Treat-to-target or high-intensity statin treatment in older adults with coronary artery disease: a post hoc analysis of the LODESTAR trial

Abstract

Background

The optimal statin treatment strategy that is balanced for both efficacy and safety has not been clearly determined in older adults with coronary artery disease (CAD).

Methods

In the post hoc analysis of the LODESTAR (low-density lipoprotein cholesterol-targeting statin therapy versus intensity-based statin therapy in patients with coronary artery disease) trial, the impact between a treat-to-target strategy versus a high-intensity statin therapy strategy was compared in older adults (aged 75 years or older). The goal of treat-to-target low-density lipoprotein cholesterol (LDL-C) level was 50–70 mg/dl. The primary endpoint comprised the three-year composite of all-cause death, myocardial infarction, stroke or coronary revascularisation.

Results

Among 4,400 patients with CAD enrolled in the LODESTAR trial, 822 (18.7%) were aged 75 years or older. Poor clinical outcomes and risk factors for atherosclerosis were more frequently observed in older adults than in younger population (<75 years old). Among these older adults with CAD, the prescription rate of high-intensity statin was significantly lower in the treat-to-target strategy group throughout the study period (P < 0.001). The mean LDL-C level for three years was 65 ± 16 mg/dl in the treat-to-target strategy group and 64 ± 18 mg/dl in the high-intensity statin group (P = 0.34). The incidence of primary endpoint occurrence was 10.9% in the treat-to-target strategy group and 12.0% in the high-intensity statin group (hazard ratio 0.92, 95% confidence interval 0.61–1.38, P = 0.69).

Conclusions

High-intensity statin therapy is theoretically more necessary in older adults because of worse clinical outcomes and greater number of risk factors for atherosclerosis. However, the primary endpoint occurrence with a treat-to-target strategy with an LDL-C goal of 50–70 mg/dl was comparable to that of high-intensity statin therapy and reduced utilisation of a high-intensity statin. Taking efficacy as well as safety into account, adopting a tailored approach may be considered for this high-risk population.

Trial Registration

ClinicalTrials.gov, NCT02579499.

Key Points

• In this post hoc analysis of the randomised LODESTAR trial of older adults (≥75 years old) with coronary artery disease (CAD), the treat-to-target strategy was non-inferior to the high-intensity statin strategy for the 3-year composite of all-cause death, myocardial infarction, stroke or coronary revascularisation.

• The mean low-density lipoprotein cholesterol (LDL-C) level and the proportion of patients with LDL-C <70 mg/dl were similar between the two treatment strategies, while the prescription rate of high-intensity statins was significantly lower in the treat-to-target strategy group.

• The incidence of adverse events during the study period was comparable between the two strategies in older adults with CAD.

• During the 3-year study period, significantly lower prescription rates for high-intensity statins and significantly higher prescription rates for ezetimibe were observed in the treat-to-target group.

• Considering the safety concerns, a tailored approach might be reasonable for this high-risk population.

Introduction

As society ages, the proportion of older adults suffering from coronary artery disease (CAD) is gradually increasing [1, 2]. This older population is considered to be at high risk for future cardiovascular events due to their combined multiple co-morbidities as well as high risk of adverse reactions to their prescribed medications [3]. Thus, older adults are often hesitant to be included in randomised clinical trials. This has led to a lack of data on the efficacy and safety of statin therapy in this high-risk group [4, 5]. For the secondary prevention of cardiovascular events in older adults with CAD, the latest international guidelines on lipid management recommend the use of high-intensity statin based on patient’s tolerance [6, 7]. This recommendation is similar to that for those younger than 75 years and is supported by robust evidence showing the efficacy of statin therapy in reducing cardiovascular events in older adults with atherosclerotic cardiovascular disease [8]. However, consideration of individual co-morbidities and overall health status, as well as the potential risk for adverse drug reactions and drug interactions, is of great importance when selecting appropriate lipid-lowering therapy in older adults. The recent LODESTAR (low-density lipoprotein cholesterol-targeting statin therapy versus intensity-based statin therapy in patients with coronary artery disease) trial has demonstrated that a targeted approach of titrating statin intensity to achieve a low-density lipoprotein cholesterol (LDL-C) goal of 50–70 mg/dl is non-inferior to high-intensity statin therapy in patients with CAD with regard to 3-year cardiovascular outcomes. This post hoc analysis aims to clarify whether this effect is also clinically effective for older adults with CAD.

