Bleeding risk factors affecting warfarin therapy in the elderly with atrial fibrillation.

PURPOSE: Inadequate anticoagulation among elderly individuals with atrial fibrillation (AF) is a common problem. This synthesis of the literature review describes the pathophysiology of AF, explains the mechanism of action of warfarin (Coumadin), identifies factors that contribute to warfarin (Coumadin)-associated bleeding in the elderly population, and explores alternatives to warfarin (Coumadin) therapy. Implications for advanced practice nurse practice, education, and research will be discussed. METHODS: A literature search was conducted using Academic Search Premier, CINAHL Plus with Full Text, and Medline from 1999 to 2012. Search terms included warfarin (Coumadin), warfarin (Coumadin) genetics, diet, interactions, bleeding, atrial fibrillation, genetics, anticoagulation clinic, dabigatran, apixaban, rivaroxaban, and elderly. RESULTS: The literature indicates that the potential bleeding risk associated with warfarin (Coumadin) therapy limits its use in the elderly population. However, some studies have found warfarin (Coumadin) to be more effective than aspirin in preventing stroke. The safety profiles of both medications were comparable; also, effective alternatives to warfarin (Coumadin) that do not require routine testing are now available. CONCLUSIONS: Atrial fibrillation increases the probability of an embolic stroke, especially for the elderly population. Stroke risk and bleeding risk tools, in conjunction with patient preference, determine the best stroke prevention treatment. Anticoagulant clinics manage long-term warfarin (Coumadin) therapy effectively. Newer anticoagulants offer effective alternatives to warfarin (Coumadin) therapy.

Effect of platelet inhibition with cangrelor during PCI on ischemic events.

BACKGROUND: The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours. RESULTS: The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups. CONCLUSIONS: Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

Quantification of the effect of clopidogrel on enzymatic infarct size related to a percutaneous coronary intervention in patients with acute coronary syndromes: insights from the CHAMPION percutaneous coronary intervention trial.

OBJECTIVES: Using data from the CHAMPION percutaneous coronary intervention (PCI), we determined the relationship between clopidogrel started at least 5 days before PCI (maintenance of clopidogrel) and PCI-related enzymatic infarct size. BACKGROUND: Clopidogrel is recommended in patients with acute coronary syndrome (ACS) managed with PCI, but its effect on PCI-related myonecrosis in contemporary patients has not been quantified. PATIENTS AND METHODS: Patients with ACS (with or without ST-segment elevation) who underwent PCI and had at least three creatine kinase-MB (CK-MB) samples after PCI were included. Enzymatic infarct size was defined as the peak CK-MB concentration indexed by its upper limit of normal. Associations between maintenance clopidogrel and enzymatic infarct size were explored using multivariable linear regression (with and without missing data imputation) and propensity score analysis using inverse probability weighting. RESULTS: Of 8877 patients randomized, 6327 (71.3%) were included (median age 61 years, 73% male, 13% ACS with ST-segment elevation). Of these 6327 patients, 2015 (31.8%) were on maintenance clopidogrel. After multivariable adjustment, maintenance clopidogrel was associated with a reduction in enzymatic infarct size {ß=-0.63; 47% decrease in peak CK-MB [95% confidence interval (CI) 35, 56%]}. Multivariable linear regression with multiple imputations and inverse probability weighting propensity score analysis yielded similar results, with maintenance clopidogrel associated with 44% (95% CI 33, 53%) and 29% (95% CI 24, 33%) infarct size reductions. CONCLUSION: In this subgroup analysis of modern ACS patients, clopidogrel maintenance was independently associated with smaller enzymatic infarct size after PCI. These results are consistent with previous observations suggesting a benefit of clopidogrel on the procedural outcome and quantify this benefit.

Implications of pre-procedural TIMI flow in patients with non ST-segment elevation acute coronary syndromes undergoing percutaneous coronary revascularization: insights from the ACUITY trial.

