Comparison of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing an invasive strategy: A meta-analysis of randomized clinical trials

Objective

This meta-analysis was performed to assess the efficacy and safety of bivalirudin compared with unfractionated heparin or enoxaparin plus glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI).

Background

Pharmacotherapy for patients undergoing PCI includes bivalirudin, heparin, and GP IIb/IIIa inhibitors. We sought to compare ischemic and bleeding outcomes with bivalirudin versus heparin plus GP IIb/IIIa inhibitors in patients undergoing PCI.

Methods

A literature search was conducted to identify fully published randomized trials that compared bivalirudin with heparin plus GP IIb/IIIa inhibitors in patients undergoing PCI.

Results

A total of 19,772 patients in 5 clinical trials were included in the analysis (9785 patients received bivalirudin and 9987 patients received heparin plus GP IIb/IIIa inhibitors during PCI). Anticoagulation with bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, results in no difference in major adverse cardiovascular events (odds ratio [OR] 1.07, 95% confidence interval [CI] 0.96 to 1.19), death (OR 0.93, 95% CI 0.72 to 1.21), or urgent revascularization (OR 1.06, 95% CI 0.86 to 1.30). There is a trend towards a higher risk of myocardial infarction (OR 1.12, 95% CI 0.99 to 1.28) but a significantly lower risk of TIMI major bleeding with bivalirudin (OR 0.55, 95% CI 0.44 to 0.69).

Conclusion

In patients who undergo PCI, anticoagulation with bivalirudin as compared with unfractionated heparin or enoxaparin plus GP IIb/IIIa inhibitors results in similar ischemic adverse events but a reduction in major bleeding.     

Combining enoxaparin and glycoprotein IIb/IIIa antagonists for the treatment of acute coronary syndromes: final results of the National Investigators Collaborating on Enoxaparin-3 (NICE-3) study

Background

In high-risk patients with acute coronary syndromes (ACS), there have been concerns relating to the safety of using low molecular weight heparins (LMWH) in combination with a glycoprotein (GP) IIb/IIIa antagonist, and the continued use of LMWH in patients brought to the cardiac catheterization laboratory for percutaneous coronary intervention (PCI).

Methods

The National Investigators Collaborating on Enoxaparin-3 (NICE-3) study was an open-label observational study of enoxaparin in combination with any 1 of 3 available GP IIb/IIIa antagonists in patients presenting with non-ST-elevation ACS. The primary end point was the incidence of major bleeding not related to coronary artery bypass graft (CABG) surgery. Data were also recorded on the incidence of death, myocardial infarction (MI), and urgent revascularization for repeat ischemia.

Results

A total of 671 patients with validated data were treated with enoxaparin; 628 of these patients also received a GP IIb/IIIa antagonist (tirofiban, n = 229; eptifibatide, n = 272; abciximab, n = 127); 283 of 628 underwent percutaneous coronary intervention (PCI). The 30-day incidence of non-CABG major bleeding was 1.9%, and was not significantly higher than a prespecified historical control rate of 2.0%. Outcome events included death (1.0% at hospital discharge and 1.6% at 30 days), MI (3.5% and 5.1%, respectively), and urgent revascularization (2.7% and 6.8%, respectively).

Conclusions

The safety of enoxaparin plus a GP IIb/IIIa antagonist was comparable to that of unfractionated heparin plus a GP IIb/IIIa antagonist, as reported in other recent major trials. Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.     

Gp IIb/IIIa receptor antagonists in acute coronary syndromes with no ST elevation

Gp IIb/IIIa receptor antagonists have been the subject of much work in patients presenting with acute coronary syndrome with no ST elevation (ACS ST-). The initial studies (PRISM, PRISM-PLUS, PURSUIT, PARAGON, CAPTURE, GUSTO IV-ACS) were performed at the end of the 1990s and universally showed a significant reduction in an endpoint combining death and myocardial infarction, especially in patients with an elevation of troponin and treated by angioplasty. However, these studies were performed at a time when clopidogrel was not being used regularly for this indication. Four randomised studies have recently re-evaluated the significance of Gp IIb/IIIa blockers prescribed either on admission to coronary intensive care (ELISA-2, PRACTICE) or in the coronary angiography suite during angioplasty (ADVANCE, ISAR-REACT 2) in patients presenting with ACS ST- pre-treated with clopidogrel in association with aspirin and heparin. The results of these studies suggest that Gp IIb/IIIa blockers initiated at the start of angioplasty significantly reduce an endpoint combining death, myocardial infarction and the need for emergency revascularisation. On the other hand, studies in which Gp IIb/IIIa blockers are initiated in coronary intensive care have been negative, but they have only been carried out on small numbers. The results of the ACUITY study comparing bivalirudin and Gp IIb/IIIa blockers in this context have recently been published. Bivalirudin seems to compare well with Gp IIb/IIIa blockers in terms of ischemia, but it significantly reduces the occurrence of hemorrhagic events.     

