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10 January 2018

Addressing residual cardiovascular risk – back to basics?

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco While 2017 has certainly been a ‘rollercoaster of a year’ for lipid research, it has also provided important insights for the management of residual cardiovascular risk. The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial was the first to lead the attack, demonstrating incremental benefit with a ‘lower is better’ approach targeting low-density lipoprotein cholesterol (LDL-C) with the PCSK9 inhibitor evolocumab in patients with stable atherosclerotic cardiovascular disease (ASCVD) on intensive statin therapy 1. The landmark trial, CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), followed up in providing proof-of-concept for the relevance of targeting residual inflammatory risk with canakinumab, a monoclonal antibody to interleukin-1? in patients with a previous myocardial infarction and elevated levels of C-reactive protein, well-treated with statin therapy 2. Finally, COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies), discussed as this month’s Landmark trial 3, showed superiority for the combination of rivaroxaban plus aspirin versus aspirin alone in patients with stable ASCVD, prompting early termination of the trial, albeit at the cost of increased bleeding. Clearly each of these strategies has the potential to address residual cardiovascular risk, even offering the opportunity for tailoring therapy to the type of residual cardiovascular risk. Despite these insights, however, are we perhaps missing a couple of fundamental tenets of care that should be prioritized before considering novel and more costly approaches?

To prevent residual cardiovascular risk we need to go back to basics, ensuring guidelines are appropriately implemented, treatments targeted effectively and adherence assured. This month’s Focus raises the issue of eligibility for lipid-lowering therapy. As shown by this report 4, primary prevention patients considered ineligible for statin therapy based on current European guidelines 5 but with elevated triglycerides (?3.0 mmol/L) are at high ASCVD risk. In a general population, this would affect 7% - or 1 in 14 - subjects. Of course, guidelines are by necessity evidence-based and the lack of conclusive findings from major outcomes studies to date has been the obstacle to the inclusion of elevated triglycerides in risk prediction scores. Three trials, two with n-3 fatty acids therapy (REDUCE-IT, ClinicalTrials number NCT01492361 and STRENGTH; NCT02104817) and one with the selective peroxisome proliferator activator receptor-alpha modulator pemafibrate (PROMINENT; NCT03071692), are in progress aiming to address this gap in evidence. So, hopefully, we should have definitive information about the extent that triglyceride-rich lipoproteins and their remnants contribute to lipid-related residual cardiovascular risk in the future.

Second, we need to ensure that guidelines are appropriately implemented and patients requiring therapy are actually taking their treatment. For example, in an analysis of statin use in more than 500,000 high risk patients in real-world practice in the USA, only 15% started treatment with a high-intensity statin (the guideline-recommended approach), and of these, about one in five was subsequently switched to a moderate- to low-intensity statin 6. Furthermore, adherence to medication is a profound problem in the secondary prevention setting with marked impact on goal attainment and clinical outcome. In EUROASPIRE IV, a cross-sectional survey of secondary prevention care in 14 European regions, of dyslipidaemic patients prescribed treatment, less than one-third attained an LDL-C <2.6?mmol/l (100 mg/dl), and even fewer the recommended goal of <1.8 mmol/L (70 mg/dl). Not to mention poor uptake of lifestyle intervention strategies ; with nearly one in five patients still smoking 7, and specific aspects related to clinical inertia.

With cost an increasingly relevant issue given the finite resources of healthcare systems, it is important to focus on these basics. Undoubtedly, novel treatments do provide added value in very high-risk patients 8. However, ensuring that guidelines are appropriately implemented and that patients take their prescribed evidence-based treatment – both lifestyle and pharmacotherapy – are essential for reducing the overall burden of residual cardiovascular risk.


1. 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.
2. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377:1119-31.
3. Eikelboom JW, Connolly SJ, Bosch J et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-30.
4. Madsen CM, Varbo A, Nordestgaard BG. Unmet need for primary prevention in individuals with hypertriglyceridaemia not eligible for statin therapy according to European Society of Cardiology/European Atherosclerosis Society guidelines: a contemporary population-based study. Eur Heart J 2017; doi:10.1093/eurheartj/ehx659.
5. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37:2999-3058.
6. Lin I, Sung J, Sanchez R et al. Patterns of Statin Use in a Real-World Population of Patients at High Cardiovascular Risk. J Manag Care Spec Pharm. 2016 Jun;226:685-98
7. Kotseva K, De Bacquer D, De Backer G et al. Lifestyle and risk factor management in people at high risk of cardiovascular disease. A report from the European Society of Cardiology European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) IV cross-sectional survey in 14 European regions. Eur J Prev Cardiol. 2016 Dec;2318:2007-2018.
8. Annemans L, Packard CJ, Briggs A, Ray KK. 'Highest risk-highest benefit' strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J 2017. doi: 10.1093/eurheartj/ehx710. [Epub ahead of print]