William J. French

Platelet inhibition with cangrelor in patients undergoing PCI

BACKGROUND Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y(12). This agent might have a role in the treatment of patients who require rapid, predictable, and profound but reversible platelet inhibition. METHODS We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. RESULTS We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14). CONCLUSIONS Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopidogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. (ClinicalTrials.gov number, NCT00305162.)

The volume of primary angioplasty procedures and survival after acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators.

BACKGROUND There is an inverse relation between mortality from cardiovascular causes and the number of elective cardiac procedures (coronary angioplasty, stenting, or coronary bypass surgery) performed by individual practitioners or hospitals. However, it is not known whether patients with acute myocardial infarction fare better at centers where more patients undergo primary angioplasty or thrombolytic therapy than at centers with lower volumes. METHODS We analyzed data from the National Registry of Myocardial Infarction to determine the relation between the number of patients receiving reperfusion therapy (primary angioplasty or thrombolytic therapy) and subsequent in-hospital mortality. A total of 450 hospitals were divided into quartiles according to the volume of primary angioplasty. Multiple logistic-regression models were used to determine whether the volume of primary angioplasty procedures was an independent predictor of in-hospital mortality among patients undergoing this procedure. Similar analyses were performed for patients receiving thrombolytic therapy at 516 hospitals. RESULTS In-hospital mortality was 28 percent lower among patients who underwent primary angioplasty at hospitals with the highest volume than among those who underwent angioplasty at hospitals with the lowest volume (adjusted relative risk, 0.72; 95 percent confidence interval, 0.60 to 0.87; P<0.001). This lower rate, which represented 2.0 fewer deaths per 100 patients treated, was independent of the total volume of patients with myocardial infarction at each hospital, year of admission, and use or nonuse of adjunctive pharmacologic therapies. There was no significant relation between the volume of thrombolytic interventions and in-hospital mortality among patients who received thrombolytic therapy (7.0 percent for patients in the highest-volume hospitals vs. 6.9 percent for those in the lowest-volume hospitals, P=0.36). CONCLUSIONS Among hospitals in the United States that have full interventional capabilities, a higher volume of angioplasty procedures is associated with a lower mortality rate among patients undergoing primary angioplasty, but there is no association between volume and mortality for thrombolytic therapy.

A composite view of cardiac rupture in the United States National Registry of Myocardial Infarction.

OBJECTIVES This study was done to determine the incidence, timing and prevalence as a cause of death from cardiac rupture in patients with acute myocardial infarction. BACKGROUND Several clinical trials and overview analyses have suggested that the survival benefit conferred by thrombolytic therapy may be offset by a paradoxic increase in early deaths from cardiac rupture. METHODS Demographic, procedural and outcome data from patients with acute myocardial infarction were collected at 1,073 United States hospitals collaborating in the United States National Registry of Myocardial Infarction. RESULTS Among the 350,755 patients enrolled, 122,243 received thrombolytic therapy. In-hospital mortality for the overall patient population, those not treated with thrombolytics (n = 228,512) and those given thrombolytics were 10.4%, 12.9% and 5.9%, respectively (p<0.001). Cardiogenic shock was the most common cause of death in each patient group. Although the incidence of cardiac rupture was low (<1.0%), it was responsible for 7.3%, 6.1% and 12.1%, respectively, of in-hospital deaths (p<0.001). Death from rupture occurred earlier in patients given thrombolytic therapy, with a clustering of events within 24 h of drug administration. Despite the early risk, death rates were comparatively low in thrombolytic-treated patients on each of the first 30 days. By multivariable analysis, thrombolytics, prior myocardial infarction, advancing age, female gender and intravenous beta-blocker use were independently associated with cardiac rupture. CONCLUSIONS This large registry experience, including over 350,000 patients with myocardial infarction, suggests that thrombolytic therapy accelerates cardiac rupture, typically to within 24 to 48 h of treatment. The possibility that rupture represents an early hemorrhagic complication of thrombolytic therapy should be investigated.

