Acute elevated levels of myocardial necrosis biomarkers following CABG surgery, no matter how incrementally small, are prognostic for death, even out to five years, which has implications for clinical trial design, according to a study in the Feb. 9 issue of the Journal of the American Medical Association.
"We have quantified the relationship between creatine kinase and troponin elevation and mortality post-bypass surgery," lead author Michael J. Domanski, MD, director of heart failure research at Mount Sinai Cardiovascular Institute in New York City, told Cardiovascular Business News. "It's been discussed in other smaller studies, but this nails it down. What has not been previously reported, however, is the intermediate- and long-term significance of modest-sized infarcts."
Domanski and colleagues arrived at their findings by analyzing data from seven randomized clinical trials or registries of patients who had undergone CABG and had elevated levels of creatine kinase (CK-MB) or troponin in the 24 hours following surgery. Follow-up varied from three months to five years.
For each patient, the CK-MB ratio was calculated as the ratio between the peak CK-MB and the upper limit of normal for the participating laboratory of each study. The researchers found that higher ratios were associated with greater risk of death. The 30-day mortality rates by categories of CK-MB ratio were:
- 0.63 percent for 0 to < 1;
- 0.86 percent for 1 to < 2;
- 0.95 percent for 2 to < 5;
- 2.09 percent for 5 to < 10;
- 2.78 percent for 10 to < 20, and
- 7.06 percent for 20 to >40.
"This is the largest study of the relationship between post-CABG surgery enzyme elevation and mortality and shows a strong, graded, independent association of elevation of markers of myocardial necrosis—CK-MB and troponin levels—and mortality following CABG surgery for all CK-MB and troponin ratios greater than 1," researchers concluded.
The researchers also found that of the variables in the model, including CK-MB ratio, age, history of kidney dysfunction and prior heart attack, the CK-MB ratio was the strongest predictor of death and remained significant even after adjusting for baseline risk factors. This result was strongest at 30 days, but the adjusted association persisted from 30 days to one year and a trend was present from one year to five years. The findings were similar when the troponin ratio, rather than CK-MB ratio, was examined.
"There are two implications to the study," Domanski said. "The first deals with how we define a heart attack in a clinical trial. Surgeons might say that small enzyme elevations aren't important, but they are important and this finding should inform our design of clinical trials. The definition of a heart attack should be operational; it should mean that the patient's prognosis is made worse by the event."
The second implication, he said, deals with the potential to use the degree and severity of enzyme elevation as a quality assurance indicator. "However, we need to know how to lower the levels of these enzymes and that idea, right now, is speculation. Clearly, one would suspect a very good surgical technique would improve infarct rate, but we don't know that for sure. And if the variance among institutions is important, then we would like to know what the institutions at the higher end of the quality spectrum are doing differently."
Domanski also would like to have a better understanding of the mode of death in these patients, which was difficult to ascertain from the available data. "One would expect their death to be an arrhythmic focus because the infarct size for many is generally not large, which would rule out progressive heart failure. Such knowledge could potentially inform long-term patient management."
While the researchers did not examine enzyme elevations associated with PCI, there are data to suggest these elevations are associated with a mortality risk. "If in angioplasties, the mechanism for producing infarcts is different yet has similar prognostic implications as with CABG, it will be clear that it is the infarct, or the extent of necrosis, that is important regardless of how it occurred," Domanski said.