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. 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. High-risk patients not achieving their recommended low-density lipoprotein cholesterol (LDL-C) goals despite the availability of statin therapy remain at high residual cardiovascular risk.1Lin I. Sung J. Sanchez R.J. Mallya U.G. Friedman M. Panaccio M. Koren A. Neumann P. Menzin J. Patterns of statin use in a real-world population of patients at high cardiovascular risk.J Manag Care Spec Pharm. 2016; 22: 685-698Crossref PubMed Scopus (58) Google Scholar, 2Wong N.D. Young D. Zhao Y. Nguyen H. Caballes J. Khan I. Sanchez R.J. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011–2012.J Clin Lipidol. 2016; 10: 1109-1118Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 3Graham J.H. Sanchez R.J. Saseen J.J. Mallya U.G. Panaccio M.P. Evans M.A. Clinical and economic consequences of statin intolerance in the United States: results from an integrated health system.J Clin Lipidol. 2017; 11 (e71): 70-79Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 4Karalis D.G. Victor B. Ahedor L. Liu L. Use of lipid-lowering medications and the likelihood of achieving optimal LDL-cholesterol goals in coronary artery disease patients.Cholesterol. 2012; 2012: 861-924Crossref Scopus (50) Google Scholar, 5Huang Q. Grabner M. Sanchez R. Willey V. Cziraky M. Palli S. Power T. Clinical characteristics and unmet need among patients with atherosclerotic cardiovascular disease stratified by statin use.Am Health Drug Benefits. 2016; 9: 434-444PubMed Google Scholar In recognition of this, the American College of Cardiology (ACC) published their first Expert Consensus Decision Pathway (ECDP) in 2016, describing the role of nonstatin therapies for LDL-C lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk.6Lloyd-Jones D.M. Morris P.B. Ballantyne C.M. Birtcher K.K. Daly Jr, D.D. DePalma S.M. Minissian M.B. Orringer C.E. Smith Jr, S.C. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.J Am Coll Cardiol. 2016; 68: 92-125Crossref PubMed Scopus (350) Google Scholar In the nonstatin therapy options,6Lloyd-Jones D.M. Morris P.B. Ballantyne C.M. Birtcher K.K. Daly Jr, D.D. DePalma S.M. Minissian M.B. Orringer C.E. Smith Jr, S.C. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.J Am Coll Cardiol. 2016; 68: 92-125Crossref PubMed Scopus (350) Google Scholar proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have demonstrated efficacy and safety in randomized controlled trials in a range of high-risk patients,7McDonagh M. Peterson K. Holzhammer B. Fazio S. A systematic review of PCSK9 inhibitors alirocumab and evolocumab.J Manag Care Spec Pharm. 2016; 22 (641–653q)PubMed Google Scholar and also a reduction of the risk of cardiovascular events.8Sabatine M.S. Giugliano R.P. Keech A.C. Honarpour N. Wiviott S.D. Murphy S.A. Kuder J.F. Wang H. Liu T. Wasserman S.M. Sever P.S. Pedersen T.R. Fourier Steering Committee InvestigatorsEvolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722Crossref PubMed Scopus (3202) Google Scholar, 9Ridker P.M. Revkin J. Amarenco P. Brunell R. Curto M. Civeira F. Flather M. Glynn R.J. Gregoire J. Jukema J.W. Karpov Y. Kastelein J.J.P. Koenig W. Lorenzatti A. Manga P. Masiukiewicz U. Miller M. Mosterd A. Murin J. Nicolau J.C. Nissen S. Ponikowski P. Santos R.D. Schwartz P.F. Soran H. White H. Wright R.S. Vrablik M. Yunis C. Shear C.L. Tardif J.C. Cardiovascular efficacy and safety of bococizumab in high-risk patients.N Engl J Med. 2017; 376: 1527-1539Crossref PubMed Scopus (436) Google Scholar This study sought to identify treatment patterns in PCSK9 inhibitor-eligible patients and to determine whether the ACC-ECDP recommendations are followed in real-world clinical practice. A retrospective analysis was conducted on electronic medical record data from Accenture's 'Predictive Health Intelligence Environment' database. Patients