At a breakfast symposium during the CSANZ 70th Annual Scientific Meeting, evidence supporting the benefits of earlier intensive lipid lowering post-myocardial infarction (MI) provided the basis for discussion on how to improve secondary prevention for acute coronary syndrome (ACS) patients.

During the Amgen-sponsored symposium ‘Lipid Management in Acute Coronary Syndrome,’  Doctor Adam Nelson, coronary interventional fellow at Monash Health, presented the case for increasing the urgency in lowering LDL-C in ACS patients, and Associate Professor Peter Psaltis, academic interventional cardiologist from South Australian Health and Medical Research Institute (SAHMRI), described how early intensive lipid lowering leads to fewer patients with high-risk plaques.^1,2

A multi-drug approach to achieve lipid targets

Dr Nelson summarised the recommendations in the ESC/EAS Guidelines for the management of dyslipidaemias³ in patients at high and very high cardiovascular (CV) risk: “The mantra of lower for longer, and now earlier, is very clear across the guidance,” he said. Despite these recommendations, data suggests that many patients are not achieving recommended LDL-C goals following ACS.^4-6

Real-world registry data from the Asia-Pacific region (n = 1,567) found that, in those with follow-up LDL-C measurements, more than half (52.9%) were not achieving the LDL-C goal (< 1.8 mmol/L), despite a relatively higher uptake of high-intensity statin therapy than recorded in other studies.⁴ Similarly, data from the CONCORDANCE registry (n = 2,671) found that although 73% of patients received high-intensity statins at discharge, 45% of patients did not achieve an LDL-C < 1.8 mmol/L in the assessment at their most recent consultation 6 to 12 months following discharge.⁵

Dr Nelson explained that clinical inertia to intensify statins after an index ACS admission has been attributed as a reason why many patients do not achieve LDL-C targets.⁶ However, there is a growing recognition that a multi-drug approach to lipid lowering may also be required. “We’ve become comfortable with this approach in hypertension – that patients don’t need to go home on just one agent. In fact, we’re comfortable starting patients on two or three [antihypertensive] drugs at sub-maximal doses, in the same way we treat COPD [chronic obstructive pulmonary disease] and rheumatoid arthritis, and we need to now recognise that cholesterol management is based around the need for more than just one agent,” he suggested.

The European DA VINCI observational study⁷ assessed the implementation across Europe of ESC/EAS guideline recommendations for lipid-lowering therapies. It found that current guidelines LDL-C goals were achieved in around one in five (22%) very-high risk secondary prevention patients with high-intensity statin alone. The authors concluded that there are gaps between clinical guidelines and clinical practice for lipid management across Europe, and suggest, “Even with optimized statins, greater utilization of non-statin LLT [lipid lowering therapies] is likely needed to reduce these gaps for patients at highest risk.” In patients who received a moderate to high intensity statin in combination with ezetimibe (9% of patients), the 2019 LDL-C goal was attained in 20% of patients; in those who received any lipid lowering therapy with a PCSK9 inhibitor, the goal was attained in 58% of patients.⁷

Dr Nelson emphasised the need to identify ACS as a “very high risk status”, thus generating greater urgency to lower LDL-C. He argued that the principles of “lower, longer and earlier” should be the basis of discussions and clinical practice during an ACS admission, and that a move towards a multi-drug approach as standard post-ACS management may help overcome the current situation where many patients do not achieve LDL-C targets.

Lower is better for CV outcomes

A/Prof. Psaltis reminded the audience that landmark trials have illustrated the CV outcomes benefit of driving down LDL-C levels. Additionally, data shows that patients who achieve very low LDL-C levels have a lower risk of major CV events compared to those achieving moderately low levels.⁸  “LDL-C levels on statin treatment predict residual CV risk after ACS,” noted A/Prof Psaltis.

The FOURIER⁹ and ODYSSEY¹⁰ trials have highlighted the benefit of lowering LDL-C even further with the PCSK9 inhibitors evolocumab and alirocumab, respectively. A/Prof Psaltis presented outcomes data from these trials illustrating a 15% relative risk reduction compared to placebo (P<0.001) in cumulative incidence of cardiovascular events when a PCSK9 inhibitor was added to therapy.^9,10

Earlier LDL-C lowering post-ACS: a new treatment paradigm

A/Prof. Psaltis described the emerging treatment paradigm that recognises the early post-ACS period as being the highest period of vulnerability. “The notion here is that, the more recent an MI, the hotter, the more inflamed, the more aggressive those plaques are going to be, and therefore the higher the risk of secondary cardiovascular events,” he explained.

