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1.  Access to catheterisation facilities in patients admitted with acute coronary syndrome: multinational registry study 
BMJ : British Medical Journal  2005;330(7489):441.
Objective To investigate the relation between access to a cardiac catheterisation laboratory and clinical outcomes in patients admitted to hospital with suspected acute coronary syndrome.
Design Prospective, multinational, observational registry.
Setting Patients enrolled in 106 hospitals in 14 countries between April 1999 and March 2003.
Participants 28 825 patients aged ≥ 18 years.
Main outcome measures Use of percutaneous coronary intervention or coronary artery bypass graft surgery, death, infarction after discharge, stroke, or major bleeding.
Results Most patients (77%) across all regions (United States, Europe, Argentina and Brazil, Australia, New Zealand, and Canada) were admitted to hospitals with catheterisation facilities. As expected, the availability of a catheterisation laboratory was associated with more frequent use of percutaneous coronary intervention (41% v 3.9%, P < 0.001) and coronary artery bypass graft (7.1% v 0.7%, P < 0.001). After adjustment for baseline characteristics, medical history, and geographical region there were no significant differences in the risk of early death between patients in hospitals with or without catheterisation facilities (odds ratio 1.13, 95% confidence interval 0.98 to 1.30, for death in hospital; hazard ratio 1.05, 0.93 to 1.18, for death at 30 days). The risk of death at six months was significantly higher in patients first admitted to hospitals with catheterisation facilities (hazard ratio 1.14, 1.03 to 1.26), as was the risk of bleeding complications in hospital (odds ratio 1.94, 1.57 to 2.39) and stroke (odds ratio 1.53, 1.10 to 2.14).
Conclusions These findings support the current strategy of directing patients with suspected acute coronary syndrome to the nearest hospital with acute care facilities, irrespective of the availability of a catheterisation laboratory, and argue against early routine transfer of these patients to tertiary care hospitals with interventional facilities.
PMCID: PMC549651  PMID: 15665006
2.  Reduction in Overall Occurrences of Ischemic Events With Vorapaxar: Results From TRACER 
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).
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: Unique identifier: NCT00527943.
PMCID: PMC4310394  PMID: 25012288
acute coronary syndromes; recurrent events; vorapaxar
3.  Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients 
Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD.
Methods and results:
We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (ORadj 0.15; 95% CI, 0.11–0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (ORadj 0.19 (0.14–0.25) and 0.37 (0.28–0.49), respectively).
Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.
PMCID: PMC3932771  PMID: 24562802
Acute coronary syndromes; angiography; atherosclerosis; coronary disease; infarction
4.  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.
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.
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.
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.
PMCID: PMC3821813  PMID: 24222836
Acute coronary syndrome; glycoprotein IIb/IIIa inhibitor; percutaneous coronary intervention
5.  Management and outcomes of patients presenting with STEMI by use of chronic oral anticoagulation: results from the GRACE registry 
To describe the characteristics, treatment, and mortality in patients with ST-elevation myocardial infarction (STEMI) by use of chronic oral anticoagulant (OAC) therapy.
Using data from the Global Registry of Acute Coronary Syndromes (GRACE), patient characteristics, treatment, and reperfusion strategies of STEMI patients on chronic OAC are described, and relevant variables compared with patients not on chronic OAC. Six-month post-discharge mortality rates were evaluated by Cox proportional hazard models.
Of 19,094 patients with STEMI, 574 (3.0%) were on chronic OAC at admission. Compared with OAC non-users, OAC users were older (mean age 73 vs. 65 years), more likely to be female (37 vs. 29%), were more likely to have a history of atrial fibrillation, prosthetic heart valve, venous thromboembolism, or stroke/transient ischaemic attack, had a higher mean GRACE risk score (166 vs. 145), were less likely to be Killip class I (68 vs. 82%), and were less likely to undergo catheterization/percutaneous coronary intervention (52 vs. 66%, respectively). Of the patients who underwent catheterization, fewer OAC users had the procedure done within 24 h of admission (56.5 vs. 64.5% of OAC non-users). In propensity-matched analyses (n=606), rates of in-hospital major bleeding and in-hospital and 6-month post-discharge mortality were similar for OAC users and OAC non-users (2.7 and 3.7%, p=0.64; 15 and 13%, p=0.56; 15 and 12%, p=0.47, respectively), rates of in-hospital recurrent myocardial infarction (8.6 and 2.0%, p<0.001) and atrial fibrillation (32 and 22%, p=0.004) were higher in OAC patients, and rates of 6-month stroke were lower (0.6 and 4.3%, p=0.038). Patients in both groups who underwent catheterization had lower mortality than those who did not undergo catheterization.
