This prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ATP Citrate Lyase (ACL)–Inhibiting Regimen (CLEAR) Outcomes trial investigates if bempedoic acid is associated with a reduction in the total burden of cardiovascular events in patients at high risk for cardiovascular disease.
Key Points
Question
Does bempedoic acid reduce the total burden of cardiovascular events in high-risk patients?
Findings
In this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ATP Citrate Lyase (ACL)–Inhibiting Regimen (CLEAR) Outcomes trial of 13 970 patients with high cardiovascular risk, intolerance of statin or high-intensity statin medication, and elevated low-density lipoprotein cholesterol (LDL-C) levels, treatment with bempedoic acid compared with placebo was associated with a reduction in the total burden of major cardiovascular events. A lower hazard ratio was observed in favor of bempedoic acid for the incidence of an increasing number of clinical events for a given patient.
Meaning
This analysis emphasizes the importance of lowering LDL-C levels in patients at high cardiovascular risk to reduce the totality of cardiovascular events over time.
Abstract
Importance
The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remain unknown.
Objective
To determine the impact of bempedoic acid on the total incidence of MACE.
Design, Setting, and Participants
Included in this prespecified analysis of the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial were patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and inability to take guideline-recommended statins. Study data were analyzed from December 2016 to November 2022.
Interventions
Patients were randomly assigned to treatment with bempedoic acid or placebo daily.
Main Outcomes and Measures
The primary end point was the time to first event for a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (MACE-4). The key secondary end point was time to first event for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE-3). This prespecified analysis compared the total number of cardiovascular events in the treatment groups.
Results
A total of 13 970 patients (mean [SD] age, 65 [9] years; 7230 male [51.8%]) were included in the study. A total of 9764 participants (69.9%) had prior atherosclerotic cardiovascular disease and a baseline LDL-C level of 139 mg/dL; treatment with bempedoic acid resulted in a 21% reduction in LDL-C level and a 22% reduction in high-sensitivity C-reactive protein (hsCRP) level at 6 months. Median (IQR) follow-up was 3.4 (3.1-3.9) years. A total of 1746 positively adjudicated first MACE-4 events and 915 additional MACE events in 612 patients were recorded, with coronary revascularization representing 32.8% (573 of 1746) of first events and 69.4% (635 of 915) of additional events. For the total incidence of cardiovascular events, treatment with bempedoic acid was associated with a reduction in risk of MACE-4 (hazard ratio [HR], 0.80; 95% CI, 0.72-0.89; P <.001), MACE-3 (HR, 0.83; 95% CI, 0.73-0.93; P = .002), myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001), although no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03). A lower HR for protection with bempedoic acid was observed with increasing number of MACE events experienced by patients.
Conclusion and Relevance
Lowering LDL-C level with bempedoic acid reduced the total number of cardiovascular events in patients with high cardiovascular risk, statin therapy intolerance, and elevated LDL-C levels.
Introduction
Preclinical, cohort, and genetic studies have established the pivotal role that low-density lipoprotein cholesterol (LDL-C) plays in the causality of atherosclerotic cardiovascular disease.1 These data led to randomized clinical trials demonstrating that lowering LDL-C level with statins, both as monotherapy and in combination with other agents, decreased the rate of major adverse cardiovascular events (MACE)2,3,4,5,6 and reduced the progression of coronary atherosclerosis.7,8,9,10 Current prevention guidelines emphasize the importance of LDL-C lowering with statins as a cornerstone to reducing cardiovascular risk.11,12 However, long-term adherence to statin therapy is poor,13,14 resulting in suboptimal achievement of LDL-C goals, which limits the ability of treatment to reduce the risk of cardiovascular events.15 A major factor contributing to poor adherence is statin intolerance, which limits the ability to administer effective doses.16
Bempedoic acid is a pharmacological inhibitor of ATP citrate lyase (ACL), an enzyme involved in the hepatic cholesterol synthesis pathway.17 Bempedoic acid is inactive and requires in vivo activation by a hepatic isozyme that is undetectable in skeletal muscle.17 This feature of bempedoic acid provides a rationale for lipid lowering with less likelihood for myalgias commonly experienced with statin treatment. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial, demonstrated that compared with placebo, bempedoic acid reduced LDL-C level by 21.1%, high sensitivity C-reactive protein (hsCRP) level by 22.2%, and the risk of first event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and coronary revascularization (MACE-4) by 13% in patients at high cardiovascular risk with hypercholesterolemia who were unable or unwilling to take guideline-recommended doses of statins.6
Large randomized clinical trials of cardiovascular agents typically focus on the time to first event of any of the components of the composite primary end point. However, patients at high cardiovascular risk may experience multiple clinical events over time. The totality of cardiovascular events presents considerable health, social, and economic challenges for these patients. In the current, prespecified analysis of the CLEAR Outcomes trial, the impact of bempedoic acid on the total incidence of MACE was investigated.
