Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial

Context  In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI). Objective  To determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 year. Design, Setting, and Participants  Follow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002. Interventions  Patients were randomly assigned to receive intravenously bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. Main Outcome Measures  Incidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollment. Results  At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43-1.14; P = .15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93-1.34; P = .24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91-1.23; P = .45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55-1.11; P = .16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients. Conclusion  Long-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI.      

Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: a meta-analysis

Context  Glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors improve myocardial reperfusion and clinical outcomes of patients undergoing primary percutaneous coronary intervention (PCI), but optimal timing of administration remains unclear. No systematic reviews have comprehensively examined the effects of early vs delayed administration of these agents. Objective  To perform a meta-analysis of randomized trials of early (prior to transfer to the catheterization laboratory) vs late (at the time of PCI) intravenous administration of Gp IIb/IIIa inhibitors in acute ST-segment elevation myocardial infarction (STEMI). Data Sources  MEDLINE and the Cochrane Controlled Trials Register search of the literature over the past 10 years; papers presented at major cardiac conferences; consultation with national and international colleagues as well as Gp IIb/IIIa inhibitor drug manufacturers; and text and journal article bibliographies. Study Selection and Data Extraction  We examined trials of randomized comparisons between early administration at the point of initial contact (emergency department or ambulance) and late administration (catheterization laboratory) of Gp IIb/IIIa inhibitors in STEMI. Outcome data had to be available on both culprit artery patency evaluated by Thrombolysis in Myocardial Infarction (TIMI) flow grades on admission and mortality. Two authors independently reviewed abstracts or complete articles. Six studies met inclusion criteria. Independent data extraction was performed by 2 reviewers and confirmed by consensus. Data Synthesis  The 6 trials enrolled 931 STEMI patients treated with abciximab (3 trials) or tirofiban (3 trials) in combination with primary PCI. TIMI grade 2 or 3 flow (41.7% [194/465 vs 29.8% [139/466]) as well as TIMI grade 3 flow (20.3% [84/413] vs 12.2% [51/418]) were significantly more frequent in the early group compared with the late group (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.28-2.22; P<.001; and OR, 1.85; 95% CI, 1.26-2.71; P<.001, respectively). The early administration of Gp IIb/IIIa inhibitors was associated with a 28% reduction of mortality from 4.7% to 3.4%, which was not significant but consistent with similar trends for reinfarction and the composite ischemic end point. Conclusions  In a meta-analysis of 6 randomized trials, early administration of Gp IIb/IIIa inhibitors in STEMI appeared to improve coronary patency with favorable trends for clinical outcomes. These findings are supportive of a strategy of facilitated PCI. Further evaluations in adequately powered large trials are awaited to confirm the clinical benefit of this strategy.      

Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial

Context  In patients with moderate- and high-risk acute coronary syndromes (ACS) who undergo an early, invasive treatment strategy, current guidelines recommend administration of platelet glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors, either upstream to all patients prior to angiography or deferred for selective use in the catheterization laboratory just prior to angioplasty. The preferred approach is undetermined. Objective  To determine the optimal strategy for the use of Gp IIb/IIIa inhibitors in patients with moderate- and high-risk ACS undergoing an early, invasive treatment strategy. Design  Prospective, randomized, open-label trial with 30-day clinical follow-up. Setting  Four hundred fifty academic and community-based institutions in 17 countries. Patients  A total of 9207 patients with moderate- and high-risk ACS undergoing an invasive treatment strategy. Interventions  Patients were randomly assigned to receive either routine upstream (n=4605) or deferred selective (n=4602) Gp IIb/IIIa inhibitor administration, respectively. Main Outcome Measures  The primary outcome was assessment of noninferiority of deferred Gp IIb/IIIa inhibitor use compared with upstream administration for the prevention of composite ischemic events (death, myocardial infarction, or unplanned revascularization for ischemia) at 30 days, using a 1-sided level of .025. Major secondary end points included noninferiority or superiority of major bleeding and net clinical outcomes (composite ischemia or major bleeding). Results  Glycoprotein IIb/IIIa inhibitors were used more frequently (98.3% vs 55.7%, respectively) and for a significantly longer duration (median, 18.3 vs 13.1 hours; P<.001) in patients in the upstream group compared with the deferred group. Composite ischemia at 30 days occurred in 7.9% of patients assigned to deferred use compared with 7.1% of patients assigned to upstream administration (relative risk, 1.12; 95% confidence interval, 0.97-1.29; P = .044 for noninferiority; P = .13 for superiority); as such, the criterion for noninferiority was not met. Deferred use compared with upstream use resulted in reduced 30-day rates of major bleeding (4.9% vs 6.1%, respectively; P<.001 for noninferiority; P = .009 for superiority) and similar rates of net clinical outcomes (11.7% vs 11.7%; P<.001 for noninferiority; P = .93 for superiority). Conclusions  Among patients with moderate- and high-risk ACS undergoing an invasive treatment strategy, deferring the routine upstream use of Gp IIb/IIIa inhibitors for selective administration in the cardiac catheterization laboratory only to patients undergoing percutaneous coronary intervention resulted in a numerical increase in composite ischemia that, while not statistically significant, did not meet the criterion for noninferiority. This finding was offset by a significant reduction in major bleeding. Trial Registration  ClinicalTrials.gov Identifier: NCT00093158      

