Author + information
- Received August 27, 2007
- Revision received November 5, 2007
- Accepted November 13, 2007
- Published online April 29, 2008.
- Frederick Feit, MD, FACC⁎,⁎ (, )
- Steven V. Manoukian, MD, FACC†,
- Ramin Ebrahimi, MD, FACC‡,
- Charles V. Pollack, MD§,
- E. Magnus Ohman, MD, FACC∥,
- Michael J. Attubato, MD, FACC⁎,
- Roxana Mehran, MD, FACC# and
- Gregg W. Stone, MD, FACC#
- ↵⁎Reprint requests and correspondence:
Dr. Frederick Feit, Cardiac Catheterization Laboratory, Room H576, Tisch Hospital, 550 First Avenue, New York, New York 10016.
Objectives We sought to evaluate clinical outcomes of patients with diabetes mellitus in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, overall and by treatment arm.
Background In the ACUITY trial, 13,819 patients with moderate- or high-risk acute coronary syndromes (ACS) were randomized to heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI, or bivalirudin monotherapy. Compared with heparin plus GPI, bivalirudin monotherapy resulted in similar protection from ischemic events with less major bleeding. Whether these results apply to patients with diabetes is unknown.
Methods We evaluated the impact of diabetes on 30-day net adverse clinical outcomes (composite ischemia [death, myocardial infarction, or unplanned ischemic revascularization] or major bleeding), overall and by antithrombotic strategy.
Results Diabetes was present in 3,852 randomized patients (27.9%). Compared with nondiabetic patients, diabetic patients had higher 30-day rates of net adverse clinical outcomes (12.9% vs. 10.6%; p < 0.001), composite ischemia (8.7% vs. 7.2%; p = 0.003), and major bleeding (5.7% vs. 4.2%; p < 0.001). Among diabetic patients, compared with heparin plus GPI, bivalirudin plus GPI resulted in similar rates of net adverse clinical outcomes (14.0% vs. 13.8%; p = 0.89), while bivalirudin monotherapy resulted in a similar rate of composite ischemia (7.9% vs. 8.9%; p = 0.39) and less major bleeding (3.7% vs. 7.1%; p < 0.001), yielding fewer net adverse clinical outcomes (10.9% vs. 13.8%; p = 0.02).
Conclusions Diabetic patients with ACS managed invasively have higher rates of composite ischemia and major bleeding. Compared with treatment with heparin plus GPI, bivalirudin monotherapy provides similar protection from ischemic events with less major bleeding, resulting in a significant reduction in net adverse clinical outcomes.
Although mortality from coronary artery disease is decreasing for the general population in the U.S., this is not true for those with diabetes mellitus, who account for approximately 30% of patients presenting with acute coronary syndromes (ACS) (1,2). Despite technological and pharmacologic advances in the treatment of heart disease, diabetic patients continue to have worse outcomes than nondiabetic patients (2,3). A recent meta-analysis supports the clinical recommendation that administration of a glycoprotein IIb/IIIa inhibitor (GPI) should be considered to be the standard of care for diabetic patients with ACS, given a significant reduction in periprocedural ischemic events and mortality at 30 days and 6 months (4). However, GPIs result in an increased incidence of hemorrhagic complications and thrombocytopenia, both of which have been associated with early and late mortality in the ACS population (5–9).
Bivalirudin, a direct thrombin inhibitor, is theoretically an attractive alternative to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), given its ability to inhibit both circulating and clot-bound thrombin as well as thrombin-mediated platelet activation, its linear pharmacokinetics, and short half-life (∼25 min) (10,11). An analysis of diabetic patients undergoing elective or urgent percutaneous coronary intervention (PCI) in the REPLACE (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events)-2 trial showed similar protection from ischemic events and significantly decreased minor bleeding with bivalirudin monotherapy compared with UFH plus a GPI (12).
Limited data exist in diabetic patients comparing bivalirudin, either alone or in combination with a GPI, to an indirect thrombin inhibitor (either UFH or enoxaparin) plus a GPI in the ACS population. The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial was the first large-scale investigation to examine whether clinical outcomes of patients with moderate- or high-risk ACS treated with all class I agents recommended in the American College of Cardiology/American Heart Association guidelines could be further improved by a new pharmacologic regimen using bivalirudin (13). That trial demonstrated that bivalirudin monotherapy was associated with a significant reduction in 30-day net adverse clinical outcomes (composite ischemia or major bleeding) and significantly reduced major bleeding compared to heparin plus a GPI (13).
