Impact of anticoagulation regimen prior to revascularization in patients with non-ST-segment elevation acute coronary syndromes: The ACUITY trial.

AIM: To evaluate the impact of antithrombotic regimens during the medical phase of treatment among 13,819 patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) treated with an early invasive strategy in the acute catheterization and urgent intervention triage strategy (ACUITY) trial. METHODS AND RESULTS: Endpoints included composite major adverse cardiac events (MACE), major bleeding, and net adverse clinical events (NACE; MACE or major bleeding). The median (interquartile range) duration of antithrombin use in the medical only treatment phase was 6.5 (1.8-22.5) hours. MACE, major bleeding, and NACE during the medical only phase occurred in 63 (0.5%), 117 (0.9%), and 178 (1.3%) patients, respectively. MACE rates in the medical-treatment-only phase were not significantly different between the four randomized medical regimens used (heparin alone, bivalirudin alone, heparin plus a glycoprotein IIb/IIIa inhibitor [GPI], and bivalirudin plus GPI) (Ptrend = 0.65). The lowest rates of major bleeding and NACE during the medical treatment phase occurred in patients treated with bivalirudin alone (Ptrend = 0.0006 and Ptrend = 0.0004, respectively). CONCLUSIONS: In patients with NSTE-ACS undergoing an early invasive strategy, treatment with bivalirudin alone significantly reduced major bleeding and improved net clinical outcomes during the upstream medical management phase with comparable rates of MACE. © 2015 Wiley Periodicals, Inc.

Perindopril and ß-blocker for the prevention of cardiac events and mortality in stable coronary artery disease patients: A EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) subanalysis.

BACKGROUND: ß-Blockers relieve angina/ischemia in stable coronary artery disease (CAD), and angiotensin-converting enzyme inhibitors prevent CAD outcomes. In EUROPA, the angiotensin-converting enzyme inhibitor perindopril reduced cardiovascular outcomes in low-risk stable CAD patients over 4.2 years. This post hoc analysis examined whether the addition of perindopril to ß-blocker in EUROPA had additional benefits on outcomes compared with standard therapy including ß-blocker. METHODS: EUROPA was a multicenter, double-blind, placebo-controlled, randomized trial in patients with documented stable CAD. Randomized EUROPA patients who received ß-blocker at baseline were identified, and the effect on cardiovascular outcomes of adding perindopril or placebo was analyzed. Endpoints were the same as those in EUROPA. RESULTS: At baseline, 62% (n = 7534 [3789 on perindopril and 3745 on placebo]) received ß-blocker. Treatment with perindopril/ß-blocker reduced the relative risk of the primary end point (cardiovascular death, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 24% compared with placebo/ß-blocker (HR, 0.76; 95% CI, 0.64-0.91; P = .002). Addition of perindopril also reduced fatal or nonfatal myocardial infarction by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and hospitalization for heart failure by 45% (HR, 0.55; 95% CI, 0.33-0.93; P = .025). Serious adverse drug reactions were rare in both groups, and cardiovascular death and hospitalizations occurred less often with perindopril/ß-blocker. CONCLUSIONS: The addition of perindopril to ß-blocker in stable CAD patients was safe and resulted in reductions in cardiovascular outcomes and mortality compared with standard therapy including ß-blocker.

Automated 3D analysis of multislice computed tomography to define the line of perpendicularity of the aortic annulus and of the implanted valve: benefit on planning transcatheter aortic valve replacement.

AIMS: We aimed to determine whether preprocedural analysis of multislice computed tomography (MDCT) scan could accurately predict the "line of perpendicularity" (LP) of the aortic annulus and corresponding C-arm angulations required for prosthesis delivery. METHODS AND RESULTS: A 3D analysis of preprocedural MDCT dedicated to define the LP of the aortic annulus was performed in 60 consecutive patients referred for transcatheter aortic valve replacement (TAVR). In 24 patients, the analysis was performed retrospectively to evaluate reproducibility. In 11 patients of this cohort, additional fluoroscopy and MDCT were performed postprocedure to compare the LP of the aortic annulus and the LP of the implanted bioprosthesis. In 36 patients, the analysis was performed prospectively and the results were available at the time of the procedure. In those 36 patients, the postprocedure fluoroscopy-defined LP of the implanted bioprosthesis was used to validate the LP of the aortic annulus as predicted by MDCT. Intraobserver and interobserver reproducibility of the 3D analysis of MDCT to define the LP of the aortic annulus (κ = 1 and 0.94, respectively) and of the bioprosthesis (κ= 1 and 1, respectively) were excellent. Comparison between the LP of the aortic annulus and the LP of the bioprosthesis showed that the two LPs were virtually identical, demonstrating both self-centering of the device during implantation and the possibility to use the LP of the implanted bioprosthesis as a surrogate of the LP of the aortic annulus. In the prospective cohort, the ability of MDCT analysis to predict the LP of the aortic annulus was very good (accuracy = 94% and κ = 0.89). CONCLUSION: Automated 3D analysis of preimplantation MDCT accurately predicts the LP of the aortic annulus and the corresponding C-arm position required for TAVR.

