co the emerging role of proprotein convertase subtilisin ... · proprotein convertase subtilisin/...

CE: Namrta; HCO/320508; Total nos of Pages: 9;

HCO 320508

REVIEW

C

CURRENTOPINION The emerging role of proprotein convertasesubtilisin/kexin type-9 inhibition in secondaryprevention: from clinical trials to real-worldexperience

0268-4705 Copyright � 2017 Wolte

opyright © 2017 Wolters

a,b c,d e
Amritanshu S. Pandey , Harpreet S. Bajaj , Vinay Garg ,Avinash Pandeya,f,g, and Subodh Vermah,i
Purpose of reviewThe recent advent of a highly efficacious class of low-density lipoprotein cholesterol (LDL-C) loweringagents, the proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, has transformed dyslipidaemiamanagement in patients with cardiovascular disease as well as those with familial hypercholesterolemia.

Recent findingsRecent positive results of the landmark Further Cardiovascular Outcomes Research with PCSK9 Inhibition inSubjects with Elevated Risk cardiovascular outcome trial with evolocumab as an add-on to statin therapydemonstrate further reduction of cardiovascular events. Additional safety outcomes from this largerandomized trial, as well as the EBBINGHAUS substudy, allay fears of neurocognitive disorder as anadverse effect of achieving very low LDL-C levels with these agents.

Summary and implicationsWidespread clinical adoption of PCSK9 inhibitors will depend on the results from ongoing and plannedcardiovascular efficacy and safety trials with PCSK9 inhibitors. In addition, understanding the practicalchallenges and barriers to usage of these injectable agents by high cardiovascular risk patients will alsoaffect clinical adoption of this class of agents. Analysis of cost-benefit models, along with anticipatedupdates to practice guidelines for dyslipidaemia management are likely to strengthen the clinical utility ofPCSK9 inhibitors. Importantly, the potency of this new class of agents provides a huge opportunity toextend further the ‘lower LDL-C is better’ hypothesis in an effort to reduce rates of cardiovascular morbidityand mortality on a population level.

Keywordscardiovascular disease, dyslipidaemia, evolocumab, familial hypercholesterolemia, proprotein convertasesubtilisin/kexin type-9 inhibition

a b
Cambridge Cardiac Care Centre, Cambridge, Department of Medi-cine, McMaster University, Hamilton, cLMC Diabetes & Endocrinology,Brampton, dLeadership Sinai Centre for Diabetes, Mount Sinai Hospital,eDepartment of Internal Medicine, University of Toronto, Toronto,fUniversity of Western Ontario, London, Ontario, Canada, gCenter forHealthcare Delivery Sciences, Brigham and Women’s Hospital, HarvardUniversity Medical School, Boston, Massachusetts, USA, hDivision ofCardiac Surgery, Keenan Research Centre for Biomedical Science, Li KaShing Knowledge Institute of St. Michael’s Hospital and iDepartments ofSurgery, Pharmacology and Toxicology, University of Toronto, Toronto,Ontario, Canada
Correspondence to Amritanshu S. Pandey, BSc, MD, FRCPC, ABIM,CBNC, Cambridge Cardiac Care Centre, 150 Hespeler Road,Cambridge, ON N1R 6V6, Canada. Tel: +1 519 624 3511;fax: +1 519 624 3411; e-mail: [email protected]

Curr Opin Cardiol 2017, 32:000–000

DOI:10.1097/HCO.0000000000000424

INTRODUCTION

The linear relationship between low-density lipopro-tein cholesterol (LDL-C) levels and cardiovasculardisease is well established, not only from observatio-nal study data [1–3] but also from multiple landmarkrandomized controlled trials (RCTs) with LDL-C low-ering medications in both the primary and secondaryprevention settings [4–10]. Because most of thesecardiovascular outcome trial data have originatedfrom RCTs involving 3-hydroxy-3-methyl-glutarylCoA reductase inhibitors (known as statins), world-wide guidelines recommend statins as first-linetherapy for cardiovascular prevention[11–13]. How-ever, a significant proportion of patients are eitherunable to tolerate these medications or are unable to

rs Kluwer Health, Inc. All rights reserved. www.co-cardiology.com

Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]


HCO 320508

KEY POINTS

� PCSK9 inhibitors are a novel class of lipid-loweringmedications that can be prescribed for patients whohave above target LDL-C levels or are at high risk forcardiovascular events such as those withfamilial hypercholesterolemia.