Methods

Study design and population

The LODESTAR trial was an investigator-initiated, prospective, multicentre, randomised, open-label, noninferiority clinical trial that included 4,400 patients with CAD from 12 centers in South Korea and compared the therapeutic effect of a treat-to-target strategy using titrated-intensity statin therapy with an LDL-C level of 50–70 mg/dl as a target versus high-intensity statin strategy without a target goal. The design and protocols for the LODESTAR trial have been previously described in detail [9]. Eligible participants for the trial were patients with a clinical diagnosis of CAD, including stable ischaemic heart disease and acute coronary syndrome [9]. The inclusion and exclusion criteria are provided in Table S1 in the Supplement. In this post hoc analysis, patients in the LODESTAR trial were divided into two groups according to age: those aged 75 years or older (older adults) and those younger than 75 years. The cut-off value for age (75 years) was selected based on recent dyslipidaemia management guidelines focusing on age [6, 7]. The trial adhered to the ethical principles of the Declaration of Helsinki and received approval from the Institutional Review Board of each participating centre. Written informed consent was obtained from all participants prior to their participation in the trial. Study coordination, data management and site management services were conducted by the Cardiovascular Research Center (Seoul, South Korea).

Study procedures

Eligible patients were randomly assigned in a 1:1 ratio to receive statin therapy through either a treat-to-target strategy or high-intensity statin therapy strategy using web-response permuted-block randomisation with mixed blocks of four or six. Patients were stratified by presence of diabetes mellitus, baseline LDL-C levels greater than 100 mg/dl and acute coronary syndrome [9]. According to the classification of statin intensity based on the 2013 American College of Cardiology/American Heart Association guidelines on the management of dyslipidaemia [10], patients received either rosuvastatin 10 mg or atorvastatin 20 mg for moderate-intensity statin therapy and rosuvastatin 20 mg or atorvastatin 40 mg for high-intensity statin therapy. In the treat-to-target group, the goal was to achieve an LDL-C level below 70 mg/dl, which was the lowest recommended LDL-C level for the population in the most recent guidelines at the time of trial design (August 2015) [11–13]. Statin intensity was adjusted to reach this target as previously described [9]. For patients in the high-intensity statin group, high-intensity statin therapy was initiated and maintained regardless of the patients’ LDL-C levels at randomisation and follow-up [9]. The use of non-statin agents such as ezetimibe was not strongly recommended in order to focus on the effects of statin therapy and avoid confounding by any imbalances in their use. In addition to the study intervention, guideline-directed medical therapy was strongly recommended for other medical treatments. Modification of risk factors, such as blood pressure control and glucose management, weight reduction, exercise, dietary changes and smoking cessation, was also encouraged. Follow-up assessments included monitoring of general health status, drug use and occurrence of study outcomes or adverse events at 6 weeks and 3, 6, 12, 24 and 36 months.

Study endpoints and definition

In accordance with the LODESTAR trial protocol, the primary endpoint was major adverse cardiac and cerebrovascular events defined as a composite of all-cause death, myocardial infarction, stroke and any coronary revascularisation within 3 years [9]. Death was categorised as cardiovascular death or non-cardiovascular death. Cardiovascular death was defined as death resulting from myocardial infarction, sudden cardiac arrest, heart failure, stroke, cardiovascular procedures, cardiovascular bleeding or any death for which a cardiovascular cause could not be excluded. Myocardial infarction was defined as a clinical event accompanied by symptoms, changes in electrocardiograms or abnormal findings during imaging studies along with an increase in the creatine kinase myocardial band fraction above the upper normal limit or an increase in troponin-T or troponin-I level > the 99th percentile of the upper normal limit [9, 14]. Stroke was defined as an acute cerebrovascular event causing a neurologic deficit for >24 hours or the presence of an acute infarction on imaging studies [15]. Coronary revascularisation included percutaneous coronary intervention or coronary artery bypass graft surgery with clinically indicated revascularisation defined as an invasive angiographic percent diameter stenosis of ≥50% with ischemic symptoms or signs or a percent diameter stenosis of ≥70% in the absence of symptoms or signs. Secondary outcomes included: (i) new-onset diabetes mellitus, (ii) discontinuation of study drugs due to intolerance, (iii) deep vein thrombosis or pulmonary thromboembolism, (iv) endovascular revascularisation for peripheral artery disease, (v) hospitalisation due to heart failure, (vi) a composite of laboratory abnormalities, (vii) cataract surgery and (viii) end-stage kidney disease [9]. The definitions for each of the secondary endpoints are provided in Table S2 in the Supplement.

