Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: comparing and contrasting guidance across the Atlantic

This editorial refers to ‘European Society of Cardiology/European Atherosclerosis Society Task Force consensus statement on proprotein convertase subtilisin/kexin type 9 inhibitors: practical guidance for use in patients at very high cardiovascular risk’^†, by U. Landmesser et al., on page 2245.

The approval of two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, in both Europe and the USA has provided clinicians with a powerful new tool in their armamentarium that, on top of high-intensity statin therapy, can lower LDL-cholesterol (LDL-C) approximately another 60%.¹ The question now is for which of our patients should it be used?

In the USA, the 2013 ACC/AHA Cholesterol Guidelines largely focused on defining populations who should receive high-intensity statin therapy.² In a departure from previous guidelines, the Expert Panel felt there was no evidence to support titrating cholesterol-lowering therapy to achieve specific LDL-C levels. The guidelines did note that one could consider adding a non-statin to a statin in an individual who had less than the anticipated therapeutic response (i.e. <50% reduction in LDL-C when treated with a high-intensity statin), but noted that the percentage reduction in LDL-C was not in itself a treatment goal.

Since those guidelines, the IMPROVE-IT trial has shown that adding ezetimibe to a post-acute coronary syndrome (ACS) population with well-controlled LDL-C on a statin lowered LDL-C from 70 to 54 mg/dL and reduced major adverse cardiovascular events to a degree entirely consistent with what would have been expected from the same LDL-C reduction with a statin.³ Moreover, pooled exploratory data from the Phase II and Phase III studies of PCSK9 inhibitors showed significant reductions in cardiovascular outcomes.^4,5

Indeed an analysis of 49 trials of LDL-C-lowering therapy demonstrated that for all interventions that ultimately act by up-regulating the LDL receptor (including statins, ezetimibe, and PCSK9 inhibitors), the relative risk reduction in cardiovascular events was similarly directly proportional to the absolute LDL-C reduction, such that each 1 mmol/L reduction in LDL-C results in a 23% reduction in major cardiovascular events, regardless of the specific intervention.⁶ Moreover, there was a direct, linear correlation between achieved LDL-C and the rate of cardiovascular outcomes.

To address the new clinical trial data, an ACC Expert Consensus Decision Pathway was developed to tackle the role of non-statin therapies for LDL-C lowering.⁷ The writing committee noted that not only the percentage reduction but also absolute LDL-C levels could serve as thresholds that, if not achieved by a patient, could be used as a factor to decide to initiate such further therapy. Indeed the committee adopted thresholds that are remarkably similar to the targets espoused by the NCEP ATP III Focused Update 12 years ago.⁸ Specifically, the committee noted that clinicians may want to consider adding a PCSK9 inhibitor in patients with stable atherosclerotic cardiovascular disease (ASCVD) who have an LDL-C ≥100 mg/dL (≥2.6 mmol/L) despite being on a high-intensity statin plus ezetimibe. For even higher risk patients with a recent ACS or other co-morbidities, the threshold to consider adding a PCSK9 inhibitor was lower, ≥70 mg/dL (≥1.8 mmol/L). Lastly, for patients with very high baseline LDL-C (≥190 mg/dL), who are more likely to have familial hypercholesterolaemia (FH), given the lifetime exposure to high LDL-C, a threshold of 70 mg/dL (≥1.8 mmol/L) was recommended in secondary prevention and 100 mg/dL (≥2.6 mmol/L) in primary prevention. Outside of these groups, the committee did not endorse considering use of a PCSK9 inhibitor.

In terms of European Guidelines, the ESC Dyslipidaemia Guidelines have endorsed absolute LDL-C targets. In the 2016 iteration, for very high-risk patients the target is < 1.8 mmol/L.⁹ This group includes both secondary prevention patients with known ASCVD (defined as a prior ACS, stroke, or transient ischaemic attack, arterial revascularization, or documented coronary, cerebrovascular, or peripheral arterial disease) as well as primary prevention patients with either (i) diabetes with either target organ damage or a major risk factor such as marked hypercholesterolaemia, hypertension, or smoking; (ii) severe chronic kidney disease; or (iii) a calculated SCORE of ≥ 10% for 10-year risk of fatal cardiovascular disease (which is roughly equivalent to a ≥ 30% 10-year risk of fatal cardiovascular disease or non-fatal events). The guidelines noted that PCSK9 inhibitors are an option for such very high-risk patients and patients with heterozygous FH, both of whom should be on maximally tolerated doses of first- and second-line therapy (e.g. statin plus ezetimibe).

