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Two new PCSK9 inhibitors that lower LDL cholesterol also seemed to reduce cardiovascular outcomes, according to the results of two trials.

Both evolocumab (Repatha) and alirocumab (Praluent) showed relative reductions in composite cardiovascular events of approximately 50% at 12 to 18 months in patients with high LDL cholesterol levels despite the use of statins.

"Much work remains to be done, but PCSK9 inhibitors appear on track to become important arrows in our quiver for targeting reduction of cardiovascular events among higher-risk patients when statins are not enough," , and , both of Northwestern University in Chicago, wrote in an editorial in the New England Journal of Medicine, where both studies appeared.

OSLER and Evolocumab

Evolocumab was studied in the open-label OSLER extension study program, which included 4,465 patients from 12 phase II and III clinical trials. Patients had various degrees of cardiovascular risk and were randomized to treatment with evolocumab (140 mg subcutaneously every 2 weeks or 420-mg monthly) added to standard therapy versus standard therapy alone over about 1 year.

Along with publication in NEJM, findings were reported by , of Brigham and Women's Hospital in Boston, and chair of the Thrombolysis in Myocardial Infarction (TIMI) Study Group, at the American College of Cardiology conference in San Diego.

Statins will likely remain the foundation of therapy given that their effectiveness, safety, and relatively low cost, Sabatine said, adding that "I don't view these [PCSK9 inhibitors] as competitors to statins."

But the new class of drug could be used for patients who have elevated cholesterol levels even after maximum-dose statin therapy, as well as for patients who are statin-intolerant, he said.

Evolocumab reduced LDL cholesterol levels by 61% at 12 weeks (73 mg/dL decrease) and cardiovascular outcomes by 53% over 1 year.

Cardiovascular outcomes were death, coronary events (myocardial infarction or MI, hospitalization for unstable angina, or revascularization), cerebrovascular events (stroke or transient ischemic attack), and hospitalizations for heart failure.

The rate of cardiovascular events was 2.18% in the standard therapy group and 0.95% in the intervention group. The hazard ratio was 0.47 in favor of evolocumab (95% CI 0.28-0.78, P=0.003).

The results were consistent across major patient subgroups, Sabatine noted at an ACC press briefing.

Serious adverse events occurred in 7.5% of patients in both the evolocumab and standard therapy groups. A total of 2.4% of patients in the evolocumab group discontinued the drug due to adverse events.

Adverse events in the evolocumab group included injection-site reactions (4.3%), muscle-related events (6.4%), and neurocognitive effects (0.9%).

ODYSSEY and Alirocumab

Alirocumab was studied in the ODYSSEY LONG TERM trial, which included 2,341 patients at high risk for cardiovascular events on maximum statin doses who were randomized to double-blind treatment with alirocumab (150 mg administered subcutaneously every 2 weeks) or placebo for 78 weeks.

Findings were reported by , from the University of Iowa in Iowa City, at an earlier presentation at the European Society of Cardiology meeting.

Alirocumab reduced LDL cholesterol levels by an average of 61% over 24 weeks.

Post-hoc data from the trial showed that alirocumab had a 1.7% rate of cardiovascular events compared with 3.3% rate with placebo over 78 weeks. The HR was 0.52 (95% CI, 0.31-0.90) for those who received the drug versus those who did not.

Cardiovascular events included death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.

Still No Floor on LDL Levels

The findings from OSLER also suggested that researchers still have not found a floor for LDL cholesterol for which patients do not derive benefit, Sabatine said.

Earlier treatment of high cholesterol before cardiovascular events occur seems to be the trend, said panel discussant , executive director of the Duke Clinical Research Institute in Durham, N.C.

Some worry that driving LDL to low levels could cause neurological deficits, but the trial did not find that to be the case, Peterson added.

The neurocognitive event rate for those in the evolocumab group was greater for patients on evolocumab compared with those in the standard care group (0.3%).

In ODYSSEY LONG TERM, the neurocognitive adverse event rate was 1.2% with alirocumab versus 0.5% in the placebo group.

There were no adverse events that increased at lower LDL levels, even at less than 25 mg/dL, Sabatine said.

Sabatine cautioned that his group's analysis was exploratory with a low event rate.

Large outcomes trials will further investigate the two drugs: adds evolocumab to statins for people with pre-existing heart disease, and compares alirocumab with placebo in conjunction with medical and lifestyle management after a recent acute coronary syndrome.

The FDA is expected to decide whether to approve the drugs this summer.

From the American Heart Association: