SELECT-ACS: Novel Drug Limits Myocardial Damage After PCI for NSTEMI

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Infusion of the drug inclacumab at least 1 hour prior to percutaneous coronary intervention (PCI) reduces markers of myocardial damage in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Findings from the SELECT-ACS trial were presented March 10, 2013, at the American College of Cardiology/i2 Scientific Session in San Francisco, CA, and simultaneously published online ahead of print in the Journal of the American College of Cardiology.

Inclacumab (F. Hoffmann La Roche, Basel, Switzerland) is a recombinant monoclonal antibody that inhibits P-selectin, a molecule that “affects both the inflammatory and thrombotic cascades, induces formation of procoagulant microparticles, and mediates microparticle and leukocyte recruitment to thrombi,” the paper notes.

For SELECT-ACS, Jean-Claude Tardif, MD, of the Montreal Heart Institute (Montreal, Canada), and colleagues enrolled 544 NSTEMI patients slated for coronary angiography and, if necessary, PCI at 66 centers. Patients were randomized in a 1:1:1 ratio to preprocedural infusion of inclacumab 5 mg/kg, inclacumab 20 mg/kg, or placebo.

Benefit Restricted to Higher Dose

Efficacy was evaluated only in the 322 patients who underwent PCI, received either inclacumab or placebo, and had available data.

The 20-mg/kg inclacumab dose produced positive results for the primary endpoint of placebo-adjusted change in troponin I compared with baseline at 24 hours (-24.4%; P = 0.05) and showed a positive trend at 16 hours (-22.4%; P = 0.07). Peak troponin I also was lower with the 20-mg/kg dose (-23.8%; P = 0.05). Though the difference was not significant, the area under the curve over 24 hours dropped by 33.9% (P = 0.08).

CK-MB levels, meanwhile, trended lower in patients receiving the 20-mg/kg dose at 16 hours (-16.3%; P = 0.09) and 24 hours (-17.4%; P = 0.06). The incidence of CK-MB increase greater than 3 times the upper limit of normal within 24 hours with the higher dose was about half that of placebo (8.9% vs. 18.3%; P = 0.05).

Diabetes status had no influence on the effect of inclacumab 20 mg/kg. No benefits were observed with the 5-mg/kg dose.

In addition, patients not receiving glycoprotein IIb/IIIa inhibitors showed an even more substantial change in troponin I with inclacumab 20 mg/kg (-36.1%; P = 0.008).

Of the 530 patients who received study medication, 22.6% reported at least 1 serious adverse event. Most adverse events were mild or moderate and then resolved. Overall, rates were numerically higher for inclacumab vs. placebo but low and similar among the 3 groups. There were no apparent effects on infection rates or bleeding.

Promising but Requires Confirmation

“These are encouraging results supporting beneficial biological effects of this P-selectin antagonist, which need to be confirmed in a larger trial,” Dr. Tardif and colleagues conclude, noting that SELECT-ACS was not powered to evaluate clinical endpoints.

“PCI can induce an inflammatory response, even during apparently uneventful procedures. Damage to the vascular wall during intervention leads to activation of endothelial cells, leucocytes, and platelets,” the investigators explain, adding that statins and viral serpin have both shown promising anti-inflammatory effects capable of limiting such damage. Inclacumab’s benefit may stem in part from its ability to reduce platelet-leukocyte aggregation, which in turn “may contribute to a reduction in the risk of micro-embolization during PCI,” they say.

Overall, the “consistency” of the data suggests a reduction in myocardial damage, the researchers conclude. “Further clinical investigation will be required to determine the clinical value (benefit or harm) of inclacumab in patients presenting with myocardial infarction whether or not they undergo PCI.”

Mechanism Plausible

In an editorial accompanying the paper, Fernando Alfonso, MD, PhD, of Clinico San Carlos University Hospital (Madrid, Spain), and Dominick J. Angiolillo MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), note that the availability of “uniquely sensitive and specific biomarkers of cardiac injury [while controversial] also represents a new opportunity to further scrutinize the potential clinical value of several new adjuvant therapies aimed to optimize the results of coronary revascularization.

“In this regard,” they continue, “drugs able to reduce the extent of myocardial injury at an ‘analytical level’ may then gain further promise and eventually emerge as prime time strategies to effectively reduce episodes of clinically relevant myonecrosis and, more importantly, improve long-term stenosis.”

Patients with NSTEMI are especially high-risk and “have already suffered some degree of myocardial necrosis,” Drs. Alfonso and Angiolillo comment. “In this scenario, both systemic and local inflammation, together with an enhanced thrombogenic milieu, provide a uniquely challenging underlying pathophysiologic substrate.” As such, therapies that address these challenges are welcome, they add.

P-selectin, the molecule targeted by inclacumab, appears to have a “central role . . . in linking inflammatory and thrombotic pathological physiological pathways at the vessel wall, making it a uniquely attractive therapeutic target,” the physicians write.

CABG Setting Being Explored

Many of the efficacy endpoints in SELECT-ACS show only “weak statistical certainty,” they point out, and the trial’s per protocol analyses cannot fully address clinical efficacy. Despite these and other limitations, the findings of SELECT-ACS “are exciting and hold clear clinical promise,” Drs. Alfonso and Angiolillo conclude.

Future research will help determine whether there is any effect on long-term outcomes, they say, whether the benefit might extend to other settings such as CABG. The SELECT-CABG trial, slated for completion in October 2013, is evaluating inclacumab’s potential to prevent saphenous vein graft disease.

Study Details

In the efficacy analysis, most patients were white (96.0%) and male (78.9%), and the median age was 61.1 years. DES were implanted in 58.1% and BMS in 36.7%.

 

 

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Sources: 
1. Tardif J-C, Tanguay J-F, Wright SS, et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST elevation myocardial infarction: Results of the SELECT-ACS trial. J Am Coll Cardiol. 2013;Epub ahead of print. 

2. Alfonso F, Angiolillo DJ. Targeting P-selectin during coronary interventions: The elusive link between inflammation and platelets to prevent myocardial damage. J Am Coll Cardiol. 2013;Epub ahead of print. 

 

 

 

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