Urgent Intervention Triage Strategy Research Articles

Reperfusion After Fibrinolytic Therapy (RAFT): An open-label, multi-centre, randomised controlled trial of bivalirudin versus heparin in rescue percutaneous coronary intervention.

BackgroundThe safety and efficacy profile of bivalirudin has not been examined in a randomised controlled trial of patients undergoing rescue PCI.ObjectivesWe conducted an open-label, multi-centre, randomised controlled trial to compare bivalirudin with heparin ± glycoprotein IIb/IIIa inhibitors (GPIs) in patients undergoing rescue PCI.MethodsBetween 2010–2015, we randomly assigned 83 patients undergoing rescue PCI to bivalirudin (n = 42) or heparin ± GPIs (n = 41). The primary safety endpoint was any ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) bleeding at 90 days. The primary efficacy endpoint was infarct size measured by peak troponin levels as a multiple of the local upper reference limit (Tn/URL). Secondary endpoints included periprocedural change in haemoglobin adjusted for red cells transfused, TIMI (Thrombolysis in Myocardial Infarction) bleeding, ST-segment recovery and infarct size determined by the Selvester QRS score.ResultsThe trial was terminated due to slow recruitment and futility after an interim analysis of 83 patients. The primary safety endpoint occurred in 6 (14%) patients in the bivalirudin group (4.8% GPIs) and 3 (7.3%) in the heparin ± GPIs group (54% GPIs) (risk ratio, 1.95, 95% confidence interval [CI], 0.52–7.3, P = 0.48). Infarct size was similar between the two groups (mean Tn/URL, 730 [±675] for bivalirudin, versus 984 [±1585] for heparin ± GPIs, difference, 254, 95% CI, -283-794, P = 0.86). There was a smaller decrease in the periprocedural haemoglobin level with bivalirudin than heparin ± GPIs (-7.5% [±15] versus -14% [±17], difference, -6.5%, 95% CI, -0.83–14, P = 0.0067). The rate of complete (≥70%) ST-segment recovery post-PCI was higher in patients randomised to heparin ± GPIs compared with bivalirudin.ConclusionsWhether bivalirudin compared with heparin ± GPI reduces bleeding in rescue PCI could not be determined. Slow recruitment and futility in the context of lower-than-expected bleeding event rates led to the termination of this trial (ANZCTR.org.au, ACTRN12610000152022).

Comparison of standard versus ultrasound guidance in radial and femoral access: a subanalysis of the randomised SURF trial

Abstract Background Ultrasound (US) guidance in facilitating arterial access may reduce vascular complications and possible bleeding. There are still limited trials assessing real-time US guidance for coronary angiography. The SURF (Standard versus ultrasound-guided radial and femoral access in coronary angiography and intervention) trial showed no difference in primary outcome when the combined radial and femoral ultrasound analysis compared with standard (SD) technique, but significantly improved access efficiency and success rate. Purpose This subanalysis compared clinical and procedural outcomes of the individual radial and femoral access with US guidance versus standard technique. Methods Patients (n=1388) undergoing coronary angiography and percutaneous coronary intervention were randomised (1:1) into radial or femoral access, and (1:1) to SD or US guidance. The primary outcome was a composite of ACUITY (Acute Catheterisation and Urgent Intervention Triage strategY) major bleeding, MACE (death, stroke, myocardial infarction or urgent target lesion revascularisation) and vascular complications at 30 days. Secondary outcomes were access time, number of attempts, venepuncture, difficult accesses and first-pass success. Results Compared to standard, US guidance produced no difference in composite endpoint for both radial (1.4% vs 1.2%, p=0.78) and femoral (3.1% vs 3.8%, p=0.65) accesses. ACUITY major bleeding (radial: 0.9% US vs 0.6% SD, p=0.69; femoral: 1.9% US vs 2.3% SD, p=0.69), vascular complications (radial: 0.3% US vs 0.3% SD, p=0.98; femoral: 1.3% US vs 0.9% SD, p=0.63) and MACE (radial: 0.6% US vs 0.3% SD, p=0.59; femoral: 0.9% US vs 1.2% SD, p=0.78) were similar in the US and SD approaches, respectively. However, US guidance resulted in improved procedural outcomes for both accesses. Femoral access derived the most benefit from US, with reduced mean access time (73 sec vs 97 sec, p=0.006), attempts (1.35 vs 1.84, p≤0.0001), difficult accesses (1.8% vs 6.2%, p=0.004), venepuncture (5.8% vs 12.6%, p=0.002) and improved first-pass success (77.2% vs 58.8%, p≤0.0001). For radial, US reduced attempts (1.59 vs 1.97, p=0.0007), difficult accesses (6.9% vs 12.3%, p=0.02), venepuncture (2.5% vs 5.6%, p=0.04) and improved first-pass success (69.2% vs 60.7%, p=0.02). There was no difference in radial mean access time (111 sec vs 126 sec, p=0.18). Conclusions US guidance in radial and femoral access did not reduce primary outcome compared to standard technique. The use of US significantly improved the efficiency and success rate of arterial cannulation, with femoral access derived the most benefit. Funding Acknowledgement Type of funding source: None