We sought in the present report to evaluate the pre-specified subgroup of diabetic patients in the ACUITY trial to assess 30-day clinical outcomes: 1) in patients with versus without diabetes mellitus; and 2) in diabetic patients treated with bivalirudin with and without routine GPI, compared with those treated with a heparin-based regimen plus routine GPI.
Patient population, randomization, and study protocol
The design and primary results of the ACUITY trial have been previously published (13,14). Briefly, 13,819 patients with ACS undergoing an invasive management strategy were randomly assigned in an open-label fashion equally to 1 of 3 antithrombotic regimens starting immediately after randomization: a heparin (UFH or enoxaparin) plus a GPI (the control group), bivalirudin plus a GPI, or bivalirudin monotherapy, in which GPI administration was permitted only for limited pre-specified indications. The UFH was administered as an intravenous (IV) bolus of 60 IU/kg body weight plus an infusion of 12 IU/kg/h to achieve an activated partial thromboplastin time of 50 to 75 s before angiography and an activated clotting time of 200 to 250 s during PCI. One milligram of enoxaparin per kg was administered subcutaneously (SC) twice daily before angiography. An IV bolus of an additional 0.3 mg/kg was administered before PCI if the most recent SC dose had been given >8 h earlier, or an IV bolus of an additional 0.75 mg/kg was administered before PCI if the most recent SC dose had been given >16 h earlier. Bivalirudin was begun before angiography, with an IV bolus of 0.1 mg/kg and an infusion of 0.25 mg/kg/h. Before PCI, an additional IV bolus of 0.5 mg/kg was administered, and the infusion was increased to 1.75 mg/kg/h.
Patients assigned to the heparin plus GPI or bivalirudin plus GPI arms were randomized again in a 2 × 2 factorial design to either upstream GPI initiation in all patients immediately after randomization or to deferred GPI initiation for selective use in PCI patients only starting in the catheterization laboratory. Crossover to upfront GPI administration was permitted for patients assigned to deferred GPI initiation for refractory ischemia before angiography. According to the Food and Drug Administration–approved labeling, either eptifibatide or tirofiban was permitted for upstream use and either eptifibatide or abciximab was permitted for deferred selective use. Dosages of all GPIs followed the package insert and were adjusted for renal impairment.
Coronary angiography was performed within 72 h of randomization with subsequent triage to PCI, coronary artery bypass graft surgery (CABG), or medical management according to the standard of care. Aspirin was administered before angiography. Clopidogrel dosing and timing were left to the discretion of the investigators, but the protocol required 300 mg clopidogrel in all cases no later than 2 h after PCI. The study was approved by the institutional review board or ethics committee at each participating center, and all patients signed written informed consent. The authors had full access to the data and take responsibility for its integrity. All of the authors have read and agree to the manuscript as written.
End points and statistical methods
The ACUITY trial was powered for 3 primary 30-day end points: 1) net adverse clinical outcome (composite ischemia or major bleeding); 2) composite ischemia, defined as death from any cause, nonfatal myocardial infarction (MI), or unplanned revascularization for ischemia; and 3) major bleeding (non-CABG related), defined as intracranial, intraocular, or retroperitoneal bleeding, access site hemorrhage requiring intervention, ≥5 cm diameter hematoma, reduction in hemoglobin of ≥4 g/dl without or ≥3 g/dl with an overt bleeding source, reoperation for bleeding, or blood product transfusion. All primary and secondary end points were adjudicated with the use of source documents by a blinded clinical events committee.
Diabetes was defined as diagnosed hyperglycemia requiring therapy with diet, oral agents, and/or insulin. The present analysis examined the baseline features and 30-day outcomes: 1) of diabetic versus nondiabetic patients; 2) within the diabetic cohort by randomized group comparing each of the bivalirudin groups against the heparin plus GPI reference group; and 3) of insulin-treated diabetic patients comparing the bivalirudin monotherapy group with the heparin plus GPI group.