Angiographic and clinical outcomes of bivalirudin versus heparin in patients with acute coronary syndrome undergoing percutaneous coronary intervention

BACKGROUND: Heparin with adjunctive glycoprotein IIb/IIIa platelet receptor (GP IIb/IIIa) inhibitors has demonstrated its effectiveness in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Bivalirudin, a direct thrombin inhibitor, has recently been shown to be an effective alternative for patients undergoing elective PCI. OBJECTIVES: To assess the angiographic and clinical outcomes of adjunctive pharmacological strategies in a high-risk population presenting with ACS. METHODS: Of 891 consecutive PCI patients with ACS, 304 received bivalirudin (60.5% male, 68+/-11 years) and were compared with 283 who received heparin (58.7% male, 66+/-12 years). A 30-day major adverse cardiac event was defined as the occurrence of cardiac death, nonfatal myocardial infarction, urgent revascularization or major hemorrhage. RESULTS: Adjunctive GP IIb/IIIa inhibitors were used in 14.1% of the bivalirudin group and in 72.4% of the heparin group (P<0.010). The occurrence of Thrombolysis In Myocardial Infarction (TIMI) flow less than grade 3 was lower and the achievement of angiographic success was higher in the bivalirudin group than in the heparin group (5.2% versus 8.2%, 94.7% versus 89.7%, P=0.039 and P<0.010, respectively). There was no difference between groups in the incidence of bleeding events (bivalirudin 2.0% versus heparin 3.5%, P not significant) and in 30-day major adverse cardiac events (bivalirudin 8.3% versus heparin 5.7%, P=0.223). CONCLUSIONS: In the high-risk cohort undergoing PCI, bivalirudin with provisional GP IIb/IIIa inhibitors achieved better angiographic results. Although not powered to show a difference, and while acknowledging that a selection bias could have affected the data, the present study showed that bivalirudin may be as clinically effective and safe as heparin with adjunctive GP IIb/IIIa inhibitors.     

Outcomes of Patients with Coronary Artery Perforation Complicating Percutaneous Coronary Intervention and Correlations with the Type of Adjunctive Antithrombotic Therapy: Pooled Analysis from REPLACE-2, ACUITY, and HORIZONS-AMI Trials

Background: The lack of a specific counteragent to bivalirudin may complicate the management of patients with coronary artery (CA) perforation during percutaneous coronary intervention (PCI).
Aim: Assess outcomes of patients with CA perforation from three PCI trials comparing intravenous bivalirudin with provisional glycoprotein (GP) IIb/IIIa inhibition versus unfractionated heparin (UFH) plus GP IIb/IIIa.
Methods: A pooled analysis of patients treated with PCI in three randomized trials including REPLACE-2, ACUITY, and HORIZONS-AMI.
Results: Among a total of 12,921 patients, CA perforation occurred in 35 patients (0.27%). By multivariable analysis, baseline creatinine clearance was the only independent predictor of CA perforation (per 10 mL/min decrease, odds ratio [95% confidence interval]= 1.28 [1.11, 1.47], P = 0.0007). At 30 days, patients with versus without CA perforation had significantly (all P values ≤0.001) higher rates of 30-day mortality (11.4% vs. 1.0%), myocardial infarction (MI) [Q wave: 22.9% vs. 5.7%; non-Q wave: 17.1% vs. 4.9%], target vessel revascularization (TVR) [20.1% vs. 1.8%], and composite end-point of death/MI/TVR (31.4% vs. 7.8%). Patients assigned to bivalirudin versus UFH plus a GP IIb/IIIa inhibitor had nonsignificantly lower rates of death (0% vs. 18.8%, P = 0.08), similar rates of MI (26.7% vs. 25.0%, P = 0.92), significantly lower rates of TVR (6.7% vs. 37.5%, P = 0.04), and similar rates of the composite end-point of death/MI/TVR (35.5% vs. 26.7%, P = 0.54).
Conclusion: In three PCI trials, treatment of patients experiencing CA perforation with adjunctive antithrombotic therapy of bivalirudin monotherapy was not associated with worse outcomes compared to treatment with UFH plus GP IIb/IIIa inhibitors.     