Methods
Study Design
The study design18 and primary results6 of the CLEAR Outcomes trial have been published previously (Supplement 1). This was a randomized, double-blind, placebo-controlled, clinical trial undertaken at 1250 sites in 32 countries. Patients aged 18 to 85 were eligible for enrollment if they had either sustained a previous cardiovascular event (secondary prevention) or were considered at high risk for a cardiovascular event (primary prevention), with a baseline LDL-C level of at least 100 mg/dL (2.6 mmol/L; to convert to millimoles per liter, multiply by 0.0259). Patients had to report being unable or unwilling to receive recommended doses of statins owing to an adverse effect that started or increased during statin therapy and resolved or improved after discontinuation. Concomitant treatment with a very low average daily statin dose (below the lowest approved dose) without adverse effects was permitted, as was administration of other lipid-lowering therapy such as ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. Patients from the following self-reported race and ethnicity categories were included: American Indian or Alaska Native, Asian, Black, multiracial, Native Hawaiian or Other Pacific Islander, White, and other; ethnicity was reported as Hispanic/Latino or non-Hispanic/Latino. Race and ethnicity were collected in order to evaluate any possible differences in other analyses for these and other demographic characteristics.
Ethics committee approvals for the trial were obtained locally via relevant authorities or through a central institutional review board with each patient providing written informed consent. The primary end point was time to first occurrence of the 4-component composite MACE-4. Key secondary end points included a 3-component composite of cardiovascular death, myocardial infarction, and stroke (MACE-3), as well as the individual components of the composite outcomes. End points were adjudicated by a clinical events committee managed by the Cleveland Clinic Center for Clinical Research blinded to trial-group assignment. End point definitions have been published previously.18 This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Statistical Analysis
This prespecified analysis used the intention-to-treat population of the trial to compare the total number of primary end points, key composite secondary end points, and individual nonfatal components of the MACE composite between patients treated with bempedoic acid or placebo. Baseline clinical characteristics are presented as frequencies for categorical variables and medians and IQRs for continuous variables. Race was classified into groups by investigators. Comparisons between baseline characteristics for patients with no events, 1 event, or at least 2 events were made using χ2 test for categorical variables and Wilcoxon rank sum test for continuous variables.
The number, timing from randomization, and gaps between nonfatal cardiovascular events and death were summarized. For MACE-4, MACE-3, and nonfatal cardiovascular events, an Andersen-Gill model was applied as the prespecified analysis. Mean cumulative function curves were plotted for MACE-4, MACE-3, and nonfatal cardiovascular events. This model assumes that the hazard of the event for each patient is not modified by having experienced an earlier event. Hazard ratios (HRs) and their 95% CIs are reported. As sensitivity analyses, a Wei-Lin-Weissfeld (WLW) marginal model and a negative binomial regression model were performed. The marginal model preserves the randomization by considering that every patient is at risk for all events (the first and beyond). For simplicity, only the first 4 events were evaluated in the model because few patients experienced more than 4 events. The HRs of experiencing the first, second, etc, events are reported with 95% CIs. The negative binomial model assumes that the patient’s risk was constant over time and was used to calculate the risk difference (ARR) between treatment groups and the corresponding 95% CI. In addition, absolute risk reduction (ARR) in total events is calculated as the difference in the cumulative risk at year 5, modeled to account for patients who were not treated for this duration of time during the study. Study data were analyzed from December 2016 to November 2022. All statistical analyses were 2-sided with a nominal significance level of .05, without multiplicity adjustment. Analyses were conducted with SAS, version 9.4 (SAS Institute). All analyses for this manuscript were performed by an academic statistician at the Cleveland Clinic Coordinating Center for Clinical Research (D.B.).
