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Dr Paul Brady MD, ST7 cardiology SpR, Bristol Heart Institute
Dr Paul Brady MD, ST7 cardiology SpR, Bristol Heart Institute
Introduction
Elevated LDL concentrations remains a powerful risk factor for cardiovascular disease. Importantly, every 1 mmol/L reduction results in a 22% reduction in risk of cardiovascular events. (1) It is therefore incumbent upon cardiologists to continue to wave the banner for aggressive lipid management to ensure the best possible outcome for patients presenting with acute coronary syndrome (ACS).
The publication of the PROVE IT–TIMI 22 trial in 2004 had an immediate and major impact on the management of patients presenting with ACS. (2) This study compared atorvastatin 80 mg daily (intensive therapy) with pravastatin 40 mg daily (standard therapy) in patients following ACS and demonstrated a 16% reduction in the hazard ratio for death or major cardiovascular events. (3) European Society of Cardiology dyslipidaemia guidelines (2019) define high risk as any clinical or imaging evidence of atherosclerotic cardiovascular disease. They recommend a 50% reduction in LDL concentration and a target LDL concentration of ≤1.4mol/L. (4) However, it is now recognised that only 20% of patients will achieve an LDL-C ≤1.4mmol/L with high-intensity statin monotherapy. (5, 6) In patients ineligible for injectable lipid therapies, a target of <1.4mmol/L may be difficult to acheive. In these circumstances, it may be appropriate to consider using the Joint British Societies’ consensus recommendation’s (JBS3) guideline-derived target of non-HDL-c of <2.5 mmol/L which is broadly equivalent to an LDL-c of <1.8 mmol/L. (7) Alternatively, NICE 2014 guidelines recommend a 40% reduction in non-HDL cholesterol. (8)
For many years, statins have been the mainstay of treatment for patients with non-familial primary hypercholesterolaemia. Statins inhibit hydroxymethylglutaryl coenzyme A (HMG–CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. (9) High Intensity Statin Therapy, defined as a dose expected to reduce LDL- C by greater than or equal to 50%, includes atorvastatin 40-80mg and rosuvastatin 20-40mg. (10) While high-intensity statin therapy has improved outcomes in patients presenting ACS, we now also have access to further treatments that can optimise lipids in patients with high-risk cardiovascular disease. Due to therapeutic inertia, these medications remain under-prescribed. (11)
Ezetimibe
Ezetimibe is an oral cholesterol absorption inhibitor and reduces LDL-c by up to 20%. Ezetimibe acts by blocking the uptake of cholesterol in the bowel, targeting the Niemann–Pick C1–like 1 (NPC1L1) protein, thereby inhibiting the absorption of dietary cholesterol. According to the IMPROVE-IT trial, the addition of ezetimibe to moderated intensity statin was associated with further reduction in LDL and a small but significant cardiovascular benefit by reducing the risk of adverse cardiovascular outcomes (hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). (12) In patients with ACS already established on high-intensity statin therapy, ezetimibe should be considered in patients if their LDL cholesterol concentration is >1.4mmol/L but <2.6mmol/L.
PCSK9 inhibitors
Monoclonal antibodies targeting circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that binds to LDL receptors facilitating degeneration, are potent lipid therapies that reduce LDL-C by 50–70%. (13) Alirocuman and evolocumab, both PCSK9 inhibitors given as fortnightly subcutaneous injections, are very effective at reducing LDL-C levels. The ODYSSEY OUTCOMES study, published in 2018, demonstrated that in patients with previous ACS with an LDL-C >1.8mmol/L despite high-intensity statin therapy, alirocumab significantly reduced major adverse cardiovascular events by 15% (hazard ratio [HR] 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). (14) Likewise, the FOURIER trial published in 2017 demonstrated that in patients with previous myocardial infarction, stroke, or symptomatic peripheral arterial disease and an LDL-C >1.8mmol/L, who are already receiving statin therapy, evolocumab also significantly reduced major adverse cardiovascular events by 15% (HR, 0.85; 95% CI, 0.79 to 0.92; P<0.001). (15) However, these medications remain expensive and the majority of patients in the UK with atherosclerotic cardiovascular disease remain ineligible. In patients with non-familial primary hypercholesterolaemia who have experienced an ACS event, NICE guidelines stipulate that these therapies can only be used if LDL-C is persistently above 4.0 mmol/L despite at least maximal tolerated lipid-lowering therapy or if LDL-C is persistently above 3.5 mmol/L in patients with recurrent cardiovascular events or polyvascular disease. (16) Prescribing in the UK therefore tends to be initiated and retained within secondary care, predominantly by consultant chemical pathologists or endocrinologists in the lipid clinic stetting.