OBJECTIVES: The purpose of this study was to evaluate the prognostic implications of preprocedural TIMI flow in ACS patients undergoing early invasive management. BACKGROUND: Although the negative prognostic impact of reduced Thrombolysis in Myocardial Infarction (TIMI) flow before percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) has been well described, whether this relationship holds in patients with acute coronary syndromes (ACS; unstable angina and non-STEMI) has not been examined. METHODS: We evaluated 3582 moderate and high-risk patients with ACS undergoing PCI enrolled in the ACUITY trial. Patients were divided in 3 groups according to pre-procedural culprit vessel TIMI flow (TIMI 0/1, TIMI 2 and TIMI 3 flows), determined by an independent angiographic core laboratory. RESULTS: Baseline culprit vessel flow was absent (TIMI 0/1) in 453 patients (12.6%), reduced (TIMI 2) in 389 patients (10.9%) and normal (TIMI 3) in 2740 patients (76.5%) patients. Post-PCI TIMI 3 flow was achieved in 87.2%, 86.8% and 98.8% of the 3 groups, respectively (P<0.0001). At 1 year, mortality occurred in 2.7%, 2.4% and 3.0% of patients with baseline TIMI 0/1, 2 and 3 flows, respectively (P=0.82). By multivariable analysis, pre-PCI TIMI flow 0/1 (vs. TIMI 3) was not an independent predictor of 1-year mortality (P=0.61). CONCLUSIONS: Reduced baseline TIMI flow in moderate and high-risk patients with ACS undergoing PCI does not appear to affect survival at 1 year, in contrast to that described in patients with STEMI.

Are adverse events following an invasive strategy in patients with non-ST-segment elevation acute coronary syndromes more frequent at US sites versus non-US sites? Analysis from the ACUITY trial.

OBJECTIVE: To compare outcomes between US and non-US (OUS) sites in patients with non ST-elevation acute coronary syndromes (NSTEACS) and to evaluate potential reasons for differences in outcomes. BACKGROUND: There are little data comparing outcomes at US versus OUS sites in patients with NSTEACS managed with an invasive strategy. METHODS: The ACUITY trial randomized 13,819 patients with NSTEACS in 17 countries to an invasive approach with one of three strategies: (1) heparin plus glycoprotein platelet inhibitors (GPI), (2) bivalirudin plus GPI, or (3) bivalirudin alone. RESULTS: US patients were more often female, were younger, heavier, and had more diabetes, prior myocardial infarction (MI), and prior bypass surgery. US patients were less often treated with percutaneous coronary intervention but had more frequent drug-eluting stent use. US patients had lower mortality and higher MI rates at 30 days and 1 year and higher composite ischemic outcome at 30 days. After adjusting for differences in baseline variables, US patients had higher rates of MI and composite ischemic outcome at 30 days and higher rates of MI at 1 year {HR [95% confidence interval (CI)] = 1.36 [1.18-1.56], P < 0.0001} with no differences in mortality. There were no differences in treatment effects comparing bivalirudin with the other strategies between US and OUS sites. CONCLUSIONS: US versus OUS patients with NSTEACS had higher adjusted rates of MI and ischemia. The reasons for these differences are not clear but may be due to unmeasured confounders, different thresholds for event reporting, or valid differences in systems of care which may impact outcomes.

Outcomes of patients with prior coronary artery bypass grafting and acute coronary syndromes: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial.

OBJECTIVES: This study sought to assess the contemporary outcomes of patients with prior coronary artery bypass graft (CABG) who present with moderate and high-risk acute coronary syndromes (ACS) and are treated with an early invasive strategy and contemporary antithrombin regimens. BACKGROUND: The prognosis of patients with ACS and prior CABG in relation to triage strategy and contemporary antithrombotic regimens is unknown. METHODS: In the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, 2,475 of 13,764 patients (18.0%) with ACS managed with an early invasive strategy had previously undergone CABG. Their outcomes were examined according to treatment and randomized antithrombin regimen. RESULTS: Prior CABG was associated with older age, more frequent comorbidities, higher Thrombolysis In Myocardial Infarction risk score, and lower left ventricular ejection fraction. Patients with versus without prior CABG were less likely to undergo (repeat) CABG and were more likely to be managed medically. At 1 year, patients with versus without prior CABG had higher rates of major adverse cardiac events (MACE) (22.5% vs. 15.2%, p < 0.0001) due to greater mortality (5.4% vs. 3.9%, p < 0.0001), myocardial infarction (10.0% vs. 6.8%, p < 0.0001), and unplanned revascularization (13.1% vs. 8.2%, p < 0.0001). History of CABG was an independent predictor of MACE. The 1-year MACE rates were not significantly different after randomization to bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor (odds ratio: 1.24, 95% confidence interval: 0.90 to 1.70). CONCLUSIONS: Despite the progress in the treatment of coronary artery disease, patients with prior CABG and ACS have a poor prognosis, substantially worse than for those without prior CABG. Whereas bivalirudin monotherapy was an acceptable treatment for these patients, it did not improve their prognoses.

