Inhibition of PCSK9 in high-risk patients. Less LDL-C is more.
Instituto Cardiovascular de Rosario (ICR).
Rosario, Santa Fe. Argentina E-mail
Recibido 06-ENE-2019 – ACEPTADO 17-ENERO-2019.
There are no conflicts of interest to disclose.
The CTT (Cholesterol Treatment Trialists) meta-analysis  shows that therapy with statins reduces the risk of major vascular events (death, nonfatal myocardial infarctions, nonfatal strokes and coronary artery revascularization) in approximately 20 to 25% per every 40 mg/Dl of LDL reduction per year in different categories of patients. Significantly, the relative reduction (proportional) of risk is independent from basal LDL cholesterol (LDL-C) levels, from the presence or absence of previous vascular disease and the inherent risk of patients; the magnitude of risk reduction is stable since the second year of exposition to the treatment (risk reduction is lower during the first year). We should highlight that therapy with statins significantly reduces approximately 10% of vascular mortality and overall mortality.
The clinical trial IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)  showed that ezetimibe associated to proper doses of statins, moderately reduces vascular events. However, in spite of using optimal doses of the available therapeutic resources (statins and ezetimibe), some patients presented vascular events in the short and mid-term. This, defined by some as residual risk, is the focus of concern both from a practical perspective and clinical research.
Proprotein convertases activate a series of proteins that regulate critical cellular steps. The main LDL-C clearance mechanism of the bloodstream is at the level of hepatocyte surface via endocytosis; a process mediated by LDL-C binding with the LDL receptor (LDL-R) in the hepatocyte cell membrane. LDL-R may recirculate and recycle this process approximately 150 times . Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL-R and leads it to destruction in the intracellular lysosome preventing its recirculation. Therefore, PCKS9 plays a counterregulatory role on LDL-R metabolism, the mutations producing PCKS9 overexpression determining a lower density of LDL-R, and thus, very high levels of LDL-C; while the mutations reducing its expression lead to a greater density of LDL-R and smaller values of LDL-C.
PCSK9 inhibition by monoclonal antibodies have produced reductions in LDL-C serum levels, from 50 to 70%, with scant adverse effects. From these, alirocumab and evolocumab are completely human monoclonal antibodies that inactivate the PCSK9 protein, that were approved by the FDA in 2015 by reducing LDL-C safely in up to 60%, in patients previously treated with statins, have been extensively studied in phase 2, and there were two trials completed in phase 3. Bococizumab, a third partially human monoclonal antibody, was interrupted during its clinical investigation stage .
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was the first stage III clinical trial completed and published with a PCSK9 inhibitor, evolocumab , that included 27,564 patients with proven atherosclerotic disease (secondary prevention); all of them stable and with LDL-C values ≥70 mg/Dl; in spite of treatment with high- or moderate-intensity statins (approximately 5% used associated ezetimibe). The patients were randomized to receive evolocumab (at doses of 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously per month) or placebo. The mean duration of the trial was 2.2 years. Mean reduction of LDL-C was approximately 60% and was maintained over the clinical trial. Evolocumab produced a significant risk reduction of the primary composite endpoint of 15% (cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, hospital admission by unstable angina, and myocardial revascularization) (1,344 patients [9.8%] vs 1,563 patients [11.3%]; HR 0.85; 95% CI, 0.79 to 0.92; P<0.001) and 20% of the secondary main endpoint (816 [5.9%] vs 1,013 [7.4%]; HR 0.80; 95% CI, 0.73 to 0.88; P<0.001). Evolocumab did not impact on cardiovascular mortality (1.8% vs 1.7%; HR 1.05; 95% CI, 0.88–1.25; P = 0.62) or overall mortality (3.2% vs 3.1%; HR 1.04; 95% CI, 0.91–1.19; P = 0.54 for evolocumab and placebo respectively). The results were consistent in all the analyzed subgroups and regardless of LDL-C values in admission. No adverse effects were observed, attributed to the drug, except for skin reactions on the injection site.
ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab)  published at the end of 2018, included 18,924 patients between one and twelve months after an acute coronary event, with LDL-C levels in admission ≥70 mg/Dl and were treated with optimal doses of atorvastatin or rosuvastatin: these were randomized to alirocumab (75 or 150 mg subcutaneously every 2 weeks) titrated to reach LDL-C levels between 25 and 50 ms/Dl or placebo. The mean time of follow-up was 2.8 years; LDL-C levels were reduced between 62.7% and 54.7% along the follow-up when compared with placebo.
The primary composite endpoint (death by coronary origin, nonfatal acute myocardial infarction, ischemic stroke and admission by unstable angina) in 903 patients (9,5%) in the arm assigned to alirocumab and in 1052 patients (11.1%) in the placebo arm, corresponding to a Kaplan-Meier probability of risk at 4 years of 12.5% in the alirocumab arm and 14.5% in the placebo arm (HR 0.85; 95% CI 0.78-0.93; P <0.001).