Meta-Analysis of Bleeding Scores Performance for Acute Coronary Syndrome

Bleeding is a common and frequently devastating complication in acute coronary syndrome (ACS). It is critical to evaluate in the current era of ACS management involving invasive strategies and potent anti-thrombotics. Risk models remain under-utilised in this setting but may guide the choice and duration of therapy. We compared their performances for predicting bleeding in ACS patients in this meta-analysis. Medline, EMBASE, Cochrane and Scopus were searched for relevant articles from 1980 to 31 December 2017 assessing external validation of risk scores for bleeding after ACS. Two (2) authors independently reviewed the searched studies for eligibility, followed by pooled analyses using random effects models. Amongst 1,843 articles searched, 73 full-texts were reviewed and 17 studies totalling 18,155 patients were included for analysis. C-statistics (95% confidence interval) for predicting in-hospital major bleeding by risk model were Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) 0.714 (0.659-0.779), Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) 0.711 (0.626-0.797), Acute Coronary Treatment and Intervention Outcomes Network (ACTION) 0.767 (0.737-0.797), Global Registry of Acute Coronary Events (GRACE) 0.689 (0.473-0.905) and HAS-BLED 0.636 (0.460-0.812). CRUSADE also predicted bleeding during medium-term follow-up c=0.704 (0.644-0.765). It performed better for radial versus femoral access (c=0.826 and 0.734), invasive versus non-invasive strategy (c=0.752 and 0.625) and similarly for ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) (c=0.791 and 0.760). Heterogeneities of studies and paucity of studies assessing risk scores beyond CRUSADE were important limitations. Acute coronary syndrome-specific bleeding scores had moderate discrimination for bleeding, while the GRACE and HAS-BLED scores could not. The ACTION score had the highest pooled c-statistic, while the CRUSADE score was the most widely studied, and also performed better for invasive strategy and radial access subgroups.

Safety and efficacy of bivalirudin monotherapy in patients with non-ST-segment elevation acute coronary syndromes with positive biomarkers undergoing percutaneous coronary intervention: a report from the Acute Catheterization and Urgent Intervention Triage Strategy trial

There are limited data on bivalirudin monotherapy in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) with positive biomarkers of myocardial necrosis (troponin and/or creatine kinase-myocardial band isoenzyme). We sought to evaluate the safety and efficacy of bivalirudin monotherapy in patients with positive biomarkers from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. We compared the net adverse clinical events [composite ischemia - (death, myocardial infarction, or unplanned ischemic revascularization) - or noncoronary artery bypass graft surgery (CABG)-related major bleeding] among patients with biomarker-positive NSTE-ACS in the ACUITY trial overall and by antithrombotic strategy. Among 13 819 patients with NSTE-ACS enrolled in ACUITY, 4728 patients presented with positive biomarkers and underwent an early invasive strategy. Of those, 1547 were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), 1555 to bivalirudin plus GPI, and 1626 to bivalirudin monotherapy. Compared with biomarker-negative patients, biomarker-positive patients had higher 30-day rates of net adverse clinical events (14.0 vs. 12.4%; P = 0.04), all-cause death (1.3 vs. 0.5%; P = 0.001), cardiac death (1.1 vs. 0.5%; P = 0.005), and non-CABG-related major bleeding (6.5 vs. 5.2%, P = 0.03). At 30 days, bivalirudin monotherapy was associated with significantly less non-CABG-related major bleeding (bivalirudin monotherapy 4.1% vs. bivalirudin plus GPI 8.4% vs. heparin plus GPI 7.1%) with comparable rates of composite ischemia (bivalirudin monotherapy 9.2% vs. bivalirudin plus GPI 9.9% vs. heparin plus GPI 8.4%). In a multivariable model, bivalirudin monotherapy was associated with a significant reduction in non-CABG-related major bleeding but was not associated with an increased risk of death, myocardial infarction, unplanned revascularization or stent thrombosis. Compared with heparin plus GPI or bivalirudin plus GPI, bivalirudin monotherapy provides similar protection from ischemic events with less major bleeding at 30 days among patients with NSTE-ACS and positive biomarkers.

Standard versus ultrasound-guided radial and femoral access in coronary angiography and intervention (SURF): a randomised controlled trial.

