Circulation: Cardiovascular Interventions Editors’ Picks

Abstract

HomeCirculation: Cardiovascular InterventionsVol. 6, No. 2Circulation: Cardiovascular Interventions Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation: Cardiovascular Interventions Editors’ PicksMost Important Articles in Anticoagulant Therapy The Editors The Editors Search for more papers by this author Originally published1 Apr 2013https://doi.org/10.1161/CIRCINTERVENTIONS.113.000343Circulation: Cardiovascular Interventions. 2013;6:e21–e25BivalirudinBivalirudin Versus Heparin Plus a Glycoprotein IIb/IIIa Inhibitor in Patients With Non–ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention After Clopidogrel Pretreatment: Pooled Analysis from the ACUITY and ISAR-REACT 4 TrialsSummary: Patients with non–ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention benefit from unfractionated heparin plus abciximab. Bivalirudin, a direct thrombin inhibitor, has improved outcomes of patients with a broad spectrum of acute coronary syndromes as compared with a regimen of heparin plus a glycoprotein IIb/IIIa inhibitor. This pooled analysis of patients in the ACUITY and ISAR-REACT 4 randomized trials, who underwent a percutaneous coronary intervention after clopidogrel treatment, showed a 46% reduction of the bleeding risk with bivalirudin compared with heparin plus a glyocoprotein IIb/IIIa inhibitor. The risk of ischemic complications (a composite of death, myocardial infarction, or urgent target vessel revascularization) was not affected by bivalirudin. The treatment effect of bivalirudin was consistent across various subgroups and not dependent on the type of heparins (unfractionated heparin or enoxaparin) and glycoprotein IIb/IIIa inhibitor (abciximab versus eptifibatide versus tirofiban) assigned in the control group.Conclusions: NACE rates were not significantly different between bivalirudin and heparin plus a GPI in patients with non–ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention after clopidogrel pretreatment. Although no significant difference in efficacy was seen in terms of suppression of adverse ischemic events, bivalirudin was superior to heparin plus a GPI in terms of reducing bleeding events.1Bivalirudin Is a Dual Inhibitor of Thrombin and Collagen-Dependent Platelet Activation in Patients Undergoing Percutaneous Coronary InterventionSummary: Adjunctive therapy during percutaneous coronary intervention (PCI) with the direct thrombin inhibitor bivalirudin is an effective antithrombotic agent. Despite widespread use, the antiplatelet effects of bivalirudin are not well understood. Thrombin, the most potent activator of platelets and arterial thrombosis, exerts its cellular effects by cleaving the G protein-coupled protease-activated receptors PAR1 and PAR4. The authors found that bivalirudin completely blocked thrombin-mediated platelet aggregation in patients undergoing PCI by preventing cleavage of the PAR1 receptor. Bivalirudin also significantly inhibited collagen-mediated platelet aggregation while reducing circulating thrombin-ATIII levels by >50%. These data suggest that, during PCI, bivalirudin has a previously underacknowledged ability to inhibit both thrombin- and collagen-mediated platelet aggregation as well as platelet procoagulant activity. These findings quantify the potent antiplatelet effects of bivalirudin in PCI patients and provide a mechanistic framework to explain the clinical efficacy of this drug documented in large clinical trials.Conclusions: Bivalirudin effectively suppresses thrombin-dependent platelet activation via inhibition of PAR1 cleavage and inhibits collagen-induced platelet procoagulant activity as well as systemic thrombin levels in patients undergoing PCI.2Bivalirudin for Primary Percutaneous Coronary Interventions Outcome Assessment in the Ottawa STEMI RegistrySummary: The HORIZONS AMI trial demonstrated a reduction in bleeding and mortality with bivalirudin use compared with a glycoprotein IIb/IIIa inhibitor and heparin in primary percutaneous coronary intervention. Observational data from the Swedish Coronary Angiography and Angioplasty Registry registry suggest that adding unfractionated heparin to bivalirudin may be beneficial. Direct comparisons of bivalirudin to heparin alone in primary percutaneous coronary intervention are lacking. The current study confirms the efficacy and safety of bivalirudin compared with glycoprotein IIb/IIIa inhibitor and heparin in a real-world contemporary cohort. A benefit of bivalirudin compared with heparin alone could not be demonstrated, highlighting the need for randomized studies between these antithrombotic strategies.Conclusions: Bivalirudin use compared with glycoprotein IIb/IIIa inhibitors plus heparin as an antithrombotic strategy in primary percutaneous coronary intervention results in less major bleeding in contemporary practice. A benefit of bivalirudin compared with heparin could not be established with this registry and requires additional investigations to either confirm or refute.3Prognostic Significance of Elevated Baseline Troponin in Patients With Acute Coronary Syndromes and Chronic Kidney Disease Treated With Different Antithrombotic Regimens: A Substudy From the ACUITY TrialSummary: