Artery Bypass Graft-related Major Bleeding Research Articles

Usefulness of Rivaroxaban for Secondary Prevention of Acute Coronary Syndrome in Patients With History of Congestive Heart Failure (from the ATLAS-ACS-2 TIMI-51 Trial)

Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study.

Radial versus femoral access and bivalirudin versus unfractionated heparin in invasively managed patients with acute coronary syndrome (MATRIX): final 1-year results of a multicentre, randomised controlled trial

The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme. MATRIX was a programme of three nested, randomised, multicentre, open-label, superiority trials in patients with acute coronary syndrome in 78 hospitals in Italy, the Netherlands, Spain, and Sweden. Patients with ST-elevation myocardial infarction were simultaneously randomly assigned (1:1) before coronary angiography to radial or femoral access and to bivalirudin, with or without post-percutaneous coronary intervention infusion or unfractionated heparin (one-step inclusion). Patients with non-ST-elevation acute coronary syndrome were randomly assigned (1:1) before coronary angiography to radial or femoral access and, only if deemed eligible to percutaneous coronary intervention after angiography (two-step inclusion), entered the antithrombin type and treatment duration programmes. Randomisation sequences were computer generated, blocked, and stratified by intended new or current use of P2Y12 inhibitor (clopidogrel vs ticagrelor or prasugrel), and acute coronary syndrome type (ST-elevation myocardial infarction, troponin-positive, or troponin-negative non-ST-elevation acute coronary syndrome). Bivalirudin was given as a bolus of 0·75 mg/kg, followed immediately by an infusion of 1·75 mg/kg per h until completion of percutaneous coronary intervention. Heparin was given at 70-100 units per kg in patients not receiving glycoprotein IIb/IIIa inhibitors, and at 50-70 units per kg in patients receiving glycoprotein IIb/IIIa inhibitors. Clinical follow-up was done at 30 days and 1 year. Co-primary outcomes for MATRIX access and MATRIX antithrombin type were major adverse cardiovascular events, defined as the composite of all-cause mortality, myocardial infarction, or stroke up to 30 days; and net adverse clinical events, defined as the composite of non-coronary artery bypass graft-related major bleeding, or major adverse cardiovascular events up to 30 days. The primary outcome for MATRIX treatment duration was the composite of urgent target vessel revascularisation, definite stent thrombosis, or net adverse clinical events up to 30 days. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01433627. Between Oct 11, 2011, and Nov 7, 2014, we randomly assigned 8404 patients to receive radial (4197 patients) or femoral (4207 patients) access. Of these 8404 patients, 7213 were included in the MATRIX antithrombin type study and were randomly assigned to bivalirudin (3610 patients) or heparin (3603 patients). Patients assigned to bivalirudin were included in the MATRIX treatment duration study, and were randomly assigned to post-procedure infusion (1799 patients) or no post-procedure infusion (1811 patients). At 1 year, major adverse cardiovascular events did not differ between patients assigned to radial access compared with those assigned to femoral access (14·2% vs 15·7%; rate ratio 0·89, 95% CI 0·80-1·00; p=0·0526), but net adverse clinical events were fewer with radial than with femoral access (15·2% vs 17·2%; 0·87, 0·78-0·97; p=0·0128). Compared with heparin, bivalirudin was not associated with fewer major adverse cardiovascular (15·8% vs 16·8%; 0·94, 0·83-1·05; p=0·28) or net adverse clinical events (17·0% vs 18·4%; 0·91, 0·81-1·02; p=0·10). The composite of urgent target vessel revascularisation, stent thrombosis, or net adverse clinical events did not differ with or without post-procedure bivalirudin infusion (17·4% vs 17·4%; 0·99, 0·84-1·16; p=0·90). In patients with acute coronary syndrome, radial access was associated with lower rates of net adverse clinical events compared with femoral access, but not major adverse cardiovascular events at 1 year. Bivalirudin with or without post-procedure infusion was not associated with lower rates of major adverse cardiovascular events or net adverse clinical events. Radial access should become the default approach in acute coronary syndrome patients undergoing invasive management. Italian Society of Invasive Cardiology, The Medicines Company, Terumo, amd Canada Research Chairs Programme.