Predictive value of C-reactive protein on 30-day and 1-year mortality in acute coronary syndromes: an analysis from the ACUITY trial.

We sought to evaluate the association between C-reactive protein (CRP) sampled on admission and short- and long-term mortality in patients with acute coronary syndromes (ACS) undergoing early invasive treatment. Baseline levels of CRP were determined in 2,974 patients with moderate and high-risk ACS undergoing an early invasive treatment strategy in the large-scale randomized ACUITY trial. The relationship of CRP to 30-day and 1-year clinical outcomes were assessed according to quartiles of CRP values. Patients with CRP levels in the fourth quartile compared to the first quartile had significantly higher 30-day mortality (2.3 vs. 0.3%, P = 0.0004) and 1-year mortality (5.5 vs. 2.8%, P = 0.0003). CRP level as a continuous variable was associated with 30-day mortality (OR [95% CI] for one unit increase in logarithmically transformed CRP level = 1.42 [1.08-1.89], P = 0.01) and 1-year mortality (OR [95% CI] = 1.24, [1.04-1.47], P = 0.02). By multivariable analysis, higher baseline CRP levels independently predicted 30-day and 1-year mortality, a relationship that was particularly strong for patients with the highest quartile of CRP (OR [95% CI] = 5.19 [1.14-23.68], P = 0.009). In troponin-positive patients, increasing quartiles of CRP were associated with a trend for 30-day mortality (P (trend) = 0.08) and a significant increase in 1-year mortality (P (trend) = 0.02); this relationship was not present in troponin-negative patients. Baseline CRP level is a powerful independent predictor of both early and late mortality in patients with ACS being treated with an early invasive strategy, especially in troponin positive patients.

Comparison of catheterization laboratory initiated abciximab and eptifibatide during percutaneous coronary intervention in acute coronary syndromes (an ACUITY substudy).

Abciximab and eptifibatide have been shown to reduce ischemic complications compared with heparin alone in patients with acute coronary syndromes who undergo percutaneous coronary intervention. Whether 1 agent is safer and/or more effective has not been prospectively examined. The aim of this study was to assess the outcomes related to downstream glycoprotein IIb/IIIa inhibitor treatment selection during percutaneous coronary intervention in 2,211 patients with moderate and high-risk acute coronary syndromes in the prospective multicenter Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. The protocol permitted operator selection of abciximab (n = 835) or eptifibatide (n = 1,376) for routine use in the trial. Multivariate and propensity-based adjustments were used to assess the independent association of glycoprotein IIb/IIIa inhibitor treatment selection with prespecified study end points. Compared to patients receiving eptifibatide, those administered abciximab were older, more likely to be enrolled outside of North America, more frequently had biomarker elevations and ST-segment deviation, but had fewer baseline cardiac risk factors and previous revascularization procedures. After multivariate propensity-based adjustment, abciximab was independently associated with significantly fewer net clinical adverse events (odds ratio 0.61, 95% confidence interval 0.42 to 0.90, p = 0.01), mediated by composite ischemia (odds ratio 0.61, 95% confidence interval 0.38 to 0.98, p = 0.04) and major bleeding (odds ratio 0.58, 95% confidence interval 0.34 to 1.00, p = 0.051). In conclusion, in this prespecified but nonrandomized comparison in patients with acute coronary syndromes who underwent percutaneous coronary intervention with catheterization laboratory initiation of glycoprotein IIb/IIIa inhibitors, the use of abciximab rather than eptifibatide was associated with improved clinical outcomes at 30 days. These findings should be viewed as exploratory in light of the nonrandomized and heterogeneous nature of the comparator groups and significant potential for residual confounding.

Impact of femoral vascular closure devices and antithrombotic therapy on access site bleeding in acute coronary syndromes: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.

