PCSK9 INHIBITORS


















  • All values expressed as average percent change from baseline
  • PCSK9 inhibitor was added to statin therapy in all trials
  • References [2,3]
Effects of PCSK9 inhibitors on Lipid Parameters
Drug LDL Total Non-HDL Apo B
Alirocumab 150 mg every 2 weeks for 24 weeks -58% -36% -49% -50%
Evolocumab 140 mg every 2 weeks for 12 weeks -63% -36% -53% -49%
Evolocumab 420 mg once monthly for 12 weeks -59% -34% -50% -46%


Overview
  • The effects of PCSK9 inhibitors on CVD outcomes have been studied in two large randomized controlled trials
  • The ODYSSEY trial compared alirocumab to placebo in patients with recent acute coronary syndrome and the FOURIER trial compared evolocumab to placebo in patients with documented CVD. Both studies are detailed below.
ODYSSEY Trial - Alirocumab vs Placebo for Secondary Prevention of CVD, NEJM (2018) [PubMed abstract]
  • The ODYSSEY trial enrolled 18,924 patients with a recent history of acute coronary syndrome (myocardial infarction or unstable angina)
Main inclusion criteria
  • Acute coronary syndrome 1 to 12 months prior to randomization
  • LDL ≥ 70 mg/dl, non-HDL level ≥ 100 mg/dl, or Apo B level ≥ 80 mg/dl after ≥ 2 weeks of atorvastatin (40 - 80 mg) or rosuvastatin (20 - 40 mg)
Main exclusion criteria
  • Uncontrolled BP (>180/110)
  • NYHA class III or IV heart failure
  • Fasting triglycerides > 400 mg/dl
  • LFTs > 3 X ULN
Baseline characteristics
  • Average age 58 years
  • Diabetes - 29%
  • Average LDL - 92 mg/dl
  • Qualifying event: STEMI - 34% | NSTEMI - 48% | Unstable angina - 17%
Randomized treatment groups
  • Group 1 (9462 patients) - Alirocumab 75 mg SQ every 2 weeks
  • Group 2 (9462 patients) - Placebo injection every 2 weeks
  • All patients continued statins during the study
  • Among patients assigned to the alirocumab group, protocol-specified dose-adjustment algorithms were used to target an LDL cholesterol level of 25 to 50 mg/dl and to avoid sustained levels below 15 mg/dl
Primary outcome: Composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization
Results

Duration: Median of 2.8 years
Outcome Alirocumab Placebo Comparisons
Primary outcome 9.5% 11.1% HR 0.85, 95%CI [0.78 - 0.93], p<0.001
Overall mortality 3.5% 4.1% HR 0.85, 95%CI [0.73 - 0.98]
Nonfatal myocardial infarction 6.6% 7.6% HR 0.86, 95%CI [0.77 - 0.96]
Ischemic stroke 1.2% 1.6% HR 0.73, 95%CI [0.57 - 0.93]
Average LDL level at 1 year 48 mg/dl 96 mg/dl N/A
  • The incidence of adverse events and laboratory abnormalities was similar between the groups with the exception of injection site reactions (Group 1 - 3.8%, Group 2 - 2.1%)
  • Neutralizing antidrug antibodies were detected in 0.5% of alirocumab-treated patients

Findings: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo
FOURIER Trial - Evolocumab vs Placebo for Secondary Prevention of CVD, NEJM (2017) [PubMed abstract]
  • The FOURIER trial enrolled 27,564 patients with cardiovascular disease and an LDL ≥ 70 mg/dl
Main inclusion criteria
  • Age 40 - 85 years
  • History of myocardial infarction, nonhemorrhagic stroke, or symptomatic peripheral artery disease + one major risk factor for CVD (e.g. diabetes, smoker, age ≥ 65 years) or two minor risk factors (e.g. HDL < 40, CRP > 2.0, metabolic syndrome)
  • LDL ≥ 70 mg/dl or non-HDL cholesterol ≥ 100 mg/dl while taking a statin at least equivalent to atorvastatin 20 mg
Main exclusion criteria
  • Stroke or MI within 4 weeks
  • NYHA class III or IV heart failure or EF < 30%
  • SBP > 180, DBP > 110
  • GFR < 20 ml/min
  • AST/ALT > 3 X ULN
Baseline characteristics
  • Average age 63 years
  • Diabetic - 37%
  • Smoker - 28%
  • Taking moderate-to-high intensity statin - 99%
  • Median LDL - 92 mg/dl
  • Median HDL - 44 mg/dl
  • Qualifying event: MI - 81% | Stroke - 19% | PAD - 13%
Randomized treatment groups
  • Group 1 (13,784 patients) - Evolocumab 140 mg every 2 weeks or 420 mg every month
  • Group 2 (13,780 patients) - Placebo
  • Two week or once monthly dosing was based on patient preference
  • Statins were continued
Primary outcome: Major cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization
Results