This is the largest study to describe the characteristics and treatment of STEMI patients on chronic OAC. The findings suggest that patients on chronic OAC are less likely to receive guideline-indicated management, but have similar adjusted rates of in-hospital and 6-month mortality.
PMCID: PMC3821815  PMID: 24222840
Acute coronary syndrome; anticoagulant; guidelines; myocardial infarction
6.  Transfer Times and Outcomes in ST-Elevations Myocardial Infarction Patients Undergoing Inter-Hospital Transfer for Primary Percutaneous Coronary Intervention: APEX-AMI Insights 
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.
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:, Unique Identifier: NCT00091637
PMCID: PMC3571720  PMID: 22589297
STEMI; Primary PCI; Transfer
7.  Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection 
European Heart Journal  2012;34(25):1930-1941.
The cardiac extracellular matrix is highly involved in regulating inflammation, remodelling, and function of the heart. Whether matrix alterations relate to the degree of inflammation, fibrosis, and overall rejection in the human transplanted heart remained, until now, unknown.
Methods and results
Expression of matricellular proteins, proteoglycans, and metalloproteinases (MMPs) and their inhibitors (TIMPs) were investigated in serial endomyocardial biopsies (n = 102), in a cohort of 39 patients within the first year after cardiac transplantation. Out of 15 matrix-related proteins, intragraft transcript and protein levels of syndecan-1 and MMP-9 showed a strong association with the degree of cardiac allograft rejection (CAR), the expression of pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β, and with infiltrating CD3+T-cells and CD68+monocytes. In addition, SPARC, CTGF, TSP-2, MMP-14, TIMP-1, Testican-1, TSP-1, Syndecan-1, MMP-2, -9, and -14, as well as IL-6 and TGF-β transcript levels and inflammatory infiltrates all strongly relate to collagen expression in the transplanted heart. More importantly, receiver operating characteristic curve analysis demonstrated that syndecan-1 and MMP-9 transcript levels had the highest area under the curve (0.969 and 0.981, respectively), thereby identifying both as a potential decision-making tool to discriminate rejecting from non-rejecting hearts.
Out of 15 matrix-related proteins, we identified synd-1 and MMP-9 intragraft transcript levels of as strong predictors of human CAR. In addition, a multitude of non-structural matrix-related proteins closely associate with collagen expression in the transplanted heart. Therefore, we are convinced that these findings deserve further investigation and are likely to be of clinical value to prevent human CAR.
PMCID: PMC4051259  PMID: 23139380
Heart transplantation; Rejection; Metalloproteinases; Matricellular proteins; Cardiac matrix; Inflammation; Biomarker
8.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study 
Voight, Benjamin F | Peloso, Gina M | Orho-Melander, Marju | Frikke-Schmidt, Ruth | Barbalic, Maja | Jensen, Majken K | Hindy, George | Hólm, Hilma | Ding, Eric L | Johnson, Toby | Schunkert, Heribert | Samani, Nilesh J | Clarke, Robert | Hopewell, Jemma C | Thompson, John F | Li, Mingyao | Thorleifsson, Gudmar | Newton-Cheh, Christopher | Musunuru, Kiran | Pirruccello, James P | Saleheen, Danish | Chen, Li | Stewart, Alexandre FR | Schillert, Arne | Thorsteinsdottir, Unnur | Thorgeirsson, Gudmundur | Anand, Sonia | Engert, James C | Morgan, Thomas | Spertus, John | Stoll, Monika | Berger, Klaus | Martinelli, Nicola | Girelli, Domenico | McKeown, Pascal P | Patterson, Christopher C | Epstein, Stephen E | Devaney, Joseph | Burnett, Mary-Susan | Mooser, Vincent | Ripatti, Samuli | Surakka, Ida | Nieminen, Markku S | Sinisalo, Juha | Lokki, Marja-Liisa | Perola, Markus | Havulinna, Aki | de Faire, Ulf | Gigante, Bruna | Ingelsson, Erik | Zeller, Tanja | Wild, Philipp | de Bakker, Paul I W | Klungel, Olaf H | Maitland-van der Zee, Anke-Hilse | Peters, Bas J M | de Boer, Anthonius | Grobbee, Diederick E | Kamphuisen, Pieter W | Deneer, Vera H M | Elbers, Clara C | Onland-Moret, N Charlotte | Hofker, Marten H | Wijmenga, Cisca | Verschuren, WM Monique | Boer, Jolanda MA | van der Schouw, Yvonne T | Rasheed, Asif | Frossard, Philippe | Demissie, Serkalem | Willer, Cristen | Do, Ron | Ordovas, Jose M | Abecasis, Gonçalo R | Boehnke, Michael | Mohlke, Karen L | Daly, Mark J | Guiducci, Candace | Burtt, Noël P | Surti, Aarti | Gonzalez, Elena | Purcell, Shaun | Gabriel, Stacey | Marrugat, Jaume | Peden, John | Erdmann, Jeanette | Diemert, Patrick | Willenborg, Christina | König, Inke R | Fischer, Marcus | Hengstenberg, Christian | Ziegler, Andreas | Buysschaert, Ian | Lambrechts, Diether | Van de Werf, Frans | Fox, Keith A | El Mokhtari, Nour Eddine | Rubin, Diana | Schrezenmeir, Jürgen | Schreiber, Stefan | Schäfer, Arne | Danesh, John | Blankenberg, Stefan | Roberts, Robert | McPherson, Ruth | Watkins, Hugh | Hall, Alistair S | Overvad, Kim | Rimm, Eric | Boerwinkle, Eric | Tybjaerg-Hansen, Anne | Cupples, L Adrienne | Reilly, Muredach P | Melander, Olle | Mannucci, Pier M | Ardissino, Diego | Siscovick, David | Elosua, Roberto | Stefansson, Kari | O'Donnell, Christopher J | Salomaa, Veikko | Rader, Daniel J | Peltonen, Leena | Schwartz, Stephen M | Altshuler, David | Kathiresan, Sekar
Lancet  2012;380(9841):572-580.
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10).
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
PMCID: PMC3419820  PMID: 22607825
9.  From abstract to impact in cardiovascular research: factors predicting publication and citation 
European Heart Journal  2012;33(24):3034-3045.
Through a 4-year follow-up of the abstracts submitted to the European Society of Cardiology Congress in 2006, we aimed at identifying factors predicting high-quality research, appraising the quality of the peer review and editorial processes, and thereby revealing potential ways to improve future research, peer review, and editorial work.
Methods and results
All abstracts submitted in 2006 were assessed for acceptance, presentation format, and average reviewer rating. Accepted and rejected studies were followed for 4 years. Multivariate regression analyses of a representative selection of 10% of all abstracts (n= 1002) were performed to identify factors predicting acceptance, subsequent publication, and citation. A total of 10 020 abstracts were submitted, 3104 (31%) were accepted for poster, and 701 (7%) for oral presentation. At Congress level, basic research, a patient number ≥ 100, and prospective study design were identified as independent predictors of acceptance. These factors differed from those predicting full-text publication, which included academic affiliation. The single parameter predicting frequent citation was study design with randomized controlled trials reaching the highest citation rates. The publication rate of accepted studies was 38%, whereas only 24% of rejected studies were published. Among published studies, those accepted at the Congress received higher citation rates than rejected ones.
Research of high quality was determined by study design and largely identified at Congress level through blinded peer review. The scientometric follow-up revealed a marked disparity between predictors of full-text publication and those predicting citation or acceptance at the Congress.
PMCID: PMC3530902  PMID: 22669850
Scientific quality; Peer review; Publication; Impact
10.  Impact of TIMI 3 patency before primary percutaneous coronary intervention for ST-elevation myocardial infarction on clinical outcome: results from the ASSENT-4 PCI study 
Early restoration of blood flow of the infarct-related artery is associated with an improved outcome in patients with ST-elevation myocardial infarction (STEMI). Previous studies have shown a low mortality in patients with TIMI 3 flow before primary percutaneous coronary intervention (PCI). Most likely these patients had spontaneous recanalization of the infarct vessel and might constitute a low-risk subgroup. The purpose of the present analysis was to investigate whether TIMI 3 flow obtained with fibrinolysis before PCI is associated with a clinical outcome comparable to that in patients with spontaneous TIMI 3 flow.
Patients with STEMI <6 hours enrolled in the ASSENT-4 PCI study were randomized to facilitated PCI with tenecteplase or primary PCI. For this analysis, patients were divided into three groups according to the TIMI flow of the infarct vessel before PCI: TIMI 0/1, TIMI 2, and TIMI 3.
