The enigma of the 'smoker's paradox': Results from a single-center registry of patients with STEMI undergoing primary percutaneous coronary intervention.

BACKGROUND: Smoker's paradox usually refers to the observation of a favorable outcome of smoking patients in acute myocardial infarction. METHODS: From April 2006 to December 2018 a population of 2456 patients with ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI) were prospectively enrolled in the MATRIX registry. Ischemic time, clinical, demographics, angiographic data, and 1-year follow-up were collected. RESULTS: Among 2546 patients admitted with STEMI, 1007 (41 %) were current smokers. Smokers were 10 years younger and had lower crude in-hospital and 1-year mortality (1.5 % vs 6 %, p < 0.0001 and 5 % vs 11 %, p < 0.0001), shorter ischemic time (203 [147-299] vs 220 [154-334] minutes, p = 0.002) and shorter decision time (60 [30-135] vs 70 [36-170] minutes, p = 0.0063). Smoking habit [OR:0.37(95 % CI:0.18-0.75)-p < 0.01], younger age [OR 1.06 (95%CI:1.04-1.09)-p < 0.001] and shorter ischemic time [OR:1.01(95%CI:1.01-1.02)-p < 0.05] were associated to lower in-hospital mortality. Only smoking habit [HR:0.65(95 % CI: 0.44-0.9)-p = 0.03] and younger age [HR:1.08 (95%CI:1.06-1.09)-p < 0.001] were also independently associated to lower all-cause death at 1-year follow-up. After propensity matching, age, cardiogenic shock and TIMI flow <3 were associated with in-hospital mortality, while smoking habit was still associated with reduced mortality. Smoking was also associated with reduced mortality at 1-year follow-up (HR 0.54, 95 % CI [0.37-0.78]; p < 0.001). CONCLUSIONS: Smoking patients show better outcome after PCI for STEMI at 1-year follow-up. Although "Smoking paradox" could be explained by younger age of patients, other factors may have a role in the explanation of the phenomenon.

The Evolving Field of Acute Coronary Syndrome Management: A Critical Appraisal of the 2023 European Society of Cardiology Guidelines for the Management of Acute Coronary Syndrome.

Acute coronary syndromes (ACS), encompassing conditions like ST-elevation myocardial infarction (STEMI) and non-ST-elevation acute coronary syndromes (NSTE-ACS), represent a significant challenge in cardiovascular care due to their complex pathophysiology and substantial impact on morbidity and mortality. The 2023 European Society of Cardiology (ESC) guidelines for ACS management introduce several updates in key areas such as invasive treatment timing in NSTE-ACS, pre-treatment strategies, approaches to multivessel disease, and the use of imaging modalities including computed tomography (CT) coronary angiography, magnetic resonance imaging (MRI), and intracoronary imaging techniques, such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS). They also address a modulation of antiplatelet therapy, taking into consideration different patient risk profiles, and introduce new recommendations for low-dose colchicine. These guidelines provide important evidence-based updates in practice, reflecting an evolution in the understanding and management of ACS, yet some potentially missed opportunities for more personalized care and technology adoption are discussed.

Monotherapy with P2Y12-inhibitors after dual antiplatelet therapy: Filling gaps in evidence.

BACKGROUND: Whether P2Y12 inhibitor monotherapy (P2Y12-I) is superior to aspirin following DAPT discontinuation post-PCI remains to be established. METHODS: We updated our prior network meta-analysis where P2Y12-I and aspirin had been compared with DAPT or directly with each other. The focus is specifically on the available direct evidence, now consisting of the three head-to-head comparisons of P2Y12-I and aspirin in event-free PCI patients after DAPT. We include a Trial Sequential Analysis of the direct evidence based on meta-analytical literature. RESULTS: The main finding reveals a 39% significantly lower risk of myocardial infarction with P2Y12-I (RR 0.61, 95% CI 0.47-0.78, p = 0.0001, I2 = 0%) with no difference in bleeding. Trial Sequential Analysis demonstrates clinically meaningful evidence for a reduction in the incidence of myocardial infarction with P2Y12-I that is also supported by statistical significance. CONCLUSIONS: Accruing data highlight that P2Y12-I following DAPT discontinuation after PCI is associated with lower risk for MI and a similar risk for bleeding as compared with ASA. In light of potential limitations to the widespread adoption of life-long P2Y12-I treatment, clinicians should consider identifying selected patients who are expected to derive the highest benefit.

Coronary calcification in patients presenting with acute coronary syndromes: insights from the MATRIX trial.

AIMS: The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS. METHODS AND RESULTS: The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46). CONCLUSION: Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy.

