Evolocumab for cholesterol: After one year, patients on new drug fare better than standard therapy

In this open-label study, the rate of cardiovascular events was 2.18 percent after one year in the standard of care group, most of whom were on moderate or high intensity statin therapy. In contrast, patients treated with evolocumab had approximately half the risk or a 0.95 percent event rate after one year.

Previous trials have shown the drug can substantially lower low-density lipoprotein cholesterol, known as LDL or "bad" cholesterol because it contributes to plaque, a thick, hard deposit that can clog arteries and make them less flexible. Evolocumab reduced bad cholesterol by 61 percent. Evolocumab is a human monoclonal antibody that works by blocking proprotein convertase subtilisin-kexin 9 (PCSK9), a protein that reduces the liver's ability to remove LDL cholesterol from the blood.

"The reduction in LDL was profound and that may be why we saw a marked reduction in cardiovascular events so quickly," said Marc Sabatine, M.D., chairman of the TIMI Study Group and a senior physician in the Division of Cardiovascular Medicine at Brigham and Women's Hospital in Boston, and the study's lead author. "It suggests that if we can drive a patient's LDL cholesterol down a large amount to a very low level, we may start to see a benefit sooner than would be expected with a more modest intervention."

At the start of the study, the average LDL cholesterol measure was 120 milligrams per deciliter, which is similar to the average LDL cholesterol level among Americans. Patients receiving evolocumab were able to achieve an absolute reduction of more than 70 milligrams per deciliter reaching 48 milligrams per deciliter on average. Sabatine said this achieved level of LDL cholesterol is much lower than that achieved in the treatment arm of most other trials.

Researchers studied a total of 4,465 patients who, upon completing one of 12 phase II or III trials that evaluated the drug's ability to lower LDL cholesterol, subsequently enrolled in this one-year extension study to investigate the therapy's effect on long-term safety, LDL-lowering and cardiovascular outcomes. Researchers re-randomized patients 2:1 to receive evolocumab injected under the skin either every two or four weeks plus standard care, or standard care alone, which consisted of the lipid-lowering therapy recommended by their treating physician, usually moderate or high-intensity statin therapy. A central committee that was blinded to the treatment groups then reviewed the data and reported the number of deaths, major coronary events, heart attack, stroke, unstable angina requiring hospitalization and coronary revascularization.

The 53 percent reduction in cardiovascular events in the evolocumab group was consistent across each of the major cardiovascular events included in the composite endpoint--death, heart attack, stroke, hospitalization and angioplasty--and among patient subgroups; no differences were found based on age, baseline LDL levels, statin use, primary or secondary prevention or whether they had valve disease.

Adverse events were largely balanced between the two-week and four-week treatment arms and evolocumab was well-tolerated.

Still, the results are limited by the nature of the trial, in which there were relatively few cardiovascular outcomes (only 60). An ongoing, highly anticipated trial of 27,500 patients to investigate evolocumab's effect on cardiovascular outcomes is underway; however, data are not expected until 2017. But, as Sabatine explained, between now and then there will be a two-year gap in data at a time when this drug may be available for clinical use pending review by the U.S. Food and Drug Administration later this year.

"We won't have any definitive answers until this larger trial we are doing is complete, but these data now give us a sense for the potential clinical benefit of these drugs," Sabatine said. "We know from previous research that evolocumab lowers LDL cholesterol, but these data offer support for their potential to reduce major adverse cardiovascular events in our patients."

The drug makes sense biologically too, he said. "Patients who genetically have lower levels of PCSK9 activity also have a lower rate of adverse cardiovascular outcomes. Now in our analyses, we see this PCSK9 inhibitor appears to reduce adverse cardiovascular outcomes."

He said the findings are especially good news for patients who, despite taking a statin, are not able to lower LDL cholesterol enough or who cannot tolerate statins for a variety of reasons. Evolocumab is one of three PCSK9 inhibitors being studied in large clinical trials.

One out of three American adults is estimated to have high LDL cholesterol, according to the Centers for Disease Control and Prevention. Elevated LDL cholesterol is recognized as a major risk factor for cardiovascular disease, which remains the leading cause of death worldwide.