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1.  Would Tirofiban Have Been Shown Non-Inferior to Abciximab Had the TENACITY Trial Not Been Terminated for Financial Reasons? 
To investigate whether tirofiban would have been non-inferior to abciximab had the trial completed enrollment, and we place the termination of this trial in a broader research ethics context.
TENACITY was terminated by the sponsor for financial reasons. At the time, event rates for the 2 treatment arms were unknown.
TENACITY was designed to compare tirofiban with abciximab in approximately 8000 patients; however, enrollment was terminated after 383 (4.8%) patients. The primary endpoint was a composite of 30-day death, myocardial infarction, and urgent target vessel revascularization. Non-inferiority was defined as the likelihood that tirofiban would preserve at least 50% of the ability of abciximab to reduce the primary endpoint at 30 days, based on abciximab’s demonstrated ability to reduce such events by 43% (relative risk, 0.573; 95% confidence interval [CI], 0.507–0.648; P<0.001). To determine the probability of non-inferiority given the patients already enrolled, a Bayesian approach was used.
The primary composite endpoint occurred in 8.8% of patients randomized to abciximab vs. 6.9% receiving high-bolus-dose tirofiban (odds ratio, 0.77; 95% CI, 0.37–1.64). The estimated conditional power for the test that tirofiban would be non-inferior to abciximab if all patients been enrolled is 93.7%. Using the estimated predictive power method, the likelihood was 84.8%.
TENACITY was well-powered to identify non-inferiority with tirofiban vs. abciximab, and the patients enrolled strengthened the probability that this would have been the outcome had the trial been completed. When a clinical trial is terminated solely for financial reasons, it is incumbent upon the sponsor to provide proper patient follow-up and publication of the findings.
PMCID: PMC4156852  PMID: 23379785
glycoprotein IIb/IIIa inhibitors; clinical trial; tirofiban; abciximab
2.  Challenges and Solutions to Pre- and Post-Randomization Subgroup Analyses 
Current Cardiology Reports  2014;16(10):531.
Subgroup analyses are commonly performed in the clinical trial setting with the purpose of illustrating that the treatment effect was consistent across different patient characteristics or identifying characteristics that should be targeted for treatment. There are statistical issues involved in performing subgroup analyses, however. These have been given considerable attention in the literature for analyses where subgroups are defined by a pre-randomization feature. Although subgroup analyses are often performed with subgroups defined by a post-randomization feature—including analyses that estimate the treatment effect among compliers—discussion of these analyses has been neglected in the clinical literature. Such analyses pose a high risk of presenting biased descriptions of treatment effects. We summarize the challenges of doing all types of subgroup analyses described in the literature. In particular, we emphasize issues with post-randomization subgroup analyses. Finally, we provide guidelines on how to proceed across the spectrum of subgroup analyses.
PMCID: PMC4200313  PMID: 25135344
Subgroup analyses; Post-randomization; Causal inference; Multiplicity; Tests of interaction; Bias; A priori hypotheses
3.  Serious Infection Following Acute Myocardial Infarction: Incidence, Clinical Features, and Outcomes 
JACC. Cardiovascular interventions  2012;5(7):10.1016/j.jcin.2012.03.018.
Little is known about the incidence, location, etiologic organisms, and outcomes of infection in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI).
To address this knowledge gap using the database of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. We also assessed the association between serious infections and 90-day death or death/MI.
We analyzed data from 5745 STEMI patients enrolled in the APEX-AMI trial. Detailed information on infection was collected on all patients. We describe characteristics of patients according to infection and details of infection. Cox proportional hazards models were used to assess 90-day outcomes among patients with and without infections after adjusting for associated clinical variables and using infection as a time-dependent covariate.
