Trial Fails to Meet Primary Objective, Opens New Possibilities for Improving Survival With a Novel Heart Attack Drug
CHICAGO, IL -- While the results of a new trial showed that a novel drug intended to reduce the extent of cell death after heart attack did not do so, the surprising finding that it reduced the death rate in patients who received angioplasties opens an intriguing new line of investigation, according to Duke University Medical Center researchers.
The drug, known as pexelizumab, was tested in a Phase II trial in conjunction with either clot-busting medications or angioplasty in acute heart attack patients to reduce the amount of tissue death, or infarct size, following treatment. The researchers, led by Duke cardiologists Christopher Granger, M.D., and Kenneth Mahaffey, M.D., found that while the infarct size remained the same in the treated and untreated groups, there was a greater than three times reduction (1.8 percent vs. 5.9 percent) in the death rate after 90 days in the patients who received the drug in conjunction with angioplasty.
"Unexpected findings like these can in many ways be the most exciting, because they open up whole new avenues of investigation," Granger said. He presented the results of the trial (Nov. 18, 2002) at the 75th annual scientific session of the American Heart Association.
"Although pexelizumab did not reduce the size of infarcts, the results may be pointing toward a novel mechanism that seems to benefit some patients with acute heart attacks," Granger continued. "This is quite exciting and worthy of further study."
In many ways, heart attack patients suffer twice. First, when blood flow is cut off to heart muscle during the attack, the resulting lack of oxygen kills or damages heart muscle cells. Then, after blood flow is restored, either by medication or angioplasty, the starved muscle cells are damaged again as a result of the sudden return of oxygen-rich blood, a condition known as reperfusion injury.
To date, no effective therapy has been discovered to reduce or stop the damage of reperfusion injury. According to Granger, while the mechanisms of this reperfusion injury are poorly understood, it is believed that the immune system plays some role in the process. For that reason, researchers initially theorized that pexelizumab, which blocks a component of the immune system known as complement, might be able to protect hearts during this period.
The complement system is made up of many distinct proteins that react in a "cascade, one after the other, when faced with a stimulus. The end result of this cascade is an inflammatory response that destroys foreign substances. Pexelizumab is a fragment of an antibody that blocks one of the proteins early in the complement cascade.
"The rationale for the trial was to use this very targeted drug to inhibit a particular part of the complement cascade to decrease the amount of inflammatory damage when blood flow is restored and thereby improve patient outcomes," Grange said. "This drug is particularly appealing because it seems to inhibit the complement cascade at a point where the ability to fight infection is preserved but the negative effects of complement in causing tissue damage are prevented."
The trial, dubbed CARDINAL, (Complement and Reduction of Infarct Size After Angioplasty or Lytics), had two arms that treated a total of 1,734 patients who suffered a heart attack within six hours. In one arm, 920 patients received thrombolytic, or clot-busting, treatment; and in the other arm, 814 patients received angioplasty. Participants in both arms were randomized to either placebo, or to one of two different doses of pexelizumab in conjunction with treatment.
In the thrombolytic arm of the trial, there was no effect on infarct size or composite cardiac event rate (death, heart failure, shock or stroke) after 90 days in all three groups. In the angioplasty arm (dubbed COMMA), there was also no effect on infarct size.
"Interestingly, if we looked solely at the death rates after 90 days in the group that received angioplasty, there was a significant reduction," Granger said. "This effect on mortality not only appeared early, but became greater over time. It appears that there is something beneficial going on, we just don?t understand the exact mechanism yet."
While the main goals of Phase II trials, such as CARDINAL, are to test the safety and efficacy of a drug, researchers also use the findings to determine whether or not to proceed to Phase III trials. Granger believes that new studies are warranted to explore pexelizumab?s effect on outcome, as well as to better understand the mechanisms of its action.
"We have a tremendous opportunity to further investigate the mechanisms of action and to retest pexelizumab in a large clinical trial to see if we can confirm this finding of reduced mortality," Granger said.
Clues to the mechanism of action may be provided by animal models, which have shown that complement inhibition -- like that provided by pexelizumab -- reduces the production of cytokines, cellular messengers that stimulate immune responses. Complement inhibition also appears to reduce apoptosis, or programmed cell death, with may play a role in the long-term recovery of muscle cells after reperfusion injury, Granger said. Complement inhibition may also decrease the effects of oxidative stress, he added.
Pexelizumab was developed by Procter and Gamble Pharmaceuticals, Cincinnati, and Alexion Pharmaceuticals, Chesire, Conn., which jointly sponsored the trials. Granger has no financial interest in either company.