Statin Therapy in Patients With Low Serum Levels of Low-Density Lipoprotein Cholesterol

Statin Therapy in Patients With Low Serum Levels of Low-Density Lipoprotein Cholesterol Tetsuro Tsujimoto, MD, PhDa,*, Hiroshi Kajio, MD, PhDa, and Takehiro Sugiyama, MD, MSHS, PhDb,c Recommendations for the management of low-density lipoprotein cholesterol (LDL-C) and the strategy of statin therapy differ between current guidelines. We performed a prospective cohort study using data from the National Health and Nutrition Examination Survey from 1999 to 2010. For all-cause, cardiovascular, and noncardiovascular mortalities, we used Cox proportional hazards models to analyze unadjusted and multivariable-adjusted hazard ratios (HRs). We included age, gender, race and ethnicity, educational attainment, smoking status, body mass index, previous history of cardiovascular disease and cancer, diabetes, hypertension, LDL-C levels, high-density lipoprotein cholesterol levels, log-transferred triglyceride levels, estimated glomerular filtration rate levels, and the presence or absence of macroalbuminuria for the adjustment. The present study included 1,500 patients with LDL-C levels of <120 mg/dl (mean LDL-C level 88.7 mg/dl) who were at high risk of cardiovascular disease. A total of 99% patients completed the follow-up. Using multivariable Cox proportional hazards models, all-cause mortality was significantly lower in patients receiving statins than in those not on statins (HR 0.62, 95% confidence interval 0.45 to 0.85, p = 0.004). Analyses limited to propensity score-matched patients and patients with LDL-C levels of <100 mg/dl (mean LDL-C level 78.6 mg/dl) showed similar results. All-cause mortality in patients receiving statins was not significantly lower in those with LDL-C levels of <70 mg/dl than in those with LDL-C levels of 70 to 120 mg/dl (HR 1.27, 95% confidence interval 0.76 to 2.10, p = 0.35). In conclusion, statin therapy was effective in reducing all-cause death in high-risk patients, even with low levels of LDL-C. All-cause mortality did not differ between patients receiving statins with lower levels of LDL-C. © 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;120:1947–1954) Low-density lipoprotein cholesterol (LDL-C) has been shown to be strongly associated with the development of atherosclerosis. Many studies have demonstrated the beneficial effects of lowering LDL-C levels.1–8 However, the use of statins based on LDL-C levels alone remains controversial. In addition, there is a lack of consensus regarding the most appropriate target levels of LDL-C.9–11 Almost all previous clinical trials of statin therapy have demonstrated the beneficial effects of fixed dose of statins but did not set target LDL-C levels after the initiation of statin therapy.1–8 Therefore, it is very difficult to determine whether the benefits of statin therapy are derived from statins themselves or from the lowering of LDL-C levels. A recent meta-analysis of randomized control trials (RCTs), in which the mean LDL-C levels of all included patients are approximately 140 mg/dl before treatment, has reported that the use of statins is a

Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan; bDiabetes and Metabolism Information Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; and cDepartment of Public Health/ Health Policy, The University of Tokyo, Tokyo, Japan. Manuscript received June 22, 2017; revised manuscript received and accepted August 8, 2017. The present study was supported by Grant Number 26860701 of a Grantin-Aid for Scientific Research from the Japan Society for the Promotion of Science and in part by Grant Number 26A201 of a Grant-in-Aid for Research from the National Center for Global Health and Medicine. See page 1953 for disclosure information. *Corresponding author: Tel: +81-3-3202-7181; fax: +81-3-3207-1038. E-mail address: [email protected] (T. Tsujimoto). 0002-9149/© 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2017.08.011

