ODYSSEY LONG TERM

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Robinson JG, et al. "Efficacy and safety of alirocumab in reducing lipids and cardiovascular events". The New England Journal of Medicine. 2015. 372(16):1489-1499.
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Clinical Question

Among patients at high risk for cardiovascular events, does the addition of the PCSK-9 inhibitor alirocumab to high-intensity statin therapy reduce LDL cholesterol levels versus placebo?

Bottom Line

In patients at high risk for cardiovascular events by virtue of a confirmed diagnosis of heterozygous familial hypercholesterolemia, established coronary disease, or a coronary disease equivalent followed for 1.5 years, the use of the monoclonal antibody alirocumab in addition to high-intensity statin therapy resulted in an additional 62% reduction in LDL cholesterol with no significant increase in serious adverse events. Furthermore, a post-hoc analysis demonstrated a 2% absolute risk reduction in major adverse cardiovascular events with alirocumab therapy.

Major Points

Multiple studies including the landmark 4S trial have established statins as standard of care in both primary and secondary prevention of cardiovascular events among high-risk patients. Although statins may work via multiple mechanisms, slowing endogenous cholesterol production through inhibition HMG-CoA reductase with resultant LDL lowering is thought to be the primary means by which statin therapy improves cardiovascular outcomes. The recent IMPROVE-IT trial demonstrated that additional LDL reduction with ezetimibe added to statin therapy results in incremental improvement in cardiovascular outcomes, suggesting that further reduction of LDL cholesterol levels may optimize cardiovascular risk.

PCSK-9 (proprotein convertase subtilisin/kexin type 9) is a novel target for lipid-lowering therapy. PCSK-9 is an enzyme whose activity results in internalization and destruction of LDL receptors. Thus, reduction of PCSK-9 activity may lead to increased LDL receptor expression and subsequent reduction in circulating LDL levels. Inhibition of PCSK-9 with the use of monoclonal antibodies has been demonstrated to reduce LDL cholesterol levels by 40-70% when added to background statin therapy in small subsets of patients in phase II studies followed over the short term[1][2]. However, their role in larger populations of patients at high risk for cardiovascular events has not been established.

The 2015 Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) was the first phase III trial investigating the use of the PCSK-9 inhibitor alirocumab. ODYSSEY LONG TERM demonstrated that in 2341 patients at high risk for cardiovascular events by virtue of a confirmed diagnosis of heterozygous familial hypercholesterolemia (HeFH), established coronary disease, or a coronary disease equivalent followed for 1.5 years, the use of the monoclonal antibody alirocumab in addition to statin therapy (high-intensity in 50%) resulted in an additional 62% reduction in LDL cholesterol with no significant increase in adverse events. Furthermore, a post-hoc analysis demonstrated a 2% absolute risk reduction in major adverse cardiovascular events. Notably, the OSLER study[3] demonstrated very similar results with an alternative PCSK-9 inhibitor, evolocumab. In light of the results of ODYSSEY LONG TERM, alirocumab received FDA approval as an adjunct to maximal statin therapy and lifestyle modification in patients with HeFH or patients with clinical atherosclerotic disease who require additional lowering of LDL cholesterol.[4] Despite ODYSSEY LONG TERM's encouraging results, it is important to note that the trial was not designed to assess cardiovascular outcomes prospectively, and so these results should be interpreted with caution. ODYSSEY OUTCOMES is an ongoing trial designed specifically to investigate the effects of alirocumab on cardiovascular endpoints over long-term follow up.

Guidelines

Focused Update of the 2016 ACC Non-Statin Guidelines[5]

  • If a decision is made to proceed with the addition of non-statin therapy to maximally tolerated statin therapy in patients with clinical CV disease with comorbidities and baseline LDL 70–189 mg/dL, it is reasonable to consider the addition of either ezetimibe or a PCSK9 inhibitor based on considerations of the additional percent LDL reduction desired, patient preferences, costs, route of administration, and other factors. Clinicians should preferentially prescribe drugs that have been shown in RCTs to provide CV risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions, and consider patient preferences.
  • Considerations that may favor the initial choice of ezetimibe include: patients who require <25% additional lowering of LDL, patients with recent ACS <3 months, cost considerations with recent availability of generic ezetimibe and future cost savings, ease of use as oral agent with low pill burden, patient preferences, heart failure, hypertension, age >75 years, diabetes, stroke, CABG, PVD, eGFR <60, and smoking.
  • If patients with clinical CV disease and comorbidities require >25% additional lowering of LDL, a PCSK9 inhibitor may be preferred as the initial non-statin agent. The clinician–patient discussion should consider the extent of available scientific evidence for net CV risk-reduction benefit, cost, administration by subcutaneous injection, every 14-day or monthly dosing schedule, and storage requirements (refrigeration).
  • The following factors that may be considered for the identification of higher-risk patients with clinical CV disease: age ≥65 years, prior MI or non-hemorrhagic stroke, current daily cigarette smoking, symptomatic PVD with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with ≥40% stenosis in ≥2 large vessels, HDL <40 mg/dL for men and <50 mg/dL for women, hs-CRP >2 mg/L, or metabolic syndrome.

