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1.  Independent data monitoring committees: Preparing a path for the future 
American heart journal  2014;168(2):135-41.e1.
Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.
doi:10.1016/j.ahj.2014.05.003
PMCID: PMC4181557  PMID: 25066551
2.  Reduction in Overall Occurrences of Ischemic Events With Vorapaxar: Results From TRACER 
Background
Clinical trials traditionally use time‐to‐first‐event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.
Methods and Results
TRACER randomized 12 944 patients with non‐ST‐segment elevation acute coronary syndromes to placebo or to protease‐activated receptor 1 antagonist vorapaxar with a median follow‐up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).
Conclusions
Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.
Clinical Trial Registration
URL: ClinicalTrials.gov. Unique identifier: NCT00527943.
doi:10.1161/JAHA.114.001032
PMCID: PMC4310394  PMID: 25012288
acute coronary syndromes; recurrent events; vorapaxar
3.  Implementation of standardized assessment and reporting of myocardial infarction in contemporary randomized controlled trials: a systematic review 
European Heart Journal  2013;34(12):894-902.
Myocardial infarction (MI) is a key endpoint in randomized controlled trials (RCTs), but heterogeneous definitions limit comparisons across RCTs or meta-analyses. The 2000 European Society of Cardiology/American College of Cardiology MI redefinition and the 2007 universal MI definition consensus documents made recommendations to address this issue. In cardiovascular randomized trials, we evaluated the impact of implementation of three key recommendations from these reports—troponin use to define MI; separate reporting of spontaneous and procedure-related MI; and infarct size reporting. We searched ClinicalTrials.gov and MEDLINE databases for cardiovascular RCTs with more than 500 patients in which enrolment began between September 2000 and July 2012 and that listed MI in the primary endpoint. We searched English-language publications with primary results or design papers. Of 3222 studies screened, 96 (3.0%) met our criteria. We extracted enrolment start date, number of patients and MI events, follow-up duration, and coronary revascularization rate. Data extraction quality was assessed by duplicated extractions. Of 96 RCTs, 80 had a primary results publication, comprising 608 091 patients and 43 621 endpoint MIs. Myocardial infarction represented 45.3% (95% confidence interval, 40.2–50.4) of events in the primary composite endpoint. Troponin defined MI in 57% (53/93) of trials with an MI definition available. Of these RCTs, three used troponin only if creatine kinase-MB was unavailable, six used troponin to define peri-procedural MI, seven specified the 99th percentile as the MI decision limit, and three reported spontaneous and procedure-related MI separately. None reported biomarker-based infarct size, but five reported MI as multiples of the assay upper limit of normal. Although MI is a major component of cardiovascular RCT primary endpoints, standardized MI reporting and implementation of consensus document recommendations for MI definition are limited. Developing appropriate strategies for uniform implementation is required.
doi:10.1093/eurheartj/eht003
PMCID: PMC3604645  PMID: 23355654
Myocardial infarction; Clinical trials; Systematic reviews
4.  Baseline Q waves as a prognostic modulator in patients with ST-segment elevation: insights from the PLATO trial 
Background:
Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial
Methods:
Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality.
Results:
Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29–2.45, p < 0.001). Complete ST-segment resolution was greatest and all-cause mortality lowest among those with symptom onset three hours or less before percutaneous coronary intervention and no baseline Q waves. After multivariable adjustment, baseline Q waves, but not time from symptom onset, were associated with a significant increase in all-cause mortality (adjusted HR 1.42, 95% CI 1.10–2.01, p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09–2.28, p = 0.02).
Interpretation:
The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872
doi:10.1503/cmaj.111683
PMCID: PMC3394819  PMID: 22546885
5.  Serious Infection Following Acute Myocardial Infarction: Incidence, Clinical Features, and Outcomes 
JACC. Cardiovascular interventions  2012;5(7):10.1016/j.jcin.2012.03.018.
Background
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).
Objectives
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.jcin.2012.03.018
PMCID: PMC3883036  PMID: 22814783
ST-segment elevation myocardial infarction; percutaneous coronary intervention; infection; outcomes
6.  Duration of eptifibatide infusion after percutaneous coronary intervention and outcomes among high-risk patients with non-ST-segment elevation acute coronary syndrome: insights from EARLY ACS 
Background and Objectives:
Eptifibatide is indicated during percutaneous coronary intervention (PCI) with continuation for 18–24 hours post procedure but is associated with bleeding. We examined the efficacy and safety of shorter post-PCI eptifibatide infusions in high-risk non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients.
Methods:
EARLY ACS patients treated with PCI and eptifibatide were grouped by post-procedure infusion duration: <10, 10–13, 13–17, and 17–25 (per protocol) hours. Adjusted estimated event rates for 96-hour death/myocardial infarction (MI)/recurrent ischaemia requiring urgent revascularization (RIUR), 30-day death/MI, post-PCI packed red blood cell (PRBC) transfusion, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate/severe bleeding were obtained using inverse-propensity weighting to account for informative censoring of infusions.