Inclisiran
In view of the cost and stringent prescribing criteria for PCSK9 inhibitors, the introduction of inclisiran is a major step forward for lipid management in patients with cardiovascular disease. NICE has now determined that it is cost-effective to prescribe inclisiran for secondary prevention in patients with established atherosclerotic cardiovascular disease and a persistent LDL-C level of 2.6mmol/L or more, despite maximum tolerated lipid-lowering therapies. (17) This particular threshold was selected based on the PCSK9 inhibitor trial data. A pre-specified analysis of the ODYSSEY OUTCOMES trial demonstrated that in patients with baseline LDL-C levels >2.6 mmol/L, alirocumab had a more pronounced effect, reducing their risk of MACE by 24% (HR=0.76, CI: 0.65-0.87). (14) Inclisiran is a small interfering RNA molecule which limits the production of PCSK9 and has been found to lower LDL-C by about 50% in people not responding to other lipid lowering therapies. (18) It is an injectable drug with an excellent safety profile that requires only biannual administration, which may improve adherence. The main side-effects of inclisiran are injection site reactions and injection site pain which occurs in 3% and 2% of patients respectively. It should be avoided in severe hepatic disease and pregnancy due to a lack of safety data in these patient groups. The recommended dose of inclisiran is 284 mg administered as a subcutaneous injection: One dose initially, a second dose at 3 months, followed by a dose every 6 months. (17) Since being approved by NICE, a patient-level pooled analysis of 3655 patients over 18 months from the ORION-9, −10 and −11 trials have demonstrated that inclisiran significantly reduced composite MACE [odds ratio (95% CI): 0.74 (0.58–0.94)]. (19)
The approach of NHS England and NICE Technology appraisal guidance (TA733) is for inclisiran to be prescribed in primary care. (17) Therefore, effective collaborative practice with primary care remains essential. Now that this evidence-based treatment is available, there is now a greater necessity to ensure that arrangements are in place so that LDL-C is checked at approximately 12 weeks post-discharge in those patients presenting with ACS newly initiated on high-intensity statin therapy so that inclisiran can be offered if LDL-C is ≥2.6mmol/L. In those patients admitted with ACS who are already on high-intensity statin therapy with LDL-C ≥2.6mmol/L, inclisiran may be initiated in secondary care using the Blueteq High-Cost Drug Management System. While this process may represent a potential obstacle to initiating this therapy for eligible patients in secondary care, it is nonetheless important to pursue to help ensure that this treatment gets initiated in eligible patients post-ACS.
Bempedoic acid
Statin-associated muscle symptoms (SAMS) are common with registries showing that between 7-29% of patients have these side effects. These symptoms contributed to very high discontinuation rates (up to 70%) in the first 2 years of commencing treatment. (20) NICE guidelines recommend initially reducing the dose and observing if symptoms improve. If no improvement, another option would be to stop and try again when symptoms resolve. This can help clarify if the patient’s symptoms are statin related. (21) If symptoms resolve on withdrawal, a different statin in the lower intensity group could be tried e.g. water-soluble statin such rosuvastatin 5mg or 10mg.
Bempedoic acid is a novel muscle-sparing lipid-lowering agent which decreases LDL-C by inhibiting adenosine triphosphate-citrate lyase (ACL) in the liver. This enzyme upstream form statin-associated target HMG–CoA. The activity of bempedoic acid is restricted to the liver and as such, unlike statins, there is no associated risk of myopathy. (22) It is taken orally as a tablet at a dose of 180 mg daily and is also available as combination product with ezetimibe (Nustendi®). Bempedoic acid reduced LDL-c by approximately 21%. The CLEAR OUTCOMES study demonstrated that among patients who could not take a statin because of intolerance, the use of bempedoic acid reduced the relative risk of the primary endpoint of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or coronary revascularization by 13% compared with placebo (HR 0.87; 95% CI 0.79-0.96). This reduction in risk was driven primarily by a 23% lower risk of fatal or nonfatal MI and a 19% lower risk of coronary revascularization. (23) While the impact of bempedoic acid monotherapy on LDL-C is modest, combining bempedoic acid and ezetimibe reduces LDL by 36% and this combination should therefore be considered in patients with statin intolerance. (24) It should however be avoided in patients with a previous history of gout as it can exacerbate this condition. (25) NICE guidelines now recommend bempedoic acid with ezetimibe as an option if statins are contraindicated or not tolerated. (26) It would therefore seem sensible to commence ezetimibe first-line in patients with statin intolerance post ACS and consider bempedoic if LDL-C is >1.4mmol/L but <2.6mmol/L or inclisiran if LDL-C is ≥2.6mmol/L.
Icosapent ethyl
Hypertriglyceridemia is independently associated with increased mortality in patients with coronary heart disease. (27) Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been shown to lower triglyceride levels (28). The landmark REDUCE-IT trial demonstrated that icosapent ethyl
(a pure eicosapentaenoic ethyl ester) significantly reduces major cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularisation, or unstable angina) in patients with either established atherosclerotic cardiovascular disease or diabetes with other risk factors despite statin therapy. (29) NICE guidelines now recommend Icosapent ethyl in patients with a high risk of cardiovascular events and raised fasting triglycerides (1.7 mmol/L or above) and who are already taking statins. (30) Icosapent ethyl (brand name Vazkepa®) is taken orally at a dose 2 capsules twice daily.
When to refer to lipid clinic?
While cardiologists now have the tools to effectively manage primary hypercholesterolaemia and mixed dyslipidaemia, it is important to ensure that patients with possible familial hypercholesterolaemia are referred to the lipid clinic for cascade testing. In particular, this should be considered in young patients presenting with premature cardiovascular disease. Simon Broome diagnostic criteria for familial hypercholesterolemia can be used to identify patients who should be referred to a lipid clinic and include total cholesterol > 7.5 mmol/L or LDL-C > 4.9 mmol/L and personal or family history of tendon xanthomas or, personal or family history of premature myocardial infarction or, family history of hypercholesterolaemia. (31)
Conclusion
A “fire and forget” approach using atorvastatin 80mg monotherapy is not sufficient in patients presenting with ACS. The target LDL concentration for patients post-ACS is ≤1.4mol/l. Inclisiran should be offered to all patients post ACS if LDL-C is ≥2.6mmol/L despite statin therapy. More novel therapies such as ezetimibe, bempedoic acid and Icosapent ethyl are also available and NICE-approved and when indicated, should be considered in this high-risk group to reduce the risk of MACE post-ACS.
References