This study aimed to compare outcomes in unselected patients undergoing cardiac catheterisation via transradial versus transfemoral access and standard versus ultrasound-guided arterial access. This was a prospective, randomised (radial vs. femoral and standard vs. ultrasound), 2x2 factorial trial of 1,388 patients undergoing coronary angiography and percutaneous coronary intervention. The primary outcome was a composite of ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) major bleeding, MACE (death, stroke, myocardial infarction or urgent target lesion revascularisation) and vascular complications at 30 days. Transradial access reduced the primary outcome (RR 0.37, 95% CI: 0.17-0.81; p=0.013), mostly driven by ACUITY major bleeding (RR 0.343, 95% CI: 0.123-0.959; p=0.041) when compared with the transfemoral approach. There was no difference in the primary outcome between standard and ultrasound guidance (p=0.76). Ultrasound guidance, however, reduced mean access time (93 sec vs. 111 sec; p=0.009), attempts (1.47 vs. 1.9; p<0.0001), difficult accesses (4.5% vs. 9.2%; p=0.0007), venepuncture (4.1% vs. 9.2%; p<0.0001) and improved first-pass success (73% vs. 59.7%; p<0.0001). Transradial access significantly reduced the composite outcome compared to transfemoral access. Ultrasound guidance did not reduce the primary outcome compared to the standard technique, but significantly improved the efficiency and overall success rate of arterial access.

Cangrelor or Clopidogrel in Patients with Type 2 Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials.

IntroductionWith recent advances in interventional cardiology where percutaneous coronary intervention (PCI) has become the most preferred invasive strategy and with advances in adjunctive pharmacotherapy, several newer oral P2Y12 inhibitors have reached the market. In this analysis, we aimed to compare the cardiovascular outcomes and bleeding events which were associated with the use of cangrelor versus clopidogrel in patients with type 2 diabetes mellitus (T2DM) 48 h after PCI. MethodsThe electronic databases MEDLINE (PubMed), www.ClinicalTrials.gov, EMBASE, and Cochrane central were searched for relevant publications comparing canagrelor with clopidogrel during PCI. Patients with T2DM were extracted. Adverse cardiovascular outcomes and bleeding events at 48 h follow-up were considered as the end points. This meta-analysis was carried out with the latest RevMan software (5.30). Odds ratios (OR) and 95% confidence intervals (CI) were used to represent the data.ResultsThis analysis consisted of a total number of 5031 participants with T2DM (enrolled between the years 2006 and 2012). Compared to clopidgrel, use of cangrelor in these patients with T2DM was not associated with significantly different primary end point (OR 0.94, 95% CI 0.75–1.16; P = 0.55), myocardial infarction (OR 0.96, 95% CI 0.76–1.20; P = 0.71), all-cause death (OR 0.70, 95% CI 0.25–1.96; P = 0.49), ischemia-driven revascularization (OR 0.66, 95% CI 0.32–1.36; P = 0.26), and stent thrombosis (OR 0.45, 95% CI 0.17–1.17; P = 0.10). Thrombolysis in myocardial infarction (TIMI)-defined major and minor bleedings were similarly manifested: (OR 1.02, 95% CI 0.38–2.74; P = 0.96) and (OR 1.39, 95% CI 0.70–2.79; P = 0.35), respectively. Global use of strategies to open occluded arteries (GUSTO)-defined moderate and severe bleeding were also not significantly different: (OR 1.36, 95% CI 0.70–2.67; P = 0.37) and (OR 1.21, 95% CI 0.41–3.59; P = 0.74), respectively. However, GUSTO-defined mild bleeding and acute catheterization and urgent intervention triage strategy (ACUITY)-defined major and minor bleedings were significantly in favor of clopidogrel in comparison to cangrelor in these patients with T2DM: (OR 1.28, 95% CI 1.09–1.50; P = 0.003), (OR 1.43, 95% CI 1.05–1.94; P = 0.02), and (OR 1.23, 95% CI 1.04–1.46; P = 0.02), respectively. Other bleeding outcomes were not significantly different.ConclusionsIn these patients with T2DM, cangrelor was comparable to clopidogrel in terms of efficacy at 48 h following PCI. However, it was associated with significantly higher mild GUSTO bleeding and major and minor ACUITY bleeding, therefore requiring further workups on its safety side. This hypothesis should be explored further and confirmed in other forthcoming trials based strictly on patients with T2DM.

Evaluation of CRUSADE and ACUITY-HORIZONS Scores for Predicting Long-term Out-of-Hospital Bleeding after Percutaneous Coronary Interventions.