Long-term efficacy of platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention

Context  In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, treatment with eptifibatide, a platelet glycoprotein IIb/IIIa integrin blocker, was found to reduce the ischemic complications of nonurgent coronary stent implantation at 48 hours and 30 days. Objective  To determine whether eptifibatide treatment continues to provide durable, long-term benefit after coronary stent intervention. Design and Setting  The ESPRIT trial was a randomized, double-blind, placebo-controlled, parallel-group, crossover-permitted trial conducted from June 1999 through February 2000 at 92 tertiary care centers in the United States and Canada. Participants  A total of 2064 patients scheduled to undergo nonurgent percutaneous coronary intervention with stent implantation. Intervention  Patients were randomly assigned to receive placebo (n = 1024) or eptifibatide (two 180-µg/kg boluses, 10 minutes apart, with a continuous infusion of 2.0 µg/kg per minute; n = 1040), started immediately before stent implantation and continued for 18 to 24 hours. Patients also received aspirin, heparin, and a thienopyridine. Main Outcome Measures  Composite rates of death or myocardial infarction (MI) and death, infarction, or target vessel revascularization during the 12 months after enrollment. Results  Complete follow-up data were available for 988 patients given eptifibatide (95.0%) and 976 patients given placebo (95.3%). By 12 months, the composite of death or MI had occurred in 8.0% of eptifibatide-treated patients and in 12.4% of placebo-treated patients (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.48-0.83; P = .001). The composite rate of death, MI, or target vessel revascularization was 17.5% in eptifibatide-treated patients vs 22.1% in placebo-treated patients (HR, 0.76; 95% CI, 0.63-0.93; P = .007). Conclusions  Long-term outcomes of nonurgent coronary stent implantation appear to be improved through blockade of the platelet glycoprotein IIb/IIIa integrin with eptifibatide.      

Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial

Gregg W. Stone, MD; James H. Ware, PhD; Michel E. Bertrand, MD; A. Michael Lincoff, MD; Jeffrey W. Moses, MD; E. Magnus Ohman, MD; Harvey D. White, MD; Frederick Feit, MD; Antonio Colombo, MD; Brent T. McLaurin, MD; David A. Cox, MD; Steven V. Manoukian, MD; Martin Fahy, MSc; Tim C. Clayton, MSc; Roxana Mehran, MD; Stuart J. Pocock, PhD; for the ACUITY Investigators

JAMA. 2007;298(21):2497-2506.

Context  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.

Objective  To determine 1-year ischemic outcomes for patients in the ACUITY trial.

Design, Setting, and Patients  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.

Interventions  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.

Main Outcome Measure  Composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) at 1 year.

Results  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).

Conclusions  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00093158

     

Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial

Context  Enoxaparin has demonstrated advantages over unfractionated heparin in low- to moderate-risk patients with non–ST-segment elevation acute coronary syndromes (ACS) treated with a conservative strategy. Objectives  To compare the outcomes of patients treated with enoxaparin vs unfractionated heparin and to define the role of enoxaparin in patients with non–ST-segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach. Design, Setting, and Participants  The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10 027 high-risk patients with non–ST-segment elevation ACS to be treated with an intended early invasive strategy were recruited. Interventions  Subcutaneous enoxaparin (n = 4993) or intravenous unfractionated heparin (n = 4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician. Main Outcome Measures  The primary efficacy outcome was the composite clinical end point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke. Results  The primary end point occurred in 14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed between enoxaparin and unfractionated heparin groups, respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%] vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P = .008) but nonsignificant excess in GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P = .08) and transfusions (17.0% vs 16.0%, P = .16). Conclusions  Enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with non–ST-segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the advantages of convenience should be balanced with the modest excess of major bleeding.      

