardiac catheterization, and 33% were treated with a PCI (29). These numbers illustrate that findings from invasively managed older adults from clinical trials might have an even greater impact on practice considering the higher proportion of older patients in registries.

Despite the large number of antithrombotic strategy studies in NSTE-ACS (30- 38), these age-dependent changes in biology underscore the need for age-subgroup analyses that confirm safety and efficacy of specific antithrombotic and antiplatelet regimens in patients with NSTE-ACS. For example, the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) trial, which compared enoxaparin and unfractionated heparin for high-risk patients with NSTE-ACS (31), found no difference in the combined end point of 30-day death or MI between these heparins. However, a subsequent pre-specified age-subgroup analysis showed a nonsignificant trend toward more bleeding in older patients treated with enoxaparin (39). Similarly, the PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial showed a significant reduction in 30-day death or MI in patients treated with eptifibatide when compared with placebo, with a 23% relative increase overall in moderate and severe bleeding (5). However, an age-subgroup analysis from PURSUIT showed that bleeding with eptifibatide was most notable in those ≥80 years old, a subgroup that also experienced a 5.6% absolute and 23.6% relative increase in death or MI at 30 days with this strategy (40). The OASIS 5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial randomized patients with NSTE-ACS to enoxaparin or fondaparinux (41). Fondaparinux, a factor Xa inhibitor, was similar to enoxaparin in reducing the risk of ischemic events, but with substantially less major bleeding. A subgroup analysis from the OASIS 5 trial in patients with renal dysfunction, a common concern in elderly patients, showed that the benefits of fondaparinux were most marked in patients with renal dysfunction, primarily because of lower rates of bleeding (42). The ISAR-REACT 3 (Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment 3) study randomized patients undergoing PCI with normal troponin and pre-treatment with 600 mg of clopidogrel to bivalirudin or unfractionated heparin (43). In this study, the use of bivalirudin did not provide ischemic benefit when compared with UFH, but bivalirudin was associated with significantly less bleeding. The present analysis from the ACUITY trial extends and magnifies these findings in the oldest subgroup with NSTE-ACS undergoing an invasive strategy.

Differences in antithrombotic safety may represent opportunities to further optimize clinical outcomes in vulnerable patients, particularly when ischemic protection is uncompromised. We show that a strategy of bivalirudin alone was associated with significantly lower rates of bleeding when compared with heparin plus GP IIb/IIIa inhibitors in patients with NSTE-ACS. The significantly lower rates of bleeding in those who were older (age ≥75 years) translated to the lowest NNT with bivalirudin to prevent 1 major bleed (23 overall and 16 if undergoing a PCI). Another concern is that comparisons of strategies should be based on correct delivery of agents based on weight and renal function. Excess dosing of antithrombotic agents occurs more frequently in clinical practice, particularly among older patients (29). After excluding a relatively small number of patients with excess dosing, elderly patients treated with a strategy of bivalirudin alone continue to show less major bleeding compared with those treated with heparin plus GP IIb/IIIa inhibitors. The NNT in this cohort of older patients (age ≥75 years) to avoid 1 major bleeding was nearly identical at 24 overall and 15 in those undergoing a PCI. In prior registry studies, the rates of excess dosing of antithrombotic agents were higher (20% to 35%) than noted in the ACUITY trial population (44- 45). This underscores an additional difference between clinical trials and registries in patient characteristics and management. Thus, the lower rate of bleeding with the bivalirudin strategy might have an even greater impact in terms of bleeding reduction in a real-world setting where antithrombotic overdosing and bleeding are more prevalent than in the present study.

Current ACC/AHA guidelines emphasize that an invasive strategy may be particularly beneficial for older adults despite a higher risk of complications (9,28,46- 48). Interestingly, in a nonrandomized registry, invasive revascularization procedures are associated with better 6-month outcomes in the elderly (age >70 years) and very elderly (age >80 years) patients with NSTE-ACS (49), but concern over complications results in paradoxically lower rates of PCI among the elderly with NSTE-ACS (39). Bleeding, which is 3-fold higher in older adults, increases the long-term risk of death, stroke, and MI (3,12- 15). In the present study, we confirm higher 30-day and 1-year mortality among patients who experienced a non-CABG major bleed compared with those who did not across all age categories. While bleeding may be a surrogate for greater comorbidity may itself be an adverse clinical event, it is partly modifiable. Although the association between age and bleeding is confounded by lower creatinine clearance, anemia, and female sex, advanced age remains an independent predictor of bleeding even after adjusting for the key baseline variables, in-hospital therapies, and invasive procedures (50). Therefore, the use of antithrombotic strategies that lessen bleeding complications are attractive options to optimize the safety of care for older adults. Furthermore, superior safety may also translate to clinical impact in the vulnerable elderly for whom bleeding-associated prolonged length of stay, anemia, and functional impairment are hazardous. Thus, a strategy of bivalirudin alone can preserve the benefits of ischemic outcomes, and improve bleeding outcomes in the elderly with NSTE-ACS.

Across the spectrum of age, the use of bivalirudin alone is associated with significantly lower rates of major bleeding compared with heparin plus a GP IIb/IIIa inhibitor in an NSTE-ACS population treated with an invasive strategy. Because rates of bleeding increase with age, the benefit of bivalirudin in terms of the NNT to prevent 1 bleeding event is most notable for patients ≥75 years of age, especially those undergoing PCI. Importantly, the reduction in the risk of bleeding with bivalirudin is not confined to older patients and is seen in younger age groups (<55, 55 to 64, and 64 to 74 years) as well. Superior bleeding outcomes for the elderly may translate into shorter hospital stays and improved clinical outcomes.

The authors thank Weihong Fan, MS, for statistical support.