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Big data (BD) in pediatric medication safety research provides many opportunities to improve the safety and health of children. The number of pediatric medication and device trials has increased in part because of the past 20 years of US legislation requiring and incentivizing study of the effects of medical products in children (Food and Drug Administration Modernization Act of 1997, Pediatric Rule in 1998, Best Pharmaceuticals for Children Act of 2002, and Pediatric Research Equity Act of 2003). There are some limitations of traditional approaches to studying medication safety in children. Randomized clinical trials within the regulatory context may not enroll patients who are representative of the general pediatric population, provide the power to detect rare safety signals, or provide long-term safety data. BD sources may have these capabilities. In recent years, medical records have become digitized, and cell phones and personal devices have proliferated. In this process, the field of biomedical science has progressively used BD from those records coupled with other data sources, both digital and traditional. Additionally, large distributed databases that include pediatric-specific outcome variables are available. A workshop entitled "Advancing the Development of Pediatric Therapeutics: Application of 'Big Data' to Pediatric Safety Studies" held September 18 to 19, 2017, in Silver Spring, Maryland, formed the basis of many of the ideas outlined in this article, which are intended to identify key examples, critical issues, and future directions in this early phase of an anticipated dramatic change in the availability and use of BD., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Objectives: Identifying high-risk heart failure (HF) patients at hospital discharge may allow more effective triage to management strategies., Background: Heart failure severity at presentation predicts outcomes, but the prognostic importance of clinical status changes due to interventions is less well described., Methods: Predictive models using variables obtained during hospitalization were created using data from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial and internally validated by the bootstrapping method. Model coefficients were converted to an additive risk score. Additionally, data from FIRST (Flolan International Randomized Survival Trial) was used to externally validate this model., Results: Patients discharged with complete data (n = 423) had 6-month mortality and death and rehospitalization rates of 18.7% and 64%, respectively. Discharge risk factors for mortality included BNP, per doubling (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.15 to 1.75), cardiopulmonary resuscitation or mechanical ventilation during hospitalization (HR: 2.54, 95% CI: 1.12 to 5.78), blood urea nitrogen, per 20-U increase (HR: 1.22, 95% CI: 0.96 to 1.55), serum sodium, per unit increase (HR: 0.93, 95% CI: 0.87 to 0.99), age >70 years (HR: 1.05, 95% CI: 0.51 to 2.17), daily loop diuretic, furosemide equivalents >240 mg (HR: 1.49, 95% CI: 0.68 to 3.26), lack of beta-blocker (HR: 1.28, 95% CI: 0.68 to 2.41), and 6-min walk, per 100-foot increase (HR: 0.955, 95% CI: 0.99 to 1.00; c-index 0.76). A simplified discharge score discriminated mortality risk from 5% (score = 0) to 94% (score = 8). Bootstrap validation demonstrated good internal validation of the model (c-index 0.78, 95% CI: 0.68 to 0.83)., Conclusions: The ESCAPE study discharge risk model and score refine risk assessment after in-hospital therapy for advanced decompensated systolic HF, allowing clinicians to focus surveillance and triage for early life-saving interventions in this high-risk population. (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE]; NCT00000619)., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate the impact of on-site cardiac interventional facilities on the management and outcome of patients with versus those without ST elevation acute coronary syndromes (ACS) in the Canadian-American Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb population., Methods: Data from 4605 patients were analyzed in relation to the admitting hospital's capability to perform coronary procedures (noninvasive, angiography-capable and interventional hospitals). Differences in medication use, revascularization rate and patient outcome were determined., Results: Whereas medication use during hospitalization and at discharge differed between non-ST elevation ACS patients treated in the three groups, these were generally more comparable among ST elevation ACS patients. In both ST segment cohorts, patients treated in interventional hospitals underwent coronary procedures more often (angiography rate greater than 70% versus 40% for noninvasive hospitals) and sooner (median two to three days versus four days in noninvasive hospitals) than those treated in other hospitals. Recurrent ischemia was significantly less common in non-ST elevation ACS patients treated in interventional hospitals (32% versus 36% in angiography-capable and 40% in noninvasive hospitals, P<0.001) and tended to be less common among ST elevation ACS patients treated in interventional hospitals. Patients treated in interventional hospitals tended to have lower mortality in the non-ST elevation ACS cohort but significantly fewer died in the ST elevation ACS during hospitalization and at 30 days, six months and one year (8.8% versus 11% in angiography-capable and 15% in noninvasive hospitals, P=0.015). These differences in mortality persisted after adjustment for key baseline covariates. Separate analysis of Canadian and American patients revealed similar mortality patterns, as to the total population, in both ST segment cohorts., Conclusions: Presence of an on-site cardiac interventional facility favourably affected the management and outcome of ACS patients in both non-ST and ST elevation cohorts.