Background:There is scanty evidence concerning the ability of Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) and Acute Catheterization and Urgent Intervention Triage Strategy and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (ACUITY-HORIZONS) scores to predict out-of-hospital bleeding risk after percutaneous coronary interventions (PCIs) with drug-eluting stents (DES) in patients receiving dual antiplatelet therapy. We aimed to assess and compare the long-term prognostic value of these scores regarding out-of-hospital bleeding risk in such patients.Methods:We performed a prospective observational study of 10,724 patients undergoing PCI between January and December 2013 in Fuwai Hospital, China. All patients were followed up for 2 years and evaluated through the Fuwai Hospital Follow-up Center. Major bleeding was defined as Types 2, 3, and 5 according to Bleeding Academic Research Consortium Definition criteria.Results:During a 2-year follow-up, 245 of 9782 patients (2.5%) had major bleeding (MB). CRUSADE (21.00 [12.00, 29.75] vs. 18.00 [11.00, 26.00], P < 0.001) and ACUITY-HORIZONS (9.00 [3.00, 14.00] vs. 6.00 [3.00, 12.00], P < 0.001) risk scores were both significantly higher in the MB than non-MB groups. Both scores showed a moderate predictive value for MB in the whole study cohort (area under the receiver-operating characteristics curve [AUROC], 0.565; 95% confidence interval [CI], 0.529–0.601, P = 0.001; AUROC, 0.566; 95% CI, 0.529–0.603, P < 0.001, respectively) and in the acute coronary syndrome (ACS) subgroup (AUROC: 0.579, 95% CI: 0.531–0.627, P = 0.001; AUROC, 0.591; 95% CI, 0.544–0.638, P < 0.001, respectively). However, neither score was a significant predictor in the non-ACS subgroup (P > 0.05). The value of CRUSADE and ACUITY-HORIZONS scores did not differ significantly (P > 0.05) in the whole cohort, ACS subgroup, or non-ACS subgroup.Conclusions:CRUSADE and ACUITY-HORIZONS scores showed statistically significant but relatively limited long-term prognostic value for out-of-hospital MB after PCI with DES in a cohort of Chinese patients. The value of CRUSADE and ACUITY-HORIZONS scores did not differ significantly (P > 0.05) in the whole cohort, ACS subgroup, or non-ACS subgroup.

Relation of Baseline Hemoglobin Levels and Adverse Events in Patients With Acute Coronary Syndromes (from the Acute Catheterization and Urgent Intervention Triage strategY and Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction Trials)

The association between anemia at admission and adverse outcomes in patients with acute coronary syndrome (ACS) has been incompletely studied. Anemia was defined as serum hemoglobin <12g/dl in women or <13g/dl in men in 2 large trials of patients with ACS. We plotted hazard functions for major bleeding at 30days and all-cause mortality, myocardial infarction, and stent thrombosis at 1year according to baseline hemoglobin. Among 16,318 patients, 3070 (18.8%) had anemia at baseline. All-cause death at 1year (2.9% vs 1.5%), major bleeding (7.6% vs 3.6%, p <0.001), and transfusions (6.7% vs 1.5%, p <0.001) were more common in patients with baseline anemia. Spline transformations of the hazard for adverse events as a function of hemoglobin level on admission showed that adverse outcomes increased in a nonlinear fashion with lower levels of baseline hemoglobin; the lowest rates were observed at a level of ∼14g/dl. Baseline hemoglobin and anemia were independent predictors of major bleeding and death. In conclusion, in patients with ACS, baseline hemoglobin carries important independent prognostic information and demonstrates a nonlinear association with major bleeding and mortality.

Bleeding Events Before Coronary Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome

BackgroundUpstream administration of antithrombotic drugs to patients with non–ST-segment elevation acute coronary syndromes before coronary angiography is a common practice despite an incomplete understanding of the risks and benefits. ObjectivesThe authors analyzed the incidence of bleeding and ischemic events occurring before angiography and assessed their association with antithrombotic drugs and mortality risk. MethodsAll patients from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial with planned angiography after enrollment were included. Bleeding events were classified according to the ACUITY scale as major or nonmajor bleeding. Kaplan-Meier and Cox proportional hazards analyses were performed. ResultsOf 13,726 patients, 275 (2.0%) bled before angiography, including 52 (0.4%) with major bleeding. Forty-four (0.3%) experienced myocardial infarction. The median time from randomization to coronary angiography was 4.5 h (interquartile ratio [IQR]: 1.7 to 19.7 h) for patients who did not bleed while waiting for angiography and 27.9 h (IQR: 21.9 to 65.6 h) for patients who bled while waiting for angiography (p < 0.001). Bleeding events accrued linearly over time, reaching 10.4% at 96 h post-randomization. Independent predictors of bleeding before angiography included age (adjusted hazard ratio [HR]: 1.03 per year of age; 95% confidence interval [CI]: 1.01 to 1.04; p < 0.001), renal insufficiency (adjusted HR: 1.48; 95% CI: 1.07 to 2.04; p = 0.02), and use of multiple antithrombotic drugs (adjusted HR: 1.33; 95% CI: 1.14 to 1.56; p < 0.001). Bleeding before coronary angiography was associated with longer hospitalization (4.8 days [IQR: 3.0 to 8.9 days] vs. 3.0 days [IQR: 1.9 to 5.9 days]; p < 0.001). Patients who bled before angiography were more likely to die within 1 year than patients who did not bleed (8.5% vs. 4.1%; p < 0.001; adjusted HR: 1.89 (95% CI: 1.23 to 2.90; p = 0.004). ConclusionsUpstream antithrombotic treatment of patients with non–ST-segment elevation acute coronary syndromes awaiting coronary angiography is associated with excess bleeding with mortality implications. Bleeding avoidance strategies before angiogram, including early angiography, may negate the need to prolong upstream antithrombotic treatment and improve the overall risk-benefit balance for these patients. (Acute Catheterization and Urgent Intervention Triage Strategy [ACUITY]; NCT00093158)

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.