In-Hospital Outcome Comparing Bivalirudin to Heparin in Real-World Primary Percutaneous Coronary Intervention

Randomized controlled trials have shown conflicting results regarding the outcome of bivalirudin in primary percutaneous coronary intervention (PPCI). The aim of this study was to evaluate the in-hospital outcomes of patients receiving heparin or bivalirudin in a real-world setting of PPCI: 7,023 consecutive patients enrolled in the Austrian Acute PCI Registry were included between January 2010 and December 2014. Patients were classified according to the peri-interventional anticoagulation regimen receiving heparin (n = 6430) or bivalirudin (n = 593) with or without GpIIb/IIIa inhibitors (GPIs). In-hospital mortality (odds ratio [OR] 1.13, 95% confidence interval [CI] 0.57 to 2.25, p = 0.72), major adverse cardiovascular events (OR 1.18, 95% CI 0.65 to 2.14, p = 0.59), net adverse clinical events (OR 1.01, 95% CI 0.57 to 1.77, p = 0.99), and TIMI non-coronary artery bypass graft-related major bleeding (OR 0.41, 95% CI 0.09 to 1.86, p = 0.25) were not significantly different between the groups. However, we detected potential effect modifications of anticoagulants on mortality by GPIs (OR 0.12, 95% CI 0.01 to 1.07, p = 0.06) and access site (OR 0.25, 95% CI 0.06 to 1.03, p = 0.06) favoring bivalirudin in femoral access. In conclusion, this large real-world cohort of PPCI, heparin-based anticoagulation showed similar results of short-term mortality compared with bivalirudin. We observed a potential effect modification by additional GPI use and access favoring bivalirudin over heparin in femoral, but not radial, access.

Safety and Efficacy of Bivalirudin in Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: From the REPLACE-2, ACUITY and HORIZONS-AMI Trials

Optimal antithrombotic pharmacotherapy in patients affected by diabetes mellitus (DM) undergoing percutaneous coronary intervention is unclear. We sought to evaluate the safety and efficacy of bivalirudin compared with heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) in patients with DM undergoing percutaneous coronary intervention. We pooled patient-level data from the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events-2, Acute Catheterization and Urgent Intervention Triage strategy, and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trials. The primary efficacy end point was the incidence of major adverse cardiac events, defined as the composite of death, myocardial infarction, or unplanned revascularization at 30days. The primary safety end point was the incidence of 30-day non-coronary artery bypass graft-related major bleeding. All-cause mortality was reported at 30days and 1year. Of the 14,737 patients included in the pooled database, 3,641 (24.7%) had DM. Patients with DM had higher rates of 30-day major bleeding and 30-day and 1-year all-cause mortality. There were no differences in 30-day major adverse cardiac events between bivalirudin versus heparin plus GPI in patients with DM (6.9% vs 7.8%; relative risk [RR] 0.89, 95% CI 0.71 to 1.12) or without DM (7.5% vs 6.7%; RR 1.11, 95% CI 0.97 to 1.27; pinteraction= 0.10). Bivalirudin treatment was associated with reduced risk of major bleeding in similar magnitude in patients with DM (4.3% vs 6.6% RR 0.68, 95% CI 0.51 to 0.89) or without DM (3.2% vs 6.1%; RR 0.51, 95% CI 0.43 to 0.61; pinteraction= 0.15). The hemorrhagic benefit of bivalirudin was noted for both access site- and non-access site-related bleeding. Overall, bivalirudin treatment was associated with a significant 1-year mortality benefit (2.7% vs 3.3%; RR 0.82, 95% CI 0.68 to 0.98; p= 0.03), which was consistent between patients with or without DM (pinteraction= 0.30). In conclusion, compared with heparin plus GPI, bivalirudin was associated with similar 30-day antithrombotic efficacy and better 30-day freedom from bleeding and 1-year mortality, irrespective of diabetic status.

