Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non–ST-Segment Elevation Myocardial Infarction

Tardif, Jean‐Claude; Tanguay, Jean François; Wright, Scott S.; Duchatelle, Valérie; Petroni, Thibaut; Grégoire, Jean; Ibrahim, Réda; Heinonen, Therèse; Robb, Stephen; Bertrand, Olivier; Cournoyer, Daniel; Johnson, Dominique; Mann, Jessica; Guertin, Marie Claude; L’Allier, Philippe L.

doi:10.1016/j.jacc.2013.03.003

Cited by 184 publications

(116 citation statements)

References 21 publications

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“…Therapeutic targeting of P-selectin-mediated adhesion using PSGL-1-Ig fusion proteins or Abs had beneficial effects following coronary artery injury induced by balloon in pigs (39) or arterial injury induced in apolipoprotein-E-deficient mice (40). In a study of percutaneous coronary intervention in patients with non-ST-segment elevation myocardial infarction, high doses of the specific P-selectin antagonist, inclacumab, reduced the extent of myocardial injury (measurements of troponin I and creatine kinase-myocardial band) (41). The underlying mechanism of action of inclacumab in vivo remains to be determined, although inclacumab treatment reduced the levels of soluble P-selectin (41), and a recent study demonstrated that inclacumab reduced the formation of platelet-leukocyte and platelet-monocyte complexes both in vitro and in vivo, as well as leukocyte aMb2 activation detected by mAb CBRM1/5 (42).…”

Section: Discussionmentioning

confidence: 99%

“…In a study of percutaneous coronary intervention in patients with non-ST-segment elevation myocardial infarction, high doses of the specific P-selectin antagonist, inclacumab, reduced the extent of myocardial injury (measurements of troponin I and creatine kinase-myocardial band) (41). The underlying mechanism of action of inclacumab in vivo remains to be determined, although inclacumab treatment reduced the levels of soluble P-selectin (41), and a recent study demonstrated that inclacumab reduced the formation of platelet-leukocyte and platelet-monocyte complexes both in vitro and in vivo, as well as leukocyte aMb2 activation detected by mAb CBRM1/5 (42). It would be interesting to investigate the impact of P-selectin antagonism on the acquisition of a proinflammatory monocyte phenotype in vivo.…”

Section: Discussionmentioning

confidence: 99%

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The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

Stephen

Emerson

Fox

et al. 2013

The Journal of Immunology

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Induction of an inflammatory monocyte phenotype by activated platelets is implicated in the pathogenesis of inflammatory diseases, including atherosclerosis. In this study, we investigated the early signaling events associated with this platelet-induced inflammatory phenotype. We report that coculture of human monocytes with activated platelets induces phosphorylation of Akt, together with rapid mobilization of intracellular Ca2+, and show that these signaling events can be uncoupled from monocyte binding to activated platelets. Specifically, Ab-inhibition studies and incubation of monocytes with activated platelet supernatant highlighted a role for secreted product(s) of activated platelets. We also identified a role for pertussis toxin–sensitive G protein–coupled receptors and excluded key candidates platelet-activating factor receptor and CCR5. Our results suggest that inhibition of monocyte–platelet interactions via PSGL-1 or P-selectin is not sufficient to prevent platelet-mediated monocyte activation in an inflammatory context. These findings have important implications for the development of therapeutics to treat diseases in which platelet–monocyte complexes are implicated in pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

Stephen

Emerson

Fox

et al. 2013

The Journal of Immunology

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“…This observation may at least in part explain the modest statistical significance of inclacumab effects observed in the SELECT‐ACS trial, in which the study drug was administered within 24 hours before PCI 14. Pathophysiological mechanisms linking the time point of drug administration to inclacumab effects are not yet known.…”

