LDL-C indicates low-density lipoprotein cholesterol.
CRP indicates C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein. Error bars for LDL-C and HDL-C represent standard errors. Error bars for triglycerides and log CRP represent interquartile ranges. P values for LDL-C, HDL-C, and CRP are by t test. P value for triglycerides is by Wilcoxon rank sum test for percentage change.
The primary efficacy outcome was a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Patients were randomized to receive either varespladib (500 mg/d) or placebo for 16 weeks. HR indicates hazard ratio. Y-axis scale shown in blue indicates range from 0% to 4%.
The primary efficacy outcome was a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Patients were randomized to receive either varespladib (500 mg/d) or placebo for 16 weeks. Non-STEMI indicates non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction. Because of missing data, number of patients in the subgroups do not sum to total number of patients randomized to receive placebo or varespladib.
eTable 1. Concomitant medication use during the treatment period
eTable 2. Discontinuation due to adverse events and biochemical abnormalities in patients treated with placebo and varespladib
Nicholls SJ, Kastelein JJP, Schwartz GG, Bash D, Rosenson RS, Cavender MA, Brennan DM, Koenig W, Jukema JW, Nambi V, Wright RS, Menon V, Lincoff AM, Nissen SE, for the VISTA-16 Investigators. Varespladib and Cardiovascular Events in Patients With an Acute Coronary SyndromeThe VISTA-16 Randomized Clinical Trial. JAMA. 2014;311(3):252-262. doi:10.1001/jama.2013.282836
Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown.
To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes.
Design, Setting, and Participants
A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012).
Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies.
Main Outcomes and Measures
The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated.
At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04).
Conclusions and Relevance
In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS.
clinicaltrials.gov Identifier: NCT01130246
Despite a high rate of use of contemporary therapies, patients with acute coronary syndrome (ACS) face a substantial risk of early, recurrent adverse cardiovascular events.1 Increasing evidence supports a potential role of inflammation in the progression and clinical instability of coronary heart disease.2 Necropsy studies show inflammatory cells within atherosclerotic plaques,3 and clinical outcomes trials show an association between systemic inflammatory markers and cardiovascular risk.4 Conversely, reductions in inflammatory markers associate with reductions in cardiovascular events in clinical trials and may contribute to the benefit of statins.4 These observations provide a rationale to test novel agents that target specific inflammatory factors implicated in atherosclerosis to determine if it reduces cardiovascular risk.5
The secretory phospholipase A2 (sPLA2) family of enzymes hydrolyze fatty acids of glycophospholipids, generating bioactive lipid species involved in inflammation.6 However, although some sPLA2 isoforms are proatherogenic (groups IIA and V), other isoforms are protective (group X).7 Considerable evidence implicates a potential role for groups IIA and V sPLA2 in cardiovascular disease. Higher circulating levels of sPLA2-IIA concentration and activity associate with cardiovascular risk in asymptomatic individuals and patients with established coronary disease.8 Pathologic studies demonstrate the presence of sPLA2 isoforms groups IIA, III, V, and X in atherosclerotic lesions and myocardial regions that have sustained ischemic injury.6,9,10 These observations have stimulated interest in the potential value of sPLA2 inhibition as a cardioprotective strategy.5
Varespladib methyl is a nonspecific pan-sPLA2 inhibitor with favorable effects on atherosclerotic lesions in animal studies.11 Initial studies demonstrated that varespladib reduced levels of sPLA2-IIA by more than 90%, in addition to lowering low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) in patients with stable coronary disease and ACS.12- 14 The Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) study was designed to evaluate the effects of varespladib on cardiovascular risk in patients with ACS.15
Details of the study design and study protocol have been published previously.15 Patients aged 40 years or older hospitalized with an ACS who provided written, informed consent were eligible to participate. Documentation of ACS required either (1) elevation of biomarkers accompanied by symptoms of acute myocardial ischemia and/or new or presumed new ischemic electrocardiographic abnormalities or (2) symptoms in combination with new or presumed new electrocardiographic changes in patients without elevated biomarkers. Patients were also required to have 1 additional risk factor for recurrent events, including diabetes, metabolic syndrome, a high-density lipoprotein cholesterol (HDL-C) level of less than 42 mg/dL (to convert to millimoles per liter, multiply by 0.0259), calculated glomerular filtration rate of less than 60 mL/min, peripheral vascular disease, prior history of ischemic stroke, or transient ischemic attack, myocardial infarction (MI), or coronary revascularization. Patients were excluded from enrollment if LDL-C measured before the index ACS event was not at target levels according to local guidelines, despite current treatment with the maximum labeled dose of a statin. Other key exclusion criteria included advanced congestive heart failure, glycated hemoglobin value of at least 11% (to convert to proportion of total hemoglobin, multiply by 0.01), malignancy, severe liver or renal disease, malignancy, statin intolerance, and fasting triglyceride levels of at least 400 mg/dL (to convert to millimoles per liter, multiply by 0.0113).
The protocol specified that enrolled patients be treated with individualized, evidence-based management of ACSs, including diet and atorvastatin at a dose of at least 20 mg. Patients who met all inclusion criteria were randomized within 96 hours of presentation of the index event in a 1:1 ratio to treatment with varespladib (500 mg/d) or matching placebo, stratified by use of any lipid-modifying therapy before the index event and the type of qualifying index event (ST-elevation MI [STEMI], non–ST-elevation MI, or unstable angina). Any clinically indicated coronary revascularization during the index event was performed before randomization. Patients reported for study visits at weeks 1, 2, 4, 8, and 16 during the treatment phase. Patients with an LDL-C level of at least 100 mg/dL (to convert to millimoles per liter, multiply by 0.0259) at week 8 underwent atorvastatin dose escalation. Telephone follow-up to ascertain vital status was scheduled to occur 6 months following cessation of study drug.