Mortality at 1 year with combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose fibrinolytic therapy vs conventional fibrinolytic therapy for acute myocardial infarction: GUSTO V randomized trial

Context  Among patients with acute myocardial infarction, combination reperfusion therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab) and a half dose of a plasminogen activator (reteplase) did not significantly reduce mortality at 30 days compared with a full dose of reteplase. Rates of nonfatal ischemic complications were significantly diminished. Objective  To determine if the beneficial effects of abciximab and reteplase (combination therapy) on early nonfatal complications would translate into a reduction in the risk of death by 1 year. Design, Setting, and Patients  One-year follow-up of a randomized controlled trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V). Of 16 588 patients who had been treated in 820 community and referral hospitals in 20 countries between July 1999 and February 2001, mortality data were available for 16 453 (99.2%). Intervention  Patients were randomly assigned to receive (intravenously) a standard dose of reteplase (two 10-U boluses, 30 minutes apart) or the combination of a standard dose of abciximab (0.25 mg/kg bolus, 0.125 µg/kg per minute infusion [maximum 10 µg/min for 12 hours]) and a half dose of reteplase (two 5-U boluses, 30 minutes apart). Main Outcome Measure  One-year all-cause mortality rates. Results  All-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients in the reteplase group and 698 (8.38%) of the 8328 patients in the combination therapy group (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7 days occurred in 3.5% of patients in the reteplase group and 2.3% of patients in the combination therapy group, and was significantly associated with 1-year mortality (22.6% in patients with reinfarction vs 8.0% in patients without reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001). However, treatment assignment did not significantly influence time of mortality regardless of reinfarction status. Conclusion  Combination therapy (abciximab and reteplase) did not reduce mortality over 1 year compared with fibrinolytic therapy with reteplase alone.      

Diabetes and coronary revascularization

Context  Patients with diabetes mellitus account for approximately 25% of the nearly 1.5 million coronary revascularization procedures performed each year in the United States and experience worse outcomes compared with nondiabetic patients. Objectives  To summarize the current state of evidence comparing the effectiveness and safety of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) in diabetic patients and to examine developments that may affect future outcomes in this high-risk group. Evidence Acquisition  Using the key terms diabetes mellitus, revascularization, coronary artery bypass, angioplasty, and coronary intervention, we searched MEDLINE from 1985 to 2004 for all randomized controlled trials (RCTs) comparing CABG surgery and PCI that reported outcomes in diabetic patients. Bibliographies and the Web sites of cardiology conferences were also reviewed. Studies comparing drug-eluting stents and bare-metal stents were identified in a similar fashion. The literature was reviewed to identify clinical measures that may impact revascularization outcomes in diabetic patients. Evidence Synthesis  We identified 6 RCTs comparing CABG surgery and PCI in a total of 950 diabetic patients. A mortality benefit for CABG over balloon-only PCI has been demonstrated in diabetic patients with multivessel coronary artery disease but has not been clearly established against stent-assisted PCI or in high-risk CABG patients. Use of glycoprotein IIb/IIIa receptor inhibitors has improved survival in diabetic patients undergoing PCI. Restenosis after PCI in diabetic patients has led to substantially higher repeat revascularization rates than after CABG. The use of drug-eluting stents has led to dramatic reductions in restenosis in diabetic patients. Ongoing RCTs comparing CABG and PCI using drug-eluting stents in diabetic patients will clarify the impact of these advances on outcomes. Conclusions  There is a relative lack of data from RCTs specifically comparing CABG surgery and PCI as currently practiced in diabetic patients. The mortality advantage and decreased rates of revascularization seen with CABG in subgroups from early trials may not be applicable in the era of drug-eluting stents, glycoprotein IIb/IIIa inhibitors, and the latest medical therapies.      

Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes

Context  Effective medical care assumes delivery of evidence-based medicines to appropriate patients with doses comparable to those studied. Objective  To investigate dosing of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and glycoprotein IIb/IIIa inhibitors, and the association between dosing and major outcomes. Design, Setting, and Participants  A prospective observational analysis in 387 US academic and nonacademic hospitals of 30 136 patients from 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 Registry who had non–ST-segment elevation acute coronary syndromes (NSTE ACS) with chest pain and either positive electrocardiograms or cardiac biomarkers between January 1 and September 30, 2004. Main Outcome Measures  Excessive dosing of UFH, LMWH, and glycoprotein IIb/IIIa inhibitors and major clinical outcomes, including bleeding, in-hospital mortality, and length of stay. Results  A total of 3354 patients (42%) with NSTE ACS who were administered antithrombotic agents received at least 1 initial dose outside the recommended range. An excess dose was administered to 2934 patients (32.8%) treated with UFH, 1378 (13.8%) treated with LMWH, and 2784 (26.8%) treated with glycoprotein IIb/IIIa inhibitors. Factors associated with excess dosing included older age, as well as female sex, renal insufficiency, low body weight, diabetes mellitus, and congestive heart failure. Relative to those patients not administered excess dosages, patients with excess dosages of UFH, LMWH, and glycoprotein IIb/IIIa inhibitors either tended toward or had higher risks for major bleeding (adjusted odds ratio [OR], 1.08; 95% confidence interval [CI], 0.94-1.26; OR, 1.39; 95% CI, 1.11-1.74; and OR, 1.36; 95% CI, 1.10-1.68; respectively). Bleeding increased relative to the degree of excess dose and to the number of agents administered in excess (6.6% [237/3590] if neither heparin nor glycoprotein IIb/IIIa excess vs 22.2% [93/419] if both excess). Mortality and length of stay were also higher among those patients administered excess dosing. We estimated that 15% (400/2766) of major bleeding in this population may be attributable to excess dosing. Conclusions  Patients with NSTE ACS treated in the community often receive excess doses of antithrombotic therapy. Dosing errors occur more often in vulnerable populations and predict an increased risk of major bleeding.      

Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes

CONTEXT: The central role of platelet-rich thrombus in the pathogenesis of acute coronary syndromes (ACSs) is well-known. Glycoprotein IIb/IIIa (Gp IIb/IIIa) receptor antagonists are potent inhibitors of platelet function that may be expected to affect favorably the natural history of ACSs. OBJECTIVE: To define the optimal role of Gp IIb/IIIa inhibitors in treatment strategies for ACSs. DATA SOURCES: A MEDLINE search was performed to identify all English-language articles regarding use of Gp IIb/IIIa inhibitors in ACSs published between 1966 and June 2000. In addition, relevant abstracts from the annual meetings of the American Heart Association, American College of Cardiology, and the European Society of Cardiology were reviewed. STUDY SELECTION: Only studies of 500 or more patients were included. Of 15 studies identified, 10 randomized, placebo-controlled, double-blind trials of Gp IIb/IIIa inhibitors in ACSs were selected for review. DATA EXTRACTION: Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society-sponsored meeting, as well as by verification with the primary author. DATA SYNTHESIS: Three members of this class of drugs are available for intravenous use. Abciximab, eptifibatide, and tirofiban hydrochloride, each have data demonstrating their value in improving the outcomes of patients presenting with ACSs. Current evidence supports use of these drugs in both conservative and invasive treatment strategies. Glycoprotein IIb/IIIa-blocking therapy is safe, and with proper precautions, bleeding risks can be minimized. Biological differences exist among these agents, but as of yet, no head-to-head comparisons have been made of their clinical efficacy. Unlike intravenous Gp IIb/IIIa inhibitors, available data regarding any role of oral Gp IIb/IIIa inhibitors are not favorable. CONCLUSION: Current data indicate that intravenous Gp IIb/IIIa inhibitor therapy merits a prominent role in the initial management of patients with ACSs. JAMA. 2000;284:1549-1558.     

Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention

Context  Low-molecular-weight heparins (LMWHs) possess several potential pharmacological advantages over unfractionated heparin as an antithrombotic agent. Objective  To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated heparin across the spectrum of acute coronary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI). Data Sources  We searched MEDLINE for articles from 1990 to 2002 using the index terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight heparin, myocardial infarction, unstable angina, coronary angiography, coronary angioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Additional data sources included bibliographies of articles identified on MEDLINE, inquiry of experts and pharmaceutical companies, and data presented at recent national and international cardiology conferences. Study Selection  We selected for review randomized trials comparing LMWHs against either unfractionated heparin or placebo for treatment of ACS, as well as trials and registries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis. Data Extraction  Data quality was determined by publication in the peer-reviewed literature or presentation at an official cardiology society–sponsored meeting. Data Synthesis  The LMWHs are recommended by the American Heart Association and the American College of Cardiology for treatment of unstable angina/non–ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with LMWHs compared with unfractionated heparin in the setting of PCI and in conjunction with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction. Conclusions  The LMWHs could potentially replace unfractionated heparin as the antithrombotic agent of choice across the spectrum of ACSs. In addition, they show promise as a safe and efficacious antithrombotic agent for PCI. However, further study is warranted to define the benefit of LMWHs in certain high-risk subgroups before their use can be universally recommended.      

Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial

Context  No specifically designed studies have addressed the role of the glycoprotein IIb/IIIa inhibitor abciximab in patients with non–ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) after pretreatment with 600 mg of clopidogrel. Objective  To assess whether abciximab is associated with clinical benefit in high-risk patients with ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. Design, Setting, and Patients  International, multicenter, randomized, double-blind, placebo-controlled study conducted from March 2003 through December 2005, enrolling 2022 patients (mean age, 66 years) with non–ST-segment elevation ACS undergoing PCI. Interventions  Patients were assigned to receive either abciximab (0.25 mg/kg of body weight bolus, followed by a 0.125-µg/kg per minute [maximum, 10 µg/min] infusion for 12 hours, plus heparin, 70 U/kg of body weight) or placebo (placebo bolus and infusion of 12 hours, plus heparin bolus, 140 U/kg). All patients received clopidogrel, 600 mg, at least 2 hours prior to the procedure, as well as 500 mg of oral or intravenous aspirin. Main Outcome Measures  The primary end point was a composite of death, myocardial infarction, or urgent target vessel revascularization occurring within 30 days after randomization; secondary end points were rates of in-hospital major and minor bleeding. Results  Of 2022 patients enrolled, 1012 were assigned to abciximab and 1010 to placebo. The primary end point was reached in 90 patients (8.9%) assigned to abciximab vs 120 patients (11.9%) assigned to placebo, a 25% reduction in risk with abciximab (relative risk [RR], 0.75; 95% CI, 0.58-0.97; P = .03). Among patients without an elevated troponin level, there was no difference in the incidence of primary end point events between the abciximab group (23/499 patients [4.6%]) and the placebo group (22/474 patients [4.6%]) (RR, 0.99; 95% CI, 0.56-1.76; P = .98), whereas among patients with an elevated troponin level, the incidence of events was significantly lower in the abciximab group (67/513 patients [13.1%]) compared with the placebo group (98/536 patients [18.3%]), which corresponds to an RR of 0.71 (95% CI, 0.54-0.95; P = .02) (P = .07 for interaction). There were no significant differences between the 2 groups regarding the risk of major and minor bleeding as well as need for transfusion. Conclusions  Abciximab reduces the risk of adverse events in patients with non–ST-segment elevation ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. The benefits provided by abciximab appear to be confined to patients presenting with an elevated troponin level. Trial Registration  ClinicalTrials.gov Identifier: NCT00133003      

Thrombolytic therapy vs primary percutaneous coronary intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery: a randomized controlled trial

Context  Trials comparing primary percutaneous coronary intervention (PCI) and thrombolytic therapy for treatment of acute myocardial infarction (MI) suggest primary PCI is the superior therapy, although they differ with respect to the durability of benefit. Because PCI is often limited to hospitals that have on-site cardiac surgery programs, most acute MI patients do not have access to this therapy. Objective  To determine whether treatment of acute MI with primary PCI is superior to thrombolytic therapy at hospitals without on-site cardiac surgery and, if so, whether superiority is durable. Design  The Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial, a prospective, randomized trial conducted from July 1996 through December 1999. Setting  Eleven community hospitals in Massachusetts and Maryland without on-site cardiac surgery or extant PCI programs. Patients  Four hundred fifty-one thrombolytic-eligible patients with acute MI of less than 12 hours' duration associated with ST-segment elevation on electrocardiogram. Interventions  After a formal primary PCI development program was completed at all sites, patients were randomly assigned to receive primary PCI (n = 225) or accelerated tissue plasminogen activator (bolus dose of 15 mg and an infusion of 0.75 mg/kg for 30 minutes followed by 0.5 mg/kg for 60 minutes; n = 226). After initiation of assigned treatment, all care was determined by treating physicians. Main Outcome Measures  Six-month composite incidence of death, recurrent MI, and stroke; median hospital length of stay. Results  The incidence of the composite end point was reduced in the primary PCI group at 6 weeks (10.7% vs 17.7%; P = .03) and 6 months (12.4% vs 19.9%; P = .03) after index MI. Six-month rates for individual outcomes were 6.2% vs 7.1% for death (P = .72), 5.3% vs 10.6% for recurrent MI (P = .04), and 2.2% vs 4.0% for stroke (P = .28) for primary PCI vs thrombolytic therapy, respectively. Median length of stay was also reduced in the primary PCI group (4.5 vs 6.0 days; P = .02). Conclusions  Compared with thrombolytic therapy, treatment of patients with primary PCI at hospitals without on-site cardiac surgery is associated with better clinical outcomes for 6 months after index MI and a shorter hospital stay.      

Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study

Context  The benefit of clopidogrel pretreatment before percutaneous coronary intervention (PCI) remains debated and its use has not been universally adopted. Objective  To determine if clopidogrel pretreatment before PCI in patients with recent ST-segment elevation myocardial infarction (STEMI) is superior to clopidogrel treatment initiated at the time of PCI in preventing major adverse cardiovascular events. Design, Setting, and Participants  The PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) study was a prospectively planned analysis of the 1863 patients undergoing PCI after mandated angiography in CLARITY–Thrombolysis in Myocardial Infarction (TIMI) 28, a randomized, double-blind, placebo-controlled trial of clopidogrel in patients receiving fibrinolytics for STEMI. Patients were enrolled at 319 sites in 23 countries from February 2003 through October 2004. Interventions  Patients received aspirin and were randomized to receive either clopidogrel (300 mg loading dose, then 75 mg once daily) or placebo initiated with fibrinolysis and given until coronary angiography, which was performed 2 to 8 days after initiation of the study drug. For patients undergoing coronary artery stenting, it was recommended that open-label clopidogrel (including a loading dose) be administered after the diagnostic angiogram. Main Outcome Measures  The primary outcome was the incidence of the composite of cardiovascular death, recurrent MI, or stroke from PCI to 30 days after randomization. Secondary outcomes included MI or stroke before PCI and the aforementioned composite from randomization to 30 days. Results  Pretreatment with clopidogrel significantly reduced the incidence of cardiovascular death, MI, or stroke following PCI (34 [3.6%] vs 58 [6.2%]; adjusted odds ratio [OR], 0.54 [95% CI, 0.35-0.85]; P = .008). Pretreatment with clopidogrel also reduced the incidence of MI or stroke prior to PCI (37 [4.0%] vs 58 [6.2%]; OR, 0.62 [95% CI, 0.40-0.95]; P = .03). Overall, pretreatment with clopidogrel resulted in a highly significant reduction in cardiovascular death, MI, or stroke from randomization through 30 days (70 [7.5%] vs 112 [12.0%]; adjusted OR, 0.59 [95% CI, 0.43-0.81]; P = .001; number needed to treat = 23). There was no significant excess in the rates of TIMI major or minor bleeding (18 [2.0%] vs 17 [1.9%]; P>.99). Conclusions  Clopidogrel pretreatment significantly reduces the incidence of cardiovascular death or ischemic complications both before and after PCI and without a significant increase in major or minor bleeding. These data add further support to the early use of clopidogrel in STEMI and the strategy of routine clopidogrel pretreatment in patients undergoing PCI.      

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial

Context  Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied. Objectives  To evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy. Design, Setting, and Participants  The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001. Interventions  Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study. Main Outcome Measures  One-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population. Results  At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P = .02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, -14.2% to 41.8%; P = .23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, -1.6% to 62.9%; P = .051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P = .07). Conclusions  Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.      

Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: a randomized controlled trial

Context  Atheromatous and thrombotic embolization during percutaneous coronary intervention (PCI) in acute myocardial infarction is common and may result in microcirculatory dysfunction, the prevention of which may improve reperfusion success, reduce infarct size, and enhance event-free survival. Objective  To determine whether protection of the distal microcirculation from thromboembolic debris liberated during primary PCI results in improved reperfusion and decreased infarct size. Design, Setting, and Patients  Prospective randomized controlled trial at 38 academic and community-based institutions in 7 countries enrolling 501 patients aged 18 years or older with ST-segment elevation myocardial infarction (STEMI) presenting within 6 hours of symptom onset and undergoing primary PCI or rescue intervention after failed thrombolysis. Interventions  Patients were randomized between May 20, 2002, and November 21, 2003, to receive PCI with a balloon occlusion and aspiration distal microcirculatory protection system vs angioplasty without distal protection. Main Outcome Measures  Coprimary end points were ST-segment resolution (STR) measured 30 minutes after PCI by continuous Holter monitoring and infarct size measured by technetium Tc 99m sestamibi imaging between days 5 and 14. Secondary end points included major adverse cardiac events. Results  Among 252 patients assigned to distal protection, aspiration was performed in 97% (242/251), all angioplasty balloon inflations were fully protected in 79% (193/245), and visible debris was retrieved from 73% (182/250). Complete STR was achieved in a similar proportion reperfused with vs without distal protection (63.3% [152/240] vs 61.9% [148/239], respectively; absolute difference, 1.4% [95% confidence interval, –7.7% to 10.5%; P = .78]), and left ventricular infarct size was similar in both groups (median, 12.0% [n = 229] vs 9.5% [n = 208], respectively; P = .15). Major adverse cardiac events at 6 months occurred with similar frequency in the distal protection and control groups (10.0% vs 11.0%, respectively; P = .66). Conclusions  A distal balloon occlusion and aspiration system effectively retrieves embolic debris in most patients with acute STEMI undergoing emergent PCI. Nonetheless, distal embolic protection did not result in improved microvascular flow, greater reperfusion success, reduced infarct size, or enhanced event-free survival.      

Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation

Context  Although reperfusion therapy, aspirin, -blockers, and angiotensin-converting enzyme inhibitors reduce mortality when used early in patients with acute myocardial infarction (MI), mortality and morbidity remain high. No antithrombotic or newer antiplatelet drug has been shown to reduce mortality in acute MI. Objective  To evaluate the effects of reviparin, a low-molecular-weight heparin, when initiated early and given for 7 days in addition to usual therapy on the primary composite outcome of death, myocardial reinfarction, or strokes at 7 and 30 days. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled trial (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation [CREATE]) of 15 570 patients with ST-segment elevation or new left bundle-branch block, presenting within 12 hours of symptom onset at 341 hospitals in India and China from July 2001 through July 2004. Intervention  Reviparin or placebo subcutaneously twice daily for 7 days. Main Outcome Measure  Primary composite outcome of death, myocardial reinfarction, or stroke at 7 and 30 days. Results  The primary composite outcome was significantly reduced from 854 (11.0%) of 7790 patients in the placebo group to 745 (9.6%) of 7780 in the reviparin group (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96; P = .005). These benefits persisted at 30 days (1056 [13.6%] vs 921 [11.8%] patients; HR, 0.87; 95% CI, 0.79-0.95; P = .001) with significant reductions in 30-day mortality (877 [11.3%] vs 766 [9.8%]; HR, 0.87; 95% CI, 0.79-0.96; P = .005) and reinfarction (199 [2.6%] vs 154 [2.0%]; HR, 0.77; 95% CI, 0.62-0.95; P = .01), and no significant differences in strokes (64 [0.8%] vs 80 [1.0%]; P = .19). Reviparin treatment was significantly better when it was initiated very early after symptom onset at 7 days (<2 hours: HR, 0.70; 95% CI, 0.52-0.96; P = .03; 30/1000 events prevented; 2 to <4 hours: HR, 0.81; 95% CI, 0.67-0.98; P = .03; 21/1000 events prevented; 4 to <8 hours: HR, 0.85; 95% CI, 0.73-0.99; P = .05; 16/1000 events prevented; and 8 hours: HR, 1.06; 95% CI, 0.86-1.30; P = .58; P = .04 for trend). There was an increase in life-threatening bleeding at 7 days with reviparin and placebo (17 [0.2%] vs 7 [0.1%], respectively; P = .07), but the absolute excess was small (1 more per 1000) vs reductions in the primary outcome (18 fewer per 1000) or mortality (15 fewer per 1000). Conclusions  In patients with acute ST-segment elevation or new left bundle-branch block MI, reviparin reduces mortality and reinfarction, without a substantive increase in overall stroke rates. There is a small absolute excess of life-threatening bleeding but the benefits outweigh the risks.      

Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial

Context  Reperfusion with percutaneous transluminal coronary intervention (PCI) is effective at improving outcomes in patients with acute ST-elevation myocardial infarction (STEMI). However, in patients without prompt reestablishment of brisk coronary flow and tissue perfusion, mortality remains high, providing an opportunity for novel treatments, including anti-inflammatory agents. Objective  To evaluate the effectiveness of pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement, as an adjunct to PCI in improving 30-day mortality from STEMI. Design, Setting, and Patients  This trial was a prospective, multicenter, double-blind, placebo-controlled, phase 3 study of the intravenous administration of pexelizumab in conjunction with primary PCI in STEMI with prespecified high-risk electrocardiographic findings. The trial was intended to enroll 8500 patients, but in conjunction with the US Food and Drug Administration enrollment was modified to 5745 patients presenting from 296 hospitals in 17 countries from July 13, 2004, to May 11, 2006. Interventions  Two thousand eight hundred eighty-five patients were randomly assigned to receive placebo and 2860 to receive pexelizumab given as a 2-mg/kg intravenous bolus prior to PCI followed by 0.05-mg/kg per hour infusion over the subsequent 24 hours. Patients were randomized within 6 hours of symptom onset. Main Outcome Measures  The primary end point was all-cause mortality through day 30. Secondary end points were death through day 90 and the composite of death, cardiogenic shock, or congestive heart failure through days 30 and 90. Results  No difference in mortality through day 30 was observed between the pexelizumab and placebo treatment groups, with 116 patients (4.06%) and 113 patients (3.92%) who died in the respective groups (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.80-1.35; log-rank P = .78). The composite end points of death, shock, or heart failure were also similar with 257 patients (8.99%) receiving pexelizumab and 265 patients (9.19%) receiving placebo at 30 days (HR, 0.98; 95% CI, 0.83-1.16; P = .81) and 293 patients (10.24%) receiving pexelizumab and 293 patients (10.16%) receiving placebo at 90 days (HR, 1.01; 95% CI, 0.86-1.19; P = .91). Conclusion  In this large clinical trial of patients treated with primary PCI for STEMI, mortality was low and unaffected by administration of pexelizumab. Trial Registration  clinicaltrials.gov Identifier: NCT00091637      