Results
Clinical Characteristics and Incidence of Clinical Events
A total of 13 970 patients mean [SD] age, 65 [9] years; 7230 male [51.8%]; 6740 female [48.2%]) were randomly assigned to treatment groups between December 2016 and August 2019 and were followed for a median (IQR) of 3.4 (3.1-3.9) years. The clinical characteristics of 13 970 patients treated with bempedoic acid and placebo in the CLEAR Outcomes study have been described previously (eFigure 1 in Supplement 2) Overall, 9764 patients (69.9%) had a history of atherosclerotic cardiovascular disease, and 6373 (45.6%) had diabetes. Patients self-identified with the following race categories: 487 American Indian or Alaska Native (3.5%), 266 Asian (1.9%), 328 Black (2.3%), 118 multiracial (0.8%), 37 Native Hawaiian or Other Pacific Islander (0.3%), 12 732 White (91.1%), and 2 other (<0.1%); patients self-identified with the following ethnic groups: 2333 Hispanic/Latino (16.7%) and 11 637 non-Hispanic/Latino (83.3%). A total of 3174 patients (22.7%) were treated with very low doses of statin therapy on study entry, baseline mean (SD) LDL-C level was 139 (35) mg/dL, and median (IQR) hsCRP level was 2.3 (1.2-4.5) mg/L (to convert to milligrams per deciliter, divide by 10). Treatment with bempedoic acid was associated with reductions in LDL-C level by 21.1% and hsCRP level by 22.2% at 6 months.
During the study, a total of 1746 patients (12.5%) positively adjudicated first MACE-4 events and 915 additional MACE events (612 patients [4.4%]) were recorded. Of patients experiencing more than 1 MACE event, 437 recorded 2 events, 114 recorded 3 events, and 61 recorded at least 4 clinical events (Figure 1). The maximum number of total events experienced by a single patient was 11, occurring in 2 placebo-treated participants. Cardiovascular death accounted for 24.4% (426 of 1746) of first MACE events and 10.9% (100 of 915) of additional MACE events. Coronary revascularization accounted for 32.8% (573 of 1746) of first MACE events and 69.4% (635 of 915) of additional MACE events (Figure 2 and eFigure 2 in Supplement 2).
Figure 1. Distribution of Major Adverse Cardiovascular Events (MACE) Components in First and Additional Cardiovascular (CV) Events.
Relative distribution of individual MACE components in patients who experienced a first or additional clinical event. Cor indicates coronary; MI, myocardial infarction.
Figure 2. First and Total Incidence of Cardiovascular (CV) Events.
Kaplan-Meier curves for the incidence of first and total incidence of the primary major adverse CV event end point of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, and coronary revascularization (A), key secondary composite end point of CV death, nonfatal MI, and nonfatal stroke (B), nonfatal MI (C), and coronary revascularization (D). Results expressed as hazard ratio (HR) and 95% CI. For total events, the curves are the estimated mean cumulative risks from the Andersen-Gill Cox regression model. The numbers at risk represent patients at risk for first and additional events.
