LDL-C and hs-CRP Targets More Frequent With Ezetimibe + Simvastatin
What is the relationship between the change in and achieved low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP) and outcome in the IMPROVE-IT trial?
The IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study investigators randomly assigned 18,144 patients at least 50 years of age, and clinically stable within 10 days of an acute coronary syndrome, to simvastatin 40 mg or ezetimibe 10 mg + simvastatin 40 mg. If LDL-C remained >79 mg/dl on treatment, simvastatin was increased to 80 mg and may have been reduced to 40 mg after the Food and Drug Administration (FDA) guidance. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C <70 mg/dl and hs-CRP <2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. Patients on long-term prescription lipid-lowering therapy were required to have an LDL-C level of 50-100 mg/dl; otherwise, LDL-C levels were required to be 50-125 mg/dl.
Of 15,179 eligible patients, mean age was 64 years; mean LDL-C was 95 (±20) mg/dl; median hs-CRP (mean of 5 days post-presentation) was 10 mg/L; 24% were women; 39% achieved the dual LDL-C (<70 mg/dl) and hs-CRP (<2 mg/L) targets at 1 month; 14% met neither target; 14% met only the hs-CRP target; and 33% met only the LDL-C target. Those achieving dual targets had lower primary endpoint rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% vs. 28.0%; adjusted hazard ratio, 0.73; 0.66–0.81; p < 0.001). More patients treated with ezetimibe + simvastatin met dual targets than those treated with simvastatin alone (50% vs. 29%, p < 0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (p-interaction = 0.65) and gender. Similar findings were observed with targets of LDL-C <50 mg/dl and hs-CRP <1 mg/L.
Significantly more patients treated with ezetimibe + simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment.
This analysis was prespecified and provides important data. The reduction in events was related to the LDL-C and hs-CRP cutpoints achieved, with lower is better for both, and not related to the specific treatment. This very interesting finding places the pleiotropic effects of statin therapy back into the picture and the potential value of measuring hs-CRP response to help decide intensifying treatment. Considering the length of the trial, it is reasonable to assume the findings would be similar in stable coronary artery disease.
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