Bivalirudin in PCI: an overview of the REPLACE-2 trial

The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial is one of the largest acute randomized controlled trials evaluating the efficacy of two anticoagulant strategies during contemporary urgent or elective percutaneous coronary intervention (PCI). The direct thrombin inhibitor, bivalirudin, with provisional use of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor was compared to low-dose unfractionated heparin (UFH) plus planned GP IIb/IIIa inhibitor. At 30-day follow-up, the primary quadruple composite endpoint (death, myocardial infarction (MI), urgent repeat revascularization, or in-hospital major bleeding) occurred in 9.2% of patients in the bivalirudin group versus 10.0% of patients in the UFH plus GP IIb/IIIa inhibitor group. The secondary triple composite endpoint (death, MI, urgent repeat revascularization) occurred in 7.6% of patients in the bivalirudin group compared with 7.1% of patients in the UFH plus GP IIb/IIIa inhibitor group. Both endpoints met formal statistical criteria for noninferiority to UFH plus GP IIb/IIIa inhibitor. By imputed comparison from historic GP IIb/IIIa trials between bivalirudin versus UFH alone, REPLACE-2 demonstrated that bivalirudin was superior to UFH alone with respect to the quadruple and triple composite endpoints. Furthermore, bivalirudin plus provisional GP IIb/IIIa blockade was associated with a significant reduction in in-hospital bleeding (2.4% vs. 4.1%; p < 0.001). At 6 months' follow-up, there was no significant difference in rates of death, MI, or revascularization between the two groups. Furthermore, there was no evidence that the early, nonsignificant 0.5% excess non-Q-wave MI in the bivalirudin group translated into later mortality. There was a trend toward decreased mortality at 6 months in the bivalirudin arm (0.95% vs. 1.35%; p = 0.148). The relative efficacy of bivalirudin versus UFH plus GP IIb/IIIa inhibitor was similar in several high-risk subgroups, including patients with diabetes mellitus or prior MI, women, the elderly (age > 65 years), and patients undergoing PCI of bypass grafts. Bivalirudin represents an exciting alternative to UFH plus GP IIb/IIIa inhibitor in patients undergoing urgent and elective PCI with similar suppression of ischemic events, fewer bleeding complications, and the potential for greater cost savings and ease of administration.     

Evaluating the benefits of glycoprotein IIb/IIIa inhibitors in heart failure at baseline in acute coronary syndromes

Background

We evaluated whether the use of glycoprotein IIb/IIIa receptor inhibitors, in addition to heparin and aspirin, imparts an incremental benefit in a subgroup of patients with acute coronary syndromes (ACS) who had congestive heart failure (CHF) symptoms at presentation.

Methods

We analyzed patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized, double-blind, placebo-controlled study evaluating the use of eptifibatide versus placebo for patients with ACS without persistent ST-elevation. We compared the clinical characteristics and 30-day outcomes for 861 patients who had Killip class II or III CHF symptoms with those of 8558 patients who had no CHF symptoms.

Results

Odds ratios for the primary end point, 30-day death or non-fatal myocardial infarction, in the placebo group versus the eptifibatide group were similar for patients with and without CHF (odds ratio, 1.11; 95% CI, 0.8-1.5; odds ratio, 1.13; 95% CI, 1.0-1.3). However, adverse events were almost twice as frequent for patients with CHF compared with patients with no CHF (24.5% vs 14%).

Conclusions

Although patients with non-ST-segment elevation ACS who have CHF have markedly worse outcomes than patients without CHF symptoms, we did not find an incremental benefit from the use of eptifibatide in this seriously ill subgroup.     