Duration: Median of 2.2 years
Outcome Evolocumab Placebo Comparisons
Primary outcome 9.8% 11.3% HR 0.85, 95%CI [0.79 - 0.92], p<0.001
Overall mortality 3.2% 3.1% HR 1.04, 95%CI [0.91 - 1.19], p=0.54
Myocardial infarction 3.4% 4.6% HR 0.73, 95%CI [0.65 - 0.82], p<0.001
Stroke 1.5% 1.9% HR 0.79, 95%CI [0.66 - 0.95], p=0.01
Cardiovascular death 1.8% 1.7% HR 1.05, 95%CI [0.88 - 1.25], p=0.62
Coronary revascularization 5.5% 7.0% HR 0.78, 95%CI [0.71 - 0.86], p<0.001
Injection site reactions 2.1% 1.6% p<0.001
  • Besides injection site reactions, there was no significant difference between groups for other adverse outcomes
  • The average LDL in the evolocumab group was 56 mg/dl lower than the placebo group at week 48

Findings: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.
Professional recommendations



Injection site reactions
Alirocumab (Praluent®)
  • Injection site reactions including erythema, itching, swelling, and pain were reported more frequently in patients receiving alirocumab than placebo (7.2% vs 5.1%)
  • Injection site reactions rarely led to discontinuation (0.2%) [1]
Evolocumab (Repatha®)
  • Injection site reactions including erythema, pain, and bruising have occurred. In trials, 3.2% of evolocumab-treated patients reported reactions compared to 3% of placebo patients. [3]
  • Injection site reactions rarely led to discontinuation (0.1%) [3]

Elevated liver function tests (alirocumab)

Drug antibodies
Overview
  • Biologic proteins like PCSK9 inhibitors have the potential to stimulate the production of host antibodies against the medication
  • These antibodies may or may not affect the efficacy of the medication
Alirocumab (Praluent®)
  • In trials presented in the PI, 4.8% of patients treated with alirocumab produced anti-alirocumab antibodies. Patients with anti-alirocumab antibodies had a higher incidence of injection site reactions compared to patients without antibodies (10.2% vs 5.9%). Anti-alirocumab antibodies were associated with a loss of drug efficacy in 0.3% of patients [1]
  • In another study that pooled data from 10 trials (n=4747), anti-alirocumab antibodies were observed in 5.1% of alirocumab-treated patients and 1% of control patients. Persistent anti-alirocumab antibodies (defined as ≥ 2 consecutive positive samples over ≥ 12 weeks) were observed in 1.4% of alirocumab-treated patients. Anti-alirocumab antibodies had no significant effect on efficacy, but they did increase the risk of injection site reactions. [4]
Evolocumab (Repatha®)
  • In pooled trials, 0.1% of patients who received at least one dose of evolocumab developed anti-evolocumab antibodies
  • Anti-evolocumab antibodies were not associated with a loss of efficacy, but long-term effects are unknown [3]






Kidney disease
Alirocumab (Praluent®)
  • CrCl ≥ 30 ml/min - no dose adjustment necessary
  • CrCl < 30 ml/min - has not been studied
Evolocumab (Repatha®)
  • No dose adjustment necessary in renal impairment

Liver disease
Alirocumab (Praluent®)
  • Mild-moderate (Child-Pugh A and B) - no dose adjustment necessary
  • Severe (Child-Pugh C) - has not been studied
Evolocumab (Repatha®)
  • Mild-moderate (Child-Pugh A and B) - no dose adjustment necessary
  • Severe (Child-Pugh C) - has not been studied

Allergic reactions
Alirocumab (Praluent®)
  • Allergic reactions including hypersensitivity, nummular eczema, and hypersensitivity vasculitis have been reported in patients taking alirocumab [1]
Evolocumab (Repatha®)
  • Allergic reactions including angioedema, rash, eczema, erythema, and urticaria have been reported in patients receiving evolocumab
  • In trials, allergic reactions were reported in 5.1% of evolocumab-treated patients and 4.6% of placebo patients [3]