Although patients with diabetes in ACUITY represented a pre-specified subgroup for analysis, the ACUITY trial was not powered for formal noninferiority or superiority analysis of this or any subgroup. Statistical comparisons were conducted for the purpose of hypothesis generation. All analyses used the intention-to-treat population. Medians and interquartile ranges are presented for continuous variables. Nonparametric Wilcoxon rank sum test was used for comparison of continuous variables. Categoric variables were compared by the chi-square test. Relative risk and the corresponding confidence intervals using normal approximation are presented for subgroups of the diabetic population.
Diabetic status and outcome
In the ACUITY trial, diabetes mellitus was present in 3,852 of 13,819 randomized patients (27.9%). Baseline characteristics and treatment strategies by diabetic status are detailed in Table 1. Compared with nondiabetic patients, diabetic patients were more likely to be older, female, and to have higher body weight, history of hypertension, or hyperlipidemia. They were also more likely to have had a previous MI and to have undergone prior PCI or CABG. Conversely, diabetic patients were less likely to be smokers and were less commonly classified as high-risk upon enrollment (defined as elevated creatine kinase isoenzyme MB fraction or troponin levels and/or ST-segment deviation). Angiography was performed in 98.6% and 99.3% of diabetic and nondiabetic patients, respectively; diabetic patients were similarly likely to undergo PCI, more frequently managed by CABG, and less often managed medically than nondiabetic patients.
Clinical outcomes at 30 days in patients with versus without diabetes are presented in Table 2. Diabetic compared with nondiabetic patients had significantly higher rates of composite ischemia (8.7% vs. 7.2%; p = 0.003) and major bleeding (5.7% vs. 4.2%; p < 0.001), with a resultant increase in net adverse clinical outcomes (12.9% vs. 10.6%; p < 0.001). Among the components of the composite ischemia end point, death was significantly higher (2.1% vs. 1.3%; p < 0.001) in diabetic than in nondiabetic patients.
Impact of antithrombotic regimen on clinical outcomes of diabetic patients
Baseline and procedural characteristics of diabetic patients assigned to each of the 3 treatment arms are presented in Table 3. Between the 2 GPI treatment groups, patients in the bivalirudin plus GPI group had a slightly lower incidence of prior MI or high-risk characteristics. Among diabetic patients assigned to bivalirudin monotherapy, 6.4% received provisional use of GPIs for pre-specified angiographic or clinical criteria. There were no other significant differences in any of the baseline demographic, clinical, or procedural characteristics between either of the bivalirudin groups and the heparin plus GPI active-control group.
Clinical outcomes at 30 days are presented in detail in Table 4. Diabetic patients treated with bivalirudin monotherapy compared with those treated with heparin plus GPI had a significantly lower rate of net adverse clinical outcomes (10.9% vs. 13.8%; p = 0.02), driven primarily by a reduction in non-CABG major bleeding (3.7% vs. 7.1%; p < 0.001), with no significant difference in the rate of ischemic events (7.9% vs. 8.9%; p = 0.39), although a trend was present toward a reduction in the occurrence of Q-wave MI with bivalirudin monotherapy (0.8% vs. 1.6%; p = 0.05). Protocol-defined major bleeding, Thrombolysis In Myocardial Infarction (TIMI) major bleeding, TIMI minor bleeding, non-CABG minor bleeding, access site hemorrhage, hemoglobin decreases of ≥3 g/dl with overt bleeding, thrombocytopenia, and blood transfusions all occurred significantly less frequently in the bivalirudin monotherapy group compared with the heparin plus GPI group. In contrast, there were no significant differences in the clinical outcomes of diabetic patients treated with bivalirudin plus a GPI compared with those treated with heparin plus a GPI at 30 days. Event rates at 30 days for the 1,193 insulin-treated diabetic patients receiving bivalirudin monotherapy compared with heparin plus a GPI were: net adverse clinical outcomes (12.7% vs. 15.7%; p = 0.23), composite ischemia (9.1% vs. 9.8%; p = 0.74), and non-CABG major bleeding (4.7% vs. 8.2%; p = 0.04).