Statistical analysis

The primary and secondary endpoints were analysed in the intention-to-treat population, and sensitivity analyses were performed in the per-protocol population. Categorical data are presented as numbers and percentages, and continuous data are presented as means and standard deviations or medians (interquartile ranges) as appropriate. Cumulative incidence of the primary endpoint at 3 years was estimated using Kaplan–Meier curves for time-to-event analysis, and event rates between the two groups were compared using log-rank tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression analysis. The heterogeneity for the effect of therapy (treat-to-target strategy vs. high-intensity statin therapy) was evaluated for interaction with age using Cox proportional hazard regression models. Statistical significance was defined as P < 0.05 without adjustment for multiple comparisons. Statistical analyses were conducted using IBM SPSS version 25.0 (IBM Corporation, Chicago, IL, USA) and R 3.5.3 software (R Foundation for Statistical Computing, Vienna, Austria).

Results

Among 4,400 patients with CAD (mean age, 65 ± 10 years old) who were enrolled in the LODESTAR trial, 822 (18.7%) were older adults (aged 75 years or older). The baseline characteristics including the lipid profiles and medication status at the time of randomisation between older adults and those younger than 75 years are presented in Table S3. Older adults exhibited a higher proportion of females than younger patients (39.9% vs. 25.2%, P < 0.001) and had a lower body mass index (24.3 kg/m² vs. 24.8 kg/m², P < 0.001). Older adults had a higher prevalence of co-morbidities, including hypertension (77.6% vs. 64.3%, P < 0.001), diabetes mellitus (38.8% vs. 32.1%, P < 0.001), chronic kidney disease (18.0% vs. 4.8%, P < 0.001), previous coronary artery bypass graft surgery (11.1% vs. 6.8%, P < 0.001) and previous stroke (8.5% vs. 5.4%, P < 0.001) than those younger than 75 years. Compared to patients younger than 75 years, older adults already received more statin (83.8% vs. 88.0%, P < 0.001), resulting in lower mean LDL-C levels (88 mg/dl vs. 80 mg/dl, P < 0.001) and triglyceride levels (141 mg/dl vs. 126 mg/dl, P < 0.001). The incidence of acute coronary syndrome was higher in patients aged 75 years or older than in younger patients (23.7% vs. 20.1%, P = 0.03). Older adults were associated with a significantly higher occurrence of the primary endpoint (11.4% vs. 7.6%, HR 1.53, 95% CI 1.21–1.94, P < 0.001), all-cause death (6.4% vs. 1.5%, HR 4.29, 95% CI 2.94–6.26, P < 0.001) and stroke (2.1% vs. 0.8%, HR 2.82, 95% CI 1.54–5.18, P < 0.001) compared to patients younger than 75 years (Table S4 in the Supplement).

There were no statistically significant differences in baseline characteristics of older adults between the treat-to-target group and the high-intensity statin group (Table 1). Temporal trends in the change in statin intensity according to treatment strategies in older adults are shown in Figure 1. During the 3-year study period, significantly lower prescription rates for high-intensity statins (P < 0.001) and significantly higher prescription rates for ezetimibe (P < 0.01) were observed in the treat-to-target group. The mean LDL-C level for 3 years was 65 ± 16 mg/dl in the treat-to-target strategy group and 64 ± 18 mg/dl in the high-intensity statin group (P = 0.34). Throughout the 3-year study period, no statistically significant differences were observed in the mean LDL cholesterol level and the proportion of patients with LDL-C < 70 mg/dl between the two groups (all P > 0.05, Table 2). Patients were followed for a median of 3.0 years (interquartile range, 3.0–3.0 years). The incidences of primary and secondary endpoints stratified by age and treatment strategy are shown in Table 3. Primary endpoint incidence was 10.9% in the treat-to-target group and 12.0% in the high-intensity statin group (HR 0.92, 95% CI 0.61–1.38, P = 0.69; Figure 2). There was no significant heterogeneity of the therapeutic effect across the age groups (P for interaction = 0.65). The incidences of each component of the primary endpoint were also comparable between the two treatment strategies in older adults (all P > 0.05) with no significant heterogeneity in therapeutic effect. No significant interaction was observed between the clinical presentation as acute coronary syndrome within 1 year of randomisation and treatment strategy in patients aged 75 years or older (P for interaction = 0.27) and those younger (P for interaction = 0.19). In a sensitivity analysis of the per-protocol population (Table S5 in the Supplement), a comparable impact of the two treatment strategies on the primary and secondary endpoints was consistently observed (Table S6).

