LLT use and LDL-c goal attainment among patients with high/very high CVD risk

In the prospective SANTORINI study among patients with high or very high CVD risk, lipid-lowering therapy (LLT) use and LDL-c control increased during 1-year follow-up. Yet, ~70% of the patients did not meet the 2019 ESC/EAS-recommended LDL-c targets after 1 year.

This summary is based on the publication of Ray KK, Aguiar C, Arca M, et al. - Use of combination therapy is associated with improved LDL cholesterol management: 1-year follow-up results from the European observational SANTORINI study. Eur J Prev Cardiol. 2024 Jun 11:zwae199 [Online ahead of print]. doi: 10.1093/eurjpc/zwae199

Introduction and methods

Background

Following publication of more stringent LDL-c goals in the 2019 ESC/EAS Guidelines for the management of dyslipidemias [1], the SANTORINI (treatment of high- and very-high-riSk dyslipidemic pAtients for the preveNTion of cardiOvasculaR events in Europe—a multInatioNal observatIonal) study was conducted to evaluate the treatment of patients with high or very high CVD risk in the period 2020–2021 [2]. The baseline analysis of the SANTORINI study showed 22% of patients had no documented evidence of lipid-lowering therapy (LLT) use and only 20% of all patients achieved the 2019 risk-based LDL-c goals [3].

Aim of the study

In a prospective follow-up study of the SANTORINI cohort, the authors assessed whether implementation of the 2019 ESC/EAS dyslipidemia guidelines improved with respect to LLT use at 1 year compared with baseline and whether changes in LLT use had an effect on LDL-c control and attainment of risk-based LDL-c goals.

Methods

The SANTORINI study was a multinational, prospective, observational, and descriptive study in which 9559 patients (aged ≥18 years) with high or very high CVD risk were enrolled across 14 European countries (Austria, Belgium, Denmark, Finland, France, Germany, Italy, the Netherlands, Portugal, Republic of Ireland, Spain, Sweden, Switzerland, and the UK) from March 17, 2020, to February 11, 2021, followed by 1 year of prospective follow-up (database was locked on May 31, 2022). There were no specific exclusion criteria, although study participants had to have an anticipated life expectancy >1 year.

For 9136 patients, any 1-year follow-up data were available, of whom 2626 (28.7%) had high CVD risk and 6504 (71.2%) had very high CVD risk (full analysis set). For 7210 patients (2033 with high CVD risk (28.2%) and 5173 with very high CVD risk (71.8%)), baseline and follow-up LDL-c data were available (LDL-c dataset).

Outcomes

Primary endpoints were changes in LLT use and attainment of the 2019 ESC/EAS risk-based LDL-c goals (defined as <1.8 mmol/L for patients at high CVD risk and <1.4 mmol/L for those at very high CVD risk) at 1 year. The secondary endpoint was the risk of CV events, including included CV death, 3-component MACE (CV death, nonfatal MI, or nonfatal stroke), and 4-component MACE (CV death, nonfatal MI, nonfatal stroke, or coronary revascularization), at 1 year. The incidence of all-cause mortality was an exploratory endpoint.

Main results

Changes in lipid-lowering therapy use

• In the overall population (full analysis set, n=9136), the proportion of patients not receiving LLT decreased from 20.9% at baseline to 3.3% at 1 year. When stratified by CVD risk status, the proportion of high-risk patients not receiving LLT decreased from 22.8% to 5.8% and the proportion of very high–risk patients not on LLT fell from 20.1% to 2.3%.
• During 1-year follow-up, the use of LLT as monotherapy increased from 53.6% to 57.1%, whereas the use of combination LLT rose from 25.6% to 37.9%.
• There was an escalation of LLT use in 2674 patients (29.3%), no change in treatment in 6080 patients (66.6%), and de-escalation of LLT use in 227 patients (2.5%). Similar patterns were observed when participants were stratified by high- and very high–risk status.

