Is the premise behind statins in error?

That's a question arising from a surprising Mayo Clinic Health System study published with little notice last month on the relationship between LDL cholesterol and mortality among survivors of cardiac events.

The matched case control study, published in December in the journal BMJ Open, looked at the risk of death from any cause for 23,000 patients hospitalized at Mayo Clinic between 1996 and 2015 for either myocardial infarction, or sudden worsening of heart failure.

After matching 14,000 of these patients according to demographic characteristics, the researchers examined the relationship between mortality and hyperlipidemia, which was defined as LDL greater than 100 mg/dL.

Current practice guidelines hold that the higher your LDL or so-called "bad cholesterol," the greater your chances for heart failure and early death. This is the argument for statins, the LDL-lowering medications taken by millions of Americans, as well as the next generation of LDL-lowering medications known as PCSK9 inhibitors, drugs including Repatha.

"Among patients who had heart attack or heart failure, and who had concurrent hyperlipdemia or no hyperlipidemia, there was a clear difference in mortality," says Dr. Mohammed Yousufuddin, a specialist in internal medicine for Mayo Clinic Health System in Austin and lead author on the paper. "Patients who had hyperlipidemia had lower mortality than patients who had no hyperlipdemia. That's the primary finding."

Yousufuddin said that high LDL cholesterol decreased the risk of mortality by 24 percent after heart attack, and 20 percent after heart failure. The study also found this seemingly protective effect of high LDL effect was dose-dependent. In other words, the higher the LDL, the lower the risk of mortality after a cardiac event, and the lower the LDL, the higher the risk.

Finally, the authors found that elevated LDL proved protective for patients with a host of comorbid conditions, including cancer, kidney disease, COPD and diabetes. "When these comorbidities occur in association with concomitant hyperlipidemia," Yousufuddin said, "the mortalities appear to be attenuated. Patients with cancer who have hyperlipidemia have lower mortality than those who have cancer and don't have hyperlipidemia. So that's a very interesting finding."

Trials of statins have shown the medications lower the risk of mortality when taken as secondary prevention, which is to say, for those who've suffered a cardiac event. The authors believe this positive effect of statins may be due to so-called pleitropic effects, or effects unrelated to the drugs' lowering of LDL. Like aspirin, statins have anti-inflammatory effects.

For heart attack patients with high LDL, the authors concluded that "clinical care should not focus on lipid targets; rather, evidence-based secondary prevention strategies should be initiated."

"This data is mostly for patients in the hospital with a heart attack," said Yousufuddin. "Most studies of LDL cholesterol assess the association between high cholesterol and subsequent heart attack in relatively healthy patient populations."

That, said, the authors concluded as follows: "Further studies are needed to understand the complex relationship between high LDL and mortality ... and to define appropriate (LDL) targets to maximize benefits."