aged 18 years or older with evidence of clinical ASCVD or heterozygous familial hypercholesterolemia (HeFH) from July 28, 2013 to July 26, 2015 (index period) were included in the analysis. Criteria for HeFH and ASCVD definitions are shown in the Supplementary Data. Patients were excluded from the analysis if they did not have at least 1 LDL-C measurement of >70 mg/dl within the 2-year index period. LDL-C was calculated based on the last LDL-C level in the electronic medical record during the index period. Additionally, patients were excluded if they did not receive a prescription for an LDL-C-lowering therapy including statins (moderate-to-low-intensity statin or high-intensity statin, depending on dose and statin type), ezetimibe, and other nonstatins (niacin, cholestyramine, colesevelam, fibrates, and colestipol), at least once within the index period. Patients were followed up from the index date (July 27, 2015, the date of US Food and Drug Administration approval of alirocumab) to January 4, 2017. Patients were stratified according to whether they had a PCSK9 inhibitor prescription during follow-up. Baseline was recorded from the index date for the 2 cohorts. Demographic data, clinical characteristics (including preindex co-morbid conditions [International Classification of Diseases codes are listed in Supplementary Table S1], preindex cardiovascular events, and cardiovascular risk categories) and treatment characteristics (such as preindex and current concomitant medications, and lipid-modifying therapies, including high-intensity statin [daily dose of atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg]) were examined. Cardiovascular risk categories have been described previously.10Steen D.L. Khan I. Song X. Sanchez R.J. Gorcyca K. Hollenbeak C. Foody J. Cardiovascular event rates in a high-risk managed care population in the United States.J Am Coll Cardiol. 2015; 61: A1647Crossref Google Scholar Patient demographics, clinical characteristics, and treatment characteristics were evaluated descriptively for the groups with and without a PCSK9 inhibitor prescription. In addition, univariate and multivariate analyses comparing the patients with a PCSK9 inhibitor prescription with those without were performed. Statistical comparisons were determined and calculated using chi-square tests for proportions and t tests for continuous variables. Subgroup analyses were performed for patients with ASCVD and LDL-C >100 mg/dl (without co-morbidities) and for patients with ASCVD and LDL-C >70 mg/dl (with ≥1 co-morbidity) to represent the high- and very high-risk patient populations described in the ACC-ECDP.6Lloyd-Jones D.M. Morris P.B. Ballantyne C.M. Birtcher K.K. Daly Jr, D.D. DePalma S.M. Minissian M.B. Orringer C.E. Smith Jr, S.C. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.J Am Coll Cardiol. 2016; 68: 92-125Crossref PubMed Scopus (350) Google Scholar Co-morbidities in this study included those described in the ACC-ECDP: diabetes; recent acute coronary syndrome (<3 months); LDL-C ≥190 mg/dl; chronic kidney disease; and cigarette smoking, which included any history of and current cigarette smoking.6Lloyd-Jones D.M. Morris P.B. Ballantyne C.M. Birtcher K.K. Daly Jr, D.D. DePalma S.M. Minissian M.B. Orringer C.E. Smith Jr, S.C. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.J Am Coll Cardiol. 