TY - JOUR
T1 - Optimal target of LDL cholesterol level for statin treatment
T2 - challenges to monotonic relationship with cardiovascular events
AU - Sakuma, Masashi
AU - Iimuro, Satoshi
AU - Shinozaki, Tomohiro
AU - Kimura, Takeshi
AU - Nakagawa, Yoshihisa
AU - Ozaki, Yukio
AU - Iwata, Hiroshi
AU - Miyauchi, Katsumi
AU - Daida, Hiroyuki
AU - Suwa, Satoru
AU - Sakuma, Ichiro
AU - Nishihata, Yosuke
AU - Saito, Yasushi
AU - Ogawa, Hisao
AU - Matsuzaki, Masunori
AU - Ohashi, Yasuo
AU - Taguchi, Isao
AU - Toyoda, Shigeru
AU - Inoue, Teruo
AU - Nagai, Ryozo
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Background: Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the “The lower is the better” concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a “threshold” value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. Methods: For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the “threshold” value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C − threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. Results: For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01–1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. Conclusions: Our analysis model suggests that a “threshold” value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. Trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT01042730.
AB - Background: Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the “The lower is the better” concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a “threshold” value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. Methods: For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the “threshold” value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C − threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. Results: For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01–1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. Conclusions: Our analysis model suggests that a “threshold” value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. Trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT01042730.
KW - Bottoming-out model
KW - Coronary artery disease
KW - LDL cholesterol
KW - Proportional hazard
KW - Statin
KW - Target value
KW - Threshold value
UR - https://www.scopus.com/pages/publications/85141716414
UR - https://www.scopus.com/pages/publications/85141716414#tab=citedBy
U2 - 10.1186/s12916-022-02633-5
DO - 10.1186/s12916-022-02633-5
M3 - Article
C2 - 36372869
AN - SCOPUS:85141716414
SN - 1741-7015
VL - 20
JO - BMC Medicine
JF - BMC Medicine
IS - 1
M1 - 441
ER -