� PCSK9 inhibitors have profound LDL-C loweringcapabilities, even in patients already on backgroundstatin therapy.

� PCSK9 inhibitors are well tolerated, with no evidenceof neurocognitive dysfunction.

� The magnitude of LDL-C reduction efficacy for PCSK9inhibitors, together with the accumulatingcardiovascular benefit evidence demonstrated in recentcardiovascular outcome trials extends further the ‘lowerLDL-C is better’ hypothesis for cardiovascular diseasereduction in high-risk patients.

� Our single centre experience with PCSK9 inhibitionover a 1-year time frame suggests a potential forsignificant improvement in cholesterol management inthe real world with this novel medication class, but alsohighlights barriers to effective implementation ofthis therapy.

Complex issues in coronary revascularization

Cop

achieve target LDL-C levels on statins. There alsoexists the distinct possibility of additional cardiovas-cular benefit from reducing LDL-C beyond thatachieved by statin medications or by add-on ezeti-mibe or bile acid sequestrants. This concept of ‘loweris better’ is supported by the observation of lowestcardiovascular disease risk among those achievingthe lowest levels of LDL-C in post hoc analysesof the Treating to New Targets (TNT) trial, theJustification for the Use of Statins in Preventions:an Intervention Trial Evaluating Rosvastatin trial,and the Pravastatin or Atorvastatin Evaluationand Infection Therapy-Thrombolysis in MyocardialInfarction 22 (PROVE-IT-TIMI 22) trials [14–16].Many add-on therapies to statins have either hadlimited impact on cardiovascular risk or lackadequate data. [10,17–20] The need for an effectiveadd-on therapy to achieve target LDL-C levels in asignificant number of patients remains unmet.Accordingly, a novel class of lipid-lowering medi-cations has been introduced with the mechanismof proprotein convertase subtilisin/kexin type-9(PCSK9) inhibition. The objectives for this revieware to highlight recent efficacy, safety, and outcomedata from PCSK9 inhibitor trials, in addition tosharing our own experience in 114 patients whowere prescribed the PCSK9 inhibitor evolocumab ina real-world cardiology practice.

2 www.co-cardiology.com

yright © 2017 Wolters Kluwer Health, Inc. Unaut

THE LOW-DENSITY LIPOPROTEINHYPOTHESISIn large lipid trials such as PROVE-IT-TIMI 22 andTNT, more potent LDL-C reduction with higherintensity statins resulted in significant reductionsin cardiovascular disease progression and events[21,22]. These trials compared a simple approachof high intensity vs. moderate-intensity statintherapy. The resultant data supported the hypo-thesis that LDL-C lowering alone is the likely mech-anism of benefit with higher intensity statin therapyrather than their ‘pleiotropic’ effects [23]. A meta-analysis conducted by the Cholesterol TreatmentTrialists’ collaborators with over 90 000 patients,(423 263 patient-years) from major lipid trials showsa reduction in the 5-year incidence of major coron-ary events, revascularization, and stroke by approxi-mately 23% for every 1 mmol/l reduction in LDL-C.This benefit was attributed to the absolute reductionin LDL-C achieved regardless of the mechanism ofLDL-C reduction [24]. Further support for the LDL-Chypothesis comes from the results of the IMProvedReduction of Outcomes: Vytorin Efficacy Inter-national Trial (IMPROVE-IT), which was the firsttrial to show the benefit of adding a nonstatin lipidmodifying medication to statin therapy [10]. Thefact that the addition of ezetimibe to a moderate-dose statin demonstrated a reduction in cardio-vascular mortality emphasizes the significanceand potential therapeutic benefits of further LDL-Creduction.