The Future REvascularization Evaluation in patients with Diabetes mellitus: optimal management of Multivessel disease (FREEDOM) trial: clinical and angiographic profile at study entry.

BACKGROUND: The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy. METHODS: A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients. RESULTS: The randomized cohort was 63.1 ± 9.1 years old and 29% female, with a median diabetes duration of 10.2 ± 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 ± 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 ± 1.7 mg/dL, 29% had low-density lipoprotein <70 mg/dL, and mean systolic blood pressure was 134 ± 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts. CONCLUSIONS: The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD.

Predictors of outcomes in medically treated patients with acute coronary syndromes after angiographic triage: an Acute Catheterization And Urgent Intervention Triage Strategy (ACUITY) substudy.

BACKGROUND: Outcomes of patients presenting with acute coronary syndromes are improved with an early invasive approach; however, approximately one third of these patients are treated medically after angiographic screening. We sought to assess the predictors of adverse cardiac events in patients with acute coronary syndrome assigned to medical management. METHODS AND RESULTS: This substudy of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial included 4491 acute coronary syndrome patients treated medically after angiographic triage. Rates of bleeding and composite ischemia (death, myocardial infarction, revascularization) were compared among the 3 antithrombotic treatment arms. Composite ischemia occurred in 399 patients (9.5%) at 1 year. Treatment with bivalirudin glycoprotein IIb/IIIa inhibitors significantly reduced major bleeding at 30 days (2.5% bivalirudin monotherapy; P=0.005, 2.0% bivalirudin plus glycoprotein IIb/IIIa inhibitors; P=0.0002 versus 4.4% heparin with glycoprotein IIb/IIIa inhibitors). Composite ischemic events at 1 year were not significantly different in the 3 groups (bivalirudin monotherapy, 9.6%; bivalirudin plus glycoprotein IIb/IIIa inhibitors, 9.7%; heparin plus glycoprotein IIb/IIIa inhibitors, 9.1%). Independent predictors of composite ischemia were mostly angiographic factors at 30 days, including jeopardy score and coronary ectasia, and at 1 year, including previous percutaneous coronary intervention, jeopardy score, coronary ectasia, and increasing number of diseased vessels. CONCLUSIONS: Among the ACUITY acute coronary syndrome patients treated medically after angiographic triage, bivalirudin therapy significantly reduced bleeding complications compared with heparin without any negative impact on ischemic outcomes at 1 year. The most powerful predictors of ischemic outcomes were angiographic rather than traditional clinical parameters, supporting the early use of angiographic screening in the moderate- and high-risk but medically treated acute coronary syndrome population. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00093158.

Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial.

BACKGROUND: Both ischemic and hemorrhagic complications increase mortality rate in acute coronary syndromes. Their frequency and relative importance vary according to individual patient risk profiles. We sought to develop prognostic models for the risk of myocardial infarction (MI) and major bleeding to assess their impact on risk of death and to examine the manner in which alternative antithrombotic regimens affect these risks in individual patients. METHODS AND RESULTS: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial randomized 13 819 patients with acute coronary syndrome to heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. By logistic regression, there were 5 independent predictors of MI within 30 days (n=705; 5.1%) and 8 independent predictors of major bleeding (n=645; 4.7%), only 2 of which were common to both event types. In a covariate-adjusted, time-updated Cox regression model, both MI and major bleeding significantly affected subsequent mortality rate (hazard ratios, 2.7 and 2.9, respectively; both P<0.001). Treatment with bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor was associated with a nonsignificant 8% increase in MI and a highly significant 50% decrease in major bleeding. Given the individual patient risk profiles and the fact that bivalirudin prevented approximately 6 major bleeds for each MI that might occur from its use, the estimated reduction in bleeding was greater than the estimated increase in MI by bivalirudin alone rather than heparin plus a glycoprotein IIb/IIIa inhibitor for nearly all patients. CONCLUSIONS: Consideration of the individual patient risk profile for MI and major bleeding and the relative treatment effects of alternative pharmacotherapies permits personalized decision making to optimize therapy of patients with acute coronary syndrome. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00093158.

