Bivalirudin Monotherapy Research Articles

Early intervention in acute coronary syndrome: is bivalirudin monotherapy an effective antithrombotic strategy?

Early intervention in acute coronary syndrome: is bivalirudin monotherapy an effective antithrombotic strategy?

Safety and Efficacy of Bivalirudin Monotherapy in Patients With Diabetes Mellitus and Acute Coronary Syndromes: A Report From the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) Trial

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. 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. 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. 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). 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.

Antithrombotic Strategies in Patients With Acute Coronary Syndromes Undergoing Early Invasive Management

At 30-day follow-up, patients with moderate- and high-risk acute coronary syndromes (ACS) undergoing early invasive treatment in the ACUITY trial with bivalirudin monotherapy vs heparin plus glycoprotein (GP) IIb/IIIa inhibitors had noninferior rates of adverse ischemic events with reduced rates of major bleeding. Deferred upstream use of GP IIb/IIIa inhibitors for selective administration to patients undergoing percutaneous coronary intervention (PCI) resulted in a significant reduction in major bleeding, although a small increase in composite ischemia could not be excluded. To determine 1-year ischemic outcomes for patients in the ACUITY trial. A prospective, randomized, open-label trial with 1-year clinical follow-up at 450 academic and community-based institutions in 17 countries. A total of 13,819 patients with moderate- and high-risk ACS undergoing invasive treatment were enrolled between August 23, 2003, and December 5, 2005. Patients were assigned to heparin plus GP IIb/IIIa inhibitors (n = 4603), bivalirudin plus GP IIb/IIIa inhibitors (n = 4604), or bivalirudin monotherapy (n = 4612). Of these patients, 4605 were assigned to routine upstream GP IIb/IIIa administration and 4602 were deferred to selective GP IIb/IIIa inhibitor administration. Composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) at 1 year. Composite ischemia at 1 year occurred in 15.4% of patients assigned to heparin plus GP IIb/IIIa inhibitors and 16.0% assigned to bivalirudin plus GP IIb/IIIa inhibitors (compared with heparin plus GP IIb/IIIa inhibitors, HR, 1.05; 95% CI, 0.95-1.16; P = .35), and 16.2% assigned to bivalirudin monotherapy (HR, 1.06; 95% CI, 0.95-1.17; P = .29). Mortality at 1 year occurred in an estimated 3.9% of patients assigned to heparin plus GP IIb/IIIa inhibitors, 3.9% assigned to bivalirudin plus GP IIb/IIIa inhibitors (HR, 0.99; 95% CI, 0.80-1.22; P = .92), and 3.8% assigned to bivalirudin monotherapy (HR, 0.96; 95% CI, 0.77-1.18; P = .67). Composite ischemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (HR, 1.08; 95% CI, 0.97-1.20; P = .15). At 1 year, no statistically significant difference in rates of composite ischemia or mortality among patients with moderate- and high-risk ACS undergoing invasive treatment with the 3 therapies was found. There was no statistically significant difference in the rates of composite ischemia between patients receiving routine upstream administration of GP IIb/IIIa inhibitors vs deferring their use for patients undergoing PCI. clinicaltrials.gov Identifier: NCT00093158.

Efficacy and Safety of Bivalirudin Versus Heparins in Reduction of Cardiac Outcomes in Acute Coronary Syndrome and Percutaneous Coronary Interventions