associated with a significant reduction in major vascular events.6,8 However, a recent study has found that targeting LDL-C levels of <100 mg/dl achieves the same cardiovascular risk reduction as more aggressive LDL-C targets in patients with coronary heart disease taking long-term statin therapy.12 The present study aimed to determine the association between the use of statins and the risk of all-cause death in patients with low serum levels of LDL-C. Methods We performed a prospective cohort study using data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010.13 The NHANES was conducted by the National Center for Health Statistics at the Centers for Disease Control and Prevention using a stratified, multistage probability sampling design that enabled representation of the noninstitutionalized US civilian population. We focused on participants aged 20 years or older on the date of home interview (survey participation) and those at high risk of cardiovascular disease, which resulted in a sample number of 2,826. We excluded patients with missing information on all other potential confounders of our analyses (n = 249) and those with LDL-C levels of ≥120 mg/dl (n = 1,077), which resulted in a final sample of 1,500. We prospectively followed up data for study patients from the date of survey participation until December 31, 2011. Written informed consent was obtained from all participants of the NHANES. The National Center for Health Statistics Research Ethics Review Board approved the NHANES www.ajconline.org

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protocols.14 Patients considered at high-risk of cardiovascular disease had one of the following criteria: a previous history of cardiovascular disease, severe chronic kidney disease, or diabetes with proteinuria, or with 1 or more major risk factors such as current smoking, hypertension, or dyslipidemia.9–11 Cardiovascular disease was defined as stroke or coronary heart disease including a previous diagnosis of coronary heart disease, myocardial infarction, or angina pectoris. Severe chronic kidney disease was defined as a glomerular filtration rate (GFR) of <30 ml/min/1.73 m2. We defined diabetes according to the presence of 1 of the following 5 criteria: a previous diagnosis of diabetes, intake of antidiabetic medications or insulin, a glycated hemoglobin level of ≥6.5%, a fasting glucose level of ≥126 mg/dl, or a 2-hour glucose level of ≥200 mg/dl after an oral glucose tolerance test.15 Proteinuria was defined as a urine albumin level of ≥300 mg/gCr. Hypertension was defined as either a previous diagnosis of hypertension or intake of antihypertensive medications. Dyslipidemia was defined as a previous diagnosis of hyperlipidemia, intake of lipid-lowering medications, an LDL-C level of 140 mg/dl, high-density lipoprotein cholesterol (HDLC) levels of <40 mg/dl, or triglyceride levels of ≥200 mg/dl. The use of statins was defined on the basis of interviewerconfirmed medication containers. We identified 7 types of statins being used by study participants: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, and rosuvastatin. We further recorded whether individual statins were administered as a separate pill or as a fixed-dose combination. We divided patients into statin users and nonusers accordingly. The main outcome measure was all-cause mortality. We used mortality follow-up data provided by the publicuse linked mortality files.16 To identify the causes of death of the study participants, the NHANES used the International Classification of Diseases, Tenth Revision, for deaths occurring in or after 1999. The specific codes for cardiovascular death were I00 to I09, I11, I13, I20 to I51, and I60 to I69. Noncardiovascular death was defined as death from any other cardiovascular cause. We extracted data on potential confounders, including age, gender, race and ethnicity, educational attainment, smoking status, body mass index (BMI, calculated as weight [kg] divided by height [m] squared), previous history of cardiovascular disease and cancer, diabetes, hypertension, LDL-C levels, HDL-C levels, triglyceride levels, estimated GFR levels, and presence or absence of macroalbuminuria. Age was divided into 4 categories: 20 to 39, 40 to 59, 60 to 79, and ≥80 years. To test validity, continuous age (20 to 79 years) was used for additional analyses. Race and ethnicity were classified into 4 categories: non-Hispanic white; non-Hispanic black; Mexican American; and others, including other Hispanics, Asian, and multiracial participants. We classified educational attainment as below high school, high school graduation or general education development certificate, and above high school. BMI levels were classified into 5 categories: <18.5, 18.5 to 24.9, 25.0 to 29.9, 30.0 to 34.9, and ≥35.0 kg/m2. Cancer was defined as a previous diagnosis of cancer or malignancy. Levels of LDL-C, HDL-C, triglyceride, estimated GFR, and urine albumin were measured during mobile examination centers’ examinations in the present survey. In addition, self-reported health conditions (5 categories: excellent, very good, good, fair, or poor) were added for sensitivity analyses. The