Discussion

The post-hoc analysis of the LODESTAR trial among older adults with CAD showed that clinical outcomes were comparable between the treat-to-target strategy targeting an LDL-C goal of 50–70 mg/dl and high-intensity statin therapy in regard to adverse cardiovascular events, LDL-C control and drug-related adverse events during the 3-year follow-up. Notably, the utilisation of high-intensity statin was observed in less than half of the treat-to-target strategy group.

Prescription of statins in older adults with atherosclerotic cardiovascular disease continues to be a widely acknowledged clinical practice. This approach is supported by substantial evidence of the benefit of intensive lipid-lowering therapy even in the older adults [16]. In a meta-analysis involving 14,483 patients aged 75 years or older who were undergoing statin therapy across 28 randomised clinical trials, a 40 mg/dl reduction in LDL-C through more intensive lipid-lowering therapy correlated with a 28% risk reduction in major cardiovascular events [8]. Consequently, recent international guidelines provide supportive recommendations for the use of high- or moderate-intensity statins in older adults with CAD for secondary prevention. The 2018 American Heart Association/American College of Cardiology (AHA/ACC) guidelines suggest that continuation of high-intensity statin therapy in older adults is a reasonable approach if the statin is well tolerated. Moderate-intensity statin therapy could be also considered as an initial therapy [6]. The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guideline advocates for applying high-intensity statin therapy using an approach consistent with that for younger patients, suggesting an LDL-C target of less than 55 mg/dl, irrespective of age [7].

Despite the benefits of intensive statin therapy in older adults with CAD, the risk of drug-related adverse events remains a critical consideration when prescribing statins to this population. Older adults often present with multiple comorbidities necessitating use of multiple drugs with a high risk of drug interactions, and these patients are more vulnerable to drug-related adverse events such as statin-associated muscle symptoms, new-onset diabetes mellitus or hepatic toxicity. This concern becomes even more pronounced with the use of high-intensity statin therapy [5, 16, 17]. Therefore, both guidelines emphasise the necessity of individualised risk assessment for treatment decisions, which may encompass factors such as patient’s age, functional ability, multiple co-morbidities, multiple drug use, fragility, cognitive status, mental health and the potential for drug-related adverse events [6, 7, 18]. Despite these challenging clinical circumstances, there are a striking lack of data on appropriate therapeutic approaches for this population that is usually underrepresented in randomised clinical trials. In the Study Assessing Goals in the Elderly (SAGE) trial, which exclusively enrolled older adults aged 65–85 years with CAD, high-intensity statin therapy was shown to be superior to moderate-intensity statin therapy in reducing major cardiovascular events and death [19]. In a post hoc analysis of the Improved Reduction of Outcomes: Vytolin Efficacy International Trial (IMPROVE-IT) trial with a subset of older adults aged 75 years or older, more intensive lipid-lowering therapy by the combination of ezetimibe and moderate-intensity statin proved more effective in reducing adverse cardiovascular events than moderate-intensity statin monotherapy in patients with acute coronary syndrome [20, 21]. These significant findings justify statin treatment in older adults by demonstrating the importance of reduction of LDL-C level. However, efficacy and safety data to determine optimal treatment for older adults are still limited.

