Rod Stables

Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial

BACKGROUND Bivalirudin, with selective use of glycoprotein (GP) IIb/IIIa inhibitor agents, is an accepted standard of care in primary percutaneous coronary intervention (PPCI). We aimed to compare antithrombotic therapy with bivalirudin or unfractionated heparin during this procedure. METHODS In our open-label, randomised controlled trial, we enrolled consecutive adults scheduled for angiography in the context of a PPCI presentation at Liverpool Heart and Chest Hospital (Liverpool, UK) with a strategy of delayed consent. Before angiography, we randomly allocated patients (1:1; stratified by age [<75 years vs ≥75 years] and presence of cardiogenic shock [yes vs no]) to heparin (70 U/kg) or bivalirudin (bolus 0·75 mg/kg; infusion 1·75 mg/kg per h). Patients were followed up for 28 days. The primary efficacy outcome was a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation. The primary safety outcome was incidence of major bleeding (type 3-5 as per Bleeding Academic Research Consortium definitions). This study is registered with ClinicalTrials.gov, number NCT01519518. FINDINGS Between Feb 7, 2012, and Nov 20, 2013, 1829 of 1917 patients undergoing emergency angiography at our centre (representing 97% of trial-naive presentations) were randomly allocated treatment, with 1812 included in the final analyses. 751 (83%) of 905 patients in the bivalirudin group and 740 (82%) of 907 patients in the heparin group had a percutaneous coronary intervention. The rate of GP IIb/IIIa inhibitor use was much the same between groups (122 patients [13%] in the bivalirudin group and 140 patients [15%] in the heparin group). The primary efficacy outcome occurred in 79 (8·7%) of 905 patients in the bivalirudin group and 52 (5·7%) of 907 patients in the heparin group (absolute risk difference 3·0%; relative risk [RR] 1·52, 95% CI 1·09-2·13, p=0·01). The primary safety outcome occurred in 32 (3·5%) of 905 patients in the bivalirudin group and 28 (3·1%) of 907 patients in the heparin group (0·4%; 1·15, 0·70-1·89, p=0·59). INTERPRETATION Compared with bivalirudin, heparin reduces the incidence of major adverse ischaemic events in the setting of PPCI, with no increase in bleeding complications. Systematic use of heparin rather than bivalirudin would reduce drug costs substantially. FUNDING Liverpool Heart and Chest Hospital, UK National Institute of Health Research, The Medicines Company, AstraZeneca, The Bentley Drivers Club (UK).

Long-Term Safety and Efficacy of Percutaneous Coronary Intervention With Stenting and Coronary Artery Bypass Surgery for Multivessel Coronary Artery Disease: A Meta-Analysis With 5-Year Patient-Level Data From the ARTS, ERACI-II, MASS-II, and SoS Trials

Background— Randomized trials that studied clinical outcomes after percutaneous coronary intervention (PCI) with bare metal stenting versus coronary artery bypass grafting (CABG) are underpowered to properly assess safety end points like death, stroke, and myocardial infarction. Pooling data from randomized controlled trials increases the statistical power and allows better assessment of the treatment effect in high-risk subgroups. Methods and Results— We performed a pooled analysis of 3051 patients in 4 randomized trials evaluating the relative safety and efficacy of PCI with stenting and CABG at 5 years for the treatment of multivessel coronary artery disease. The primary end point was the composite end point of death, stroke, or myocardial infarction. The secondary end point was the occurrence of major adverse cardiac and cerebrovascular accidents, death, stroke, myocardial infarction, and repeat revascularization. We tested for heterogeneities in treatment effect in patient subgroups. At 5 years, the cumulative incidence of death, myocardial infarction, and stroke was similar in patients randomized to PCI with stenting versus CABG (16.7% versus 16.9%, respectively; hazard ratio, 1.04, 95% confidence interval, 0.86 to 1.27; P=0.69). Repeat revascularization, however, occurred significantly more frequently after PCI than CABG (29.0% versus 7.9%, respectively; hazard ratio, 0.23; 95% confidence interval, 0.18 to 0.29; P<0.001). Major adverse cardiac and cerebrovascular events were significantly higher in the PCI than the CABG group (39.2% versus 23.0%, respectively; hazard ratio, 0.53; 95% confidence interval, 0.45 to 0.61; P<0.001). No heterogeneity of treatment effect was found in the subgroups, including diabetic patients and those presenting with 3-vessel disease. Conclusions— In this pooled analysis of 4 randomized trials, PCI with stenting was associated with a long-term safety profile similar to that of CABG. However, as a result of persistently lower repeat revascularization rates in the CABG patients, overall major adverse cardiac and cerebrovascular event rates were significantly lower in the CABG group at 5 years.