Measuring and targeting aldosterone and renin in atherosclerosis-a review of clinical data.

Our understanding of the development and progression of atherosclerosis has increased substantially over the past decades. A significant role for the renin-angiotensin-aldosterone system (RAAS) in this process has gained appreciation in recent years. Preclinical and clinical studies have associated components of the RAAS with various cardiovascular disease conditions. Classically known for its contribution to hypertension, dysregulation of the system is now also believed to promote vascular inflammation, fibrosis, remodeling, and endothelial dysfunction, all intimately related to atherosclerosis. The reduction in cardiovascular mortality and morbidity, as seen with the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, supports the concept that RAAS is involved in the pathogenesis of atherosclerotic disease. However, the underlying molecular mechanisms of the pathophysiology remain to be completely understood. Evidence points toward additional benefit from therapeutic approaches aiming at more complete inhibition of the system and the possible utility of renin or aldosterone in the prediction of cardiovascular outcome. This review will summarize the current knowledge from clinical studies regarding the presumptive role of renin and aldosterone in the prediction and management of patients with atherosclerosis. For this purpose, a literature search was performed, focusing on available clinical data regarding renin or aldosterone and cardiovascular outcome.

Impact of chronic antiplatelet therapy before hospitalization on ischemic and bleeding events in invasively managed patients with acute coronary syndromes: the ACUITY trial.

AIMS: Presentation with an acute coronary syndrome (ACS) on chronic aspirin therapy is an independent predictor of adverse short-term outcomes. Whether this finding applies to chronic thienopyridine use, and with the contemporary invasive management of ACS, is unknown. METHODS AND RESULTS: In ACUITY, 13819 patients with moderate and high-risk ACS were studied; patients transferred from an outside hospital were excluded from the present analysis, given uncertain preadmission antiplatelet status. Endpoints included major adverse cardiovascular events (MACE: death, myocardial infarction, or unplanned revascularization), major bleeding, and net adverse clinical events (NACE). Among 11313 study patients, 31 % were naive for antiplatelet agent, 49% were receiving aspirin alone, and 20% were on dual antiplatelet therapy. Chronic antiplatelet users were older and had a higher risk profile. After adjusting for baseline differences, chronic antiplatelet therapy (single or dual) was not associated with an increased incidence of 30-day MACE, bleeding, or NACE. However, patients on chronic aspirin or dual antiplatelet therapy at presentation had significantly higher 1-year rates of MACE [odds ratio (95% confidence interval) = 1.17 (1.01­1.36), P = 0.03 and 1.29 (1.02­1.64), P = 0.03, respectively]. Patients presenting on dual antiplatelet therapy had significantly greater adjusted MACE at 1-year than those on aspirin alone [odds ratio (95% confidence interval) = 1.34 (1.15­1.56), P < 0.0001]. CONCLUSION: Contrary to earlier studies, prior antiplatelet therapy was not associated with an increased risk of adverse outcomes at 30 days in invasively managed patients. Such use did, however, independently predict 1-year ischemic MACE, with outcomes worse for patients presenting on chronic dual antiplatelet therapy compared with aspirin alone.

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.

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.

Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study.

BACKGROUND: The purposes of the study were to determine the effects of addition of perindopril to long-term continuous treatment with calcium-channel blocker (CCB) on cardiac outcomes in the stable coronary artery disease (CAD) population of EUROPA and to explore the presence of synergy between perindopril and CCB in secondary prevention. METHODS: We identified participants receiving CCB at every visit during the 4.2-year follow-up and analyzed the effect of addition of perindopril (n = 1,022 perindopril/CCB vs n = 1,100 placebo/CCB). RESULTS: Addition of perindopril to CCB significantly reduced total mortality by 46% (P < .01 vs placebo) and primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P < .05 vs placebo). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively. Comparison of hazard ratios suggests the presence of a clinical synergy between perindopril and CCB, with a greater effect than addition of individual effects. CONCLUSION: Addition of perindopril to CCB in stable CAD patients had a significant supplementary impact on cardiac outcomes and mortality.

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].).

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.

Efficacy of perindopril in reducing risk of cardiac events in patients with revascularized coronary artery disease.