The primary efficacy outcome was a composite of cardiovascular mortality, nonfatal MI, nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization. Secondary efficacy outcomes included the composite of cardiovascular mortality, nonfatal MI, and nonfatal stroke; each component of the primary outcome; total mortality; and changes in circulating lipid and inflammatory markers. All investigator-reported outcomes were adjudicated by a central committee at the Cleveland Clinic Coordinating Center for Clinical Research (C5Research).
Primary efficacy analysis was based on time to first occurrence of any positively adjudicated primary end point event by intention-to-treat, including all events in all patients from randomization to trial termination. The trial was designed to enroll 6500 patients, assuming an 8.5% primary end point event rate in the placebo group, with 80% power to detect a 25% reduction in the relative risk of the varespladib group, necessitating the adjudication of 385 primary end point events. An interim end point analysis for futility was specified at approximately 50% of the required primary end point events. Estimates of hazard ratios (HRs) and 95% CIs for varespladib compared with placebo were calculated by Cox proportional hazards regression models. Continuous data are presented as mean (SD), unless otherwise indicated. Race/ethnicity was self-reported by participants. Significance testing was performed using 2-sided tests (α = .05) using SAS version 9.2 (SAS Institute). Additional analytical methods are described in the previously published study protocol.15
A total of 5145 patients were enrolled at 362 sites in 17 countries between June 1, 2010, and March 7, 2012, and entered into the intention-to-treat analysis. The patient disposition during the study is shown in Figure 1. The qualifying ACS event was biomarker positive in 85% of the patients. The median (interquartile range [IQR]) time from presentation with the index event to randomization and first study drug administration was 57 (39-76) hours. Baseline characteristics of patients at randomization were well matched in the 2 treatment groups (Table 1). A high rate of cardiovascular risk factors and established atherosclerotic disease was observed in both groups. Before the index ACS event, 36% of patients had been treated with a lipid-modifying agent. At randomization, patients were well treated in both groups with a high rate of use of antiplatelet agents, statins, β-blockers, angiotensin-converting enzyme inhibitors, or receptor blockers (see eTable 1 in the Supplement). Coronary revascularization in response to the index event was performed in 80% of the patients. At randomization, mean LDL-C was 105 mg/dL and HDL-C was 43 mg/dL. Median (IQR) CRP was 10.4 (4.0-28.7) mg/L in the placebo group and 11.4 (4.5-33.0) mg/L in the varespladib group. (To convert CRP to nmol/L, multiply by 9.524.)
On March 9, 2012, at the prespecified interim analysis, when 212 primary outcomes had been recorded in 5012 randomized patients, the independent data and safety monitoring board recommended termination of the trial for futility according to predetermined criteria. The executive steering committee and sponsor (Anthera Pharmaceuticals) accepted this recommendation and terminated the trial on this date, with median (IQR) patient follow-up of 16.1 (13.4-16.4) weeks. Patients were treated for a mean (SD) of 13.4 (4.4) weeks. The mean (SD) follow-up of patients for the treatment period was 13.5 (4.6) weeks. All 5145 patients were included in the 16-week analysis. Time to event was calculated from randomization date to the date of the event, or censored at the last known follow-up for each patient if no event occurred. Only 1588 patients were contacted for the 6-month assessment.
Before study termination, premature discontinuation of treatment for reasons other than death occurred in 11.0% of the patients receiving varespladib and 10.4% of the patients receiving placebo. During treatment, 96% of patients in both groups remained at least 80% adherent with prescribed study drug doses. In the varespladib and placebo groups, 4.2% and 3.7%, respectively, of patients withdrew consent and an additional 0.8% and 1.1%, respectively, were lost to follow-up with unknown final vital status.
Changes in biochemical parameters during the course of the study are shown in Figure 2. Per protocol, atorvastatin was used in nearly all patients, with a median dosage of 40 mg/d. Slightly fewer than 20% of patients received 80 mg/d. Between randomization and week 16 of the study, LDL-C decreased by 28.8% in the varespladib group and 25.1% in the placebo group (P = .008). At week 16, the mean LDL-C was 69.1 mg/dL in the varespladib group and 73.8 mg/dL in the placebo group. During assigned treatment, levels of triglycerides and HDL-C did not differ between groups. The CRP levels were initially very high in both groups due to the index ACS event. Between randomization and week 16, CRP decreased by 85.0% in the varespladib group and 82.1% in the placebo group (P = .008). At week 16, median CRP was 1.4 mg/L in the varespladib group and 1.5 mg/L in the placebo group.
The primary outcome of cardiovascular mortality, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization occurred in 6.1% of patients treated with varespladib and 5.1% of patients treated with placebo (HR, 1.25; 95% CI, 0.97-1.61; log-rank P = .08) (Table 2). The composite secondary outcome of cardiovascular mortality, MI, and stroke occurred in 4.6% of patients in the varespladib group and 3.8% of patients in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). This was due primarily to a greater incidence of MI in the varespladib group compared with the placebo group (3.4% vs 2.2%; HR, 1.66; 95% CI, 1.16-2.39; P = .005) (Figure 3). Cardiovascular mortality at the end of the randomized treatment period was nonsignificantly greater in the varespladib group (1.5% vs 1.4%; P = .54), although risks of stroke (0.4% vs 0.6%; P = .81) and hospitalization for unstable angina (1.9% vs 1.4%; P = .47) were similar in both groups. There was no subgroup in which varespladib reduced risk. However, greater rates of MI with varespladib were observed in patients who did not undergo percutaneous coronary intervention, meeting statistical significance for heterogeneity (P = .04). Furthermore, there was a higher rate of MI associated with varespladib among patients whose index event was not a STEMI, although this did not reach statistical significance (P = .06 for heterogeneity) (Figure 4). At 6 months after discontinuation of study treatment, all-cause mortality in those patients whose survival status was established was 2.7% in the varespladib group and 2.0% in the placebo group (P = .15).