From a total of 1617 patients, 861 had TIMI 0/1, 279 had TIMI 2, and 477 TIMI 3 flow. The rates of TIMI 3 flow after PCI were 84.6, 89.7, and 95.6%, respectively. Complete ST resolution was observed most often in the TIMI 3 flow group (47.5, 53.6, and 58.6%). The incidence of cardiogenic shock (6.2, 5.5, and 3.6%) and 90-day mortality (6.1, 4.7, and 4.0%) were lowest in the group with TIMI 3 patency before PCI, respectively. The rate of TIMI 3 flow before PCI was higher in the facilitated PCI group than in the primary PCI group (43.9 vs. 15.2%). The 90-day mortality in patients with TIMI 3 before PCI was identical in the facilitated and the primary PCI groups (14/353, 4.0% vs. 5/124, 4.0%).
In this post-hoc analysis of ASSENT-4 PCI, TIMI grade 3 flow in the infarct-related artery before PCI, occurring either spontaneously or obtained by fibrinolysis, is associated with a higher TIMI patency after PCI, better improved ST resolution and a trend towards a favourable clinical outcome after 90 days.
PMCID: PMC3760529  PMID: 24062901
Facilitated PCI; patency; primary percutaneous coronary intervention; ST-elevation myocardial infarction
11.  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
12.  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
13.  Summary statement: EHRA Summit 2010 with the Participation of Central-Eastern European Countries: ‘ICD for Life’ Initiative—Fighting against Sudden Cardiac Death in Emerging Economies 
Europace  2011;13(8):1209-1210.
PMCID: PMC3148819  PMID: 21810867
14.  A variant at chromosome 9p21 is associated with recurrent myocardial infarction and cardiac death after acute coronary syndrome: The GRACE Genetics Study 
European Heart Journal  2010;31(9):1132-1141.
Recent genetic studies identified the rs1333049 variant on chromosome 9p21 as a major susceptibility locus for coronary artery disease and myocardial infarction (MI). Here, we evaluated whether this variant also contributes to recurrent MI or cardiac death following an acute coronary syndrome (ACS).
Methods and results
A total of 3247 patients with ACS enrolled in the Global Registry of Acute Coronary Events (GRACE) in three distinct populations (UK, Belgium and Poland) were prospectively followed for 6 months and genotyped for rs1333049, in addition to 3004 and 2467 healthy controls from the UK and Belgium. After having confirmed that the at-risk C allele of rs1333049 was associated with index ACS in the UK and Belgian populations, we found that the rs1333049 at-risk C allele was significantly and independently associated with recurrent MI [age- and gender-adjusted hazard ratio (HR) 1.48, CI = 1.00–2.19, P = 0.048; and multivariable-adjusted HR 1.47, CI = 0.99–2.18; P = 0.053] and with recurrent MI or cardiac death (age- and gender-adjusted HR 1.58, CI = 1.00–2.48; P = 0.045; and multivariable adjusted HR 1.49, CI = 1.03–1.98; P = 0.028) within 6 months after an index ACS. Inclusion of rs1333049 into the GRACE risk score significantly improved classification for recurrent MI or cardiac death (P = 0.040), as calculated by the integrated discrimination improvement method.
In this large observational study, the 9p21 variant was independently associated with adverse cardiac outcome after ACS.
PMCID: PMC2862180  PMID: 20231156
Chromosome 9p21; Rs1333049; Genetics; Acute coronary syndrome; Myocardial infarction; Plaque rupture
15.  Sex Differences in Mortality Following Acute Coronary Syndromes 
There is conflicting information about whether sex-differences modulate short-term mortality following acute coronary syndromes (ACS).
To investigate the relationship between sex and 30-day mortality in ACS, and determine whether this relationship is modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.
Design Setting and Participants
Data from 11 ACS trials from 1993 to 2006 were pooled. Of 136,247 patients, 38,048 (28%) were women; 102,004 (26% women) STEMI, 14,466 (29% women) NSTEMI and 19,777 (40% women) unstable angina (UA).
Main Outcome Measure
Thirty-day mortality following ACS.
Mortality at 30 days was 9.6% in women and 5.3% in men (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.83–2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR 1.06, 95% CI 0.99–1.15). Importantly, a significant sex by type of ACS interaction was demonstrated (P<0.001). In STEMI, 30-day mortality was higher among women (adjusted OR 1.15, 95% CI 1.06–1.24), whereas NSTEMI (adjusted OR 0.77, 95% CI 0.63–0.95), and UA mortality was lower among women (adjusted OR 0.55, 95% CI 0.43–0.70). In a cohort of 35,128 patients with angiographic data, women more often had non-obstructive (15% vs. 8%,) and less often had 2-vessel (25% vs. 28%) and 3-vessel (23% vs. 26%) coronary disease regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (p-value for interaction =0.70),
Sex-based differences exist in 30-day mortality among ACS patients and vary depending on clinical presentation. However, these differences are markedly attenuated following adjustment for clinical differences and angiographic data.