ADDITIONAL NEED FOR LOW-DENSITYLIPOPROTEIN CHOLESTEROL LOWERING

Despite the establishment of clinical guidelines forinitiation of statin therapy in high cardiovascularrisk patient populations, there remains a significantproportion of patients who are not achieving appro-priate LDL-C targets. A Canadian observationalstudy of 2436 patients treated with a statin foundthat 37% of the study sample did not achieve targetLDL-C levels, including 45% of patients in the high-risk category [25]. Furthermore, a study of 7998patients with established coronary artery diseasefrom 78 centres in 24 different European countriesfound that 80.5% of patients had an LDL-C greaterthan the European target of less than 1.8 mmol/l,despite 85% of the study participants having a pre-scription for statin therapy [26].

In an effort to address this care gap, adjunctivetherapies such as niacin, fibrates, and cholesterolreuptake inhibitors were investigated in cardiovas-cular outcome trials. Niacin [17,18] and fenofibrate[19,20] did not show any cardiovascular benefitwhen they were added to statin therapy. In contrast,

Volume 32 � Number 00 � Month 2017

horized reproduction of this article is prohibited.


HCO 320508

Proprotein convertase subtilisin/kexin type-9 Pandey et al.

C

the IMPROVE-IT trial did show a modest cardiovas-cular benefit of adding ezetimibe to moderate-inten-sity statin therapy in a trial of 18 144 patients withrecent acute coronary syndrome [10]. The mediantime-weighted average LDL-C achieved was1.4 mmol/l for the ezetimibe and simvastatin armvs. 1.8 mmol/l for the placebo and simvastatin armat the end of 6-year trial period. The primary com-posite outcome of cardiovascular mortality, majorcardiovascular event, or nonfatal stroke was mod-estly reduced by an absolute risk of 2% or a relativerisk reduction of 6%.

Statin intolerance is a concept, that is, fiercelydebated by lipid experts and poses a significantproblem for clinicians [27]. Statin intolerancelargely consists of subjective complaints of musclepain and weakness, which is seldom supportedby clinical biomarkers such as muscle enzymeelevation. It is reported by 5–20% of patients startedon statin therapy and thus has significant implica-tions on treatment decisions for a relatively largeproportion of the treated population [28]. Evenmore concerning are recent findings that those withstatin intolerance could have an approximately50% greater chance of myocardial infarction (MI)or need for coronary revascularization [29].

In addition, patients with heterozygous familialhypercholesterolemia (HeFH) pose an even greaterchallenge with adequately lowering LDL-C. Thisautosomal dominant, hereditary disorder causedby a mutation in the LDL receptor (LDL-R) genehas prevalence between 1/200 and 1/500 peopleworldwide [30]. Patients with this disorder haveup to a 13-fold increased risk of coronary heartdisease. In a cross-sectional study conducted inthe Netherlands of 1249 patients with HeFH, ofwhich nearly all were on statin therapy, only 21%reached the target LDL-C of less than 2.5 mmol/l[31]. Moreover, among those who did not achievetarget LDL-C, 27% were on combination therapywith maximum dose statin in addition to ezetimibe.The lack of efficacious, evidence-based alternativelipid-lowering therapies highlight the critical needfor new lipid-lowering medications that modifycardiovascular risk.

The introduction of PCSK-9 inhibitors as thenewestclassof lipidmodifyingagentswith thepoten-tial for potent LDL-C reduction and the results oftheir initial studies have offered new hope to achievelow LDL-C targets in these high-risk patients.

PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE-9 INHIBITION

The protein PCSK9 was first identified in 2003. Itis highly expressed in the liver and found to

0268-4705 Copyright � 2017 Wolters Kluwer Health, Inc. All rights rese

opyright © 2017 Wolters Kluwer Health, Inc. Una

contribute to cholesterol homeostasis [32]. Instudying DNA from 23 French families with auto-somal dominant hypercholesterolemia, missensemutations in PCSK9 were found and thought torepresent gain of function mutations that led toincreased cardiovascular risk [33]. Henceforth,PCSK9 became a target for the pharmaceuticalindustry for the development of lipid-loweringdrugs.