Background: Improved patient selection may optimize the efficiency of cardiac catheterization in both high- and low-rate regions. The purpose of this study was to develop and validate a clinical model for predicting high-risk coronary artery disease (CAD) after myocardial infarction (MI) and to examine the model's potential impact on the use rate of both US and Canadian catheterization practices., Methods and Results: By the use of baseline clinical variables from 1122 patients in the angiographic substudy of the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-1) trial, we developed a model that was predictive of severe CAD (left main or triple-vessel disease). The final model, which included prior MI, age, sex, hyperlipidemia, and decreased left ventricular ejection fraction (C-index = 0.70), was externally validated in 781 patients in the GUSTO IIb trial. Although the probability of severe CAD predicted 5-year survival, the frequency of catheterization in both Canada and the United States bore no relationship to severe CAD risk in the GUSTO-1 trial. By use of the model, we estimated that as much as 15% of US catheterizations from both GUSTO-1 and GUSTO IIb might have been avoided, without significantly compromising the number of patients with severe CAD who were identified (sensitivity = 0.94). By applying the model to Canadian practices, an additional 30 cases of severe CAD might have been identified per every 1000 catheterizations performed, without increasing the catheterization rate., Conclusions: The likelihood of severe CAD after ST-elevation MI may be predicted from simple baseline clinical variables. The use of a severe CAD predictive model to guide patient selection might enhance the cost-effectiveness of both aggressive and conservative catheterization practices.

Aims: We used the GUSTO-I and GUSTO-III databases to evaluate our performance in treating cardiogenic shock patients over much of the 1990s., Methods and Results: GUSTO-I (1990-1993) and GUSTO-III (1995-1997) prospectively identified all patients with cardiogenic shock complicating acute myocardial infarction. Demographics, clinical presentation and outcomes for cardiogenic shock patients in the two trials were compared. Only patients enrolled with cardiogenic shock in countries common to both trials were included in these analysis. The 695 patients with cardiogenic shock in GUSTO-III were compared with the 2814 patients with cardiogenic shock in GUSTO-I. GUSTO-III patients were older (P=0.0001) and more likely to be diabetic (P=0.009) and hypertensive (P=0.025). They had a higher Killip class (P=0.002) and significantly greater index anterior infarction than cardiogenic shock patients enrolled in GUSTO-I. Time to treatment, presentation heart rate, and diastolic blood pressure were similar; however, systolic blood pressure at presentation was higher among GUSTO-III patients (P=0.002). Rates of coronary angiography, pulmonary artery catheterization, and mechanical ventilation declined in GUSTO-III compared with GUSTO-I (P=0.001); rates of angioplasty and bypass surgery were similar. Cardiogenic shock mortality in GUSTO-III was significantly higher than in GUSTO-I (62 vs 54%, P=0.001), as were rates of reinfarction (14 vs 11%, P=0.013) and recurrent ischaemia (35 vs 27%, P=0.00001). Mortality at non-U.S. sites (68 and 64%) was higher than at U.S. sites (53 and 50%) in both GUSTO-I and GUSTO-III studies, respectively. Angioplasty, bypass surgery, and balloon pump rates were lower for non-U.S. patients., Conclusions: Cardiogenic shock continues to be associated with high mortality in thrombolytic-treated patients. Lower mortality observed in the U.S.A. supports consideration for percutaneous and surgical revascularization., (Copyright 2000 The European Society of Cardiology.)