Use of Lipid-Lowering Medications at Discharge in Patients With Acute Myocardial Infarction Data From the National Registry of Myocardial Infarction 3

Background—The present study aimed to assess use of lipid-lowering medication at discharge in a current national sample of patients hospitalized with acute myocardial infarction and to evaluate factors associated with prescribing patterns. Methods and Results—Demographic, procedural, and discharge medication data were collected from 138 001 patients with acute myocardial infarction discharged from 1470 US hospitals participating in the National Registry of Myocardial Infarction 3 from July 1998 to June 1999. Lipid-lowering medications were part of the discharge regimen in 31.7%. Among patients with prior history of CAD, revascularization, or diabetes, less than one half of the patients were discharged on treatment. In multivariate analysis, factors independently related to lipid-lowering use included history of hypercholesterolemia (odds ratio [OR] 4.93; 95% CI 4.79 to 5.07), cardiac catheterization during hospitalization (OR 1.29; 95% CI 1.24 to 1.34), care provided at a teaching hospital, (OR 1.26; 95% CI 1.22 to 1.32), use of &bgr;-blocker (OR 1.43; 95% CI 1.39 to 1.48), and smoking cessation counseling (OR 1.51; 95% CI 1.44 to 1.59). Lipid-lowering medications were given less often to patients who were older (65 to 74 versus <55 years of age; OR 0.82; 95% CI 0.78 to 0.86), those with a history of hypertension (OR 0.92; 95% CI 0.89 to 0.95), and those undergoing coronary artery bypass graft surgery (OR 0.58; 95% CI 0.55 to 0.60). Conclusions—Analysis of current practice patterns for the use of lipid-lowering medications in patients hospitalized with acute myocardial infarction reveals that a significant proportion of high-risk patients did not receive treatment at time of discharge.

Clinical Experience With Primary Percutaneous Transluminal Coronary Angioplasty Compared With Alteplase (Recombinant Tissue-Type Plasminogen Activator) in Patients With Acute Myocardial Infarction : A Report From the Second National Registry of Myocardial Infarction (NRMI-2)

OBJECTIVES We sought to compare outcomes after primary percutaneous transluminal coronary angioplasty (PTCA) or thrombolytic therapy for acute myocardial infarction (MI). BACKGROUND Primary PTCA and thrombolytic therapy are alternative means of achieving reperfusion in patients with acute MI. The Second National Registry of Myocardial Infarction (NRMI-2) offers an opportunity to study the clinical experience with these modalities in a large patient group. METHODS Data from NRMI-2 were reviewed. RESULTS From June 1, 1994 through October 31, 1995, 4,939 nontransfer patients underwent primary PTCA within 12 h of symptom onset, and 24,705 patients received alteplase (recombinant tissue-type plasminogen activator [rt-PA]). When lytic-ineligible patients and patients presenting in cardiogenic shock were excluded, baseline characteristics were similar. The median time from presentation to initiation of rt-PA in the thrombolytic group was 42 min; the median time to first balloon inflation in the primary PTCA group was 111 min (p < 0.0001). In-hospital mortality was higher in patients in shock after rt-PA than after PTCA (52% vs. 32%, p < 0.0001). In-hospital mortality was the same in lytic-eligible patients not in shock: 5.4% after rt-PA and 5.2% after PTCA. The stroke rate was higher after lytic therapy (1.6% vs. 0.7% after PTCA, p < 0.0001), but the combined end point of death and nonfatal stroke was not significantly different between the two groups (6.2% after rt-PA and 5.6% after PTCA). There was no difference in the rate of reinfarction (2.9% after rt-PA and 2.5% after PTCA). CONCLUSIONS These findings suggest that in lytic-eligible patients not in shock, PTCA and rt-PA are comparable alternative methods of reperfusion when analyzed in terms of in-hospital mortality, mortality plus nonfatal stroke and reinfarction.

The prehospital electrocardiogram in acute myocardial infarction : Is its full potential being realized?