NHANES is a cross-sectional survey with linked follow-up data that is conducted every 2 years by the National Center for Health Statistics in the United States. Because the recommendation for statins and the effects of potential confounders may have changed over time, the NHANES periods in 1999 to 2010 (1999 to 2000, 2001 to 2002, 2003 to 2004, 2005 to 2006, 2007 to 2008, and 2009 to 2010) were included in the analysis. Demographic data were presented as numbers with proportions (%) or as means with standard deviations. Study patients receiving statins were compared with those not receiving statins using the t test for continuous variables and the chi-square test for categorical variables. For all-cause, cardiovascular, and noncardiovascular mortalities, we used Cox proportional hazards models to analyze the unadjusted and multivariable-adjusted hazard ratios (HRs) in study patients receiving statins compared with those not receiving statins. We included age, gender, race and ethnicity, educational attainment, smoking status, BMI, previous history of cardiovascular disease and cancer, diabetes, hypertension, LDL-C levels, HDL-C levels, log-transferred triglyceride levels, estimated GFR levels, and the presence or the absence of macroalbuminuria for the adjustment of model 1. In the adjustment of model 2, we used continuous age (20 to 79 years) instead of age category. In the adjustment of model 3, to minimize confounding by indication, we added health conditions to the adjustment of model 1. Furthermore, we performed a sensitivity analysis, with adjustment for confounders, of model 3 and the NHANES periods. We performed similar analyses limited to patients with LDL-C levels of <100 mg/dl and those with and without cardiovascular disease or diabetes. In addition, we performed further sensitivity analyses to evaluate the HRs for all-cause mortality in study patients receiving statins compared with those not receiving statins using propensity score-matched Cox proportional analyses. The propensity score was used to estimate the proportion of patients receiving statins and was derived using a logistic regression model that included the predictors age, gender, race and ethnicity, educational attainment, smoking status, BMI, previous history of cardiovascular disease and cancer, diabetes, hypertension, LDL-C levels, HDL-C levels, logtransferred triglyceride levels, estimated GFR levels, and presence or absence of macroalbuminuria. Standardized differences of <0.10 were considered inconsequential. KaplanMeier survival curves were constructed for all-cause mortality in patients receiving and not receiving statins. Furthermore, to evaluate the association between LDL-C levels and mortality in patients receiving statins at high risk of cardiovascular disease, we used a Cox proportional hazards model to analyze unadjusted and multivariable-adjusted HRs in patients with LDL-C levels of <70 mg/dl compared with those with LDL-C levels of 70 to 120 mg/dl. Multivariable adjustment was made by age, gender, race and ethnicity, educational attainment, smoking status, BMI, previous history of cardiovascular disease and cancer, diabetes, hypertension, HDL-C levels, logtransferred triglyceride levels, estimated GFR levels, and presence or absence of macroalbuminuria. Accounting for the complex survey design, all statistical analyses were conducted using Stata software (version 14.1; Stata Corp, College Station, Texas). With the exception of the propensity scorematched analyses, we used an appropriate weight for each

Preventive Cardiology/Statin Therapy for Low LDL-C Levels

analysis based on the variables selected. These weights accounted for unequal probabilities of selection and nonresponses to make unbiased national estimates. p values of <0.05 were considered statistically significant for all tests.

Table 1 Baseline characteristics of study patients receiving and not receiving statins* Characteristics