Results:
Among 3271 eptifibatide-treated PCI patients, there were 66 96-hour death/MI/RIUR events, 94 30-day death/MI events, 127 PRBC transfusions, and 115 GUSTO moderate/severe bleeds. Compared with per protocol, patients receiving post-PCI infusions <10 hours had similar adjusted estimated rates of 96-hour death/MI/RIUR (absolute difference 0.021 higher; 0.040 vs. 0.019, 95% CI −0.023 to 0.064; p=0.35) and 30-day death/MI (0.020 higher; 0.046 vs. 0.026, 95% CI −0.021 to 0.062; p=0.34). There were also no differences in ischaemic outcomes between infusions of 10–17 hours and per-protocol infusions. Adjusted estimated rates of PRBC transfusion were higher for the <10-hour infusion group compared with per protocol (0.048 higher; 0.079 vs. 0.031, 95% CI 0.005 to 0.091, p=0.03) but were similar for other groups. Adjusted GUSTO moderate/severe bleeding rates were similar to per-protocol rates for all groups.
Conclusions:
In high-risk NSTE ACS patients, post-PCI eptifibatide infusions <18 hours were not associated with worse ischaemic outcomes. Shorter eptifibatide infusions in this population may be feasible.
doi:10.1177/2048872612474922
PMCID: PMC3821813  PMID: 24222836
Acute coronary syndrome; glycoprotein IIb/IIIa inhibitor; percutaneous coronary intervention
7.  [No title available] 
Heart  2007;93(10):1293.
PMCID: PMC2000926
elderly; clopidogrel; glycoprotein IIb/IIIa blockers
8.  Transfer Times and Outcomes in ST-Elevations Myocardial Infarction Patients Undergoing Inter-Hospital Transfer for Primary Percutaneous Coronary Intervention: APEX-AMI Insights 
Background
Transfer delays for primary percutaneous coronary intervention (PPCI) may increase mortality in patients with ST-segment elevation myocardial infarction (STEMI). We examined the association between door 1 to door 2 (D1D2) time, a measure capturing the entire transfer process, and outcomes in patients undergoing inter-hospital transfer for primary PCI.
Methods and Results
We evaluated the relationship between D1D2 time and the 90 day incidence of death, shock, and heart failure in the sub-set of 2075 (36.1%) of 5745 patients who underwent inter-hospital transfer for PPCI in the APEX-AMI trial. There was no significant difference in the 90 day incidence of death, shock, and heart failure between the transferred and the non-transferred groups (10.3% vs 10.2%, p=0.89). The median difference in symptom to balloon time between the two groups was 45 minutes (229 vs 184, p<0.001). The primary outcome per 30 minute delay was higher for patients with a D1D2 time ≤ 150 minutes (HR 1.19: 95% Confidence Interval [CI], 1.06 to 1.33 p=0.004) but not for D1D2 times > 150 minutes (HR, 0.99: 95% CI, 0.96 to 1.02; p=0.496). The association between longer D1D2 time and worsening outcome was no longer statistically significant after multivariable adjustment.
Conclusion
Longer transfer times were associated with higher rate of death, shock, and heart failure among patients undergoing inter-hospital transfer from PPCI, although this difference did not persist after adjusting for baseline characteristics.
Clinical Trial Registration Information
URL: www.clincaltrials.gov, Unique Identifier: NCT00091637
doi:10.1161/CIRCOUTCOMES.112.965160
PMCID: PMC3571720  PMID: 22589297
STEMI; Primary PCI; Transfer
9.  Effects of platelet glycoprotein IIb/IIIa receptor blockers in non‐ST segment elevation acute coronary syndromes: benefit and harm in different age subgroups 
Heart  2006;93(4):450-455.
Objective
To investigate whether the beneficial and harmful effects of platelet glycoprotein IIb/IIIa receptor blockers in non‐ST elevation acute coronary syndromes (NSTE‐ACS) depend on age.
Methods
A meta‐analysis of six trials of platelet glycoprotein IIb/IIIa receptor blockers in patients with NSTE‐ACS (PRISM, PRISM‐PLUS, PARAGON‐A, PURSUIT, PARAGON‐B, GUSTO IV‐ACS; n = 31 402) was performed. We applied multivariable logistic regression analyses to evaluate the drug effects on death or non‐fatal myocardial infarction at 30 days, and on major bleeding, by age subgroups (<60, 60–69, 70–79, ⩾80 years). We quantified the reduction of death or myocardial infarction as the number needed to treat (NNT), and the increase of major bleeding as the number needed to harm (NNH).
Results
Subgroups had 11 155 (35%), 9727 (31%), 8468 (27%) and 2049 (7%) patients, respectively. The relative benefit of platelet glycoprotein IIb/IIIa receptor blockers did not differ significantly (p = 0.5) between age subgroups (OR (95% CI) for death or myocardial infarction: 0.86 (0.74 to 0.99), 0.90 (0.80 to 1.02), 0.97 (0.86 to 1.10), 0.90 (0.73 to 1.16); overall 0.91 (0.86 to 0.99). ORs for major bleeding were 1.9 (1.3 to 2.8), 1.9 (1.4 to 2.7), 1.6 (1.2 to 2.1) and 2.5 (1.5–4.1). Overall NNT was 105, and overall NNH was 90. The oldest patients had larger absolute increases in major bleeding, but also had the largest absolute reductions of death or myocardial infarction. Patients ⩾80 years had half of the NNT and a third of the NNH of patients <60 years.