Dual Antiplatelet Therapy with Parenteral P2Y12 Inhibitors: Rationale, Evidence, and Future Directions.

Dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and an inhibitor of the platelet P2Y12 receptor for ADP, remains among the most investigated treatments in cardiovascular medicine. While a substantial amount of research initially stemmed from the observations of late and very late stent thrombosis events in the first-generation drug-eluting stent (DES) era, DAPT has been recently transitioning from a purely stent-related to a more systemic secondary prevention strategy. Oral and parenteral platelet P2Y12 inhibitors are currently available for clinical use. The latter have been shown to be extremely suitable in drug-naïve patients with acute coronary syndrome (ACS), mainly because oral P2Y12 inhibitors are associated with delayed efficacy in patients with STEMI and because pre-treatment with P2Y12 inhibitors is discouraged in NSTE-ACS, and in patients with recent DES implantation and in need of urgent cardiac and non-cardiac surgery. More definitive evidence is needed, however, about optimal switching strategies between parenteral and oral P2Y12 inhibitors and about newer potent subcutaneous agents that are being developed for the pre-hospital setting.

Pathophysiology and Treatment of the No-Reflow Phenomenon in ST-Segment Elevation Myocardial Infarction: Focus on Low-Dose Fibrinolysis during Primary Percutaneous Intervention.

Primary percutaneous coronary intervention (PCI) is the current class I therapeutic approach to treat acute ST-elevation myocardial infarction (STEMI). While primary PCI can restore adequate flow in the infarcted artery in the majority of cases, some patients experience the 'no-reflow' phenomenon, i.e., an abnormal myocardial reperfusion occurring even after the occluded coronary artery has been opened. No-reflow occurs when microvascular obstruction arises from embolization of thrombus or components of the atheromatous plaques. These embolic materials travel downstream within the infarct-related artery at time of primary PCI, leading to compromised blood flow. Currently, no expert consensus documents exist to outline an optimal strategy to prevent or treat no-reflow. Interventional cardiologists frequently employ intracoronary adenosine, calcium channel blockers, nicorandil, nitroprusside or glycoprotein IIb/IIIa inhibitors. However, evidence suggests that these interventions consistently enhance myocardial blood flow in only a specific subset of patients experiencing no-reflow. A recent and innovative therapeutic approach gaining attention is low-dose fibrinolysis during primary PCI, which offers the potential to augment coronary flow post-myocardial revascularization.

Nonbacterial Thrombotic Endocarditis with Atypical Presentation as Overt Congestive Heart Failure.

Nonbacterial thrombotic endocarditis (NBTE) is a form of endocarditis associated with malignancy or autoimmune disorders. Diagnosis remains a challenge as patients are often asymptomatic up to embolic events or rarely, valve dysfunction. We report a case of NBTE with uncommon clinical presentation and identified with multimodal echocardiography. An 82-year-old man presented to our outpatient clinic reporting dyspnea. Past medical history included hypertension, diabetes, kidney disease, and unprovoked deep-vein thrombosis. On physical examination, he was apyretic, mildly hypotensive, and hypoxemic, had a systolic murmur and lower limbs edema. Transthoracic echocardiography revealed severe mitral regurgitation due to verrucous thickening of the free margin of both leaflets, increased pulmonary pressure, and dilated inferior vena cava. Multiple blood cultures were negative. Transesophageal echocardiography confirmed "thrombotic" thickening of mitral leaflets. Nuclear investigations were highly suggestive of multi-metastatic pulmonary cancer. We did not further proceed with the diagnostic workup and prescribed palliative care. Lesions seen on echocardiography were suggestive of NBTE: they involved both sides of mitral leaflets, close to the edges, had irregular shape and echo density, a broad base, and no independent motion. Criteria for infective endocarditis were not met and the final diagnosis was paraneoplastic NBTE due to underlying lung cancer. We remark the lack of definitive recommendations about the treatment of NBTE and the only role of anticoagulation to prevent systemic embolism. We have reported a case of NBTE presenting with atypical symptoms and likely related to the prothrombotic state induced by underlying lung cancer. Provided the unconclusive microbiological tests, multimodal imaging has played a crucial role in the final diagnosis.

Prediction of radial crossover in acute coronary syndromes: derivation and validation of the MATRIX score.