Results The characteristics of the study patients receiving and not receiving statins are presented in Table 1. The present study included 1,500 patients at high-risk of cardiovascular disease. Patients receiving statins were older, were more likely to be male, had a greater prevalence of cardiovascular disease, and had lower levels of LDL-C and estimated GFR compared with patients not receiving statins. The mean LDL-C level among the study patients was 88.7 (±19.1) mg/dl (statin users 83.9 [±18.5] mg/dl and statin nonusers 94.6 [±18.2] mg/dl). Event rates for all-cause deaths among patients receiving and not receiving statins are listed in Table 2. The mean (±standard deviation) follow-up periods in patients receiving statins were 5.2 (±2.9) years in those receiving statins and 6.0 (±3.3) years in those not receiving statins. Overall, 99.9% of the patients completed the follow-up. The event rates for all-cause death in patients receiving and not receiving statins were 20.7 and 29.9 per 1,000 person-years, respectively. The unadjusted Kaplan-Meier survival curves for all-cause death in the patients receiving and not receiving statins are shown in Figure 1. The unadjusted HR (95% confidence interval [CI]) for allcause death was 0.72 (0.49 to 1.04) for those receiving statins compared with those not receiving statins (p = 0.08). Using multivariable Cox proportional hazards models, all-cause mortality was significantly lower in those receiving statins than in those not receiving statins (model 1: HR 0.62, 95% CI 0.45 to 0.85, p = 0.004; and model 2: HR 0.59, 95% CI 0.37 to 0.95, p = 0.03). Further analyses with adjustments for health condition and NHANES periods did not change the result (model 3: HR 0.65, 95% CI 0.44 to 0.98, p = 0.04; and model 3 and NHANES periods: HR 0.66, 95% CI 0.43 to 0.99, p = 0.04). Similarly, all-cause mortality in patients with LDL-C levels of <100 mg/dl (mean LDL-C level of 78.6 [± 15.5]) was significantly lower in those receiving statins than in those not receiving statins (model 1: HR 0.50, 95% CI 0.34 to 0.74, p = 0.001; model 2: HR 0.36, 95% CI 0.21 to 0.64, p = 0.001; and model 3: HR 0.49, 95% CI 0.30 to 0.79, p = 0.004). In both patients with cardiovascular disease and those without diabetes, all-cause mortality was significantly lower in patients receiving statins than in those not receiving statins. Allcause mortalities in patients without cardiovascular disease and in those with diabetes were comparable between patients receiving statins and those not receiving statins, with no statistically significant difference observed. In addition, cardiovascular and noncardiovascular mortalities were lower in patients receiving statins than in those not receiving statins. Using the NHANES data, we have performed similar analyses in patients having a moderate to high risk of cardiovascular disease. The analyses of moderate- to high-risk patients showed similar results (Supplementary Table S1). There was no significant difference in baseline characteristics between propensity score-matched patients receiving and not receiving statins, with the standardized differences found to be sufficiently small (Supplementary Table S2). All-cause mortality was significantly lower in patients

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Age, years 20–39 40–59 60–79 ≥80 Women Non-Hispanic white Non-Hispanic black Mexican American Others† Education attainment < High school High school or GED > High school Smoker Never Former Current Body mass index (kg/m2)‡ < 18.5 18.5–24.9 25.0–29.9 30.0–34.9 ≥ 35.0 Cardiovascular disease Cancer Diabetes Mellitus Hypertension LDL cholesterol (mg/dL)§ HDL cholesterol (mg/dL) Triglyceride (mg/dL) Estimated GFR (ml/min/1.73 m2)¶ Macroalbuminuria (%)**

Statin therapy

p value

No

Yes

(n = 692)

(n = 808)

13.2% 38.3% 37.9% 10.6% 49.1% 65.2% 15.4% 8.2% 11.2%

3.0% 29.0% 56.6% 11.4% 40.9% 79.1% 8.2% 4.3% 8.4%

<0.001 0.006 0.001 0.06 0.01 <0.001 <0.001 <0.001 0.16

31.0% 24.0% 45.0%

23.8% 29.2% 47.1%

0.01 0.07 0.58

41.7% 30.4% 27.9% 31.3 (7.5) 1.2% 18.9% 27.6% 24.7% 27.6% 40.4% 18.8% 67.8% 65.9% 94.6 (18.2) 48.9 (16.8) 152.5 (76.9) 85.1 (31.6) 4.8%

41.1% 43.5% 15.4% 30.6 (6.3) 0.4% 19.4% 32.9% 24.8% 22.5% 54.5% 16.8% 67.3% 71.7% 83.9 (18.5) 50.0 (12.7) 148.2 (70.2) 75.0 (21.2) 3.7%

