Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of ß-Glucocerebrosidase.

ß-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher's disease and are a major genetic risk factor for Parkinson's disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and increase delivery of degradation-prone mutant GCase to the lysosome is a strategy under active investigation. Here, we describe the first use of fragment-based drug discovery (FBDD) to identify pharmacological chaperones of GCase. The fragment hits were identified by using X-ray crystallography and biophysical techniques. This work led to the discovery of a series of compounds that bind GCase with nM potency and positively modulate GCase activity in cells.

Evaluation of deep-learning TSE images in clinical musculoskeletal imaging.

In this study, we compared the fat-saturated (FS) and non-FS turbo spin echo (TSE) magnetic resonance imaging knee sequences reconstructed conventionally (conventional-TSE) against a deep learning-based reconstruction of accelerated TSE (DL-TSE) scans. A total of 232 conventional-TSE and DL-TSE image pairs were acquired for comparison. For each consenting patient, one of the clinically acquired conventional-TSE proton density-weighted sequences in the sagittal or coronal planes (FS and non-FS), or in the axial plane (non-FS), was repeated using a research DL-TSE sequence. The DL-TSE reconstruction resulted in an image resolution that increased by at least 45% and scan times that were up to 52% faster compared to the conventional TSE. All images were acquired on a MAGNETOM Vida 3T scanner (Siemens Healthineers AG, Erlangen, Germany). The reporting radiologists, blinded to the acquisition time, were requested to qualitatively compare the DL-TSE against the conventional-TSE reconstructions. Despite having a faster acquisition time, the DL-TSE was rated to depict smaller structures better for 139/232 (60%) cases, equivalent for 72/232 (31%) cases and worse for 21/232 (9%) cases compared to the conventional-TSE. Overall, the radiologists preferred the DL-TSE reconstruction in 124/232 (53%) cases and stated no preference, implying equivalence, for 65/232 (28%) cases. DL-TSE reconstructions enabled faster acquisition times while enhancing spatial resolution and preserving the image contrast. From these results, the DL-TSE provided added or comparable clinical value and utility in less time. DL-TSE offers the opportunity to further reduce the overall examination time and improve patient comfort with no loss in diagnostic accuracy.

Pressure-Controlled Intermittent Coronary Sinus Occlusion (PiCSO) in Acute Myocardial Infarction: The PiCSO-AMI-I Trial.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) has improved clinical outcomes in patients with ST-segment-elevation myocardial infarction. However, as many as 50% of patients still have suboptimal myocardial reperfusion and experience extensive myocardial necrosis. The PiCSO-AMI-I trial (Pressure-Controlled Intermittent Coronary Sinus Occlusion-Acute Myocardial Infarction-I) evaluated whether PiCSO therapy can further reduce myocardial infarct size (IS) in patients undergoing pPCI. METHODS: Patients with anterior ST-segment-elevation myocardial infarction and Thrombolysis in Myocardial Infarction flow 0-1 were randomized at 16 European centers to PiCSO-assisted pPCI or conventional pPCI. The PiCSO Impulse Catheter (8Fr balloon-tipped catheter) was inserted via femoral venous access after antegrade flow restoration of the culprit vessel and before proceeding with stenting. The primary end point was the difference in IS (expressed as a percentage of left ventricular mass) at 5 days by cardiac magnetic resonance. Secondary end points were the extent of microvascular obstruction and intramyocardial hemorrhage at 5 days and IS at 6 months. RESULTS: Among 145 randomized patients, 72 received PiCSO-assisted pPCI and 73 conventional pPCI. No differences were observed in IS at 5 days (27.2%±12.4% versus 28.3%±11.45%; P=0.59) and 6 months (19.2%±10.1% versus 18.8%±7.7%; P=0.83), nor were differences between PiCSO-treated and control patients noted in terms of the occurrence of microvascular obstruction (67.2% versus 64.6%; P=0.85) or intramyocardial hemorrhage (55.7% versus 60%; P=0.72). The study was prematurely discontinued by the sponsor with no further clinical follow-up beyond 6 months. However, up to 6 months of PiCSO use appeared safe with no device-related adverse events. CONCLUSIONS: In this prematurely discontinued randomized trial, PiCSO therapy as an adjunct to pPCI did not reduce IS when compared with conventional pPCI in patients with anterior ST-segment-elevation myocardial infarction. PiCSO use was associated with increased procedural time and contrast but no increase in adverse events up to 6 months. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03625869.

Complex percutaneous coronary intervention in patients unable to undergo coronary artery bypass grafting during the COVID-19 pandemic: insights from the UK-ReVasc Registry.