The clinical characteristics, baseline use of lipid-lowering therapies, and laboratory values for patients, stratified according to the number of MACE events experienced, are summarized in the eTable in Supplement 2. Several differences were observed between patients stratified according to the number of clinical events experienced during the trial. A greater number of cardiovascular events was associated with patients who were older (median [IQR] age, multiple events: 67 [61-74] years vs no events: 66 [60-71] years), male (multiple events: 407 male [66.5%] vs 205 female [33.5%]), and with an established history of atherosclerotic cardiovascular disease, particularly involving the coronary vasculature (number of patients, multiple events: 476 of 612 [77.8%] vs no events: 5831 of 12 224 [47.7%]). Baseline use of very-low-dose statin therapy was lowest and ezetimibe was highest in those patients who experienced more than 1 cardiovascular event (number of patients, statin multiple events: 96 of 612 [15.7%] vs statin no events: 2841 of 12 224 [23.2%]; ezetimibe multiple events: 100 of 612 [16.3%] vs ezetimibe no events: 1351 of 12 224 [11.1%]). Patients who subsequently experienced the greatest number of MACE events had higher levels of LDL-C (median [IQR], multiple events: 139.3 [118.5-163.5] mg/dL vs no events: 134.5 [115.0-158.5] mg/dL), triglycerides (median [IQR], multiple events: 167.0 [119.0-233.3] mg/dL vs no events: 158.5 [117.5-214.0] mg/dL; to convert to millimoles per liter, multiply by 0.0113), and hsCRP (median [IQR], multiple events: 2.7 [1.4-4.9] mg/L vs no events: 2.3 [1.1-4.4] mg/L) and lower levels of high-density lipoprotein cholesterol (median [IQR], multiple events: 44.0 [38.3-53.0] mg/dL vs no events: 47.5 [40.5-57.0] mg/dL; to convert to millimoles per liter, multiply by 0.0259).
Total Cardiovascular Events
The incidence of total cardiovascular events in patients treated with bempedoic acid and placebo are summarized in the Table, Figure 2, and Figure 3. The estimated cumulative incidences demonstrated increasing widening of event curves for both first and total incidence of these major cardiovascular end points. Treatment with bempedoic acid resulted in a lower incidence of the primary MACE-4 events per 100 patient-years (5.0 vs 6.2; HR, 0.80; 95% CI, 0.72-0.89; P <.001) and key secondary composite MACE-3 end point (2.8 vs 3.3; HR, 0.83; 95% CI, 0.73-0.93; P = .002). These event frequencies produced a 20% reduction in the total incidence of the primary end point, compared with the 13% reduction in first end point and a 17% reduction in the total incidence of the key composite secondary end point (MACE-3), compared with the 15% reduction in first incidence. Significant reductions in the total incidence of nonfatal myocardial infarction (1.1 vs 1.6 events per 100 patient-years; HR, 0.69; 95% CI, 0.58-0.83; P <.001) and coronary revascularization (2.2 vs 2.8 events per 100 patient-years; HR, 0.78; 95% CI, 0.68-0.89; P <.001) were also observed. Although fewer total strokes were observed in the bempedoic acid group (127 vs 157), this comparison failed to meet the nominal statistical significance (HR, 0.80; 95% CI, 0.63-1.03; P = .09) (eFigure 3 in Supplement 2).
Table. Primary and Secondary End Pointsa,b.
| Clinical end point | First events (event rate) | HR (95% CI) for first event analysis | P value | |
|---|---|---|---|---|
| Placebo (n = 6978) | Bempedoic acid (n = 6992) | |||
| First event analysis | ||||
| CV death, nonfatal MI, nonfatal stroke, coronary revascularization | 927 (13.3) | 819 (11.7) | 0.87 (0.79-0.96) | .004 |
| CV death, nonfatal MI, nonfatal stroke | 663 (9.5) | 575 (8.2) | 0.85 (0.76-0.96) | .006 |
| Fatal and nonfatal MI | 334 (4.8) | 261 (3.7) | 0.77 (0.66-0.91) | .002 |
| Coronary revascularization | 529 (7.6) | 435 (6.2) | 0.81 (0.72-0.92) | .001 |
| Fatal and nonfatal stroke | 158 (2.3) | 135 (1.9) | 0.85 (0.67-1.07) | NA |
| Cardiovascular death | 257 (3.7) | 269 (3.8) | 1.04 (0.88-1.24) | NA |
| All-cause death | 420 (6.0) | 434 (6.2) | 1.03 (0.90-1.18) | NA |
| Clinical end point | Total events (event rate/100 patient-years) | HR (95% CI) for total event analysis | P value | |
| Placebo (n = 6978) | Bempedoic acid (n = 6992) | |||
| CV death, nonfatal MI, nonfatal stroke, coronary revascularization | 1471 (6.2) | 1190 (5.0) | 0.80 (0.72-0.89) | <.001 |
| CV death, nonfatal MI, nonfatal stroke | 793 (3.3) | 660 (2.8) | 0.83 (0.73-0.93) | .002 |
| Nonfatal MI | 379 (1.6) | 264 (1.1) | 0.69 (0.58-0.83) | <.001 |
| Nonfatal stroke | 157 (0.7) | 127 (0.5) | 0.80 (0.63-1.03) | .09 |
| Coronary revascularization | 678 (2.8) | 530 (2.2) | 0.78 (0.68-0.89) | <.001 |
Abbreviations: CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; NA, not applicable.