BACKGROUND: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial demonstrated that bivalirudin monotherapy significantly reduces major bleeding compared with heparin (unfractionated or enoxaparin) or bivalirudin plus a glycoprotein IIb/IIIa inhibitor in acute coronary syndromes. Whether vascular closure devices (VCD) impact these results is unknown. Therefore, this study sought to determine whether VCD impact major access site bleeding (ASB) in patients with acute coronary syndromes undergoing early invasive management by the femoral approach. METHODS AND RESULTS: Major ASB in ACUITY was defined as ASB requiring interventional or surgical correction, hematoma > or =5 cm at the access site, retroperitoneal bleeding, or hemoglobin drop > or =3 g/dL with ecchymosis or hematoma <5 cm, oozing blood, or prolonged bleeding (>30 minutes) at the access site. Stepwise logistical regression was performed to identify the independent determinants of ASB. Of 11 621 patients undergoing angiography with or without percutaneous coronary intervention by the femoral approach, 4307 (37.1%) received a VCD and 7314 (62.9%) did not. Rates of major ASB were lower with VCD compared with no VCD (2.5% versus 3.3%, relative risk, 0.76; 95% CI, 0.61 to 0.94; P=0.01) and were lowest in patients treated with bivalirudin monotherapy and a VCD (0.7%). Stepwise logistic regression revealed that a VCD (odds ratio, 0.78; 95% CI, 0.61 to 0.99; P=0.04) and bivalirudin monotherapy (odds ratio, 0.35; 95% CI, 0.25 to 0.49; P<0.0001) were both independent determinates of freedom from major ASB. CONCLUSIONS: In patients with acute coronary syndromes undergoing an early invasive management strategy by the femoral approach, the use of a VCD, bivalirudin monotherapy, or both minimizes rates of major ASB. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00093158.

A randomized comparison of the Endeavor zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de novo native coronary lesions 12-month outcomes from the ENDEAVOR IV trial.

OBJECTIVES: The ENDEAVOR IV (Randomized Comparison of Zotarolimus-Eluting and Paclitaxel-Eluting Stents in Patients with Coronary Artery Disease) trial evaluated the safety and efficacy of the zotarolimus-eluting stent (ZES) compared with the paclitaxel-eluting stent (PES). BACKGROUND: First-generation drug-eluting stents have reduced angiographic and clinical restenosis, but long-term safety remains controversial. A second-generation drug-eluting stent, which delivers zotarolimus, a potent antiproliferative agent, via a biocompatible phosphorylcholine polymer on a cobalt alloy thin-strut stent has shown promising experimental and early clinical results. METHODS: This is a prospective, randomized (1:1), single-blind, controlled trial comparing outcomes of patients with single de novo coronary lesions treated with ZES or PES. The primary end point was noninferiority of 9-month target vessel failure defined as cardiac death, myocardial infarction, or target vessel revascularization. RESULTS: Among a total of 1,548 patients assigned to ZES (n = 773) or PES (n = 775), at 9 months, ZES was noninferior to PES with rates of target vessel failure 6.6% versus 7.1%, respectively (p(noninferiority) < or = 0.001). There were fewer periprocedural myocardial infarctions with ZES (0.5% vs. 2.2%; p = 0.007), whereas at 12 months, there were no significant differences between groups in rates of cardiac death, myocardial infarction, target vessel revascularization, or stent thrombosis. Although incidence of 8-month binary angiographic in-segment restenosis was higher in patients treated with ZES versus PES (15.3% vs. 10.4%; p = 0.284), rates of 12-month target lesion revascularization were similar (4.5% vs. 3.2%; p = 0.228), especially in patients without planned angiographic follow-up (3.6% vs. 3.2%; p = 0.756). CONCLUSIONS: These findings demonstrate that ZES has similar clinical safety and efficacy compared with PES in simple and medium complexity single de novo coronary lesions. (ENDEAVOR IV Clinical Trial; NCT00217269).

Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial.

OBJECTIVES: The aim of this study was to evaluate the relative impact of spontaneously occurring and periprocedural myocardial infarction (MI) on survival after percutaneous coronary intervention (PCI). BACKGROUND: The clinical significance of periprocedural MI after PCI remains uncertain. METHODS: Outcomes during a 1-year follow-up were evaluated among 7,773 patients enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial with a non-ST-segment elevation acute coronary syndrome in whom PCI was performed. RESULTS: Periprocedural MI developed in 466 patients (6.0%), and spontaneous MI unrelated to PCI subsequently developed in 200 patients (2.6%). Patients developing spontaneous and periprocedural MI compared with those patients without MI had significantly greater unadjusted rates of mortality at 30 days (5.0% vs. 3.2% vs. 0.8%, respectively, p < 0.0001) and at 1 year (16.0% vs. 6.0% vs. 2.6%, respectively, p < 0.0001). In a time-updated multivariable analysis, after adjusting for differences in baseline and procedural characteristics between the groups, we found that spontaneous MI was a powerful independent predictor of subsequent mortality (hazard ratio: 7.49, 95% confidence interval: 4.95 to 11.33, p < 0.0001), whereas periprocedural MI was not a significant predictor of mortality (hazard ratio: 1.30, 95% confidence interval: 0.85 to 1.98, p = 0.22). CONCLUSIONS: Among patients with acute coronary syndrome undergoing PCI, the spontaneous development of an MI unrelated to PCI is a powerful predictor of subsequent mortality. In contrast, periprocedural MI is a marker of baseline risk, atherosclerosis burden, and procedural complexity but in most cases does not have independent prognostic significance. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial.

