20150402LDLCAlirocumab&StatinToPregnant

Journal Club
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES,
Langslet G, Raal FJ, Shahawy ME, Koren MJ, Lepor NE, Lorenzato C, Pordy R,
Chaudhari U, Kastelein JJ; ODYSSEY LONG TERM Investigators.
Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular
Events.
N Engl J Med. 2015 Mar 15. [Epub ahead of print]
Bateman BT, Hernandez-Diaz S, Fischer MA, Seely EW, Ecker JL, Franklin
JM, Desai RJ, Allen-Coleman C, Mogun H, Avorn J, Huybrechts KF.
Statins and congenital malformations: cohort study.
BMJ. 2015 Mar 17;350:h1035. doi: 10.1136/bmj.h1035.
2015年4月2日 8:30-8:55
８階医局
埼玉医科大学総合医療センター内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田昌文
Matsuda, Masafumi
http://www.pcsk9forum.org/
Treatment of homozygous familial hypercholesterolaemia
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statins
ezetimibe
partial ileal bypass
portacaval shunt
liver transplantation
LDL apheresis
mipomersen
lomitapide
• (ALN-PCS)
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alirocumab
evolocumab
bococizumab
PCSK9 target
KYNAMROTM (mipomersen sodium)
KYNAMROTM is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis
Lancet 2010; 375: 998–1006
Lomitapide (INN, marketed as Juxtapid) is a drug for the treatment of familial hypercholesterolemia,
developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and
in combinations with atorvastatin, ezetimibe and fenofibrate.
The US Food and Drug Administration (FDA) approved lomitapide on 21 December 2012, as an
orphan drug to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density
lipoprotein (non-HDL) cholesterol in patients with homozygous familial hypercholesterolemia
(HoFH).
Lomitapide inhibits the
microsomal triglyceride transfer
protein (MTP or MTTP) which is
necessary for very low-density
lipoprotein (VLDL) assembly and
secretion in the liver.
http://en.wikipedia.org/wiki/Lomitapide
Proprotein convertase subtilisin/kexin type 9
PCSK9 (neural apoptosis-regulated convertase, NARC-1) is a 692-residue
extracellular protein representing the 9th member of the secretory subtilase
family expressed primarily in the kidneys, liver and intestines.
Genetic studies mapped PCSK9 along with LDLR and APOB to cause autosomal
dominant hypercholesterolemia (ADH). Gain-of-function mutations increased
plasma levels of low-density lipoprotein cholesterol (LDL-C), whereas nonsense or
missense (loss-of-function) mutations, which interfere with folding or secretion of
PCSK9, led to a reduction of plasma levels of LDL-C and an 88% decrease in the
risk of coronary heart disease (CHD).
http://caltagmedsystems.blogspot.jp/2012/04/pcsk9-attractive-drug-target-for.html
Lancet. 2014 Jan 4;383(9911):60-8.
Alirocumab SAR236553 (REGN727)
抗体治療！！
single ascending-dose studies of REGN727
N Engl J Med 2012;366:1108-18.
抗体治療+スタチン
Alirocumab SAR236553 (REGN727)
primary hypercholesterolemia
N Engl J Med 2012;367:1891-900. DOI: 10.1056/NEJMoa1201832
Effect of ALN-PCS treatment on serum LDL cholesterol
Lancet. 2014 Jan 4;383(9911):60-8.
ALN-PCS:a small interfering RNA that inhibits PCSK9 synthesis
Lancet. 2015 Jan 24;385(9965):341-50.
the University of Iowa, Iowa City (J.G.R.); Point Médical, Dijon (M.F.), Centre Hospitalier Universitaire de Nantes–
Hôpital Nord Laennec, Saint-Herblain (M.K.), University Hospital of Lille, Lille (G. Luc), and Sanofi, Chilly-Mazarin
(C.L.) — all in France; Clinique des Maladies Lipidiques de Québec, Quebec, QC, Canada (J.B.); Università di
Palermo–Policlinico P. Giaccone, Palermo, Italy (M.A.); the Department of Vascular Medicine, Academic Medical
Center, Amsterdam (E.S.S., J.J.P.K.); Lipid Clinic, Oslo University Hospital, Oslo (G. Langslet); University of the
Witwatersrand, Johannesburg (F.J.R.); Cardiovascular Center of Sarasota, Sarasota (M.E.S.), and Jacksonville
Center for Clinical Research, Jacksonville (M.J.K.) — both in Florida; Westside Medical Associates of Los Angeles,
Beverly Hills, CA (N.E.L.); Regeneron Pharmaceuticals, Tarrytown, NY (R.P.); and Sanofi, Bridgewater, NJ (U.C.).