OBJECTIVES: Cardiac surgery for coronary artery disease was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with disease ordinarily treated with coronary artery bypass grafting (CABG) instead underwent percutaneous coronary intervention (PCI). We sought to describe 12-month outcomes following PCI in patients who would typically have undergone CABG. METHODS: Between March 1 and July 31, 2020, patients who received revascularization with PCI when CABG would have been the primary choice of revascularization were enrolled in the prospective, multicenter UK-ReVasc Registry. We evaluated the following major adverse cardiovascular events at 12 months: all-cause mortality, myocardial infarction, repeat revascularization, stroke, major bleeding, and stent thrombosis. RESULTS: A total of 215 patients were enrolled across 45 PCI centers in the United Kingdom. Twelve-month follow up data were obtained for 97% of the cases. There were 9 deaths (4.3%), 5 myocardial infarctions (2.4%), 12 repeat revascularizations (5.7%), 1 stroke (0.5%), 3 major bleeds (1.4%), and no cases of stent thrombosis. No difference in the primary endpoint was observed between patients who received complete vs incomplete revascularization (residual SYNTAX score £ 8 vs > 8) (P = .22). CONCLUSIONS: In patients with patterns of coronary disease in whom CABG would have been the primary therapeutic choice outside of the pandemic, PCI was associated with acceptable outcomes at 12 months of follow-up. Contemporary randomized trials that compare PCI to CABG in such patient cohorts may be warranted.

The identification and management of depression in UK Kidney Care: Results from the Mood Maps Study.

BACKGROUND: Depression is common in people with chronic kidney disease, yet little is known about how depression is identified and managed as part of routine kidney care. OBJECTIVES: The primary objective was to survey all UK adult kidney centres to understand how depression is identified and managed. A secondary objective was to broadly describe the variability in psychosocial care. DESIGN: Online survey. METHODS: The survey comprised of three sections: (1) general kidney care, (2) psychological provision and (3) social work provision. RESULTS: 48/68 (71%) of centres responded to the general survey with 20 and 13 responses from psychological and social work module respectively. Only 31.4% reported having both in centre psychological and social work practitioners. Three centres reported no access to psychosocial provision. Of the 25 centres who reported on pathways, 36.0% reported having internal pathways for the identification and management of depression. Within services with psychological provision, screening for depression varied across modality/group (e.g., 7.1% in mild/moderate chronic kidney disease vs. 62.5% in kidney donors). Cognitive Behavioural Therapy and Acceptance and Commitment Therapy were the most common interventions offered. Most psychosocial services were aware of the National Institute for Health and Care Excellence guidelines for managing depression in long-term conditions (n = 18, 94.7%) yet few fully utilised (n = 6, 33.3%). Limited workforce capacity was evident. CONCLUSIONS: There is considerable variability in approaches taken to identify and treat depression across UK kidney services, with few services having specific pathways designed to detect and manage depression. Workforce capacity remains a significant issue.

Approaches to the identification and management of depression in people living with chronic kidney disease: A scoping review of 860 papers.

BACKGROUND: Depression is prevalent across the spectrum of Chronic Kidney Disease and associated with poorer outcomes. There is limited evidence regarding the most effective interventions and care pathways for depression in Chronic Kidney Disease. OBJECTIVES: To investigate how depression is identified and managed in adults with Chronic Kidney Disease. DESIGN: Scoping review. METHODS: Systematic search of eight databases with pre-defined inclusion criteria. Data relevant to the identification and/or management of depression in adults with Chronic Kidney Disease were extracted. RESULTS: Of 2147 articles identified, 860 were included. Depression was most identified using self-report screening tools (n = 716 studies, 85.3%), with versions of the Beck Depression Inventory (n = 283, 33.7%) being the most common. A total of 123 studies included data on the management of depression, with nonpharmacological interventions being more frequently studied (n = 55, 45%). Cognitive Behavioural Therapy (n = 15) was the most common nonpharmacological intervention, which was found to have a significant effect on depressive symptoms compared to controls (n = 10). However, how such approaches could be implemented as part of routine care was not clear. There was limited evidence for antidepressants use in people with Chronic Kidney Disease albeit in a limited number of studies. CONCLUSIONS: Depression is commonly identified using validated screening tools albeit differences exist in reporting practices. Evidence regarding the management of depression is mixed and requires better-quality trials of both pharmacological and nonpharmacological approaches. Understanding which clinical care pathways are used and their evidence, may help facilitate the development of kidney care specific guidelines for the identification and management of depression.

