Simulation of the Impact of Statin Intolerance on the Need for Ezetimibe and/or Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor for Meeting Low-Density Lipoprotein Cholesterol Goals in a Population With Atherosclerotic Cardiovascular Disease.

In a population with atherosclerotic cardiovascular disease, previous research indicated that approximately 86% can achieve low-density lipoprotein cholesterol (LDL-C) of <70 mg/dL with oral lipid-lowering therapies (LLT) only, whereas 14% would require a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. We aim to estimate these values accounting for varying levels of statin intolerance. A simulation model described previously was used to estimate the utilization of LLT needed to achieve LDL-C <70 mg/dL via an intensification algorithm which maximized statins before adding ezetimibe or a PCSK9 inhibitor. The current analysis took into account varying background rates of statin intolerance. We defined statin intolerance as either partial (inability to tolerate high-intensity statin) or full (inability to tolerate any statin). With treatment intensification and 10% of patients having partial statin intolerance, the use of ezetimibe (± statin ± PCSK9 inhibitor) increased from 32.7% to 34.9%, and the need for a PCSK9 inhibitor (+ ezetimibe ± statin) increased from 14.0% to 15.5%. If, instead, 10% were fully statin intolerant, the use of ezetimibe (± statin ± PCSK9 inhibitor) increased from 32.7% to 38.5%, and the use of a PCSK9 inhibitor (+ ezetimibe ± statin) increased from 14.0% to 19.7%. In conclusion, in our simulation-based study, partial statin intolerance increased the need for nonstatins only modestly (by an absolute 2.2%), whereas having 10% of patients with full statin intolerance increased the need for PCSK9 inhibitors from 14% overall to approximately 20%.

Cannon CP ，Sanchez RJ ，Klimchak AC ，Khan I ，Sasiela WJ ，Reynolds MR ，Rosenson RS ... -  《-》

Simulation of Lipid-Lowering Therapy Intensification in a Population With Atherosclerotic Cardiovascular Disease.

Cannon CP ，Khan I ，Klimchak AC ，Reynolds MR ，Sanchez RJ ，Sasiela WJ ... -  《-》

Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial.

Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co-primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.

Nissen SE ，Dent-Acosta RE ，Rosenson RS ，Stroes E ，Sattar N ，Preiss D ，Mancini GB ，Ballantyne CM ，Catapano A ，Gouni-Berthold I ，Stein EA ，Xue A ，Wasserman SM ，Scott R ，Thompson PD ，GAUSS-3 Investigators ... -  《-》

Variation in Lipid-Lowering Therapy Use in Patients With Low-Density Lipoprotein Cholesterol ≥190 mg/dL: Insights From the National Cardiovascular Data Registry-Practice Innovation and Clinical Excellence Registry.

Patients with low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at high risk of atherosclerotic cardiovascular disease events. Treatment guidelines recommend intensive treatment in these patients. Variation in the use of lipid-lowering therapies (LLTs) in these patients in a national sample of cardiology practices is not known. Using data from the American College of Cardiology National Cardiovascular Data Registry-Practice Innovation and Clinical Excellence registry, we assessed the proportion of patients with LDL-C ≥190 mg/dL (n=49 447) receiving statin, high-intensity statin, LLT associated with ≥50% LDL-C lowering, ezetimibe, or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor between January 2013 and December 2016. We assessed practice-level rates and variation in LLT use using median rate ratio (MRR) adjusted for patient and practice characteristics. MRRs represent the likelihood that 2 random practices would differ in treatment of identical patients with LDL-C ≥190 mg/dL. The proportion of patients receiving a statin, high-intensity statin, LLT associated with ≥50% LDL-C reduction, ezetimibe, or PCSK9 inhibitor were 58.5%, 31.9%, 34.6%, 8.5%, and 1.5%, respectively. Median practice-level rates and adjusted MRR for statin (56% [interquartile range, 47.3%-64.8%]; MRR, 1.20 [95% confidence interval [CI], 1.17-1.23]), high-intensity statin (30.2% [interquartile range, 12.1%-41.1%]; MRR, 2.31 [95% CI, 2.12-2.51]), LLT with ≥50% LDL-C lowering (31.8% [interquartile range, 15.3%-45.5%]; MRR, 2.12 [95% CI, 1.95-2.28]), ezetimibe (5.8% [interquartile range, 2.8%-9.8%]; MRR, 2.42 [95% CI, 2.21-2.63]), and PCSK9 inhibitors (0.16% [interquartile range, 0%-1.9%]; MRR, 2.38 [95% CI, 2.04-2.72]) indicated significant gaps and >200% variation in receipt of several of these medications for patients across practices. Among those without concomitant atherosclerotic cardiovascular disease, even larger treatment gaps were noted (proportion of patients on a statin, high-intensity statin, LLT with ≥50% LDL-C reduction, ezetimibe, or PCSK9 inhibitor were 50.8%, 25.25%, 26.8%, 4.9%, and 0.74%, respectively). Evidence-based LLT use remains low among patients with elevated LDL-C with significant variation in care. System-level interventions are needed to address these gaps and reduce variation in care of these high-risk patients.

Virani SS ，Kennedy KF ，Akeroyd JM ，Morris PB ，Bittner VA ，Masoudi FA ，Stone NJ ，Petersen LA ，Ballantyne CM ... -  《Circulation-Cardiovascular Quality and Outcomes》

Prescribing Patterns of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in Eligible Patients With Clinical Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia.

Two proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are approved for patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who require additional low-density lipoprotein cholesterol (LDL-C) lowering. This retrospective study sought to determine differences between eligible patients who were prescribed and those who were not prescribed a PCSK9 inhibitor. Patients from an electronic medical record database were included in the analysis, and their demographic, clinical, and treatment characteristics were evaluated. Of 368,624 PCSK9 inhibitor-eligible patients, 1,752 (<0.5%) received a PCSK9 inhibitor prescription. Patients who received a PCSK9 inhibitor were more frequently associated with a higher cardiovascular disease risk category and a higher baseline LDL-C level (139.4 vs 103.5 mg/dl; p <0.0001) compared with those who did not. Patients with a PCSK9 inhibitor prescription were significantly more likely to be on ezetimibe, alone or in combination with a statin, at baseline compared with those without (29% vs 5%; p <0.0001). The use of a PCSK9 inhibitor was very low in the 2 groups of patients identified as PCSK9 inhibitor-eligible based on the American College of Cardiology Expert Consensus Decision Pathway. In conclusion, this study demonstrates that most PCSK9 inhibitor-eligible patients do not receive a PCSK9 inhibitor prescription, highlighting that many high-risk patients could benefit from additional LDL-C lowering with a PCSK9 inhibitor.

Karalis DG ，Mallya UG ，Ghannam AF ，Elassal J ，Gupta R ，Boklage SH ... -  《-》