Head-to-head comparison of bivalirudin versus heparin without glycoprotein IIb/IIIa inhibitors in patients with acute myocardial infarction undergoing primary angioplasty

BackgroundIn patients receiving primary percutaneous coronary intervention for ST elevation myocardial infarction (STEMI), bivalirudin with provisional glycoprotein (GP) IIb/IIIa inhibitors has been demonstrated to be noninferior to heparin plus systematic GP IIb/IIIa inhibitors in preventing recurrent ischemic events with improved safety in terms of bleeding. However, no study has been performed comparing head-to-head bivalirudin with heparin without GP IIb/IIIa inhibitor infusion in STEMI patients.MethodsWe retrospectively studied 899 consecutive patients who presented with STEMI treated by primary angioplasty within 12 h after symptoms. Among them, 566 received bivalirudin and 333 received unfractionated heparin. Their in-hospital outcome in terms of efficacy and safety was assessed using rates of major adverse cardiac events (MACE) and major bleeding, respectively. Clinical, angiographic and procedural characteristics were well matched between the two groups.ResultsPatients in the heparin group more frequently required intra-aortic balloon pumping (6.6% vs. 3.6%, P=.037). Regarding the safety end point, the MACE rate, including death, ischemic stroke and urgent repeated revascularization, was low and similar in both groups (2.7% bivalirudin vs. 1.2% heparin, P=.15). The rate of major bleeding, including major hematoma, gastrointestinal bleeding and hematocrit drop >15% during hospitalization, was high and identical in the two groups (4.1% bivalirudin vs. 4.2% heparin, P=.92).ConclusionThis study suggests that bivalirudin and heparin present similar safety and efficacy profiles when used without GP IIb/IIIa inhibitor infusion during primary angioplasty.     

Improved clinical outcomes with abciximab therapy in acute myocardial infarction: a systematic overview of randomized clinical trials

Background

Investigations of glycoprotein (GP) IIb/IIIa inhibition in primary percutaneous coronary intervention (PCI) have suggested the efficacy of abciximab in improving clinical and angiographic outcomes, but sample-size limitations and variability in trial design preclude the ability to generalize these results to a broader patient population.

Methods

Meta-analytic techniques were used to evaluate clinical outcomes from randomized trials comparing GP IIb/IIIa inhibition with placebo or control therapy in primary PCI for acute myocardial infarction (MI).

Results

In 3266 patients, treatment with abciximab significantly reduced the 30-day composite end point of death, reinfarction, or ischemic or urgent target-vessel revascularization (TVR; odds ratio [OR], 0.54; 95% CI, 0.40-0.72), with trends toward reduced 30-day death and death or reinfarction. Abciximab resulted in an increased likelihood of major bleeding (OR, 1.74; 95% CI, 1.11-2.72). By 6 months, abciximab significantly reduced the occurrence of death, reinfarction, or any TVR (OR, 0.80; 95% CI, 0.67-0.97), and there were positive trends favoring a decrease in mortality alone and the composite of death or reinfarction.

Conclusions

Treatment with abciximab significantly reduces early adverse ischemic events, a clinical benefit that is maintained at 6-month follow-up. These findings support the use of adjunctive GP IIb/IIIa inhibition in primary PCI.     

Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial)

To assess the efficacy of the direct thrombin inhibitor bivalirudin relative to heparin during contemporary coronary intervention, 1,056 patients who underwent elective or urgent revascularization were randomized in a large-scale pilot study to receive heparin (70 U/kg initial bolus) or bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). All patients received aspirin; pretreatment with clopidogrel was encouraged, and glycoprotein (GP) IIb/IIIa blockade was at the physician's discretion. Stents were placed in 85% of patients; 72% received a GP IIb/IIIa inhibitor, and 56% were pretreated with clopidogrel. Activated clotting times were higher among patients randomized to bivalirudin than among those given heparin before device activation (median 359 vs 293 seconds, p <0.001). The composite efficacy end point of death, myocardial infarction, or repeat revascularization before hospital discharge or within 48 hours occurred in 5.6% and 6.9% of patients in the bivalirudin and heparin groups, respectively (p = 0.40). Major bleeding occurred in 2.1% versus 2.7% of patients randomized to bivalirudin or heparin, respectively (p = 0.52). This trial represents the largest prospective dataset of bivalirudin administered concomitantly with planned GP IIb/IIIa blockade and provides evidence of the safety and efficacy of this combined antithrombotic approach.     

