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Two trials with heart
October 2017
by Mel J. Yeates  |  Email the author
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  Amgen

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THOUSAND OAKS, Calif.—At the end of August, Amgen announced new analyses from the Repatha (evolocumab) cardiovascular outcomes study FOURIER, as well as the GLACOV study. Data from both studies were presented in Late-Breaking Clinical Trials sessions at the European Society of Cardiology Congress 2017.
 
The FOURIER study showed a statistically significant relationship between lower achieved low-density lipoprotein cholesterol (LDL-C) levels and lower cardiovascular event rates in patients with established atherosclerotic cardiovascular disease. There was no evidence of a leveling off of effect, and no new safety concerns were identified in this analysis. The results were simultaneously published in The Lancet.
 
“With this analysis, we’ve further demonstrated the safety and efficacy of achieving an LDL-C well below current targets,” said Dr. Robert P. Giugliano of Brigham and Women’s Hospital and Harvard Medical School, lead author on the analysis. “These findings from the first analysis of a large cohort of patients to achieve such ultra-low LDL-C levels support the use of intensive lipid-lowering therapies, such as the combination of evolocumab and statin therapy, in high-risk patients to safely reduce the risk of another cardiovascular event.”
 
Approximately 26,000 patients from the Repatha cardiovascular outcomes study were followed for a median of 2.2 years and stratified post-randomization into five prespecified groups irrespective of treatment allocation based on achieved LDL-C at week four from baseline. Rates for the primary and secondary composite endpoints and cognitive function testing, as well as safety events, including cancer, hemorrhagic stroke, new onset diabetes, cataract, neurocognitive dysfunction and non-cardiovascular death were compared across these five groups.
 
The analysis demonstrated a highly significant progressive relationship between lower LDL-C and a lower risk of the primary composite endpoint. A similar progressive reduction in the key secondary composite endpoint, which included heart attack, stroke or cardiovascular death, was observed across all five groups. There was no meaningful difference in the safety profile across the five groups, including the group with the lowest achieved LDL-C level. Patients were more likely to achieve very low LDL-C levels when treated with Repatha and statin therapy versus statin alone.
 
“Scientific evidence demonstrating the strong progressive association between lowering LDL-C and the risk reduction of cardiovascular events in patients with established atherosclerotic cardiovascular disease continues to grow,” commented Dr. Sean E. Harper, executive vice president of research and development at Amgen. “For patients who have already experienced an event, such as a heart attack or stroke, this analysis reinforces that the intensive LDL-C lowering provided with Repatha helps patients reduce their risk of another cardiovascular event.”
 
The risk of the primary composite efficacy endpoint, which included cardiovascular death, heart attack, stroke, coronary revascularization or hospitalization for unstable angina, was progressively lower as the achieved LDL-C at week 4 was reduced. No new safety concerns were identified in this large clinical trial with roughly 60,000 patient-years of follow-up.
 
The primary analysis included 27,564 patients with established cardiovascular disease. The study was statistically powered around the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death (key secondary composite endpoint), and found that adding Repatha to optimized statin therapy resulted in a statistically significant 20-percent reduction in these events. The study also found a 15-percent reduction in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death.
 
Amgen also announced new analysis which showed that lowering LDL-C levels with Repatha reduced the risk of cardiovascular events in a sub-group of FOURIER patients with a history of stroke. No new safety concerns were identified in this cohort of more than 5,000 patients.
 
“The clinical benefits of PCSK9 inhibition in stroke patients have not been previously reported. The reduction in cardiovascular event risk in this analysis is similar to what we saw in the broader 27,564-patient FOURIER study, supporting Repatha’s role in reducing the risk of future cardiovascular events for patients with a history of stroke,” said Terje Pedersen, professor emeritus in the Department of Endocrinology, Morbid Obesity and Preventive Medicine at the University of Oslo Institute of Clinical Medicine.
 
“The cardiovascular outcomes study FOURIER unequivocally showed that lowering LDL-C with Repatha results in a powerful risk reduction for patients at high risk of a cardiovascular event,” Harper remarked. “The fact that we were able to detect a meaningful reduction in the risk of cardiovascular events in the much smaller sub-group of stroke patients is remarkable and demonstrates the importance of the intensive LDL-C lowering Repatha provides for patients with established atherosclerotic cardiovascular disease.”
 
In addition, Amgen announced results from an exploratory virtual histology sub-study of the Repatha GLAGOV Phase 3 coronary intravascular ultrasound imaging trial, which looked at coronary artery plaque composition. While virtual histology demonstrated an increase in dense calcium in coronary artery plaques in both the statin and Repatha arms, it did not detect a statistically significant difference between the two treatment groups. However, the observed directional trend in increased dense calcium with corresponding reduction in LDL-C is consistent with findings from previous statin studies. The sub-study also showed reductions in LDL-C and percent atheroma volume consistent with the primary GLAGOV results.
 
“The community has long understood that changes to the individual components of plaque, including an increase in dense calcium, could favorably impact future cardiovascular events, yet we’ve had limited visibility to how treatment choices may change plaque composition,” said Dr. Stephen J. Nicholls, professor of cardiology and deputy director of the South Australian Health & Medical Research Institute. “As we expected, evolocumab dramatically lowered LDL-C and regressed plaques as assessed by proven measures. We also saw directional changes in plaque composition that we have seen in prior statin studies. However, the inability of virtual histology to demonstrate an incremental effect with evolocumab suggests that we need to find alternative ways to look at the effects of LDL-C reduction on plaque components.”
 
This sub-study included 331 patients enrolled in the GLAGOV trial, and explored whether Repatha produced changes in individual plaque components (dense calcium, fibrous, fibrofatty, necrotic core) compared to placebo using virtual histology.
 
“Plaque instability has been linked to rupture and subsequent blood clots associated with atherosclerotic cardiovascular disease and cardiovascular events such as stroke and heart attack,” said Harper. “The directional data in this Repatha sub-study supports the hypothesis that lowering LDL-C may play a role in changing the composition of the coronary artery plaque.”
 
Code: E101716

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