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      Real-world use of PCSK-9 inhibitors by early adopters: cardiovascular risk factors, statin co-treatment, and short-term adherence in routine clinical practice

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          Inconsistency of real-world medication use with labeled indications may affect cost and clinical value of pharmacotherapy. PCSK-9 inhibitors are labeled in the US for use with statins to reduce low-density lipoprotein cholesterol in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH).


          To assess consistency with labeled indications and treatment persistency for early (first 5 post-launch months) adopters of PCSK-9 inhibitor pharmacotherapy.


          Retrospective analysis of commercially insured cohorts derived from the Truven Health MarketScan ® database was performed. Subjects were aged 18–64 years, initiated PCSK-9 inhibitor or highest-intensity statin (rosuvastatin 40 mg/day or atorvastatin 80 mg/day) pharmacotherapy from August to December 2015, and were enrolled throughout 2015 and during separate baseline (pre-treatment) periods of 6 and 18 months. Baseline ASCVD, FH, and ASCVD events (myocardial infarction, transient ischemic attack, and cerebrovascular occlusion) were measured. Persistency was measured through December 2015 for subcohorts of patients initiating treatment from August to September 2015.


          Baseline disease rates were higher for patients treated with PCSK-9 inhibitors (n=390) compared with highest-intensity statins (n=26,306): ASCVD (68.5% vs 33.4%, respectively); FH (39.7% vs 15.5%); both P<0.001. In 18 months pre-treatment, 35.6% of PCSK-9 inhibitor-treated patients had ≥1 ASCVD event, and 87.9% had a labeled indication. Rates of 60-day nonpersistency for PCSK-9 inhibitors and highest-intensity statins were 33.3% and 39.8%, respectively ( P=0.207). During PCSK-9 inhibitor pharmacotherapy, 33.8% of patients had evidence of statin supply and, of those initiating treatment from August to September, 40.9% filled ≥1 statin prescription. Of those with sustained pre-treatment statin use, 34.8% had no statin supply during PCSK-9 inhibitor pharmacotherapy.


          Among early-adopting PCSK-9 inhibitor-treated patients, the off-label diagnosis rate was 12%; a majority lacked statin co-treatment; and one third filled prescriptions for ≤60 days. Inconsistency with labeled uses may reflect prescriber/patient decisions, health-insurance coverage determinations, or statin intolerance not reported on claims.

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          Most cited references 42

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          Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism.

          HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
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            Suboptimal statin adherence and discontinuation in primary and secondary prevention populations.

            To compare statin nonadherence and discontinuation rates of primary and secondary prevention populations and to identify factors that may affect those suboptimal medication-taking behaviors. Retrospective cohort utilizing pharmacy claims and administrative databases. A midwestern U.S. university-affiliated hospital and managed care organization (MCO). Non-Medicaid MCO enrollees, 18 years old and older, who filled 2 or more statin prescriptions from January 1998 to November 2001; 2258 secondary and 2544 primary prevention patients were identified. Nonadherence was assessed by the percent of days without medication (gap) over days of active statin use, a measurement known as cumulative multiple refill-interval gap (CMG). Discontinuation was identified by cessation of statin refills prior to the end of available pharmacy claims data. On average, the primary and secondary groups went without medication 20.4% and 21.5% of the time, respectively (P=.149). Primary prevention patients were more likely to discontinue statin therapy relative to the secondary prevention cohort (relative risk [RR], 1.24; 95% confidence interval [CI], 1.08 to 1.43). Several factors influenced nonadherence and discontinuation. Fifty percent of patients whose average monthly statin copayment was US dollars 10 but US dollars 20 discontinued by 2.2 and 1.0 years, respectively (RR, 1.39 and 4.30 relative to
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              Management of patients with familial hypercholesterolaemia.

              Familial hypercholesterolaemia (FH) is an autosomal inherited disorder characterized by markedly elevated LDL-cholesterol (LDL-C) levels and an increased risk of premature atherosclerotic cardiovascular disease. Although FH is one of the most common genetic disorders, this disorder remains mostly undetected and its management is often suboptimal. High-intensity statins are standard treatment for patients with FH, but LDL-C levels in most patients treated with statin monotherapy remain above those recommended by guidelines. Combination therapy to lower LDL-C levels further-such as treatment with statins plus ezetimibe-has been successful, and combination of apheresis with high-intensity statin treatment is used in patients with homozygous FH and in those with heterozygous FH who are statin-refractory. Mipomersen, an inhibitor of apolipoprotein B-100 synthesis, and lomitapide, a microsomal triglyceride transfer protein inhibitor, reduce LDL-C levels further when added to high-intensity statin treatment in homozygous FH, but both have important adverse effects, such as increasing liver fat content. At present, PCSK9 inhibition (with alirocumab or evolocumab) is well tolerated and reduces LDL-C levels considerably in patients receiving the maximally tolerated statin treatment, and seems the most promising emerging treatment option. Nevertheless, data from outcome trials with hard end points for PCSK9 inhibitors, mipomersen, and lomitapide are still needed before these therapies become standard for patients with FH.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                03 August 2017
                : 13
                : 957-965
                Department of Pharmacy Practice, College of Pharmacy, Midwestern University-Glendale, Glendale, AZ, USA
                Author notes
                Correspondence: Kathleen A Fairman, Department of Pharmacy Practice, College of Pharmacy, Midwestern University, 19555 N 59th Avenue, Glendale, AZ 85308, USA, Tel +1 480 356 9296, Email kfairm@ 123456midwestern.edu
                © 2017 Fairman et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research


                specialty medications, off-label use, evolocumab, alirocumab, pcsk-9 inhibitors, hyperlipidemia


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