Conference Update

Evolocumab + Statins: Additional reduction of CV event shown in the FOURIER trial

Cardiology
10 months ago, OP Editor

Statins have long been the predominant choice for hyperlipidemia patients due to the well-substantiated clinical efficacy in low density lipoprotein – cholesterol (LDL-C) reduction and cardiovascular risk reduction. The recently published trial – FOURIER – demonstrated that adding evolocumab (Repatha, Amgen), a PCSK9 inhibitor, to statin significantly reduced cardiovascular morbidity and mortality by 15% when compared to statin alone, in patients with atherosclerotic cardiovascular disease.1

The lead investigator of the study, Dr. Marc Sabatine, MD, Brigham and Women’s Hospital, Boston, presented the impactful results at the American College of Cardiology (ACC) 2017 Scientific Sessions. The results were also simultaneously published in the New England Journal of Medicine online.

“With this trial, we now have definitive data that by adding evolocumab to a background of statin therapy, we can significantly improve cardiovascular outcomes and do so safely,” said Dr. Sabatine. “I think these results are very good news for patients with atherosclerotic disease, who remain at high risk for these events.”2

Large scale randomized trial showcasing the efficacy and safety of evolocumab adjunct to statin

27,564 patients (mean age: 63) with clinically evident atherosclerotic cardiovascular disease* and LDL-C level ≥ 1.8 mmol/L, despite using optimized statin regimen, were recruited and randomly assigned to receive evolocumab (n=13,784) 140 mg Q2W or 420 mg QM, or matching subcutaneous placebo (n=13,780).1

After a follow-up of median 2.2 years, both the primary endpoint – a composite of cardiovascular death, myocardial infarction (MI), stroke and hospitalization for unstable angina or coronary revascularization; and the key secondary endpoint – a composite of cardiovascular death, MI or stroke, as well as the safety profile, were measured.1

Promising efficacy and safety data for evolocumab

The adjunct evolocumab led to a remarkable 15% and 20% reduction in the primary and the key secondary efficacy endpoints (p<0.001 for both endpoints) in different cardiovascular risk categories respectively, when compared with placebo after 3 years (Figure 1).1

 

issue4_CU-chart-1

The risk reductions in various types of cardiovascular outcomes after 3 years are briefly summarized in table 1. Evolocumab generally performed well across different cardiovascular outcomes and led to better outcomes in primary and key secondary endpoints, regardless of baseline LDL-C levels, initial lipid medications and dosing regimens.1

 

issue4_CU-table-1

The LDL-C reduction was consistent throughout the study period that patients with adjunct evolocumab achieved an average of 59% LDL-C reduction to a median of 0.78 mmol/L. “They really pushed it, with (LDL-C) levels that almost approached those of new borns,” Dr. Richard Chazal, the president of ACC, emphasized. “These were really, really low levels.”3

Potential influence on the clinical practice

Numerous physicians were optimistic of the results presented, comprising Dr. Steve Nissen, MD from the Cleveland Clinic, Ohio State. “Like a lot of people who do clinical trials, I think the hard endpoints of cardiovascular death and stroke and MI are the more important, even though they were listed as secondary. What we care about are the irrevocable events,” Dr. Nissen said, adding that he was impressed with the 20% reduction in the composite key secondary outcome. It was also noted that FOURIER was a relatively short-term trial, “so this event reduction was seen relatively quickly, which I think is important.”3

Despite the short period of trial, the diverging trend of both the primary and the key secondary endpoints shown in the Kaplan-Meier curve was highlighted by Dr. Valentin Fuster, the editor-in-chief of the Journal of the American College of Cardiology. “I’m most impressed with the curves that were diverging over time. It seems to me that the future is brighter than the present.”3 Dr. Fuster theorized that the 2% absolute benefit might grow to 4% by 4 years and by that time there might also be a measurable mortality benefit.4

However, physicians were also cautious in some of the results shown, including lack of benefit for the cardiovascular death with the use of evolocumab. Professor David Siu, clinical professor of the University of Hong Kong and the investigator of FOURIER in Hong Kong, suggested a possible rationale. It was pointed out that the cardiovascular death in FOURIER comprised causes such as heart failure or venous thromboembolism, on which evolocumab should, in terms of the mechanism of action, have no impact. Reducing the lipid level and the subsequent atherosclerosis, evolocumab is deemed to help arteriosclerosis-related morbidities instead, and such claim was demonstrated with the aforesaid FOURIER results.

Also, Dr. Steven Ellis, an interventional cardiologist from the Cleveland Clinic, pinpointed the small absolute difference of the cardiovascular event reduction. Dr. Ellis questioned whether a 1.5%-2.0% absolute risk reduction would be sufficient to support the expansion of use of evolocumab in hyperlipidemia patients.4

Revolution of lipid guidelines?

Meanwhile, FOURIER also consolidated the correlation between cardiovascular outcomes and absolute LDL-C reduction, which is different from the current ACC/AHA lipid guidelines. Dr. Chazal believed that this trial substantiates the correlation between LDL-reduction and cardiovascular outcome. “We also saw benefit with incremental LDL reduction, all the way down into the 20s and 30s. And frankly, that blows up the ACC/AHA prevention guidelines. In 2013, the guidelines were based on dosing of therapeutics and not based so much on level of LDL. But there’s a lot of new science, including this trial, that’s been published since then. And there are deliberations going on right now about updates,” commented Dr. Chazal.3

Such view was echoed in the European Atherosclerosis Society (EAS) 2017 Annual Congress in April. “There is a dose-dependent, log-linear association between absolute LDL cholesterol and cardiovascular risk, and this association is independent of other cardiovascular risk factors and is consistent across the multiple lines of evidence,” mentioned Professor John Chapman, EAS consensus panel cochair from the Pitié-Salpétrière University Hospital in Paris, during a late-breaking session of EAS 2017 Annual Congress.5

The consensus document published in the European Heart Journal is based on >200 prospective epidemiologic, genetic, Mendelian randomization studies and randomized clinical trials, which comprises >2 million participants and >20 million person-years of follow-up.6

Professor Chapman perceived an evaluation of the totality of evidence was necessary to determine if LDL cholesterol is simply a biomarker. “You might say ‘why do we need a consensus panel on this topic? Do we not know enough already about HDL and LDL cholesterol?’ Well, the answer is no, we don’t. And even the regulatory bodies across the world are continuing to refer to LDL as a surrogate marker or as a biomarker of cardiovascular risk,” Professor Chapman said.5

Future prospects

Dr. Sabatine believed the result was encouraging that “with this trial, we now have definitive data that by adding evolocumab to a background of statin therapy, we can significantly improve cardiovascular outcomes and do so safely.”2 He also reported that an open-label extension trial involving 6,000 FOURIER participants would be conducted to assess the long-term safety profile.3

  1. Sabatine MS et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017 (doi: 10.1056/NEJMoa1615664.)
  2. FOURIER: Evolocumab Significantly Reduces Risk of Cardiovascular Events. American College of Cardiology. 2017. (Accessed 6 April 2017, at ://www.acc.org/latest-in-cardiology/articles/2017/03/10/19/18/fri-9am-fourier-further-cv-outcomes-research-with-pcsk9-inhibition-in-elevated-risk-patients-acc-2017)
  3. Evolocumab Added to Statins Cuts CV Events in FOURIER Trial. Medscape. 2017. (Accessed 6 April 2017, at http://www.medscape.com/viewarticle/877348)
  4. FOURIER Opens ACC With a Bang – Big LDL reduction, prevents MI, but with big price tag. Medpage Today. 2017. (Accessed 6 April 2017, at https://www.medpagetoday.com/meetingcoverage/acc/63909)
  5. ‘LDL Hypothesis’ More Than Just ‘Hypothesis’ in EAS Document. Medscape. 2017. (Accessed 6 April 2017, at http://www.medscape.com/viewarticle/879063)
  6. Ference BA, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017 (doi: 10.1093/eurheartj/ehx144)

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