N Engl J Med. 2015 Mar 15. [Epub ahead of print]
Background
Alirocumab, a monoclonal antibody that inhibits
proprotein convertase subtilisin–kexin type 9
(PCSK9), has been shown to reduce low-density
lipoprotein (LDL) cholesterol levels in patients
who are receiving statin therapy. Larger and
longer-term studies are needed to establish
safety and efficacy.
Methods
We conducted a randomized trial involving 2341
patients at high risk for cardiovascular events who
had LDL cholesterol levels of 70 mg per deciliter (1.8
mmol per liter) or more and were receiving treatment
with statins at the maximum tolerated dose (the
highest dose associated with an acceptable sideeffect profile), with or without other lipid-lowering
therapy. Patients were randomly assigned in a 2:1
ratio to receive alirocumab (150 mg) or placebo as a
1-ml subcutaneous injection every 2 weeks for 78
weeks. The primary efficacy end point was the
percentage change in calculated LDL cholesterol
level from baseline to week 24.
Figure S1. Study Design
Abbreviations: CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia;
LDL-C, lowdensity lipoprotein cholesterol; LLT, lipid-lowering therapy; Q2W, every other
week; SC, subcutaneous; W, week.
ClinicalTrials.gov identifier: NCT01507831
Figure 1. Randomization and Treatment.
The intention-to-treat population
included all randomly assigned
patients who had both a baseline
calculated low-density lipoprotein
(LDL) cholesterol value and at least
one calculated LDL cholesterol value
during one of the analysis windows
up to week 24. The three patients in
the alirocumab group who underwent
randomization but did not receive
treatment are included in the
intention-to-treat population.
Completion of the study was defined,
as per the electronic case-report
form, in the following way: the last
study-drug injection was received
(week 76), and the end-of-treatment
visit (week 78) occurred within 21
days after the last injection and at
least 525 days after randomization.
* Plus–minus values are means ±SD. The P
value for all between-group comparisons was
greater than 0.05, indicating no significant
differences. To convert the values for
cholesterol to millimoles per liter, multiply by
0.02586. To convert the values for
triglycerides to millimoles per liter, multiply by
0.01129. HDL denotes high-density
lipoprotein, and LDL low-density lipoprotein.
† Race was self-reported.
‡ The body-mass index is the weight in
kilograms divided by the square of the height
in meters.
§ Heterozygous familial hypercholesterolemia
was diagnosed by means of genotyping in
40.2% of the patients in the two groups
combined and by clinical criteria (World
Health Organization–Simon Broome
diagnostic criteria) in 59.8% of the patients in
the two groups combined.
¶ Coronary heart disease risk equivalents were
defined as peripheral arterial disease,
ischemic stroke, moderate chronic kidney
disease (estimated glomerular filtration rate,
30 to <60 ml per minute per 1.73 m2 of bodysurface area), or diabetes mellitus plus two or
more additional risk factors (hypertension;
ankle–brachial index of ≤0.90;
microalbuminuria, macroalbuminuria, or a
urinary dipstick result of >2+ protein;
preproliferative or proliferative retinopathy or
laser treatment for retinopathy; or a family
history of premature coronary heart disease).
‖ High-dose statin therapy was defined as a
daily dose of 40 to 80 mg of atorvastatin, 20
to 40 mg of rosuvastatin, or 80 mg of
simvastatin.
** LDL cholesterol levels were calculated with
the use of the Friedewald formula and also
measured by means of betaquantification
(see Table S1 in the Supplementary
Appendix).
* Plus–minus values are least-squares means ±SE, unless otherwise indicated. Primary and secondary efficacy analyses were performed with the use of an intention-to-treat approach, which
included patients with a baseline calculated LDL cholesterol value and at least one calculated LDL cholesterol value during or after receipt of the study drug within one of the analysis windows up to
week 24. A prespecified analysis that included only patients who were receiving the study drug was also performed (Table S3 in the Supplementary Appendix). Least-squares means (±SE) and P
values were calculated with the use of a mixed-effects model with repeated-measures analysis (except for end points noted in the footnotes below). The P values are significant according to the fixed
hierarchical approach used to ensure control of the overall type I error rate at the 0.05 level. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. CI denotes confidence
interval.
† Plus–minus values are means ±SD.