BACKGROUND: The clinical and angiographic predictors of early (<30 days) stent thrombosis (ST) have not been reported in high-risk patients with acute coronary syndromes. METHODS AND RESULTS: Qualitative and quantitative coronary angiographic analyses were performed in 3405 patients with moderate- and high-risk acute coronary syndromes in whom stents were implanted in the prospective randomized Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, including 3043 patients (89.4%) in whom drug-eluting stents were implanted. Within 30 days, definite or probable ST occurred in 48 patients (1.4%). ST rates were not significantly different in patients treated with bare metal stents compared with drug-eluting stents (1.4% versus 1.4%; P=1.00) or with heparin plus glycoprotein IIb/IIIa inhibitors (1.1%) compared with bivalirudin with or without IIb/IIIa inhibitors (1.6% and 1.5%, respectively; P=0.26 and P=0.37, respectively). Compared with patients without ST, patients with ST more frequently had insulin-requiring diabetes mellitus and baseline renal insufficiency, a greater overall burden of coronary atherosclerosis, and suboptimal final angiographic results. ST also was more common in patients without preprocedural thienopyridine administration and with inconsistent antiplatelet drug use within 30 days. By multivariable analysis, the strongest independent predictors of definite ST were a smaller final stent minimal lumen diameter, a lack of preprocedural thienopyridine administration, the extent of coronary artery disease, and higher baseline hemoglobin level. CONCLUSIONS: Occurring in nearly 1 in 70 patients, early ST is relatively common in acute coronary syndromes, occurs with similar frequency after anticoagulation with either heparin plus glycoprotein IIb/IIIa inhibitors or bivalirudin with or without IIb/IIIa inhibitors, and is predicted by diffuse atherosclerosis, suboptimal angiographic results, and inadequate pharmacotherapy.

Late safety, efficacy, and cost-effectiveness of a zotarolimus-eluting stent compared with a paclitaxel-eluting stent in patients with de novo coronary lesions: 2-year follow-up from the ENDEAVOR IV trial (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions).

OBJECTIVES: The aim of this study was to assess, after 2 years of follow-up, the safety, efficacy, and cost-effectiveness of a zotarolimus-eluting stent (ZES) compared with a paclitaxel-eluting stent (PES) in patients with native coronary lesions. BACKGROUND: Early drug-eluting stents were associated with a small but significant incidence of very late stent thrombosis (VLST), occurring >1 year after the index procedure. The ZES has shown encouraging results in clinical trials. METHODS: The ENDEAVOR IV trial (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions), a randomized (1:1), single-blind, controlled trial (n = 1,548) compared ZES versus PES in patients with single de novo coronary lesions. Two-year follow-up was obtained in 96.0% of ZES and 95.4% of PES patients. The primary end point was target vessel failure (TVF), and safety end points included Academic Research Consortium-defined stent thrombosis. Economic end points analyzed included quality-adjusted survival, medical costs, and relative cost-effectiveness of ZES and PES. RESULTS: The TVF at 2 years was similar in ZES and PES patients (11.1% vs. 13.1%, p = 0.232). There were fewer myocardial infarctions (MIs) in ZES patients (p = 0.022), due to fewer periprocedural non-Q-wave MIs and fewer late MIs between 1 and 2 years. Late MIs were associated with increased VLST (PES: 6 vs. ZES: 1; p = 0.069). Target lesion revascularization was similar comparing ZES with PES (5.9% vs. 4.6%; p = 0.295), especially in patients without planned angiographic follow-up (5.2% vs. 4.9%; p = 0.896). The cost-effectiveness of ZES and PES was similar. CONCLUSIONS: After 2 years of follow-up, ZES demonstrated efficacy and cost-effectiveness comparable to PES, with fewer MIs and a trend toward less VLST. (The ENDEAVOR IV Clinical Trial: A Trial of a Coronary Stent System in Coronary Artery Lesions; NCT00217269).

Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes.

OBJECTIVES: The aim of this study was to determine the economic impact of several anticoagulation strategies for moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients managed invasively. BACKGROUND: The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial demonstrated that bivalirudin monotherapy yields similar rates of ischemic complications and less bleeding than regimens incorporating glycoprotein IIb/IIIa receptor inhibitors (GPI) for moderate- and high-risk NSTE-ACS. METHODS: In ACUITY, 7,851 U.S. patients were randomized to: 1) heparin (unfractionated or enoxaparin) + GPI; 2) bivalirudin + GPI; or 3) bivalirudin monotherapy. Patients assigned to GPI were also randomized to upstream GPI before catheterization or selective GPI only with percutaneous coronary intervention. Resource use data were collected prospectively through 30-day follow-up. Costs were estimated with standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule. RESULTS: At 30 days, ischemic events were similar for all groups. Major bleeding was reduced with bivalirudin monotherapy compared with heparin + GPI or bivalirudin + GPI (p < 0.001). Length of stay was lowest with bivalirudin monotherapy or bivalirudin + catheterization laboratory GPI (p = 0.02). Despite higher drug costs, aggregate hospital stay costs were lowest with bivalirudin monotherapy (mean difference range: $184 to $1,081, p < 0.001 for overall comparison) and at 30 days (mean difference range: $123 to $938, p = 0.005). Regression modeling demonstrated that hospital savings were primarily due to less major and minor bleeding with bivalirudin ($8,658/event and $2,282/event, respectively). CONCLUSIONS: Among U.S. patients in the ACUITY trial, bivalirudin monotherapy compared with heparin + GPI resulted in similar protection from ischemic events, reduced bleeding, and shorter length of stay. Despite higher drug costs, aggregate hospital and 30-day costs were lowest with bivalirudin monotherapy. Thus bivalirudin monotherapy seems to be an economically attractive alternative to heparin + GPI for patients with moderate- and high-risk NSTE-ACS. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial.

OBJECTIVES: This study was designed to determine the impact of bivalirudin on 1-year outcomes in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial demonstrated that in moderate- and high-risk ACS patients undergoing PCI, bivalirudin alone compared to unfractionated heparin (UFH) or enoxaparin plus a glycoprotein (GP) IIb/IIIa inhibitor resulted in less major bleeding and similar ischemic outcomes at 30 days. The impact of bivalirudin on 1-year outcomes in ACS patients undergoing PCI is unknown. METHODS: In the ACUITY trial, 13,819 patients were enrolled, and 7,789 (56.4%) patients had PCI. Composite ischemia (death, myocardial infarction, or unplanned revascularization) and mortality at 1 year were assessed. RESULTS: Among patients undergoing PCI, 2,561, 2,609, and 2,619 were randomized to UFH or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, and bivalirudin monotherapy, respectively. At 1 year, there were no differences in composite ischemia (17.8% vs. 19.4% vs. 19.2%, p = NS) or mortality (3.2% vs. 3.3% vs. 3.1%, p = NS) among the 3 groups, respectively. CONCLUSIONS: Bivalirudin compared with UFH or enoxaparin plus a GP IIb/IIIa inhibitor results in similar rates of composite ischemia and mortality at 1 year in moderate- and high-risk ACS patients undergoing PCI.

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

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.

Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial.