Six-month outcomes of percutaneous coronary balloon angioplasty in acute coronary syndromes: Results from the PURSUIT trial

BACKGROUND: Potent inhibition of the platelet glycoprotein IIb/IIIa receptor has improved the acute outcome of patients presenting with acute coronary syndromes (ACS). For patients with ACS undergoing percutaneous balloon angioplasty without coronary stenting in the era of platelet glycoprotein IIb/IIIa blockade, the long-term prognosis is less clear. OBJECTIVE: To examine the six-month outcome of patients who received eptifibatide within a randomized clinical trial and subsequently underwent balloon angioplasty. METHODS: Patients included in this substudy were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized study evaluating the efficacy of eptifibatide in reducing the incidence of death or nonfatal myocardial infarction (MI) in non-ST segment elevation ACS. During the index hospitalization, 1151 (12.2%) of the PURSUIT patients underwent percutaneous balloon angioplasty without coronary stenting. RESULTS: Eptifibatide was associated with a significant reduction in the adjudicated composite end point of death or MI at six months after randomization in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) (P=0.037). A trend toward a beneficial effect was evident before the procedure (4.7% versus 6.9%; P=0.13) and at 30 days (12.1% versus 15.3%; P=0.12). The incidence of repeat revascularization was relatively low for patients undergoing PTCA, with no difference observed between the eptifibatide and placebo groups (16.3% versus 14.8%; P=0.51). CONCLUSIONS: Eptifibatide was associated with a sustained beneficial effect to six months in patients with ACS undergoing PTCA. It reduced the incidence of preprocedural MI. The rate of repeat revascularization at six months was low and was not significantly altered by eptifibatide.     

Direct thrombin inhibition appears to be a safe and effective anticoagulant for percutaneous bypass graft interventions.

BACKGROUND: Percutaneous coronary interventions (PCI) of coronary artery bypass grafts (CABG) are associated with worse outcomes compared with those of native coronary PCI. Little is known concerning the use of direct thrombin inhibition during CABG intervention. The objective of this report is to examine the safety and efficacy of bivalirudin with GPIIb/IIIa blockade inhibition in patients undergoing CABG PCI. GP IIb/IIIa use was provisional in REPLACE-2 and planned in REPLACE-1. METHODS AND RESULTS: A post hoc analysis of patients undergoing CABG PCI in the REPLACE-1 and -2 trials was performed. In REPLACE-1, patients were randomized to either heparin or bivalirudin, with GP IIb/IIIa inhibitor use at the operator's discretion. In REPLACE-2, patients were randomized to heparin plus GP IIb/IIIa inhibition versus bivalirudin with provisional GP IIb/IIIa blockade. In both studies, randomized treatment groups were well matched. In unadjusted and logistic regression analysis, there were no significant differences in the combined endpoint of death, myocardial infarction, urgent revascularization, or major bleeding when patients were treated with either heparin or bivalirudin. Individual safety and efficacy endpoints were also similar. Minor bleeding was significantly reduced in patients treated with bivalirudin (14.8% vs. 22.7%, P = 0.037). Follow-up data available from the REPLACE-2 trial at 12 months found similar efficacy between groups with a trend towards decreased 12 month mortality in the bivalirudin vs. heparin groups (4.2% vs. 7.8%, P = 0.16). CONCLUSION: CABG PCI using bivalirudin with provisional GPIIb/IIIa inhibition appears to provide similar safety and efficacy to heparin with GPIIb/IIIa inhibition.     

Primary angioplasty with routine stenting compared with thrombolytic therapy in elderly patients with acute myocardial infarction

Background

Prior studies have yielded conflicting data on the advantage of primary angioplasty compared with thrombolysis in elderly patients with acute myocardial infarction (AMI). These studies, however, were performed before the contemporary widespread use of intracoronary stents and glycoprotien IIb/IIIa antagonists.

Methods

We prospectively compared the outcome of 130 consecutive elderly patients (aged ≥70 years) with ST-elevation AMI who were admitted to 2 similar neighboring medical centers. Patients were assigned to receive either thrombolytic therapy with accelerated tissue-type plasminogen activator (center I) or primary angioplasty with routine stenting (center II).

Results

Of the patients assigned to receive primary angioplasty, 91% underwent stenting. At 6 months, patients treated with primary angioplasty, compared with those treated with thrombolytic therapy, had a lower incidence of reinfarction (2% vs 14%, P = .053) and revascularization for recurrent ischemia (9% vs 61%, P < .001) and a significant reduction in the prespecified combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P < .01). Primary angioplasty remained an independent predictor of the triple combined end point after controlling for potential covariables (relative risk 0.63, 95% CI 0.38-0.84). Major bleeding complications were also significantly reduced in the primary angioplasty group (0% vs 17%, P = .03).