The potential cost-effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for treating de novo, severely calcified coronary lesions: an economic modeling approach.

Background:Patients who undergo percutaneous coronary intervention (PCI) for severely calcified coronary lesions have long been known to have worse clinical and economic outcomes than patients with no or mildly calcified lesions. We sought to assess the likely cost-effectiveness of using the Diamondback 360® Orbital Atherectomy System (OAS) in the treatment of de novo, severely calcified lesions from a health-system perspective.Methods and results:In the absence of a head-to-head trial and long-term follow up, cost-effectiveness was based on a modeled synthesis of clinical and economic data. A cost-effectiveness model was used to project the likely economic impact. To estimate the net cost impact, the cost of using the OAS technology in elderly (⩾ 65 years) Medicare patients with de novo severely calcified lesions was compared with cost offsets. Elderly OAS patients from the ORBIT II trial (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) [ClinicalTrials.gov identifier: NCT01092426] were indirectly compared with similar patients using observational data. For the index procedure, the comparison was with Medicare data, and for both revascularization and cardiac death in the following year, the comparison was with a pooled analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI)/Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trials. After adjusting for differences in age, gender, and comorbidities, the ORBIT II mean index procedure costs were 17% (p < 0.001) lower, approximately US$2700. Estimated mean revascularization costs were lower by US$1240 in the base case. These cost offsets in the first year, on average, fully cover the cost of the device with an additional 1.2% cost savings. Even in the low-value scenario, the use of the OAS is cost-effective with a cost per life-year gained of US$11,895.Conclusions:Based on economic modeling, the recently approved coronary OAS device is projected to be highly cost-effective for patients who undergo PCI for severely calcified lesions.

Impact of Bleeding and Bivalirudin Therapy on Mortality Risk in Women Undergoing Percutaneous Coronary Intervention (from the REPLACE-2, ACUITY, and HORIZONS-AMI Trials)

Women have higher bleeding complication and mortality rates after percutaneous coronary interventions (PCI). The contribution of female gender to bleeding and mortality is poorly understood. We evaluated the effect of gender and bleeding on outcomes of patients treated with bivalirudin during PCI by performing a patient-level pooled analysis of 3 randomized controlled trials (the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events, Acute Catheterization and Urgent Intervention Triage strategY, and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) comparing bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitor (GPI) treatment in patients undergoing PCI. Of 14,784 patients, 7,413 patients received bivalirudin (1,870 women) and 7,371 patients received heparin + GPI (1,910 women). Women had significantly higher 30-day non-coronary artery bypass grafting (CABG)-related major bleeding rates (7.6% vs 3.8%, p <0.0001). After multivariate adjustment, female gender increased the hazard of major bleeding by 80% (hazard ratio 1.80, 95% confidence interval 1.52 to 2.11, p <0.001). Furthermore, women had a higher 1-year mortality rate (3.7% vs 2.7%, p = 0.002) than men; 30-day major bleeding was the strongest independent predictor of 1-year mortality in women (hazard ratio 2.48, 95% confidence interval 1.57 to 3.91, p = 0.001). Bivalirudin therapy in women reduced 30-day non-CABG-related major bleeding (5.6% vs 9.7%, p <0.0001) and 1-year mortality (2.9% vs 4.4%, p = 0.02) compared to standard therapy. In conclusion, in this cohort of patients treated for acute coronary syndrome and ST-segment elevation myocardial infarction, women have a near 2-fold increase in bleeding complications compared to men after PCI. Bleeding complications rather than gender is the strongest independent predictor of 1-year mortality in patients undergoing PCI. Furthermore, we observed a more pronounced clinical benefit in women treated with bivalirudin including a 44% reduction in major bleeding and a significant reduction in mortality rates at 1 year.

Incremental Value of the CRUSADE, ACUITY, and HAS-BLED Risk Scores for the Prediction of Hemorrhagic Events After Coronary Stent Implantation in Patients Undergoing Long or Short Duration of Dual Antiplatelet Therapy.

