Washington, DC - In a recently presented study investigating the safety and efficacy of mild systemic hypothermia as an adjunctive therapy in acute MI patients undergoing PCI, investigators found that mild hypothermia failed to reduce the size of the infarct in patients randomized to cooling therapy.
Investigators did report the therapy was safe and well tolerated and noted that there were no significant differences in MACE at 30 days between patients receiving the mild hypothermic therapy and the control arm.
Presenting the results at a late-breaking session of the 2003 TCT meeting in Washington, DC, principal investigator Dr William W O'Neill (William Beaumont Hospital, Royal Oak, MI) noted that the new therapy is still an attractive option for physicians looking to slow down the patient's metabolism and prevent myocardial injury.
"The first result, in terms of safety, demonstrated that this technique can be safely used in patients and there was no increase in adverse events," said O'Neill. The disappointing failure to reduce infarct size, said O'Neill, probably stems from the inability to reduce body temperature quickly enough. He added that to reduce infarct size in these patients, a body temperature of less than 35 C is necessary.Getting cold fast
The Cooling as an Adjunctive Therapy to Percutaneous Intervention in Patients with Acute Myocardial Infarction (COOL-MI) study was the first prospective, randomized, multicenter clinical trial designed to evaluate the safety and effectiveness of endovascular cooling in the setting of acute MI.
In patients receiving adjunctive cooling therapy, a catheter is inserted into the inferior vena cava through the femoral vein. Saline is circulated through the catheter and cools the blood as it comes into contact with the catheter.
A total of 357 patients were included in the study. Of these, 180 patients were randomized to the control arm of the study and 177 patients were randomized to receive the endovascular cooling therapy (ReprieveTM, Radiant Medical, Redwood City, CA). Baseline characteristics between the control and cooling study arms were nearly identical and included patients with diabetes, smokers, and patients with previous MI. In both study arms, there were a greater percentage of patients with inferior MI than anterior MI, note investigators.
The study failed to meet the primary end point of reducing infarct size. Overall, there was no significant difference in final infarct size between patients randomized to cooling therapy and the control arm. The investigators reported that endovascular cooling was safe, noting nonsignificant differences in MACE at 30 days between the two groups, despite trends favoring the control arm.
The incidence of shock was significantly higher and there were nonsignificant trends toward higher rates of vascular bleeding, deep vein thrombosis, and pulmonary edema in the cooling arm compared with the control arm.Adverse events at 30 days
Control (n=180), No. (%)
Cooling therapy (n=177), No. (%)
Target vessel revascularization
"We found that mild systemic hypothermia is safe and well tolerated during angioplasty therapy of an acute myocardial infarction," said O'Neill. "As administered in the COOL-MI trial, cooling did not result in a reduction in infarct size."Prespecified subanalysis between different types of MI
As part of a predetermined subanalysis, the COOL-MI investigators looked at the efficacy of the adjunctive hypothermic therapy based on infarct location. The investigators noted an unexplained difference in the efficacy of cooling patients with anterior and inferior MIs.
"Although we saw some important trends of benefit in patients with anterior MI, we really saw no sign of benefit in patients with inferior myocardial infarction," said O'Neill.
Stratifying the anterior MI subgroup, the investigators also found that patients cooled to temperatures less than 35 C at the time of reperfusion had significantly smaller infarct size compared with the control group (9.3% vs 18.2%; p=0.05).
O'Neill noted the benefit seen in anterior MI patients cooled to temperatures less than 35 C was not an aberration, as there were also trends toward higher left ventricular ejection fraction values and lower peak CK-MB values in these patients.Adjunctive cooling therapy in PCI not there yet
During his presentation, O'Neill said there were many logistical problems involved in the cooling process, noting the problems that arose were primarily of not being able to get the core temperature cool quickly enough.
"Unfortunately the centers that we were working with were just too good and too expert at infarct angioplasty," said O'Neill. "It took them, on average, 18 minutes from the time of administration at the cath lab to get the artery open. One of the challenges we've got to be looking at in the future is to increase the speed of cooling." The average time required to cool body temperature to less than 35 C was 31 minutes, said O'Neill.
I think understanding optimal hypothermia, however, is still in its infancy.
O'Neill said it might be possible to cool body temperatures in transit to the catheterization labs, suggesting ice and saline may be employed in the ER and ambulances to start the cooling process before the administration of the hypothermic cooling catheter. However, once in the cath lab, it becomes a "very interesting scientific question" as to whether or not to delay opening the artery to cool the patient before initiation of reperfusion therapy.
While the evidence presented here is not enough to justify FDA approval of the device or to be used regularly in clinical practice, O'Neill said it is optimistic, and further studies will explore the issue of mild hypothermia as an adjunctive therapy in acute MI patients undergoing PCI.
"I think that this study is an important first step in the clinical trial and clinical evaluation of systemic hypothermia," said O'Neill. "Very important and very positive conclusions can be reached from the fact that systemic hypothermia is safe and extremely well tolerated....I think understanding optimal hypothermia, however, is still in its infancy."Would high-risk patients benefit most?
Commenting on the results for heartwire , Dr Gishel New (Monash University, Victoria, Australia) said the trial may have lacked sufficient patient numbers to achieve the primary end point. More likely, however, was the inability to get the patient cool quickly enough.
"I think the concept is a great concept," said New. "We now have angioplasty, IIb/IIIa inhibitors, clopidogrel, and aspirin, but now what we want is to protect the heart muscle during infarction."
New added that patients with anterior MI may benefit the most from the hypothermic therapy as they have the most to gain from cooling therapy. Patients with anterior MI typically have more damage to the heart muscle than patients with inferior MI, said New.
Dr David Kandzari (Duke Clinical Research Institute, Durham, NC) also told heartwire that patients at highest risk might benefit the most from cooling therapy.
He added that the benefit observed in patients who achieved sufficient hypothermia before reperfusion is consistent with preclinical data and justifies further study.
"The challenge becomes this: are the data sufficient to withhold reperfusion therapy to achieve hypothermia when the efficacy is not definitely established?" said Kandzari.
Heartwire from Medscape © 2003
Cite this: COOL-MI: No reduction in infarct size in acute MI patients undergoing cooling therapy before PCI - Medscape - Sep 17, 2003.