Pamela B. Morris
LAS VEGAS — Nonstatin therapies, including ezetimibe and the PCSK9 inhibitors, safely reduce the risk for CVD in very high-risk patients who require additional LDL lowering, according to a presentation at the National Lipid Association Scientific Sessions.
In the past couple years, exciting data have emerged regarding the role of nonstatin therapies, but issues remain in the use of statin therapies, according to Pamela B. Morris, MD, FACC, FAHA, FASPC, FNLA, director of the Seinsheimer Cardiovascular Health Program and co-director of women’s heart care at the Medical University of South Carolina in Charleston.
“It’s critically important for us to realize that evidence-based statin therapy is underutilized,” Morris said in the presentation.
According to a study published in the Journal of the American College of Cardiology in 2017, only approximately 60% to 70% of high-risk patients are on appropriate high-intensity statin therapy.
The role of nonstatin therapy was addressed in the 2017 focused update of the 2016 American College of Cardiology Expert Consensus Decision Pathway, endorsed by the NLA. This document included consideration of the results of IMPROVE -IT and FOURIER and was based upon the 2013 ACC/American Heart Association cholesterol guidelines, which identified the four patient groups who have net clinical benefit from statin therapy. For high-risk patients, one important consideration when choosing a nonstatin therapy is the efficacy of additional LDL lowering when added to maximally tolerated statin therapy.
In the IMPROVE-IT trial, patients who received ezetimibe with simvastatin had an additional 24% reduction in LDL compared with those assigned simvastatin alone.
In the FOURIER trial, the PCSK9 inhibitor evolocumab (Repatha, Amgen) also reduced LDL by 59% in patients.
“This benefit was durable at least over the time frame of the trial,” Morris said.
In the ODYSSEY Outcomes trial, an intention-to-treat analysis found that alirocumab (Praluent, Sanofi/Regeneron) reduced LDL by an estimated 50% at 12 months vs. placebo, which decreased to 36% at 48 months. In an on-treatment analysis, there was a reduction of 62.7% at 4 months and 54.7% at 48 months.
The 2017 ACC decision pathway incorporated these findings and indicated that ezetimibe may be considered initially in patients who require less than 25% additional lowering of LDL. For those who require greater than 25% LDL reduction, PCSK9 inhibitors may be preferred as the initial nonstatin agent.
The IMPROVE-IT trial also assessed safety in patients assigned ezetimibe with simvastatin vs. simvastatin alone. There were no statistically significant differences for most of the adverse effects, including new-onset diabetes and neurocognitive adverse events, at 6 years. The incidence of adverse effects also did not differ in patients who achieved very low LDL levels, even in those patients who achieved LDL levels below 30 mg/dl.
Safety has also been established with evolocumab in the FOURIER trial, as there were no statistically significant differences in events such as injection-site reactions and new-onset diabetes. In patients who achieved very low levels of LDL, there was a monotonic relationship between the achieved LDL levels and major CV outcomes without an increase in adverse effects at very low levels of on-treatment LDL, according to the presentation.
No statistically significant differences were seen among patients in the ODYSSEY Outcomes trial who were assigned alirocumab, although there was a modest increase in injection-site reactions.
“The clinical implications are that the nonstatin therapies are safe when added to moderate- or high-intensity statin therapy, at least over the duration of currently available clinical trials” Morris said.
In the FOURIER and ODYSSEY trials, the inclusion criteria were either LDL or non-HDL levels, although LDL-targeted therapy was used in these patients.
There were no specific lipid or lipoprotein goals of therapy in the IMPROVE-IT trial, although those patients with LDL greater than 79 mg/dL on two consecutive measurements could have the dose of simvastatin was increased to 80 mg.
The FOURIER trial had no dose titration and no discontinuation of the study drug based on non-HDL or LDL levels. In the ODYSSEY Outcomes trial, alirocumab therapy was discontinued in patients with LDL-C less than 15 mg/dL on two consecutive measurements.
“All trials prioritized evidence-based statin therapy prior to adding a nonstatin agent,” Morris said.
When relying on randomized controlled trial design and protocol, the evidence supports the current thresholds, according to the presentation.
The 2017 decision pathway also addressed how to identify patients who would benefit from this therapy based on inclusion criteria from the FOURIER and ODYSSEY Outcomes trials. The FOURIER trial included patients with stable atherosclerotic CVD and additional high-risk features or comorbidities (current smoking, age greater than 65 years, residual coronary stenosis and recent ACS, among other factors). The ODYSSEY Outcomes trial included patients with ACS within the past 1 to 12 months. Patients with recent ACS less than 3 months were included in the IMPROVE-IT trial, thus the decision pathway recommends that patients with atherosclerotic CVD and comorbidities or recent ACS may be considered for other ezetimibe or a PCSK9 inhibitor, depending upon other considerations (percentage of additional LDL-C lowering desired, cost, route of administration, patient preferences).
“Patients who are candidates for a PCSK9 inhibitor include those with atherosclerotic CVD or patients with baseline LDL cholesterol greater than 190 mg/dL, consistent with familial hypercholesterolemia based on current FDA-approved indications,” Morris said.
Currently, there are no FDA-approved primary prevention indications for patients with diabetes or a 10-year risk greater than 7.5% except for those patients with extreme LDL levels in familial hypercholesterolemia, according to the presentation.
“We can continue to feel confident with the current thresholds for consideration of addition of nonstatin therapy to maximally tolerated statin therapy based on the available evidence,” Morris said. “Systematic reviews of the evidence for new dyslipidemia guidelines are underway and may inform the decision to reduce LDL to even lower levels.” – by Darlene Dobkowski
Morris PB. Session II – Clinical Updates on PCSK9 Inhibition. Presented at: National Lipid Association Scientific Sessions; April 26-29, 2018; Las Vegas.
Disclosure: Morris reports she serves on the advisory board for Amgen and Sanofi/Regeneron and the steering committee for Amgen and Esperion.