Overall, 138 patients developed a serious infection (2.4%), most of whom presented with a single-site infection. The median (25th, 75th percentile) time until diagnosis of infection was 3 (1, 6) days. The most commonly identified organism was Staphylococcus aureus, and the main location of infection was the bloodstream. These patients had more comorbidities and lower procedural success at index PCI than those without infections. Serious infection was associated with significantly higher rates of 90-day death (adjusted hazard ratio [HR] 5.6; 95% confidence interval [CI] 3.8-8.4) and death or MI (adjusted HR 4.9; 95% CI 3.4-7.1).
Infections complicating the course of patients with STEMI are uncommon but associated with markedly worse 90-day clinical outcomes. Mechanisms for early identification of these high-risk patients, as well as design of strategies to reduce their risk of infection, are warranted.
PMCID: PMC3883036  PMID: 22814783
ST-segment elevation myocardial infarction; percutaneous coronary intervention; infection; outcomes
4.  Inference on treatment effects from a randomized clinical trial in the presence of premature treatment discontinuation: the SYNERGY trial 
Biostatistics (Oxford, England)  2010;12(2):258-269.
The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) was a randomized, open-label, multicenter clinical trial comparing 2 anticoagulant drugs on the basis of time-to-event endpoints. In contrast to other studies of these agents, the primary, intent-to-treat analysis did not find evidence of a difference, leading to speculation that premature discontinuation of the study agents by some subjects may have attenuated the apparent treatment effect and thus to interest in inference on the difference in survival distributions were all subjects in the population to follow the assigned regimens, with no discontinuation. Such inference is often attempted via ad hoc analyses that are not based on a formal definition of this treatment effect. We use SYNERGY as a context in which to describe how this effect may be conceptualized and to present a statistical framework in which it may be precisely identified, which leads naturally to inferential methods based on inverse probability weighting.
PMCID: PMC3062147  PMID: 20797983
Dynamic treatment regime; Inverse probability weighting; Potential outcomes; Proportional hazards model
5.  Departures from the Protocol During Conduct of a Clinical Trial: A Pattern from the Data Record Consistent with a Learning Curve 
Quality & safety in health care  2010;19(5):405-410.
Recognition of learning curves in medical skill acquisition has enhanced patient safety through improved training techniques. Clinical trials research has not been similarly scrutinized. We retrospectively evaluated VALIANT, a large multinational, pragmatic, randomized, double-blind, multicenter trial, for evidence of research conduct consistent with a performance “learning curve.”
Records provided protocol departure (deviations/violations) and documentation query data. For each site, analysis included patient order (e.g., first, second), recruitment rate, and first enrollment relative to study start date.
Computerized data from a trial coordinated by an academic research organization collaborating with 10 academic and two commercial research organizations and an industry sponsor.
931 sites enrolled 14,703 patients. Departures were restricted to the first year. Exclusions included: patient’s death or loss to follow-up within twelve months and subjects 80th or higher at a site. Departures were assessed for variance with higher patient rank, more frequent recruitment, and later start date.
Methods and Results
12,367 patients at 931 sites were analyzed. Departures were more common for patients enrolled earlier at a site (P<0.0001). For example, compared to the 30th patient the first had 47% more departures. Departures were also more common with slower enrollment and site start closer to the trial start date (P<0.0001). Similar patterns existed for queries.
Research performance improved during VALIANT consistent with a “learning curve.” Although effects were not related to a change in outcome (mortality), learning curves in clinical research may have important safety, ethical, research quality, and economic implications for trial conduct.
PMCID: PMC3258507  PMID: 20702441
Cardiology; Ethics; Health Services; Medical Informatics; Therapeutics
6.  Antiarrhythmic Drug Therapy for Sustained Ventricular Arrhythmias Complicating Acute Myocardial Infarction 
Critical care medicine  2011;39(1):78-83.
Few data exist to guide antiarrhythmic drug therapy for sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) after acute myocardial infarction (MI). The objective of this analysis was to describe survival of patients with sustained VT/VF post-MI according to antiarrhythmic drug treatment.
