Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

Sandy Liu, Mercer University College of Pharmacy

A 2016 guideline from the American College of Cardiology stated that the inability to achieve a 30%-50% low-density lipoprotein cholesterol (LDL-C) reduction with statins and/or dietary interventions may necessitate the initiation of the following medications: ezetimibe, bile acid sequestrants and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.  [1]

Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 by binding to low-density lipoprotein receptors on hepatocyte surfaces to promote LDL-receptor degradation within the liver, thereby lowering LDL-C levels. [2]

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease [3]
Design Multinational, randomized, double-blind, placebo-controlled; N= 27,564
Objective To determine if the addition of evolocumab with statin therapy reduces major cardiovascular (CV) events compared to placebo
Study Groups Evolocumab (n= 13,784); placebo (n= 13,780)
Methods Patients with established cardiovascular disease (CVD) on statin therapy were assigned to receive subcutaneous injections of evolocumab (either 140 mg every 2 weeks or 420 mg every month, according to patient preference) or matching placebo.  Stratification was done according to the final screening LDL cholesterol level (
Although the median follow-up period was planned to be 4 years, an event rate approximately 50% higher than had been postulated led to a ultimate duration of follow-up of 2.2 years. Major CV events included CV death, MI, stroke, hospitalization for unstable angina or coronary revascularization.
Duration February 2013 to June 2015
Primary Outcome Measure Major CV events
Baseline Characteristics
Evolocumab Placebo
Mean age, years ± SD 62.5 ± 9.1 62.5 ± 8.9
Male, n (%) 10,397 (75.4) 10,398 (75.5)
Caucasian, n (%) 11,748 (85.2) 11,710 (85.0)
Weight, kg ± SD 85.0 ± 17.3 85.5 ± 17.4
Type of atherosclerosis, n (%):
      MI 11,145 (80.9) 11,206 (81.3)
  Nonhemorrhagic stroke 2,686 (19.5) 2,651 (19.2)
  Peripheral artery disease 1,858 (13.5) 1,784 (12.9)
Cardiovascular risk factors, n (%)
       Hypertension 11,045 (80.1) 11,038 (80.1)
       Diabetes mellitus 5,054 (36.7) 5,027 (36.5)
       Cigarette use 3,854 (28.0) 3,923 (28.5)
Statin use, n (%)
     High intensity statin 9,585 (69.5) 9,518 (69.1)
     Moderate intensity statin 4,161 (30.2) 4,231 (30.7)
Low/unknown intensity statin 38 (0.3) 31 (0.2)
Ezetimibe, n (%) 726 (5.3) 714 (5.2)
Median lipid measures, mg/dL (IQR):
     Total 168 (151-188) 168 (151-189)
     LDL 92 (80-109) 92 (80-109)
     HDL 44 (37-53) 44 (37-53)
     Triglycerides 134 (101-183) 133 (99-181)
Results
Evolocumab, n (%) Placebo, n (%) HR

(95% CI)

p-value
Composite CV event 1344 (9.8) 1563 (11.3) 0.85 (0.79-0.92) p< 0.001
Cardiovascular death, MI, stroke 816 (5.9) 1013 (7.4) 0.80

(0.73-0.88)

p< 0.001
Cardiovascular death 251 (1.8) 240 (1.7) 1.05

(0.88-1.25)

p= 0.62
All-cause death 444 (3.2) 426 (3.1) 1.04

(0.91-1.19)

p= 0.54
MI 468 (3.4) 639 (4.6) 0.73

(0.65-0.82)

p< 0.001
Hospitalization for unstable angina 236 (1.7) 239 (1.7) 0.99

(0.82-1.18)

p= 0.89
Stroke 207 (1.5) 262 (1.9) 0.79

(0.66-0.95)

p= 0.01
Coronary revascularization 759 (5.5) 965 (7.0) 0.78 (0.71-0.86) p< 0.001
Adverse Events Common Adverse Events (evolocumab vs placebo): Injection site reaction (2.1% vs 1.6%), allergic reaction (3.1% vs 2.9%), muscle-related event (5.0% vs 4.8%), new onset diabetes (8.1% vs 7.7%)
Serious Adverse Events (evolocumab vs placebo): Rhabdomyolysis (0.1% in both groups), cataract (1.7% vs 1.8%)
Percentage that Discontinued due to Adverse Events: evolocumab (1.6%); placebo (1.5%)
Study Author Conclusions Evolocumab lowered LDL cholesterol levels to a median of 30 mg per deciliter and reduced the risk of CV events.

Due to the high cost of PCSK9 inhibitors, insurance companies continue to restrict patient access.  This trial’s follow-up was 2.2 years, compared to the typical 5-year follow ups in previous lipid-lowering studies, as a result of the consistent benefit seen with evolocumab, regardless of statin therapy or ezetimibe use.  However, long-term safety data may have been missed for evolocumab.  While lower LDL levels are associated with decreased CV events, outcomes of drastically low LDL continue to remain unknown and may result in deleterious effects.  

References

[1] Lloyd-jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68(1):92-125.

[2] Evolocumab. Martindale The Complete Drug Reference. Micromedex 2.0 [database online]. Greenwood Village, CO; Truven Health Analytics; 2013.  Accessed March 19, 2017.

[3] Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017.

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