March 6, 2023The Lancet
Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials
Key result
Highest hsCRP quartile is linked to ~31% higher MACE risk in statin-treated patients.
- HR 1.31
- 95% CI 1.20-1.43
- P<0.0001
- n=31,245
Why the study?
The relative contributions of inflammation and hyperlipidaemia to cardiovascular risk among patients receiving intensive statin therapy were unclear, affecting adjunctive treatment choices.
Does residual inflammatory risk (hsCRP) or residual cholesterol risk (LDLC) better predict future cardiovascular events and mortality in statin-treated patients with or at high risk of atherosclerotic disease?
Key Points
- To assess the relative importance of high-sensitivity C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDLC) as determinants of major adverse cardiovascular events, cardiovascular death, and all-cause mortality among patients receiving contemporary statins.
- Collaborative analysis of 31,245 patients with or at high risk of atherosclerotic disease on contemporary statins from three multinational randomized trials: PROMINENT (n=9,988; NCT03071692), REDUCE-IT (n=8,179; NCT01492361), and STRENGTH (n=13,078; NCT02104817).
- Multivariable-adjusted hazard ratios (HRs) for cardiovascular events and death were calculated across baseline quartiles of high-sensitivity CRP and LDLC, adjusting for cardiovascular risk factors and randomized treatment group.
- Residual inflammatory risk (highest vs lowest high-sensitivity CRP quartile) strongly predicted major adverse cardiovascular events (adjusted HR 1.31, 95% CI 1.20–1.43; p<0.0001), cardiovascular mortality (adjusted HR 2.68, 95% CI 2.22–3.23; p<0.0001), and all-cause mortality (adjusted HR 2.42, 95% CI 2.12–2.77; p<0.0001).
- Residual cholesterol risk (highest vs lowest LDLC quartile) was not significantly linked to major adverse cardiovascular events (adjusted HR 1.07, 95% CI 0.98–1.17; p=0.11), and showed smaller effects on cardiovascular mortality (adjusted HR 1.27, 95% CI 1.07–1.50; p=0.0086) and all-cause mortality (adjusted HR 1.16, 95% CI 1.03–1.32; p=0.025).
Study Design
Type
Meta-Analysis (n=31,245)
Multicenter
Yes
Structured PICO
Does residual inflammatory risk (hsCRP) or residual cholesterol risk (LDLC) better predict future cardiovascular events and mortality in statin-treated patients with or at high risk of atherosclerotic disease?
P
Population
31,245 patients with or at high risk of atherosclerotic disease receiving contemporary statins pooled from three multinational trials.
E
Exposure
Higher quartiles of baseline high-sensitivity C-reactive protein (hsCRP, marker of residual inflammatory risk) and low-density lipoprotein cholesterol (LDLC, marker of residual cholesterol risk).
C
Comparator
Lowest quartiles of baseline high-sensitivity CRP and LDLC.
O
Outcome
Major adverse cardiovascular events, cardiovascular death, and all-cause death.hard clinical
Main Result
Hazard Ratio: 1.31 (95% CI 1.2–1.43)
p-value: p=<0.0001
Among statin-treated patients with or at high risk of atherosclerotic disease, residual inflammation (assessed by hsCRP) is a stronger predictor of future cardiovascular events and mortality than residual cholesterol (assessed by LDLC).
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Virtually all patients with or at risk for atherosclerotic disease are appropriately treated with aggressive statin therapy. Yet, in our study of patients already taking a statin, hsCRP — a measure of residual inflammatory risk — was a more powerful determinant of having a future heart attack or dying from cardiovascular disease than was LDL-cholesterol — a measure of residual cholesterol risk. The data are a powerful demonstration that to beat heart disease, we need to lower both cholesterol and inflammation, not just cholesterol alone.”
“This is a very provocative paper because what it says is in contemporary, guideline-directed care on high intensity statins, we have done a very good job of lowering LDL, but we are not really attacking that inflammation in any fundamentally, useful way.”
“It's very powerful, because we all agree that lowering LDL cholesterol is fundamental to preventing this disease, but, I would argue, we're not even measuring hsCRP in most of our patients.”
Implication
Residual inflammation warrants priority over further LDL-C lowering for risk stratification in statin-treated patients; confirms hsCRP as dominant prognostic marker across three large RCTs.
Abstract
BACKGROUND: Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDLC) as determinants of risk for major adverse cardiovascular events, cardiovascular death, and all-cause-death among patients receiving statins. METHODS: We did a collaborative analysis of patients with-or at high risk of-atherosclerotic disease, who were receiving contemporary statins and were participants in the multinational PROMINENT (NCT03071692), REDUCE-IT (NCT01492361), or STRENGTH (NCT02104817) trials. Quartiles of increasing baseline high-sensitivity CRP (a biomarker of residual inflammatory risk) and of increasing baseline LDLC (a biomarker of residual cholesterol risk) were assessed as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Hazard ratios (HRs) for cardiovascular events and deaths were calculated across quartiles of high-sensitivity CRP and LDLC in analyses adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomised treatment group assignment. FINDINGS: 31 245 patients were included in the analysis from the PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) trials. The observed ranges for baseline high-sensitivity CRP and LDLC, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials. Residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (highest high-sensitivity CRP quartile vs lowest high-sensitivity CRP quartile, adjusted HR 1·31, 95% CI 1·20-1·43; p<0·0001), cardiovascular mortality (2·68, 2·22-3·23; p<0·0001), and all-cause mortality (2·42, 2·12-2·77; p<0·0001). By contrast, the relationship of residual cholesterol risk was neutral for major adverse cardiovascular events (highest LDLC quartile vs lowest LDLC quartile, adjusted HR 1·07, 95% CI 0·98-1·17; p=0·11), and of low magnitude for cardiovascular death (1·27, 1·07-1·50; p=0·0086) and all-cause death (1·16, 1·03-1·32; p=0·025). INTERPRETATION: Among patients receiving contemporary statins, inflammation assessed by high-sensitivity CRP was a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by LDLC. These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.
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Cite This Study
Ridker et al. (2023) conducted a meta-analysis in Atherosclerotic disease (n=31,245). High-sensitivity C-reactive protein (hs-CRP) quartile vs. Lowest hs-CRP quartile was evaluated on Major adverse cardiovascular events (HR 1.31, 95% CI 1.20-1.43, p=<0.0001). Among statin-treated patients, highest vs lowest quartile of high-sensitivity CRP was significantly associated with incident major adverse cardiovascular events (HR 1.31; 95% CI 1.20-1.43; p<0.0001).