OBJECTIVES This study sought to examine the management and subsequent outcomes of patients with a prehospital electrocardiogram (ECG) in a large, voluntary registry of myocardial infarction. BACKGROUND The prehospital ECG has been proposed as a means of rapidly identifying patients with acute myocardial infarction who might be eligible for reperfusion therapy. METHODS The characteristics and outcomes of patients with a prehospital ECG were compared with those without a prehospital ECG in the National Registry of Myocardial Infarction 2 data base. Included in the analysis were those patients who presented to the hospital within 12 h of an acute myocardial infarction. Excluded were patients with an in-hospital infarction, transferred-in referrals and self-transported patients. RESULTS Prehospital ECGs were obtained in 3,768 (5%) of 66,995 National Registry of Myocardial Infarction 2 patients meeting study criteria. Median time from myocardial infarction symptom onset until hospital arrival was longer among those having a prehospital ECG (152 vs. 91 min, p < 0.001). However, once in the hospital, the prehospital ECG group experienced a shorter median time to the initiation of either thrombolysis (30 vs. 40 min, p < 0.001) or primary angioplasty (92 vs. 115 min, p < 0.001). The prehospital ECG group was more likely to receive thrombolytic therapy (43% vs. 37%, p < 0.001) and to undergo primary angioplasty (11% vs. 7%, p < 0.001). Also, the prehospital ECG group was more likely to undergo coronary arteriography (55% vs. 40%, p < 0.001), angioplasty (24% vs. 16%, p < 0.001) or bypass surgery (10% vs. 6%, p < 0.001). The in-hospital mortality rate was 8% in patients with a prehospital ECG and 12% in those without a prehospital ECG (p < 0.001). After adjusting for baseline covariates utilizing multiple logistic regression analysis, this mortality difference remained statistically significant (odds ratio 0.83, 95% confidence interval 0.71 to 0.96, p = 0.01). CONCLUSIONS The prehospital ECG is infrequently utilized for diagnosing myocardial infarction, and among patients with a prehospital ECG, is associated with a longer time from symptom onset to hospital arrival. Despite these shortcomings, the prehospital ECG is a test that may potentially influence the management of patients with acute myocardial infarction through wider, faster in-hospital utilization of reperfusion strategies and greater usage of invasive procedures, factors that may possibly reduce shortterm mortality. Efforts to implement the prehospital ECG more widely and more rapidly may be indicated.

Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Participants in the National Registry of Myocardial Infarction 2