BACKGROUND: The radial artery is recommended by international guidelines as the default vascular access in patients with acute coronary syndromes (ACS) managed invasively. However, crossover from radial to femoral access is required in 4-10% of cases and has been associated with worse outcomes. No standardised algorithm exists to predict the risk of radial crossover. AIMS: We sought to derive and externally validate a risk score to predict radial crossover in patients with ACS managed invasively. METHODS: The derivation cohort consisted of 4,197 patients with ACS undergoing invasive management via the randomly allocated radial access from the MATRIX trial. Using logistic regression, we selected predictors of radial crossover and developed a numerical risk score. External validation was accomplished among 3,451 and 491 ACS patients managed invasively and randomised to radial access from the RIVAL and RIFLE-STEACS trials, respectively. RESULTS: The MATRIX score (age, height, smoking, renal failure, prior coronary artery bypass grafting, ST-segment elevation myocardial infarction, Killip class, radial expertise) showed a c-index for radial crossover of 0.71 (95% CI: 0.67-0.75) in the derivation cohort. Discrimination ability was modest in the RIVAL (c-index: 0.64; 95% CI: 0.59-0.67) and RIFLE-STEACS (c-index: 0.66; 95% CI: 0.57-0.75) cohorts. A cut-off of ≥41 points was selected to identify patients at high risk of radial crossover. CONCLUSIONS: The MATRIX score is a simple eight-item risk score which provides a standardised tool for the prediction of radial crossover among patients with ACS managed invasively. This tool can assist operators in anticipating and better addressing difficulties related to transradial procedures, potentially improving outcomes.

Downstream or upstream administration of P2Y12 receptor blockers in non-ST elevated acute coronary syndromes: study protocol for a randomized controlled trial.

BACKGROUND: The optimal timing to administer a P2Y12 inhibitor in patients presenting with a non-ST elevation acute coronary syndrome remains a topic of debate. Pretreatment with ticagrelor before coronary anatomy is known as a widely adopted strategy. However, there is poor evidence on how this compares with administration of a P2Y12 inhibitor after defining coronary anatomy (i.e., downstream administration). Moreover, there are limited head-to-head comparisons of the two P2Y12 inhibitors-ticagrelor and prasugrel-currently recommended by the guidelines. STUDY DESIGN: DUBIUS is a phase 4, multicenter, parallel-group, double randomized study conducted in NSTE-ACS patients designed to compare a pretreatment strategy (including only ticagrelor) versus a downstream strategy (including prasugrel or ticagrelor) and to compare downstream prasugrel with downstream ticagrelor. A total of 2520 patients will be randomly assigned to pretreatment with ticagrelor or to no pretreatment. The PCI group of the downstream arm will be further randomized to receive prasugrel or ticagrelor. The two primary hypotheses are that the downstream strategy is superior to the upstream strategy and that downstream ticagrelor is non-inferior to downstream prasugrel, both measured by the incidence of a composite efficacy and safety endpoint of death from vascular causes, non-fatal MI, or non-fatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleedings. CONCLUSIONS: The DUBIUS study will provide important evidence related to the benefits and risks of pretreatment with ticagrelor compared with a strategy of no pretreatment. Moreover, the clinical impact of using downstream ticagrelor compared with downstream prasugrel will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02618837 . Registered on 1 December 2015.

Timing of Oral P2Y12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Although oral P2Y12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined. OBJECTIVES: The purpose of this study was to compare downstream and upstream oral P2Y12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment. METHODS: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit). RESULTS: We randomized 1,449 patients to downstream or upstream oral P2Y12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment). CONCLUSIONS: Downstream and upstream oral P2Y12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837).

Long-term benefit of renal denervation on blood pressure control in a patient with hemorrhagic stroke.

A 49-year-old man with malignant hypertension had been admitted with hemorrhagic stroke. Refractory hypertension had been observed during hospitalization and the decision had been made to perform renal denervation. A significant blood pressure reduction was obtained immediately after renal denervation and persists at 2-year follow-up. This case demonstrates the long-term sustained efficacy of renal denervation performed in the acute phase of hemorrhagic stroke. In addition, it supports the notion that renal denervation-induced normalization of blood pressure may contribute to better outcomes in a challenging setting such as intracranial bleeding.

Obstructive sleep apnoea syndrome and endothelial function: potential impact of different treatment strategies-meta-analysis of prospective studies.

PURPOSE: Previous studies have shown an association between obstructive sleep apnoea syndrome (OSAS) and cardiovascular events. Whether this association is mediated by an impairment of endothelial function, which is itself a driver of elevated cardiovascular risk, has yet to be clarified, as it is the eventual protective role of several OSAS treatments. The aim of our meta-analysis is to evaluate the effect of various OSAS treatments on endothelial function calculated by means of flow-mediated dilatation (FMD). METHODS: We conducted a meta-analysis of prospective studies including patients affected by mild to severe OSAS treated with continuous positive airway pressure (CPAP), surgery, oral appliance and medical treatments. FMD was measured before and after treatment RESULTS: After pooling results from different treatment strategies, OSAS treatment showed a positive impact on endothelial function (Mean Difference [MD] = 2.58; 95% CI 1.95-3.20; p < 0.00001). CONCLUSIONS: Our study supports the hypothesis that several modalities of treatment for OSAS positively impact endothelial function. Whether this effect also associates with an improvement of clinical outcomes remains to be ascertained.

