The PCSK9 inhibitor alirocumab appeared to be superior to ezetimibe for lowering LDL cholesterol levels after 24 weeks of treatment in patients who cannot tolerate statin therapy, according to new data presented at the American Heart Association’s Scientific Sessions 2014.
In the ODYSSEY ALTERNATIVE study, researchers compared alirocumab with ezetimibe and atorvastatin in statin-intolerant patients with LDL cholesterol levels of 70 mg/dL or greater at very high cardiovascular (CV) risk or 100 mg/dL or greater at moderate or high risk. All patients had coronary heart disease (CHD) or other CV risk factors.
In this study, patients underwent a 4-week placebo run-in period as well as a statin re-challenge to document statin intolerance. They were then randomly assigned to alirocumab 75 mg or 150 mg, self-administered via 1 mL prefilled pen every 2 weeks; ezetimibe 10 mg per day; or atorvastatin 20 mg per day for 24 weeks.
“This study had a novel design. These patients were statin-intolerant, and we had a 4 week run-in placebo period that patients did not know about,” said lead study author Patrick Moriarty, MD, professor of medicine at the University of Kansas Medical Center in Kansas City. “Even though it was placebo, we had patients drop out due to side effects.”
After 24 weeks, patients treated with alirocumab achieved greater LDL reductions than those treated with ezetimibe.
In an intention-to-treat analysis, least square mean change in LDL was –45.0% for the alirocumab group vs. –14.6% for the ezetimibe group (least square mean difference, –30.4%; P<.0001).
Similarly, in an on-treatment analysis, least square mean change in LDL was –52.2% for those treated with alirocumab vs. –17.1% for those treated with ezetimibe (least square mean difference, –35.1%; P<.0001).
Additionally, mean baseline LDL cholesterol was 191.1 mg/dL in the alirocumab group. In the intention-to-treat analysis, mean achieved LDL was 108.5 mg/dL, while in the on-treatment analysis, mean achieved LDL was 92 mg/dL.
The study also showed that 42% of patients treated with alirocumab, as compared with 4% of those treated with ezetimibe, achieved their LDL cholesterol goals of less than 70 mg/dL for very high-risk patients or less than 100 mg/dL for moderate- and high-risk patients. Further, 61% achieved LDL cholesterol of less than 100 mg/dL with alirocumab vs. 10% with ezetimibe.
A safety analysis revealed similar rates of treatment-emergent adverse events among patients assigned alirocumab, ezetimibe or atorvastatin. However, during the double blind treatment period, 18.3% of patients on alirocumab discontinued due to adverse events vs. 25.0% on ezetimibe and 25.4% on atorvastatin.
Further, treatment-related skeletal muscle events were more likely in the atorvastatin group vs. the alirocumab group (HR=1.63; 95% CI, 1.01-2.62).
During the open label treatment period following the double blind treatment period, only 2.8% of patients discontinued alirocumab.
“This is even less discontinuation than previous phase 2 and 3 studies comparing alirocumab (5.3%) to placebo (5.1%). So basically, in patients who were 100% intolerant to statin therapy, over 97% were able to tolerate open label alirocumab. This again demonstrates the complexity in diagnosing and treating this patient population,” explained Dr. Moriarty.
“There is a great unmet clinical need. These patients are at very high risk because they have such high LDL cholesterol levels. LDL cholesterol has been shown to be a very important component of risk and now physicians can consider treating these patients based on this trial. This is just the beginning of the data we will be mining from it,” said Dr. Moriarty.
- Moriarty PM et al. LBCT.02 – Anti-Lipid Therapy and Prevention of CAD. ODYSSEY ALTERNATIVE: Efficacy And Safety of the Proprotein Convertase Subtilisin/kexin Type 9 Monoclonal Antibody, Alirocumab, versus Ezetimibe, in Patients With Statin Intolerance as Defined by a Placebo Run-in and Statin Rechallenge Arm. Presented at: American Heart Association’s Scientific Sessions 2014; Nov. 15-19, 2014; Chicago.