Focus – Insights from CLEAR-Outcomes trial: Targeting LDL cholesterol alone is not enough
20 May 2024
According to this trial analysis, high-sensitivity C-reactive protein (hsCRP) predicts cardiovascular events more strongly than low-density lipoprotein cholesterol (LDL-C) in high-risk statin-intolerant patients.
Ridker PM, Lei L, Louie MJ, et al. Inflammation and cholesterol as predictors of cardiovascular events among 13970 contemporary high-risk patients with statin intolerance. Circulation 2024;149:28–35.
STUDY SUMMARY
| Objective | To investigate the relative effect of inflammation and hyperlipidaemia as predictors of cardiovascular risk in statin-intolerant patients. |
| Study design | CLEAR-Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) was a randomized, double-blind, placebo-controlled, multinational trial which compared 180 mg oral bempedoic acid daily or matching placebo. |
| Study population | 13,970 statin-intolerant patients (mean age 65.5 years, 48.2% with diabetes, 69.9% with a prior cardiovascular event) were randomized in CLEAR-Outcomes. Patients either had a previous cardiovascular event or were at high risk for cardiovascular events and reported being unable or unwilling to take statin therapy owing to an adverse effect that had started or increased during statin therapy and resolved or improved after statin discontinuation. |
| Study outcomes | Primary: Cardiovascular events (a composite 4-point outcome of myocardial infarction, stroke, coronary revascularization, cardiovascular death), and all-cause mortality |
| Methods | Quartiles of increasing baseline hsCRP and LDL-C were assessed as predictors of future adverse events. Proportional hazard models were used to assess the risk for each endpoint after adjustment for traditional risk factors (age, sex, ethnicity, diabetes, body mass index, estimated glomerular filtration rate, blood pressure, alcohol use, smoking status and known atherosclerotic cardiovascular disease) and randomized treatment assignment. |
RESULTS
Over the median follow-up period of 40.6 months, there were 1746 cardiovascular events; 854 deaths occurred of which 526 were adjudicated as cardiovascular deaths.
Baseline hsCRP was more strongly associated with risk for cardiovascular events, cardiovascular death and all-cause mortality than baseline LDL-C (Table 1).
Irrespective of baseline LDL-C, the risk of cardiovascular events, cardiovascular death and all-cause death was significantly higher for patients with baseline hsCRP above the median than below the median (p<0.001).
Table 1. Association of baseline hsCRP and LDL-C with cardiovascular events, cardiovascular death and all-cause mortality
|
Variable (highest vs. lowest quartile) |
Cardiovascular events |
Cardiovascular death |
All-cause death |
|
hsCRP |
1.43 (1.24-1.65) |
2.00 (1.53-2.61) |
2.21 (1.79-2.73) |
|
LDL-C |
1.19 (1.04-1.37) |
0.90 (0.70-1.17) |
0.95 (0.78-1.16) |
Data are given as hazard ratio and 95% confidence interval.
| Author conclusion | Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidaemia assessed by LDL-C. |
COMMENT
Inflammation, a driver of atherosclerosis and its complications, is well recognized as a contributor to residual cardiovascular risk (1). Moreover, trials have demonstrated that targeting inflammation in patients receiving evidence-based preventive therapy reduces cardiovascular event rates (2,3). Statins, one of the major preventive treatments for patients with or at high risk of atherosclerotic cardiovascular disease, lower both hsCRP and LDL-C. In a recent analysis of secondary prevention patients receiving contemporary guideline-directed treatment including a statin, hsCRP was a stronger predictor of cardiovascular risk than LDL-C (4). However, the relative contribution of hsCRP and LDL-C to cardiovascular risk among patients unable to tolerate a statin is uncertain.
The results of this analysis from the CLEAR-Outcomes trial show that hsCRP predicts cardiovascular events and death at least as strongly as LDL-C in statin-intolerant patients. This finding, added to findings from the aforementioned recent analysis (4), supports low-grade inflammation, as measured by hsCRP, as a driver of cardiovascular risk irrespective of statin therapy and LDL-C level. The authors are careful not to detract from the importance of lowering LDL-C levels to reduce cardiovascular risk. Instead, based on the growing evidence base, they argue for measurement of both hsCRP and LDL-C in clinical practice, so as to quantify cardiovascular risk and inform on the most appropriate therapeutic strategies for preventing cardiovascular events.
| References | 1. Everett BM. Residual inflammatory risk: a common and important risk factor for recurrent cardiovascular events. J Am Coll Cardiol 2019;73:2410-2. 2. Ridker PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31. 3. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505. 4. Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomized trials. Lancet 2023;401:1293–301. |
| Key words | inflammation; LDL cholesterol; statin-intolerant; CLEAR-Outcomes trial; cardiovascular events |