2016; 68: 92-125Crossref PubMed Scopus (350) Google Scholar The ACC-ECDP also includes an ASCVD event while on a statin and elevated levels of lipoprotein(a) as co-morbidities; however, this information was not available in our database. The group of patients with familial hypercholesterolemia and no ASCVD (LDL-C 70 to 100 mg/dl) were not analyzed as they were within their LDL-C target levels per current guidelines. To compare practices in the real world with those recommended in the ACC-ECDP, a further analysis was performed to assess lipid-modifying therapy use in the group of patients with a PCSK9 inhibitor prescription and baseline LDL-C ≥190 mg/dl (the group in which PCSK9 inhibitors may be used as the initial nonstatin therapy before ezetimibe or bile acid sequestrants according to the ACC-ECDP). There were 368,624 identified patients with ASCVD or HeFH with LDL-C values ≥70 mg/dl who were eligible for a PCSK9 inhibitor, of whom 1,752 (0.5%) received a PCSK9 inhibitor prescription (Figure 1). Eligible patients with a PCSK9 inhibitor prescription were younger than those without a PCSK9 inhibitor prescription (Table 1). A greater proportion of patients with versus patients without a PCSK9 inhibitor prescription were aged <65 years, with 29% of patients with a prescription (vs 23% of patients without) aged 55 to 64 years (Supplementary Table S1), whereas a significantly greater proportion of older patients (>80 years) were without a prescription (Table 1). Significant differences with respect to insurance plans were observed, with a greater proportion of patients with a PCSK9 inhibitor prescription being commercially insured (Table 1); similar results were seen when excluding patients for which the insurance plan was unknown (Supplementary Table S3).Table 1Baseline characteristicsCharacteristicsAll eligible PCSK9i patients (n = 368,624)PCSK9i prescriptionp-valueNo (n = 366,872)Yes (n = 1,752)Age (years), mean (standard deviation)68.2 (12.1)68.2 (12.1)64.9 (10.2)<0.0001 Median (Q1 : Q3)69 (60 : 77)69 (60 : 77)66 (58 : 88)<0.0001*p Value determined using non-parametric methods (Mann-Whitney U/Wilcoxon rank-sum test). Min:Max18:8918:8927:88Age groups (years)<0.0001 <65†Descriptive statistics and further breakdown of the <65 years group are shown in Supplementary Table S2.135,447 (37%)134,662 (37%)785 (45%) 65–6957,877 (16%)57,522 (16%)355 (20%) 70–7455,212 (15%)54,904 (15%)308 (18%) 75–8056,080 (15%)55,860 (15%)220 (13%) 80 +64,008 (17%)63,924 (17%)84 (5%)Men200,629 (54%)199,702 (54%)927 (53%)0.2016Race<0.0001 White310,666 (84%)309,064 (84%)1,602 (91%) Black41,068 (11%)40,979 (11%)89 (5%) Other6,806 (2%)6,774 (2%)32 (2%) Unknown10,084 (3%)10,055 (3%)29 (2%)Insurance<0.0001 Commercial95,193 (26%)94,595 (26%)598 (34%) Medicaid17,955 (5%)17,893 (5%)62 (4%) Medicare179,838 (49%)179,056 (49%)782 (45%) Other6,856 (2%)6,826 (2%)30 (2%) Unknown68,782 (19%)68,502 (19%)280 (16%)Cardiovascular risk category‡Co-morbidities described in the American College of Cardiology Expert Consensus Decision Pathway (ACC-ECDP). Atherosclerotic cardiovascular disease (ASCVD) risk categories evaluated included acute coronary syndrome <3 months with other ASCVD events included according to risk; heterozygous familial hypercholesterolemia patients had LDL-C ≥190 mg/dl. Other non-ASCVD comorbidities according to the ACC-ECDP included diabetes, LDL-C ≥190 mg/dl, and chronic kidney disease. Heterozygous familial hypercholesterolemia§Patients with both heterozygous familial hypercholesterolemia and ASCVD were categorized as having heterozygous familial hypercholesterolemia. A total of 9,646 of all PCSK9i eligible patients, 9,423 of those without a PCSK9i prescription, and 223 of those with a PCSK9i prescription had both heterozygous familial hypercholesterolemia and ASCVD.34,955 (9%)34,582 (9%)373 (21%)<0.0001 ASCVD333,669 (91%)332, 290 (91%)1,379 (79%)<0.0001 All coronary heart disease233,986 (63%)232,794 (63%)1,192 (68%) Acute coronary syndrome <3 months†Descriptive statistics and further breakdown of the <65 years group are shown in Supplementary Table S2.11,383 (3%)11,301 (3%)82 (5%) Acute coronary syndrome <12 months32,126 (9%)31,929 (9%)197 (11%) Ischemic stroke67,297 (18%)67,163 (18%)134 (8%) Peripheral artery disease32,386 (9%)32,333 (9%)53 (3%)Comorbidities‡Co-morbidities described in the American College of Cardiology Expert Consensus Decision Pathway (ACC-ECDP). Atherosclerotic cardiovascular disease (ASCVD) risk categories evaluated included acute coronary syndrome <3 months with other ASCVD events included according to risk; heterozygous familial hypercholesterolemia patients had LDL-C ≥190 mg/dl. Other non-ASCVD comorbidities according to the ACC-ECDP included diabetes, LDL-C ≥190 mg/dl, and chronic kidney disease. Diabetes mellitus151,052 (41%)150,374 (41%)678 (39%)0.052 Low-density lipoprotein cholesterol ≥190 mg/dl26,561 (7%)26,270 (7%)291 (17%)<0.0001 Chronic kidney disease70,716 (19%)70,463 (19%)253 (14%)<0.0001 Smoker191,860 (52%)190,993 (52%)867 (49%)<0.0001 Hypertension (history)322,180 (87%)320,632 (87%)1,548 (88%)0.230 Heart failure84,115 (23%)83,816 (23%)299 (17%)<0.0001Baseline lipids (mg/dl), mean ± standard deviation Low-density lipoprotein cholesterol103.6 ± 43.8103.5 ± 43.7139.4 ± 57.9<0.0001 High-density lipoprotein cholesterol47.5 ± 24.247.5 ± 24.347.0 ± 14.50.150 Total cholesterol178.7 ± 51.1178.5 ± 51.0219.6 ± 64.7<0.0001Pre-index cardiovascular events All cardiovascular events50,245 (14%)49,947 (14%)298 (17%)<0.0001 Ischemic stroke14,678 (4%)14,652 (4%)26 (1%)<0.0001 Unstable angina with hospitalization6,744 (2%)6,669 (2%)75 (4%)<0.0001 Coronary revascularization14,632 (4%)14,509 (4%)123 (7%)<0.0001 Non-fatal myocardial infarction14,191 (4%)14,117 (4%)74 (4%)0.410Medication High-dose statin125,779 (34%)125,239 (34%)540 (31%)<0.0001 Lower-dose statin230,385 (62%)229,542 (63%)843 (48%)<0.0001 Ezetimibe + statins13,007 (4%)12,730 (3%)277 (16%)<0.0001 Angiotensin-converting enzyme inhibitors125,436 (34%)124,906 (34%)530 (30%)<0.0001 Angiotensin II antagonist31,213 (8%)31,036 (8%)177 (10%)0.014 Calcium channel blockers52,341 (14%)52,089 (14%)252 (14%)0.820 Beta blockers151,282 (41%)150,504 (41%)778 (44%)0.004 Diuretics14,807 (4%)14,741 (4%)66 (4%)0.590 All insulins107,913 (29%)107,372 (29%)541 (31%)0.140 All oral antidiabetics93,313 (25%)92,612 (25%)701 (40%)<0.0001 Other hypertensive112,561 (31%)111,997 (31%)564 (32%)0.130PCSK9i = PCSK9 inhibitor.* p Value determined using non-parametric methods (Mann-Whitney U/Wilcoxon rank-sum test).† Descriptive statistics and further breakdown of the <65 years group are shown in Supplementary Table S2.‡ Co-morbidities described in the American College of Cardiology Expert Consensus Decision Pathway (ACC-ECDP). Atherosclerotic cardiovascular disease (ASCVD) risk categories evaluated included acute coronary syndrome <3 months with other ASCVD events included according to risk; heterozygous familial hypercholesterolemia patients had LDL-C ≥190 mg/dl. Other non-ASCVD comorbidities according to the ACC-ECDP included diabetes, LDL-C ≥190 mg/dl, and chronic kidney disease.§ Patients with both heterozygous familial hypercholesterolemia and ASCVD were categorized as having heterozygous familial hypercholesterolemia. A total of 9,646 of all PCSK9i eligible patients, 9,423 of those without a PCSK9i prescription, and 223 of those with a PCSK9i prescription had both heterozygous familial hypercholesterolemia and ASCVD. Open table in a new tab PCSK9i = PCSK9 inhibitor. Across all ASCVD categories and for HeFH, PCSK9 inhibitor utilization was very low (Table 1). A greater proportion of patients with HeFH or coronary heart disease and a lower proportion of patients with ischemic stroke or peripheral artery disease were found in the group with a PCSK9 inhibitor prescription versus the group without. Baseline mean LDL-C levels were significantly higher in patients with a PCSK9 inhibitor prescription than those for patients without (Table 1). A greater proportion of patients with a PCSK9 inhibitor prescription had baseline LDL-C in the >130 mg/dl categories compared with those without (49% vs 19% [p <0.0001], of whom 17% vs 7% [p <0.0001] had LDL-C >190 mg/dl, Figure 2). In eligible patients with any LDL-C measurements ≥70 mg/dl at baseline, 