Until last Friday, cardiologists thought they were on the verge of a new frontier in treating heart disease.
Three companies were conducting large clinical trials on experimental drugs that slash levels of a blood protein, Lp(a), thought to cause heart attacks and stroke. Doctors were eagerly awaiting the results, hoping the drug could be as important as a statin.
When Novartis, the first company to complete its trial, announced its results, late Friday afternoon, after the markets closed, cardiologists were shocked. The drug could lower Lp(a) levels by 80 percent, but it did not prevent heart attacks and strokes. It had failed.
“There’s something we don’t understand here,” said Dr. John Alexander, a cardiologist at Duke.
Cardiologists regularly see patients who have had heart attacks even though their cholesterol and blood pressure levels are low. They do not have diabetes or obesity, and they do not smoke, either. All too often, though, they have high levels of Lp(a).
About 20 percent of Americans have elevated levels; people with the highest levels of the protein can have double or triple the risk of a heart attack.
So there was no question that Lp(a) was important. A drug to lower the level of the protein, cardiologists hoped, could provide a way for these patients to protect themselves.
But the failure of the Novartis study raised an uncomfortable possibility: Maybe Lp(a) is not a cause of heart disease, but instead is a marker of heart disease risk, like white hair is a mark of aging.
If Lp(a) is a marker, though, what is it marking? Is there another cause of heart disease that no one has thought of?
That is “the nagging question we are all pondering,” said Dr. David Maron, president of the American Society for Preventive Cardiology.
There may not be an easy answer, either. “Maybe we were fooled into thinking this would be simple,” Dr. Alexander said.
Still, many researchers are not ready to throw out the Lp(a) hypothesis, saying that there might be other explanations for the failure and that they need to take a close look at the study data. The company will not provide the full data set until it is presented at the American Heart Association meeting in December.
“We still have a lot to learn,” said Dr. Sadiya Khan, a cardiologist at Northwestern University’s Feinberg School of Medicine.
Cardiologists say they have good reasons to think high levels of Lp(a) cause heart disease. The blood protein inserts itself into artery walls and can cause inflammation and blood clotting.
One possible explanation for the study’s failure, said Dr. Daniel Rader, a lipid specialist at the University of Pennsylvania, might be that it involved the wrong type of patients. The participants were people with very high Lp(a) levels who had already had heart attacks or strokes. The hope was that lowering Lp(a) would prevent them from future events.
Studies are done in a patient population that is more prone to heart attacks because it is easier to see if those patients are protected. But, Dr. Rader said, it might be too late to help them. The right group to test might be people at high risk of heart disease who have not yet had a heart attack. Or maybe, he said, lowering Lp(a) by 80 percent is not enough.
But if Lp(a) is not playing a major role in causing recurrent heart attacks and strokes in people who already have heart disease, what, then, is the driver?
Dr. Harlan Krumholz, a cardiologist at Yale, has a different thought. Cholesterol levels and blood pressure levels, he notes, can be low for decades and then soar later in life. But high Lp(a) levels are set by genetics and do not vary.
“You are stuck with your Lp(a) level,” Dr. Krumholz said. Whatever the level is, it is not going to change on its own. So lowering it in adulthood might be ineffective because it is too late to make a difference. Maybe, he said, a person would have to take a drug to lower Lp(a) for 20 years or even from birth.
Other studies of drugs that target Lp(a) by the pharmaceutical companies Lilly and Amgen are still underway, and those studies will be crucial in determining if lowering those levels are helpful, cardiologists said.
If those other studies are negative, Dr. Rader said, “I am not sure we will see a whole lot of enthusiasm for Lp(a).”
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