PMCID: PMC2778841  PMID: 19706861
16.  Antithrombotic therapy and outcomes of patients with atrial fibrillation following primary percutaneous coronary intervention: results from the APEX-AMI trial 
European Heart Journal  2009;30(16):2019-2028.
To assess the incidence and timing of atrial fibrillation (AF), describe antithrombotic therapy use, and evaluate the association of AF with 90 day mortality and other secondary clinical outcomes.
Methods and results
We studied 5745 ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention (PCI) in APEX-AMI. Approximately 11% had AF during hospitalization. Atrial fibrillation prevalence at baseline and at discharge was 4.8% [confidence interval (CI) 4.3–5.4%] and 2.5% (CI 2.1–2.9%), respectively. The proportion of 5466 patients without AF at baseline who developed new onset AF was 6.3% (CI 5.6–6.9%). This corresponded to 9.3 cases of new onset AF/1000 patient days at risk. New onset AF was independently associated with 90 day mortality [adjusted hazard ratio (HR) 1.81; 95% CI 1.06–3.09; P = 0.029] after accounting for baseline covariates and in-hospital procedures and complications. New onset AF was associated with shock (adjusted HR 3.81; 95% CI 1.88–7.70; P = 0.0002), congestive heart failure (adjusted HR 2.66; 95% CI 1.74–4.06; P < 0.0001), and stroke (adjusted HR 2.98; 95% CI 1.47–6.04; P = 0.0024) in models accounting for baseline covariates. Of AF patients, 55% did not receive oral anticoagulation therapy at discharge. Among patients with coronary stents, 5.1% were discharged on triple therapy. Patients at highest risk of stroke (CHADS2 score ≥2) were least likely to receive oral anticoagulation at discharge (39%). Warfarin use in patients with AF at discharge (43.4%) was associated with lower rates of 90 day mortality and stroke.
Atrial fibrillation prevalence at baseline and at discharge was 4.8 and 2.5%, respectively. The proportion of patients who developed new onset AF was 6.3%. New onset AF was independently associated with 90 day mortality and was a marker of adverse outcomes in patients undergoing primary PCI.
PMCID: PMC2764954  PMID: 19502623
Atrial fibrillation; Myocardial infarction; Antithrombotic therapy; Outcomes
17.  Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction 
The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell–matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor β (TGF)–mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-β rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.
PMCID: PMC2626676  PMID: 19103879
19.  Angina, “Normal” Coronary Angiography, and Vascular Dysfunction: Risk Assessment Strategies 
PLoS Medicine  2007;4(2):e12.
The authors discuss how to stratify risk in patients with chest pain and a normal coronary angiogram.
PMCID: PMC1808079  PMID: 17326702
20.  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
21.  Efficacy and safety of unfractionated heparin versus enoxaparin: a pooled analysis of ASSENT-3 and -3 PLUS data 
The optimal antithrombotic therapy to accompany tenecteplase in cases of acute ST-segment elevation myocardial infarction (STEMI) remains unclear. We undertook a prespecified pooled analysis of data from the ASSENT-3 and ASSENT-3 PLUS trials.
We created a combined database of the 2040 and 818 patients who received enoxaparin in ASSENT-3 and ASSENT-3 PLUS, respectively, and compared them with the 2038 and 821 patients who received unfractionated heparin.
The primary efficacy end point, a composite of 30-day mortality, reinfarction or refractory ischemia, was 16.0% with enoxaparin versus 12.2% with unfractionated heparin (p < 0.001); the efficacy plus safety (intracranial hemorrhage [ICH] or major systemic bleeding) end point, 18.0% versus 15.0% (p = 0.003). The 1049 patients urgently revascularized had greater benefit from enoxaparin (15.4% v. 10.1%, p = 0.013), yet the excess in major systemic bleeding evident with enoxaparin (3.3% v. 2.4%, p = 0.01) was largely confined to the 3492 patients without or before revascularization. Although ICH rates in the groups were similar (1.3% v. 0.9%, p = 0.26), an excess of ICH occurred among those administered enoxaparin during the ASSENT-3 PLUS trial (6.7% v. 0.8%, p = 0.013), especially among women over 75 years of age.
These data demonstrated the benefit of enoxaparin used in conjunction with tenecteplase, but raised caution about its prehospital use to treat STEMI in elderly women.
PMCID: PMC1455417  PMID: 16682709

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