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. 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 (), REDUCE-IT (), or STRENGTH () 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. 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 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 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). 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. Kowa Research Institute, Amarin, AstraZeneca.

中文翻译：

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炎症和胆固醇作为接受他汀类药物治疗的患者心血管事件的预测因子：三项随机试验的协作分析

炎症和高脂血症共同导致动脉粥样硬化血栓性疾病。然而，当人们接受强化他汀类药物治疗时，炎症和高脂血症对未来心血管事件风险的相对影响可能会发生变化，这对辅助心血管治疗的选择具有影响。我们的目的是评估高敏 C 反应蛋白 (CRP) 和低密度脂蛋白胆固醇 (LDLC) 作为接受他汀类药物治疗的患者主要不良心血管事件、心血管死亡和全因死亡风险决定因素的相对重要性。我们对患有动脉粥样硬化疾病或处于高风险动脉粥样硬化疾病的患者进行了协作分析，这些患者正在接受当代他汀类药物治疗，并且是多国 PROMINENT ()、REDUCE-IT () 或 STRENGTH () 试验的参与者。基线高敏 CRP（残余炎症风险的生物标志物）增加和基线 LDLC（残余胆固醇风险的生物标志物）增加的四分位数被评估为未来主要不良心血管事件、心血管死亡和全因死亡的预测因子。在根据年龄、性别、BMI、吸烟状况、血压、既往心血管疾病史和随机治疗组分配进行调整的分析中，计算了高敏 CRP 和 LDLC 四分位数的心血管事件和死亡的风险比 (HR)。PROMINENT (n=9988)、REDUCE-IT (n=8179) 和 STRENGTH (n=13 078) 试验的分析纳入了 31 245 名患者。三项试验中观察到的基线高敏 CRP 和 LDLC 范围以及每种生物标志物与后续心血管事件发生率的关系几乎相同。残余炎症风险与主要不良心血管事件显着相关（最高高敏 CRP 四分位数最低高敏 CRP 四分位数，调整后 HR 1·31，95% CI 1·20–1·43；p<0·0001），心血管死亡率（2·68、2·22–3·23；p<0·0001）和全因死亡率（2·42、2·12–2·77；p<0·0001）。相比之下，残余胆固醇风险与主要不良心血管事件的关系是中性的（最高LDLC四分位数最低LDLC四分位数，调整HR 1·07，95% CI 0·98–1·17；p=0·11），并且心血管死亡（1·27、1·07–1·50；p=0·0086）和全因死亡（1·16、1·03–1·32；p=0·025）的程度较低。在接受当代他汀类药物治疗的患者中，通过高敏 CRP 评估的炎症比通过 LDLC 评估的胆固醇更能预测未来心血管事件和死亡的风险。这些数据对他汀类药物治疗之外的辅助治疗的选择具有影响，并表明可能需要联合使用积极的降脂和炎症抑制疗法，以进一步降低动脉粥样硬化风险。Kowa 研究所、Amarin、阿斯利康。