Numbers of adverse events and serious adverse events are reported in eTable 2 in the Supplement. Discontinuation of study treatment for adverse events occurred in 2.8% of patients in the varespladib group and 1.4% of patients in the placebo group. There was an excess of alanine transaminase elevations more than 3 times the upper limit of normal during the treatment phase with varespladib (38 patients) compared with placebo (6 patients), with no evidence of concomitant bilirubin elevations. Varespladib had no effect on renal function or on creatine kinase levels.
Despite experimental and observational clinical data suggesting that pan-inhibition of sPLA2 would exert beneficial cardiovascular effect, the VISTA-16 trial provides evidence to the contrary. Despite lower achieved levels of LDL-C and CRP, there was no evidence of a beneficial reduction in the primary cardiovascular outcome. In contrast, treatment with varespladib caused an excess of MI and the composite of cardiovascular mortality, MI, and stroke. Consequently, these findings suggest that short-term sPLA2 inhibition with varespladib is harmful following ACS.
The lack of any indication of cardiovascular benefit with varespladib contradicts the favorable effects on cardiovascular biomarkers in patients with ACS. Initial clinical experience with varespladib consistently demonstrated beneficial effects on lipid and inflammatory biomarkers, which theoretically should have translated to a lower propensity to plaque rupture.12- 14 We conducted the VISTA-16 trial because of the established link between sPLA2 and vascular inflammation, as well as preclinical evidence for benefit in ischemia reperfusion injury.5 Favorable effects of varespladib on LDL-C and CRP were again demonstrated in the present trial, suggesting that other unfavorable consequences of sPLA2 inhibition or other unmeasured effects of varespladib influenced the clinical outcomes of treatment. Possible explanations for the unfavorable outcomes include potentially inadequate penetration of varespladib into vascular cells to inhibit pro-inflammatory intracellular mediators. Alternatively, varespladib may have abrogated the effects of both pro-atherogenic (IIA and V) and antiatherogenic sPLA2 isoforms.6,7 Our findings with sPLA2 inhibition reemphasize that identification of a circulating marker of cardiovascular risk does not necessarily imply that pharmacologic suppression or inhibition of the marker will reduce risk. The failure to demonstrate any benefit is supported by a recent report from Mendialian randomization studies concluding that sPLA2 does not play a causative role in coronary disease16; however, such studies cannot necessarily predict the result of a pharmacologic intervention in patients with established coronary disease. Ultimately, most therapies must be tested using careful human randomized clinical trials.
The precise mechanism underlying the adverse effect on the rate of MI with varespladib remains unknown. Recurrent MI in patients with a recent ACS often results from ongoing episodes of plaque rupture and thrombosis, often at sites remote from the lesion responsible for the initial event. The increased rate of MI observed early in the trial might also suggest that the drug may have induced a prothrombotic state. However, we observed no excess rate of early stent thrombosis in the varespladib group. In fact, we observed less harm for MI with varespladib in patients who had undergone percutaneous coronary intervention for the index ACS event and in patients whose initial presentation was with STEMI. There currently exists no external information regarding potential interactions between either sPLA2 activity or varespladib and factors that influence the coagulation cascade or platelet function. Given that other therapies that modulate prostaglandin metabolites have been reported to be associated with an excess rate of MI,17 the potential effect of the varespladib molecule and sPLA2 inhibition on thrombotic and fibrinolytic pathways, in addition to plaque stability, require further investigation.
The findings may have implications for targeting other inflammatory pathways as strategies to reduce cardiovascular risk. Although the role of vascular inflammation in atherosclerosis is widely accepted, there is at present no evidence to our knowledge that targeting any specific inflammatory factor will attenuate cardiovascular risk. The complexity and redundancy of inflammatory pathways may confound such efforts.8 Evidence by other studies indicates that interventions targeting prostaglandin inflammatory pathways, such as rofecoxib, are harmful rather than protective against coronary heart disease.17 Nevertheless, other anti-inflammatory agents, including inhibitors of lipoprotein-associated phospholipase A2, are undergoing evaluation in large clinical trials.18- 20
A number of limitations should be noted with regard to our study. Survival status at 6 months was not established in a majority of patients. Accordingly, we cannot exclude that the increased rate of MI with varespladib did not ultimately result in an excess mortality rate. Given that varespladib is a pan-sPLA2 inhibitor, it is unknown whether a more selective agent would be beneficial. Patients were not selected for randomization on the basis of their underlying sPLA2 concentration or activity. The VISTA-16 trial was an evaluation of the effect of sPLA2 inhibition with varespladib in the first few months following an ACS. It is unknown whether such a strategy would be more likely to be protective in a more chronic stage of the disease. However, the finding of an excess risk of MI with varespladib makes it unlikely that this will be investigated.
The administrative actions of the sponsor and the timelines involved with the dissemination of data from this clinical trial require further comment. The sponsor took the appropriate scientific and ethical course of action to accept the recommendation by the data and safety monitoring board and prematurely stop the study for futility on March 9, 2012.21 Although the study protocol stipulated that survival status would be determined for all patients who participated in the study, data were collected by the sponsor for only 1588 of the 5145 enrolled patients. In addition, the study steering committee and the investigators did not receive the full database for analysis until May 10, 2013, approximately 1 month after the sponsor’s compound license expired and was returned to the original developer of the compound.