Patients with chronic kidney disease (CKD) may have elevated troponin levels and decreased troponin clearance. The relationship between baseline troponin elevation and outcomes in patients with CKD and acute coronary syndromes (ACS) has not been established. Patients with CKD and ACS in whom the baseline troponin levels were elevated (compared with normal baseline troponin levels) had greatly increased rates of death and myocardial infarction at 30 days and 1 year, although the magnitude of troponin elevation did not further improve discrimination for death or myocardial infarction beyond any elevation above normal. In these patients, procedural anticoagulation with bivalirudin monotherapy resulted in significant reductions in major bleeding at 30 days while effectively suppressing adverse ischemic events, compared with either heparin or bivalirudin plus a glycoprotein IIb/IIIa inhibitor. These findings demonstrate that baseline troponin elevation is an important prognostic marker in moderate and high-risk patients with ACS and CKD treated with an early invasive strategy.Conclusions: In patients with ACS and CKD, baseline troponin elevation is associated with significantly worse short- and long-term clinical outcomes. Bivalirudin monotherapy safely reduces major bleeding in ACS patients with CKD and baseline troponin elevation.4Bivalirudin Therapy Is Associated With Improved Clinical and Economic Outcomes in ST-Elevation Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention: Results From an Observational DatabaseSummary: In a randomized trial, bivalirudin compared with heparin+glycoprotein IIb/IIIa inhibition is associated with reduced bleeding complications and improved survival during STEMI treated with primary PCI. In a registry population of patients undergoing both elective and urgent PCI, bivalirudin was associated with improved outcomes. Clinical and economic outcomes among STEMI patients outside of clinical trials treated with bivalirudin are unknown. Bleeding complications are reduced with bivalirudin compared with heparin+glycoprotein IIb/IIIa inhibition in a registry population of STEMI patients treated with PCI. Economic outcomes are improved among STEMI patients treated with PCI and bivalirudin.Conclusions: This large real-world retrospective analysis demonstrates that bivalirudin therapy compared with heparin+GPI is associated with a lower rate of inpatient death, inpatient bleeding, and decreased overall in-hospital cost in STEMI patients undergoing PPCI.5WarfarinBleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention: A Nationwide Cohort StudySummary: Uncertainty remains regarding optimal antithrombotic treatment of patients with atrial fibrillation presenting with myocardial infarction or undergoing coronary intervention. Present expert statements (Level C evidence) recommend triple therapy with aspirin, clopidogrel, and vitamin K antagonist, with treatment limited to as short a time as possible because of a perceived greater risk of bleeding with prolonged treatment. In the current study, the authors examined the risk of bleeding associated with different antithrombotic treatment regimens in a nationwide real-life cohort of patients with atrial fibrillation and myocardial infarction and/or coronary intervention. They demonstrated an immediately high risk of bleeding with triple therapy that decreases over time. Nevertheless, the risk was continually elevated in comparison with less intense antithrombotic regimens, which suggests that triple therapy has no safe therapeutic window. No benefit was present for a combined thromboembolic end point of cardiovascular death, myocardial infarction, and ischemic stroke for triple therapy relative to vitamin K antagonist plus a single antiplatelet agent. Until data from randomized trials are available, these results suggest that triple therapy should only be prescribed after careful evaluation of bleeding risk.Conclusions: High risk of bleeding is immediately evident with TT after myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation. A continually elevated risk associated with TT indicates no safe therapeutic window, and TT should only be prescribed after thorough bleeding risk assessment of patients.6Net Clinical Benefit of Warfarin in Patients With Atrial Fibrillation: A Report From the Swedish Atrial Fibrillation Cohort StudySummary: Atrial fibrillation is a major cause of ischemic stroke. Oral anticoagulants give good protection against ischemic stroke, but also increase the risk of bleeding. Intracranial hemorrhage is the most feared complication with high mortality and morbidity. The authors investigated how to maximize the net clinical benefit by balancing ischemic stroke against intracranial hemorrhage in 182 678 patients with atrial fibrillation in the Swedish National Hospital Discharge Register. Patients were classified according to stroke risk (CHADS2 and CHA2DS2-VASc) and bleeding risk (HAS-BLED [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly]). As the risk of ischemic stroke increased, the risk of intracranial hemorrhage and other bleeding also increased. Patients with high bleeding risk scores had more ischemic strokes than bleeding events, and the net clinical benefit favored