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Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 June 18/25, 2019 e1115 CLINICAL STATEMENTS AND GUIDELINES

miscarriage in the statin-exposed women versus controls.S4.5.3-11 Furthermore, in a recent retrospective cohort study that used time-to-event analysis as a covariate, the adjusted hazard ratio of spontaneous pregnancy loss in the statin-exposed group was increased.S4.5.3-12 The increase in miscarriages may be related to confounders, such as older age, CVD risk factors, and other medications. 3.	 A reasonable approach is to stop statins 1 to 2 months before pregnancy is attempted. When pregnancy is unplanned, statin therapy should be stopped promptly and not restarted until after pregnancy and breastfeeding are completed. Cholesterol levels rise in pregnancy, with a similar percentage rise in normal women and those with heterozygous FH. Women with FH do not appear to have a higher risk of preterm delivery or of having infants with low birth weight or congenital malformations than unaffected women, but undetected bias cannot be ruled out.S4.5.3-16 An experienced lipid specialist should be consulted for women with homozygous FH whose care is beyond the scope of the present guideline. Also, triglyceride levels rise progressively with each trimester, and women with triglyceride levels ≥500 mg/dL (5.6 mmol/L) at the onset of pregnancy may develop severe hypertriglyceridemia during the third trimester of pregnancy, which can lead to pancreatitis.S4.5.3-17 Advising patients on lifestyle (including both diet and physical activity), optimally managing diseases like diabetes mellitus and hypothyroidism, and choosing medications that are less likely to raise triglycerides can reduce levels of triglycerides before pregnancy begins. Treatment of severe hypertriglyceridemic pregnancy is also beyond the scope of the present guideline and requires consultation with an experienced lipid specialist.

4.5.4 Adults With CKD

Recommendations for Adults With CKD Referenced studies that support recommendations are summarized in Online Data Supplements 36 to 38.

COR LOE Recommendations

IIa B-R 1.  In adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL (1.7 to 4.8 mmol/L) who are at 10-year ASCVD risk of 7.5% or higher, CKD not treated with dialysis or kidney transplantation is a risk-enhancing factor and initiation of a moderate-intensity statin or moderate-intensity statins combined with ezetimibe can be useful.S4.5.4-1,S4.5.4-2

IIb C-LD 2.  In adults with advanced kidney disease that requires dialysis treatment who are currently on LDL-lowering therapy with a statin, it may be reasonable to continue the statin.S4.5.4-2

III: No Benefit B-R 3.  In adults with advanced kidney disease who require dialysis treatment, initiation of a statin is not recommended.S4.5.4-3,S4.5.4-4 Synopsis

CKD is a risk-enhancing factor for ASCVD. In risk discussion with intermediate-risk patients, the presence of CKD favors initiation of statin therapy. In adults with advanced kidney disease requiring dialysis treatment who are currently on pharmacological LDL-lowering therapy with a statin, it may be reasonable to continue the statin.S4.5.4-2 In adults with CKD that requires dialysis treatment, initiation of a statin is not recommended on the basis of 2 large-scale RCTs.S4.5.4-3,S4.5.4-4

Recommendation-Specific Supportive Text

1.	 Reduced eGFR (<60 mL/min/1.73 m2 not on dialysis) and presence of albuminuria (albumin-tocreatinine ratio ≥30 mcg/mg) are independently associated with elevated risk of ASCVD. Hence, in intermediate-risk patients, CKD counts as a riskenhancing factor. According to some studies,S4.5.4-5 the cardiovascular risk for persons with reduced eGFR may be as high as that observed among patients with diabetes mellitus and no CKD. Presence of albuminuria with reduced eGFR multiplies this CVD risk. The risk is graded and increases with severity of eGFR impairment, with observed threshold of risk beginning around 75 mL/min/1.73 m2, whereas the risk associated with albuminuria is linear.S4.5.4-6 Trials show absolute benefit from statin use, and this benefit is consistent across eGFR stages. However, the RRR per LDL-C–lowering may be lower with more advanced CKD. Albuminuria is independently associated with CVD risk. However, the one trial done for primary prevention in persons with albuminuria and preserved eGFR had too few events to be conclusive.S4.5.4-7 2.	 According to this recommendation, in patients with CKD who are currently taking a statin, it may be reasonable to continue the statin. In support of this, in the SHARP trial (Study of Heart and Renal Protection) (simvastatin plus ezetimibe versus placebo), >30% of persons transitioned to dialysis.S4.5.4-2 After weighting for subgroup-specific reductions in LDL-C was performed, the proportional effects on major atherosclerotic events were similar in patients on dialysis and those who were not on dialysis. 3.	 Although persons on dialysis have the highest absolute risk of events (and thus potential for higher ARR), the proportion of deaths thought to be due to atherosclerotic events is lower.S4.5.4-3,S4.5.4-4 The lack of benefit in RCTs with statin initiation among persons on dialysis raises the question of competing risks. Unfortunately, there

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