The sPLA ₂ Inhibition to Decrease Enzyme Release After Percutaneous Coronary Intervention (SPIDER-PCI) Trial

Abstract

Background— Secretory phospholipase A 2 (sPLA 2 ) may play a role in myonecrosis after elective percutaneous coronary intervention (PCI). Inhibition of this enzyme may have a beneficial effect. The central hypothesis of this study was that treatment with varespladib, a small-molecule inhibitor of sPLA 2 would reduce postprocedural release of cardiac biomarkers after elective percutaneous coronary intervention. Methods and Results— Between October 2007 and June 2009, 144 stable patients were randomized in a phase II trial to receive varespladib 500 mg PO BID or placebo 3 to 5 days before and for 5 days after elective percutaneous coronary intervention. The primary end point was elevation of troponin I or creatine kinase-MB above the upper limit of normal at 6 to 8 or 18 to 24 hours after percutaneous coronary intervention. Mean age was 63±10 and 64±10 years, with 38% and 42% with diabetes mellitus and 29% and 28% with prior myocardial infarction for the varespladib and placebo groups, respectively. The primary end point occurred in 75% of varespladib and 63% of placebo patients ( P =0.14). Troponin I 3 times the upper limit of normal was observed in 57% and 50% ( P =0.39) and creatine kinase-MB 2 times the upper limit of normal in 14% and 3% ( P =0.018). Median (first and third quartiles) change in high-sensitivity C-reactive protein in these 2 groups was 0.65 mg/L (−0.18 and 1.48) and 0.70 mg/L (0.00 and 1.50) at 18 to 24 hours ( P =0.81) and 0.20 mg/L (−0.70 and 1.40) and 0.60 mg/L (−0.12 and 1.72) at 3 to 5 days ( P =0.23), whereas change in sPLA 2 activity at 3 to 5 days in a subset was −2.85 ng/ml (−3.40 and −1.85) and 0.25 ng/ml (−0.20 and 0.85) ( P <0.001). Conclusions— Inhibition of sPLA 2 by varespladib administered for 3 to 5 days before the procedure does not reduce periprocedural myonecrosis associated with elective percutaneous coronary intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00533039.

Secretory Phospholipase A2-IIA and Cardiovascular Disease

“…We identified 4 randomized clinical trials (RCTs) of the sPLA 2 inhibitor varespladib in a total of 1,300 individuals ( Online Fig. 6 , Online Table 12 ) (9,20–22) . A meta-regression suggested varespladib treatment produced a dose-dependent reduction in sPLA 2 -IIA mass (p for meta-regression = 0.06) ( Online Fig.…”

“…This is because higher sPLA 2 -IIA mass or sPLA 2 enzyme activity may be a consequence not a cause of atherosclerosis or reflect an association with causal risk factors. An evaluation of sPLA 2 as a therapeutic target is timely to help put into context the recent announcement that a phase III randomized trial (VISTA-16 [Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks] trial) (10) of varespladib, a first-in-class sPLA 2 inhibitor (9) for major vascular event (MVE) prevention in patients with acute coronary syndrome (ACS), was stopped prematurely for lack of efficacy (11) . Varespladib was designed to selectively block sPLA 2 -IIA, however, it also has minor inhibitory effects on other sPLA 2 isoenzymes ( Online Fig.…”

Cytosolic Phospholipase A2α Protects against Ischemia/Reperfusion Injury in the Heart

“…Recently, two clinical trials with a non-selective sPLA 2 inhibitor, varespladib, have been completed, one in patients with acute coronary syndromes and the other in patients going to percutaneous coronary intervention. 9, 10 Neither of these trials were positive. A third trial is recruiting patients with vaso-occlusive crisis from sickle cell disease.…”

The Roles of sPLA2s in Skin Homeostasis and Disease

“…Current indole-based sPLA 2 inhibitors, such as indoxam and varespladib, block group I/II/V/X sPLA 2 s potently but broadly, which may limit their clinical application [ 86 , 87 , 88 ]. Apparently, the development of sPLA 2 -IIF-specific inhibitors would be desirable for the treatment of skin diseases because pan-sPLA 2 inhibitors can also suppress the anti-inflammatory function of sPLA 2 -IID, which is expected to worsen, rather than ameliorate, inflammatory diseases.…”