BackgroundMultiple scores have been proposed to stratify bleeding risk, but their value to guide dual antiplatelet therapy duration has never been appraised. We compared the performance of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HAS‐BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) scores in 1946 patients recruited in the Prolonging Dual Antiplatelet Treatment After Grading Stent‐Induced Intimal Hyperplasia Study (PRODIGY) and assessed hemorrhagic and ischemic events in the 24‐ and 6‐month dual antiplatelet therapy groups.Methods and ResultsBleeding score performance was assessed with a Cox regression model and C statistics. Discriminative and reclassification power was assessed with net reclassification improvement and integrated discrimination improvement. The C statistic was similar between the CRUSADE score (area under the curve 0.71) and ACUITY (area under the curve 0.68), and higher than HAS−BLED (area under the curve 0.63). CRUSADE, but not ACUITY, improved reclassification (net reclassification index 0.39, P=0.005) and discrimination (integrated discrimination improvement index 0.0083, P=0.021) of major bleeding compared with HAS‐BLED. Major bleeding and transfusions were higher in the 24‐ versus 6‐month dual antiplatelet therapy groups in patients with a CRUSADE score >40 (hazard ratio for bleeding 2.69, P=0.035; hazard ratio for transfusions 4.65, P=0.009) but not in those with CRUSADE score ≤40 (hazard ratio for bleeding 1.50, P=0.25; hazard ratio for transfusions 1.37, P=0.44), with positive interaction (P int=0.05 and P int=0.01, respectively). The number of patients with high CRUSADE scores needed to treat for harm for major bleeding and transfusion were 17 and 15, respectively, with 24‐month rather than 6‐month dual antiplatelet therapy; corresponding figures in the overall population were 67 and 71, respectively.ConclusionsOur analysis suggests that the CRUSADE score predicts major bleeding similarly to ACUITY and better than HAS BLED in an all‐comer population with percutaneous coronary intervention and potentially identifies patients at higher risk of hemorrhagic complications when treated with a long‐term dual antiplatelet therapy regimen.Clinical Trial Registration URL: http://clinicaltrials.gov. Unique identifier: NCT00611286.

HAS-BLED score predicts risk of in-hospital major bleeding in patients with acute non-ST segment elevation myocardial infarction

BackgroundThe role of the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs or alcohol use (HAS-BLED) score in the prediction of in-hospital bleeding in non-ST segment elevation myocardial infarction (NSTEMI) patients receiving dual anti-platelet therapy plus heparin was unknown. In this study, we compared the HAS-BLED score with the Can Rapid Risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) and Acute Catheterization and Urgent Intervention Triage strategY and the Harmonizing Outcomes with RevascularIZatiON and Stents in acute myocardial infarction (ACUITY-HORIZONS) bleeding risk scores for in-hospital major bleeding risk stratification in NSTEMI patients. MethodsA real world population of 617 NSTEMI patients receiving dual anti-platelet plus heparin as initial therapy were enrolled. CRUSADE, ACUITY-HORIZONS and HAS-BLED risk scores were calculated for each patient. ResultsThis cohort had a 6.5% incidence of in-hospital major bleeding. For the prediction of in-hospital major bleeding, the discriminations between CRUSADE, ACUITY-HORIZONS and HAS-BLED were good (C-statistic 0.81, 0.82 and 0.80, respectively). There was no significant difference between these three risk scores (HAS-BLED vs. CRUSADE: z=−0.08, p=0.27; HAS-BLED vs. ACUITY-HORIZONS: z=−0.06, p=0.26; CRUSADE vs. ACUITY-HORIZONS: z=−0.15, p=0.28). ConclusionThe CRUSADE, ACUITY-HORIZONS and HAS-BLED scores were useful tools for risk stratification of in-hospital major bleeding in NSTEMI patients. The HAS-BLED score had a simpler calculation and a similar accuracy for risk assessment as the other two scores evaluated.

Incidence and impact of acute kidney injury in patients with acute coronary syndromes treated with coronary artery bypass grafting: Insights from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) and Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trials

Acute kidney injury (AKI) is a well-recognized predictor of morbidity and mortality after percutaneous coronary intervention. However, the impact of AKI on the outcome of patients with acute coronary syndromes (ACS) in relation to coronary artery bypass grafting (CABG) has not been established. Of the 17,421 patients who presented with non-ST-segment elevation ACS or ST-segment elevation myocardial infarction enrolled in the ACUITY and HORIZONS-AMI trials, 1,406 (8.0%) underwent CABG as principal treatment after coronary angiography. End points were measured at 1 month and 1 year and included death, myocardial infarction, and ischemia-driven target vessel revascularization. Acute kidney injury was defined as a rise in creatinine of ≥ 0.5 mg/dL, or > 25%, from baseline at initial angiography. Acute kidney injury occurred during hospital admission in 449 (31.9%) of the 1,406 patients treated with CABG. One-month and 1-year mortality was 6.7% vs 2.2% (P < .0001) and 10.4% vs 4.3% (P < .0001) for patients with vs without AKI, respectively. Analogously, the 1-month and 1-year incidence of composite major adverse cardiac events (MACEs; death, MI, or target vessel revascularization) was 17.6% vs 12.4% (P = .003) and 22.0% vs 15.3% (P = .002) for patients with vs without AKI, respectively. After adjustment for age, sex, race, diabetes, hypertension, and baseline creatinine clearance, AKI was an independent predictor of mortality (overall and cardiac-related) and MACE at both 1 month and 1 year in patients treated with CABG. Acute kidney injury occurred in approximately 1 of every 3 patients with ACS treated with CABG and is a powerful independent predictor of death and MACE. These data highlight the need for AKI prevention strategies in patients undergoing CABG.

