ESC/EAS Task Force published update of clinical guidance for use of PCSK9 inhibitors
2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia
The publication of the first randomized controlled cardiovascular outcomes trial earlier this year called for an update of the ESC/EAS Task Force practical clinical guidance for PCSK9 inhibition in patients with atherosclerotic CV disease or in familial hypercholesterolemia (FH). The updated clinical guidance includes novel clinical decision algorithms on when to consider a PCSK9 inhibitor, and how to monitor treatment efficacy of various types of lipid-lowering therapy. Moreover, gaps in knowledge on use of PCSK9 inhibiting therapy are discussed.
The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial that evaluated treatment with evolocumab, a fully human monoclonal PCSK9 antibody, in 27 564 patients with atherosclerotic cardiovascular disease (ASCVD), was the first CV outcomes trial to be published in this class of lipid-lowering antibodies. The Evaluation of bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects (SPIRE)-1 and -2 trials were stopped prematurely due to antibody-related adverse events.
In FOURIER, LDL-c levels were lowered by 59% (to 0.78 mmol/L) and the risk of major CV events was reduced by 15% (absolute event rates 9.8% with evolocumab vs. 11.3% on placebo over 2.2 years). The clinical benefit observed in the high-risk patients in FOURIER was mainly driven by reduction of nonfatal events (myocardial infarction and coronary revascularization).
This guidance document notes two important points for interpretation of the FOURIER trial results, the first being the relatively short duration of follow-up, as a consequence of the event-driven trial design. This is also relevant in relation to the safety of the very low achieved LDL-c levels. Moreover, no mortality benefit was observed during the 2.2 years, but it will be interesting to see whether longer follow-up of patients treated with PCSK9 inhibitors does result in reduction in mortality.
The ESC/EAS Taskforce set out to consider the impact of this new evidence on recommendations for the use of PCSK9 inhibitors in clinical practice, also recognizing that the affordability of this new treatment varies between countries. In addition to including the recent outcome data, new clinical decision algorithms are given, which differentiate three LDL-c thresholds for consideration of PCSK9 inhibitor therapy, based on consideration of absolute CV risk and the absolute LDL-c reduction required, key determinants of absolute CV risk reduction and the magnitude of LDL-reduction that may be expected with PCSK9 inhibition. Thus, these thresholds help identify high-risk patients with elevated LDL-c despite lipid-lowering therapy, who are likely to derive maximum benefit from adding a PCSK9 inhibitor. New are also indices of increased CV risk including imaging relevant for patient risk stratification.