Seven secondary endpoints were analyzed and were enumerated in a “predefined hierarchy order” to maintain the general error of type 1 in 0.05 and to minimize the potential appearance of false positives by a “multiplicity of analyses”; if the immediately above endpoint analyzed was not significant, all the other endpoints below would be assigned as nonsignificant. The first 4 in the list were highly significant (composite endpoints); the following two: mortality of coronary origin and cardiovascular mortality (fifth and sixth in the hierarchical order) showed a nonsignificant risk reduction of 8 and 12% respectively, in favor of alirocumab. On the contrary, overall mortality risk reduction was observed to be 15% (3.5% in patients assigned to alirocumab and 4.15% in those assigned to placebo; HR 0.85; 0.73, 0.98; p = 0.026) (seventh and last in the pre-established hierarchy order). From a formal point of view, this overall mortality reduction for the alirocumab arm cannot be claimed, and for this reason its P value is deemed as “nominal”. Methodological rules are clear, and the multiplicity of analyses is undoubtedly risky.
The personal clinical interpretation differs in this case from the methodological one; biologically it is highly likely for overall mortality to have been reduced; if the general pattern of the mortality endpoint is observed, there is a clear statistical gradient associated to the number of endpoints observed in each group. Approximately, 450 events in mortality of coronary origin, 530 in cardiovascular mortality and 750 in overall mortality. The estimated points of the effect are in the same direction and differ only quantitatively: 8, 12 and 15% of risk reduction for the described categories of endpoints; confidence intervals narrow as the number of events increase. This may be related to the lack of statistical significance probably being associated to an insufficient number of events in the superior categories of mortality in the hierarchical order than to a biological reality. Strength reduces as the number of events lowers. Survival (inverse to overall mortality) is more important for patients than nonfatal events; and therefore, mortality analysis requires a deeper exploration beyond statistical formalities. It is true that overall mortality is a combination of cardiovascular events (CV) and non-CV events. For the difference in overall mortality to be significant, non-CV mortality reduction should be of even greater magnitude than CV mortality and statistically significant. Although there is no obvious biological basis in a first analysis, it is also possible that many noncardiovascular deaths could be associated to the extent of the underlying vascular disease, and therefore, influenced by a drug that reduces nonfatal events.
The benefit of alirocumab in ODYSSEY OUTCOMES was consistent in all the subgroups analyzed, and no statistical heterogeneity was observed in any of them. However, the incidence of the primary endpoint in the placebo arm differed in the three categories established of basal LDL-C levels (<80, 80 to <100 and ≥100 mg/Dl). The greatest risk between the patients in the highest category of basal LDL-C corresponded, logically, to a greater absolute risk reduction; 3.4% in the primary composite endpoint, and 1.7% in all-cause mortality (no pre-specified analysis). However, the interpretation of the result of alirocumab over this subgroup could be interpreted with caution, as there is no interaction between the three subgroups (p=0.09).
No severe adverse effects were associated to alirocumab, except for a greater incidence of skin reactions in the puncture site; and in no case of clinical significance.
Undoubtedly, PCSK9-I are strong agents to reduce LDL-C; this reduction is associated to a clear risk reduction of major vascular events (consistent with the line of meta-regression, previously prepared by the CTT), with a proper safety profile. The efficacy of these drugs has been definitely verified in a wide range of high-risk patients (after recent acute coronary syndrome and in secondary prevention of high risk in stable patients) treated with doses of statins (and a few with ezetimibe) and with persistently high values of lipoproteins. Once again, the latency of the effect is verified. The efficacy of PCSK9-I is of less magnitude the first year, and enhanced on subsequent years. The pattern is similar to that observed with statins and ezetimibe. The very low levels of LDL-C obtained with treatment (<20-25 mg/Dl) are associated to a clinical benefit and no severe adverse effects or events existed. The doubts on the very low levels of LDL-C seem to have been cleared. Lipid theory was once again verified and there is no evidence of the existence of a J or U curve for LDL-C up to the reached levels.
There was no increase observed in the incidence of type 2 diabetes (it should be taken into account that the short follow-up of both studies limits a definitive exclusion of some excess potential in the long term); and neither an excess in cognitive deterioration associated to none of the two studied drugs or the extreme inferior values of LDL-C reached with these. No muscle adverse events were reported in excess.
Between the differences in the design between the ODYSSEY and the FOURIER, the following stand out: patients with recent acute coronary syndrome (ACS) in the ODYSSEY, instead of stable patients in secondary prevention in the FOURIER. A difference to remark is that the ODYSSEY titrated alirocumab between 75 and 150 mg to maintain LDL-C between 25 and 50 mg/dl and above 15 mg/dl (LDL-C target); while in the FOURIER, the dose was fixed. The ODYSSEY was a more prolonged trial, 2.8 vs 2.2 years in the mean follow-up, and more than 40% of the patients were followed for more than 3 years.
The results of the ODYSSEY and the FOURIER confirm that the treatment with PCSK9-I exceeds the limits of what we considered an optimal level of LDL-C and strongly suggests that the additional decrease of LDL-C reduces the residual risk of major vascular events; in the ODYSSEY also, a lower overall mortality was observed associated to alirocumab. Both trials reinforce the hypothesis that “less LDL-C is more”.
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