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June 18/25, 2019 Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 e1122

CLINICAL STATEMENTS AND GUIDELINES

8 LIMITATIONS AND KNOWLEDGE

GAPS 8.1. Randomized Controlled Trials

ACC/AHA guidelines are based largely on the outcomes of RCTs. Cholesterol guidelines have fortunately benefited from a large number of RCTs of cholesterol-lowering therapies. They have established that greater reductions of LDL- C are accompanied by greater reductions in risk of ASCVD. Robust RCTs exist for both primary and secondary prevention. Most of the data from RCTs have been obtained with statin therapy. Important limited data have also been obtained with nonstatins as add-on drugs to statin therapy. Nevertheless, more data are needed to determine the full scope of the benefit of nonstatin drugs. Several important questions need to be addressed by additional RCTs.

1.	 In secondary prevention, does a lower limit for LDL-C attainment exist, beyond which the incremental benefit attained is worth neither the risks nor the cost of additional therapy? 2.	 In secondary prevention, what are the indications for adding PCSK9 inhibitors to maximal statin therapy? 3.	 In patients with ASCVD who have statin-associated side effects, are PCSK9 inhibitors an effective and safe substitute for high-intensity statins? 4.	 In primary prevention for adults 45 to 75 years of age (LDL-C <90 mg/dL [<2.3 mmol/L]) with or without diabetes mellitus, what is the incremental risk reduction imparted by high-intensity statins as compared with moderate-intensity statins? 5.	 In primary prevention for adults 45 to 75 years of age (LDL-C <190 mg/dL [<4.9 mmol/L]) with or without diabetes mellitus, what is the incremental risk reduction imparted by moderate-intensity statins plus ezetimibe as compared with moderate-intensity statins alone? 6.	 Is statin therapy efficacious and safe in older patients (>75 years of age)? If so, what is a net benefit of statin therapy in this age group? 7.	 In patients with severe hypercholesterolemia, what are the efficacy and net benefit of PCSK9 inhibitors as add-on treatment to maximal statin therapy? 8.	 What is the efficacy of moderate-intensity and high-intensity statin therapy in patients with riskenhancing factors (eg, chronic inflammatory disease, CKD, metabolic syndrome)?

8.2 Risk Assessment

In primary prevention, the appropriate selection of patients for cholesterol-lowering drug therapy is highly dependent on risk assessment. Previous guidelines made

Figure 3. Cost-effectiveness analysis for PCSK9 inhibitors. Conceptual relationship between the clinical effectiveness of PCSK9 inhibitor therapy, measured in QALYs added compared with statin therapy, on the horizontal axis, and their clinical value, measured in dollars per QALY added, on the vertical axis. The top curve indicates the relationship at full U.S list price of PCSK9 inhibitor therapy ($14 000/y), the middle curve indicates the relationship if the price were reduced by 50% (ie, to $7 000/y), and the bottom curve indicates the relationship if the price were reduced by 75% (ie, to $3 500/y). Reproduced from Hlatky et al.S7.1-3 CV indicates cardiovascular; and QALY, quality-adjusted life-years.

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