Numerous large clinical trials of thrombolytic therapy have shown impressive reductions in mortality associated with the use of thrombolytic agents in the setting of acute myocardial infarction. They have also consistently shown that thrombolysis imposes an excess risk for intracranial hemorrhage [1]. Although the incidence of intracranial hemorrhage associated with thrombolytic therapy is low, this complication is characterized by high fatality rates and substantial disability among survivors. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator (tPA) for Occluded Coronary Arteries (GUSTO-I) trial, intracranial hemorrhage rates were 0.46%, 0.57%, 0.70%, and 0.88% among patients treated with streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tPA, and combination therapy, respectively. Sixty percent of patients who had intracranial hemorrhage died, and another 25% were disabled [2]. The underuse of thrombolysis in special patient populations, such as elderly persons, is usually attributed to concerns about the risk for bleeding, particularly intracranial hemorrhage [3, 4]. These concerns often dominate decisions about the use of thrombolytic agents in eligible elderly patients with acute myocardial infarction despite the potential for substantial survival benefits from treatment [1]. In the GUSTO-I trial [5], 0.42% of patients younger than 75 years of age treated with streptokinase and 0.52% of those treated with accelerated tPA experienced a hemorrhagic stroke by 30 days of follow-up. Among patients older than 75 years of age, these values were 1.23% and 2.08%, respectively. Simoons and colleagues [6] combined information from a national registry of thrombolytic therapy with data from multiple thrombolytic trials to identify 150 patients who had had intracranial hemorrhage and compared them with 294 patients with acute myocardial infarction who received thrombolytic therapy but did not experience this outcome. After adjustment for other factors, including type of thrombolytic agent, body weight, and presence of hypertension on admission, patients older than 65 years of age were significantly more likely to experience intracranial hemorrhage (odds ratio, 2.2 [95% CI, 1.4 to 3.5]). Most information on the risk for intracranial hemorrhage associated with thrombolytic therapy in acute myocardial infarction derives from the experience of patients participating in clinical trials, in which stringent enrollment criteria are applied before thrombolytic therapy is administered [2, 7, 8]. The experience in the community setting has not been well described. The extent to which the clinician can extrapolate clinical trial data on the benefits and the risks of therapeutic interventions to the general practice setting is often unclear [9]. We used data from an ongoing national registry of patients who were hospitalized for acute myocardial infarction to determine the frequency of and risk factors for intracranial hemorrhage in patients treated with tPA, with particular focus on the relation between advancing age and this complication. Methods Data Sources The National Registry of Myocardial Infarction 2 (NRMI 2) was initiated in June 1994 as an ongoing registry of patients who received therapy for acute myocardial infarction at selected U.S. hospitals. The registry is supported by Genentech, Inc. (South San Francisco, California). From 1 June 1994 to 30 September 1996, 1484 U.S. hospitals contributed patients to NRMI 2. Participation in the registry is voluntary. Registry hospitals are substantially larger than nonparticipating U.S. hospitals: Twenty-seven percent of registry hospitals have more than 350 beds compared with 8% of nonregistry hospitals. In addition, registry hospitals are more likely than nonregistry hospitals to be certified by the Joint Commission on Accreditation of Health Care Organizations (99% compared with 77%); be affiliated with a medical school (36% compared with 17%); and have a coronary care unit (73% compared with 31%), a cardiac catheterization laboratory (72% compared with 23%), and a cardiac surgery program (39% compared with 11%). Registry hospitals are encouraged to enter consecutive patients who have had acute myocardial infarction, regardless of treatment or outcome. Approval for hospital participation in the registry may include review by the local institutional review board or human research subjects committee as dictated by local policy. A study coordinator at each participating hospital completes individual data collection forms for each study patient; these forms are forwarded to an independent central data collection center (ClinTrials Research, Inc., Lexington, Kentucky) for processing. Data on individual hospitals are confidential and are available only to the contributing hospital. Patients Patients in our study had had acute myocardial infarction documented according to local hospital criteria (usually cardiac enzyme levels or results of electrocardiography or coronary angiography). For the purpose of our study, patients were those enrolled in NRMI 2 who received tPA as the initial reperfusion strategy from 1 June 1994 to 30 September 1996. To be eligible for study inclusion, patients could not have been transferred to a participating registry hospital from any other hospital (registry or otherwise) in the context of management of the acute myocardial infarction event. In addition, study patients could not have received a second dose of any thrombolytic agent. As of 30 September 1996, NRMI 2 included 389 130 patients. Of these, 99 694 had received tPA as the initial reperfusion strategy; 26 370 of these patients had been transferred from another hospital for treatment of acute myocardial infarction. Of the remaining 73 324 patients, 2115 had received a second dose of a thrombolytic agent and 136 patients had missing information on age or sex. This left 71 073 patients in the study sample. The number of study patients contributed per registry hospital ranged from 1 to 311. Definitions The occurrence of primary intracranial hemorrhage was indicated on the registry data collection form, along with the date and time of onset of neurologic symptoms and whether computed tomography or magnetic resonance imaging (MRI) was performed to confirm the event. Events reported to have been confirmed by computed tomography or MRI were of principal interest in our study. The time between administration of tPA and intracranial hemorrhage was calculated. Sequelae of intracranial hemorrhage were characterized as death during hospitalization, residual deficit at discharge, or no residual deficit at discharge. The magnitude of the residual deficit was not classified. The reported intracranial hemorrhages and the circumstances surrounding them were not independently verified; information on these events was limited to that available on the data collection form provided by the participating hospitals. We characterized patients according to age (<65 years, 65 to 74 years, or 75 years), sex, and ethnicity (white, black, or other). Clinical characteristics included history of myocardial infarction, angina, congestive heart failure, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, stroke, diabetes mellitus, hypertension, hypercholesterolemia, and smoking. Systolic and diastolic blood pressure were characterized according to the first measurement recorded at hospital presentation. Likewise, Killip class was measured at presentation (no evidence of congestive heart failure, presence of rales or jugular venous distention, pulmonary edema, or cardiogenic shock) [10]. The study sample was stratified into quartiles according to body weight (measured in kg). The dose of tPA administered was categorized as less than 1.5 mg/kg or 1.5 mg/kg or more. These categories were based on manufacturer recommendations for tPA dosing [11]. (For patients weighing >67 kg, the maximum recommended total tPA dose is 100 mg [ 1.49 mg/kg]. Dosage adjustments based on weight are advised for patients weighing 67 kg or less.) Duration of tPA infusion was categorized as 90 minutes or less (accelerated tPA) or more than 90 minutes. We also characterized patients according to use of aspirin or intravenous heparin, which may be relevant to risk for bleeding. Statistical Analysis To assess comparability with a large clinical trial population, selected characteristics of our study sample were compared with those of patients who received accelerated tPA plus intravenous heparin in the GUSTO-I trial [5]. For our study sample, we evaluated the bivariate association between intracranial hemorrhage and selected demographic and clinical patient characteristics. These variables were used to develop stepwise multivariable logistic regression models with the occurrence of intracranial hemorrhage (confirmed by computed tomography or MRI) as the dependent variable. Patients with unknown values for any variable were excluded from multivariable analyses. The models were constructed with an entry significance level of P = 0.01 and an exit significance level of P = 0.05. Estimated odds ratios for the risk for intracranial hemorrhage, adjusted for all remaining variables, were obtained by using this model. Interactions between patient age and all other variables remaining in the final regression model were assessed. The goodness-of-fit criteria of Hosmer and Lemeshow were assessed for all models [12]. In addition, we calculated an area under the receiver-operating characteristic curve for each model [13]. All tests of statistical significance were two-tailed; a P value less than 0.05 was considered statistically significant. Multiple logistic regression analyses were performed by using the SAS PROC LOGISTIC procedure in SAS, version 6 (SAS Institute, Inc., Cary, North Carolina). The main-effects models were refit by using SAS PROC PHREG to control for potential int