In normal cholesterol homeostasis, PCSK9interacts with LDL-Rs, which are responsible forthe clearance of LDL-C particles. Under conditionsof intracellular cholesterol depletion, activation ofthe sterol regulatory binding protein-2 leads toincreased expression of mRNA for both PCSK9and LDL-R. In the endoplasmic reticulum, autoca-talysis of PCSK9 creates a prosegment that remainsassociated with the mature PCSK9 protein aftercleavage. The PCSK9 protein is secreted and bindsto the extracellular domain of the LDL-R at the cellsurface. The PCSK9/LDL-R complex then enters theendosomal pathway and is directed to the lysosomefor degradation, leading to a decrease in the numberof LDL-R [32]. PCSK-9 inhibitors act by directinga mAb against PCSK9 protein, thereby reducingdegradation of LDL-R, and allowing for increasedclearance of LDL-C particles.

PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE-9 INHIBITORS: LOW-DENSITYLIPOPROTEIN CHOLESTEROL REDUCTIONEFFICACY

Currently, two human mAbs to PCSK-9, evolocu-mab and alirocumab, have been approved in manyparts of the world for LDL-C lowering in high-riskpatients not at target LDL-C with statins alone or incombination with other lipid-lowering agents.

In the Phase III MENDEL-2 and GAUSS-2 RCTs,evolocumab monotherapy reduced LDL-C by over50% [34,35]. In the RUTHERFORD-2 trial with HeFHpatients on background lipid-lowering therapy, a59.2 and 61.3% reduction in LDL-C was foundcompared with placebo for evolocumab dosed atevery 2 weeks and dosed monthly, respectively[36]. Similarly, in the LDL-C Assessment with PCSK9Monoclonal Antibody Inhibition Combined withStatin Therapy study, patients already on moder-ate-to-high-intensity statins treated with evolocu-mab had a greater than 60% further reduction inLDL-C [37]. Similar efficacy for LDL-C reduction wasobserved for alirocumab in phase III clinical trials in avariety of patient populations [38–40]. In longerterm, open-label follow-up of trials with both evolo-cumab [Open-Label Study of Long-Term Evaluationagainst LDL Cholesterol (OSLER) with 11.1 months

rved. www.co-cardiology.com 3

uthorized reproduction of this article is prohibited.


HCO 320508


Cop

mean duration] and alirocumab [Long-term Safetyand Tolerability of Alirocumab in High Cardiovas-cular Risk Patients with Hypercholesterolemia NotAdequately Controlled with Their Lipid ModifyingTherapy (ODYSSEY LONG TERM)] with 70 weeksmean duration), LDL-C reduction of 61 and 62%was maintained compared to placebo, respectively[41,42]. Exploratory, post hoc analyses of both theselonger term studies published simultaneously in2015 demonstrated a reduction in composite majorcardiovascular endpoints and raised the prospect ofpositive results in dedicated cardiovascular outcometrials with both these agents.

PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE-9 INHIBITORS:CARDIOVASCULAR BENEFITS IN FURTHERCARDIOVASCULAR OUTCOMESRESEARCH WITH PCSK9 INHIBITION INSUBJECTS WITH ELEVATED RISK TRIALWITH EVOLOCUMAB

The recently published trial with evolocumabnamed ‘Further Cardiovascular Outcomes Researchwith PCSK9 Inhibition in study participants withElevated Risk (FOURIER)’ is the first dedicated pro-spective cardiovascular outcomes trial with a PCSK9inhibitor to show cardiovascular benefit [43

&&

]. Inthis secondary prevention trial, 27 564 patients withatherosclerotic cardiovascular disease and LDL-Clevels of more than 1.8 mmol/l, receiving high ormoderate-intensity statin therapy, were randomizedto evolocumab (either 140 mg every 2 weeks or420 mg monthly) or matching placebo injections.By 48 weeks, study participants on evolocumab hadachieved a mean LDL-C of 0.78 mmol/l from a base-line of 2.4 mmol/l; and this magnitude of reductionwas maintained over a median duration of follow-upof 26 months – with 42% of the patients achievingLDL-C of less than 0.65 mmol/l. This resulted in arelative risk reduction of 15% (95% confidenceinterval¼8–21%; P


HCO 320508

FIGURE 1. Primary and Secondary End Points from the FOURIER trial. Evolocumab and Clinical Outcomes in Patients withCardiovascular Disease. Copyright � (2017) Massachusetts Medical Society. Reprinted with permission from MassachusettsMedical Society. Adapted with permission [43&&].


C

maintain a clean safety slate with no significantdifferences from the corresponding placebo armsfor premature drug discontinuation rates, allergicreactions, muscle or liver-related adverse effects,haemorrhagic stroke, cataract, new onset diabetes,or worsening of glycaemic control. A theoreticalconcern regarding prolonged exposure to extremelylow LDL-C levels leading to a negative impact onneurocognitive function has been postulated. Thisconcern is based on the fact that cholesterol is vitalin synapse formation and function and cholesterolin the brain is synthesized locally by glia [46

&

].However, it should be noted that mAbs are con-sidered to be too large to cross the blood–brainbarrier. Indeed, nonsignificant increase in neuro-cognitive disorder was reported in both the OSLER(reported incidence of 0.9% for evolocumab vs.0.3% for placebo) and ODYSSEY long term (reported



incidence of 1.2% for alirocumab vs. 0.5% forplacebo) studies – although the assessments werebased on few events and with inconsistent meth-odological testing. Nonetheless, in early 2014 the USFood and Drug Administration directed developersof PCSK9 inhibitors to monitor neurocognitiveadverse effects and consider neurocognitive testingin at least a subset of participants in ongoing late-stage trials. The as yet unpublished EBBINGHAUSstudy [46

&

,47&&

] is a prospectively designed, dedi-cated neurocognitive study within the FOURIERtrial. Results from the EBBINGHAUS substudy werepresented at a late-breaking session at the AmericanCollege of Cardiology annual conference in 2017.This substudy evaluated 1204 patients, withoutdementia or cognitive impairment at baseline. Cog-nitive function was assessed using a standardizedCambridge Neuropsychological Test Automated




HCO 320508

Table 1. Baseline demographics of ASCVD patients notmeeting low-density lipoprotein cholesterol targets on and

not on Evolocumab

Onevolocumab

(n¼57)

Not onevolocumab

(n¼59) P

Demographics

Male, n (%) 33 (58) 41 (69) 0.17

Age (years) 59 58 0.55

BMI (kg/m2) 31.3 30.7 0.55

Medical history n, (%)

Diabetes 10 (18) 15 (25) 0.37

Hypertension 45 (79) 45 (76) 0.73


Cop

Battery assessment. Over a median follow-up of 19.8months, the primary endpoint of spatial workingmemory strategy index of executive function andseveral secondary endpoints were no differentbetween the evolocumab vs. the placebo groups.There was also no evidence to suggest differencesin cognitive tests in patients attaining very lowLDL-C levels (�0.65 mmol/l). Although the robustEBBINGHAUS study design and use of an objective,well validated assessment tool strengthen the neuro-cognitive safety of PCSK9 inhibitors as well as thatof extremely low levels of LDL-C achieved, longerterm assessments in varied populations need to beundertaken.

Smoking 9 (16) 11 (19) 0.69

Prior MI 15 (26) 21 (36) 0.28

Prior stroke 2 (4) 5 (8) 0.27

Prior CABG 5 (9) 6 (10) 0.80

Prior PCI 10 (18) 12 (20) 0.70

Medications n, (%)

Aspirin 39 (68) 39 (66) 0.79

P2Y12 inhibitor 11 (19) 12 (20) 0.90

ACEI/ARB/ARNI 41 (72) 42 (71) 0.93

Statin 52 (91) 54 (91) 0.96

High dosea 32 (56) 39 (66) 0.28

Med dosea 16 (28) 12 (20) 0.34

Low dosea 4 (7) 1 (2) 0.16

Ezetimibe 19 (33) 17 (29) 0.60

Bile Acid Seq 13 (23) 17 (29) 0.46

ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin receptorblockers; ARNI, angiotensin receptor-neprilysin inhibitor; ASCVD,atherosclerotic cardiovascular disease; Bile Acid Seq, bile acid sequestrants;CABG, coronary artery bypass graft surgery; MI, myocardial infarction; PCI,percutaneous coronary intervention.aHigh-dose statin: atorvastatin 40–80 mg, rosuvastatin 20–40 mg; medium-dose statin: atorvastatin 20–40 mg, rosuvastatin 5–20 mg, simvastatin40–80 mg; low-dose statin: atorvastatin 10 mg, simvastatin


