By Michael H. Crawford, MD

Professor of Medicine, Associate Chief for Education, Division of Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: Compared to adding placebo, using the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in post-acute coronary syndrome patients on maximally tolerated, high-intensity statins with low-density lipoprotein (LDL) cholesterol levels higher than 70 mg/dL lowered LDL and reduced the number of major adverse cardiac events.

SOURCES: Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-2107.

Burnett JR, Hooper AJ. PCSK9 – A journey to cardiovascular outcomes. N Engl J Med 2018;379:2161-2162.

The authors of a study in which statins were administered with or without ezetimibe observed improved outcomes in post-acute coronary syndrome (ACS) patients compared to those receiving placebo. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of low-density lipoprotein (LDL) receptors on the liver, resulting in high serum levels of LDL cholesterol (LDL-C).

Monoclonal human antibodies to PCSK9 have been shown to reduce the risk of cardiovascular events in stable coronary artery disease or high cardiovascular risk patients in whom LDL-C remained higher than 100 mg/dL despite maximum tolerated, high-intensity statin therapy. PCSK9 inhibitors have not been tested in ACS patients.

A group of researchers conceived the ODYSSEY OUTCOMES trial. It was a multicenter, randomized, double-blind, placebo-controlled trial of adults with ACS in the one to 12 months before trial entry who had an LDL-C of higher than 70 mg/dL on at least two weeks of high-intensity statin therapy at the maximum tolerated doses. The PCSK9 inhibitor alirocumab (either 75 mg or placebo) was injected subcutaneously every two weeks. Alirocumab doses were adjusted to achieve an LDL-C of 25-50 mg/dL but not lower than 15 mg/dL. The primary endpoint was a combination of coronary death, myocardial infarction (MI), stroke, or unstable angina requiring hospitalization.

Investigators randomized 18,924 patients from 1,315 sites in 57 countries. MI was the qualifying ACS event in 83%. Ninety-two percent of patients had an LDL-C higher than 70 mg/dL, and most underwent revascularization during the qualifying event. Patients were followed for a median of 2.8 years. About 15% of patients in both groups dropped out of the study for a variety of reasons other than death.

LDL-C decreased from an average reading of 92 mg/dL to 40 mg/dL at four months, to 48 mg/dL at 12 months, and to 66 mg/dL at 48 months. For those patients on placebo, average LDL-C levels were 93 mg/dL at four months, 96 mg/dL at 12 months, and 103 mg/dL at 48 months. The primary endpoint occurred in 9.5% of the treatment group and 11.1% of the placebo group (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.78-0.93; P < 0.001). Death occurred in 3.5% of the treatment group and 4.1% of the placebo group (HR, 0.85; 95% CI, 0.73-0.98). The benefits of treatment were greater in patients who had LDL-C levels higher than 100 mg/dL.

The adverse event rates were similar in the two groups, except for injection site reactions, which happened in 3.8% of patients in the treatment group and in 2.1% of patients in the placebo group. The authors concluded that among recent ACS patients on high-intensity statins with or without ezetimibe therapy and LDL-C levels > 70 mg/dL, therapy with alirocumab was associated with lower LDL-C levels and fewer adverse cardiovascular events compared to patients on placebo.

COMMENTARY

In high-risk patients, such as the ACS patients in this study, we are abandoning the pooled risk equation and looking at LDL-C targets again. This makes sense given the old axiom was that in post-ACS patients, their LDL-C levels were too high, regardless of the measurement. However, clinicians did not really know how low those levels should go. As more studies were conducted over the last decade, the post-ACS LDL-C target decreased from lower than 130 mg/dL to lower than 100 mg/dL to lower than 70 mg/dL to lower than 50 mg/dL. These extremely low levels of LDL-C became possible for many patients after the PCSK9 inhibitors were synthesized.

Now, the issue is how low is too low. Most ACS patients on a PCSK9 inhibitor in the Schwartz et al study showed LDL-C levels lower than 50 mg/dL but higher than 25 mg/dL. Eight percent had levels lower than 15 mg/dL; for these patients, investigators ended PCSK9 drug administration. On the other hand, for 28% of patients assigned to alirocumab, researchers had to double the dose to 150 mg to reduce their LDL-C levels to lower than 50 mg/dL. It is comforting that in this trial, the incidence of adverse events was similar between the two groups (except for injection site reactions). These reactions were itching, redness, and swelling, which caused 26 patients to drop out of the trial.

The strengths of this trial included a sufficiently large group of patients in each group and an appropriate follow-up period to assess outcomes robustly. The primary composite endpoint was statistically significant, but none of the secondary endpoints, including the individual components of the primary endpoints, were. The number needed to treat was 49 for four years to prevent one primary event; the number was 16 for patients with LDL-C levels higher than 100 mg/dL.

Despite these underwhelming results, this study will change clinical practice for ACS patients. However, due to the current relatively high cost of PCSK9 inhibitors and the need to inject them, only the highest-risk patients will be targeted, such as those with LDL-C levels higher than 100 mg/dL, after maximum tolerated, high-intensity statins and ezetimibe have been prescribed. The big question going forward: How low does one lower LDL-C for primary prevention? Yes, we are going back to LDL-C levels.