Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial

Tardif, Jean‐Claude; McMurray, John J.V.; Klug, Eric; Small, Robert J.; Schumi, Jennifer; Choi, Jasmine; Cooper, Jim; Scott, Robert C.; Lewis, Eldrin F.; L’Allier, Philippe L.; Pfeffer, Marc A.

doi:10.1016/s0140-6736(08)60763-1

Cited by 180 publications

(120 citation statements)

References 28 publications

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“…Surprisingly, the ARISE study [59] showed that use of succinobucol was associated with increased incidence of new-onset AF in patients with an acute coronary syndrome. Our previous meta-analysis suggested that increased CRP levels are associated with greater risk of immediate and short-term AF recurrence following electrical cardioversion [60,61].…”

Section: Probucolmentioning

confidence: 99%

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

Liu¹,

Korantzopoulos²,

Li³

2013

Atrial Fibrillation - Mechanisms and Treatment

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Section: Probucolmentioning

confidence: 99%

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

Liu¹,

Korantzopoulos²,

Li³

2013

Atrial Fibrillation - Mechanisms and Treatment

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“…The drug (AGI-1067) had been shown to inhibit atherogenesis in animal models (42), but it failed to show any decrease in its primary composite end point of cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization above that seen with statin therapy alone (43). Data to evaluate antioxidant effect were not presented.…”

Section: Clinical Trial Datamentioning

confidence: 99%

The LDL modification hypothesis of atherogenesis: an update

Steinberg

2009

Journal of Lipid Research

373

237

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The accumulated evidence that oxidative modification of LDL plays an important role in the pathogenesis of atherosclerosis in animal models is very strong. The negative results in recent clinical studies have caused many to conclude that LDL oxidation may not be relevant in the human disease. Yet many of the lines of evidence that support the hypothesis have been demonstrated to apply also in humans. In this review, we briefly summarize the lines of evidence on which the hypothesis rests, its strengths, and its weaknesses. The defining characteristic of the fatty streak, the first visible lesion of atherosclerosis, both in animals and in humans is the "foam cell." This cell, loaded with droplets rich in cholesteryl esters, is derived mainly from arterial wall macrophages, which originate from circulating monocytes that have penetrated into the subendothelial space. Smooth muscle cells and endothelial cells in lesions also can and do accumulate lipid droplets, but monocyte-derived macrophage foam cells predominate. This being the case, an understanding of just how arterial macrophages take up and store their load of cholesterol should shed light on the mechanisms that initiate atherogenesis. ORIGINS OF THE OXIDATIVE MODIFICATION HYPOTHESISBeginning in 1979, Goldstein, Brown, and their collaborators [reviewed in (1)] decided to pursue this problem, studying the metabolism of macrophages in cell culture. They noted the following apparent paradox: in patients with homozygous familial hypercholesterolemia, even in those who express absolutely no functional LDL receptors, macrophage-derived foam cells nevertheless accumulate in the artery walls just as they do in hypercholesterolemic patients that have perfectly normal LDL receptors. The implication was that LDL must be somehow altered prior to its uptake by macrophages and then taken up, not by the native LDL receptor, but rather by some alternative macrophage receptor. Indeed, they found that the rate of uptake of native LDL by normal resident mouse peritoneal macrophages was very low even at very high LDL concentrations. There was very little increase in cell cholesterol content and certainly no generation of foam cells. They then tried modifying the LDL physically, chemically, or enzymatically, looking for some form of LDL that could turn macrophages into foam cells in vitro. Several modifications worked, but the most striking was chemical acetylation. Treatment of LDL with acetic anhydride yielded a form of LDL that bound to the macrophage specifically and with high affinity, was actively internalized, and led to intracellular cholesterol accumulation. They dubbed the putative receptor the acetyl-LDL receptor. That receptor was later cloned and characterized by Kodama et al. (2) in the laboratory of Monty Krieger. Because of its possible role in the LDL receptor-independent uptake of LDL and because of its broad ligand specificity, it was redesignated scavenger receptor A (SRA). However, acetyl-LDL itself is not a biological product and has never been f...

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“…The reader is refered to Gómez et al (2014), where a survey of the use of composite endpoints in the Cardiovascular Literature is described , other interesting cases of clinical trials are presented and a set of recommendations for future design choice between relevant and composite endpoints for cardiovascular clinical trials is discussed. Case study 1: Treating patients after an acute coronary syndrome with succinobucol Tardif et al (2008) designed a randomized clinical trial to test the effect of the antioxidant succinobucol on cardiovascular outcomes in patients with recent acute coronary syndrome. The primary efficacy endpoint, denoted by E * , was the union of E 1 and E 2 , where E 1 was the first occurrence between cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction and non-fatal stroke; and E 2 was the first occurrence of hospitalization due to either unstable angina with objective evidence of ischaemia or coronary revascularisation.…”

Section: The Are In Terms Of Interpretable Parametersmentioning

confidence: 99%

“…Among the many clinical trials that use composite endpoints, we have chosen the studies by Packer et al (2001) and Tardif et al (2008) to illustrate the ARE method. The goal of Packer's study is to test the effect of carvedilol in patients who had symptoms of heart failure at rest or on minimal exertion.…”

mentioning

confidence: 99%

Selecting the primary endpoint in a randomized clinical trial: The ARE method

Plana‐Ripoll

Gómez

2016

Journal of Biopharmaceutical Statistics

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The decision on the primary endpoint in a randomized clinical trial is of paramount importance and the combination of several endpoints might be a reasonable choice. Gómez and Lagakos (2013) have developed a method that quantifies how much more efficient it could be to use a composite instead of an individual relevant endpoint. From the information provided by the frequencies of observing the component endpoints in the control group and by the relative treatment effects on each individual endpoint, the Asymptotic Relative Efficiency (ARE) can be computed. This paper presents the applicability of the ARE method as a practical and objective tool to evaluate which components, among the plausible ones, are more efficient in the construction of the primary endpoint. The method is illustrated with two real cardiovascular clinical trials and is extended to allow for different dependence structures between the times to the individual endpoints. The influence of this choice on the recommendation on whether or not to use the composite endpoint as the primary endpoint for the investigation is studied. We conclude that the recommendation between using the composite or the relevant endpoint only depends on the frequencies of the endpoints and the relative effects of the treatment.

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Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial

Cited by 180 publications

References 28 publications

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

Antioxidant Therapies in the Prevention and Treatment of Atrial Fibrillation

The LDL modification hypothesis of atherogenesis: an update

Selecting the primary endpoint in a randomized clinical trial: The ARE method

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