Magnetic resonance imaging of breast implants: Optimizing tissue contrast.

INTRODUCTION: Patients with breast implants need to undergo regular screening MRI procedures. One of the key requirements of this screening scan is the ability to suppress one or more tissues (water, fat, or silicone) simultaneously. However, the presence of "foreign" implants within the breast biological space affects the MRI scanner's normal operating mode. Often, this requires operator's supervision to make sure the correct image contrast is achieved. METHODS: We built a phantom that represents the commonly encountered tissues (water, fat, and silicone) in breast implant imaging. The phantom was used to optimise imaging parameters and highlight common challenges encountered while imaging breast implants. We scanned the phantom on seven different MRI scanners (including 1.5T and 3T) and produced vendor-specific cheat-sheets on how to image breast implants. Ethical approval was not required for this article type. CONCLUSION: Performing a breast MRI procedure with implants in-situ can be challenging. Employing a purpose-built phantom, we provide easy-to-use cheat sheets, with examples, outlining steps that can be taken to ensure appropriate tissue suppression and image contrast in breast implant MRI. We hope these cheat-sheets will help MRI practitioners to confidently and efficiently achieve accurate image contrasts across a number of implant scenarios which will aid in improving diagnostic accuracy, treatment plans, and thus prognosis for the patient.

Outcomes following PCI in CABG candidates during the COVID-19 pandemic: The prospective multicentre UK-ReVasc registry.

OBJECTIVES: To describe outcomes following percutaneous coronary intervention (PCI) in patients who would usually have undergone coronary artery bypass grafting (CABG). BACKGROUND: In the United Kingdom, cardiac surgery for coronary artery disease (CAD) was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with "surgical disease" instead underwent PCI. METHODS: Between 1 March 2020 and 31 July 2020, 215 patients with recognized "surgical" CAD who underwent PCI were enrolled in the prospective UK-ReVasc Registry (ReVR). 30-day major cardiovascular event outcomes were collected. Findings in ReVR patients were directly compared to reference PCI and isolated CABG pre-COVID-19 data from British Cardiovascular Intervention Society (BCIS) and National Cardiac Audit Programme (NCAP) databases. RESULTS: ReVR patients had higher incidence of diabetes (34.4% vs 26.4%, P = .008), multi-vessel disease with left main stem disease (51.4% vs 3.0%, P < .001) and left anterior descending artery involvement (94.8% vs 67.2%, P < .001) compared to BCIS data. SYNTAX Score in ReVR was high (mean 28.0). Increased use of transradial access (93.3% vs 88.6%, P = .03), intracoronary imaging (43.6% vs 14.4%, P < .001) and calcium modification (23.6% vs 3.5%, P < .001) was observed. No difference in in-hospital mortality was demonstrated compared to PCI and CABG data (ReVR 1.4% vs BCIS 0.7%, P = .19; vs NCAP 1.0%, P = .48). Inpatient stay was half compared to CABG (3.0 vs 6.0 days). Low-event rates in ReVR were maintained to 30-day follow-up. CONCLUSIONS: PCI undertaken using contemporary techniques produces excellent short-term results in patients who would be otherwise CABG candidates. Longer-term follow-up is essential to determine whether these outcomes are maintained over time.

International Prospective Registry of Acute Coronary Syndromes in Patients With COVID-19.

BACKGROUND: Published data suggest worse outcomes in acute coronary syndrome (ACS) patients and concurrent coronavirus disease 2019 (COVID-19) infection. Mechanisms remain unclear. OBJECTIVES: The purpose of this study was to report the demographics, angiographic findings, and in-hospital outcomes of COVID-19 ACS patients and compare these with pre-COVID-19 cohorts. METHODS: From March 1, 2020 to July 31, 2020, data from 55 international centers were entered into a prospective, COVID-ACS Registry. Patients were COVID-19 positive (or had a high index of clinical suspicion) and underwent invasive coronary angiography for suspected ACS. Outcomes were in-hospital major cardiovascular events (all-cause mortality, re-myocardial infarction, heart failure, stroke, unplanned revascularization, or stent thrombosis). Results were compared with national pre-COVID-19 databases (MINAP [Myocardial Ischaemia National Audit Project] 2019 and BCIS [British Cardiovascular Intervention Society] 2018 to 2019). RESULTS: In 144 ST-segment elevation myocardial infarction (STEMI) and 121 non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients, symptom-to-admission times were significantly prolonged (COVID-STEMI vs. BCIS: median 339.0 min vs. 173.0 min; p < 0.001; COVID NSTE-ACS vs. MINAP: 417.0 min vs. 295.0 min; p = 0.012). Mortality in COVID-ACS patients was significantly higher than BCIS/MINAP control subjects in both subgroups (COVID-STEMI: 22.9% vs. 5.7%; p < 0.001; COVID NSTE-ACS: 6.6% vs. 1.2%; p < 0.001), which remained following multivariate propensity analysis adjusting for comorbidities (STEMI subgroup odds ratio: 3.33 [95% confidence interval: 2.04 to 5.42]). Cardiogenic shock occurred in 20.1% of COVID-STEMI patients versus 8.7% of BCIS patients (p < 0.001). CONCLUSIONS: In this multicenter international registry, COVID-19-positive ACS patients presented later and had increased in-hospital mortality compared with a pre-COVID-19 ACS population. Excessive rates of and mortality from cardiogenic shock were major contributors to the worse outcomes in COVID-19 positive STEMI patients.