HCO 320508

Table 2. Impact of evolocumab on lipid profile at 1 year

On evolocumab (n¼57) Not on evolocumab (n¼59)Baseline 1-year follow-up P Baseline 1-year follow-up P

Total cholesterol (SD) (mmol/l) 4.84 (1.25) 3.18 (1.09)


HCO 320508


Cop

Financial support and sponsorship

H.S.B. has received grants or personal fees outside thesubmittedwork, from Abbott,Amgen,AstraZeneca, Boeh-ringer Ingelheim, Eli Lilly and Company, Janssen Phar-maceutical, Merck & Co., Novo Nordisk, Sanofi, Pfizer,Takeda Pharmaceuticals and Valeant Pharmaceuticals.

S.V. has received research funding and/or honorariafrom Abbott, Amgen, AstraZeneca, Bayer, BoehringerIngelheim, Bristol-Myers Squibb, Eli Lilly, Medtronic,Merck, and Sanofi.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDEDREADINGPapers of particular interest, published within the annual period of review, havebeen highlighted as:

& of special interest&& of outstanding interest

1. O’Donnell CJ, Elosua R. [Cardiovascular risk factors. Insights from Framing-ham heart study]. Rev Esp Cardiol 2008; 61:299–310.

2. Virani SS, Catellier DJ, Pompeii LA, et al. Relation of cholesterol andlipoprotein parameters with carotid artery plaque characteristics: the Athero-sclerosis Risk in Communities (ARIC) carotid MRI study. Atherosclerosis2011; 219:596–602.

3. Stamler J, Wentworth D, Neaton JD. Is relationship between serum choles-terol and risk of premature death from coronary heart disease continuous andgraded? Findings in 356,222 primary screenees of the Multiple Risk FactorIntervention Trial (MRFIT). JAMA 1986; 256:2823–2828.

4. The lipid research clinics coronary primary prevention trial results I. Reductionin incidence of coronary heart disease. JAMA 1984; 251:351–364.doi:10.1001/jama.1984.03340270029025.

5. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease withpravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1308.

6. Randomised trial of cholesterol lowering in 4444 patients with coronary heartdisease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389.

7. Ridker PM, Danielson ED, Fonseca FA, et al., JUPITER Study Group.Rosuvastatin to prevent vascular events in men and women with elevatedC-reactive protein. N Engl J Med 2008; 359:2195–2207.

8. Schwartz GG, Olsson AG, Ezekowitz MD, et al., Myocardial Ischemia Re-duction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators.Effects of atorvastatin on early recurrent ischemic events in acute coronarysyndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–1718.

9. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention ofcardiovascular disease with atorvastatin in type 2 diabetes in the Collabora-tive Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet 2004; 364:685–696.

10. Cannon CP, Blazing MA, Giugliano RP, et al., IMPROVE-IT Investigators.Ezetimibe added to statin therapy after acute coronary syndromes. N Engl JMed 2015; 372:2387–2397.

11. Stone NJ, Robinson J, Lichtenstein AH, et al., American College of Cardiol-ogy/American Heart Association Task Force on Practice Guidelines. 2013ACC/AHA guidelines on the treatment of blood cholesterol to reduceatherosclerotic cardiovascular risk in adults: a report of the American collegeof cardiology/American heart association task force on practice guidelines.Circulation 2013; 129:S1–S45.

12. Anderson TJ, Gregoire J, Pearson GJ, et al. 2016 Canadian cardiovascularsociety guidelines for the management of dyslipidemia for the prevention ofcardiovascular disease in the adult. Can J Cardiol 2016; 32:1263–1282. doi:http://dx.doi.org/10.1016/j.cjca.2016.07.510.

13. Catapano AL, Graham I, De Backer G, et al., Authors/Task Force Members;Additional Contributor. 2016 ESC/EAS guidelines for the management ofdyslipidaemias. Eur Heart J 2016; 37:2999–3058. doi: https://doi.org/10.1093/eurheartj/ehw272.