Prognostic impact of multivessel versus culprit vessel only percutaneous intervention for patients with multivessel coronary artery disease presenting with acute coronary syndrome.

To determine whether multivessel (MV) percutaneous coronary intervention (PCI) performed in one procedure improves outcomes when compared to single-vessel (SV) PCI for the culprit lesion(s) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). We utilised the Acute Catheterisation and Urgent Intervention Triage StrategY (ACUITY) study database to analyse the outcomes of 2,255 patients with MV disease who underwent SV PCI compared to 609 patients who underwent MV PCI in the setting of NSTE-ACS. The primary endpoint was the one-year rate of major adverse cardiac events (MACE): death from any cause, myocardial infarction (MI), or ischaemia-driven revascularisation. At one year, patients undergoing MV PCI compared to SV PCI had similar rates of MACE (24.1% vs. 21.7%, respectively, p=0.11). However, death/MI was significantly higher in the MV PCI group (15.7% vs. 12.6%, p=0.05), primarily driven by higher rates of periprocedural non-Q-wave MI. Rates of death, ischaemia-driven revascularisation, stent thrombosis, acute renal failure and major bleeding were similar in both groups. By multivariable analysis with propensity score adjustment, MV PCI was not an independent predictor of one-year MACE (HR=1.22; 95% confidence interval [CI]: 0.96, 1.55; p=0.12) or death/MI (HR=1.28; 95% CI: 0.95, 1.74; p=0.15). In patients with NSTE-ACS and MV disease, MV PCI does not appear to provide a clear clinical benefit over SV PCI. Randomised clinical trials specifically addressing these two strategies in this population, with attention to quality of life and symptom relief, are warranted.

Enhancing the Benefit of Bivalirudin in Percutaneous Coronary Intervention: Is High Risk of Bleeding the Key?

Bivalirudin is a potent direct thrombin inhibitor that can reduce thrombus burden during acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) by blocking formation of fibrin and by suppressing platelet aggregation [1]. When compared with heparin, bivalirudin has several theoretical mechanistic advantages that include activity against clot-bound thrombin, inhibition of thrombin-induced platelet activation, short plasma half-life, linear pharmacokinetics less affected by plasma proteins and renal insufficiency, and an unaffected platelet activation during PCI [1]. These properties of bivalirudin provide a more predictable inhibition of coagulant activity than does heparin, with less degree of inter-patient variability in anticoagulation response. Moreover, its binding to thrombin is non-competitive and reversible, and hemostatic capacity is more readily restored; hence bleeding, as well as ischemic complications, may be reduced [2]. In the first randomized trial (HAS [Hirulog Angioplasty Study]) comparing bivalirudin with heparin in over 4000 patients undergoing PCI for unstable or post-infarction angina, bivalirudin was at least as effective as high-dose heparin in preventing ischemic complications, and it carried a lower risk of bleeding [3]. Nevertheless, development of bivalirudin was suspended because of the unfavorable cost comparison with heparin. Only recently did the development of a less expensive manufacturing process encourage interest from researchers to further support the efficacy and safety of this anticoagulant therapy. Re-analysis of the original HAS using contemporary endpoints and intention-to-treat analysis showed a 22 % reduction in major adverse cardiac events (including death, ACS, and revascularization) and a 62 % reduction in bleeding with bivalirudin at 7 days [4]. In the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) trial [5], bivalirudin with provisional glycoprotein IIb/IIIa blockade (which was administered in about 7 % of patients) was proven to be statistically non-inferior to heparin plus planned glycoprotein IIb/IIIa inhibitors during PCI with regard to suppressing ischemic events after PCI, but was superior in preventing hemorrhagic complications. More recently, bivalirudin provided similar protection from ischemic events as glycoprotein IIb/IIIa inhibitors, but with lower bleeding rates in the ACUITY (Acute Catheterisation and Urgent Intervention Triage strategy) trial [6]. Although the evidentiary landscape in support of antithrombotic treatment choices during PCI has been enriched by these trials, recent data from clinical trials and pooled analyses questioned the role of bivalirudin in the setting of planned and primary PCI [7–12]. In the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, the use of bivalirudin was associated with a This comment refers to the article available at doi:110.1007/s40256015-0113-8.

