OSLER Shows Cholesterol-Lowering Evolocumab Improves Cardiovascular Outcomes

March 15, 2015—Patients taking evolocumab—an investigational therapy previously shown to dramatically lower low-density lipoprotein cholesterol (LDL-C)—were half as likely to die, experience a heart attack or stroke, be hospitalized, or need a procedure to open blocked arteries compared with those who received standard care, according to findings from the OSLER-1 and OSLER-2 studies presented at the American College of Cardiology’s 64th annual scientific session in San Diego, California.

The findings from the OSLER open-label studies of long-term evaluation against LDL-C were simultaneously published online in The New England Journal of Medicine.

Marc Sabatine, MD, is the lead investigator of the OSLER-1 and OSLER-2 studies, which are funded by Amgen, the manufacturer of the investigational drug evolocumab (AMG 145), a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). Previous trials have shown evolocumab can substantially lower LDL-C by 61%, according to the ACC announcement.

In OSLER, the rate of cardiovascular events was 2.18% after 1 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 a 0.95% event rate after 1 year.

In the ACC press release, Dr. Sabatine commented, “The reduction in LDL was profound and that may be why we saw a marked reduction in cardiovascular events so quickly. 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.” Dr. Sabatine is Chairman of the TIMI Study Group and a senior physician in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital in Boston, Massachusetts.

At the start of OSLER, the average LDL-C was 120 mg/dL, which is similar to the average level among Americans. Patients receiving evolocumab were able to achieve an absolute reduction of more than 70 mg/dL, reaching 48 mg/dL on average. Dr. Sabatine said this achieved level of LDL cholesterol is much lower than that achieved in the treatment arm of most other trials.

The OSLER investigators 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-C, subsequently enrolled in this 1-year extension study to investigate the therapy’s effect on long-term safety, LDL-lowering, and cardiovascular outcomes. Patients were re-randomized 2:1 to receive evolocumab injected under the skin either every 2 or 4 weeks plus standard care, or standard care alone, which consisted of the lipid-lowering therapy recommended by the patient’s 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 investigators found that the 53% 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 2-week and 4-week treatment arms and evolocumab was well tolerated.

As noted in the ACC summary, the results are limited by the nature of the trial, in which there were relatively few cardiovascular outcomes (a total of 60). There is an ongoing, highly anticipated trial of 27,500 patients to investigate evolocumab’s effect on cardiovascular outcomes; however, data are not expected until 2017. Dr. Sabatine explained that between now and then there will be a 2-year gap in data at a time when this drug may be available for clinical use pending review by the US Food and Drug Administration later this year.

Dr. Sabatine stated in the ACC press release, “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. 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.” Additionally, he said that he drug makes sense biologically. “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,” concluded Dr. Sabatine.