Is sequential treatment of dyslipidaemia effective in clinical practice?

Is sequential treatment of dyslipidaemia effective in clinical practice?

This article is based on a presentation by Prof Evangelos Liberopoulos of the University of Ioannina (Greece) at the virtual European Society of Cardiology (ESC) congress held from 27-30 August. The topic of his presentation was Sequential Treatment Strategy in Dyslipidemia versus Earlier Use of Combination Therapies: Decision-Making Factors.1

High low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk of cardiovascular (CV) events. The cornerstone of secondary prevention is treatment with LDL lowering agents.

LDL-C targets

To lower the risk of CV events in very high-risk patients, the ESC/European Atherosclerosis Society (EAS) dyslipidaemia guideline sets lower and more challenging LDL-C goals:2

» In primary prevention for individuals at very-high risk but without familial hypocholesteraemia (FH), an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.4mmol/L

» In primary prevention for individuals with FH at very-high risk, an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.4mmol/L

» For patients with atherosclerotic CVD (ASCVD) who experience a second vascular event within two years (not necessarily of the same type as the first event) while taking maximally tolerated statin-based therapy, an LDL-C goal of <1mmol/L may be considered.

Guidelines recommend a sequential management approach

The latest international guidelines recommend a sequential management approach.2,3,4

The ESC/EAS guideline recommends:2

» A high-intensity statin up to the highest tolerated dose to reach the goals set for the specific level of risk

» If the goals are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended

» For primary prevention patients at very-high risk, but without FH, if the LDL-C goal is not achieved on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor may be considered

» For secondary prevention, patients at very-high risk not achieving their goal on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended » For very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goal on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended

» If a statin-based regimen is not tolerated at any dosage (even after re-challenge), ezetimibe should be considered

» If a statin-based regimen is not tolerated at any dosage (even after re-challenge), a PCSK9 inhibitor added to ezetimibe may also be considered

» If the goal is not achieved, statin combination with a bile acid sequestrant may be considered.

Why do guidelines recommend a sequential approach?

The recently published Da Vinci study showed that among patients receiving high-intensity statins as monotherapy, LDL-C goals were achieved in 22% of very high-risk patients and 45% in patients with established ASCVD.5

So why then do guidelines recommend a sequential approach and not early initiation of combination therapy? According to Prof Liberopoulos all the evidence that support a sequential approach comes from statin trials. The majority of these trials compared CVD risk reduction with high- or moderate intensity statin therapy versus placebo. These trials all show the superiority of statin therapy versus placebo.1

A second reason may be because of the variability in LDL-C lowering with a statin. For example, a 2015 Cochrane Review showed that atorvastatin consistently lowered LDL-C over the dose range of 2.5mg/d to 80mg/d. The effect was greater with higher doses than with lower doses. For example, doses of 10mg/d to 80 mg/day resulted in 36% to 53% decreases in risk reduction.7

The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin, showed that the agent (20mg) was associated with a 50% reduction in CV events.8

However, stressed Prof Liberopoulos, these findings do not take into consideration that some patients may be hyper-responders and achieve 70%-80% reductions in LDL-C, which influence mean reported reduction rates.1

The greater the LDL-C reduction, the lower the incidence of CV events during follow up, he added. Therefore, it made sense that guideline support the use of a high intensity statin and a wait and see approach to how it affects LDL-C lowering, he added.1

Furthermore, studies showed that not all patients need the addition of a second agent, he said. For example, Sachdeva et al, analysed admission lipid levels in 136 905 patients hospitalised with coronary artery disease between 2000 and 2006. About 50% had admission LDL levels <2.5mmol/L and highdensity lipoprotein (HDL) levels <1.03mmol/L, while <10% had HDL ≥1.5mmol/L. Before admission, only 21.1% of patients were receiving lipid-lowering medications.9

The remaining patients were started on statin therapy and half achieved a 50% LDL-C reduction, and therefore did not need a second agent, said Prof Liberopoulos.1

How effective is sequential treatment in clinical practice?

The efficacy of statins to lower LDL-C is not questioned. However, in clinical practice, following the sequential approach has not been that successful, because the majority of veryhigh risk patients do not reach recommended LDL-C targets (<1.4mmol/L) despite guideline recommended treatment as shown in the Da Vinci study.1,5

In addition, the sequential approach does not address therapeutic inertia. Many primary care physicians will not intensify (or even de-intensify) treatment at follow-up, noted Prof Liberopoulos.1

The approach is also not in line with the current concept of the lower the better, the earlier the better and the longer the better for LDL-C lowering.1

Guidelines for hypertension recommend monotherapy for patients at low-risk of CVD and combination therapy in a single pill for high-risk patients. Triple combination therapy is recommended for those patients who do not reach blood pressure targets and the addition of spironolactone or other agents in patient with treatment resistant hypertension. The time has come for a paradigm shift in the approach to dyslipidaemia management in patients at very high-risk of CVD, said Prof Liberopoulous.1

This approach incorporates:

Step 1: Dual combination therapy ideally in a single pill of a high intensity statin and ezetimibe

Step 2: Triple combination ideally with a single pill high intensity statin and ezetimibe and the addition of a PCSK9i

Step 3: Triple combination with a single pill high intensity statin and ezetimibe and the addition of a PCSK9i and bebedoic acid or other agents.

References

1. European Society of Cardiology Virtual Summit (2021). Sequential treatment strategy in dyslipidemia vs earlier use of combination therapies: decisionmaking factors. https://esc365.escardio.org/ presentation/235327?resource=video

2. Mach F, Baigent C, Catapano AL, 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). European Heart Journal, 2020.

3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol, 2019.

4. Yehuda Handelsman Y, Jellinger PS, Guerin CK, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm – 2020 Executive Summary. Endocrine Practice, 2020.

5. Murphy J, Banach M, and Gaita D. EU-Wide Cross- Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: the DA VINCI study. European Journal of Preventive Cardiology, 2020.

6. Maron DJ, Fazio S and Linton MF. Current Perspectives on Statins. Circulation, 2000.

7. Adams SP, Tsang M, and Wright JM. Atorvastatin for lowering lipids. Cochrane Review, 2015. https://www. cochranelibrary.com/cdsr/doi/10.1002/14651858. CD008226.pub3/full

8. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. Circulation, 2009.

9. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J, 2009. SF