番茄社区

A novel agent to tackle reperfusion injury with stenting for ST-segment elevation myocardial infarction (STEMI) flopped in early-phase research.

The mitochondrial-targeted peptide Bendavia , , of Beth Israel Deaconess Medical Center in Boston, and colleagues found in the phase II EMBRACE STEMI trial.

The primary endpoint of serum creatine kinase MB (CK-MB) over the first 72 hours came out similar (5,570 versus 5,785 ng.h/mL).

So did early infarct expansion by CK-MB at 6 hours and cardiac MRI-measured infarct volume at days four and 30 as well as STEMI resolution, post-stenting angiographic measures, and outcomes at 30 days and 6 months, according to results presented at the American College of Cardiology annual meeting in San Diego.

However, there were some suggestive secondary and exploratory findings that mean the story isn't finished on this agent, suggested , executive director of the Duke Clinical Research Institute, and study discussant at an ACC press conference.

"Stay tuned," Peterson said.

The new-onset heart failure rate in the first 24 hours after percutaneous coronary intervention (PCI) was 13.8% with Bendavia versus 25% on placebo, albeit not a significant difference.

Kidney injury appeared reduced as well in an exploratory analysis, with significantly less change in creatinine over the first 12 hours (P=0.03) and lower area under the curve for creatinine over the first 48 hours after adjusting for baseline level and dye load (P=0.04).

Also, nonprespecified analysis by hypertension status due to an imbalance in the 118-patient trial (38% with hypertension on Bendavia versus 60% in the placebo group, P=0.02) showed that those with hypertension had no advantage for the primary endpoint with Bendavia, but with it they did have:

• Smaller day four infarct volume (P=0.03)
• Better ST-segment resolution at 24 hours (P=0.05)
• Possible lower volume of edema at that point (P=0.053)

Gibson cautioned that the trial was "grossly underpowered," so neutral results weren't surprising.

EMBRACE STEMI included patients with a first anterior STEMI with little or no blood flow to the proximal or mid-left anterior descending coronary artery, no shock, and anticipated PCI within 4 hours.

They were randomized to blinded treatment with IV Bendavia (0.05 mg/kg/hour) or a volume-matched placebo infusion given 15 minutes before and 60 minutes after PCI.

Treatment-emergent adverse events were similar between groups.

Reperfusion injury has been a tough nut to crack, Gibson noted. Few "bright spots" have emerged from the dozens of studies trying to prevent it, he told reporters at a press conference for the late-breaking clinical trial session.

As blood flows back into ischemic heart tissue after revascularization, injury usually sets in from inflammatory processes, he explained.

Bendavia cuts inflammatory reactive oxygen species generation and works on the electron transport chain to "stabilize the mitochondria," based on animal models.

"It has been very difficult in our field to find agents that would translate from the animal models, which have been able to show effects on reperfusion injury, and those that would actually work in humans," Peterson said.

Bendavia is still in development in ongoing studies for systolic heart failure and in percutaneous transluminal renal artery angioplasty.

Other reperfusion injury strategies are still in development, such as cyclosporine in the phase II and phase III .

Comment