Conclusions

Compared with thrombolysis, primary angioplasty with routine stenting in elderly patients with AMI is associated with better clinical outcomes and a lower risk of bleeding complications.     

Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy

OBJECTIVES: The purpose of this study was to assess if clopidogrel pretreatment affects the relative efficacy of bivalirudin versus heparin with glycoprotein (GP) IIb/IIIa blockade for percutaneous coronary interventions (PCI). BACKGROUND: Although thienopyridine pretreatment may improve clinical outcomes with PCI, it is unknown if bivalirudin's efficacy compared with heparin is dependent upon such pretreatment. METHODS: The Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE-2) trial was a double-blind, triple-dummy, randomized-controlled trial comparing heparin plus routine GP IIb/IIIa blockade (heparin group) with bivalirudin plus provisional GP IIb/IIIa blockade (bivalirudin group) during PCI. The primary end point was a composite of death, myocardial infarction (MI), urgent revascularization at 30 days, and major in-hospital bleeding. The secondary end point was a 30-day composite of death, MI, and urgent revascularization. Clopidogrel pretreatment was encouraged (300 mg loading, 75 mg/day). RESULTS: Of 6,010 patients enrolled, 5,893 received clopidogrel, with 85.8% in the bivalirudin and 84.6% in the heparin group receiving clopidogrel pretreatment. Bivalirudin (provisional GP IIb/IIIa blockade 7.2%) was noninferior to the heparin group for both primary and secondary end points. Clopidogrel pretreatment did not affect the relative efficacy of bivalirudin versus heparin with GP IIb/IIIa blockade, irrespective of pretreatment duration. Pretreatment was associated with significantly lower primary end point with bivalirudin (8.7% pretreatment vs. 12.9% no pretreatment, p = 0.007), and nonsignificantly with heparin (9.7% vs. 11.7%, respectively, p = 0.20). Multivariable models showed a trend toward lower primary and secondary end points with clopidogrel pretreatment. CONCLUSIONS: Clopidogrel pretreatment at the doses and time administered in this trial did not influence the relative efficacy of bivalirudin versus heparin plus GP IIb/IIIa blockade for PCI. However, pretreatment was associated with a trend towards lower clinical events after PCI.     

Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET)

Background The direct thrombin inhibitor bivalirudin has previously been associated with better efficacy and lower hemorrhage risk than heparin during balloon angioplasty. This agent has not yet been tested with stenting or in combination with platelet glycoprotein IIb/IIIa antagonists. Methods and Results In a pilot trial, 268 patients who underwent coronary intervention were randomized in 3 sequential phases to treatment with bivalirudin (with or without abciximab) or the control regimen of low-dose weight-adjusted heparin with abciximab. Patients in the bivalirudin arms received bivalirudin (1.0 mg/kg bolus, infusion of 2.5 mg/kg/h for 4 hours) plus abciximab in phase A, bivalirudin (0.5 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional (“rescue”) abciximab in phase B, or bivalirudin (0.75 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional abciximab in phase C. Abciximab was necessitated on a provisional basis in 24% of the patients in the bivalirudin arms of phases B and C. A composite clinical endpoint of death, myocardial infarction, repeat revascularization, or major bleeding by 7 days occurred in 3.3%, 5.9%, 0, and 10.6% of the patients in the bivalirudin phase A, bivalirudin phase B, bivalirudin phase C, and heparin plus planned abciximab arms, respectively (P = .018 for the pooled bivalirudin groups versus the heparin group). Conclusion Bivalirudin with planned or provisional abciximab may be at least as safe and effective as low-dose heparin plus abciximab during percutaneous coronary intervention. (Am Heart J 2002;143:847-53.)     

Efficacy and safety of abciximab on acute myocardial infarction treated with percutaneous coronary interventions: a meta-analysis of randomized, controlled trials

Objective

To evaluate the efficacy and safety of abciximab following acute myocardial infarction (AMI) treated with percutaneous coronary interventions.

