Dr. Steven Nissen expects an audible gasp when he presents the results of a major cardiovascular trial at the American Heart Association’s annual conference. The experimental drug pelacarsen failed to reduce major cardiovascular events despite sharply lowering its intended target.

Many doctors already know the study missed its key measure, but some may still hope the drug succeeded among certain patients or against particular outcomes. Nissen, a preventive cardiologist at the Cleveland Clinic in Ohio, offered little room for such optimism.

“It wasn’t a near miss. It just didn’t have an effect on outcomes, and I don’t think virtually anybody’s prepared to hear that,” Nissen told CNN. Novartis, which invested tens of millions of dollars in the drug’s development, has decided to abandon it.

Pelacarsen was designed to lower lipoprotein (a), also called Lp(a), a sticky, protein wrapped fat in the blood. Excess Lp(a) is thought to promote clotting in arteries around the heart and increase inflammation.

Some people inherit a tendency to produce more Lp(a) than others. According to the American Heart Association, people with the highest blood levels are two to four times more likely to have a heart attack than those with the lowest levels.

Nissen and his colleagues spent seven years testing pelacarsen. The study included 8,350 people who had high Lp(a) levels and had previously experienced a cardiovascular event such as a heart attack or stroke.

Participants were randomly divided into two groups, with half receiving pelacarsen and the other half receiving a placebo. Neither the patients nor investigators knew who received the drug, and most participants were followed for nearly five years.

Researchers focused on major adverse cardiovascular events, an outcome known as MACE. It included heart related death, nonfatal heart attacks, strokes and urgent procedures to treat blocked blood vessels, including heart bypass surgery.

Once the results were revealed, patients taking pelacarsen had much lower Lp(a) levels but virtually the same cardiovascular risk as those taking the placebo. Roughly 12% of patients in each group experienced a serious heart related event during the study.

The medication lowered Lp(a) levels by an average of about 77%, performing as expected against the biomarker. Yet it showed no impact on cardiovascular death, heart attacks, strokes or the need for a stent or bypass surgery.

The full results were published Saturday in the New England Journal of Medicine. Researchers examined the data in several ways, including by underlying conditions such as diabetes and by separate cardiovascular outcomes, but found essentially no difference.

“I am flabbergasted,” said Dr. Fatima Rodriguez, chief of preventive cardiology at Stanford University, who was not involved in the research. “There is no signal.”

There is currently no treatment aimed specifically at the risk associated with high Lp(a). Dr. Karol Watson, a cardiologist and professor at the David Geffen School of Medicine at UCLA, had questioned whether universal screening was premature when nothing directly treated the finding.

Expectations had been high when pelacarsen entered the final stage of clinical testing in 2019. Earlier studies, including Nissen’s research, showed the drug could reduce Lp(a) levels by 70% to 80%, and it was expected to lead a new wave of treatments.

Rodriguez said the failed trial remains highly important because its clear findings may force scientists to reconsider what they know about Lp(a). Researchers must now examine whether the problem was the marker, the medication, the patient population or the theory connecting Lp(a) directly to cardiovascular risk.

Nissen noted that trial participants were older and already had well controlled LDL cholesterol. He also suggested that lowering Lp(a) by nearly 80% may not be enough, with reductions of 90% to 95% potentially needed to demonstrate lower heart risk.

Other, stronger medications targeting Lp(a) are already in clinical trials. Nissen believes such drugs may be more beneficial earlier, before a person experiences a first heart attack or stroke, an approach known as primary prevention.

For now, Nissen advises people with high Lp(a) to address other known contributors to heart risk through exercise, weight loss and statin treatment to lower LDL cholesterol. He plans to finish two ongoing trials of newer medications and continue searching for better results.