16% had an LDL-C measurement <70 mg/dl as their last recorded measurement. Significant differences between the 2 groups were observed for preindex cardiovascular events (Table 1). Ischemic stroke was more frequent in patients without a PCSK9 inhibitor prescription compared with patients with a prescription. Unstable angina with hospitalization and coronary revascularization procedures were more frequent in patients with a PCSK9 inhibitor prescription compared with those without. Immediately before index, nonstatin lipid-modifying therapies were more frequently used in patients with a PCSK9 inhibitor prescription versus those without (Figure 3). High-intensity statin treatment was received by a higher proportion of patients without versus those with a PCSK9 inhibitor prescription (Figure 3). In the analysis of the subgroup of patients with a PCSK9 inhibitor prescription and LDL-C ≥190 mg/dl (n = 291) immediately before index, high-intensity statin treatment was received by 23% of the patients and ezetimibe was received by 30% of the patients (14% ezetimibe alone, 16% with statins). Co-morbidities described in the ACC-ECDP that were significantly more frequent in the group with a PCSK9 inhibitor prescription included recent acute coronary syndrome and LDL-C ≥190 mg/dl. A greater proportion of patients with a PCSK9 inhibitor prescription had a recent acute coronary syndrome versus those without a prescription (Table 1). ACC-ECDP co-morbidities that were significantly more frequent in those without a PCSK9 inhibitor prescription included chronic kidney disease and cigarette smoking. The incidence of diabetes was not significantly different between the 2 groups. The non–ACC-ECDP defined co-morbidity, congestive heart failure, was less frequent in patients with a PCSK9 inhibitor prescription versus those without; history of hypertension was not significantly different between the 2 groups (Table 1). The ASCVD and LDL-C >100 mg/dl without ACC-ECDP co-morbidities subgroup included 238 (0.9%) patients with a PCSK9 inhibitor prescription, and the ASCVD and LDL-C >70 mg/dl with ≥1 ACC-ECDP co-morbidity group included 953 (0.5%) patients with a PCSK9 inhibitor prescription. PCSK9 inhibitor use was very low in the 2 groups of patients identified as PCSK9 inhibitor-eligible based on the ACC-ECDP. Results of the subanalyses were consistent with the overall analysis (Figure 4). Patients with a PCSK9 inhibitor prescription were more likely to have elevated LDL-C levels and belong to higher cardiovascular risk categories compared with remaining eligible patients. Although PCSK9 inhibitors were prescribed more frequently in patients belonging to higher risk categories, overall PCSK9 inhibitor utilization was still very low even in high-risk patients. Further clinical characteristics of the patient subgroups are listed in Supplementary Table S4. In this retrospective analysis of real-world PCSK9 inhibitor prescribing data in ASCVD and HeFH patients, a total of 368,624 PCSK9 inhibitor-eligible patients were identified, of whom only 1,752 (<0.5%) received a PCSK9 inhibitor prescription. In our study, of all PCSK9 inhibitor-eligible patients, including those with ASCVD and HeFH, only 34% were receiving high-intensity statin during baseline. The underutilization of high-intensity statins in high-risk patients with ASCVD in the United States is a major reason as to why up to 80% of high-risk patients are unable to achieve their LDL-C goal.2Wong N.D. Young D. Zhao Y. Nguyen H. Caballes J. Khan I. Sanchez R.J. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011–2012.J Clin Lipidol. 2016; 10: 1109-1118Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 3Graham J.H. Sanchez R.J. Saseen J.J. Mallya U.G. Panaccio M.P. Evans M.A. Clinical and economic consequences of statin intolerance in the United States: results from an integrated health system.J Clin Lipidol. 