Impact of In-Hospital Major Bleeding on Late Clinical Outcomes After Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction: The HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial

We aimed to investigate the long-term prognosis of patients with in-hospital major bleeding (IHMB). The effect of IHMB on the long-term prognosis of patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction is unknown. Primary PCI was performed in 3,345 (92.9%) of 3,602 patients in the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial; in-hospital protocol-defined non-coronary artery bypass graft-related major bleeding developed in 231 (6.9%). We examined medication use at discharge, mortality, and major adverse cardiovascular events (composite of death, reinfarction, stroke, or ischemic target vessel revascularization) at 3-year follow-up in patients with and without IHMB. At 3-year follow-up, patients with IHMB had higher mortality (24.6% vs. 5.4%, p < 0.0001) and major adverse cardiovascular events (40.3% vs. 20.5%, p < 0.0001). The deleterious effect of major bleeding was observed within 1 month, between 1 month and 1 year, and between 1 and 3 years. IHMB was an independent predictor of mortality (hazard ratio: 2.80; 95% confidence interval: 1.89 to 4.16, p < 0.0001) at 3-year follow up. Patients with IHMB after primary PCI have significantly increased 3-year rates of morbidity and mortality. Further investigation is warranted to understand the mechanisms underlying this relationship and to further improve outcomes in patients with ST-segment myocardial infarction. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966).

Design and rationale of the RadIal Vs. femorAL access for coronary intervention (RIVAL) trial: A randomized comparison of radial versus femoral access for coronary angiography or intervention in patients with acute coronary syndromes

Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes. The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy. This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) non-coronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites. The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS.

Critical appraisal of ticagrelor in the management of acute coronary syndrome

Ticagrelor is a novel P2Y12 receptor antagonist which, like clopidogrel and prasugrel, functions by blocking adenosine diphosphate-mediated platelet aggregation. However, unlike the aforementioned agents, the binding of ticagrelor to this receptor is reversible. Ticagrelor is also believed to mediate some of its beneficial effects by augmenting the effects of adenosine, which is another unique pharmacologic property of this drug. In terms of antiplatelet effect, ticagrelor is more potent than clopidogrel and produces a faster and stronger inhibition of platelet aggregation. This may also be an advantage of ticagrelor over prasugrel, but this has not been adequately studied. Due to the reversible nature of the binding of ticagrelor to the platelet receptor, ticagrelor has a relatively fast offset of effect, with platelet aggregation approaching pretreatment levels about 3 days after discontinuation of therapy. This has advantages in patients requiring invasive procedures, but also makes medication adherence very important in order to be able to maintain an effective antiplatelet effect. Ticagrelor has been shown to be clinically superior to clopidogrel when given to patients with an acute coronary syndrome, resulting in significantly lower rates of myocardial infarction and vascular death. However, ticagrelor is indicated to be administered with aspirin, and the clinical benefits of ticagrelor may be less when daily dosages of aspirin exceed 100 mg. As expected, bleeding is the most common adverse effect with ticagrelor, although it occurs at rates comparable with those seen for clopidogrel with the exception of noncoronary artery bypass graft-related major bleeding and fatal intracranial bleeds, the latter of which occurs only rarely. Dyspnea is another common adverse effect with ticagrelor, although this is usually not severe and resolves with drug discontinuation. Unlike clopidogrel, there are no known pharmacogenomic concerns with ticagrelor, and emerging data suggest ticagrelor to be effective in patients resistant to clopidogrel, although more study is needed on this topic. While preliminary data suggest ticagrelor to be cost effective when compared with generic clopidogrel, the acquisition cost of ticagrelor is not insignificant and this will likely be an issue for many health care organizations. Currently, ticagrelor is well positioned to assume an active role in the treatment of coronary artery disease due to an impressive efficacy profile and reasonable safety. Its ultimate role in therapy will continue to evolve as studies on this drug continue eg, (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin, PEGASUS) and more information hopefully becomes available on its use in clopidogrel nonresponders and relative safety and efficacy compared with prasugrel.