Last I week I got my first query from a GP about prescribing Repatha (Evolocumab by Amgen), the monoclonal antibody that inhibits PCSK9, for a patient with atherosclerotic cardiovascular disease (ASCVD). This new group of medications are a fantastic piece of translational science, but in our financially pressured healthcare system are they a therapeutic step too far for our patients?
The referral detailed that the patient had a previous CABG, had been intolerant of statins and now had a modestly unfavourable lipid profile. More often in recent years I’ve found myself in clinic persuading patients to stay on statins. The “Statin debate” in the medical and then the lay press has unquestionably influenced patients perceptions and raised much doubt and scepticism, which is difficult to undo.
Following on from this, I became aware of the nocebo effect and it’s very elegant description in a recent Lancet paper in relation to statin prescription. In this analysis there was only an excess of muscle-related adverse effects when patients and their doctors were aware that statin therapy was being used, and not when its use was blinded. The authors concluded that this should help counter the adverse effect on public health of exaggerated claims of statin side-effects.
Accepting the patients statin intolerance, how should I answer the GPs question?
Interestingly, one of my colleagues said we should simply pass on this type of referral to the lipid clinic; I know not all cardiologists will have that luxury. I countered that we should be involved in the decision making, even if we are not the final prescribers or are continuing to follow the patients up. We should not only keep ourselves informed and in a position to give advice but also be able to refer on appropriately. Is there a correct or best path here?
Certainly, our increasing awareness of familial hypercholesterolaemia has seen a greater interaction between us, clinical biochemistry, and clinical genetics but we don’t have joint clinics or formal MDT, we probably should be working towards that. On further reflection, we don’t have a consultant specifically active in preventive cardiology, this role is present in some centres and other developed countries. I don’t think any of us have time to develop a new sub-specialist interest but maybe someone should, we’re not training anyone specifically in it either!
The answer to the question is the translation of the data from the FOURIER study to the real-life setting. Evolocumab produced a 60% LDL-C reduction, and a 15-20% relative risk reduction in both the primary and secondary composite end points, over a 2-year period in a population already on statins with stable ASCVD. The absolute risk reduction was modest, with the authors estimating that 74 patients would need to take Evolocumab to prevent one cardiovascular death, MI, or stroke; there was no reduction in CV or death from any cause alone.
The significant costs of PCSK9 inhibitors leave us considering the law of diminishing returns, can we afford them for this relatively modest benefit? Well, with both NICE and the SMAC in Scotland approving their use this quandary has in effect been solved, but it reasonably remains much discussed, especially in North America. In the USA Repatha’s annual cost per patient is $14 500, but it appears the NHS annual cost is a good bit lower, about £4,500 for 140mg per two weeks, and £6000 for 420 mg monthly.
As with all breakthrough products it’s certain that the price will fall as competition comes into the market. Praluent (Alirocumab by Sanofi-Aventis) has already been extensively tested and approved for use, with the FOURIER equivalent ODYSSEY OUTCOMES study coming soon. But it will take time before other medications come to market, and last year we saw Pfizer discontinue studies of their PCSK9 inhibitor Bococizumab, due to lower efficacy and increased side-effects.
But just when the jobbing clinician has started to understand PCSK9 inhibitors and started to wrestle with their clinical applicability, we can’t ignore dazzling on the horizon further therapies born of the detailed scientific understanding of this area.
Synthesis of PCSK9 requires mRNA. Inclisiran (Alnylam Pharmaceuticals/ the Medicines Company) is the first in class PCSK9 RNA interference agent; wow, good name, more impressive than enzyme inhibitor!? In the recently published ORION-1 phase 2 clinical trial it was shown that a single or double dose reduced LDL-cholesterol by at least 30%, and up to 50% for six months. The authors shared that this could result in patients getting twice yearly injections, similar to having a vaccination.
Brave new vaccine
And in fact, vaccination is the ultimate vision in this brave new world of cholesterol management. Already a vaccine that induces antibodies against PCSK9 has been developed and tested in animals with clear efficacy in lowering LDL-cholesterol. The vaccine uses a virus-like particle (VLP) as an immunogenic carrier of an antigenic PCSK9 peptide. VLPs are viruses that have had their DNA removed so that they retain their external structure for antigen display but are unable to replicate, they induce an immune response without causing infection. What fantastic science and probably only a few years away from human use.
Other advances in ASCVD treatment are on the doorstep. At the upcoming European Cardiac Society there will be a great deal of anticipation about the results of the CANTOS study.
For years we’ve had an understanding of the role of inflammation and its determination of poor prognosis in ASCVD patients. Many unsuccessful anti-inflammatory therapies have been trialled but now there appears to be a positive step forward.
Ilaris (Canakinumab by Novartis) a monoclonal antibody inhibiting the inflammatory cytokine interleukin-1β and already in use for cryopyrin-associated periodic syndromes, was tested versus placebo in combination with standard therapies in 10,000 patients with a prior MI and a CRP level of ≥2 mg/L. Apparently, quarterly dosing of Canakinumab lowers MACE risk, but wait for it, the cost of it is nearly 4 times as much as Evolocumab; a single 150mg dose is £10 000! Despite this, discussion has already started about how both PCSK9 and Il-1β therapies could be used together in high-risk ASCVD patients.
There is no doubt that these advances in drug therapy will be beneficial for ASCVD patients and are available because of truly great scientific research, but how to deliver this ever more sophisticated and costly care will be a great challenge for us all.
And to close, it is worth reflecting that the NNT to prevent an MI in secondary prevention with a Mediterranean diet was 18 and for primary prevention it is 61. It is cheap, easy to deliver and nobody will ever come to harm from it in the long-term!