14. LaRosa JC, Grundy SM, Kastelein JJ, et al., Treating to New Targets (TNT)Steering Committee and Investigators. Safety and efficacy of atorvastatin-induced very low-density lipoprotein cholesterol levels in patients with coro-nary heart disease (a post hoc analysis of the Treating to New Targets [TNT]study). Am J Cardiol 2007; 100:747–752.

8 www.co-cardiology.com

yright © 2017 Wolters Kluwer Health, Inc. Unaut

15. Hsia J, MacFadyen JG, Monyak J, et al. Cardiovascular event reduction andadverse events among subjects attaining low-density lipoprotein cholesterol


HCO 320508


C

38. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety ofthe proprotein convertase subtilisin/kexin type 9 inhibitor alirocumabamong high cardiovascular risk patients on maximally tolerated statintherapy: the ODYSSEY COMBO I study. Am Heart J 2015; 169:906–915.

39. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab inhigh cardiovascular risk patients with adequately controlled hyper-cholesterolemia on maximally tolerated doses of statins: the ODYSSEYCOMBO II randomized controlled trial. Eur Heart J 2015; 36:1186–1194.

40. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH1 and FH II:78 week results with alirocumab treatment in 735 patients with hetero-zygous familial hypercholesterolemia. Eur Heart J 2015; 36:2996–3003.

41. Sabatine MS, Giugliano RP, Wiviott SD, et al., Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy andsafety of evolocumab in reducing lipids and cardiovascular events. N Engl JMed 2015; 372:1500–1509.

42. Robinson JG, Farnier M, Krempf M, et al., ODYSSEY LONG TERM Inves-tigators. Efficacy and safety of alirocumab in reducing lipids and cardiovas-cular events. N Engl J Med 2015; 372:1489–1499.

43.&&

Sabatine MS, Giugliano RP, Keech AC, et al., FOURIER SteeringCommittee and Investigators. Evolocumab and clinical outcomes inpatients with cardiovascular disease. N Engl J Med 2017; 376:1713–1722.

The large prospective cardiovascular outcomes trial demonstrated cardiovascularbenefit from use of evolocumab in patients already on background statin therapy,and further supports the hypothesis of lower LDL-C is better



44.&&

Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression ofcoronary disease in statin-treated patients: the GLAGOV randomized clinicaltrial. JAMA 2016; 316:2373–2384.

Through the use of intravascular ultrasound, this trial demonstrated reduction incoronary atherosclerotic plaque volume over 18 months in those patients treatedwith a PCSK9 inhibitor.45. Ridker PM, Revkin J, Amarenco P, et al., SPIRE Cardiovascular Outcome

Investigators. Cardiovascular Efficacy and Safety of Bococizumab in HighRisk Patients. N Engl J Med 2017; 376:1527–1539.

46.&

Giugliano RP, Mach F, Zavitz K, et al., EBBINGHAUS Investigators. Designand rationale of the EBBINGHAUS trial: a phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitivefunction in patients with clinically evident cardiovascular disease and receiv-ing statin background lipid lowering therapy-A cognitive study of patientsenrolled in the FOURIER trial. Clin Cardiol 2017; 40:59–65.

The trial was designed as a subset of the large cardiovascular outcomes trial withevolocumab, FOURIER, to address the effect of PCSK9 inhibition on cognitivefunction.47.&&

Results from the EBBINGHAUS Study. American College of Cardiology 2017:66th Annual Scientific Session. 18 March 2017 Washington, D.C, USA

The final publication for the EBBINGHAUS study is not yet available, however theresults released at this scientific session were significant in that there was nonegative effect on cognitive function found with the use of PCSK9 inhibitors andfurther lowering LDL-C levels.48. Sanofi. Odyssey Outcomes: Evaluation of Cardiovascular Outcomes After an

Acute Coronary Syndrome During Treatment with Alirocumab. 1 April 2017.Available at https://clinicaltrials.gov/ct2/show/NCT01663402. [Accessed 1April 2017].


https://clinicaltrials.gov/ct2/show/NCT01663402

co the emerging role of proprotein convertase subtilisin ... · proprotein convertase subtilisin/...

Documents