0.87 <0.001 <0.001 0.15 0.05 0.83 0.06 0.96 0.09 <0.001 0.33 0.88 0.07 <0.001 0.29 0.47 <0.001 0.16

GED = General Educational Development; LDL = low-density lipoprotein; HDL = high-density lipoprotein; GFR = glomerular filtration rate. * Data are represented as number of participants, %, or mean (SD). † The category includes other Hispanics and other races, including multiracial participants. ‡ Body mass index was calculated as the weight in kilograms divided by the square of height in meters. § LDL cholesterol was calculated using the Friedewald equation (total cholesterol − HDL cholesterol − triglycerides/5) for fasting participants examined in the morning, with triglyceride levels of ≤400 mg/dL (to convert triglycerides to millimoles per liter, multiply by 0.0113). ¶ The estimated GFR was calculated by the Modification of Diet in Renal Disease (MDRD) Study equation: estimated GFR (mL/min/1.73 m2) = 175 × (Scr)−1.154 × (Age)−0.203 (×0.742 for female × 1.212 for African Americans). ** Macroalbuminuria was defined as albuminuria of ≥300 mg/gCre.

receiving statins than in those not receiving statins (propensity score-adjusted HR, 0.65; 95% CI, 0.48 to 0.89; p = 0.006; Figure 2). Similarly, all-cause mortality in patients with LDL-C levels <100 mg/dl was significantly lower in patients receiving statins than in those not receiving statins (propensity score-adjusted HR 0.50, 95% CI 0.34 to 0.74, p = 0.001; Figure 2).

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Table 2 Risk of all-cause mortality in patients receiving and not receiving statins* Events

All-cause death All study patients No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1† Adjusted HR (95% CI), model 2‡ Adjusted HR (95% CI), model 3§ Patients with LDL-C levels of <100 mg/dL No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1 Adjusted HR (95% CI), model 2 Adjusted HR (95% CI), model 3 Patients with cardiovascular disease No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1 Adjusted HR (95% CI), model 2 Adjusted HR (95% CI), model 3 Patients without cardiovascular disease No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1 Adjusted HR (95% CI), model 2 Adjusted HR (95% CI), model 3 Patients with diabetes No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1 Adjusted HR (95% CI), model 2 Adjusted HR (95% CI), model 3 Patients without diabetes No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1 Adjusted HR (95% CI), model 2 Adjusted HR (95% CI), model 3 Cardiovascular death All study patients No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1 Adjusted HR (95% CI), model 2 Adjusted HR (95% CI), model 3 Non-cardiovascular death All study patients No. of events / total patients Event rate (per 1000 person-year) Unadjusted HR (95% CI) Adjusted HR (95% CI), model 1

Statin therapy

p value

No

Yes

151 / 692 29.9 1.00 [ref] 1.00 [ref] 1.00 [ref] 1.00 [ref]

112 / 808 20.7 0.72 (0.49–1.04) 0.62 (0.45–0.85) 0.59 (0.37–0.95) 0.65 (0.44–0.98)

0.08 0.004 0.03 0.04

84 / 376 32.1 1.00 [ref] 1.00 [ref] 1.00 [ref] 1.00 [ref]

84 / 630 20.6 0.69 (0.45–1.04) 0.50 (0.34–0.74) 0.36 (0.21–0.64) 0.49 (0.30–0.79)

0.07 0.001 0.001 0.004

86 / 289 46.9 1.00 [ref] 1.00 [ref] 1.00 [ref] 1.00 [ref]

79 / 443 24.7 0.52 (0.34–0.81) 0.54 (0.37–0.80) 0.55 (0.31–0.98) 0.55 (0.33–0.93)

0.005 0.002 0.04 0.02

65 / 403 19.6 1.00 [ref] 1.00 [ref] 1.00 [ref] 1.00 [ref]

33 / 365 15.4 0.86 (0.48–1.55) 0.80 (0.44–1.45) 0.94 (0.40–2.19) 0.84 (0.37–1.94)

