FOURIER: Evolocumab Follow-up Shows No Cognitive Adverse Effects

Mitchel L. Zoler

May 05, 2020

Treatment with a PCSK9 inhibitor, as well as achieving dramatically lowered cholesterol levels, did not mess with patients' minds. Results from a cognition self-assessment completed by more than 22,000 patients when they finished participation in the FOURIER pivotal outcomes trial for evolocumab showed no signal of mental harm from either treatment with this PCSK9 inhibitor or from reaching a serum level of low-density lipoprotein cholesterol (LDL-C) of less than 20 mg/dL.

"We observed that patients treated with evolocumab, as well as those who achieved progressively very low LDL-C at 4 weeks in the FOURIER trial, had similar self-reported cognition in comparison with those receiving placebo and those with higher achieved LDL-C levels," wrote a team of researchers from the trial in an article published online on May 4 (J Am Coll Cardiol. 2020 May 12;75[18]: 2283-93). "These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while reducing recurrent CV [cardiovascular] events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients."

The findings added to prior results documenting the cognitive safety of evolocumab (Repatha) from a much smaller FOURIER substudy that involved more intensive testing, the EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study with 1,204 patients drawn from the broader study and tested after a median 19 months on treatment (N Engl J Med. 2017 Aug 17;377[17]: 633-43), as well as reports of neurocognitive safety for the other U.S. approved PCSK9 (proprotein convertase subtilisin kexin 9) inhibitor, alirocumab (Praluent) (N Engl J Med. 2015 Apr 16;372[16]:1489-99), various statins (J Gen Intern Med. 2015 Mar;30[3]: 348-58), and a third type of LDL-C–lowering agent, ezetimibe (JAMA Cardiol. 2017 May;2[5]:547-55).

Despite this evidence from across several drug classes that all cut LDL-C a long-standing but unsubstantiated belief persists among some that lipid lowering, especially by statins, blunts mental function, misinformation that's easy to find on the Internet. "I estimate that about 20% of patients prescribed a statin won't take it because of something they've heard" including that statins make you stupid. "It's hard to undo that," said Robert P. Giugliano, MD, a cardiologist at Brigham and Women's Hospital in Boston and senior author for the new FOURIER study as well as for EBBINGHAUS. The same stigma has not gained nearly as much traction for PCSK9 inhibitors, however, and Dr. Giugliano said he has also recently sensed what may be a downtrend in statin apprehension.

"The information added by this study is very important," commented Massimo R. Mannarino, MD, an atherosclerotic disease researcher at the University of Perugia (Italy). "The prejudice and misinformation regarding possible side effects of statins among patients and also some physicians unfortunately remains very strong today," he said in an interview. "My impression is that PCSK9 inhibitors are less affected by this negative bias and are seen as a safer alternative to statins." Concerns about PCSK9 inhibitors have especially focused on "the possible risks from very low cholesterol levels on the brain." The evidence from both studies and clinical experience "allows for a very positive opinion about the efficacy and safety of PCSK9 inhibitors, although the long-term effects still require a few more years of observation," said Dr. Mannarino, who led a review of the evidence that clears this class from links to neurocognitive loss (J Clin Lipid. 2018 Sep 1;12[5]:1123-32).

FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27,564 patients with atherosclerotic cardiovascular disease and elevated LDL cholesterol despite maximally tolerated standard treatment. Treatment with evolocumab for a median of 2.2 years resulted in a statistically significant 15% reduction in the study's primary efficacy endpoint, compared with placebo (N Engl J Med. 2017 May 4;376[18]:1713-22), and led to the drug receiving an indication for lowering rates of MI, stroke, and symptom-driven coronary revascularization.

The prespecified substudy reported by Dr. Giugliano and his associates focused on a 23-question, validated, self-assessment survey of cognitive function completed by 22,655 of the FOURIER patients (82%). The more than 4,900 other patients in the study who did not complete the survey had modestly higher prevalence rates of various comorbidities at baseline, and also higher rates of adverse outcomes during follow-up, and in many cases these adverse outcome may have contributed to these patients not being able to complete their end-of-study cognitive assessment. For example, almost a quarter of the patients who did not complete their end-of-study cognitive assessment failed to do so because they had already died.

Overall, the prevalence of patients indicating a cognitive decline was virtually identical among 11,363 patients who had been maintained on evolocumab, with a 3.7% rate, and the 11,292 patients in the placebo group, with a 3.6% rate. When analyzed by achieved level of LDL-C after 4 weeks on treatment, the 2,338 patients with a level below 20 mg/dL had a 3.8% rate of self-reported cognitive loss, compared with a 4.5% rate among 3,613 patients who had an LDL-C level of at least 100 mg/dL when measured 4 weeks into the study.

One of the strengths of the new cognitive analysis is that, although it did not use the more sophisticated assessment tests employed on fewer patients in the EBBINGHAUS substudy, it used the Everyday Cognition scale (Neuropsychiatry. 2008 Jul;22[4]: 531-44). "We asked patients what they have experienced, and in the end that is what's important, so this adds to the neurocognitive testing," run in EBBINGHAUS, Dr. Giugliano said in an interview.

"The neurocognitive results in the present study were self-reported, and that might be a limitation, as it is less specific and objective, but it is also a strength, as it could be more sensitive" especially for a "nocebo effect common to all lipid-lowering drugs linked to the bad reputation historically attributed to statins," Dr. Mannarino said.

Should the new FOURIER data "be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 monoclonal antibodies has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats," Jennifer G. Robinson, MD, a professor of epidemiology at the University of Iowa College of Public Health in Iowa City, said in an editorial that accompanied the new report (J Am Coll Cardiol. 2020 May 12;75[18]:2294-6). Her three caveats are the missing 18% of patients who never took the end-of-study assessment, the relative paucity of patients at very advanced age in FOURIER, in which patients averaged 62.5 years old, and the exclusion from FOURIER of patients with a history of hemorrhagic stroke. Dr. Robinson also cited the 2.2 year median follow-up as leaving unsettled the potential cognitive impact of longer treatment.

In response, Dr. Giugliano noted that the very large size of FOURIER and the 22,655 patients who completed their survey provided substantial numbers of patients to address some of these concerns in robust subgroup analyses. For example, the new report showed no signal of excess cognitive complaints with evolocumab treatment among 1,999 patients who were at least 75 years old when entering the study, or in more than 5,000 patients with a history of cerebrovascular disease at baseline, or in 1,990 patients with a history of a nonstroke neurologic disease. In addition, while he conceded that the 18% of patients not accounted for in the new study placed some limits on generalizability of the findings, he also maintained that this unavoidable failure to collect data from a modest percentage of patients doesn't scuttle the overarching signal of cognitive safety for most patients. And regarding the duration of treatment monitored, he noted that 5-year follow-up cognitive assessments are planned.

FOURIER was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has received personal fees and research support from Amgen and from several other companies. Dr. Mannarino had no disclosures. Dr. Robinson has been a consultant to The Medicines Company, Novartis, and Pfizer, and she has received research funding to her institution from Amgen and several other companies.

SOURCE: Gencer B et al. J Am Coll Cardiol. 2020 May 12;75[18]:2283-93.

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