The results of the ODYSSEY Outcomes trial of Alirocumab (Praluent) were presented today at the American College of Cardiology Scientific sessions. Alirocumab is an injectable antibody PCSK9 inhibitor that has been shown to significantly reduce LDL-cholesterol levels in prior trials.

ODYSSEY Background

ODYSSEY was a very large randomized, double-blind controlled trial of patients at high risk for recurrent coronary heart disease events. In a double-blind trial neither the patient or physician knows whether they are receiving active drug or not (placebo).

The main question of this study was whether the addition of Alirocumab could reduce the rates of major adverse cardiovascular events (death caused by coronary heart disease, myocardial infarction, stroke and unstable angina) when added on top of optimal medical care. Optimal medical care was defined as the maximally tolerated dose of a high potency statin (atorvastatatin or rosuvastatin) in patients with LDL-cholesterol that remained > 70 mg/dL despite these therapies.

The expectation was that there would be a 15% reduction in events in those treated with Alirocumab compared to placebo.

In total ~18900 patients were enrolled across the world in 57 countries with half receiving Alirocumab and half receiving placebo. Overall, the patients in this trial were high risk as all had experienced a myocardial infarction on average about 3 months prior to enrollment. 25% of the patients were women.

The patients were followed for a median of 2.8 years and very few patients were lost to follow up. At baseline all the patients had an LDL-cholesterol of 87 mg/dl with 89% receiving high dose atorvastatin or rosuvastatin.

Alirocumab was effective and reduced LDL-cholesterol by 55% throughout the trial.

In terms of the main outcome, Alirocumab improved outcomes. Fewer patients receiving Alirocumab had a cardiovascular event compared to those receiving placebo: 903 patients (9.5%) of patients receiving Alirocumab had an event compared to 1052 (11.1%) receiving placebo (a 15% relative risk reduction).

Secondary analyses showed that the overall death rate (by any cause) was also lower in the Alirocumab treated group (3.5% versus 4.1%).

There did not seem to be differences in the effect between men and women.

However, patients that had a higher LDL-cholesterol at enrollment seemed to derive special benefit, those with LDL-cholesterol > 100 mg/dL at baseline seemed to do better.

Side effects were rare and there was no difference in serious side effects between the groups. People that got Alirocumab did not have an increased risk of diabetes, hemorrhagic stroke or neurocognitive problems.

Important take away points for Familial Hypercholesterolemia (FH) patients include:

While the results today did not include FH-specific analyses, there is undoubtedly an enrichment of FH patients in the subset that showed the most benefit in the ODYSSEY trial, those with an entry level LDL-C > 100 mg/dL. In the pre-PCSK9i era, data show that only 25% of FH patients achieve an LDL <100 mg/dL.

• Alirocumab was effective in lowering LDL-cholesterol by about 55%
• Alirocumab was also effective in decreasing cardiovascular events by about 15% with a decrease in overall death.
• Side effects were rare and there was no increase in serious side effects

How will these results impact care?

People with familial hypercholesterolemia (FH) are at high lifetime risk of early heart disease, resulting in early heart attacks and strokes. Research consistently shows that LDL-C is the key determinant of cardiovascular risk and primary target for treatment. For many people with FH, high-intensity statins are not enough and a combination of therapies to lower LDL-C are required.

View ODYSSEY Slide Presentation

“The results of the ODYSSEY Outcomes trial confirms the benefit of LDL cholesterol reduction with PCSK9 inhibition.  Particularly notable are the findings that overall mortality was reduced in the group receiving alirocumab, and that patients who had an LDL > 100 at the start of the study had an even greater benefit from treatment.  There is little question that PCSK9 inhibition is clinically beneficial in many patients with FH, but that a large number of FH patients who would benefit from these medications are not currently gaining access to them.”
— Daniel J. Rader, MD, Perelman School of Medicine at the University of Pennsylvania

“ODYSSEY demonstrated impressive safety data. In addition, lower LDL-C is better for those at increased or high risk of heart disease and mortality, such as individuals with FH. We are now in a new era of treating vascular medicine. This era is moving into biologics with PCSK9 inhibitors, therapies to reduce inflammation and target Lp(a). Very excited by the results and what it means for our ability to treat those most at risk.”

— Laurence S. Sperling, MD, Emory Heart Disease Prevention Center, Rollins School of Public Health at Emory University

“We believe today’s ODYSSEY results are exciting for the FH community because we now know that PCSK9 inhibitors can increasingly play an important role in reducing morbidity and mortality in those with heart disease and at highest risk”
— Katherine Wilemon, Founder and CEO of the Family Heart Foundation

“The findings from ODYSSEY Outcomes were largely consistent with that of the previously reported FOURIER trial. Though ODYSSEY enrolled higher risk patients and followed them for a longer period, the risk reduction in the primary outcome was similar. Whether that was due to the more intensive background statin treatment or the reality that we have reached the limits of what dramatic LDL-C reduction can deliver is uncertain. In any event, this confirms that PCSK9 inhibition is an effective strategy for high risk patients. It is a success for clinical science and our patients.”
— Michael Shapiro DO, Family Heart Foundation Board Member, Oregon Health & Science University, Knight Cardiovascular Institute