In conclusion, sPLA2 inhibition with varespladib administration did not reduce cardiovascular ischemic complications and resulted in an excess rate of MI and the composite of cardiovascular mortality, MI, and stroke in patients with ACS. Whether this represents an adverse effect of the varespladib molecule or a consequence of pan-sPLA2 inhibition remains to be determined.
Corresponding Author: Stephen J. Nicholls, MBBS, PhD, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA 5001, Australia (email@example.com).
Published Online: November 18, 2013. doi:10.1001/jama.2013.282836.
Author Contributions: Dr Nicholls had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Kastelein, Schwartz, Bash, Rosenson, Menon, Nissen, Nicholls.
Acquisition of data: Schwartz, Cavender, Koenig, Jukema, Menon, Nicholls.
Analysis and interpretation of data: Kastelein, Schwartz, Bash, Rosenson, Brennan, Koenig, Jukema, Nambi, Wright, Menon, Lincoff, Nissen, Nicholls.
Drafting of the manuscript: Bash, Rosenson, Menon, Nicholls.
Critical revision of the manuscript for important intellectual content: Kastelein, Schwartz, Bash, Rosenson, Cavender, Brennan, Koenig, Jukema, Nambi, Wright, Menon, Lincoff, Nissen.
Statistical analysis: Brennan, Menon, Nicholls.
Obtained funding: Menon.
Administrative, technical, or material support: Bash, Rosenson, Cavender, Wright, Menon, Lincoff, Nissen, Nicholls.
Study supervision: Kastelein, Schwartz, Bash, Cavender, Koenig, Jukema, Menon, Lincoff, Nissen, Nicholls.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nicholls reported having received research support from Anthera, AstraZeneca, Cerenis, Eli Lilly, InfraReDx, Roche, Resverlogix, Novartis, Amgen, and LipoScience; and consulting fees from AstraZeneca, Abbott, Atheronova, Esperion, Merck, Takeda, Roche, Amgen, LipoScience, Novartis, Omthera, CSL Behring, Boehringer Ingelheim, and Pfizer. Dr Kastelein reported serving as a consultant to and receiving honoraria from Anthera, MSD, Eli Lilly, The Medicines Company, CSL Behring, AstraZeneca, Resverlogix, Boehringer Ingelheim, Cerenis, Novartis, and Catabasis. Dr Schwartz, through his institution, reported receiving research grants from Anthera, Resverlogix, Roche, and sanofi. Dr Rosenson reported receiving consulting fees from Aegerion, Abbott, Amgen Roche, LipoScience, Pfizer, Regeneron, and sanofi; receiving research support from AstraZeneca, Amgen, and sanofi; owning stock in LipoScience and The Medicines Company; and receiving royalties from UpToDate. Dr Koenig reported receiving consulting fees from Roche, BioInvent, diaDexus, Cerenis, Novartis, Servier, Amgen, The Medicines Company, Genzyme, Aegerion, and AstraZeneca; receiving honoraria for lectures from Roche, Novartis, and Merck; and receiving research support from Roche. Dr Jukema reported receiving research grants from and speaking on (CME accredited) meetings sponsored by Astellas, Anthera, Astra-Zeneca, Bayer, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Genzyme, Medtronic, Merck-Schering-Plough, Pfizer, Orbus Neich, Novartis, Roche, Servier, sanofi aventis, the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework KP7 Programme. Dr Wright reported having received consulting fees from Roche, Genentech, and sanofi. Dr Nissen reported that the Cleveland Clinic Center for Clinical Research receives funding performing clinical trials from AstraZeneca, Anthera, Amgen, Pfizer, The Medicines Company, Novartis, Takeda, Resverlogix, Ethicon, Orexigen, Vivus, and Eli Lilly. Dr Nissen is involved in these clinical trials, but receives no personal remuneration for his participation. He also consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Drs Cavender, Nambi, Menon, and Lincoff and Mss Bash and Brennan reported no disclosures.
Funding/Support: The study was funded by Anthera Pharmaceuticals.
Role of the Sponsors: Anthera Pharmaceuticals participated actively in designing the study, developing the protocol, and provided logistical support during the trial. The protocol was developed by members of the independent academic Executive Steering Committee, in conjunction with Anthera Pharmaceuticals. The study design was approved by responsible regulatory agencies and ethics committees. Collecting the data and monitoring of the study was performed by WorldWide Clinical Trials (Los Angeles, California). Anthera Pharmaceuticals maintained the trial database. Although the executive steering committee and coordinating center had confidentiality agreements with the sponsor, the study contract specified that a copy of the study database be provided to the coordinating center for independent analysis and granted the academic authors the unrestricted rights to publish the results. After completion of the trial, as specified in the study contract, a complete copy of the database was transferred to the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), where statistical analyses were performed by an independent statistician, Danielle Brennan, MPH. The results reported in the manuscript are the results of the analyses performed by Ms Brennan. The manuscript was prepared by the corresponding author and modified after consultation with coauthors. The final decision on content was exclusively retained by the academic authors.
Data and Safety Monitoring Board: Charles Hennekens (chair), W Virgil Brown, David DeMets, Marc Pfeffer, John Roleau.
Clinical Events Committee: JoEllyn Abraham, James Gebel, Christopher Huff, Irene Katzan, Medhi Shishehbor, Andrew Rassi, Ken Uchino, Amanda Vest, Edwin Zishiri, Mary Jo Heckman.
Statistical Programming Support: Craig Balog.
VISTA-16 Investigators: Australia: Anthony Dart (Alfred Hospital); John Amerena (Barwon Health–Geelong Hospital); Challa Prasad (Cairns Base Hospital); Ahmad Farshid (Canberra Hospital); Brendan Gunalingam (Gosford Hospital); Peter Thompson (Heart Research Institute); Nicholas Collins (John Hunter Hospital); Margaret Arstall (Lyell McEwin Hospital); William van Gaal (Northern Hospital); Con Aroney (Queensland Cardiology); Leo Mahar (Royal Adelaide Hospital); George Youssef (St George Hospital); John Horowitz (The Queen Elizabeth Hospital); Dharmesh Anand (Townsville Hospital). Canada: Josep Rodes-Cabau (Hopital Laval); Petr Polasek (Interior Clinical Research Consultants); Christopher Lai (Intermountain Research Consultants); Thao Huynh (McGill University Health Centre); Jaroslav Hubacek (New Brunswick Heart Centre); Andre Kokis (Centre Hospitalier de l'Universite de Montreal–Hotel Dieu); Jean-Michel Paradis (CHUQ–Hotel Dieu de Quebec); Ashok Mukherjee (CorCare Cardiology); Manohara Senaratne (Grey Nuns Community Hospital and Health Centre); Christian Constance (Hopital Maisonneuve-Rosemont); Gilbert Gosselin (Hopital Pierre-Le Gardeur); Shahar Lavi (London Health Sciences Centre); John Parker (Mt Sinai Hospital); Remo Zadra (Newmarket Cardiology Research Group); Beth Abramson (St Michael's Hospital); Anthony Della-Siega (Victoria Heart Institute). Czech Republic: Jindrich Spinar (Fakultni nemocnice Brno); Radek Pudil (Fakultni nemocnice Hradec Kralove); Zuzana Motovska (Fakultni nemocnice Kralovske nemocnice); Martin Maly (Fakultni nemocnice Motol); Martin Hutyra (Fakultni nemocnice Olomouc); Leos Pleva (Fakultni nemocnice Ostrava); Otto Mayer (Fakultni nemocnice Plzen); Jiri Semenka (Fakultni nemocnice u Sv Anny v Brne); Tomas Klimovic (Klaudianova nemocnice Mlada Boleslav); David Horak (Krajska nemocnice Liberec); Pavel Cervinka (Masarykova nemocnice Usti nad Labem); Zdenek Klimsa (Nemocnice Jihlava); Vaclav Hulinsky (Nemocnice Nymburk); Petr Reichert (Nemocnice Teplice); Zdenek Monhart (Nemocnice Znojmo); Helena Rotterova (Vseobecna fakultni nemocnice v Praze). Georgia: Bondo Kobulia (Cardio-Reanimation Centre LTD); Tamaz Shaburishvili (Diagnostic services LTD); Merab Mamatsashvili (Limited Company [ADAPTI] the Clinic of Angicardiology); Gulnara Chapidze (LLC Emergency Cardiology Center by Academician G. Chapidze); Vakhtang Chumburidze (National Center of Therapy); Irakli Megreladze (Tbilisi LTD Cardiology clinic); Irakli Khintibidze (TSMU Alexandre Aladashvili University clinic). Germany: Boris Leithäuser (Asklepios Klinik Harburg); Hans-Friedrich Voehringer (DRK Kliniken Berlin-Koepenick); Rolf Wachter (Georg-August-Universitaet/Universitaetsmedizin Goettingen); Klaus Nogai (Havelland Klinik GmbH); Harald Lapp (Helios Klinikum Erfurt GmbH); Georg Haltern (HELIOS Universitaetsklinikum Wuppertal); Stephan Gielen (Herz-Zentrum Leipzig); Thomas Dorsel (Josephs-Hospital Warendorf); Helge Möllmann (Kerckhoff-Klinik GmbH); Christoph Stellbrink (Klinikum Bielefeld); Christian Hengstenberg (Klinikum der Universität Regensburg); Thomas Dengler (SLK-Kliniken Heilbronn); Hubertus Heuer (St Johannes Hospital Dortmund); Joerg Kreuzer (St Vincenz Krankenhaus Limburg); Matthias Leschke (Städtische Kliniken Esslingen); Harald Mudra (Städtisches Klinikum München GmbH); Nikos Werner (Universitaetsklinikum Bonn); Ruediger Braun-Dullaeus (Universitaetsklinikum Magdeburg); Mark Rosenberg (Universitaetsklinikum Schleswig-Holstein (Campus Kiel)); Norbert Frey (Universitaetsklinikum Schleswig-Holstein (Campus Kiel)); Wolfgang Koenig (Universitaetsklinikum Ulm); Ruth Strasser (Universitätsklinik an der Technischen Universität Dresden); Sabine Genth-Zotz (Universitätsklinikum d Johannes-Gutenberg-Universität Mainz). Hungary: Robert Kiss (Allami Egeszsegugyi Kozpont); Andras Nagy (Bacs-Kiskun Megyei Onkormanyzat Korhaza); Zsolt Kovacs (Bajai Korhaz); Kalman Csapo (Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz); Istvan Edes (Debreceni Egyetem Orvos-Es Egeszsegtudomanyi Centrum); Matyas Sereg (Fejer Megyei Szent Gyorgy Korhaz); Andras Vertes (Fovarosi Onkormanyzat); Aladar Ronaszeki (Fovarosi Onkormanyzat); Sandor Kancz (Gottsegen György Országos Kardiológiai Intézet); Bela Benczur (Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointez); Peter Polgar (Josa Andras Oktatokorhaz); Gabor Muller (Markhot Ferenc Korhaz); Gabor Simonyi (Pest Megyei Flor Ferenc Korhaz); Csaba Dezsi (Petz Aladar Megyei Oktato Korhaz); Bela Merkely (Semmelweis Egyetem Általános Orvostudományi Kar); Jozsef Dinnyes (Vaszary Kolos Korhaz); Geza Lupkovics (Zala Megyei Kórház). India: Dhiman Kahali (B.M. Birla Heart Research Centre); Darshan Banker (Banker Heart Institute); Shailendra Trivedi (CHL Apollo Hospitals); Rajeeve Rajput (Indraprastha Apollo Hospitals); Rajendra Premchand (Krishna Institute of Medical Sciences); Sameer Dani (Lifecare Institute of Medical Sciences & Research); Prakash Vadaganelli (MS Ramaiah Memorial Hospital); Sandeep Gupta (MV Hospital and Research Centre); Sarat Chandra (Nizams Institute of Medical Sciences); Mahesh Fulwani (Shrikrishna Hrudayalaya and Critical Care Centre); Kamaldeep Chawla (Sterling Hospital); Keyur Parikh (The Heart Care Clinic). Italy: Francesco Prati (Az Osp Complesso Ospedaliero San Giovanni Addolorata); Giulio Speciale (Azienda Complesso Ospedaliero San Filippo Neri); Marco Valgimigli (Azienda Ospedaliera Arcispedale Sant'Anna di Ferrara); Patrizia Suriano (Azienda Ospedaliera Maggiore della Carita); Andrea Berni (Azienda Ospedaliera Sant'Andrea); Giuseppe Sangiorgi (Azienda Ospedaliera Universitaria Policlinico Di Modena); Massimo Fineschi (Azienda Ospedaliera Universitaria Senese); Raffaele Merenda (Azienda Ospedaliera Vincenzo Monaldi); Giancarlo Marenzi (Centro Cardiologico Monzino - IRCCS); Sergio Berti (Fond G Monasterio-CNR RegToscana Osp del Cuore G Pasquinucci); Elena Corrada (Istituto Clinico Humanitas IRCCS); Claudio Cuccia (Istituto Ospedaliero Fondazione Poliambulanza); Roberto Testa (Ospedale Civile di Cecina); Luciano Moretti (Ospedale Gen.le Prov.le C.G.Mazzoni); Mauro Mennuni (Ospedale Parodi Delfino); Luigi Marzio Biasucci (Policlinico Agostino Gemelli); Ernesto Lioy (Policlinico Casilino); Carla Auguadro (Policlinico di Monza); Enrico Magagnini (Spedali Riuniti); Francesco Fedele (Univerdegli Studi di Roma La Sapienza Policlinico Umberto I); Federico Piscione (Universita degli Studi di Napoli Federico II). Lebanon: Rabih Azar (Hotel Dieu de France Hospital). the Netherlands: Mieke D. Trip (Academic Medical Center); AnHo Liem (Admiraal de Ruyter Ziekenhuis); Maarten den Hartoog (Amstelland Ziekenhuis); Timo Lenderink (Atrium Medisch Centrum Heerlen); Machiel L. J. M. van de Wetering (BovenIJ ziekenhuis); Dirk; Lok (Deventer Ziekenhuis); Fanny Oei (Franciscus Ziekenhuis); Jan Geert Tans (Gemini Ziekenhuis); Ben Ilmer (Havenziekenhuis); Mitran Keijzers (Kennemer Gasthuis); Pascalle Monraats (LUMC); Elvin Kedhi (Maasstad Ziekenhuis); Rob W. Breedveld (MC Leeuwarden); J. P. R. Herrman (Onze Lieve Vrouwe Gasthuis); L. M. van Wijk (Refaja Hospital); Eelko Ronner (Reinier de Graaf Gasthuis); Peter Nierop (Sint Franciscus Gasthuis); Mike Bosschaert (St Antonius Ziekenhuis); Walter Hermans (St Elisabeth Ziekenhuis Tilburg); Pieter Doevendans (UMC Utrecht); Roland Troquay (VieCuri MC Noord-Limburg); Rob van der Heijden (Vlietland Ziekenhuis); Gerrit Veen (VU Medisch Centrum); Marcel J. J. A. Bokern (Waterlandziekenhuis); Patrick N. A. Bronzwaer (Zaans Medisch Centrum); Salem Hong Kie ( the Ziekenhuis Bethesda); Frank Den Hartog (Ziekenhuis Gelderse Vallei). New Zealand: John Elliott (Christchurch Hospital); Gerard Wilkins (Dunedin Hospital); Hamish Hart (North Shore Hospital); Gerard Devlin (Waikato Hospital); Scott Harding (Wellington Hospital). Poland: Piotr Ponikowski (4 Wojskowy Szpital Kliniczny); Andrzej Madej (Centralny Szpital Kliniczny); Marek Kochmanski (Centralny Szpital Kliniczny Ministerstwa Spraw Wewnetrznych); Adam Witkowski (Instytut Kardiologii); Wladyslaw Pluta (Publiczny Samodzielny Zaklad Opieki Zdrowotnej Wojewodzkie C); Marek Bronisz (Publiczny Specjalistyczny ZOZ w Inowroclawiu); Zdzislawa Kornacewicz-Jach (Samodzielny Publiczny Szpital Kliniczny nr 2 Pomorska Akadem); Andrzej Wysokinski (Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie); Marek Ujda (SP ZOZ Powiatowy Szpital Specjalistyczny); Jaroslaw Drozdz (SP ZOZ USK im. WAM UM w £odzi - Centralny Szpital Weteranów); Boguslaw Derlaga (Specjalistyczny Szpital im E Szczeklika); Jacek Gessek (Specjalistyczny Szpital Miejski im M Kopernika); Marek Dabrowski (Szpital Bielanski im ks J Popieluszki Samodzielny Publicz); Pawel Miekus (Szpital Miejski); Artur Kozlowski (Szpital Powiatowy); Jacek Gniot (Szpital Specjalistyczny; SP ZOZ w Puawach); Wlodzimierz Musial (Uniwersytecki Szpital Kiliniczny w Bialymstoku; SPZOZ); Slawomir Dobrzycki (Uniwersytecki Szpital Kliniczny w Biaymstoku SPZOZ); Andrzej Rynkiewicz (Uniwersyteckie Centrum Kliniczne); Piotr Psuja (Wielospecjalistyczny Szpital Miejski im J Strusia z Zaklad); Jerzy Rekosz (Wojewodzka Stacja Pogotowia