Methods

A meta-analysis of randomized controlled trials of platelet glycoprotein IIb/IIIa inhibitor abciximab as adjunctive therapy to percutaneous coronary interventions for AMI was performed. Main outcomes measured were: (1) mortality, (2) reinfarction, (3) target vessel revascularization (TVR), (4) major cardiac events (MACE) that were a composite endpoint of death, reinfarction, and TVR, and (5) major bleeding.

Results

Six trials randomized 3755 patients who were followed for a mean of 5.5 months. Compared with the control, abciximab significantly reduced mortality (OR 0.70, 95% CI 0.50-0.97), TVR (0.79, 95% CI 0.65-0.96) and MACE (0.76, 95% CI 0.65-0.90). Reduction on TVR and MACE was confirmed in stent patients, but not in balloon angioplasty patients. Abciximab was associated with an increased risk of major bleeding (OR 1.39, 95% CI 1.03-1.87), but bleeding was observed only with a 100U/kg heparin bolus followed by a maintenance infusion (OR 1.89, 95% CI 1.10-3.28) and not with a bolus of 70U/kg (OR 1.22, 95% CI 0.85-1.73).

Conclusions

Abciximab, as adjunctive therapy to percutaneous coronary interventions, reduces mortality, TVR and MACE following AMI. The reduction of clinical outcomes occurs with stent implantation but not with balloon angioplasty. A 70U/kg heparin bolus must be used to avoid major bleeding.     

Effect of platelet glycoprotein IIb/IIIa receptor blockade with tirofiban on adverse cardiac events in women with unstable angina/non-ST-elevation myocardial infarction (PRISM-PLUS Study)

Background

Previous trials demonstrated the efficacy of platelet glycoprotein IIb/IIIa receptors blockade with tirofiban in reducing acute ischemic events in patients with unstable angina/non-ST-elevation myocardial infarction. Little is known about the effect of tirofiban among women with acute coronary syndromes.

Objective

We aimed to determine the benefit and safety of tirofiban plus heparin versus heparin alone on cardiac ischemic events among women with unstable angina/non-ST-elevation myocardial infarction.

Method and results

We performed a post hoc analysis of all women enrolled in the PRISM-PLUS trial. At early time points, there appeared to be a reduction of the primary composite end point of death, myocardial infarction, or refractory ischemia among women treated with tirofiban plus heparin (RR, 0.78 and 0.67) compared with women treated with heparin alone. However, at 30 and 180 days, there was no significant reduction of events with the combination therapy of tirofiban plus heparin (treatment-by-sex interaction, P = .05). Death or myocardial infarction was not significantly reduced by the combination therapy among women at all time points.

Conclusions

Although the effects of tirofiban in reducing the primary composite outcome were similar among men and women early in the study, there appeared to be a difference at the later time points. In particular, tirofiban was effective among men, but there was no clear effect among women at 30 and 180 days.     

Predictors of repeat revascularization after nonemergent, first percutaneous coronary intervention in the community

Background

We sought to determine the incidence of and risk factors for repeat revascularization after nonemergent, first percutaneous coronary intervention (PCI) performed in contemporary community practice.

Methods

We analyzed a prospective registry of consecutive patients undergoing isolated PCI in the state of Washington. Multivariate Cox regression analysis was used to determine predictors of repeat revascularization (by PCI or bypass surgery) within 1 year after first PCI.

Results

Between January 1, 1999, and December 31, 1999, there were 3571 nonemergent first PCIs, 87.7% of which involved stent placement. Repeat revascularization occurred in 577 (16.2%) patients. Repeat revascularization was predicted by multivessel disease (hazard ratio [HR] 1.36, 95% CI 1.12-1.66), stable versus no angina (HR 1.27, 95% CI 1.03-1.57), and maximum stent length used (per 1 mm longer: HR 1.01, 95% CI 1.002-1.02), while prior myocardial infarction (HR 0.77, 95% CI 0.62-0.96) and creatinine >1.2 mg/dL (HR 0.74, 95% CI 0.56-0.98) were associated with lower risk of repeat revascularization. Diabetes was a significant predictor only when the outcome was limited to revascularization by coronary artery bypass surgery (HR 1.52, 95% CI 1.03-2.23). Although glycoprotein IIb/IIIa inhibitor use was a significant univariate predictor of freedom from early repeat revascularization (within 60 days after first PCI), after controlling for potential confounders, it was no longer significant.