2017; 11 (e71): 70-79Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 4Karalis D.G. Victor B. Ahedor L. Liu L. Use of lipid-lowering medications and the likelihood of achieving optimal LDL-cholesterol goals in coronary artery disease patients.Cholesterol. 2012; 2012: 861-924Crossref Scopus (50) Google Scholar High-risk patients who are unable to maintain use of moderate or high-intensity statin, or who are unable to achieve their LDL-C target goal, are at increased risk of recurrent myocardial infarction and coronary heart disease events compared with those demonstrating high adherence to moderate- or high-intensity statin regimens who reach their LDL-C goals.3Graham J.H. Sanchez R.J. Saseen J.J. Mallya U.G. Panaccio M.P. Evans M.A. Clinical and economic consequences of statin intolerance in the United States: results from an integrated health system.J Clin Lipidol. 2017; 11 (e71): 70-79Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 11Serban M.C. Colantonio L.D. Manthripragada A.D. Monda K.L. Bittner V.A. Banach M. Chen L. Huang L. Dent R. Kent S.T. Muntner P. Rosenson R.S. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction.J Am Coll Cardiol. 2017; 69: 1386-1395Crossref PubMed Scopus (196) Google Scholar Of patients who were eligible for add-on therapy to lower their LDL-C levels according to current guidelines, only 4% were prescribed ezetimibe and even fewer (<0.5%) were prescribed a PCSK9 inhibitor. This is consistent with current literature on suboptimal treatment of the ASCVD and HeFH high-risk populations in real-world settings, and provides further evidence that large proportions of these patient groups remain undertreated and are at risk of cardiovascular events and would benefit from newer therapies to lower LDL-C.1Lin I. Sung J. Sanchez R.J. Mallya U.G. Friedman M. Panaccio M. Koren A. Neumann P. Menzin J. Patterns of statin use in a real-world population of patients at high cardiovascular risk.J Manag Care Spec Pharm. 2016; 22: 685-698Crossref PubMed Scopus (58) Google Scholar, 2Wong N.D. Young D. Zhao Y. Nguyen H. Caballes J. Khan I. Sanchez R.J. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011–2012.J Clin Lipidol. 2016; 10: 1109-1118Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 5Huang Q. Grabner M. Sanchez R. Willey V. Cziraky M. Palli S. Power T. Clinical characteristics and unmet need among patients with atherosclerotic cardiovascular disease stratified by statin use.Am Health Drug Benefits. 2016; 9: 434-444PubMed Google Scholar The findings from this study show that since the availability of PCSK9 inhibitors in clinical practice, they have been used mainly in patients with higher ASCVD risk and in those whose LDL-C levels were far from guideline-recommended targets. Patients prescribed a PCSK9 inhibitor were more likely to have LDL-C >130 mg/dl. However, even in eligible patients with on-treatment very high levels of LDL-C, few are prescribed a PCSK9 inhibitor. Of 26,561 patients with LDL-C ≥190 mg/dl and eligible to receive a PCSK9 inhibitor, only 1.1% were prescribed one. The observed utilization of PCSK9 inhibitors in this high-risk patient group in need of additional LDL-C lowering is likely to increase, as we anticipate that initial barriers preventing their prescription will be overcome with time. Importantly, physician awareness and recognition of when it is appropriate to prescribe PCSK9 inhibitors per guidelines is likely to improve particularly as several professional organizations have recently updated their guidelines on the use of PCSK9 inhibitors. In patients with hypercholesterolemia, adherence to guideline-based therapy has been associated with lower direct medical costs and hospitalization rates.12Aubert R.E. Yao J. Xia F. Garavaglia S.B. Is there a relationship between early statin compliance and a reduction in healthcare utilization?.Am J Manag