The recently published LODESTAR trial is distinct in that this trial assesses an efficacious treatment approach in patients with CAD [9] and concentrates on an alternative treatment strategy to high-intensity lipid-lowering therapy by augmenting statin potency [22]. A treat-to-target strategy aiming for LDL-C levels of 50–70 mg/dl was non-inferior to high-intensity statin therapy with respect to the occurrence of adverse cardiovascular events and the management of LDL-C levels during a 3-year follow-up period. This finding was observed despite a significantly lower use of high-intensity statin therapy [9]. Given that clinical outcomes were comparable when adequate LDL-C reduction was achieved regardless of the mandatory utilisation of high-intensity statin, safety becomes a significant concern in older adults. Considering that statin-related adverse events are more evident with the use of high-intensity statin [16], early combination therapy with non-statin lipid-lowering agents is a reasonable treatment approach that satisfies both attaining adequate reduction of LDL-C level and minimising the risk of statin-associated adverse events. A recent subgroup analysis that compared early ezetimibe combination with moderate-intensity statin to high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease and aged ≥75 years showed comparable clinical outcomes in terms of three-year composite cardiovascular events between the two treatment groups. Lower rates of drug intolerance leading to discontinuation or dose reduction and greater reductions in LDL-C levels in the combination therapy group with ezetimibe and moderate-intensity statin were also observed [17]. Particularly, the rate of new-onset diabetes mellitus significantly higher in older adults treated with high-intensity statin (18.7% vs. 10.0%, P = 0.025). Concordantly, in the present study, the occurrence of new-onset diabetes mellitus was numerically lower in the treat-to-target group than high-intensity statin group. Additionally, the randomised EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial On PreventIon of Atherosclerosis in 75 or Older) trial showed that the use of ezetimibe reduced adverse cardiovascular events in individuals aged >75 years with elevated LDL-C level [23]. In the present study targeting older adults with CAD from the LODESTAR trial, the prescription rate of ezetimibe remained consistently higher in the treat-to-target group compared to the high-intensity statin group throughout the 3-year study period, suggesting the need for broader utilisation of ezetimibe to achieve target LDL-C goals. These results are consistent with a previous study that demonstrated favourable drug adherence associated with early combination therapy of ezetimibe with moderate-intensity statins compared to high-intensity statin therapy in patients with atherosclerotic cardiovascular disease aged >75 years [17]. Notably, older adults with CAD exhibited lower LDL and triglyceride levels, as well as a reduced incidence of acute coronary syndrome, compared to younger patients. These findings highlight the importance of considering these distinct characteristics when establishing optimal treatment strategy for secondary prevention in older adults with CAD. In this context, the present study paves a new way forward by demonstrating the feasibility and potential benefits of a treat-to-target approach in this population.

Limitations

The current study has several limitations. First, the power of the investigation is limited as a result of the limited number of older adults, and the outcomes derived from patient subgroups are not individually powerful enough to yield conclusive evidence on the comparative effects of the treat-to-target strategy versus high-intensity statin therapy. Therefore, the possibility of a chance finding cannot be excluded. Second, this study was conducted as an open-label trial, which may introduce potential biases due to the lack of blinding. However, an independent clinical endpoint committee, blinded to treatment allocations, adjudicated all clinical outcomes to mitigate these biases. Third, the LODESTAR trial exclusively included patients with CAD; thus, the generalisability of the observed findings to patients with atherosclerotic cardiovascular disease other than CAD or those necessitating primary prevention remains uncertain. Fourth, the follow-up period in the present study was 3 years. This may be relatively short to adequately compare the long-term effects of the two strategies. The findings of this study should, therefore, be regarded as hypothesis-generating and require further prospective validation. Finally, the assessment of frailty and cognitive functions related to geriatric conditions, which could influence outcomes, was not feasible in this study.

Conclusions

In older adults with CAD, a treat-to-target LDL-C strategy of 50–70 mg/dl as the goal was comparable to high-intensity statin therapy in terms of adverse cardiovascular outcomes and LDL-C management during 3-year follow-up. The use of high-intensity statin was significantly lower. Because of safety concerns, a tailored approach may be considered reasonable for this high-risk population.

Declaration of Conflicts of Interest

Dr Myeong-Ki Hong has received speaker’s fees from Medtronic, Edward Lifesciences and Viatris Korea and institutional research grants from Sam Jin Pharmaceutical and Chong Kun Dang Pharmaceutical.

Declaration of Sources of Funding

This study was funded by Sam Jin Pharmaceutical, Seoul, Korea and Chong Kun Dang Pharmaceutical, Seoul, Korea and supported by the Cardiovascular Research Center, Seoul, Korea. No funder/sponsor had any role in the design or conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.

References

Author notes