This new ESC/EAS consensus statement on PCSK9 inhibitors is a much welcomed deeper foray into this important area.¹⁰ The authors underscore that the key issue is achieving LDL-C levels <1.8 mmol/L in very high-risk patients, similar to the threshold used for very high-risk patients in the 2016 ACC Consensus Document. In contrast, however, the ESC/EAS statement also recognizes financial constraints and thus recommends considering adding a PCSK9 inhibitor only when LDL-C levels are substantially above the target LDL-C of < 1.8 mmol/L in order to yield more compelling absolute risk reductions.

Therefore, the authors recommend considering a PCSK9 inhibitor for very high-risk patients (in this case limited to the subset with ASCVD or diabetes with either target organ damage or a major risk factor) who, despite maximally tolerated statin plus ezetimibe (or just ezetimibe for those who are statin intolerant), require >50% reduction in LDL-C levels (i.e. have an LDL-C of > 3.6 mmol/L) to reach the goal of < 1.8 mmol/L. In this case, by requiring an absolute LDL-C reduction of > 1.8 mmol/L, the authors are effectively anticipating a relative risk reduction of > 38% in major vascular events.⁶ If the 10-year risk of major fatal and non-fatal cardiovascular events is ≥ 30% in this group, a > 38% reduction in that risk would translate into an absolute risk reduction of > 1.1%/year.

The authors go on to note that for patients with rapid progression of ASCVD (e.g. repeated ACS, unplanned coronary revascularizations, or strokes) one might consider treating patients at a lower threshold, including those with an LDL-C >2.6 mmol/L. In this case, assuming at least a 50% reduction in LDL-C, the absolute LDL-C reduction would be > 1.3 mmol/L which should translate into a relative risk reduction of > 29% in major vascular events.⁶ The authors note that the 10-year risk of major cardiovascular events in such patients is likely to be > 40%. A > 29% reduction in that risk would translate into an absolute risk reduction of > 1.2%/year (NB: not the >2%/year noted in the footnote to figure 1 in the article by Landmesser et al.).

For patients with FH, the authors propose restricting this treatment to patients with ASCVD as outlined above or considering it in those without ASCVD if they have an LDL-C >5 mmol/L (or > 4.5 mmol/L if the patient has additional risk factors). Such thresholds would result in achieved LDL-C close to the target for patients with heterozygous FH without ASCVD (<2.6 mmol/L). For such large reductions of LDL-C, PCSK9 inhibition should probably reduce cardiovascular events by ≥50%. As patients with FH have a very high risk of major cardiovascular events due to the lifelong exposure to very high LDL-C levels, one might consider lower thresholds.

As a whole, the ESC/EAS recommendations tend to use more conservative thresholds than do the ACC recommendations (Table 1). As rightly noted by the authors, decisions to use these medications may unfortunately be tempered by the financial constraints of particular healthcare systems. Of note, in very high-risk patients, such as those with a prior hard cardiovascular event, the 10-year rate of major cardiovascular events is ∼45%, and thus treatment with a PCSK9 inhibitor for those with an LDL-C >1.8 mmol/L (the ACC 2016 threshold) should achieve an absolute risk reduction of ∼1%/year, similar to the absolute risk reductions likely to be achieved from other ESC/EAS recommendations. Of course, all of these guidelines are predicated on the dedicated PCSK9 inhibitor cardiovascular outcomes trials demonstrating reductions in clinical events per mmol/L reduction in LDL-C consistent with what has been seen for statins and other interventions that up-regulate the LDL receptor.^11,12 Based on the genetic and clinical data to date, such a supposition is reasonable,^6,13 and thus the guidelines on both sides of the Atlantic are a very good start to help clinicians target this promising new class of LDL-C-lowering therapy to the most appropriate patients.

Conflict of interest: none declared.

References

Author notes