ODYSSEY Outcomes Published as New Cholesterol Guidelines Loom

The ODYSSEY Outcomes trial, an 18,924-patient study demonstrating that alirocumab (Praluent; Sanofi/Regeneron) reduced the risk of recurrent ischemic events, is now published in the New England Journal of Medicine.

The large cardiovascular outcomes study testing the PCSK9 inhibitor in patients with acute coronary syndromes was first presented at the American College of Cardiology (ACC) 2018 Scientific Session in Orlando, FL, and reported by TCTMD at that time.

To recap: the ODYSSEY Outcomes trial showed treatment with alirocumab on top of high-intensity statin therapy reduced the risk of coronary heart disease mortality, nonfatal MI, ischemic stroke, or unstable angina by 15% when compared with statin therapy alone. Although there was no significant reduction in the risk of coronary heart disease or cardiovascular death, there was a relative 15% reduction in all-cause mortality among ACS patients who received the PCSK9 inhibitor. The absolute benefit of treatment with alirocumab was most pronounced among patients with higher baseline LDL cholesterol levels, such as those with levels greater than 100 mg/dL.

The final results, which were published online November 7, 2018, are unchanged from the late-breaking clinical trials session, according to lead investigator Gregory Schwartz, MD, PhD (University of Colorado School of Medicine, Aurora).    

To TCTMD, Schwartz said one of the key questions still not known is just how far physicians should lower cholesterol levels in patients with coronary artery disease. The consensus from the statin trials is that “lower is better,” but that isn’t entirely helpful in the new era of powerful lipid-lowering therapy. In ODYSSEY, the goal of therapy was to reduce LDL cholesterol to a target range of 25 to 50 mg/dL. Although physicians were allowed to treat patients to a level of 15 to 25 mg/dL, the trial mandated avoiding sustained levels less than 15 mg/dL.

“Very few patients in statin trials got down to levels of LDL cholesterol of 15 mg/dL or less,” said Schwartz. “Whether there is any additional cardiovascular efficacy of going from, say, 30 mg/dL to 10 mg/dL is unknown. However, most biological relationships have a floor, and it’s unlikely there is a great deal of incremental benefit in this range. Moreover, although no safety signals have arisen with PCSK9 inhibitors in short- to intermediate-term observation, we don’t know the long-term safety of sustained, very low LDL cholesterol levels.”

Schwartz also noted there is unavoidable confounding in analyses that attempt to determine relative benefits of low versus even lower LDL cholesterol levels. Patients who achieve very low levels on a PCSK9 inhibitor likely started treatment at lower LDL cholesterol levels, and as a result have had lower lifetime exposure to atherogenic lipoproteins, he said. 

“It’s possible, although unproven, that a more favorable prognosis in this group might be related to lesser severity or extent of atherosclerosis rather than the therapeutic reduction in LDL cholesterol to very low levels,” said Schwartz. “The ‘low hanging fruit’ in this arena is to bring down LDL cholesterol levels aggressively in patients who start high. Whether there’s benefit in going to extremely low levels will always be difficult to know using postrandomization data.” 

New Cholesterol Guidelines Coming Soon

On Saturday, November 10, 2018, at the American Heart Association (AHA) 2018 Scientific Sessions, new guidelines for the treatment of elevated cholesterol are scheduled for presentation. The ACC provided an update in 2017 on the use of non-statin therapies for the management of atherosclerotic cardiovascular disease, but the new cholesterol guidelines are first update in the PCSK9 inhibitor era. It’s also unknown whether the cholesterol guidelines will return to a target-based treatment approach, as they had prior to 2013.

“I’m confident that the results of FOURIER, SPIRE, and ODYSSEY Outcomes will be reflected in the new guidelines, but I don’t have an ‘inside track’ on anything specific,” said Schwartz. “I share the anticipation that all of us feel ahead of the unveiling of the new guidelines on November 10th.”    

Aside from the guidelines, more data on alirocumab will be available at the AHA meeting. Deepak Bhatt, MD (Brigham and Women's Hospital, Boston, MA), is scheduled to present a cost-effectiveness analysis based on data from the ODYSSEY Outcomes trial.  

The manufacturers of alirocumab, as well as evolocumab (Repatha; Amgen), had both been under fire for initially pricing the drugs too high, but changes in recent months have seen the cost of both PCSK9 inhibitors reduced. In May, Regeneron and Sanofi worked out an exclusive deal with the Express Scripts national formulary to reduce the annual price of alirocumab to between $4,000 and $8,000. In October, Amgen announced that they too reduced the list price of evolocumab, cutting the cost down to $5,850 per year from $14,500.