anticoagulation for almost all patients except those patients with very low embolic risk; the CHA2DS2-VASc was able to identify those patients (3.9% of all patients) who had no net clinical benefit or even some disadvantage from anticoagulant treatment with warfarin.Conclusions: In almost all patients with atrial fibrillation, the risk of ischemic stroke without anticoagulant treatment is higher than the risk of intracranial bleeding with anticoagulant treatment. Analysis of the net benefit indicates that more patients may benefit from anticoagulant treatment.7New Oral AnticoagulantsComparative Efficacy and Safety of New Oral Anticoagulants in Patients With Atrial FibrillationSummary: Dabigatran, an oral thrombin inhibitor, and rivaroxaban and apixaban, oral factor Xa inhibitors, have been found to be safe and effective in reducing stroke risk in patients with atrial fibrillation compared with warfarin. In the absence of data from direct comparisons of these new anticoagulants, adjusted indirect comparison can be used to compare treatment effects using warfarin as a common comparator group. Patients in 3 major warfarin-controlled randomized trials were comparable when limited to those with a CHADS2 score of ≥3. The authors found no statistically significant differences among the 3 drugs in their efficacy in preventing stroke and systemic embolism, although apixaban and dabigatran were numerically superior to rivaroxaban. Apixaban produced statistically significantly fewer major hemorrhages than dabigatran and rivaroxaban.Conclusions: An indirect comparison of new anticoagulants based on existing trial data indicates that in patients with a CHADS2 score ≥3 dabigatran 150 mg, apixaban 5 mg, and rivaroxaban 20 mg resulted in statistically similar rates of stroke and systemic embolism, but apixaban had a lower risk of major hemorrhage compared with dabigatran and rivaroxaban. Until head-to-head trials or large-scale observational studies that reflect routine use of these agents are available, such adjusted indirect comparisons based on trial data are 1 tool to guide initial therapeutic choices.8Efficacy and Safety of the Novel Oral Anticoagulants in Atrial Fibrillation: A Systematic Review and Meta-Analysis of the LiteratureSummary: Novel oral anticoagulants, including direct thrombin inhibitors and factor Xa inhibitors, have been proposed as alternatives to vitamin K antagonists for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The authors conducted a systematic review and a meta-analysis of published and unpublished phase II and III randomized, controlled trials comparing the novel oral anticoagulants with the vitamin K antagonists in patients with atrial fibrillation. They retrieved 12 studies (3 administering dabigatran, 4 administering rivaroxaban, 2 administering apixaban, and 3 administering edoxaban) enrolling >50 000 patients. They found that the novel oral anticoagulants significantly reduced overall mortality, cardiovascular mortality, and stroke or systemic embolism. Furthermore, these drugs showed a trend toward reduced major bleeding, with a significant reduction of intracranial hemorrhage. The novel oral anticoagulants may potentially address some of the limitations of vitamin K antagonists because they have fewer food and drug interactions and a more predictable anticoagulant effect, thus allowing fixed-dose regimens without the need for routine laboratory monitoring. This meta-analysis also provided robust evidence on the overall clinical benefit of the novel oral anticoagulants, suggesting their cost-effectiveness in the real-life healthcare systems.Conclusions: NOACs are associated with an overall clinical benefit compared with vitamin K antagonists. Additional research is required to confirm these findings outside the context of randomized trials.9Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) TrialSummary: The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial in patients with atrial fibrillation and at least 1 additional risk factor for stroke demonstrated that dabigatran 110 mg twice a day compared with warfarin was associated with a similar risk of stroke or systemic embolism and a lower risk of major bleeding, and that dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of stroke or systemic embolism and a similar risk of major bleeding. The effects of dabigatran compared with warfarin on stroke or systemic embolism were consistent in all subgroups examined, but there was a significant treatment-by-age interaction for major bleeding such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years and a similar risk in those aged ≥75 years, whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years and a trend toward higher risk of major bleeding in those aged ≥75 years. The interaction between treatment and age was evident for extracranial bleeding but not for intracranial bleeding, which was consistently reduced with dabigatran compared with warfarin irrespective of age. These results suggest that in patients with atrial fibrillation and at least 1 additional risk factor for stroke who are aged <75 years, the higher dabigatran dose might be preferable, whereas in older patients, the lower dabigatran dose might be considered a means to reduce