0.63 0.45 0.87 0.68

81 / 475 23.0 1.00 [ref] 1.00 [ref] 1.00 [ref] 1.00 [ref]

207 / 570 20.0 0.93 (0.58–1.47) 0.71 (0.43–1.17) 0.77 (0.42–1.39) 0.78 (0.43–1.41)

0.74 0.18 0.37 0.41

70 / 217 44.7 1.00 [ref] 1.00 [ref] 1.00 [ref] 1.00 [ref]

45 / 238 21.9 0.48 (0.30–0.78) 0.54 (0.36–0.82) 0.49 (0.27–0.91) 0.59 (0.30–1.17)

0.003 0.004 0.02 0.12

40 / 692 8.9 1.00 [ref] 1.00 [ref] 1.00 [ref] 1.00 [ref]

39 / 808 8.4 0.97 (0.55–1.73) 0.64 (0.38–1.08) 0.60 (0.29–1.25) 0.62 (0.35–1.08)

0.94 0.09 0.16 0.08

110 / 692 20.9 1.00 [ref] 1.00 [ref]

73 / 808 12.3 0.61 (0.39–0.95) 0.62 (0.40–0.94)

0.03 0.02 (continued on next page)

Preventive Cardiology/Statin Therapy for Low LDL-C Levels

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Table 2 (continued) Events

Adjusted HR (95% CI), model 2 Adjusted HR (95% CI), model 3

Statin therapy

p value

No

Yes

1.00 [ref] 1.00 [ref]

0.61 (0.35–1.08) 0.65 (0.37–1.15)

0.08 0.14

LDL = low-density lipoprotein; HR = hazard ratio; CI = confidence interval. * Data are presented as number or hazard ratio (95% confidence interval). † Multivariable model 1 was made by adjusting for age (20–39, 40–59, 60–79, and ≥80 years), sex, body mass index (<18.5, 18.5–24.9, 25.0–29.9, 30.0– 34.9, ≥35.0 kg/m2), race and ethnicity (non-Hispanic white, non-Hispanic black, Mexican American, and others), educational attainment (high school), smoking status (never, former, and current smoker), history of cardiovascular disease and cancer, diabetes, hypertension, low-density lipoprotein cholesterol levels, high-density lipoprotein cholesterol levels, log transferred triglyceride levels, estimated glomerular filtration rate levels, and macroalbuminuria. ‡ Multivariable model 2 was made by adjusting for age (continuous), sex, body mass index (<18.5, 18.5–24.9, 25.0–29.9, 30.0–34.9, ≥35.0 kg/m2), race and ethnicity (non-Hispanic white, non-Hispanic black, Mexican American, and others), educational attainment (high school), smoking status (never, former, and current smoker), hypertension, history of cardiovascular disease and cancer, low-density lipoprotein cholesterol levels, high-density lipoprotein cholesterol levels, log transferred triglyceride, estimated glomerular filtration rate levels, and macroalbuminuria. § Multivariable model 3 was made by adjusting for age (20–39, 40–59, 60–79, and ≥80 years), sex, body mass index (<18.5, 18.5–24.9, 25.0–29.9, 30.0– 34.9, ≥35.0 kg/m2), race and ethnicity (non-Hispanic white, non-Hispanic black, Mexican American, and others), educational attainment (high school), smoking status (never, former, and current smoker), history of cardiovascular disease and cancer, diabetes, hypertension, low-density lipoprotein cholesterol levels, high-density lipoprotein cholesterol levels, log transferred triglyceride levels, estimated glomerular filtration rate levels, and macroalbuminuria., and health condition (excellent, very good, good, fair, or poor).