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=2,310
    • Alirocumab (n=1,530)
    • Placebo (n=780)
  • Setting: 320 sites in 27 countries
  • Mean follow-up: 1.5 years
  • Analysis: Intention-to-treat
  • Primary outcome: Percent change in LDL cholesterol from baseline to week 24

Population

Inclusion Criteria

  • Age ≥18 years
  • High risk for cardiovascular events, defined by ≥1 of the following:
    • HeFH (confirmed by genotyping or clinical criteria)
    • CHD
    • Coronary heart disease risk equivalent (PAD, ischemic stroke, moderate CKD, DM plus ≥2 CHD risk factors outlined in the supplemental appendix[6])
  • LDL cholesterol ≥70 mg/dL
  • On high-dose statin therapy or maximum tolerated statin dose for at ≥4 weeks

Exclusion Criteria

  • LDL <70 mg/dL or TG >400 mg/dL
  • Recent or future plasmapheresis plans
  • ACS, stroke, or PVD intervention in prior 3 months
  • Planned coronary or PVD intervention
  • NYHA class III or IV
  • BP >180/110
  • Prior hemorrhagic stroke
  • Optic nerve disease
  • Homozygous familial hypercholesterolemia
  • Known PCSK9 loss of function
  • Systemic corticosteroids except for adrenal insufficiency
  • eGFR <30 mL/min/1.73m2
  • HgbA1c >10%
  • ALT, AST, CPK >3x ULN

Baseline Characteristics

From the placebo group.

  • Demographics: Age 61 years, 60% male, 93% White
  • Cardiovascular History: BMI 31 kg/m2</sup, HeFH 18%, CHD 70%, CHD equivalent 41%, T2DM 34%, smoker 20%
  • Lipid Therapy: Statin 99.9%, high-intensity statin 47%, other lipid-lowering drug 28% (ezetimibe 15%)
  • Lipid Levels (mg/dL): LDL 122, non-HDL 152, apolipoprotein B 101, lipoprotein a 21, fasting triglycerides 135, HDL 50, apolipoprotein A1 147

Interventions

  • Patients were randomized in a 2:1 ratio to alirocumab 150mg subq q2weeks or placebo
  • Baseline cholesterol-lowering therapy was continued without modification
  • All patients instructed to follow a stable Therapeutic Lifestyle Changes diet

Outcomes

Comparisons are alirocumab vs. placebo

Primary Outcome

Change in LDL cholesterol from baseline to week 24
-74.2 mg/dL vs. -3.6 mg/dL (least squares mean difference -61.9%; 95% CI -64.3 to -59.4; P<0.001)

Secondary Outcomes

LDL <70 mg/dL
79.3% vs. 8.0% (P<0.001)
LDL change from baseline to week 78
-52.4 mg/dL vs. 3.6 mg/dL (least squares mean difference -56.0; 95% CI -59.1 to -52.8; P<0.001)
HDL change from baseline to week 24
4.0 mg/dL vs. -0.6 mg/dL (least square mean difference 4.6; 95% CI 3.3 to 5.9; P<0.001)

Additional Analyses

Post-hoc adjudicated major adverse CV events
1.7% vs. 3.3% (P=0.02)
CHD mortality or unknown cause of death
0.3% vs. 0.9% (P=0.26)
Nonfatal MI
0.9% vs. 2.3% (P=0.01)

Subgroup Analysis

For the primary outcome.

HeFH status
HeFH: -63.2 vs. 7.0
Non-HeFH: -62.1 vs. 1.1
Interaction P=0.60
LDL cholesterol levels at baseline
<100 mg/dL: -61.3% vs. 13.6%
≥160 mg/dL: -59.5% vs. -18.2%
Interaction P<0.0001

Adverse Events

Comparisons are alirocumab vs. placebo

Any adverse event
81.0% vs. 82.5% (P=0.40)
Serious: 18.7% vs. 19.5% (P=0.66)
Leading to study-drug discontinuation: 7.2% vs. 5.8% (P=0.26)
Leading to death: 0.5% vs. 1.3% (P=0.08)
Injection site reaction: 5.9% vs. 4.2% (P=0.10)
Myalgia: 5.4% vs. 2.9% (P=0.006)
Neurocognitive Disorder: 1.2% vs. 0.5% (P=0.17)

Criticisms

  • Study was not designed to investigate the effects of alirocumab therapy on cardiovascular outcomes and lacks optimal power and duration of follow up for doing so
  • Some CV outcome results are post-hoc and subject to bias. The protective effect of alirocumab on major adverse cardiovascular events becomes non-significant when all adjudicated cardiovascular events are included (i.e., with addition of congestive heart failure requiring hospitalization and ischemia-driven coronary revascularization)
  • Lack of formal neurocognitive assessments prevents better characterization of this possible side effect of alirocumab therapy

Funding

  • Study funded by Sanofi and Regeneron Pharmaceuticals, the makers of Praluent (the brand name of alirocumab)
  • Sponsors designed the trial protocol and were involved in data collection, management, and analysis
  • Authors with multiple disclosures

Further Reading

  1. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367(20): 1891-900
  2. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy J Am Coll Cardiol 2012;59(25):2344-53
  3. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events New Engl J Med 2015;372:1500-9
  4. FDA News release. "FDA approves Praluent to treat certain patients with high cholesterol." FDA.gov. Published 2015-07-24. Accessed 2015-09-30.
  5. Lloyd-Jones DM et al. 2017 Focused Update of the 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 Expert Consensus Decision Pathways. J. Am. Coll. Cardiol. 2017. 70:1785-1822.
  6. ODYSSEY LONG TERM Supplemental Appendix.