Effect of Baseline Thrombocytopenia on Ischemic Outcomes in Patients With Acute Coronary Syndromes Who Undergo Percutaneous Coronary Intervention

BackgroundAcquired thrombocytopenia (TP) has been associated with short- and long-term adverse outcomes after percutaneous coronary intervention (PCI), but the role of baseline TP is less well defined. We sought to evaluate the effect of TP on long-term adverse outcomes in patients with acute coronary syndromes (ACS) who undergo PCI. MethodsData from 10,603 patients who underwent PCI for non-ST-elevation ACS or ST-elevation myocardial infarction were pooled from 2 large-scale randomized trials, Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) and Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI). Patients were stratified according to baseline platelet counts. Those with platelet counts <150,000/mm3 were considered to have normal platelet counts. Adverse event rates were compared between groups with and without multivariable adjustment. ResultsBaseline TP was present in 607 (5.7%) patients. The unadjusted 1-year rates of death (6.7% vs 3.6%; P < 0.0001), occurrence of major adverse cardiac event (MACE) (20.8% vs 15.6%; P = 0.0002), and target lesion revascularization (TLR; 9.4% vs 7.2%; P = 0.01) were significantly higher in patients with baseline TP compared with patients with normal platelet counts. By multivariable analysis, the presence of TP at baseline was an independent predictor of 1-year death (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12-2.69; P = 0.01), ischemic TLR (HR, 1.37; 95% CI, 1.04-1.81; P = 0.03), and MACE (HR, 1.39; 95% CI, 1.09-1.79; P = 0.009). ConclusionsThe presence of baseline TP in the setting of ACS patients who undergo PCI was strongly predictive of death, ischemic TLR, and MACE at 1 year. Baseline TP might be a useful baseline clinical parameter to estimate future ischemic risk after PCI.

Incidence and Impact of Totally Occluded Culprit Coronary Arteries in Patients Presenting With Non–ST-Segment Elevation Myocardial Infarction

The accuracy of the 12-lead electrocardiogram in detecting coronary artery occlusion is limited. We sought to determine the incidence, distribution, and outcomes of patients who have total occlusion of the culprit artery but present with non-ST-segment elevation myocardial infarction (NSTEMI). The randomized Acute Catheterization and Urgent Intervention Triage Strategy trial enrolled 13,819 patients presenting with non-ST-segment elevation acute coronary syndromes who underwent an early invasive strategy. The present study includes 1,319 patients with baseline biomarker elevation (NSTEMI) and no history of coronary artery bypass graft who underwent percutaneous coronary intervention of a single culprit vessel. We compared the baseline characteristics and outcomes according to whether the culprit vessel was occluded (baseline Thrombolysis In Myocardial Infarction [TIMI] 0 to 1) or patent (TIMI 2 to 3 flow) by angiographic core laboratory assessment. TIMI 0 to 1 flow in the culprit artery was present in 262 of 1,319 (19.9%) patients. The incidence of coronary occlusion was 28.4%, 19.3%, and 12.6% in patients with NSTEMI because of right coronary, left circumflex, and left anterior descending artery disease, respectively. Patients with an occluded culprit artery were more commonly men and had ST-segment deviation ≥1mm. One-year outcomes, including death (3.5% vs 3.0%, p= 0.68) and myocardial infarction (8.4% vs 9.6%, p= 0.47), did not differ significantly between patients with versus without occluded culprit arteries, respectively. In conclusion, the present study demonstrates that the culprit artery is totally occluded in approximately 1 in 5 patients presenting with NSTEMI and single-vessel disease; however, the presence of total occlusion in NSTEMI was not associated with an incremental hazard of death or reinfarction at 1year.

Effect of Anemia on Frequency of Short- and Long-Term Clinical Events in Acute Coronary Syndromes (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial)

There are limited data on the impact of anemia on clinical outcomes in unstable angina and non-ST-segment elevation myocardial infarction treated with an early invasive strategy. We sought to determine the short- and long-term clinical events among patients with and without anemia enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Anemia was defined as baseline hemoglobin of <13g/dl for men and <12g/dl for women. The primary end points were composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) and major bleeding assessed in-hospital, at 1 month, and at 1 year. Among the 13,819 patients in the ACUITY trial, information regarding anemia was available in 13,032 (94.3%), 2,199 of whom (16.9%) had anemia. Patients with anemia compared with those without anemia had significantly increased adverse event rates in-hospital (composite ischemia 6.6% vs 4.8%, p= 0.0004; major bleeding 7.3% vs 3.3%, p<0.0001), at 1 month (composite ischemia 10% vs 7.2%, p <0.0001, major bleeding 8.8% vs 3.9%, p <0.0001), and 1 year (composite ischemia 21.7% vs 15.3%, p <0.0001). Anemia was an independent predictor of death at 1 year (hazard ratio 1.77, 95% confidence interval [CI] 1.29 to 2.44, p= 0.0005). Composite ischemia was significantly more common among patients who developed in-hospital non-coronary artery bypass surgery major bleeding compared with those who did not (anemic patients 1-year relative risk 2.19, 95% CI 1.67 to 2.88, p <0.0001; nonanemic patients relative risk 2.16, 95% CI 1.76 to 2.65, p <0.0001). In conclusion, in the ACUITY trial, baseline anemia was strongly associated with adverse earlyand late clinical events, especially in those who developed major bleeding.