Pharmacokinetics of new oral anticoagulants: implications for use in routine care.

INTRODUCTION: Since 2008, new oral anticoagulants (NOACs) have been approved for the prevention of venous thromboembolism (VTE) in patients receiving hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), treatment of deep vein thrombosis (DVT), and pulmonary embolism (PE). Premarketing randomized clinical trials (RCTs) of NOACs demonstrated their non-inferiority in terms of efficacy vs. warfarin (traditional oral anticoagulant - TOA), with lower risk of serious adverse drug reactions, especially cerebral hemorrhages. In clinical practice, pharmacokinetic aspects of NOACs have to be carefully taken into account to optimize the benefit-risk profile of these drugs. Areas covered: An overview of major issues related to pharmacokinetics of NOACs, such as drug-drug interactions, over- and underdosage in special populations (e.g. elderly, underweight, and chronic kidney disease patients), and impact on adherence and persistence to NOACs therapy and ultimately clinical outcomes in real-world setting, is provided. Expert opinion: NOACs have been proven to be a better option than traditional anticoagulants due to better tolerability and ease of use. However, given specific pharmacokinetic characteristics, NOAC therapy has to be carefully tailored and monitored in relation to patient characteristics with the final goal of maximizing benefits and minimizing risks.

Bivalirudin or Heparin in Patients Undergoing Invasive Management of Acute Coronary Syndromes.

BACKGROUND: Contrasting evidence exists on the comparative efficacy and safety of bivalirudin and unfractionated heparin (UFH) in relation to the planned use of glycoprotein IIb/IIIa inhibitors (GPIs). OBJECTIVES: This study assessed the efficacy and safety of bivalirudin compared with UFH with or without GPIs in patients with acute coronary syndrome (ACS) who underwent invasive management. METHODS: In the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX) program, 7,213 patients were randomly assigned to receive either bivalirudin or UFH with or without GPIs at discretion of the operator. The 30-day coprimary outcomes were major adverse cardiovascular events (MACEs) (a composite of death, myocardial infarction, or stroke), and net adverse clinical events (NACEs) (a composite of MACEs or major bleeding). RESULTS: Among 3,603 patients assigned to receive UFH, 781 (21.7%) underwent planned treatment with GPI before coronary intervention. Bailout use of GPIs was similar between the bivalirudin and UFH groups (4.5% and 5.4%) (p = 0.11). At 30 days, the 2 coprimary endpoints of MACEs and NACEs, as well as individual endpoints of mortality, myocardial infarction, stent thrombosis or stroke did not differ among the 3 groups after adjustment. Compared with the UFH and UFH+GPI groups, bivalirudin reduced bleeding, mainly the most severe bleeds, including fatal and nonaccess site-related events, as well as transfusion rates and the need for surgical access site repair. These findings were not influenced by the administered intraprocedural dose of UFH and were confirmed at multiple sensitivity analyses, including the randomly allocated access site. CONCLUSIONS: In patients with ACS, the rates of MACEs and NACEs were not significantly lower with bivalirudin than with UFH, irrespective of planned GPI use. However, bivalirudin significantly reduced bleeding complications, mainly those not related to access site, irrespective of planned use of GPIs. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX [MATRIX]; NCT01433627).

Takotsubo syndrome and estrogen receptor genes: partners in crime?

AIMS: We aimed to analyze genetic polymorphism of estrogen receptor (ESR) 1 and ESR2 in a series of postmenopausal women with Takotsubo syndrome (TS). METHODS: In total, 81 consecutive white women were prospectively enrolled: 22 with TS (TS group; mean age 71.2 ±â€Š9.8 years), 22 with acute myocardial infarction (MI group; mean age 73.2 ±â€Š8 years), and 37 asymptomatic healthy controls (CTRL group; mean age 69 ±â€Š4.2 years). Genotyping of ESR1 -397C>T (rs2234693) and -351A>G (rs9340799) and ESR2 -1839G>T (rs 1271572) and 1082G>A (rs1256049) genetic variants was performed. We estimated the odds ratio (OR) between the genotype of each examined locus with the occurrence of TS or MI. RESULTS: The risk of experiencing TS was higher for those study participants carrying the T allele at the rs2234693 locus of the ESR1 gene [OR: 2.0, 95% confidence interval (CI): 0.973-4.11, P = 0.04, TS vs. MI + CTRL; OR: 2.79, 95% CI: 1.17-6.64, P = 0.016, TS vs. MI alone]. Women carrying a T allele at the rs1271572 locus of the ESR2 gene demonstrated an even higher risk (OR: 3.23, 95% CI: 1.55-6.73, P = 0.0019, TS vs. MI + CTRL; OR: 9.13, 95% CI: 2.78-29.9, P = 0.0001, TS vs. MI alone). CONCLUSION: The study reports preliminary findings suggesting a possible link between ESR polymorphisms and the occurrence of TS. Larger studies are needed to confirm our results.