Design & Setting
We conducted a retrospective analysis of ST-segment elevation MI patients with sustained VT/VF in GUSTO IIB and III and compared all-cause death in patients receiving amiodarone, lidocaine, or no antiarrhythmic. We used Cox proportional hazards modeling and inverse weighted estimators to adjust for baseline characteristics, beta-blocker use, and propensity to receive antiarrhythmics. Due to non-proportional hazards for death in early follow-up (0–3 hours after sustained VT/VF) compared with later follow-up (>3 hours), we analyzed all-cause mortality using time-specific hazards.
Patients & Interventions
Among 19,190 acute MI patients, 1126 (5.9%) developed sustained VT/VF and met the inclusion criteria. Patients received lidocaine (n=664, 59.0%), amiodarone (n=50, 4.4%), both (n=110, 9.8%), or no antiarrhythmic (n=302, 26.8%).
In the first 3 hours after VT/VF, amiodarone (adjusted HR 0.39, 95% CI 0.21–0.71) and lidocaine (adjusted HR 0.72, 95% CI 0.53–0.96) were associated with a lower hazard of death—likely evidence of survivor bias. Among patients who survived 3 hours, amiodarone was associated with increased mortality at 30 days (adjusted HR 1.71, 95% CI 1.02–2.86) and 6 months (adjusted HR 1.96, 95% CI 1.21–3.16) but lidocaine was not at 30 days (adjusted HR 1.19, 95% CI 0.77–1.82) and 6 months (adjusted HR 1.10, 95% CI 0.73–1.66).
Among patients with acute MI complicated by sustained VT/VF who survive 3 hours, amiodarone, but not lidocaine, is associated with an increased risk of death; reinforcing the need for randomized trials in this population.
PMCID: PMC3010352  PMID: 20959785
ventricular arrhythmia; antiarrhythmic drug therapy; clinical trials; acute coronary syndrome; ventricular tachycardia; ventricular fibrillation
7.  Drug-Eluting Stents versus Bare Metal Stents in Unprotected Left Main Coronary Artery Stenosis: a Meta-Analysis 
We undertook a meta-analysis to assess outcomes for drug-eluting (DES) and bare metal stents (BMS) in percutaneous coronary intervention (PCI) for unprotected left main coronary stenosis (LMCA).
Uncertainty exits regarding the relative performance of DES versus BMS in unprotected LMCA PCI.
Of a total of 838 studies, 44 met inclusion criteria (N=10,342). The co-primary endpoints were mortality, myocardial infarction (MI), target vessel/target lesion revascularization (TVR/TLR), and major adverse cardiac events (MACE: mortality, MI, TVR/TLR).
Event rates for DES and BMS were calculated at 6–12 months, at 2 years and at 3 years. Crude event rates at 3 years were: mortality (8.8% and 12.7%), MI (4.0% and 3.4%), TVR/TLR (8.0% and 16.4%), and MACE (21.4% and 31.6%). Nine studies were included in a comparative analysis (N=5,081). At 6–12 months the adjusted odds ratio (OR) for DES vs. BMS were: mortality 0.94 (95% confidence interval [CI] 0.06–15.48; p=0.97), MI 0.64 (95% CI 0.19–2.17; p=0.47), TVR/TLR 0.10 (95% CI 0.01–0.84; p=0.01) and MACE 0.34 (95% CI 0.15–0.78; p=0.01). At 2 years the OR were: mortality 0.42 (95% CI 0.28–0.62; p<0.01), MI 0.16 (95% CI 0.01–3.53; p=0.13), and MACE 0.31 (95% CI 0.15–0.66; p<0.01). At 3 years the OR were: mortality 0.70 (95% CI 0.53–0.92; p=0.01), MI 0.49 (95% CI 0.26–0.92; p=0.03), TVR/TLR 0.46 (95% CI 0.30–0.69; p<0.01), and MACE 0.78 (95% CI 0.57–1.07; p=0.12).
Our meta-analysis suggests that DES is associated with favorable outcomes for mortality, MI, TVR/TLR, and MACE as compared to BMS in unprotected LMCA PCI.