Trends in quality of care for patients with acute myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006

BACKGROUND Trends in the use of guideline-based treatment for acute myocardial infarction (AMI) as well as its association with patient outcomes have not been summarized in a large, longitudinal study. Furthermore, it is unknown whether gender-, race-, and age-based care disparities have narrowed over time. METHODS AND RESULTS Using the National Registry of Myocardial Infarction database, we analyzed 2,515,106 patients with AMI admitted to 2,157 US hospitals between July 1990 and December 2006 to examine trends overall and in select subgroups of guideline-based admission, procedural, and discharge therapy use. The contribution of temporal improvements in acute care therapies to declines in in-hospital mortality was examined using logistic regression analysis. From 1990 to 2006, the use of all acute guideline-recommended therapies administered rose significantly for patients with ST-segment elevation myocardial infarction and patients with non-ST-segment myocardial infarction but remained below 90% for most therapies. Cardiac catheterization and percutaneous coronary intervention use increased in patients with ST-segment elevation myocardial infarction and patients with non-ST-segment myocardial infarction, whereas coronary bypass surgery use declined in both groups. Despite overall care improvements, women, blacks, and patients > or =75 years old were significantly less likely to receive revascularization or discharge lipid-lowering therapy relative to their counterparts. Temporal improvements in acute therapies may account for up to 37% of the annual decline in risk for in-hospital AMI mortality. CONCLUSION Adherence to American Heart Association/American College of Cardiology practice guidelines has improved care of patients with AMI and is associated with significant reductions in in-hospital mortality rates. However, persistent gaps in overall care as well as care disparities remain and suggest the need for ongoing quality improvement efforts.