Recent data suggest that bivalirudin, a reversible direct thrombin inhibitor, may be noninferior to heparins (unfractionated heparin/low molecular weight heparin) in providing protection against cardiovascular events, with significantly fewer bleeding complications. Whether this advantage is consistent has not been fully defined. We evaluated cardiac outcomes with bivalirudin vs the heparins in management of acute coronary syndromes (ACS), including patients undergoing percutaneous coronary interventions (PCI). Formal computer-aided searches of electronic databases (MEDLINE, PubMed, Cochrane Controlled Trials Registry) were performed by scrutiny of the reference lists of trials and review articles, abstracts, meeting proceedings, and the manufacturers of direct thrombin inhibitors. Five randomized controlled trials (BAT, 1995; CACHET, 2002; REPLACE-2, 2003; REPLACE-1, 2004; and ACUITY, 2006) comparing bivalirudin to the heparins in patients with ACS, including patients undergoing PCI, were identified. The meta-analysis consisted of 25 457 patients (bivalirudin, 15 077; heparins, 10 380). The primary safety end point was major bleeding, defined as intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss leading to a hemoglobin drop exceeding 3 g/dL (or 10% of hematocrit) and transfusion of 2 or more units of whole blood or packed red blood cells. The combined relative risks (RR) across all of the studies and the 95% confidence intervals of death, myocardial infarction (MI), and revascularization (bivalirudin vs heparins) were computed using the Mantel-Haenszel fixed-effect model, whereas the random-effect model was used for major bleeding. A 2-sided alpha error < .05 was considered to be significant. There were no significant differences in patient characteristics between the 2 groups. Compared to the heparins, the risk of death, MI, revascularization, and composite ischemic end points were similar with bivalirudin monotherapy. However, the risk of major bleeding was significantly lower with bivalirudin use (RR = 0.553; 95% CI = 0.402-0.761; P = .001). The present meta-analysis suggests that bivalirudin may be noninferior to the heparins in reducing the composite of ischemic end points. Additionally, compared to the heparins, bivalirudin monotherapy may lower the rate of major bleeding.

Abstract 3220: Bivalirudin Monotherapy Provides Similar One-Year Survival Compared to Heparin plus GP IIb/IIIa Inhibitors in Diabetic Patients with Acute Coronary Syndromes: Results from the Randomized ACUITY Trial

Background: Among diabetic patients with acute coronary syndromes (ACS) in the ACUITY trial, bivalirudin (Biv) monotherapy (Mono) provided similar survival and protection from ischemic events with significantly less major bleeding compared to heparin (unfractionated or enoxaparin) plus GP IIb/IIIa inhibitors (Hep+GPI) at 30 days. Whether this protection from ischemic events persists to one year is unknown. Methods: In the ACUITY trial, patients with moderate and high risk (ACS) were randomized to Hep+GPI, Biv+gPI, or Biv Mono. We evaluated the impact of treatment group on composite ischemia (death, MI, or unplanned revascularization) and mortality at one year in diabetic patients using Kaplan Meier survival analysis and log rank tests. Results: Of patients enrolled in the ACUITY trial, 3852 were diabetic (28.1%) and 9857 (71.9%) were non-diabetic. Compared with non-diabetics, diabetics had higher rates of mortality at one year (6.1% vs 3.4%, p&lt;0.001). There was no significant difference in the rate of composite ischemia at one year for diabetic patients who received Biv Mono vs Hep+GPI (19.7% vs 18.9%, p=0.39) or Biv+GPI vs Hep+GPI (20.9% vs 18.9%, p=0.16). Mortality rates for diabetic patients by treatment group are shown below. Conclusions: In the ACUITY Trial, diabetic patients had lower survival rates at one year than non-diabetics. Among diabetic patients, treatment with Biv Mono resulted in similar rates of composite ischemia and survival at one year compared to those treated with Hep+GPI. Combined with the early reduction in major bleeding, these findings indicate that Biv Mono is a suitable alternative to Hep + GPI for diabetic patients with moderate and high risk ACS.