BACKGROUND: The aim of this study was to assess anticoagulation with the direct thrombin inhibitor bivalirudin during percutaneous coronary intervention in individuals with moderate and high-risk acute coronary syndromes. METHODS: 13,819 individuals in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial were prospectively randomly assigned to receive heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibitors, bivalirudin plus glycoprotein IIb/IIIa inhibitors, or bivalirudin alone. Of these individuals, 7789 underwent percutaneous coronary intervention after angiography. The effect of the three regimens on the primary 30-day endpoints of composite ischaemia (death, myocardial infarction, or unplanned revascularisation for ischaemia), major bleeding, and net clinical outcomes (composite ischaemia or major bleeding) was assessed in this subgroup. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00093158. FINDINGS: Of the individuals who underwent percutaneous coronary intervention, 2561 received heparin plus glycoprotein IIb/IIIa inhibitors, 2609 received bivalirudin plus glycoprotein IIb/IIIa inhibitors, and 2619 received bivalirudin alone. 26 (0.3%) individuals dropped out or were lost to follow-up. There was no significant difference in the proportion of individuals with composite ischaemia, major bleeding, or net clinical outcomes at 30 days between those who received bivalirudin plus glycoprotein IIb/IIIa inhibitors and those who received heparin plus glycoprotein IIb/IIIa inhibitors (composite ischaemia: 243 [9%] patients vs 210 [8%] patients, p=0.16; major bleeding: 196 [8%] patients vs 174 [7%] patients, p=0.32; net clinical outcomes: 389 [15%] patients vs 341 [13%] patients, p=0.1). Rates of composite ischaemia were much the same in those who received bivalirudin alone and those who received heparin plus glycoprotein IIb/IIIa inhibitors (230 [9%] patients vs 210 [8%] patients, p=0.45); however, there were significantly fewer individuals who experienced major bleeding among those who received bivalirudin alone than among those who received heparin plus glycoprotein IIb/IIIa inhibitors (92 [4%] patients vs 174 [7%] patients, p<0.0001, relative risk 0.52, 95% CI 0.40-0.66), resulting in a trend towards better 30-day net clinical outcomes (303 [12%] patients vs 341 [13%] patients, p=0.057; 0.87, 0.75-1.00). INTERPRETATION: Substitution of unfractionated heparin or enoxaparin with bivalirudin results in comparable clinical outcomes in patients with moderate and high-risk acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors in whom percutaneous coronary intervention is done. Anticoagulation with bivalirudin alone suppresses adverse ischaemic events to a similar extent as does heparin plus glycoprotein IIb/IIIa inhibitors, while significantly lowering the risk of major haemorrhagic complications.

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 alpha 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.

Bivalirudin for patients with acute coronary syndromes.

BACKGROUND: Current guidelines for patients with moderate- or high-risk acute coronary syndromes recommend an early invasive approach with concomitant antithrombotic therapy, including aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors. We evaluated the role of thrombin-specific anticoagulation with bivalirudin in such patients. METHODS: We assigned 13,819 patients with acute coronary syndromes to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. The primary end points were a composite ischemia end point (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding. RESULTS: Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point (7.7% and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point (7.8% and 7.3%, respectively; P=0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%; P=0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97). CONCLUSIONS: In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158 [ClinicalTrials.gov].).

Normokinesia adjacent to left ventricular aneurysm: a differential risk for sudden cardiac death.

BACKGROUND: Following myocardial infarction, the ejection fraction (EF) is an indiscriminate predictor of both non-sudden cardiac death (NSCD) and sudden cardiac death (SCD). However, development of a left ventricular aneurysm (LVA) confers independent risk only for SCD. Thus, we tested the hypothesis that mechanical factors, other than the global left ventricular performance, are causally related to SCD in the presence of LVA. METHODS: A secondary analysis was conducted from a longitudinal, prospective, long-term follow-up cohort study of 66 patients with LVA (diastolic eccentricity and systolic dyskinesia) diagnosed by ventriculography. The left ventricular contour was divided into five segments and contractility scores for the residual myocardium and the segments adjacent to the aneurysm were allocated along with assessment of the EF. A normal adjacent segment was considered present when at least one segment adjacent to the aneurysm exhibited normokinesia. Presence of ventricular tachycardia was documented by Holter recording. RESULTS: At a 5.2-year median follow-up, there were 12 NSCD and 8 SCD. The EF was lower among patients who died vs. survivors (31.5% vs. 39.7%, P=0.01). Patients with NSCD and SCD, exhibited similar EF but disparate residual contractility scores (3.0 vs. 4.1, P<0.004). Among cardiac deaths, a decreasing residual contractility score differentially predicted NSCD (odds ratio=17.06, P<0.03), while a normokinetic adjacent segment differentially predicted SCD (odds ratio=21, P<0.02). Albeit a predictor of both NSCD and SCD, ventricular tachycardia increased markedly the model significance (P<0.004) only when tested with a normokinetic adjacent segment vis-a'-vis SCD. CONCLUSIONS: In the presence of LVA, the contractility of the non-aneurysmal myocardium is a differential predictor of death from pump failure. In contrast, a normal segment adjacent to LVA constitutes an independent and discriminate predictor of SCD, possibly through an arrhythmic substrate linked to the motion discordance between the expanding aneurysm and a normokinetic adjacent myocardium.