This is a copy of an email, which I have just sent to the UK National Institute for Care and Health Excellence (NICE).
1) Evolocumab is currently recommended in the following circumstances (Ref 1):
Table 1 Low-density lipoprotein cholesterol concentrations above which evolocumab is recommended
|Without CVD||With CVD|
|High risk of CVD 1||Very high risk of CVD 2|
|Primary non-familial hypercholesterolaemia or mixed dyslipidaemia||Not recommended at any LDL‑C concentration||Recommended only if LDL‑C concentration is persistently above 4.0 mmol/litre||Recommended only if LDL‑C concentration is persistently above 3.5 mmol/litre|
|Primary heterozygous-familial hypercholesterolaemia||Recommended only if LDL‑C concentration is persistently above 5.0 mmol/litre||Recommended only if LDL‑C concentration is persistently above 3.5 mmol/litre|
|1 High risk of CVD is defined as a history of any of the following: acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation); coronary or other arterial revascularisation procedures; chronic heart disease; ischaemic stroke; peripheral arterial disease.|
2 Very high risk of CVD is defined as recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed (that is, polyvascular disease).
Abbreviations: CVD, cardiovascular disease; LDL‑C, low-density lipoprotein cholesterol.
2) Until recently (Ref 2), Evolocumab had been approved on the basis that it lowered cholesterol levels. There was no evidence that it had an impact on cardiovascular events or mortality.
3) The Sabatine et al publication (Ref 2) studied people: between 40 and 85 years of age; with cardiovascular disease; with a fasting LDL cholesterol level of 70 mg per deciliter (1.8 mmol per liter) or higher; and taking at least atorvastatin at a dose of 20 mg daily or its equivalent. Any findings are thus only applicable to this population.
The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
The study claimed that “Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001.)”
4) The study also claimed “The results were consistent across key subgroups” (abstract, results). This is not true. The Supplementary Appendix contains Supplementary Figure S5 – Efficacy in Key Subgroups – on page 55 of 57 (Ref 3).
This reports that the hazard ratios (HRs) for primary endpoint were significant for baseline LDL-C for Quartile 1 (<80mg/dL) [noting that there is already a minimum level of LDL-C set at 70 mg/dL as an inclusion criterion, so this is a very narrow range] and for Quartile 2 (80 to <92 mg/dL). However, the HRs for primary endpoint were NOT significant for Quartile 3 (92-109 mg/dL) OR Quartile 4 (>109 mg/dL).
5) Cardiovascular deaths and deaths from any cause were higher in the Evolocumab intervention than the placebo. The HRs were not statistically significant, but the trial was stopped early, so we don’t know if these would have soon reached statistical significance and ended any prospects for this uncharted drug.
Notwithstanding the concern about death rates, Supplementary Figure S5 shows that Evolocumab makes no significance difference when baseline LDL-C is greater than 92 mg/dL (2.38 mmol/l)
Given that the lowest LDL-C concentration at which NICE recommends the use of Evolocumab is 3.5 mmol/l, there is no evidence of benefit for Evolocumab in any circumstance for which NICE recommends it.
6) Supplementary Figure S5 further confirms that there was no statistically significant difference for primary or secondary end points for the 17,335 patients in Europe (63% of the study population). That means that there is no evidence of benefit for Evolocumab for UK citizens for whom NICE recommendations apply.
7) Notwithstanding that there is no evidence of benefit for the NICE recommendations, even if the results found were applicable, the cost benefit would surely fail.
The study admits that 74 people would need to be administered with Evolocumab for 2 years to delay one event. The cost of this drug is £4,422.60 (Ref 4). It would cost £654,545 to delay one event; an event that could happen on the first day of the third year (you can adjust for the ‘secret’ commercial discount). That would not be a good use of NHS/taxpayer, money.
Please can NICE confirm that the recent Sabatine et al study has rendered invalid the current NICE guidelines for the use of Evolocumab.
Please can NICE confirm that NHS/taxpayer money will not be spent on this drug as a result.
I look forward to hearing from you
Dr. Zoë Harcombe, PhD
p.s. update – the reply can be seen here.
Ref 1: Table 1. “Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia.” NICE Guidance. Published: 22 June 2016. (nice.org.uk/guidance/ta394)
Ref 2: Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine 2017;0(0):null doi: doi:10.1056/NEJMoa1615664|.
Ref 3: Supplementary Appendix to Reference 2.
Ref 4: (para 2.3) “Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia.” NICE Guidance. Published: 22 June 2016. (nice.org.uk/guidance/ta394)