Primary percutaneous coronary intervention in nonagenarians: is it worthwhile?

BACKGROUND: Previous studies have demonstrated the feasibility of primary percutaneous coronary intervention (PPCI) in carefully selected nonagenarians. Although current guidelines recommend immediate revascularization in patients with ST elevation myocardial infarction (STEMI) it remains unclear whether PPCI reduces mortality in nonagenarians. The objective of this study is to compare mortality in nonagenarians presenting via the PPCI pathway who undergo coronary intervention, versus those who are managed medically. METHODS AND RESULTS: A total of 111 consecutive nonagenarians who presented to our tertiary center via the PPCI pathway between July 2013 and December 2018 with myocardial infarction were included. Clinical and angiographic details were collected alongside data on all-cause mortality. The final diagnosis was STEMI in 98 (88.3%) and NSTEMI in 13 (11.7%). PPCI was performed in 42 (37.8%), while 69 (62.2%) were medically managed. A significant number of the medically managed cohort had atrial fibrillation (23.2% vs 2.4% p = 0.003) and presented with a completed infarct (43.5% vs 4.8% p = 0.001). Other baseline and clinical variables were well matched in both groups. There was a trend towards increased 30-day mortality in the medically managed group (40.6% vs 23.8% p = 0.07). Kaplan Meier survival analysis demonstrated a significant difference in survival by 3 years (48.1% vs 21.7% p = 0.01). This was the case even when those with completed infarcts were excluded (44.3% vs 14.6%, p = 0.01). CONCLUSION: In this series of selected nonagenarians presenting with acute myocardial infarction, those undergoing PPCI appeared to have a lower mortality compared to those managed medically.

Complex Chronic Total Occlusion Revascularization - A Comparison of Biradial Versus Femoral Access.

BACKGROUND: Complex chronic total occlusion (CTO) cases often require dual access. Evidence suggests that radial access is associated with lower success rates in complex CTOs. Our primary outcome was to determine efficacy of biradial access compared with femoral access. METHODS: This was a retrospective, single-center, observational study. Patients who underwent dual-access CTO percutaneous coronary intervention (PCI) between January 2014 and January 2018 were enrolled. They were separated into biradial and femoral access groups. Data on demographics, comorbidities, complications, lesion characteristics, radiation, and contrast dose were collected. Standard univariate analyses were performed to identify predictors for revascularization failure. RESULTS: There were 150 cases identified, 109 biradial and 41 femoral access. There was no significant difference in success rate between the radial and femoral groups (87% vs 78%, respectively; P=.17). The average J-CTO score was 3 vs 4 (P=.04). Matched cohort analysis showed equivalent success rates (80.6% vs 75.0%, respectively; P=.53). Elevated body mass index, poor renal function, previous coronary artery bypass grafting, higher J-CTO, CTO >20 mm, presence of >45° bend within the diseased segment, and absence of collaterals were associated with CTO-PCI failure. Biradial access had shorter procedures (111 minutes vs 147 minutes; P<.01), reduced radiation exposure (dose-area product, 17,452 cGy•cm² vs 23,651 cGy•cm²; P<.01), less contrast (237 mL vs 315 mL; P=.11) and reduced hospital stay (0.38 ± 1.3 days vs 0.61 ± 1.1 days; P=.02). CONCLUSION: With shorter length of stay, fewer complications, and less radiation used in radial cases, we suggest biradial access is an effective and safe alternative in CTO-PCI. Prospective studies are needed to determine superiority.

Outcomes Following Percutaneous Coronary Intervention in Renal Transplant Recipients: A Binational Collaborative Analysis.