Cardiovascular outcomes and conventional risk factors in non-diabetic adult patients with GH deficiency: A long-term retrospective cohort study.

PURPOSE: To investigate the association between cardiovascular (CV) risk factors and cumulative CV events in patients with growth hormone deficiency (GHD) receiving GH replacement therapy (GHRT). METHODS: 53 non-diabetic adult GHD patients, aged 45.4±14.3years, 31 females, with a median follow up of 140months, were divided into two groups based on the presence (group A) or absence (group B) of systemic hypertension. Tertiles of age and LDL-cholesterol were considered as further potential prognosticators. Cumulative CV event rates were recorded and analyzed by Kaplan-Mayer method. Differences between patients with and without events were also evaluated. RESULTS: Seventeen patients (32%) entered the group A and 36 (68%) the group B. A composite of fatal and non-fatal CV events occurred in 22.6% of patients, 47.1% in group A and 11% in group B (p=0.01), CV deaths in 3 patients (5.7%; annual death rate 0.49%), 2 of whom were in group A. At Kaplan-Mayer analysis, hypertension and age>55years were major prognosticators. The odds ratio was 7.1 (95% CI: 1.74-29.12, p<0.003) and 6.2 (95% CI: 1.54-25.04, p<0.006), respectively. LDL-cholesterol showed borderline statistical significance. Patients with CV events also had high prevalence of left ventricular hypertrophy, left atrial enlargement and subclinical systolic dysfunction. CONCLUSIONS: In this study, outcomes were mainly related to hypertension and age (partially to LDL-cholesterol), confirming that management of GHD patients must be inclusive of treatment of conventional risk factors, being as important as GHRT. Optimal blood pressure control is crucial when a target organ damage is present and in patients older than 55years.

Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial.

BACKGROUND: It is unclear whether radial compared with femoral access improves outcomes in unselected patients with acute coronary syndromes undergoing invasive management. METHODS: We did a randomised, multicentre, superiority trial comparing transradial against transfemoral access in patients with acute coronary syndrome with or without ST-segment elevation myocardial infarction who were about to undergo coronary angiography and percutaneous coronary intervention. Patients were randomly allocated (1:1) to radial or femoral access with a web-based system. The randomisation sequence was computer generated, blocked, and stratified by use of ticagrelor or prasugrel, type of acute coronary syndrome (ST-segment elevation myocardial infarction, troponin positive or negative, non-ST-segment elevation acute coronary syndrome), and anticipated use of immediate percutaneous coronary intervention. Outcome assessors were masked to treatment allocation. The 30-day coprimary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and net adverse clinical events, defined as major adverse cardiovascular events or Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass graft surgery. The analysis was by intention to treat. The two-sided α was prespecified at 0·025. The trial is registered at ClinicalTrials.gov, number NCT01433627. FINDINGS: We randomly assigned 8404 patients with acute coronary syndrome, with or without ST-segment elevation, to radial (4197) or femoral (4207) access for coronary angiography and percutaneous coronary intervention. 369 (8·8%) patients with radial access had major adverse cardiovascular events, compared with 429 (10·3%) patients with femoral access (rate ratio [RR] 0·85, 95% CI 0·74-0·99; p=0·0307), non-significant at α of 0·025. 410 (9·8%) patients with radial access had net adverse clinical events compared with 486 (11·7%) patients with femoral access (0·83, 95% CI 0·73-0·96; p=0·0092). The difference was driven by BARC major bleeding unrelated to coronary artery bypass graft surgery (1·6% vs 2·3%, RR 0·67, 95% CI 0·49-0·92; p=0·013) and all-cause mortality (1·6% vs 2·2%, RR 0·72, 95% CI 0·53-0·99; p=0·045). INTERPRETATION: In patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events, through a reduction in major bleeding and all-cause mortality. FUNDING: The Medicines Company and Terumo.