EBM Tools for Practice: Improving Lipid Management for the Acute Coronary Syndrome Patient

Introduction

It’s been over 20 years since the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial¹ ushered in the initiation of aggressive LDL-C lowering therapy before hospital discharge for acute coronary syndrome (ACS). Three years later, the Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes (PROVE-IT TIMI 22) trial² demonstrated the superiority of high-intensity lowering over moderate-intensity lowering; with a separation of the Kaplan-Meier curves within two weeks. Possible mechanisms included early plaque healing, endothelial stabilization and the pleiotropic effects of statins. This extended beyond statins in the Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes (IMPROVE-IT) trial, where the addition of ezetimibe to simvastatin further reduced cardiovascular events and demonstrated that even more aggressive early-phase lowering is better.³ More recent studies now look to PCSK9 inhibitors for additional plaque stabilization and event reduction in ACS patients. 

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death and morbidity and also ranks among the costliest diseases to our healthcare system. Hospitalization represents a teachable moment and an opportunity to identify and halt the disease, underscored by the fact that the most likely time for a recurrent event is the ensuing 12 months. Multiple initiatives have aimed to reduce ASCVD burden and cost. Examples include discharge protocols aimed at patient and provider education, initiation of aggressive lipid-lowering therapy prior to discharge, medication adherence and reconciliation and early follow-up in specialty clinics. 

Initiation of PCSK9 Inhibitors During ACS

The Evolocumab for Early Reduction of LDL-cholesterol Levels in Patients with Acute Coronary Syndromes (EVOPACS) trial found that initiating evolocumab in addition to high-intensity statin therapy during hospitalization for ACS resulted in more patients achieving LDL-C threshold under 70 mg/dL at eight weeks compared to statins alone (95.7% versus 37.6%; p < 0.001).⁴  Further, the High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS) found that evolocumab started four weeks after a non-ST segment elevatoin myocardial infarctian (NSTEMI) stabilized high-risk plaques in patients on maximally tolerated statin therapy by thickening the fibrous cap and reducing plaque volume.⁵ Plaque progression of the non-culprit epicardial arteries was tracked with serial optical coherence tomography and intravascular ultrasound. After 52 weeks, those on evolocumab had a larger increase in minimum fibrous cap thickness (FCT) (median, 21.2 µm; IQR, 4.7, 37.7; p = 0.015) compared to those on statin alone as the primary endpoint. The evolocumab arm also had a higher average minimum FTC and more reduction in total atheroma volume. The authors found a linear relationship between LDL-C lowering and increased minimum FCT when LDL-C was between 20 - 110 mg/dL. 

The Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction (PACMAN-AMI) trial found similar results on serial intravascular ultrasonography, near-infrared spectroscopy, and optical coherence tomography after 52 weeks.⁶ Compared to 20 mg rosuvastatin alone, alirocumab started within 24 hours in addition to rosuvastatin after urgent PCI for STEMI or NSTEMI resulted in greater percent atheroma volume regression (-1.21%; 95% CI, - 1.78 to -0.65; p < 0.001) in non-infarct-related arteries as the primary endpoint. The alirocumab arm also had a larger reduction in atheroma volume, lipid core burden index, greater plaque regression, and increase in minimal and mean FCT.

Conclusions and Future Directions

Aggressive lipid-lowering in high-risk patients is especially protective if started at the index hospitalization for ACS. It has been well established that starting a statin plus or minus ezetimibe in the acute phase is beneficial. More recent data from HUYGENS and PACMAN-AMI show that adding a PCSK9 inhibitor improves plaque characteristics.

Although excitement surrounds these findings, it is important to note that these studies found improvement in plaque characteristics without assessment of cardiovascular events.

While our work on improving systems to ensure all ACS patients appropriately receive a statin unless contraindicated continues, our next challenge may be overcoming the barriers to administering a PCSK9 inhibitor at ACS hospitalization. Future directions to help with this endeavor include research into the effect on event rates in this population as well as cost-effectiveness analyses. Further development of systems algorithms to alert providers when the addition of a PCSK9 inhibitor is warranted would likely identify more patients in need of additional lipid-lowering. This is especially true when targeting an LDL-C of 55 mg/dL. ACS hospitalization is a vulnerable time for patients physically and emotionally and may be the time during which PCSK9 inhibitor initiation has the greatest impact. 

Dr. Cheung has no financial relationships to disclose. Dr. Riddock has received honoraria from Amgen. Dr. Barseghian El-Farra has no financial relationships to disclose. Dr. Benes has no financial relationships to disclose.

References

1. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes: The MIRACL Study: A Randomized Controlled Trial. JAMA. 2001;285(13):1711–1718. doi:10.1001/jama.285.13.1711
2. Cannon CP, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.
3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397
4. Koskinas KC, Windecker S, Pedrazzini G, et al. Evolocumab for Early Reduction of LDL Cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS). J Am Coll Cardiol. Nov 19 2019;74(20):2452-2462. doi:10.1016/j.jacc.2019.08.010
5. Nicholls SJ, Kataoka Y, Nissen SE, et al. Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction. JACC Cardiovasc Imaging. Jul 2022;15(7):1308-1321. doi:10.1016/j.jcmg.2022.03.002
6. Raber L, Ueki Y, Otsuka T, et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. May 10 2022;327(18):1771-1781. doi:10.1001/jama.2022.5218