Abstract 2222: Long-term Outcomes of Acute Coronary Syndrome Patients with Chronic Renal Insufficiency treated with Bivalirudin vs Heparin plus a Glycoprotein IIb/IIIa Inhibitor: One Year Results from the Randomized ACUITY Trial

Background: In the ACUITY Trial, patients (pts) with chronic renal insufficiency (CRI) had significantly higher rates of ischemic events and major bleeding compared to pts without CRI at 30 days. Bivalirudin (Biv) monotherapy provided similar protection from ischemic events but with significantly less bleeding compared to heparin + a GPIIb/IIIa inhibitor (Hep+GPI). The impact of a Biv alone strategy on one year mortality is unknown. Methods: Pts with moderate and high risk acute coronary syndromes (ACS) were randomized to Hep + GPI, Biv + GPI, or Biv monotherapy. CRI was defined as baseline creatinine clearance (CrCl) &lt;60 mL/min. We evaluated the impact of CRI and antithrombotic strategy on composite ischemia (death, MI, or revascularization) and mortality at one year. Results: Of the pts enrolled, 12,933 had baseline CrCl data: 2468 (19.1%) pts had CrCl ≥60 mL/min and 10,465 (80.9%) pts had CrCl &lt;60 mL/min. Rates of major bleeding at 30 days in pts with CRI were significantly lower with Biv alone vs Hep+GPI (6.2% vs 9.8%, p&lt;0.01). Pts with CRI had higher mortality at one year compared to those without CRI (8.7% vs 3.0%, p&lt;0.001). There was no difference in composite ischemia for pts who received Biv monotherapy vs Hep + GPI (23.0% vs 21.4%, p=0.10). One year mortality by antithrombin strategy is shown in the Figure . Conclusions: CRI in pts with ACS is associated with higher rates of one year mortality. In these high risk pts, Biv monotherapy improved early clinical outcomes compared to Hep + GPI by reducing major bleeding, and resulted in similar rates of one year mortality. Cumulative Mortality at One Year, Patients with CRI

Impact of Major Bleeding on 30-Day Mortality and Clinical Outcomes in Patients With Acute Coronary Syndromes: An Analysis From the ACUITY Trial

Impact of Major Bleeding on 30-Day Mortality and Clinical Outcomes in Patients With Acute Coronary Syndromes: An Analysis From the ACUITY Trial Steven V. Manoukian, Frederick Feit, Roxana Mehran, Michele D. Voeltz, Ramin Ebrahimi, Martial Hamon, George D. Dangas, A. Michael Lincoff, Harvey D. White, Jeffrey W. Moses, Spencer B. King III, E. Magnus Ohman, Gregg W. Stone The predictors of major bleeding and its impact on 30-day mortality in 13,819 patients with acute coronary syndromes (ACS) undergoing an early invasive strategy were assessed. Major bleeding occurred in 4.7% of patients and was less frequent with the use of bivalirudin monotherapy versus heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (3.0% vs. 5.7%, p < 0.0001). Several factors were independent predictors of major bleeding, including treatment with heparin plus glycoprotein IIb/IIIa inhibition. Major bleeding was a powerful independent predictor of 30-day mortality (odds ratio 7.55, 95% confidence interval 4.68 to 12.18, p < 0.0001). Reducing bleeding risk might improve outcomes in ACS. The purpose of this study was to determine the predictors of major bleeding and the impact of major bleeding on outcomes, including mortality, in acute coronary syndromes (ACS). Whether major bleeding independently predicts mortality in patients with ACS undergoing an early invasive strategy is undefined. Patients (n = 13,819) with moderate- and high-risk ACS were randomized to heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI, or bivalirudin monotherapy (plus provisional GPI). Logistic regression was used to determine predictors of 30-day major bleeding and mortality. Major bleeding rates in patients treated with heparin plus GPI were higher versus bivalirudin monotherapy (5.7% vs. 3.0%, p < 0.001) and similar versus bivalirudin plus GPI (5.7% vs. 5.3%, p = 0.38). Independent predictors of major bleeding were advanced age, female gender, diabetes, hypertension, renal insufficiency, anemia, no prior percutaneous coronary intervention, cardiac biomarker elevation, ST-segment deviation ≥1 mm, and treatment with heparin plus GPI versus bivalirudin monotherapy. Patients with major bleeding had higher 30-day rates of mortality (7.3% vs. 1.2%, p < 0.0001), composite ischemia (23.1% vs. 6.8%, p < 0.0001), and stent thrombosis (3.4% vs. 0.6%, p < 0.0001) versus those without major bleeding. Major bleeding was an independent predictor of 30-day mortality (odds ratio 7.55, 95% confidence interval 4.68 to 12.18, p < 0.0001). Major bleeding is a powerful independent predictor of 30-day mortality in patients with ACS managed invasively. Several factors independently predict major bleeding, including treatment with heparin plus GPI compared with bivalirudin monotherapy. Knowledge of these findings might be useful to reduce bleeding risk and improve outcomes in ACS.

