OSLER

Incomplete

Sabatine MS, et al. "Efficacy and safety of evolocumab in reducing lipids and cardiovascular events". The New England Journal of Medicine. 2015. 372(16):1500-1509.
PubMed

Clinical Question

Is evolocumab safe and effective to decrease LDL and cardiovascular events in patients who were enrolled in phase 2 and phase 3 trials of evolocumab (familial heterozygous hypercholesterolemia, intolerant to statins, high LDL-C) in the long-term?

Bottom Line

Evolocumab is effective in decreasing LDL-C on top of standard therapies and decreases cardiovascular events in an exploratory analysis.

Larger trials with cardiovascular events as primary outcome is needed to confirm the benefit on cardiovascular events.

Major Points

Phase 2 and phase 3 trials of evolocumab have suggested an decrease in LDL-C with evolocumab.

The OSLER trials confirm this decrease in LDL-C and shows that evolocumab has an adequate safety profile. The exploratory analysis also shows that evolocumab decreases cardiovascular events with a NNT of 90 during 1 year(death, non fatal MI, unstable angina requiring hospitalization, coronary revascularization, ischemic stroke, TIA, and heart failure requiring hospitalization).

However, neurocognitive events were also non-statistically increased in the evolocumab group.

Guidelines

ACC/AHA Expert Consensus Panel on Non-Statin Therapies for LDL Lowering in the Management of ASCVD Risk (2016)

Alirocumab and evolocumab may be considered if the goals of therapy have not been achieved on maximally tolerated statin and ezetimibe in higher-risk patients with clinical ASCVD or familial hypercholesterolemia. Given the lack of long-term safety and efficacy data on these agents, they are not recommended for use in primary prevention patients in the absence of familial hypercholesterolemia

Design

• Multicenter, open-label, parallel-group, randomized, controlled trial
• N=4,465
  • Evolocumab + standard (n=2,976)
  • Standard (n=1,489)
• Median follow-up: 11.1 months
• Primary outcome: adverse events

Population

Inclusion Criteria

• Completed parent study
• No adverse event leading to discontinuation of study drug
• No unstable medical condition
• Not expected to need unblinded lipid measurements or adjustment of background lipid-regulating therapy during the first 12 weeks of participation

Baseline Characteristics

• Mean Age: 58 years
• Male: 50%
• White race: 86%
• At least 1 cardiovascular risk factor: 80.4% (52% HTN, 13% DM, 15% smokers)
• Receiving statin at start of trial: 70.1% (27% high-intensity, 35% moderate-intensity)
• Median LDL: 121 mg/dL
• Median total cholesterol: 203 mg/dL

Interventions

• Evolocumab 420 mg subcutaneously once monthly (OSLER-1)
• Evolocumab 420 mg subcutaneously once monthly OR 140 mg every 2 weeks based on patient preference (OSLER-2)
• All patients received standard-of-care background therapy based on local guidelines for treatment of LDL cholesterol

Outcomes

Primary Outcomes

• Adverse events
• Serious adverse events
• Adverse events leading to drug discontinuation
• Abnormalities in CK levels and LFTs
• Development of binding and neutralizing antibodies against evolocumab

Secondary Outcome

• Percent change in LDL level

Exploratory Outcome

• Cardiovascular events (MI, UA requiring hospitalization, revascularization, stroke, TIA, heart failure requiring hospitalization)

Funding

Industry funded