Repatha Jump-Starts LDL Lowering In-Hospital

Adding a PCSK9 inhibitor to high-intensity statin treatment early after an acute coronary syndrome (ACS) -- before hospital discharge -- was safe and more effectively lowered LDL levels, the phase III EVOPACS trial found.
By week 8, the evolocumab (Repatha) cohort experienced a 77.1% reduction from baseline in mean LDL versus a 35.4% reduction for the statin plus placebo group (P<0.001), Konstantinos Koskinas, MD, MSc, of Bern University Hospital in Switzerland, reported here at the European Society of Cardiology (ESC) congress.

 

Furthermore, while only 37.6% of patients on placebo reached an LDL of <1.8 mmol/L (70 mg/dL) at this time point, nearly all patients in the evolocumab group (95.7%) hit that target.
"In this first randomized trial assessing a PCSK9 antibody in the very high-risk acute setting of ACS, evolocumab added to high-intensity statin therapy resulted in substantial reduction in LDL-C levels without raising safety concerns," Koskinas said.
A similar proportion of patients in the placebo and investigational groups (50.7% vs 50.3%) experienced any adverse event (AE), or any serious AE (7.2% vs 7.7%). And no AEs of special interest were significantly different between the placebo and evolocumab groups, respectively, including:

• Musculoskeletal pain: 2.6% vs 5.8%
• Local injection site reaction: 2.0% vs 3.2%
• Diarrhea: 2.0% vs 3.9%
• Nasopharyngitis: 2.0% vs 2.6%
• Elevated liver enzymes: 1.3% for each

Drug discontinuation due to toxicity occurred in 2.0% of placebo patients and 1.3% of evolocumab patients. Notably, two deaths were reported in the evolocumab cohort, but were deemed unrelated to treatment.
Koskinas noted that a dedicated cardiovascular outcomes trial is needed to assess the clinical impact of early LDL lowering with evolocumab in the acute setting of ACS.

 

Results of the randomized, double-blind, placebo-controlled trial were simultaneously published in the Journal of the American College of Cardiology.
In an interview with MedPage Today, session chair Alaide Chieffo, MD, of San Raffaele Scientific Institute in Milan, Italy, explained that most of the prior literature has focused on stable patients rather than addressing ACS at the time of onset.
Newly released joint guidelines from ESC and the European Atherosclerosis Society suggest that ACS patients already on ezetimibe (Zetia) and a maximally tolerated dose of statins, but with LDL levels not at the desired level, should also receive a PCSK9 inhibitor as soon as possible.
Researchers for EVOPACS randomized 308 patients 1:1 to high-intensity statins plus either placebo or evolocumab. The cohort had a mean age of 60.8 years and were mostly men (82.5%). All participants were hospitalized for ACS with elevated LDL of at least 3.2 mmol/L (124 mg/dL) for those on no stable statin dose, 2.3 mmol/L (89 mg/dL) or more for those on a low- or moderate-intensity statin, and 1.8 mmol/L (70 mg/dL) or more for those on a high-intensity statin for at least 4 weeks.
On top of 40 mg of atorvastatin (Lipitor), patients were subcutaneously given either 420 mg evolocumab or placebo, which was administered in-hospital and after 4 weeks.

 

 

Findings showed that for the primary endpoint, average LDL declined from 3.42 mmol/L at baseline to 2.06 mmol/L at week 8 in the placebo cohort, and from 3.61 to 0.79 mmol/L in the evolocumab group.
As for inflammatory biomarkers, average levels of high sensitivity C-reactive protein declined from 6.6 mg/L to 2.5 mg/L at 8 weeks, but no significant differences were seen between the cohorts. Likewise, there were no differences in the change for IL-6 and IL-1β levels.
Limitations of the study included having a short duration and modest sample size. Further, the primary endpoint could only be assessed in 90% of the cohort, though the researchers noted that directly measuring LDL in cases of very low LDL or very high triglycerides demonstrated consistent results. Another limitation cited was that they were unable to capture evolocumab's effects prior to week 4, even though the therapy lowers LDL within days.

 

The study was funded by Amgen.
Koskinas disclosed relationships with Sanofi and Amgen.

• Primary Source

  Journal of the American College of Cardiology

  Source Reference: Koskinas KC, et al "Evolocumab for early reduction of LDL-cholesterol levels in patients with acute coronary syndromes (EVOPACS)" J Am Coll Cardiol 2019; DOI: 10.1016/j.jacc.2018.08.541.

https://www.medpagetoday.com/meetingcoverage/esc/81920