In a subanalysis of the FOURIER data,¹¹ those patients who had been randomised to evolocumab who had experienced an MI less than two years previously were found to have a 24% relative risk reduction (RRR) in the key secondary endpoint of CV death, MI or stroke compared to placebo (HR 0.76; 95% CI 0.64 – 0.89. P<0.001); for those who had experienced an MI more than two years previously, the RRR for this endpoint was 13% compared to placebo (HR 0.87; 95% CI 0.76 – 0.99. P = 0.04).

A randomised, double-blind, placebo-controlled trial assessing the impact of initiating evolocumab in patients hospitalised with ACS and with elevated LDL-C levels found that the early addition of evolocumab to high-intensity statin therapy was well tolerated and resulted in significant reductions in LDL-C levels.¹² Patients (n = 308) received subcutaneous evolocumab 420 mg or placebo, administered in hospital and after 4 weeks, plus atorvastatin 40 mg.  More than 95% of patients randomised to evolocumab achieved LDL-C levels < 1.8 mmol/L by week 8 (compared with 37.6% of patients randomised to placebo). Adverse events and cardiovascular events were similar in both groups.¹²

Similarly, a trial in patients with non-ST-segment elevation myocardial infarction in which patients (n = 57)¹³ were randomised to receive either a single dose of evolocumab or matching placebo within 24 hours of presentation in addition to high-intensity statins (unless contraindicated) found that the addition of evolocumab significantly reduced LDL-C levels throughout hospitalisation and at 30-day follow-up, compared to statin alone (0.9 ± 0.6 mmol/L evolocumab versus 1.7 ± 0.7 mmol/L; P<0.01). At hospital discharge, 65.4% of patients receiving evolocumab achieved ESC guideline LDL-C targets compared with 23.8% of patients receiving placebo.

Plaque stabilisation with lower LDL-C levels

A/Prof. Psaltis described studies with PCSK9 inhibitors showing the impact on plaque regression and stabilisation with lowering LDL-C levels.^1,2 “The extra lowering of LDL-C early post-MI results in greater anti-atherosclerotic and plaque-stabilising benefits compared to a statin-alone strategy,” he explained. “The degree of benefit is directly proportional to the intensity of lipid lowering observed,” he added.

A/Prof Psaltis described the ongoing EVOLVE-MI study,¹⁴ which is evaluating the impact on CV outcomes of the early use of evolocumab in patients hospitalised with acute MI. “We now wait for this outcome data to determine whether this strategy is effective,” he said.

Disclosure

This article was sponsored by Amgen. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Repatha product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

1. Nicholls SJ et al. Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction JACC Cardiovasc Imaging 2022;15:1308–1321
2. Raber L et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: The PACMAN-AMI randomised controlled trial. JAMA 2022;327:1771–1781
3. Mach F et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2020;41(1):111–188.
4. Navar AM. Prospective evaluation of lipid management following acute coronary syndrome in non-Western countries. Clin Cardiol 2021; doi.org/10.1002/clc.23623
5. Alsadat N et al. Achieving lipid targets within 12 months of an acute coronary syndrome: an observational analysis. Med J Aust 2022; 216(9):463–468.
6. Brieger D et al. Intensive lipid-lowering therapy in the 12 months after an acute coronary syndrome in Australia: an observational analysis. MJA 2019; 210(2):80–85.
7. Ray KK EU-Wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study. Eur J Prev Cardiol 2021; 20(11): 1279–1289.
8. Boekholdt SM et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014;64(5): 485–494.
9. Sabatine MS et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–1722
10. Schwartz GG et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome N Engl J Med 2018;379:2097–2107.
11. Sabatine MS et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. Circulation 2018;138:756–766.
12. Koskinas KC et al. Evolocumab for early reduction of LDL cholesterol levels in patients with acute coronary syndromes J Am Coll Cardiol 2019;74:2452–2462
13. Leucker TM et al. Effect of evolocumab on atherogenic lipoproteins during the peri- and early postinfarction period. Circulation 2020;142;419–421
14. EVOLocumab Very Early After Myocardial Infarction (EVOLVE-MI), ClinicalTrials.gov, accessed 25 August, <https://clinicaltrials.gov/ct2/show/NCT05284747>