Changes in LDL-c control

• In the overall LDL-c dataset, the mean LDL-c level decreased from 2.4 (SD: 1.2) to 2.0 mmol/L (SD: 0.9).
• The mean LDL-c level decreased from 2.7 to 2.3 mmol/L in the high-risk group and from 2.3 to 1.9 mmol/L in the very high–risk group.

Changes in attainment of risk-based LDL-c goals

• Among the 7210 patients in the LDL-c dataset, 21.2% achieved their risk-based LDL-c goals at baseline. The same was true for 24.4% of the high-risk patients and 20.0% of the very high–risk patients.
• At 1 year, the proportion of patients at LDL-c target had increased to 30.9% (overall), 31.0% (high risk), and 30.9% (very high risk).
• This increase was largely due to an overall improvement in the group of patients not on LLT at baseline, in which goal attainment increased from 4.9% at baseline to 29.0% at 1 year. In contrast, the improvement in goal attainment in the group who did receive LLT at baseline was modest (from 25.7% to 31.4%).
• When patients not receiving LLT at baseline were stratified by treatment type at 1-year follow-up (monotherapy vs. combination therapy), 39.9% of the patients receiving combination therapy at 1 year reached their LDL-c goals compared with 27.5% of those receiving monotherapy.
• Among participants receiving LLT at baseline, goal attainment at 1 year was also greater in the group receiving combination therapy at the time than the group on monotherapy (39.4% vs. 25.5%).

CV events and all-cause mortality

• In the full analysis set, CV death occurred in 88 patients (0.96 deaths per 100 patient-years of follow-up; 95%CI: 0.76–1.17), 3-component MACE in 213 patients (2.35 events per 100 patient-years; 95%CI: 2.03–2.67), and 4-component MACE in 497 patients (5.60 events per 100 patient-years; 95%CI: 5.11–6.10).
• The rate of 3-component MACE was 49 of the 2626 high-risk patients (1.86 events per 100 patient-years; 95%CI: 1.34–2.39) and 164 of 6504 very high–risk patients (2.55 events per 100 patient-years; 95%CI: 2.16–2.94).
• The all-cause mortality rate was 1.66 deaths per 100 patient-years (95%CI: 1.40–1.93) overall, 1.14 per 100 patient-years (95%CI: 0.73–1.54) in high-risk patients, and 1.88 per 100 patient-years (95%CI: 1.55–2.22) in very high–risk patients.

Conclusion

In the European, prospective, observational SANTORINI study, conducted after publication of the 2019 ESC/EAS Guidelines for the management of dyslipidemias, LLT use was escalated in one-third of patients with high or very high CVD risk during 1-year follow-up and unchanged in two-thirds. Mean LDL-c level decreased from 2.4 mmol/L at baseline to 2.0 mmol/L at 1 year, while the proportion of patients achieving their risk-based LDL-c goals increased from 21% to 31%. More patients receiving combination LLT reached their LDL-c goals compared with those on monotherapy. Yet, 69% of all patients did not meet their LDL-c targets after 1 year, and the rate of CV events was high.

With all of the LLTs currently available to clinicians, the authors believe “it follows that the focus must now shift to evaluating strategies that better implement the 2019 ESC/EAS guidelines, with a particular focus on implementing early and greater use of combination LLTs.”

Find this article online at Eur J Prev Cardiol.

References

1. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/ EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–188.

2. Ray KK, Haq I, Bilitou A, Aguiar C, Arca M, Connolly DL, et al. Evaluation of contemporary treatment of high- and very high-risk patients for the prevention of cardiovascular events in Europe—methodology and rationale for the multinational observational SANTORINI study. Atheroscler Plus 2021;43:24–30.

3. Ray KK, Haq I, Bilitou A, Manu MC, Burden A, Aguiar C, et al. Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study. Lancet Reg Health Eur 2023;29:100624.