Outcomes in numerous subgroups within the diabetic cohort were explored (age ≥65 years, gender, pre-treatment with a thienopyridine in patients undergoing PCI, creatinine clearance <60 ml/min, high-risk presentation, revascularization strategy) and are shown in Figure 1. The findings in the subgroups are consistent with those of the overall diabetic patient population, with bivalirudin monotherapy resulting in no significant difference in rates of ischemia with less major bleeding than heparin plus GPI. Furthermore, there was no significant interaction within any of these subgroups by treatment group on the rates of ischemic or bleeding outcomes.
The present analysis reveals the following major findings in diabetic patients with ACS undergoing an invasive management strategy: 1) adverse ischemic event rates and prognosis are significantly worse than in nondiabetic patients; 2) major bleeding complication rates are significantly higher; 3) substitution of bivalirudin for heparin in patients treated with routine use of a GPI-based strategy does not reduce ischemic event rates or hemorrhagic complications; and 4) the use of bivalirudin monotherapy (compared with heparin plus a GPI, the established standard of care) results in a significantly lower rate of net adverse clinical outcomes, owing to a significant reduction in major bleeding complications with no significant reduction in ischemic efficacy. Regarding the latter treatment group comparison, we observed directionally similar outcomes to those of the overall diabetic patient population in those requiring treatment with insulin.
Pathopysiologic observations in diabetic patients: therapeutic implications
The metabolic abnormalities that characterize diabetes, such as hyperglycemia and insulin resistance, provoke molecular actions that contribute to vascular dysfunction (15). Abnormal blood glucose levels have been associated with systemic and coronary inflammation and a prothrombotic state (16–18). Diabetic patients have increased thrombin generation and higher levels of C-reactive protein, fibrinogen, von Willebrand factor, factor VII, factor VIII, and platelet factor 4 (17,19). Increased expression of platelet activation markers, such as P-selectin (which mediates platelet-leukocyte interactions), and a higher proportion of platelets expressing glycoprotein IIb/IIIa receptors, signify enhanced platelet activity, inflammatory responses, and the potential for thrombosis (20,21). Heparin also increases platelet reactivity, particularly platelet expression of P-selectin, and directly binds to the platelet glycoprotein IIb/IIIa receptor, thereby compounding the risk of ischemic events in diabetic patients (22). Glycoprotein IIb/IIIa inhibitors added to heparin attenuate platelet–platelet aggregate formation and reduce fibrinogen binding to platelets, thereby decreasing the likelihood of thrombus formation (21). These basic mechanisms provide the pathophysiologic framework for the clinical observation that the addition of a GPI to heparin improves survival in diabetic patients presenting with ACS (4).
Bivalirudin inhibits both circulating and clot-bound thrombin, with antiplatelet and anti-inflammatory effects similar to those of heparin plus a GPI (10,21,23,24). Unlike heparins, bivalirudin does not interact with platelet factor 4, and therefore the activity of bivalirudin in the vicinity of a platelet-rich thrombus is not compromised (23). Because bivalirudin also effectively inhibits thrombin-mediated platelet activation at very low concentrations and decreases P-selectin expression, platelet-leukocyte aggregates and myeloperoxidase release agents such as GPIs that block downstream aggregation of activated platelets may not be necessary (10,23,24). Consistent with this hypothesis, the present study supports the efficacy of bivalirudin monotherapy.
Our findings confirm the earlier observations that among patients with ACS, those with diabetes have worse clinical outcomes than those without (2,3). Although we have cited many pathophysiologic mechanisms that may play a role in these adverse outcomes, it is important to recognize that diabetic patients in this trial were older and more often female and had a history of hypertension, hyperlipidemia, prior MI, and prior CABG, all of which have been associated with increased rates of ischemic and bleeding events (5,9,15–22). Our analysis of the effect of antithrombotic strategy on clinical outcomes expands upon that in diabetic patients undergoing elective or urgent PCI in the REPLACE-2 trial, in which bivalirudin monotherapy resulted in similar protection from ischemic events at 1 year and a significant reduction in minor bleeding at 30 days compared with treatment with UFH plus a GPI (12). The improved clinical outcome for diabetic patients with ACS receiving bivalirudin monotherapy in the ACUITY trial resulted from similar protection from ischemic events and a marked reduction in major bleeding compared with a heparin-based regimen combined with the routine use of a GPI. It is notable that these results were consistent across a broad spectrum of pre-specified subgroups, including thienopyridine pretreatment in patients undergoing PCI. These benefits apply to diabetic patients with moderate- or high-risk ACS, whose management is guided by early coronary angiography, regardless of revascularization strategy or medical therapy. The recently revised American College of Cardiology/American Heart Association guidelines provide a class IA recommendation for the administration of an intravenous GPI for all patients presenting with unstable angina/non–ST-segment elevation MI, with perhaps an enhanced benefit in patients with diabetes mellitus (25). Our findings are particularly timely, because they indicate that bivalirudin monotherapy may be a suitable alternative for diabetic patients.