Ratunkowego i Transportu Sanitar); Andrzej Drzewiecki (Wojewodzki Szpital Zespolony). Russia: Vadim Kuznetsov (Affiliate of Institution of the Russian Academy of Medical S); Ivan Gordeev (City Clinical Hospital No 15 na OM Filatov); Boris Goloshchekin (City Hospital 115); Valentin Markov (Institution of the Russian Academy of Medical Sciences Resea); Vladimir Barbarich (Municipal Budget Healthcare Institution of Novosibirsk; City); Dmitry Belenky (Municipal Healthcare Institution; Novosibirsk Municipal Clin); Vadim Mikhin (Municipal Healthcare Institution; City Clinical Hospital); Emilia Volkova (Municipal Healthcare Institution; City Clinical Hospital No. 3); Aleksandr Timofeev (Municipal Healthcare Institution; City Hospital No. 1); Liudmila Ermoshkina (Municipal Healthcare Institution; Gatchina Central District); Olga Barbarash (Municipal Healthcare Institution; Kemerovo Cardiology Dispen); Garry Klein (Murmansk Regional Clinical Hospital na PA Bayandin); Roman Libis (Orenburg State Medical Academy); Aleksander Vishnevsky (Pokrovskaya City Hospital); Kirill Linev (Regional Budged State Healthcare Institution; Regional Clini); Larisa Khaisheva (Rostov-on-Don City Hospital for Emergency Care No. 2); Mikhail Ruda (Russian Cardiology Research and Production Complex (Moscow); Yakov Dovgalevskiy (Saratov Research Institute for Cardiology); Yury Shvarts (Saratov State Medical University); Dmitry Zateyshchikov (SHI of Moscow city; City Hospital No. 17); Victor Kostenko (St Petersburg Research Institute for Emergency Care); Vladimir Shalnev (St Petersburg Medical Academy of Postgraduate Training); Vladimir Simanenkov (St Petersburg State Healthcare Institution; City Hospital 1); Mikhail Arkhipov (State Educational Institution for Higher Professional Traini); Elena Ovcharenko (State Healthcare Institution Irkutsk Regional Clinical Hospi); Galina Guseva (State Healthcare Institution; Samara Regional Clinical Cardio); Svetlana Akhunova (State Institution; Interregional Clinical and Diagn-c Center). Spain: Antonio Ignacio Fernández Ortiz (Hospital Clinico San Carlos); Manuel Jiménez Navarro (Hospital Clinico Universitario Virgen de la Victoria); Antonio Jose Fernández Romero (Hospital de Alta Resolucion de Utrera); Iñaki Lekuona Goya (Hospital de Galdakao); Antoni Serra Peñaranda (Hospital de la Santa Creu i Sant Pau); Antonio Amaro Cendon (Hospital de Montecelo); Antoni Martinez Rubio (Hospital de Sabadell); José Julián Berrade Zubiri (Hospital General de L'Hospitalet); Francisco Ridocci Soriano (Hospital General Universitario de Valencia); Rafael Rubio Sanz (Hospital General Universitario Gregorio Marañón); Antonio Bayés Genís (Hospital Germans Trias i Pujol); Vicente Nieto Lago (Hospital Insular de Gran Canaria); José Díaz Fernández (Hospital Juan Ramón Jiménez); Andrés Iñiguez Romo (Hospital Meixoeiro); Silvestre Nicolás Franco (Hospital Rafael Méndez); Isabel Hernandez Martin (Hospital Universitari Arnau de Vilanova); Juan Sala Montero (Hospital Universitari Josep Trueta); Manuel de Mora Martin (Hospital Universitario Carlos Haya); Martín Jesús García González (Hospital Universitario de Canarias); José Maria Serrano Antolin (Hospital Universitario de Fuenlabrada); Esteban López de Sá Areses (Hospital Universitario La Paz); Jesús Martín Miranda (Hospital Universitario Ntra Sra de la Candelaria); Luís Alonso-Pulpón (Hospital Universitario Puerta de Hierro); Gonzalo Barón Esquivias (Hospital Universitario Virgen del Rocio); Elena Fernández Jarne (Clínica Universitaria de Navarra); José Manuel Gutiérrez Cortés (Hospital Arquitecto Marcide); Maurice Batlle Pérez (Hospital del Henares); Carlos Lafuente Gormaz (Hospital General Universitario de Albacete); Jose Maria Alegret (Hospital Universitari de Sant Joan de Reus); José Sergio Hevia Nava (Hospital Universitario Central de Asturias); Juan Manuel Grande Ingelmo (Hospital Universitario Severo Ochoa); Rafael Hidalgo Urbano (Hospital Universitario Virgen Macarena); Marcelo Sanmartín (Policlinico Vigo; S. A. (Povisa). Ukraine: Oleksandr Katerenchuk (Poltava Regional Cardiological Dispensary); Igor Vakaliuk (Ivano-Frankivsk Regional Clinical Ñardiological Dispensary); Oleksandr Karpenko (Kyiv City Clinical Hospital No. 1); Oleksandr Prokhorov (City Clinical Hospital No. 27); Olena Koval (Clinical Joint Emergency Hospital); Andriy Faynyk (Clinical Treatment-and-Diagnostic Cardiology Center); Mykola Kopytsya (Institute of Therapy named after L. T. Malaya); Yuriy Karpenko (Odessa Regional Clinical Hospital); Igor Kraiz (Central Clinical Hospital of