Background: Temporal changes in baseline characteristics, treatment and clinical outcomes of patients presenting with acute ST elevation myocardial infarction in Canada and the United States have not been examined comprehensively over time., Objectives: To evaluate baseline characteristics, process of care and clinical outcomes. Also, to explore whether earlier process-of-care differences between Canada and the United States had changed and, if so, whether they influenced clinical outcomes., Patients and Methods: A total of 13, 888 American and 3011 Canadian patients enrolled in 184 American and 38 Canadian hospitals that participated in both the Global Utilization of Streptokinase and Tissue Plasminogen Activator (alteplase) for Occluded Coronary Arteries (GUSTO-I) trial (1990 to 1993) and the Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial (1995 to 1997) were studied. Logistic regression was used to identify significant prognostic factors, to assess illness severity at hospital presentation and to classify trends between Canada and the United States., Results: In both countries, illness severity on admission increased, door-to-needle time for thrombolysis was reduced, intensive care unit stay was shortened and hospital stay decreased from GUSTO-I to GUSTO-III. Whereas the administration of oral nitrates, calcium blockers and beta-blockers at discharge converged over time between countries, the disparity in the use of angiography and revascularization widened; the rise in American revascularization rate was most evident in patients without in-hospital ischemia. The 30-day and one-year mortality rates were comparable and declined nonsignificantly in both countries., Conclusions: Despite increased illness severity and varying medication and procedure rates, there was no increase over time in 30-day or one-year mortality; this remained comparable between countries throughout the seven-year observation period.

Background: Significant differences are known to exist between the United States and Canada with respect to coronary catheterization and intervention. In a post hoc analysis, it was hypothesized that these differences may have the greatest impact on outcome in patients at risk for recurrent events such as those following myocardial infarction (MI)., Patients and Methods: The hypothesis was tested in a nonrandomized comparison of the catheterization and revascularization patterns for patients following acute MI in 7029 patients in the United States and 1774 patients in Canada who participated in the Coumadin/Aspirin Reinfarction Study (CARS). CARS tested the effectiveness of low dose warfarin in combination with acetylsalicylic acid (ASA) versus ASA alone in reducing cardiovascular morbidity and mortality., Results: Before study enrollment (median day 7 to 8), 84.5% of the American patients underwent coronary angiography compared with only 7.7% in Canada (P<0.01). CARS patients in the United States underwent significantly more frequent angioplasty during their hospital admission before study enrollment than their Canadian counterparts (55.8% versus 3.0%, respectively, P<0.01), and there was a more frequent use of intravenous heparin among American CARS patients (96% versus 88%, respectively, P<0.01) but less frequent administration of thrombolytic therapy (44% versus 49%, respectively, P<0.01). For follow-up of up to 32 months, American CARS patients had significantly fewer primary events (cardiovascular deaths, nonfatal MI, nonfatal ischemic stroke) than Canadian patients. Cumulative estimate of a primary end point comparing American with Canadian patients was, respectively, 2.0% versus 3.1% at one month, 8.0% versus 11.3% at one year and 11.6% versus 15.0% at two years. Thus, time to the primary event was significantly longer in American patients (P=0.0001). All-cause mortality estimates at 12 months were 2.2% and 4.0%, respectively, for the American and Canadian CARS subgroups. When management for the index MI (ie, angiography and angioplasty) is included in the model, the risk of death for Canadian versus American subgroups of CARS is not statistically different (0.9, 95% CI 0.6 to 1.2, P=0.40)., Conclusion: Among study participants, American patients experienced a better outcome than Canadian patients, which may be attributable to more aggressive management based on early coronary angiography and angioplasty. However, angioplasty before study enrollment in American patients may have resulted in enrollment of lower risk patients. This selection bias limits the scope of the comparison.

The objective of this study was to examine whether there are international variations in the use of evidence-based medical therapy in patients undergoing percutaneous coronary revascularization. We analyzed the medical therapy of patients in the United States (US) (n = 878), Europe (n = 134), and Canada (n = 274) who underwent percutaneous coronary revascularization in either the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) (enrollment from August 1991 to April 1992) or the Canadian Coronary Atherectomy Trial (CCAT) (enrollment from July 1991 to August 1992). We found that at the time of hospital admission, Canadian patients had the highest rates of treatment with aspirin (95% vs 57% US and 78% Europe; p = 0.002), calcium antagonists (75% vs 48% US and 43% Europe; p 0.0001), beta blockers (60% vs 32% US and 46% Europe; p = 0.02), and combination anti-ischemic therapy (67% vs 43% US and 56% Europe; p = 0.0001). By discharge, however, Canadian patients had the lowest rates of treatment with nitrates (12% vs 40% US and 44% Europe; p = 0.0001) and combination anti-ischemic therapy (29% vs 53% US and 47% Europe; p < 0.01). At both admission and discharge, rates of treatment with angiotensin-converting enzyme inhibitors and lipid-lowering agents were < 15% in all 3 regions. We conclude that significant international variations exist in the use of evidence-based medical therapy in patients undergoing percutaneous coronary revascularization.