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New Approval for Praluent (alirocumab): Prevention of Cardiovascular Outcomes

May 25, 2019
 
Editor: Steve Freed, R.PH., CDE

Author: Adam Chalela, B.S. Doctor of Pharmacy Candidate USF College of Pharmacy

Expansion of the original 2015 approval makes Praluent a strong lipid-lowering candidate for patients with diabetes and other cardiovascular concerns.

Praluent (alirocumab) is a monoclonal antibody that inhibits proprotein convertase subtilisin kexin type 9 (PCSK9). The PCSK9 protein is coded by a gene and plays a key role in regulating the amount of low-density lipoprotein that enters the bloodstream. It was originally approved in 2015 as an adjunct to a healthy diet and statin therapy that was already maximally tolerated in patients who required further lowering of low-density lipoprotein (LDL) cholesterol, as it demonstrated its ability throughout numerous studies. Cardiovascular benefits of Praluent were not apparent in these early studies as possible confounding, poor stratification of patient characteristics, and only following up with patients for a maximum of one year during the study period could have led the absence of these outcomes in respective study cohorts.

 

The ODESSY trial was a multicentered, randomized, double-blind, placebo-controlled study that aimed to determine any association between Praluent’s use after an acute coronary syndrome in patients already on a maximally tolerated statin and improved cardiovascular outcomes for up to five years (median follow-up of 2.8 years). Patients enrolled were at least 40 years of age or older, had a previous myocardial infarction or unstable angina requiring hospitalization within the past 1 to 12 months prior to randomization, had an LDL cholesterol level of at least 70 mg/dL. The 18,924 patients enrolled into this study received high-intensity statin therapy with either atorvastatin 40mg or 80mg or rosuvastatin 20mg or 40mg and were stable on these doses, or a maximally tolerated dose of the same statins due to unwanted side effects, for at least two weeks prior to treatment pre-randomization with placebo. After a pre-randomization phase of two weeks, randomization underwent in a 1:1 ratio of Praluent to placebo to be administered every two weeks.

The primary endpoint in the ODESSY trial was a composite incidence of mortality from coronary heart disease, nonfatal myocardial infarction, any ischemic stroke, or unstable angina requiring hospitalization; other secondary endpoints included individual pieces of the primary composite endpoint. Safety endpoints were also obtained for incidence of major adverse reactions as compared to placebo. Since the study was very large and multi-centered, patient data was stratified based solely on geographical region; clinical characteristics of patients enrolled were pooled.

Data was analyzed through Cox proportional hazard ratios and 95% confidence intervals. At study conclusion, the primary endpoint was met in 9.5% of patients randomized to Praluent (n=9462) and 11.1% of patients randomized to placebo (n=9462). The composite primary endpoint was 15% less likely (95% CI 0.78-0.93; p<0.001) to occur in the Praluent cohort than the placebo cohort. Other major secondary endpoints followed similar trends except for mortality from coronary heart disease or mortality from any cardiovascular cause which failed to show statistical significance for the true population mean. Adverse events reported within the two study cohorts were similar with a singular exception of injection site reactions (3.8% with Praluent vs 2.1% with placebo; p<0.001); major adverse events reported for both groups included, but were not limited to, increased liver enzymes (AST and ALT) and general allergic reactions. Out of the patients that were included in the intent-to-treat analysis, only 67 (0.7%) in the Praluent study arm developed antibodies to the study drug.

Practice Pearls

  • Praluent should be strongly considered as an add-on second line therapy in patients that are already on a maximally tolerated statin and are at a high risk of cardiovascular events.
  • Praluent demonstrates greater absolute risk reduction of cardiovascular events in eligible patients that have an LDL cholesterol level of greater than 100 mg/dL.
  • Praluent shows its greatest LDL lowering capabilities within the first four months of treatment.

Reference: Schwartz GG, Steg G, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-2107. DOI: 10.1056/NEJMoa1801174

Adam Chalela, B.S. Doctor of Pharmacy Candidate USF College of Pharmacy