Conclusions

In this contemporary, community-based registry of patients undergoing nonemergent first PCI, clinical practice and outcomes are consistent with evidence from clinical trials and previous controlled studies. Results from controlled studies may reasonably be extrapolated to such a community setting.     

Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy

It is still unknown whether upstream administration of glycoprotein (Gp) IIb/IIIa inhibitors, aiming at cooling the culprit lesion before angioplasty, is superior to its selective downstream administration in high-risk patients with acute coronary syndromes (ACSs) undergoing coronary angioplasty. Therefore, the aim of the present study was to perform a meta-analysis of randomized trials comparing upstream to downstream administration of Gp IIb/IIIa inhibitors in high-risk patients with ACS undergoing early invasive strategy. We obtained results from all randomized trials on this issue. The literature was scanned by formal searches of electronic databases from January 1990 to March 2010. The following key words were used: "randomized trial," "myocardial infarction," "ACS," "coronary angioplasty," "upstream," "downstream," "Gp IIb/IIIa inhibitors," "abciximab," "tirofiban," and "eptifibatide." Primary and secondary clinical end points were mortality and myocardial infarction at 30 days, respectively. Major bleeding complications were assessed as a safety end point. Seven randomized trials were included in the meta-analysis, involving 19,929 patients (9,981 or 50.0% in the upstream Gp IIb/IIIa inhibitors group and 9,948 or 50% in the downstream Gp IIb/IIIa inhibitors group). Upstream Gp IIb/IIIa inhibitors did not decrease 30-day mortality (2.0% vs 2.0%, p = 0.84) or recurrence of myocardial infarction (7.0% vs 7.6%, p = 0.11) but were associated with higher risk of major bleeding complications (1.8% vs 1.3%, p = 0.0002). In conclusion, this meta-analysis shows that in high-risk patients with ACS undergoing an early invasive strategy, upstream administration of Gp IIb/IIIa inhibitors does not improve clinical outcome compared to a downstream selective administration, and it is associated with an increased risk of major bleeding complications. Therefore, a strategy of upstream Gp IIb/IIIa inhibitors cannot be recommended.     

Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial

OBJECTIVES: The purpose of this study was to compare the cost of percutaneous coronary intervention (PCI) using bivalirudin with provisional platelet glycoprotein (GP) IIb/IIIa inhibition with that of heparin + routine GP IIb/IIIa inhibition. BACKGROUND: Although GP IIb/IIIa inhibition has been shown to reduce ischemic complications in a broad range of patients undergoing PCI, many patients currently do not receive such therapy because of concerns about bleeding complications or cost. Recently, bivalirudin with provisional GP IIb/IIIa inhibition has been validated as an alternative to heparin + routine GP IIb/IIIa inhibition for patients undergoing PCI. However, the cost-effectiveness of this novel strategy is unknown. METHODS: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, 4,651 U.S. patients undergoing non-emergent PCI were randomized to receive bivalirudin with provisional GP IIb/IIIa (n = 2,319) versus heparin + routine GP IIb/IIIa (n = 2,332). Resource utilization data were collected prospectively through 30-day follow-up on all U.S. patients. Medical care costs were estimated using standard methods including bottom-up accounting (for procedural costs), the Medicare fee schedule (for physician services), hospital billing data (for 2,821 of 4,862 admissions), and regression-based approaches for the remaining hospitalizations. RESULTS: Among the bivalirudin group, 7.7% required provisional GP IIb/IIIa. Thirty-day ischemic outcomes including death or myocardial infarction were similar for the bivalirudin and GP IIb/IIIa groups, but bivalirudin resulted in lower rates of major bleeding (2.8% vs. 4.5%, p = 0.002) and minor bleeding (15.1% vs. 28.1%, p < 0.001). Compared with routine GP IIb/IIIa, in-hospital and 30-day costs were reduced by $405 (95% confidence interval [CI] $37 to $773) and $374 (95% CI $61 to $688) per patient with bivalirudin (p < 0.001 for both). Regression modeling demonstrated that, in addition to the costs of the anticoagulants themselves, hospital savings were due primarily to reductions in major bleeding (cost savings = $107/patient), minor bleeding ($52/patient), and thrombocytopenia ($47/patient). CONCLUSIONS: Compared with heparin + routine GP IIb/IIIa inhibition, bivalirudin + provisional GP IIb/IIIa inhibition resulted in similar acute ischemic events and cost savings of $375 to $400/patient depending on the analytic perspective.