PMCID: PMC3072800  PMID: 20630453
8.  Effect of operator and institutional volume on clinical outcomes after percutaneous coronary interventions performed in Canada and the United States: A brief report from the Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) study 
The Canadian Journal of Cardiology  2009;25(8):e269-e272.
The Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial compared the use of eptifibatide with placebo in 2064 coronary intervention patients. It was previously reported that Canadian patients had reduced rates of 30-day and one-year death, myocardial infarction (MI) or target-vessel revascularization (TVR) compared with patients in the United States (US).
To examine whether operator or institutional volume differences explain the regional variation in clinical outcome.
Each site received an operator and institutional volume survey. Fifty-seven sites (62%) returned complete data on 1338 patients. In this smaller cohort, Canadian patients had reduced rates of 30-day and one-year death, MI or TVR compared with US patients (6.3% versus 10.3% and 14.9% versus 20.1%, respectively; P<0.05 for both comparisons). Among 176 physicians with a median of 13 years experience, the median operator volume was 200 cases per year. Operators with fewer than 100 cases per year had higher rates of 30-day death, MI or TVR (13.2% versus 8.7%; P=0.18) and large MI (7.7% versus 3.3%; P=0.06) than those with 100 or more cases per year. The median institutional volume was 1064 cases per year. Canadian and US centres had similar operator and institutional volumes. By multivariate modelling, operator volume was not predictive of adverse clinical events. However, the rates of 30-day and one-year death, MI or TVR fell by 3% for every 100 patients treated by the institution (OR 0.97; P=0.058 and P=0.002, respectively). Enrollment in Canada was associated with improved outcomes at 30 days (OR 0.50; P=0.001) and one year (OR 0.66; P=0.001) despite inclusion of volume variables in the models.
In the ESPRIT study, institutional volume was associated with a modest reduction in risk of death, MI or TVR over short-and long-term follow-up periods. The Canadian and US investigators and institutions selected in ESPRIT had similar annual procedural volumes. Therefore, volume variables did not explain the differential risk of clinical events observed for patients enrolled in the two countries.
PMCID: PMC2732380  PMID: 19668787
Canada; Operator volume; United States
9.  Chronic obstructive pulmonary disease is an independent predictor of death but not atherosclerotic events in patients with myocardial infarction: analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT) 
European Journal of Heart Failure  2009;11(3):292-298.
Chronic obstructive pulmonary disease is an independent predictor of mortality in patients with myocardial infarction (MI). However, the impact on mode of death and risk of atherosclerotic events is unknown.
Methods and results
We assessed the risk of death and major cardiovascular (CV) events associated with chronic obstructive pulmonary disease in 14 703 patients with acute MI enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) trial. Cox proportional hazards models were used to evaluate the relationship between chronic obstructive pulmonary disease and CV outcomes. A total of 1258 (8.6%) patients had chronic obstructive pulmonary disease. Over a median follow-up period of 24.7 months, all-cause mortality was 30% in patients with chronic obstructive pulmonary disease, compared with 19% in those without. The adjusted hazard ratio (HR) for mortality was 1.14 (95% confidence interval 1.02–1.28). This reflected increased incidence of both non-CV death [HR 1.86 (1.43–2.42)] and sudden death [HR 1.26 (1.03–1.53)]. The unadjusted risk of all pre-specified CV outcomes was increased. However, after multivariate adjustment, chronic obstructive pulmonary disease was not an independent predictor of atherosclerotic events [MI or stroke: HR 0.98 (0.77–1.23)]. Mortality was significantly lower in patients receiving beta-blockers, irrespective of airway disease.
In high-risk patients with acute MI, chronic obstructive pulmonary disease is associated with increased mortality and non-fatal clinical events (both CV and non-CV). However, patients with chronic obstructive pulmonary disease did not experience a higher rate of atherosclerotic events.
PMCID: PMC2645058  PMID: 19176539
Chronic obstructive pulmonary disease; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction
10.  Prediction of One-Year Survival in High-Risk Patients with Acute Coronary Syndromes: Results from the SYNERGY Trial 
Despite advances in pharmacologic therapy and invasive management strategies for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), these patients still suffer substantial morbidity and mortality.