Section: Discussionmentioning

confidence: 99%

“…Recent research has indicated that P‐selectin appears to be involved in the pathogenesis of myocardial damage in acute coronary syndromes and during PCI 11, 12, 13, 14, 15. The SELECT‐ACS (Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non‐ST‐Segment Elevation Myocardial Infarction) trial suggested beneficial effects of inclacumab, a monoclonal antibody directed against P‐selectin, on myocardial damage after PCI in patients with non–ST‐segment elevation myocardial infarction (NSTEMI) 14. In this trial, inclacumab (5 and 20 mg/kg) was administered as a single intravenous infusion between 1 and 24 hours before PCI.…”

Section: Introductionmentioning

confidence: 99%

Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention According to Timing of Infusion: Insights From the SELECT‐ACS Trial

Stähli

Gebhard

Duchatelle

et al. 2016

JAHA

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BackgroundThe Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non‐ST‐Segment Elevation Myocardial Infarction (SELECT‐ACS) trial suggested beneficial effects of inclacumab, a monoclonal antibody directed against P‐selectin, on periprocedural myocardial damage. This study evaluated the effect of inclacumab on myocardial damage according to varying time intervals between study drug infusion and percutaneous coronary intervention (PCI).Methods and ResultsPatients (n=544) enrolled in the SELECT‐ACS trial and randomized to receive 1 infusion of placebo or inclacumab (5 or 20 mg/kg, administered between 1 and 24 hours before PCI) were divided according to the time interval between study drug infusion and PCI. The primary end point was the change in troponin I from baseline at 16 and 24 hours after PCI. In patients receiving inclacumab 20 mg/kg with a short (less than median) time interval between infusion and PCI, placebo‐adjusted geometric mean percent changes in troponin I, creatine kinase–myocardial band, and peak troponin I at 24 hours were −45.6% (P=0.005), −30.7% (P=0.01), and −37.3% (P=0.02), respectively. No significant changes were observed in patients with a long (greater than median) time interval between infusion and PCI. Placebo‐adjusted geometric mean percent changes in troponin I and creatine kinase–myocardial band were −43.5% (P=0.02) and −26.0% (P=0.07), respectively, when inclacumab 20 mg/kg was administered between 1 and 3 hours before PCI, whereas the drug had no effect with longer intervals.ConclusionsInclacumab 20 mg/kg significantly reduces myocardial damage after PCI in patients with non–ST‐segment elevation myocardial infarction, and benefits are larger when the infusion is administered <3 hours before PCI.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01327183.

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“…It has already been shown that the expression of P-selectin is increased in human atherosclerotic lesions (79). The phase II SE-LECT-ASC trial, where angiography patients were given placebo or inclacumab (a recombinant antibody against P-selectin), revealed that inclacumab reduced myocardial damage (80). Another similar trial currently ongoing is investigating patients scheduled for coronary artery bypass surgery (SELECT-CABG) (81).…”

Section: Th Anniversarymentioning

confidence: 99%

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

et al. 2017

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SummaryEven two centuries after they were first described, atherosclerosis and atherothrombosis remain among the leading causes of death worldwide. Over the last decades it has become clear that atherosclerosis is not only a lipid-driven disease but also a multifactorial process largely driven by inflammatory mediators, an insight that has instigated additional research and drug development focussing on anti-inflammatory therapies. In this review, we will provide a brief historical overview, followed by a more general synopsis of the range of currently available state-of-the-art therapies for atherosclerosis and atherothrombosis. Finally, we will highlight some of the promising therapeutic strategies that are currently under intense investigation. We believe that the next years will witness highly interesting developments and clinical trials investigating yet more novel therapies, and at the same time looking into potential combinations of all available therapies. This prospect closes in on the ultimate goal, which is to reduce the residual risk that still persists despite present therapeutic options.

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Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non–ST-Segment Elevation Myocardial Infarction

Abstract: Inclacumab appears to reduce myocardial damage after PCI in patients with non-ST-segment elevation myocardial infarction. (A Study of RO4905417 in Patients With Non ST-Elevation Myocardial Infarction [Non-STEMI] Undergoing Percutaneous Coronary Intervention; NCT01327183).

Cited by 184 publications

References 21 publications

The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention According to Timing of Infusion: Insights From the SELECT‐ACS Trial

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

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