R3i Editorial

Stroke is a leading cause of death worldwide, second only to ischaemic heart disease. Yet, while there has been a decline in stroke mortality over the last three decades, stroke prevalence has increased, in part due to ageing populations and better risk factor management resulting in improved survival. Thus, the burden posed by the morbidity and associated disability of recurrent stroke and associated cardiovascular events is substantial.¹

Hypercholesterolaemia, globally the eighth most important indicator of stroke mortality in 2017,¹ is one example where there has been improved management. In line with the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines,² the AHA/American Stroke Association recommended intensive statin therapy to reduce the risk of stroke and cardiovascular events in patients with ischaemic stroke or transient ischaemic attack (TIA), of presumed atherosclerotic origin.³ These guidelines, however, fall short in defining low-density lipoprotein cholesterol (LDL-C) targets in this very high risk group.

This uncertainty was the focus of the Treat Stroke to Target Study,⁴ discussed as this month’s Landmark study. Despite being prematurely stopped for a number of administrative reasons, the study showed significant reduction in cardiovascular events in patients with a prior ischaemic stroke or TIA of atherosclerotic origin assigned to a lower LDL-C target (≤70 mg/dL or ≤1.87 mmol/L) compared with those assigned to a higher target (90 to 110 mg/dL or 2.3 to 2.8 mmol/L). Most of these events were cerebral infarctions or strokes of uncertain origin. Moreover, given the patient population – patients were enrolled in France and South Korea – there was no heterogeneity across the two countries with respect to the main study findings. While the number of intracranial haemorrhage events was higher in the lower-target group than in the higher-target group, the 95% confidence interval suggested that the between-group difference was not significant.

However, the advent of highly efficacious LDL-C lowering non-statin therapies, including anti-PCSK9 (proprotein convertase subtilisin/kexin type 9 monoclonal antibody therapy, now means that it is possible to attain LDL-C levels well below 70 mg/dL. Cardiovascular outcomes studies with these agents have also demonstrated substantial reduction in the risk of ischaemic stroke, by 25% in patients with established cardiovascular disease (median LDL-C on evolocumab 30 mg/dL or 0.78 mmol/L),⁵ and 27% in those with acute coronary syndrome (mean on-treatment LDL-C 53 mg/dL or 1.37 mmol/L), against a background of intense statin therapy (± ezetimibe).⁶ Taking this evidence on board, the 2019 Joint European Society of Cardiology/European Atherosclerosis Society Dyslipidaemia Guidelines have recommended an LDL-C goal of <50 mg/dL (<1.4 mmol/L) for patients at very high risk of cardiovascular events.⁷ These new findings and recommendations make the case for a new study testing the efficacy and safety of a lower LDL-C target in patients with ischaemic stroke and TIA, although whether this is feasible either practically or ethically may be questioned.

Finally, while a lower LDL-C target, against a background of best evidence-based treatment, is better for clinical outcomes, it is also clear that these very high-risk patients continue to experience cardiovascular events. This scenario highlights the need for renewed efforts to address this persistently high residual cardiovascular risk, focusing on other targets. Of the possible candidates for lipid targets, remnant cholesterol may have potential, especially in the light of recent evidence linking a higher risk of ischaemic stroke with higher remnant cholesterol levels.⁸

Residual cardiovascular risk in very high-risk patients continues to be a key challenge for the clinical community.

References

1. Avan A, Digaleh H, Di Napoli M et al. Socioeconomic status and stroke incidence, prevalence, mortality, and worldwide burden: an ecological analysis from the Global Burden of Disease Study 2017. BMC Med 2019;17 (1):191.
2. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S1-45.
3. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160-236.
4. Amarenco P, Kim JS, Labreuche J et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med 2019; DOI: 10.1056/NEJMoa1910355.
5. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
6. Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
7. Mach F, Baigent C, Catapano AL et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2019. doi: 10.1093/eurheartj/ehz455. [Epub ahead of print]
8. Varbo A, Nordestgaard BG. Remnant cholesterol and risk of ischemic stroke in 112,512 individuals from the general population. Ann Neurol 2019;85:550-9.