HR (95% CI) for comparison of treatment with bempedoic acid and placebo on the impact of first and total incidence of primary and secondary composite end points and their individual components.
HR was calculated from Cox proportional hazard model, with Andersen-Gill model used for the total event analysis. P values from log-rank tests are reported for the first event analyses. For the total event analyses, P values are from the Cox model with robust estimates of the SEs.
Figure 3. Total Events Analysis for the Primary and Key Secondary End Points.
Hazard ratio (HR) and 95% CI for the comparison of treatment with bempedoic acid and placebo and in the total incidence of primary and key secondary composite major adverse cardiovascular (CV) and individual nonfatal components. HRs and 95% CIs are estimated based on the Andersen-Gill model, using Cox regression with robust sandwich estimates of SEs. HR for CV death reflects a first-events analysis. NA indicates not applicable.
Effect of Bempedoic Acid With Increasing Number of Events
Figure 4 shows the results from the WLW model and illustrates individual HR for experiencing the first, second, third, and fourth primary composite MACE events, for the effect of bempedoic acid compared with placebo. A greater clinical benefit with bempedoic acid was observed in patients experiencing increasing numbers of total events. The HR for the treatment comparison was 0.87 (95% CI, 0.79-0.96; P = .004) for the first event, 0.74 (95% CI, 0.63-0.87; P <.001) for the second event, 0.69 (95% CI, 0.51-0.93; P = .02) for the third event, and 0.51 (95% CI, 0.31-0.88; P = .02) for the fourth event. Similar findings were observed for the effect of bempedoic acid on increasing numbers of the key secondary composite events of cardiovascular death, myocardial infarction, and stroke (eFigure 4 in Supplement 2).
Figure 4. Hazard Ratio (HR) for First, Second, Third, and Fourth or More Cardiovascular (CV) Events.
HR for treatment with bempedoic acid and placebo, stratified according to the incidence of the first, second, third, and subsequent major adverse CV events (CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization). The HRs and 95% CIs for the first through fourth events are estimated from a Wei-Lin-Weissfeld marginal model. The overall HR is estimated from the Andersen-Gill model with robust sandwich estimates of SEs.
Projected Clinical Benefit With Bempedoic Acid Treatment
The projected absolute difference in risk of total events for the overall MACE end point and individual components with treatment with bempedoic acid per 1000 patients over 5 years is summarized in eFigure 5 in Supplement 2, accounting for patients who were not treated for this duration during the study. On the basis of these comparative analyses between treatment groups, treatment with bempedoic acid would be projected to result in 66 fewer primary MACE-4 events, 25 fewer myocardial infarctions, 32 fewer coronary revascularizations, and 7 fewer strokes over a 5-year period. Potential benefits of bempedoic acid on total cardiovascular events were observed in the context of previously reported greater incidence of cholelithiasis (2.2% vs 1.2%), gout (3.1% vs 2.1%), elevated hepatic transaminases (4.5% vs 3.0%), and prespecified kidney events (11.5% vs 8.6%) in patients treated with bempedoic acid.6
Biochemical Changes and Benefit of Bempedoic Acid on Total Cardiovascular Events
eFigure 6 in Supplement 2 illustrates changes in both LDL-C and hsCRP levels in patients treated with either bempedoic acid or placebo, according to the incidence of no, 1, or more than 1 cardiovascular event. Favorable effects of bempedoic acid on both LDL-C and hsCRP levels were observed in patients across the total event continuum. A similar degree of lowering of both LDL-C and hsCRP levels with bempedoic acid compared with placebo was observed across all strata.
