Despite Setbacks, Research Into Myocardial Salvage Continues

Although hundreds of experimental studies on myocardial malperfusion have shown promise for many different agents, these apparent benefits have not translated into positive clinical trial results. Even so, research into novel approaches for myocardial salvage remains worthwhile, a speaker said at TCT 2015.

“In the clinical [setting], the results have been extremely unimpressive,” said Bernard J. Gersh, MBChB, DPhil, of the Mayo Clinic, Rochester, Minn. This lack of success does not indicate that pharmacologic and biologic approaches to enhance myocardial salvage are at a dead end, Gersh stressed, but rather that further mechanistic studies are needed.

Recent studies, neutral endpoints 

Examples of recent studies on myocardial salvage released in the past 18 months include CIRCUS, EMBRACE and PRESERVATION I. 

For the CIRCUS trial, published in the New England Journal of Medicine in August 2015, hospitalized ACS patients with anterior STEMI (mean age, 60 years; 82% men) who presented within 12 hours of symptom onset were randomly assigned to PCI with (n = 395) or without (n = 396) IV cyclosporine 2.5 mg/kg at 42 centers in Belgium, France and Spain from April 2011 to February 2014. At 1 year, there were no differences between the groups in rates of the primary endpoint (composite of death, HF and left ventricular remodeling; 59% vs. 58.1%; P = .77), its individual components or other secondary endpoints.

Results of the EMBRACE trial, presented in March 2015 at the American College of Cardiology/i2 Scientific Session, showed a similar trend for the effect of the cell-permeable peptide Bendavia (Stealth BioTherapeutics) on infarct size in anterior STEMI. Researchers randomized 297 first-time STEMI patients with anterior lesions in the proximal or mid LAD to Bendavia infusion (0.05 mg/kg/hr; n = 150) or placebo (n = 147) administered 15 minutes prior to and 1 hour after PCI. Infarct size, as measured by serum CK-MB at 6 hours, was similar between the groups (217.4 vs. 266.6 ng/mL; P = NS). The clinical composite endpoint (death, new-onset congestive HF after 24 hours of PCI or HF rehospitalization) also was similar between the groups at 30 days and 6 months (P = NS for both).

In the PRESERVATION I trial, presented in September 2015 at the European Society of Cardiology Congress, a bioabsorbable cardiac matrix (IK-5001, Bellerophon Therapeutics) was safe, but did not prevent LV remodeling or other adverse outcomes. Researchers enrolled 303 STEMI patients with large infarcts from April 2014 to December 2014 at 64 centers in nine countries. Patients were randomized to receive a 4-mL intracoronary injection of IK-5001 (n = 201) or saline (n = 102) between 2 and 5 days after the infarction as long as they had achieved TIMI 3 flow. At 6 months, there was an increase in LV end-diastolic volume index — the primary endpoint — with no difference between the groups (difference, 3.8 mL/m²; 95% CI –0.5 to 8.0). The same held true at 12 months.

Research should continue

For any agent to have a beneficial effect on myocardial salvage, Gersh said the window for administration is very narrow, likely between 1 and 3 hours, when “it’s going to be very difficult to demonstrate a difference because people who reperfuse within 2 hours have smaller infarcts and very low mortality.”

Still, Gersh said, “I think this research shall continue, but it’s a very tough field.”

Disclosures: 

• Gersh reports no relevant conflicts of interest.