Long-Term Mortality Data From the Balloon Pump–Assisted Coronary Intervention Study (BCIS-1) A Randomized, Controlled Trial of Elective Balloon Counterpulsation During High-Risk Percutaneous Coronary Intervention

Background— There is conflicting evidence on the utility of elective intra-aortic balloon pump (IABP) use during high-risk percutaneous coronary intervention (PCI). Observational series have indicated a reduction in major in-hospital adverse events, although randomized trial evidence does not support this. A recent study has suggested a mortality benefit trend early after PCI, but there are currently no long-term outcome data from randomized trials in this setting. Methods and Results— Three hundred one patients with left ventricular impairment (ejection fraction <30%) and severe coronary disease (BCIS-1 jeopardy score ≥8; maximum possible score=12) were randomized to receive PCI with elective IABP support (n=151) or without planned IABP support (n=150). Long-term all-cause mortality was assessed by tracking the databases held at the Office of National Statistics (in England and Wales) and the General Register Office (in Scotland). The groups were balanced in terms of baseline characteristics (left ventricular ejection fraction, 23.6%; BCIS-1 jeopardy score, 10.4) and the amount and type of revascularization performed. Mortality data were available for the entire cohort at a median of 51 months (interquartile range, 41–58) from randomization. All-cause mortality at follow-up was 33% in the overall cohort, with significantly fewer deaths occurring in the elective IABP group (n=42) than in the group that underwent PCI without planned IABP support (n=58) (hazard ratio, 0.66; 95% confidence interval, 0.44–0.98; P=0.039). Conclusions— In patients with severe ischemic cardiomyopathy treated with PCI, all-cause mortality was 33% at a median of 51 months. Elective IABP use during PCI was associated with a 34% relative reduction in all-cause mortality compared with unsupported PCI. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN40553718; and http://www.clinicaltrials.gov. Unique identifier: NCT00910481.

Neuropsychological Outcome After Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting Results From the Stent or Surgery (SoS) Trial

Background—Coronary artery bypass surgery (CABG) has been associated with a range of neurological and neuropsychological complications from stroke to cognitive problems such as memory and problem solving disturbance. However, little is known about the impact of percutaneous coronary intervention (PCI) on neuropsychological outcome. Methods and Results—In the Stent or Surgery Trial (SoS), 988 patients were randomized in equal proportions between PCI supported by stent implantation and CABG. As a substudy of this trial, we undertook an evaluation of neurological and neuropsychological outcomes after intervention. A clinical examination and neuropsychological assessment consisting of 5 tests (Digit Span Forwards and Backwards, Visual Reproduction, Bourdon, and Block Design) were performed at baseline and 6 and 12 months after the procedure. A total of 145 patients were included in the substudy analysis: 77 in the PCI group and 68 in the CABG group. One patient in the PCI arm had a stroke. There was no significant difference between treatment groups at 6 and 12 months for any of the 5 tests. The mean change from baseline was also similar in both groups. Conclusions—We were not able to demonstrate an important and significant difference in neuropsychological outcome in patients treated with different revascularization strategies. This important finding needs to be examined in further research.

Femoral haemostasis after transcatheter therapeutic intervention: a prospective randomised study of the angio-seal device vs. the femostop device

BACKGROUND A number of haemostatic devices are available to facilitate early haemostasis following transfemoral interventional procedures. METHODS AND RESULTS We have prospectively compared 150 patients (age: 57+/-12 years, mean+/-S.D.) who were randomly assigned to either external compression using the FemoStop device or direct closure of the arterial puncture using the Angio-Seal device. The Angio-Seal was deployed in the catheter laboratory after the conclusion of the procedure. Patients, randomised to FemoStop, had their sheath removed when the activated clotting time (ACT) was less than 100 s before applying the device. The primary endpoint was the composite of bleeding, haematoma formation, bruise, requirement for blood transfusion, clinical indication for ultrasound examination at 2 h and 24 h following the procedure and crossover to either method at 2 and 24 h after the device deployment. The 95% of the Angio-Seal and 96% of FemoStop patients were discharged on the day following the procedure. An increased number of patients in the Angio-Seal group reached a clinical end-point within the first 2 h (45% vs. 3%, P<0.0001). This difference became insignificant at 24 h (25% vs. 30%, P=0.6). CONCLUSION Although less comfortable, the overall efficacy of the FemoStop appeared to be higher than that of the Angio-Seal device.

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): A randomised clinical trial

BACKGROUND REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING Regado Biosciences Inc.

Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy: Insights From Wave Intensity Analysis and Magnetic Resonance

Background Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. Objectives Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. Methods Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. Results Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). Conclusions Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment.

Use of troponin to diagnose periprocedural myocardial infarction: effect on composite endpoints in the British Bifurcation Coronary Study (BBC ONE).