Cost and cost-effectiveness of an early invasive vs conservative strategy for the treatment of unstable angina and non-ST-segment elevation myocardial infarction

Context  In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)–Thrombolysis in Myocardial Infarction (TIMI) 18 trial, patients with either unstable angina or non–ST-segment elevation myocardial infarction (UA/NSTEMI) treated with the platelet glycoprotein (Gp IIb/IIIa) inhibitor tirofiban had a significantly reduced rate of major cardiac events at 6 months with an early invasive vs a conservative strategy. Objective  To examine total 6-month costs and long-term cost-effectiveness of an invasive vs a conservative strategy. Design  Randomized controlled trial including a priori economic end points. Setting  Hospitalization for UA/NSTEMI with 6-month follow-up period. Patients  A total of 2220 patients with UA/NSTEMI; economic data from 1722 patients at US–non-VA hospitals. Intervention  Early invasive strategy with routine catheterization and revascularization as appropriate vs a conservative strategy with catheterization performed only for recurrent ischemia or a positive stress test. Main Outcome Measure  Total 6-month costs and incremental cost-effectiveness ratio. Results  The average initial hospitalization costs among those in the invasive strategy group were $15714 vs $14047 among those in the conservative stategy group, a difference of $1667 (95% confidence interval [CI], $387-3091). The in-hospital costs were offset significantly at the 6-month follow-up, with an average cost in the invasive group of $6098 vs $7180 in the conservative group, a difference of $1082 (95% CI, -$2051 to $76). The average total costs at 6 months, including productivity costs, for the invasive group was $21 813 vs $21 227 for the conservative group, a $586 difference (95% CI, -$1087 to $2486). The average 6-month costs excluding productivity costs in the invasive group was $19 780 vs $19 111 in the conservative group, a difference of $670, 95% CI; (-$1035 to $2321). Estimated cost per year of life gained for the invasive strategy, based on projected life expectancy, was $12739 for the base case, and ranged from $8371 to $25769, based on model assumptions. Conclusions  In patients with UA/NSTEMI treated with the Gp IIb/IIIa inhibitor tirofiban, the clinical benefit of an early invasive strategy was achieved with a small increase in cost, yielding favorable projected estimates of cost per year of life gained. These results support the broader use of an early invasive strategy in these patients.      

Outcomes of percutaneous coronary interventions performed at centers without and with onsite coronary artery bypass graft surgery

Context  An ongoing debate focuses on whether institutions should perform percutaneous coronary interventions (PCIs) without an onsite coronary artery bypass graft (CABG) surgery program. Objective  To compare patient outcomes following PCI at US institutions performing this procedure without and with onsite cardiac surgery. Design, Setting, and Patients  Medicare hospital (part A) data were used to identify PCIs performed on fee-for-service Medicare enrollees (n = 625 854) aged at least 65 years at acute care facilities between January 1, 1999, and December 1, 2001. Hospitals without and with onsite cardiac surgery were identified based on the presence of claims for CABG surgery. Patients were characterized as undergoing primary/rescue PCI, defined as an emergency procedure performed on the same day of admission for an acute myocardial infarction (MI), vs all other PCIs. Main Outcome Measures  Post-PCI CABG surgery and combined in-hospital and 30-day mortality. Results  A total of 178 hospitals performed PCIs without onsite cardiac surgery and 943 hospitals performed PCIs with onsite cardiac surgery. Patients undergoing PCIs in hospitals without onsite cardiac surgery were similar to those with onsite cardiac surgery with respect to age, sex, race, and measurable comorbidities; however, patients undergoing PCIs in hospitals without onsite cardiac surgery were more likely to have a primary/rescue PCI (22.0% vs 5.6%, P < .001). Patients undergoing PCIs in hospitals without cardiac surgery were more likely to die (6.0% vs 3.3%; adjusted odds ratio [OR], 1.29; 95% confidence interval [CI], 1.14-1.47; P < .001). After accounting for baseline differences, mortality for patients with primary/rescue PCI was similar in institutions without and with cardiac surgery (adjusted OR, 0.93; 95% CI, 0.80-1.08; P = .34). However, for the larger non-primary/rescue PCI population, mortality was higher in hospitals without onsite cardiac surgery (adjusted OR, 1.38; 95% CI, 1.14-1.67; P=.001). This increase in mortality was primarily confined to hospitals performing 50 or less Medicare PCIs per year. Conclusions  Percutaneous coronary interventions in hospitals without onsite cardiac surgery are often performed for reasons other than immediate treatment of an MI and are associated with a higher risk of adverse outcomes. Policies aimed at increasing access to primary/rescue PCI through promoting PCI in hospitals without cardiac surgery may inadvertently lead to an overall increase in mortality related to PCI.