Keynote Address: From Trial Design to Treatment, Timing is Key

During the second annual Houston Shock Symposium, Richard Smalling, MD, PhD, FACC, MSCAI, delivered the keynote address, during which he shared more than three decades’ worth of research regarding left ventricle (LV) unloading in acute ischemic shock.

Dr. Smalling outlined several important questions to take into account when considering potential strategies for salvaging myocardium and improving outcomes in acute ischemic cardiogenic shock—as well as when designing trials to study these outcomes:

• How soon after the onset of myocardial ischemia must a beneficial intervention be initiated to reduce/prevent acute myocardial cell death?
• What is/are the mechanisms of acute ischemic myocardial necrosis and what is the time frame relative to duration of ischemia and presence of reperfusion?
• How can you measure acute myocardial salvage?
• Can myocardial salvage still occur if a protective intervention is initiated relatively late (>2 hours) after onset of ischemia?
• What is/are the mechanisms of delayed ischemic myocardial necrosis?
• How can you measure delayed myocardial salvage/reduced late myocardial necrosis?

One crucial theme of research, treatment, and designing trials is timing. The importance of timing when making certain interventions was highlighted by a series of previous studies, which found good outcomes in animal models receiving early intervention. In an interview, Dr. Smalling said that one of the difficult parts of early intervention is that patients are not likely to present within the first two hours of symptoms.

“To get an early benefit you have to do the intervention within two hours of symptoms—which is hard to do in today’s healthcare setting,” he explained.

During his keynote address, Dr. Smalling highlighted data from his 2011 trial, “Intra-aortic Balloon Counterpulsation and Infarct Size in Patients With Acute Anterior Myocardial Infarction Without Shock: The CRISP AMI Randomized Trial,” which was published in JAMA. The trial was designed to determine whether intra-aortic balloon counterpulsation (IABC) prior to reperfusion in ST-segment elevation myocardial infarction (STEMI) patients without shock could reduce myocardial infarct size.

However, the researchers ran into a timing issue.

“We didn’t know that you had to do the unloading way before three hours” after onset of symptoms, which is when most patients arrived, Dr. Smalling said.

“You’re not going to see a calcium overload benefit … [or] infarct size benefit, which is how we designed the trial.” The trial, therefore, yielded a  negative result.

Still, in the few patients who received early intervention, the researchers saw successful myocardium salvage. After six months, there were three deaths in the IABC plus standard care group, and nine deaths in the standard care alone group (a tripling of the mortality rate), but the sample size was too small. One of the trial’s secondary endpoints was time to death, shock, or new or worsening heart failure, which was significantly worse in the standard care group compared to the IABC group (21 events [12%] vs. 8 events [5%]). However, this was a secondary endpoint among a very small patient sample.

Still, there were observable benefits.

“What we achieved was the inhibition of apoptosis with delayed unloading. And the effect was […] across all timeframes.” Therefore, even in patients who present six to eight hours after symptoms, unloading prior to reperfusion still had a positive effect.

The most important takeaways, according to Dr. Smalling, went back to early

intervention.

“You need to do LV unloading early,” he concluded. “We showed that you can have some benefit late, and the myocardial necrosis and heart failure can be prevented with later unloading.”