the risk of bleeding.Conclusions: In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients aged <75 years. In those aged ≥75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin.10Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy SubjectsSummary: Dabigatran and rivaroxaban are new oral anticoagulants that have been evaluated for the prevention and treatment of arterial and venous thrombosis and have subsequently been licensed in the United States, Canada, and Europe for various indications. Both drugs have stable pharmacodynamic profiles, obviating repeated laboratory control and dose adjustments, thereby making them an attractive replacement for vitamin K antagonists such as warfarin. A big disadvantage of these new anticoagulant agents is the lack of a method of reversal in case of major hemorrhage or the need to perform emergency invasive procedures. In the present study, for the first time, the effect of prothrombin complex concentrate was assessed in healthy volunteers who were anticoagulated with either drug. Results from this study show that prothrombin complex concentrate completely and directly reversed the effect of rivaroxaban on the coagulation system, whereas the effect of dabigatran was unaffected. The authors think these results are highly relevant for a broad audience such as cardiologists, physicians, and other specialists treating patients with anticoagulant agents. With both drugs on the market, the risk of severe bleeding complications or the need for reversal in case of emergency surgery is clearly present, and the results from this study, when confirmed in the clinical situation, may serve to guide management for these patients.Conclusions: Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects, but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study.11Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin: Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized TrialSummary: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial demonstrated that dabigatran is well-tolerated and that, compared with warfarin, dabigatran 150 mg BID is more effective at preventing stroke and systemic embolism, whereas dabigatran 110 mg BID is associated with a lower risk of major bleeding. However, because dabigatran does not yet have a specific antidote, and its anticoagulant effect is currently difficult to measure precisely, there is concern that dabigatran may increase the risk of bleeding in patients undergoing invasive procedures, particularly if performed on an emergency basis. The RE-LY trial highlights the importance of this scenario, because 25% of patients underwent at least 1 surgery or invasive procedure within 2 years. This analysis of periprocedural outcomes from RE-LY includes data on >7500 surgeries and procedures, making it the largest evaluation of any anticoagulant strategy in the periprocedural setting. The open-label design of RE-LY allowed a real-world evaluation of the periprocedural management or anticoagulation and demonstrated that dabigatran-treated patients were 4 times more likely to have their procedure completed within 48 hours of the discontinuation of anticoagulation than patients treated with warfarin. Overall, there was no detectable difference in the rate of minor, major, or fatal bleeding between patients treated with warfarin in comparison with either dose of dabigatran, nor was there any difference in the risk of thromboembolic events. In comparison with patients receiving warfarin, the rates of major bleeding with both doses of dabigatran were also similar in the subgroups of patients having major surgery and those having surgery on an emergency basis.Conclusions: Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation.12Dabigatran Versus Warfarin in Patients With Atrial Fibrillation: An Analysis of Patients Undergoing CardioversionSummary: Cardioversion in atrial fibrillation is associated with an increased thromboembolic risk. The current recommendation is therapeutic anticoagulation with warfarin for at least 3 weeks before and 4 weeks after cardioversion; this recommendation is based on small nonrandomized observational and retrospective studies. Dabigatran is a novel oral direct thrombin inhibitor with rapid onset of action (peak levels in 2 hours) and a half-life of 12 to 17 hours. It was recently approved for stroke prevention in atrial fibrillation. The phase 3 Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial demonstrated that dabigatran 150 mg twice daily was superior and dabigatran 110 mg twice daily was noninferior to warfarin for stroke prevention in atrial fibrillation. With 18 113 patients, RE-LY is the largest atrial fibrillation trial and provided a unique opportunity to evaluate the postcardioversion thromboembolic risk in patients who underwent cardioversion. A total of 1983 cardioversions were performed during the RE-LY study: 647, 672, and 664 in the dabigatran 110 mg, dabigatran 150 mg, and warfarin groups, respectively. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin, with or without transesophageal echocardiography guidance. This post hoc analysis is the largest cardioversion experience to date and was the first to evaluate a novel anticoagulant in this setting. It also confirmed the efficacy and safety of warfarin in cardioversion in a large cohort of warfarin-treated patients. The 2 drugs are comparable, and dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion.Conclusions: This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion.13Bleeding RiskValidation of the Bleeding Academic Research Consortium Definition of Bleeding in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary InterventionSummary: Available evidence demonstrates that occurrence of bleeding in patients undergoing percutaneous coronary intervention (PCI) signifies a worse clinical outcome compared with patients who do not bleed. Differences in the bleeding definition represent an important confounding factor that hinders the ascertainment of true bleeding occurrence and its association with clinical outcome and implementation of preventive/reducing strategies. Recently, a consensus report from the Bleeding Academic Research Consortium (BARC) proposed a standardized bleeding definition with a hierarchical approach of describing bleeding severity in patients receiving antithrombotic therapy. The BARC document is a consensus report rather than a data-based analysis and has not yet been validated. In this study, the authors investigated the relationship between bleeding as defined by the BARC consensus document and 1-year mortality in patients undergoing PCI and assessed whether the BARC bleeding definition is superior to Thrombolysis in Myocardial Infarction (TIMI) and Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) bleeding definitions. The study represents a pooled patient-level analysis of 12 459 patients recruited in 6 Intracoronary Stenting and Antithrombotic Regimen (ISAR) clinical trials. The present study found a close association between bleeding defined by BARC and 1-year mortality after PCI. The BARC bleeding definition criteria offer a balanced combination of laboratory and clinical metrics for bleeding recognition and a detailed hierarchical grading system of its severity that is closely associated with increased risk of death up to 1 year after PCI. However, all 3 bleeding definitions (BARC, TIMI, and REPLACE-2) provide comparable prognostic information with respect to 1-year mortality in patients with coronary artery disease undergoing PCI.Conclusions: The present study demonstrated a close association between bleeding events defined according to BARC and 1-year mortality after PCI.14Relation of the HAS-BLED Bleeding Risk Score to Major Bleeding, Cardiovascular Events, and Mortality in Anticoagulated Patients With Atrial FibrillationSummary: Stroke risk is closely related to bleeding risk in patients with atrial fibrillation (AF). Indeed, many risk factors for thromboembolism such as advanced age, uncontrolled hypertension, and history of ischemic heart disease or cerebrovascular disease have also been identified as risk factors for bleeding. In clinical practice, estimation of both stroke and bleeding risks are essential to guide the selection of the most appropriate thromboprophylaxis. Because the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR [international normalized ratio], elderly, drugs/alcohol concomitantly) bleeding score has been demonstrated as useful in assessing major bleeding risk in patients with AF, the authors tested its usefulness for predicting both major bleeding and cardiovascular events in a cohort of anticoagulated patients with AF. The authors recruited 965 consecutive anticoagulated outpatients with permanent or paroxysmal AF who were stabilized for at least 6 months on oral anticoagulation. Follow-up was performed for >2 years, and adverse events were recorded. The HAS-BLED score was predictive for major bleeding events and all-cause mortality and shows a close relationship between thrombosis and bleeding. The main advantage of the HAS-BLED score is that it is simple and user friendly, yet offers useful prediction for bleeding. Additionally, the HAS-BLED score was not designed to simply make clinicians stop prescribing oral anticoagulation in patients with high scores but to identify patients who have to be more carefully managed and reviewed or to highlight the common correctable bleeding risk factors.Conclusions: The HAS-BLED score not only is useful in the assessment of bleeding risk, but also shows some predictive value for cardiovascular events and mortality in anticoagulated patients with AF, consistent with the relationship between thrombosis and bleeding. Nonetheless, the HAS-BLED score has been designed for predicting bleeding risk rather than thrombotic events per se, and specific risk scores for cardiovascular events and mortality should be applied for these events.15FootnotesThe following are highlights from the series, Circulation: Cardiovascular Interventions Topic Review. This series summarizes the most important articles, as selected by the editors, that have been published in the Circulation portfolio. The studies included in this article represent the most noteworthy research in anticoagulant therapy. (Circ Cardiovasc Interv. 2013;6:e21–e25.)Correspondence to The Editors, Circulation: Cardiovascular Interventions Editorial Office, 560 Harrison Ave, Suite 502, Boston, MA 02118. E-mail [email protected]