Discussion
This prespecified analysis of the CLEAR Outcomes trial demonstrated that the previously described benefit of treatment with bempedoic acid on the time to first MACE was extended to the occurrence of recurrent cardiovascular events. Approximately one-third of MACE-4 were experienced by patients as additional events, with the relative composition reflecting a greater proportional incidence of coronary revascularization. Treatment with bempedoic acid resulted in reductions in the primary composite MACE end point by 20% for total events, compared with 13% for the first event and the key secondary composite MACE end point, which was reduced by 17% for total events, compared with 15% for the first event. The total incidence of myocardial infarction was reduced by 31% and coronary revascularization by 22%. A lower HR with bempedoic acid was observed in patients with an increasing number of cardiovascular events. These findings highlight the benefits of lowering levels of LDL-C with bempedoic acid in patients at high cardiovascular risk.
Randomized clinical trials have provided evidence that establishes the therapeutic benefits of a range of medical therapies that reduce cardiovascular risk. These findings have been rapidly integrated into treatment guidelines and incorporated into clinical practice. Traditional trials have used a time-to-first-event analysis to compare the effect of a new intervention with standard of care. An alternative approach investigates the effects of interventions on the total number of clinical events that occur during a clinical trial. As cardiovascular outcomes trials typically recruit high-risk patients, many individuals experience more than 1 clinical event during follow-up.19,20,21,22 This provides the opportunity to understand whether apparent benefits on first events extend to subsequent events in patients at high cardiovascular risk. This form of analysis has been used to demonstrate the benefits of antithrombotic therapies,23,24,25,26,27 icosapent ethyl28 and a range of lipid-lowering interventions, including high-intensity statins,19,29 ezetimibe,30 and PCSK9 inhibitors.31,32
Most cardiovascular events that occur in these patients reflect the ongoing biological activity of atherosclerotic plaque burden within the vasculature. These patients retain the substrate for ongoing progression and rupture of atherosclerotic plaque, with the subsequent thrombotic complications that ensue leading to more clinical events. Accordingly, therapies that modulate these biological factors have the potential to continue to produce benefits over the course of a clinical trial, both in prevention of initial events and subsequent events. For bempedoic acid, this phenomenon is particularly evident for progression of coronary atherosclerosis with the observation that coronary revascularization becomes a more prominent source of additional cardiovascular events. From a clinical perspective, a recurrent-events analysis provides insight into the totality of effects of treatment on the overall burden of adverse cardiovascular outcomes in patients who remain at risk. Application of total-events analyses may be of greater use in the setting of use of preventive therapies and with interventions, such as lipid lowering where the benefit tends to accumulate over time. A favorable reduction in total risk results in a greater ARR after 5 years in the total number of primary MACE-4 events (4.7% vs 2.0%), and key secondary composite MACE-3 events (2.7% vs 2.0%) results in more favorable reductions in the number needed to treat (21 vs 48) and (37 vs 51) for both end points, respectively. This finding has implications for health economic analyses related to incorporation of bempedoic acid into clinical practice.
These findings provide additional validation of the benefits of lipid lowering in patients at high risk for cardiovascular events. Clinical trials have consistently demonstrated the benefits of lipid lowering, with the degree of benefit directly associated with the intensity of LDL-C–level lowering.2,3,4,5,6 These observations have prompted successive updates to treatment guidelines that advocate for goals of lower levels of LDL-C.11,12 Unfortunately, many patients fail to achieve these treatment goals and remain at high risk of future and recurrent clinical events.33,34,35 This problem is particularly challenging for patients who are either unable or unwilling to take a statin or increase statin doses. The ability to promote long-term adherence with more effective and tolerated lipid-lowering therapies has the potential to reduce progression and favorably alter the composition of atherosclerotic plaque. As the benefits of longer durations of more intensive lipid lowering are emphasized within treatment guidelines, this recommendation highlights the importance of effects on the incidence of recurrent cardiovascular events in patients at very high risk.11,12
The findings of this total-events analysis extend the cardiovascular risk reduction benefits of bempedoic acid in patients at high cardiovascular risk with elevated LDL-C levels. Approximately half of the clinical events projected to be prevented by treating 1000 patients with bempedoic acid for 5 years represent a reduction in coronary revascularization, whereas the other half reflects a reduction in cardiovascular death, myocardial infarction, and stroke. The previously reported safety findings of the CLEAR Outcomes study demonstrated that treatment with bempedoic acid was generally well tolerated, with small increases in the incidence of gout and cholelithiasis and small elevations in liver enzymes and creatinine level. These findings have implications for integration of bempedoic acid into treatment algorithms for the prevention and treatment of cardiovascular disease.