The objective of this study was to analyze independent predictors of 1-year mortality in patients with high-risk NSTE ACS.
A total of 9,978 patients were assigned to receive enoxaparin or unfractionated heparin (UFH) in this prospective, randomized, open-label, international trial.
Vital status at 1 year was collected. Univariable and multivariable predictors of 1-year mortality were identified. Three different multivariable regression models were constructed to identify: (1) predictors of 30-day mortality; (2) predictors of 1-year mortality; (3) predictors of 1-year mortality in 30-day survivors. The last model is the focus of this paper.
Overall, 9,922 (99.4%) of patients had 1-year follow-up. Of the 56 patients (37 UFH-assigned and 19 enoxaparin-assigned) without 1-year data, 11 patients were excluded because of withdrawal of consent, and 45 could not be located. One-year mortality was 7.5% (7.7% enoxaparin-assigned patients; 7.3% UFH-assigned patients; P = 0.4). In patients surviving 30 days after enrollment, independent predictors of 1-year mortality included factors known at baseline such as increased age, male sex, decreased weight, having ever smoked, decreased creatinine clearance, ST-segment depression, history of diabetes, history of angina, congestive heart failure, coronary artery bypass grafting, increased heart rate, rales, increased hematocrit, lowered hemoglobin, and higher platelet count. Factors predictive of mortality during the hospitalization and 30-day follow-up period were decreased weight at 30 days from baseline, atrial fibrillation, decreased nadir platelet, no use of beta-blockers and statins up to 30 days, and not receiving an intervention (c-index = 0.82).
Easily determined baseline clinical characteristics can be used to predict 1-year mortality with reasonable discriminative power. These models corroborate prior work in a contemporary aggressively managed population. A model to predict 1-year mortality in patients surviving at least 30 days may be quite helpful to healthcare providers in setting expectations and goals with patients after ACS.
PMCID: PMC2359476  PMID: 18196350
non-ST-segment elevation acute coronary syndrome; predictors; mortality; outcomes; low-molecular-weight heparin; unfractionated heparin
11.  Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE) 
BMJ : British Medical Journal  2006;333(7578):1091.
Objective To develop a clinical risk prediction tool for estimating the cumulative six month risk of death and death or myocardial infarction to facilitate triage and management of patients with acute coronary syndrome.
Design Prospective multinational observational study in which we used multivariable regression to develop a final predictive model, with prospective and external validation.
Setting Ninety four hospitals in 14 countries in Europe, North and South America, Australia, and New Zealand.
Population 43 810 patients (21 688 in derivation set; 22 122 in validation set) presenting with acute coronary syndrome with or without ST segment elevation enrolled in the global registry of acute coronary events (GRACE) study between April 1999 and September 2005.
Main outcome measures Death and myocardial infarction.
Results 1989 patients died in hospital, 1466 died between discharge and six month follow-up, and 2793 sustained a new non-fatal myocardial infarction. Nine factors independently predicted death and the combined end point of death or myocardial infarction in the period from admission to six months after discharge: age, development (or history) of heart failure, peripheral vascular disease, systolic blood pressure, Killip class, initial serum creatinine concentration, elevated initial cardiac markers, cardiac arrest on admission, and ST segment deviation. The simplified model was robust, with prospectively validated C-statistics of 0.81 for predicting death and 0.73 for death or myocardial infarction from admission to six months after discharge. The external applicability of the model was validated in the dataset from GUSTO IIb (global use of strategies to open occluded coronary arteries).
Conclusions This risk prediction tool uses readily identifiable variables to provide robust prediction of the cumulative six month risk of death or myocardial infarction. It is a rapid and widely applicable method for assessing cardiovascular risk to complement clinical assessment and can guide patient triage and management across the spectrum of patients with acute coronary syndrome.
PMCID: PMC1661748  PMID: 17032691

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