Background Periprocedural myocardial infarction (PMI; ESC/ACC type 4a) is diagnosed on the basis of elevation of cardiac enzymes more than three times the 99th centile upper reference limit. Recent guidelines recommend the use of troponin instead of creatine kinase (CK) to diagnose PMI, but this assay increases diagnostic sensitivity, while the clinical significance of small increases in troponin remains undetermined. We examined the effects of using the new definition on the incidence of a composite endpoint (previously defined by CK) in a contemporary clinical randomised trial—the British Bifurcation Coronary Study (BBC ONE). Methods The BBC ONE trial randomly allocated 500 patients with coronary bifurcation lesions to either a simple or complex stenting strategy. The composite primary endpoint (CPEP) included death, myocardial infarction (MI) (PMI plus subsequent MI) and target vessel failure, at 9 months. Results In BBC ONE the CPEP occurred in 8% versus 15.2% in the simple and complex groups, respectively (HR 2.02, 95% CI 1.17 to 3.47, p=0.009). This difference was largely driven by PMI, which occurred in nine (3.6%) versus 28 (11.2%) patients (HR 3.24, 95% CI 1.53 to 6.86, p=0.001). Using troponin, PMI would have occurred in 71 (28.4%) versus 114 (45.6%) patients, respectively (HR 1.61, 95% CI 1.27 to 2.05, p=0.001), and the CPEP in 32% versus 48% of patients (HR 1.50, 95% CI 1.2 to 1.87, p=0.001). Use of troponin increased MI detection fivefold, from 7.4% to 37.0% overall. Conclusions Use of troponin would have led to a fivefold increase in diagnosis of PMI in the BBC ONE trial. Incorporation of PMI into a composite endpoint may no longer be justified in many interventional trials.

High Platelet Reactivity in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: Randomised Controlled Trial Comparing Prasugrel and Clopidogrel

Background Prasugrel is more effective than clopidogrel in reducing platelet aggregation in acute coronary syndromes. Data available on prasugrel reloading in clopidogrel treated patients with high residual platelet reactivity (HRPR) i.e. poor responders, is limited. Objectives To determine the effects of prasugrel loading on platelet function in patients on clopidogrel and high platelet reactivity undergoing percutaneous coronary intervention for acute coronary syndrome (ACS). Patients Patients with ACS on clopidogrel who were scheduled for PCI found to have a platelet reactivity ≥40 AUC with the Multiplate Analyzer, i.e. “poor responders” were randomised to prasugrel (60 mg loading and 10 mg maintenance dose) or clopidogrel (600 mg reloading and 150 mg maintenance dose). The primary outcome measure was proportion of patients with platelet reactivity <40 AUC 4 hours after loading with study medication, and also at one hour (secondary outcome). 44 patients were enrolled and the study was terminated early as clopidogrel use decreased sharply due to introduction of newer P2Y12 inhibitors. Results At 4 hours after study medication 100% of patients treated with prasugrel compared to 91% of those treated with clopidogrel had platelet reactivity <40 AUC (p = 0.49), while at 1 hour the proportions were 95% and 64% respectively (p = 0.02). Mean platelet reactivity at 4 and 1 hours after study medication in prasugrel and clopidogrel groups respectively were 12 versus 22 (p = 0.005) and 19 versus 34 (p = 0.01) respectively. Conclusions Routine platelet function testing identifies patients with high residual platelet reactivity (“poor responders”) on clopidogrel. A strategy of prasugrel rather than clopidogrel reloading results in earlier and more sustained suppression of platelet reactivity. Future trials need to identify if this translates into clinical benefit. Trial Registration ClinicalTrials.gov NCT01339026

Long-Term Mortality Data from the Balloon-Pump Assisted Coronary Intervention Study (BCIS-1): A Randomized Controlled Trial of Elective Balloon Counterpulsation during High-Risk PCI

Background— There is conflicting evidence on the utility of elective intra-aortic balloon pump (IABP) use during high-risk percutaneous coronary intervention (PCI). Observational series have indicated a reduction in major in-hospital adverse events, although randomized trial evidence does not support this. A recent study has suggested a mortality benefit trend early after PCI, but there are currently no long-term outcome data from randomized trials in this setting. Methods and Results— Three hundred one patients with left ventricular impairment (ejection fraction <30%) and severe coronary disease (BCIS-1 jeopardy score ≥8; maximum possible score=12) were randomized to receive PCI with elective IABP support (n=151) or without planned IABP support (n=150). Long-term all-cause mortality was assessed by tracking the databases held at the Office of National Statistics (in England and Wales) and the General Register Office (in Scotland). The groups were balanced in terms of baseline characteristics (left ventricular ejection fraction, 23.6%; BCIS-1 jeopardy score, 10.4) and the amount and type of revascularization performed. Mortality data were available for the entire cohort at a median of 51 months (interquartile range, 41–58) from randomization. All-cause mortality at follow-up was 33% in the overall cohort, with significantly fewer deaths occurring in the elective IABP group (n=42) than in the group that underwent PCI without planned IABP support (n=58) (hazard ratio, 0.66; 95% confidence interval, 0.44–0.98; P=0.039). Conclusions— In patients with severe ischemic cardiomyopathy treated with PCI, all-cause mortality was 33% at a median of 51 months. Elective IABP use during PCI was associated with a 34% relative reduction in all-cause mortality compared with unsupported PCI. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN40553718; and http://www.clinicaltrials.gov. Unique identifier: NCT00910481.