Implementation and Integration of Prehospital ECGs Into Systems of Care for Acute Coronary Syndrome A Scientific Statement From the American Heart Association Interdisciplinary Council on Quality of Care and Outcomes Research, Emergency Cardiovascular Care Committee, Council on Cardiovascular Nursing, and Council on Clinical Cardiology

Clinical case: A 58-year-old woman called 9-1-1 with acute onset of chest pain that had persisted for 30 minutes. She had a history of hypertension, hyperlipidemia, and type 2 diabetes mellitus but no previous history of myocardial infarction or heart failure. Her medications included aspirin, atorvastatin, lisinopril, and metoprolol. Paramedics were dispatched, and a prehospital ECG demonstrated 3- to 4-mm ST-segment elevation in leads I, aVL, and V2 through V6 (Figure 1). Her examination revealed a regular pulse of 90 bpm, a blood pressure of 100/60 mm Hg, clear lungs, and normal heart sounds with no murmurs. Paramedics interpreted the prehospital ECG and activated the catheterization laboratory en route to the hospital. On hospital arrival, the patient was transported directly to the catheterization laboratory. Coronary angiography demonstrated an occluded proximal left anterior descending artery, which was successfully treated with balloon angioplasty and a stent. The pertinent time intervals were as follows: paramedic dispatch to balloon time, 56 minutes; paramedic arrival at the scene to balloon time, 46 minutes; hospital door to balloon time, 23 minutes. Her biomarkers revealed a peak troponin T of 2.42 ng/mL and a peak creatine kinase muscle-brain isoenzyme of 26.8 ng/mL. An echocardiogram demonstrated normal left ventricular ejection fraction of 55%, with mild anterior hypokinesis, and the patient was discharged on hospital day 3. Figure 1. Prehospital ECG. American Heart Association national guidelines,1–3 as well as other consensus and scientific statements,4–11 recommend that emergency medical services (EMS) acquire and use prehospital ECGs to evaluate patients with suspected acute coronary syndrome. Despite these recommendations, prehospital ECGs are used in fewer than 10% of patients with ST-segment–elevation myocardial infarction (STEMI),12,13 and this rate has not substantially changed since the mid-1990s. Furthermore, even when a prehospital ECG is acquired, the information is often not …

Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data

BACKGROUND Cangrelor is a potent, rapid-acting, reversible intravenous platelet inhibitor that was tested for percutaneous coronary intervention (PCI) in three large, double-blind, randomised trials. We did a pooled analysis of data from three trials that assessed the effectiveness of cangrelor against either clopidogrel or placebo in PCI. METHODS This prespecified, pooled analysis of patient-level data from three trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX) compared cangrelor with control (clopidogrel or placebo) for prevention of thrombotic complications during and after PCI. Trial participants were patients undergoing PCI for ST-elevation myocardial infarction (11.6%), non-ST-elevation acute coronary syndromes (57.4%), and stable coronary artery disease (31.0%). Efficacy was assessed in the modified intention-to-treat population of 24,910 patients, with a prespecified primary efficacy composite of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis at 48 h. The primary safety outcome was non-coronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe or life-threatening bleeding at 48 h. FINDINGS Cangrelor reduced the odds of the primary outcome by 19% (3.8% for cangrelor vs 4.7% for control; odds ratio [OR] 0.81, 95% CI 0.71-0.91, p=0.0007), and stent thrombosis by 41% (0.5% vs 0.8%, OR 0.59, 95% CI 0.43-0.80, p=0.0008). Cangrelor reduced the odds of the secondary triple composite (all-cause death, myocardial infarction, or ischaemia-driven revascularisation at 48 h) by 19% (3.6% vs 4.4%, OR 0.81, 95% CI 0.71-0.92, p=0.0014). Efficacy outcomes were consistent across the trials and main patient subsets. These benefits were maintained at 30 days. There was no difference in the primary safety outcome (0.2% in both groups), in GUSTO moderate bleeding (0.6% vs 0.4%), or in transfusion (0.7% vs 0.6%), but cangrelor increased GUSTO mild bleeding (16.8% vs 13.0%, p<0.0001). INTERPRETATION Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural thrombotic complications, at the expense of increased bleeding. FUNDING The Medicines Company.