Bleeding, which is the most common noncardiac complication of ACS management, is associated with increased short- and long-term mortality (5,7,9,26). Even “mild” bleeding has been associated with a statistically significant increase in an adjusted hazard for death and death or MI. In addition, recent data suggest that blood transfusion is also an independent predictor of mortality (7).
There are certain limitations to this analysis. First, the ACUITY trial was not powered for any subgroup analysis, including one of the diabetic population. Therefore, it would not be appropriate to pre-specify a formal noninferiority or superiority hypothesis by randomized treatment group for the diabetic subset or, for that matter, any other subset of the ACUITY trial, indicating that these results should be considered exploratory. However, the present analysis of nearly 4,000 diabetic patients undergoing an early invasive strategy for ACS is the largest diabetic subgroup from a randomized trial and is larger than the overall study populations of several trials which have evaluated similar end points in patients with ACS (27–30). Furthermore, these data were gathered prospectively, with all adverse events being adjudicated by an independent clinical events committee, blinded to treatment assignment. Second, because this was an open-label study, results may have been affected by treatment bias. Third, the results of the present study apply only to ACS patients in whom early diagnostic angiography is planned. Finally, the current analysis presents 30-day outcomes only. Longer-term follow-up will add further perspective.
Diabetic patients with ACS managed with an early invasive strategy have worse outcomes, in terms of both ischemic events and bleeding complications, compared with nondiabetic patients, despite contemporary antithrombin and antiplatelet therapy. Among diabetic patients, treatment with bivalirudin monotherapy rather than a heparin-based regimen plus GPI significantly reduces net adverse clinical outcomes by providing similar protection from ischemic events while significantly reducing major bleeding complications. The benefits of bivalirudin monotherapy were maintained in patients treated with insulin. These findings indicate that bivalirudin monotherapy is safe and efficacious for diabetic patients with moderate- or high-risk ACS in whom early coronary angiography is planned.
The ACUITY trial was sponsored by The Medicines Company. Dr. Feit is a consultant for the Medicines Company and a shareholder of Millennium Pharmaceuticals, Johnson & Johnson, and The Medicines Company. Dr. Manoukian is a consultant for, member of the Speakers' Bureau of, and has received honoraria from The Medicines Company. Dr. Pollack is a consultant for and has received research support from The Medicines Company, and his wife was employed by The Medicines Company during 2006. Dr. Pollack is also a consultant for Sanofi-Aventis, Bristol-Myers Squibb, and Schering-Plough, is a member of the Speakers' Bureau of Schering-Plough, Sanofi-Aventis, and Bristol-Myers Squibb, and has a research grant from GlaxoSmithKline. Dr. Ebrahimi is a consultant for and a member of the Speakers' Bureau of The Medicines Company. Dr. Ohman is a consultant for The Medicines Company, is in receipt of research grants from Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, and Millennium Pharmaceuticals, and is on the Speakers' Bureau of Schering-Plough. Dr. Attubato is a member of the Speakers' Bureau of and receives honoraria from The Medicines Company. Dr. Mehran is on the Speakers' Bureau of and receives honoraria from The Medicines Company and Johnson & Johnson. Dr. Stone is a consultant for The Medicines Company.
- Abbreviations and Acronyms
- acute coronary syndromes
- coronary artery bypass graft surgery
- glycoprotein IIb/IIIa inhibitor
- myocardial infarction
- percutaneous coronary intervention
- Thrombolysis In Myocardial Infarction
- Received August 27, 2007.
- Revision received November 5, 2007.
- Accepted November 13, 2007.
- American College of Cardiology Foundation
- ↵Can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines: the CRUSADE National Quality Improvement Initiative. http://www.crusadeqi.com. Accessed September 8, 2006.
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