Debate of Adjunctive Pharmacology for Percutaneous Coronary Intervention: Thrombin Inhibitors and Clopidogrel Are Enough

The role of adjunctive pharmacology for percutaneous coronary intervention (PCI) has been extensively studied, but controversy remains regarding the optimal regimen. While older studies suggest that glycoprotein IIb/IIIa inhibitors (GPI) should be routinely administered, much of this evidence was collected prior to the era of widespread stenting and thienopyridine use. There is now substantial clinical evidence that bivalirudin monotherapy is the optimal adjunctive pharmacology for the vast majority of patients undergoing elective or urgent percutaneous coronary intervention (PCI), including those presenting with an acute coronary syndrome (ACS). Bivalirudin monotherapy provides similar protection from ischemic complications with a reduced rate of major hemorrhage, resulting in a superior net clinical outcome compared with the use of GPI.

A Randomized Trial to Evaluate the Relative Protection Against Post-Percutaneous Coronary Intervention Microvascular Dysfunction, Ischemia, and Inflammation Among Antiplatelet and Antithrombotic Agents: The PROTECT–TIMI-30 Trial

The goal of this study was to evaluate glycoprotein IIb/IIIa inhibition with eptifibatide when administered with indirect thrombin inhibition as compared with monotherapy with direct thrombin inhibition with bivalirudin among patients with non-ST-segment elevation acute coronary syndromes (ACS). The optimal combination of antiplatelet and antithrombin regimens that maximizes efficacy and minimizes bleeding among patients with non-ST-segment elevation ACS undergoing percutaneous coronary intervention (PCI) is unclear. A total of 857 patients with non-ST-segment elevation ACS were assigned randomly to eptifibatide + reduced dose unfractionated heparin (n = 298), eptifibatide + reduced-dose enoxaparin (n = 275), or bivalirudin monotherapy (n = 284). Among angiographically evaluable patients (n = 754), the primary end point of post-PCI coronary flow reserve was significantly greater with bivalirudin (1.43 vs. 1.33 for pooled eptifibatide arms, p = 0.036). Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade more often was normal with eptifibatide treatment compared with bivalirudin (57.9% vs. 50.9%, p = 0.048). The duration of ischemia on continuous Holter monitoring after PCI was significantly longer among patients treated with bivalirudin (169 vs. 36 min, p = 0.013). There was no excess of TIMI major bleeding among patients treated with eptifibatide compared with bivalirudin (0.7%, n = 4 vs. 0%, p = NS), but TIMI minor bleeding was increased (2.5% vs. 0.4%, p = 0.027) as was transfusion (4.4% to 0.4%, p < 0.001). Among moderate- to high-risk patients with ACS undergoing PCI, coronary flow reserve was greater with bivalirudin than eptifibatide. Eptifibatide improved myocardial perfusion and reduced the duration of post-PCI ischemia but was associated with higher minor bleeding and transfusion rates. Ischemic events and biomarkers for myonecrosis, inflammation, and thrombin generation did not differ between agents.

Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin

AbstractBivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody–positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin- and bivalirudin-coated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific. The clinical consequences of this cross-reactivity are unknown but bivalirudin, targeted by antibodies of patients treated with lepirudin previously, could potentially boost antibody titers in such patients or even trigger an immune response by itself. Clinically significant antibody formation in response to bivalirudin monotherapy has not been observed, however. Yet, as lepirudin and antilepirudin antibodies have recently been implicated in severe anaphylactic reactions, caution is warranted when using bivalirudin in patients previously treated with lepirudin.