Adding evolocumab atop statin cuts LDL-C in high-risk ACS

In-hospital initiation of the PCSK9* inhibitor evolocumab, on top of high-intensity statin therapy, in the very high-risk, acute phase of ACS** significantly reduced LDL-C levels — so much so that >95 percent of the patients achieved the recommended target levels — compared with high-intensity statin alone, the EVOPACS*** study has shown.

At 8 weeks, the addition of evolocumab reduced LDL-C levels by 77.1 percent from baseline compared with a 35.4-percent reduction with atorvastatin alone in patients who had been hospitalized for ACS (p<0.001). [J Am Coll Cardiol 2019;74:2452-2462]

There were also significantly more evolocumab-treated patients who attained the currently recommended target LDL-C levels of <1.8 mmol/L at 8 weeks than those receiving atorvastatin alone (95.7 percent vs 37.6 percent; p<0.001).    

“Patients with ACS are at increased risk of recurrent ischaemic events, particularly during the early period following the index event,” the researchers stated.

Current clinical practice guidelines recommend initiating high-intensity statin early during hospitalization for ACS to lower the risk of early events. [Eur Heart J 2016;37:2999-3058; J Am Coll Cardiol 2019;73:e285–350]

“In view of the delayed onset of action of statins and the high risk of event recurrence during the first weeks after ACS, … rapid and more potent lowering of LDL-C to levels even below currently recommended targets might be of potential therapeutic benefit in this setting,” said the researchers.

Building on the rationale that earlier initiation of lipid-lowering therapy may lead to earlier appearance of benefit, the researchers conducted a phase III double-blind trial to investigate if this applies to evolocumab as well. The study randomized 308 patients with elevated LDL-C^# levels who were hospitalized for ACS (mean age 61 years) in a 1:1 ratio to receive subcutaneous evolocumab 420 mg every 4 weeks or placebo, administered in-hospital and after 4 weeks, in addition to atorvastatin 40 mg/day.

“The reduction in LDL-C levels was evident at 4 weeks and maintained at 8 weeks,” observed the researchers.

In particular, the benefits with evolocumab addition over atorvastatin alone were greater in the subgroup who had previously been treated with statin and those with baseline LDL-C levels below median.

The addition of evolocumab was also well tolerated, with similar rates of adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation between the two arms. The most commonly-reported AE of musculoskeletal pain occurred in 5.8 percent of patients in the evolocumab arm and 2.6 percent in the atorvastatin alone arm. ALT^## elevation to >3x the upper limit of normal occurred in 1.3 percent of patients in each group.

‘Can’ vs ‘should’

Commenting on the feasibility of initiating PCSK9 inhibitor in-hospital for ACS in a linked editorial, Drs Gregory Schwartz and Bernard Chaitman from University of Colorado School of Medicine, Aurora, Colorado and St Louis University School of Medicine in St Louis, Missouri, US, respectively raised the question: “[The study showed that] we can, but does that mean we should?” [J Am Coll Cardiol 2019;74:2463-2465]

Whether there is sufficient evidence currently to support initiation of PCSK9 inhibitor before discharge from hospital after ACS, the editorialists said “the answer in most cases is no,” in view of the lack of data on corresponding cardiovascular benefit.

“The therapeutic value of this approach can only be determined with a randomized controlled trial powered for MACE^### outcomes,” they pointed out.

“[In addition,] emphasizing and assessing adherence with foundational therapies such as high-intensity statin and adding others as needed may be more prudent than initiating many new treatments simultaneously at hospital discharge,” advised Schwartz and Chaitman.