Conclusions
In patients with NSTE‐ACS, the relative reduction of death or non‐fatal myocardial infarction with platelet glycoprotein IIb/IIIa receptor blockers was independent of patient age. Larger absolute outcome reductions were seen in older patients, but with a higher risk of major bleeding. Close monitoring of these patients is warranted.
doi:10.1136/hrt.2006.098657
PMCID: PMC1861476  PMID: 17065179
10.  Methods of creatine kinase-MB analysis to predict mortality in patients with myocardial infarction treated with reperfusion therapy 
Trials  2013;14:123.
Background
Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes.
Methods
Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days.
Results
In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials.
Conclusions
Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.
doi:10.1186/1745-6215-14-123
PMCID: PMC3662641  PMID: 23782531
Creatine kinase-MB; Infarct size; ST-segment elevation myocardial infarction; Clinical outcomes
11.  A Canadian context for the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF) trial 
The Canadian Journal of Cardiology  2008;24(Suppl B):30B-32B.
Congestive heart failure comprises a major public health problem destined to grow enormously over the next decade. Paradoxically, and in contrast to acute coronary disease, acute heart failure has been relatively understudied. Current standards of care involve the use of intravenous diuretics and vasodilators; inotropic agents have been restricted to in-hospital use because of concern about their potential harmful effects. The emergence of recombinant human B-type natriuretic peptide (BNP) provides an interesting therapeutic alternative because of its capacity to promote vasodilation as well as increase salt and water excretion, and improve pulmonary congestion by reducing left ventricular filling pressure. This agent will be explored in the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF), the largest ever trial conducted in acute decompensated heart failure. Patients will be studied through day 30 with end points of all-cause mortality in rehospitalization as the primary composite outcome. A variety of mechanistic substudies are planned as well as an assessment of the health care economic implications of acute heart failure and the pathophysiological elements hypothesized to modulate the expected treatment effect examined. The trial is embedded in an academic research organization motif and promises to provide a significant contribution to the body of knowledge in acute heart failure and the care of patients so afflicted.
PMCID: PMC2794443  PMID: 18629387
Clinical trial; Heart failure; Nesiritide
12.  Requiem for the sounds of silence 
doi:10.1503/cmaj.071780
PMCID: PMC2276559  PMID: 18390953
13.  N-terminal pro-brain natriuretic peptide and the timing, extent and mortality in ST elevation myocardial infarction 
AIMS
While natriuretic peptides have demonstrated diagnostic and prognostic potential in cardiac disorders, little is known about their relationship with the onset and quantification of myocardial infarction. The relationship of serial N-terminal pro-brain natriuretic peptide (NT-proBNP) with duration from symptom onset, infarct size and prognosis in ST elevation myocardial infarction (STEMI) patients treated with primary percutaneous intervention was examined.
METHODS AND RESULTS
Three hundred thirty-one STEMI patients in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial, which evaluated pexelizumab versus placebo, were studied. NT-proBNP (pg/mL) was measured at randomization, 24 h and 72 h; creatine kinase-MB area under the curve was measured at 72 h; and QRS score was assessed at discharge. Prognosis was ascertained from the 90-day composite clinical outcome of death, shock, stroke and congestive heart failure. Multivariate logistical regression was used to adjust for baseline characteristics for models at randomization, 24 h and 72 h. NT-proBNP was higher in patients with longer time from symptom onset (P<0.001) and correlated with measures of infarct size, including the area under the curve (P<0.001) and QRS score (P<0.001). Patients reaching the primary end point had markedly higher NT-proBNP at each sampling period (P<0.001). NT-proBNP at all time points was the strongest independent predictor of the primary end point in the multivariate model: in the 24 h model, only age and 24 h NT-proBNP (C-index 0.83); and only age, Killip class and NT-proBNP was in the 72 h model (C-index 0.85).
CONCLUSIONS
Higher NT-proBNP at 24 h correlated with larger infarct size and worse clinical outcomes. NT-proBNP at baseline, 24 h and 72 h after presentation with acute STEMI, is an independent predictor of a poor outcome and adds clinically useful prognostic information.
PMCID: PMC2560534  PMID: 16639474
Clinical trial; Myocardial infarction; Natriuretic peptides
17.  DO GUIDELINES INFLUENCE PRACTICE? 
Heart  2003;89(3):349-352.
PMCID: PMC1767614  PMID: 12591857
practice guidelines
24.  Swallow syncope 
Canadian Medical Association Journal  1985;132(11):1281-1284.
Swallowing is considered a rare cause of syncope. The five patients described in this report had a spectrum of gastrointestinal tract or cardiovascular disease. For each patient there was a clear association between swallowing and the onset of syncope. Prompt diagnosis of this potentially lethal condition is essential, and electrocardiographic monitoring during swallowing is advisable in all cases in which syncope is suspected.
PMCID: PMC1346334  PMID: 3995448

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