Limitations
Although the application of a total-event analysis provides additional findings of the impact of medical therapies in clinical trials, a number of limitations should be noted. Comparisons between post hoc groups defined by the number of events experienced should be interpreted with caution. Recurrent events may correlate and reflect an imbalance in other clinical factors. In this analysis, those individuals experiencing multiple clinical events differed in terms of demographics, use of other lipid-lowering therapies, and baseline levels of lipid and inflammatory biomarkers. This raises the potential for the introduction of bias with comparison between treatment groups. The first incidence of a fatal event also prevents the subsequent risk of other events. However, there was no difference in either cardiovascular or all-cause mortality in the CLEAR Outcomes study; thus, its impact on total event analysis is unlikely to be significant.
A number of other points should be considered. The CLEAR Outcomes study was conducted in patients at high cardiovascular risk, who were unable or unwilling to take guideline-recommended doses of a statin. The impact of bempedoic acid on cardiovascular events in other clinical settings remains unknown. Although the degree of cardiovascular risk reduction observed with bempedoic acid associated with the extent of LDL-C–level lowering achieved, the clinical benefit in patients experiencing more clinical events, as evidenced by both HR and ARR analysis, highlights the benefits of lipid lowering in these patients at high risk. As previously reported, a disproportionate greater increase in use of additional lipid-modifying therapies was observed in the placebo group during the trial, which may have attenuated the potential clinical benefits observed with bempedoic acid.6 The therapeutic reduction in both LDL-C and hsCRP levels with bempedoic acid was comparable in patients with either no or increasing numbers of clinical events during the study. Additional investigations will be required to determine whether bempedoic acid has other pharmacological properties, beyond lipid lowering, that contribute to its impact on recurrent cardiovascular events.
Conclusions
In summary, this prespecified analysis of the CLEAR Outcomes trial demonstrated favorable reductions in the total number of cardiovascular events in patients treated with bempedoic acid. This finding highlights the importance of lipid lowering in patients at high cardiovascular risk. More effective clinical models are required to achieve more sustainable adherence to optimized lipid-lowering strategies in order to produce greater reductions in cardiovascular risk.
Trial Protocol.
eFigure 1. CONSORT Diagram
eTable. Baseline Characteristics by Number of Total Events
eFigure 2. Timing of First and Additional Events
eFigure 3. Total Incidence of Strokes
eFigure 4. Impact of Bempedoic Acid on Increasing Numbers of Key Secondary Composite End Points
eFigure 5. Projected Risk Differences for 1000 Patients Treated for 5 Years With Bempedoic Acid Compared With Placebo
eFigure 6. Change in LDL-C and hsCRP Levels According to Incidence of Total Cardiovascular Events
Data Sharing Statement.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
eFigure 1. CONSORT Diagram
eTable. Baseline Characteristics by Number of Total Events
eFigure 2. Timing of First and Additional Events
eFigure 3. Total Incidence of Strokes
eFigure 4. Impact of Bempedoic Acid on Increasing Numbers of Key Secondary Composite End Points
eFigure 5. Projected Risk Differences for 1000 Patients Treated for 5 Years With Bempedoic Acid Compared With Placebo
eFigure 6. Change in LDL-C and hsCRP Levels According to Incidence of Total Cardiovascular Events
Data Sharing Statement.