Studies of PSCK9 Inhibition and the Reduction of Vascular Events - SPIRE-1 and SPIRE-2
Contribution To Literature:
The SPIRE-1 and -2 trials failed to show a consistent and sustained reduction in LDL-C from bococizumab compared with placebo.
Description:
The goal of the trial was to evaluate the efficacy and safety of bococizumab, a PCSK9 inhibitor (humanized antibody, >90% human), among subjects at elevated risk or with established cardiovascular disease on statin therapy.
Study Design
- Randomized
- Parallel
- Double-blind
- Placebo
Patients with established or at high risk for cardiovascular disease on statin therapy were randomized to bococizumab 150 mg subcutaneous every 2 weeks (n = 13,720) versus placebo every 2 weeks (n = 13,718).
Inclusion criteria:
- Cardiovascular disease defined as prior myocardial infarction (MI), prior stroke, or symptomatic peripheral arterial disease (PAD) (secondary prevention cohort)
- High risk for cardiovascular disease defined as diabetes, chronic kidney disease, or asymptomatic PAD (primary prevention cohort)
- On statin therapy for the last 4 weeks with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl (SPIRE-1) or LDL-C ≥100 mg/dl (SPIRE-2)
- Total number of enrollees: 27,438 patients
- Duration of follow-up: median 12 months
- Mean patient age: 63 years
- Percentage female: 30%
- Percentage with diabetes: 48%
- Mean LDL-C: 109 mg/dl
Principal Findings:
Due to lipid-lowering data, the sponsor decided to prematurely stop the SPIRE-1 and SPIRE-2 outcome trials on November 2016.
The primary outcome, incidence of cardiovascular death, MI, stroke, or hospitalization for unstable angina requiring revascularization: HRSPIRE-1 0.99 (p = 0.94) and HRSPIRE-2 0.79 (p = 0.021) and HRSPIRE-1 and -2 0.88 (p = 0.08) for bococizumab versus placebo
Secondary outcomes: There was a marked initial reduction in LDL-C (55-60%) with bococizumab versus placebo; however, there was wide individual variability with benefit that diminished over the follow-up period. Any serious adverse event: 19.6% with bococizumab versus 19.7% with placebo.
Interpretation:
Among patients with elevated cardiovascular risk on statin therapy, bococizumab versus placebo reduced LDL-C; however, this benefit diminished over time due to development of antidrug antibodies. Adverse cardiovascular events were reduced with bococizumab versus placebo in the SPIRE-2 trial, but not in the SPIRE-1 trial. Serious adverse events were similar between treatment groups. Bococizumab is not ready for clinical use.
References:
Ridker PM, Revkin J, Amarenco P, et al., on behalf of the SPIRE Cardiovascular Outcome Investigators. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med 2017;376:1527-39.
Ridker PM, Tardif JC, Amarenco P, et al., on behalf of the SPIRE Investigators. Lipid-Reduction Variability and Antidrug-Antibody Formation With Bococizumab. N Engl J Med 2017;376:1517-26.
Presented by Dr. Paul M. Ridker at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 17, 2017.
Keywords: ACC17, ACC Annual Scientific Session, Angina, Unstable, Antibodies, Monoclonal, Humanized, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Maximum Tolerated Dose, Metabolic Syndrome, Myocardial Infarction, Peripheral Vascular Diseases, Primary Prevention, Renal Insufficiency, Chronic, Secondary Prevention, Stroke
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