Ukrzaliznytsya); Olexander Feskov (Kharkiv City Clinical Hospital of Emergency Care); Leonid Rudenko (Kyiv City Clinical Hospital of Emergency Care); Sergii Kozhukhov (M. D. Strazhesko Institute of Cardiology); Borys Goloborodko (Public Institution–City Clinical Hospital No. 3). United States: Ernesto Rivera (Amarillo Heart Clinical Research Institute Inc); Stephen Broadwater (Augusta Cardiology Clinic PC); Stephen Crowley (Aurora Denver Cardiology Associates); Nampalli Vijay (Aurora Denver Cardiology Associates PC); Rajiv Goswami (Ben Taub General Hospital); L. Norman Ferrier (Black Hills Cardiovascular Research); Arnoux Blanchard (Broward General Medical Center); Kevin McCullum (Cardiac Diagnostic Associates PC); Richard Chernick (Cardiology Associates Department of Clinical Research); Barry Bertolet (Cardiology Associates Research LLC); Joseph Battaglia (Cardiology PC); John Richardson (Cardio-Thoracic Surgeons; PC); Stanley Lochridge (Cardio-Thoracic Surgeons; PC East); Scott Lieberman (Cardiovascular Associates of East Texas); Ali Amkieh (Cardiovascular Associates Research LLC); James Bradley Cavender (Cardiovascular Associates PC); Stephen Denning (Cardiovascular Consultants Aultman Hospital); Charles Treasure (Cardiovascular Research of Knoxville); James Kmetzo (Central Bucks Cardiology); Michael Stillabower (Christiana Care Health System); Emmanouil Brilakis (Dallas VA Medical Center); Gregory Schwartz (Denver VA Medical Center); Roger Acheatel (Escondido Cardiology Associates); Eugene Kukuy (Crescent City Cardiovascular); Majdi Ashchi (First Coast Cardiovascular Institute PA); Kimberly Skelding (Geisinger Clinic); Lisa Martin (George Washington University Medical Faculty Assoc); Eve Gillespie (Glacier View Cardiology); William French (Harbor–UCLA Medical Center); Stewart Pollock (Harrisonburg Medical Associates); Donna Polk (Hartford Hospital); Robert Black (Heart & Vascular Institute of Florida); David Drenning (Heart Center Research LLC); Jerome Anderson (Integris Baptist Medical Center); Mark Sanz (International Heart Institute of Montana); Elie Korban (Kore CV Research); Mark Wiley (KUMC Research Institute Inc); Shereif Rezkalla (Marshfield Clinic); Anthony Minisi (McGuire VAMC; Code 151); Ahmed Shah (Mercer University School of Medicine); Paul Silverman (MidAmerica Cardiovascular Consultants); Mohamadali Amlani (Mid-Michigan Cardiology Associates PLC); Gregory Eaton (Mid-Ohio Heart Clinic Inc); Alan Brown (Midwest Heart Specialists); Desmond Jay (Minneapolis Heart Institute Foundation); Arthur Loussararian (Mission Internal Medical Group); Gervasio Lamas (Mount Sinai Medical Center); Michael Lauer (Northwest Michigan Heart and Vascular Specialist); Jerome Williams (Novant Medical Group Inc); Abedelrahim Asfour (Oakwood Hospital & Medical Center Dearborn); Lars Runquist (Palmetto Medical Research); Roy Robertson (Parkview Research Center); Ronald Blonder (Pikes Peak Cardiology); Crispin Davies (Portland VA Medical Center); Thomas Downes (Poudre Valley Medical Group Heart Center of the Rockies); Nicolas Chronos (Saint Joseph's Research Institute); Steve Marso (Saint Lukes); Thomas Haldis (Sanford Research/USD); David Eich (Sentara Cardiovascular Research Institute); Mudassar Ahmed (SMDC Heart and Vascular Center); Cara East (Soltero Cardiovascular Research Center); Lee MacDonald (South Denver Cardiology Associates PC); Paul Seigel (South Florida Research Group LLC); Michael White (The Cardiac Center of Creighton University); Alan Camp (the Heart and Vascular Institute of Florida); Neal Kleiman (the Methodist Hospital Research Institute); Douglas Burtt (the Miriam Hospital); Janet Strain (the Valley Hospital); Brian Go (Triangle Medical Research); Phillip Henry (TriCities Medical Research); Parvez Sultan (Trinity Medical Center); Patrice Delafontaine (Tulane University Health Sciences Center); Hisham Kashou (UHS Office of Clinical Trials); Charles Lambert (University Community Hospital); M. Reza Movahed (University of Arizona); Jorge Saucedo (University of Oklahoma Health Sciences Center); Udho Thadani (VA Medical Center); Yellapraguda Chandrashekhar (VA Medical Center); David Lu (VAMC); Harish Chandna (Victoria Heart and Vascular Center); James Mann (Wake Heart Research); Geetha Ramaswamy (Washington Regional Medical Center); Kevin Browne (Watson Clinic LLP); Matthew Janik (Wilmington Medical Research); Kevin Cannon (Wilmington Medical Research); Paul Tolerico (York Hospital).
Correction: The forest plots in both panels of Figure 4 were corrected on December 20, 2013.