OBJECTIVE: To investigate the clinical and procedural characteristics in patients with a history of renal transplant (RT) and compare the outcomes with patients without RT in 2 national cohorts of patients undergoing percutaneous coronary intervention (PCI). PATIENTS AND METHODS: Data from the National Inpatient Sample (NIS) and British Cardiovascular Intervention Society (BCIS) were used to compare the clinical and procedural characteristics and outcomes of patients undergoing PCI who had RT with those who did not have RT. The primary outcome of interest was in-hospital mortality. RESULTS: Of the PCI procedures performed in 2004-2014 (NIS) and 2007-2014 (BCIS), 12,529 of 6,601,526 (0.2%) and 1521 of 512,356 (0.3%), respectively, were undertaken in patients with a history of RT. Patients with RT were younger and had a higher prevalence of congestive cardiac failure, hypertension, and diabetes but similar use of drug-eluting stents, intracoronary imaging, and pressure wire studies compared with patients who did not have RT. In the adjusted analysis, patients with RT had increased odds of in-hospital mortality (NIS: odds ratio [OR], 1.90; 95% CI, 1.41-2.57; BCIS: OR, 1.60; 95% CI, 1.05-2.46) compared with patients who did not have RT but no difference in vascular or bleeding events. Meta-analysis of the 2 data sets suggested an increase in in-hospital mortality (OR, 1.79; 95% CI, 1.40-2.29) but no difference in vascular (OR, 1.24; 95% CI, 0.77-2.00) or bleeding (OR, 1.21; 95% CI, 0.86-1.68) events. CONCLUSION: This large collaborative analysis of 2 national databases revealed that patients with RT undergoing PCI are younger, have more comorbidities, and have increased mortality risk compared with the general population undergoing PCI.

Effect of Pressure-controlled intermittent Coronary Sinus Occlusion (PiCSO) on infarct size in anterior STEMI: PiCSO in ACS study.

BACKGROUND: The aim of this clinical research was to investigate the effects of Pressure-controlled intermittent Coronary Sinus Occlusion (PiCSO) on infarct size at 5 days after primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: This comparative study was carried out in four UK hospitals. Forty-five patients with anterior STEMI presenting within 12 h of symptom onset received pPCI plus PiCSO (initiated after reperfusion; n = 45) and were compared with a propensity score-matched control cohort from INFUSE-AMI (n = 80). Infarct size (% of LV mass, median [interquartile range]) measured by cardiac magnetic resonance (CMR) at day 5 was significantly lower in the PiCSO group (14.3% [95% CI 9.2-19.4%] vs. 21.2% [95% CI 18.0-24.4%]; p = 0.023). There were no major adverse cardiac events (MACE) related to the PiCSO intervention. CONCLUSIONS: PiCSO, as an adjunct to pPCI, was associated with a lower infarct size at 5 days after anterior STEMI in a propensity score-matched population.

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.

Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD).

This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to-lead elaboration.

Long-term follow-up of elective chronic total coronary occlusion angioplasty: analysis from the U.K. Central Cardiac Audit Database.

BACKGROUND: Chronic total occlusion (CTO) is common, being reported in 18% to 30% of patients undergoing coronary angiography. Percutaneous coronary intervention (PCI) is usually performed to relieve anginal symptoms, but data are emerging to suggest that there may also be a mortality benefit. OBJECTIVES: This study aimed to compare outcomes of patients with successful versus unsuccessful PCI to a CTO. METHODS: We analyzed the U.K. Central Cardiac Audit Database for all CTO PCI cases carried out in England and Wales between January 1, 2005, and December 31, 2009. Vital status in September 2010 was obtained from the Medical Research Information Service. RESULTS: A total of 13,443 patients (78.8% male) had a mean age of 63.5 years and underwent 14,439 CTO procedures. CTO PCI was successful in 10,199 cases (70.6%). During follow-up of 2.65 years (interquartile range: 1.59 to 3.83 years), successful PCI of at least 1 CTO was associated with improved survival (hazard ratio [HR]: 0.72; 95% CI: 0.62 to 0.83; p < 0.001). Complete revascularization was associated with improved survival compared with partial revascularization (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.002) or failed revascularization (HR: 0.61; 95% CI: 0.50 to 0.74; p < 0.001). CONCLUSIONS: Successful CTO PCI was associated with improved long-term survival. The improvement was greatest in patients when complete revascularization was achieved. The identity of the successfully treated occluded vessel was not associated with differences in outcome.

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).