Care. 2010; 16: 459-466PubMed Google Scholar, 13Sokol M.C. McGuigan K.A. Verbrugge R.R. Epstein R.S. Impact of medication adherence on hospitalization risk and healthcare cost.Med Care. 2005; 43: 521-530Crossref PubMed Scopus (1354) Google Scholar Although the costs associated with PCSK9 inhibitors represent another potential barrier to prescription of these therapies, they may be offset by cost savings made in cardiovascular events avoided. At the time of this study, results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial,8Sabatine M.S. Giugliano R.P. Keech A.C. Honarpour N. Wiviott S.D. Murphy S.A. Kuder J.F. Wang H. Liu T. Wasserman S.M. Sever P.S. Pedersen T.R. Fourier Steering Committee InvestigatorsEvolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722Crossref PubMed Scopus (3202) Google Scholar the primary evidence of reduction in cardiovascular outcomes with PCSK9 inhibitors, were not published and the lack of cardiovascular outcomes data may have been another potential barrier to prescription. It is expected that, with the increased dissemination of the FOURIER data together with further evidence demonstrating reduced cardiovascular outcomes with other PCSK9 inhibitors soon to follow (results of the cardiovascular outcomes trial for the PCSK9 inhibitor alirocumab are expected in 2018), the benefit of these novel therapies in high-risk patient groups will be further supported. The strength of this study is that it is representative of real clinical practice. Study limitations include those widely recognized for retrospective study designs, including study validity being dependent on the accuracy of data used. Additionally, patient definitions for ASCVD and HeFH may be affected by regional differences, and there is potential for under- or overestimation of the true populations of some high-risk patient groups. This analysis represents the intention of a physician to prescribe therapy and does not confirm whether the prescription was approved by the patient's insurance or filled. This study lacks information on the reasons that drove decision-making in practice, and a further limitation is that the ACC-ECDP guidelines were published during the study period, and some physicians may not have been aware of these guidelines. In conclusion, this analysis of real-world prescribing patterns indicates that, despite clinical eligibility, only a limited proportion of high-risk patients receive a PCSK9 inhibitor prescription. There remains a large segment of the high-risk patient population requiring additional LDL-C lowering who could benefit from the addition of a PCSK9 inhibitor to their lipid-lowering regimen. The following from the study sponsors provided editorial comments on the manuscript: Keiko Higuchi, Robert Sanchez, Robert Pordy, and Greg Macaraeg. Medical writing assistance and editorial support, under the direction of the authors, was provided by Irene Neophytou, PhD, and Rachel Wright, PhD, both of Prime (Knutsford, United Kingdom), funded by Sanofi and Regeneron Pharmaceuticals, Inc., according to Good Publication Practice guidelines (http://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3). The sponsors were involved in the study design, collection, analysis, and interpretation of data, and data checking of information provided in the manuscript. The authors had unrestricted access to study data, were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication. D Karalis has served as a consultant for Regeneron Pharmaceuticals Inc. and Sanofi. U Mallya and A Ghannam are employees of and stockholders in Sanofi US. J Elassal and S Boklage are employees of and stockholders in Regeneron Pharmaceuticals, Inc. R Gupta is an employee of Accenture, Inc. The following is the supplementary data to this article: Download .docx (.04 MB) Help with docx files Appendix S1Supplementary Appendix, Tables S1–S4.