Background
Cardiovascular disease is the biggest cause of avoidable mortality in England and for many people can result in long-term disability. It is intrinsically linked to health inequalities.
Early detection and treatment of CVD can help patients live longer, healthier lives. The NHS is working towards this by increasing the diagnosis, monitoring and management of serious but treatable conditions such as atrial fibrillation, high blood pressure (hypertension) and high cholesterol.
With regard to cholesterol management, the priority is to take prompt action to reduce lipid levels of at risk patients (noting that 18% of patients with cardiovascular disease are not currently on any lipid lowering therapy (CVDPrevent, 2023). This has been recognised as a national priority reflected by the introduction of two new lipid management incentives into the general practice Quality and Outcomes Framework (QOF).
The majority of patients will be well managed on statins or statins and ezetimibe. However, there are a significant number of secondary prevention patients in whom statins are contraindicated, not tolerated or who simply do not adhere to statin therapy. For these patients it is important to move quickly to alternative lipid lowering therapies. There is also a group of patients whose lipid levels remain elevated despite maximal tolerated statin therapy, which puts them at risk of future cardiovascular events, and thus require the addition of further lipid lowering therapies.
Inclisiran is a NICE-recommended injectable lipid lowering therapy that addresses a current gap in the range of treatment options available for people with cardiovascular disease. It provides an effective intervention to lower lipids for secondary prevention in patients who have not had their lipids effectively lowered through the use of statins or a combination of statins and ezetimibe.
Inclisiran, delivered as part of a lipid management pathway (Summary of national guidance for lipid management, NHS England, 2020. Lipid management pathways, ASHN, 2023), has the potential to deliver significant population health gain. Achieving this requires delivery at scale in primary care; deployment in secondary care alone will not deliver the reach and, therefore, the level of impact that is needed to improve the health of at risk patients.
For eligible patients, inclisiran has the potential to increase treatment adherence, because of its twice-yearly dosing schedule following initiation, compared with more frequent dosing of other available treatments. It also reduces the clinical support that patients need to adhere to treatment, thereby reducing administration requirements for healthcare systems. Whilst true statin intolerance may only affect 10% of patients, as many as 50% take reduced or no dose due to perceived statin intolerance (Bytyci et al, 2022). There is therefore potential for inclisiran to lead to better adherence in the management of hypercholesterolaemia, with minimal burden on the healthcare system.
Evidence
There is clear evidence that cholesterol, and specifically low-density lipoprotein cholesterol (LDL-C), is a well-established modifiable risk factor in the prevention of cardiovascular disease, and it is well documented that sustained lowering of LDL-C can reduce the risk of cardiovascular disease (Health matters: preventing cardiovascular disease, 2019). Every 1 mmol/L reduction in LDL-C delivers a 22% reduction in major vascular events after one year (Mihaylova et al, 2012).
Inclisiran offers effective and sustained low-density lipoprotein cholesterol (LDL-C) reductions and is an effective LDL-C lowering therapy as shown by clinical trials (Raal et al, 2020. Raal et al, 2020). Of note:
- It is recommended by NICE as a secondary prevention treatment for patients with sub-optimal lipid management and a history of cardiovascular inclisiran is an option when statins, with or without other lipid-lowering therapies, have not reduced LDL-C levels sufficiently and is considered cost effective in people with cardiovascular disease and have persistently high LDL-C levels (2.6 mmol/l or more) despite maximum tolerated lipid-lowering therapy (Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia, 2021)
- In phase 3 trials, inclisiran provided placebo-corrected LDL-C reduction of up to 52% over 18 months and was well tolerated (Ray et al, Jan 2023).
- As shown in new data presented at ESC 202312, from the ORION-8 open label extension trial (the largest clinical trial completed to date with inclisiran), which is shortly due for publication, that:
- Inclisiran demonstrated a consistent safety profile and efficacy beyond six years;
- The trial, which included UK patients, showed inclisiran, in addition to statin therapy, provides consistent LDL-C reduction beyond six years of treatment;
- Eight in ten patients achieved target LDL-C threshold, in line with previously reported Phase III data).
The impact of inclisiran on cardiovascular disease events will need to be demonstrated through the long-term follow-up of patients. By default this needs to be conducted over a number of years. It is usual practice for drugs such as inclisiran to be approved and prescribed where they are shown to have a positive benefit on a risk factor associated with a disease, in this case LDL-C.
This practice means that patients benefit from new medicines when they are considered to be safe and effective. Without this approach drugs would not come into use for many years with the result being a loss of benefit to patients. The introduction of any new medication needs to be considered in relation to the risks that they mitigate, e.g:
- Inclisiran is for secondary prevention in a patient cohort who have uncontrolled cholesterol and are at significant risk of a cardiovascular event; and
- The risk of inclisiran being used, and the associated reduction in the risk of a further cardiovascular event, are considered to be much lower than the unadjusted risk of receiving no treatment.
Safety
It is recognised that when new medicines come to market the information from clinical trials is by default limited. This means enhanced surveillance is put in place through the Black Triangle (▼) reporting process. A medicine that is subject to enhanced monitoring through the Black Triangle process is normally subject to the enhanced reporting for five years or until the Pharmacovigilance Risk Assessment Committee (PRAC) are satisfied it can removed from the list (The Black Triangle Scheme, GOV.UK). This is the normal process for new medicines in the UK, with over 500 licensed drugs, including inclisiran, currently subject to this enhanced reporting (e.g. umeclidinium bromide (Incruse Ellipta®, Anoro Ellipta®) or insulin aspart (Trurapi®) and lispro (Lyumjev®)).
If Black Triangle medicines were only available in secondary care, this would significantly limit the number of patients that could benefit from them. The risk of not prescribing, i.e. of a patient not being able to access a medicine, needs to be considered against the risk of an adverse response. A consideration in determining whether a Black Triangle medicine is delivered in either primary or secondary care is not whether it is subject to enhanced reporting, but a consideration of the most appropriate setting in which to support patient care with a number of such drugs delivered in primary care.
Inclisiran has been shown to be well tolerated and over approximately 5 years of exposure to inclisiran there were no additional safety signals observed. Inclisiran showed no new safety signals with nothing being observed through the enhanced Black Triangle reporting and data in 3,576 patients with >9,900 patient-years exposure from 7 trials (Wright et al, 2022).
The new data from ORION-8, presented at ESC on August 28 2023 and shortly due for publication, continues to support the consistent long-term efficacy, safety profile, and tolerability of inclisiran. It represents a total exposure of more than 8,500 patient-years during the trial’s three-year follow-up. In addition, the long-term safety data was consistent with previous findings, confirming the well-established safety profile of inclisiran (Wright, 2023).
Publication reference: PRN00733_ii