The baseline characteristics of patients receiving statins with LDL-C levels of 70 to 120 mg/dl and <70 mg/dl are presented in Supplementary Table S3. All-cause mortality in patients receiving statins was nonsignificantly higher in those with LDL-C levels of <70 mg/dl than in those with levels of 70 to 120 mg/dl (unadjusted HR 1.61, 95% CI 0.90 to 2.87, p = 0.11; and unadjusted HR limited to age 20 to 79 years 1.28, 95% CI 0.56 to 2.91, p = 0.56; Supplementary Figure S1). Using multivariable analyses, all-cause mortality in patients receiving statins was not significantly different between those with LDL-C levels of 70 to 120 mg/dl and <70 mg/dl (Supplementary Table S4). Discussion In the present population-based cohort study, all-cause mortality among patients at high-risk of cardiovascular disease with low LDL-C levels was significantly lower in those receiving statins than in those not receiving statins, regardless of LDL-C levels. These results were also observed in analyses limited to propensity score-matched patients. In addition, not only cardiovascular mortality but also noncardiovascular mortality was lower in patients receiving statins. However, all-cause mortality in patients receiving statins did not significantly differ between those with LDL-C levels of 70 to 120 mg/dl and <70 mg/dl. There is controversy regarding the use of statins according to LDL-C levels. The 2013 American College of Cardiology and the American Heart Association guidelines did not establish target LDL-C levels,11 whereas the 2016 European Society of Cardiology and European Atherosclerosis Society and the 2012 Japan Atherosclerosis Society guidelines recommend the use of target LDL-C levels.9,10 In the present study, both unadjusted and adjusted HRs for all-cause, cardiovascular, and noncardiovascular mortalities were lower in patients receiving statins than in those not receiving statins. One possible

reason was the pleiotropic effects of statins. In addition to lowering LDL-C levels, statins have beneficial effects on vascular smooth muscle proliferation, platelet aggregation, endothelial function, blood flow, and reduction of vascular inflammation.17 Recent studies have indicated that the use of statins may decrease the risk of developing various diseases such as cancer,18 dementia,19 renal dysfunction,20 sepsis,21 and venous thrombosis.22 Due to these pleiotropic effects, statin therapy may be beneficial in patients at high risk of cardiovascular disease, regardless of LDL-C levels. Therefore, despite sufficiently low LDL-C levels without statin therapy, the use of statins may lead to a decreased risk of death in high-risk patients. Statins may be more appropriately regarded as agents with pleiotropic effects to improve the survival rate rather than as lipid-lowering agents for the prevention of cardiovascular events. However, as statin therapy may lead to greater caloric and fat intakes, which attenuate the beneficial effects of statins,23 lifestyle modification remains the foundation of risk reduction for cardiovascular events and all-cause mortality. Our finding that not only cardiovascular mortality but also noncardiovascular mortality was lower in patients receiving statins may support the efficacy and the safety of statin therapy, whereas this finding may also indicate unmeasured biases between patients receiving and not receiving statins. In addition, safety concerns regarding aggressive LDL-C lowering should be verified by longer follow-up studies. Further studies are needed to assess the effects of statin therapy. The most appropriate target levels for LDL-C in patients receiving statins remain unknown. The recommendations for the use of intensive statin therapy are derived from RCTs and meta-analyses of RCTs.1–8 However, whether the benefits of statin therapy result from statins themselves or from aggressive treatment of LDL-C remains to be demonstrated as higher doses of statins have been shown to result in lower levels of LDL-C. The present study found that the risk of all-cause mortality in high-risk patients receiving statins did not significantly

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A. Mortality in patients with LDL-C levels of <120 mg/dL

A. Mortality in PS-matched participants with LDL-C levels of <120 mg/dL 1.0

Event-free survival rate

Event-free survival rate

1.0

0.75

0.5 Statin (+)

Statin (+) Statin (

0.5 No.at risk Statin (+)

0

4

8

12

808

411

137

10

692

Statin ( )

P = 0.08

411

188

Years

18

Statin (

0.25

4

Statin (+)

479

258

93

8

Statin ( )

479

277

121

10

No.at risk

12

Years

B. Mortality in PS-matched participants with LDL-C levels of <100 mg/dL

B. Mortality in patients with LDL-C levels of <100 mg/dL

1.0

Event-free survival rate

Event-free survival rate

1.0

0.75

0.5 Statin (+)

Statin (+) 0.5

Statin (

0.25

P = 0.07

0

4

8

12

Statin (+)

630

316

95

5

Statin ( )

376

209

82

10

No.at risk

P = 0.006 8

0

Years

Statin (

P = 0.001

0

4

8

12

Statin (+)

314

170

54

5

Statin ( )

314

174

68

9

No.at risk

Years

Figure 1. All-cause mortality in patients receiving and not receiving statins. Graphs of all-cause mortality in patients with LDL-C levels of <120 mg/dl (A) and in those with LDL-C levels of <100 mg/dl (B).