BACKGROUND: The aim of the study was to assess the effect on cardiac events of adding perindopril 8 mg once daily to standard preventive therapy in the subgroup of EUROPA patients with previous revascularization and without previous myocardial infarction (MI). METHODS: We conducted a subgroup analysis of the EUROPA study patients according to their revascularization and previous MI history. Among the 12,218 patients of EUROPA, we identified 6709 (54.9%) patients who had a previous revascularization. Approximately equal proportions had undergone percutaneous coronary intervention (3122) or coronary artery bypass grafting (3136). Of the revascularized patients, 3047 (24.9%) patients had not experienced a previous MI. RESULTS: Out of the 6709 revascularized patients, 3340 were treated with perindopril and 3369 with placebo. Baseline characteristics were similar to the whole EUROPA population in terms of demographics, medical history, physical examination (heart rate, blood pressure), and medications at screening. The mean patient age was 60 years, and 85% were men. The relative risk reduction with perindopril 8 mg was 17.3% (95% CI 1.3%-30.8%, P = .035) for the composite primary end point of cardiovascular death, nonfatal MI, and resuscitated cardiac arrest and was 23% (95% CI 4.9%-37.6%, P = .015) for fatal and nonfatal MI. In the 3047 revascularized patients without a history of MI, perindopril was associated with a relative risk reduction of 31.7% for fatal and nonfatal MI (95% CI 4.4%-51.2%, P = .026). CONCLUSION: Perindopril 8 mg daily is beneficial for primary and secondary prevention of cardiac events in patients with coronary artery disease without clinical evidence of heart failure including those with previous revascularization.

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.

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.

Diabetes does not influence treatment decisions regarding revascularization in patients with stable coronary artery disease.

OBJECTIVE: To evaluate whether in stable angina preference for coronary revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) is influenced by diabetes status and whether this has prognostic implications. RESEARCH DESIGN AND METHODS: A total of 2,928 consecutive patients with stable angina who were enrolled in the prospective Euro Heart Survey on Coronary Revascularization were studied. Multivariable analyses were applied to evaluate the relation between diabetes, treatment decision, and 1-year outcome. RESULTS: Diabetes was documented in 587 patients (20%) who had more extensive coronary disease. Revascularization was intended in 74% of patients with diabetes and in 77% of those without diabetes. In patients selected for revascularization, CABG was intended in 35% of diabetic and in 33% of nondiabetic patients. Multivariable analyses did not change these findings, but in some subgroups diabetes influenced treatment decisions. For example, diabetic subjects with mild heart failure had more often intended revascularization (91%) than those without diabetes (67%, P < 0.001). Treatment decisions in patients with more extensive (left main, multivessel, or proximal left anterior descending artery) disease were not influenced by diabetes status. Diabetes was not associated with an increased incidence of all-cause death, nonfatal cerebrovascular accident, or nonfatal myocardial infarction at 1 year, regardless of preferred treatment. The incidence of the combined end points was 7.3% in diabetic and 6.8% in nondiabetic patients (adjusted hazard ratio 1.0 [95% CI 0.7-1.4]). CONCLUSIONS: In stable angina, treatment decisions regarding revascularization or the choice for CABG or PCI were not influenced by the presence of diabetes. Diabetes was not associated with a poor prognosis.

Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin, Perindopril, and Amlodipine.

Statins, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs) have markedly changed the clinical progression of patients with coronary artery disease (CAD). The goal of this paper is to review the rationale and evidence for combining these three drug classes in hypertensive patients with hypercholesterolemia or CAD. Data sources include a literature search for publications on the use of a statin combined with various antihypertensive drugs in patients with hypertension and hypercholesterolemia or stable CAD. Hypercholesterolemia and hypertension constitute major physiological risk factors of ischemic heart disease. Current guidelines recommend a global approach to risk management, using agents that address as many risk factors as possible. Dual combination therapies are an important component of guideline-recommended therapy in hypertension. Our review of the literature indicates that triple therapy with a statin, ACE inhibitor, and CCB is associated with a significant reduction in major cardiovascular events. For example, a post hoc analysis in 1056 patients with stable CAD participating in the EUROPA trial indicated that the addition of perindopril to a CCB and a lipid-lowering agent was associated with a 46 % reduction in the composite of cardiovascular death, myocardial infarction, and resuscitated cardiac arrest (p = 0.023). In addition, single pill formulations are known to result in better adherence to the treatment. Single-pill formulations that combine a statin, an ACE inhibitor, and a CCB appear to offer an effective approach to the management of global cardiovascular risk.

Individualized Angiotensin-Converting Enzyme (ACE)-Inhibitor Therapy in Stable Coronary Artery Disease Based on Clinical and Pharmacogenetic Determinants: The PERindopril GENEtic (PERGENE) Risk Model.

BACKGROUND: Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model. METHODS AND RESULTS: Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective. CONCLUSIONS: Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit.