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LDL-C reduction with PCSK9 inhibitors: An update on the latest evidence 26 April 2017BCS Editorial By: Francesco Papalia PCSK9 inhibitors are novel agents that target proprotein convertase subtilisin-kexin type 9, a protein involved in the degradation of the LDL receptor in the liver. Inhibiting PCSK9 results in increased expression of the LDL-C receptor, and therefore increased clearance of cholesterol through hepatic metabolism. Three agents have been developed in this class so far: the humanised monoclonal antibody Bococizumab that retains a 3% murine sequence, and the two fully human antibodies Alirocumab and Evolocumab. Pfizer halted the development of Bococizumab after phase 2 studies revealed unacceptably high rates of attenuation of the lipid lowering effect due to the development of neutralising antibodies, as well as a significant incidence of injection site reactions. On the other hand, data on Evolocumab from the OSLER
programme of trials[1]
already demonstrated the high efficacy of the drug in decreasing LDL-C to
levels significantly below what is achieved with standard therapy. There was a
signal toward possible increased incidence of neurocognitive deficits in the
PCSK9 arm, but this was not significant at one year. On the basis of these data
the FOURIER trial was launched to look at the effect of lowering LDL-C with
Evolocumab on hard outcomes. Alirocumab is yet to report the results of its
ongoing ODYSSEY outcomes trial[2]. FOURIER Study design The FOURIER trial[3]
enrolled 27,564 patients for a median follow-up of 26months. To be eligible
patients had to have atherosclerotic cardiovascular disease and LDL cholesterol
levels of 70 mg/dL (1.8 mmol/L) or higher who were receiving statin therapy.
This was a randomised, double blind, placebo controlled trial conducted all
across the globe. The primary endpoint was a composite of cardiovascular death,
myocardial infarction, stroke, hospitalization for unstable angina, or coronary
revascularization. The key secondary efficacy end point was the composite of
cardiovascular death, myocardial infarction, or stroke. Results The 61% reduction in LDL-C levels seen in the OSLER studies
was confirmed in FOURIER with a 59% reduction in LDL-C levels to a mean on
treatment level of 30 mg/dl (0.78 mmol/l). The primary endpoint was
significantly lower in the PCSK9 arm with a relative risk reduction of 15% (HR
0.85, 95% CI 0.79 – 0.92, p<0.0001) which equates to an absolute reduction
of 2% of the primary endpoint. The same was true for the key secondary endpoint
of CV death, MI or CVA (HR 0.8, 95%CI 0.73 – 0.88, p<0.00001). A breakdown
of the composite reveals that the drivers of outcome were CVA, TIA, MI and
coronary revascularisation, with no significant difference in the rates of CV
death or all-cause mortality in this study. Indeed a trend – albeit
non-significant – toward higher rates of all-cause mortality was seen in the Evolocumab
arm (4.8% vs. 4.3%, HR 1.04, 95%CI 0.91 – 1.19). These results, as report by
the trial investigators, equate to a number needed to treat of 74 patients over
a period of 2 years to prevent one cardiovascular death, myocardial infarction,
or stroke. The incidence of adverse events was not different between
groups across the spectrum of adjudicated events, in particular the rates of
adverse neurocognitive events (flagged as a possible drawback to PCSK9 therapy
in the OSLER studies) was 1.6% in the Evolocumab arm vs. 1.5% in the placebo
arm. The only adverse event that was higher in the Evolocumab arm was injection
site reactions (2.1% vs. 1.6%, p,0.001) but 90% of these were mild and only
0.1% of patients required study drug discontinuation due to injection site
reactions. Spotlight on
Neurocognitive effects The EBBINGHAUS trial[4]
was a substudy of the FOURIER trial which reported on the safety of Evolocumab
with regards to neurocognitive function. It included 1974 patients enrolled in
the main FOURIER study, and subjected them to a battery of neurocognitive tests
at baseline and during therapy with Evolocumab. The primary endpoint was the
spatial working memory strategy index of executive function performed as part
of the Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessments
(a standardized, well validated computer tablet-based testing platform). The
trial was designed as a non-inferiority study (NI margin of 20%). The results
revealed no difference between treatment and placebo arms with a change in
scores from baseline to follow-up of -0.21 and -0.29 respectively (p<0.001
for non-inferiority) for the primary endpoint. In addition patient
self-reported scores of neurocognitive function, and investigator reported
neurocognitive effects were also not statistically different between the two groups.
Crucially, an analysis of the group of patients with the lowest levels of LDL-C
(<25mg/dL, 0.65mmol/L) did not reveal detrimental effects in the Evolocumab
group either. Discussion The FOURIER trial has given us an unprecedented look at the
effects of extremely low levels of LDL on cardiovascular health. Some people
may suggest that the results largely support the theory that lower is better
when it comes to LDL levels, although this study failed to actually show any
reduction in mortality. It is likely that the effects of low LDL-C levels, both
positive and negative, will become more obvious as time goes on, and the
results of longer term follow-up beyond the 26 months reported in this analysis
will hopefully go a long way to shed light on the issue. Will the adverse
mortality trend seen in the Evolocumab arm become significant or will therapy
ultimately result in a reduction in deaths? Similarly, will a decade (or more)
of extremely low levels of LDL have a more pronounced effect on neurocognitive
function than that seen in the EBBINGHAUS study? In addition to the clinical impact of the drug, cost
considerations need to be taken into account due to the high price of these
drugs. In the USA Evolocumab is reportedly marketed at $14000/year/patient.
Given an NNT of 74 to prevent one non-fatal event over 2 years this results in
a cost of over $2’000’000 to prevent one event. In this age of tight budgets a
discussion around affordability of such drugs will inevitably be required
before widespread use becomes the norm. References 1. Sabatine, M.S., et al., Efficacy and safety of evolocumab in
reducing lipids and cardiovascular events. N Engl J Med, 2015. 372(16): p. 1500-9. 2. Schwartz, G.G., et
al., Effect of alirocumab, a monoclonal
antibody to PCSK9, on long-term cardiovascular outcomes following acute
coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am
Heart J, 2014. 168(5): p. 682-9. 3. Sabatine, M.S., et
al., Evolocumab and Clinical Outcomes in
Patients with Cardiovascular Disease. N Engl J Med, 2017. 4. Giugliano, R.P., et
al., Design and rationale of the
EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter
study to assess the effect of evolocumab on cognitive function in patients with
clinically evident cardiovascular disease and receiving statin background
lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER
trial. Clin Cardiol, 2017. 40(2):
p. 59-65. Number of hits: 3651 Add Comments |
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