Figure 2. All-cause mortality in propensity score-matched patients receiving and not receiving statins. Graphs of all-cause mortality in propensity scorematched patients with LDL-C levels of <120 mg/dl (A) and in those with LDL-C levels of <100 mg/dl (B). PS = propensity score.

differ between those with LDL-C levels of 70 to 120 mg/dl and <70 mg/dl. A recent retrospective study indicated that the clinical benefit of statin therapy may not be significant at lower LDL-C levels.12 As statin therapy may lead to adverse events, such as rhabdomyolysis and acute kidney injury, and development of diabetes,24–27 long-term follow-up studies in clinical settings are required to determine the risks and benefits of statin therapy. Although the aggressive lowering LDL-C levels with intensive statin therapy and other antilipid medications may be effective during acute events, such as acute coronary syndrome,28 further studies are required to elucidate the most appropriate strategy for the use of statins. The present study had several limitations. First, this was an observational study. Missing data and relatively small samples, events, and short-term follow-up periods may have influenced the results. Moreover, the types and doses of statins were unclear. Second, bias due to unknown and unmeasured confounders might not be excluded. Several analyses showed that significant results were observed only after the multivariable adjustment. One possible explanation was that the patients receiving statins had more risk factors for death such as advancement in age and increased prevalence of

previous cardiovascular diseases. Although multivariable adjustments were made for many possible confounders in this prospective cohort study, there might be residual confounders such as previous prescription and adherence to statins between patients receiving and not receiving statins, which could have influenced the results. In particular, poor adherence to medication regimens is common and contributes to substantially worse cardiovascular outcomes. 29 Furthermore, compared with patients with cardiovascular disease not receiving statins, those receiving statins may undergo more preventive strategies such as an increased use of aspirin and increased physical activity, resulting in the reduction of mortality. To minimize confounding by indication, we performed various analyses, including propensity-score matching and adjustments for health condition and NHANES periods. The robustness of the present study may be supported by these analyses; however, the residual confounders might still influence the results. Therefore, further largescale and long-term follow-up studies without missing data and RCTs are required to confirm the results of the present study. Third, the context for the initiation of statin therapy was unclear. The effects of statins may be different between

Preventive Cardiology/Statin Therapy for Low LDL-C Levels

the acute phase of cardiovascular events and other clinical situations. In conclusion, the present study demonstrated that statin therapy was effective in reducing all-cause death in highrisk patients, even in those with low levels of LDL-C. Allcause mortality did not differ between patients receiving statins with lower levels of LDL-C. Disclosures The authors report no relations that could be construed as a conflict of interest. Supplementary Data Supplementary data associated with this article can be found, in the online version, https://doi.org/10.1016/ j.amjcard.2017.08.011. 1. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, Yamamoto A, Mizuno K, Ohashi Y, Group MS. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368:1155–1163. 2. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, Group JS. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207. 3. Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757– 767. 4. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH, CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685–696. 5. Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Janosi A, Kamensky G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ, Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F, Wedel H, Wikstrand J, Group C. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248–2261. 6. Cholesterol Treatment Trialists’ Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681. 7. Cholesterol Treatment Trialists Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–590. 8. Cholesterol Treatment Trialists’ Collaboration, Fulcher J, O’Connell R, Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J, Pedersen TR, Tonkin A, Davis B, Sleight P, Franzosi MG, Baigent C, Keech A. Efficacy and safety of LDL-lowering therapy among men and women: metaanalysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015;385:1397–1405. 9. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Z, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL, Authors/Task Force Members, Additional C. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016;37:2999–3058.

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