‡ The analysis of this end point was performed with the use of multiple imputation, followed by logistic regression. The combined estimate of the proportion of patients was obtained by calculation of
the average of all the imputed proportions of patients meeting the level of interest.
§ The P value has not been adjusted for multiple testing and is provided for descriptive purposes only.
¶ The percentage change in levels of lipoprotein(a) and triglycerides was analyzed with the use of multiple imputation, followed by robust regression. A combined estimate for adjusted mean (±SE)
is shown.
Results
At week 24, the difference between the alirocumab and
placebo groups in the mean percentage change from
baseline in calculated LDL cholesterol level was −62
percentage points (P<0.001); the treatment effect remained
consistent over a period of 78 weeks. The alirocumab group,
as compared with the placebo group, had higher rates of
injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs.
2.9%), neurocognitive events (1.2% vs. 0.5%), and
ophthalmologic events (2.9% vs. 1.9%). In a post hoc
analysis, the rate of major adverse cardiovascular events
(death from coronary heart disease, nonfatal myocardial
infarction, fatal or nonfatal ischemic stroke, or unstable
angina requiring hospitalization) was lower with alirocumab
than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95%
confidence interval, 0.31 to 0.90; nominal P=0.02).
Conclusions
Over a period of 78 weeks, alirocumab, when
added to statin therapy at the maximum tolerated
dose, significantly reduced LDL cholesterol levels.
In a post hoc analysis, there was evidence of a
reduction in the rate of cardiovascular events with
alirocumab.
(Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY
LONG TERM ClinicalTrials.gov number, NCT01507831.)
N Engl J Med. 2015 Mar 15. [Epub ahead of print] DOI: 10.1056/NEJMoa1500858
N Engl J Med. 2015 Mar 15. [Epub ahead of print] DOI: 10.1056/NEJMoa1500858
From the Departments of Medicine and Preventive Medicine and the Bluhm
Cardiovascular Institute, Feinberg School of Medicine, Northwestern University, Chicago.
Much work remains to be done, but PCSK9
inhibitors appear on track to become important
arrows in our quiver for targeting reduction of
cardiovascular events among higher-risk
patients when statins are not enough.
Message
最大耐量スタチン治療下の患者2341人を対象に、
抗PCSK9モノクローナル抗体alirocumabのLDLコ
レステロール低下効果を無作為化試験で検討
（ODYSSEY LONG TERM試験）。プラセボと比較し
たベースラインから24週のLDLコレステロール変
化率の差は－62％（Ｐ＜0.001）で、治療効果は
78週間持続した。
https://www.m3.com/clinical/journal/15259
LDL-Cはやはり低下させればさせるほどよいので
あろうか？？？
1Division
of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine,
Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
2Division of Obstetric Anesthesia, Department of Anesthesia, Critical Care, and Pain
Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
3Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
4Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, USA
5Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, USA
BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h1035 (Published 17 March 2015)
Objective
To examine the teratogenic potential of
statins.
Design Cohort study.
Setting United States.
Participants A cohort of 886 996 completed
pregnancies linked to liveborn infants of women
enrolled in Medicaid from 2000 to 2007.
Methods We examined the risk of major
congenital malformations and organ specific
malformations in offspring associated with
maternal use of a statin in the first trimester.
Propensity score based methods were used to
control for potential confounders, including
maternal demographic characteristics, obstetric
and medical conditions, and use of other drugs.
Propensity Score
A propensity score is the probability of a unit (e.g., person, classroom, school) being
assigned to a particular treatment given a set of observed covariates. Propensity scores are
used to reduce selection bias by equating groups based on these covariates.
Suppose that we have a binary treatment T, an outcome Y, and background variables X. The
propensity score is defined as the conditional probability of treatment given background
variables:
Let Y(0) and Y(1) denote the potential outcomes under control and treatment, respectively.
Then treatment assignment is (conditionally) unconfounded if potential outcomes are
independent of treatment conditional on background variables X. This can be written
compactly as
where denotes statistical independence.[1]
If unconfoundedness holds, then
Judea Pearl has shown that existence of a simple graphical criterion called backdoor path
implies the presence of confounding variables. To estimate the effect of treatment, backdoor
paths need to be blocked. This blocking can be done either by adding the confounding
variable as a control in regression, or by matching on the confounding variable.
Results
1152 (0.13%) women used a statin during the first
trimester. In unadjusted analyses, the prevalence
of malformations in the offspring of these women
was 6.34% compared with 3.55% in those of
women who did not use a statin in the first
trimester (relative risk 1.79, 95% confidence
interval 1.43 to 2.23). Controlling for confounders,
particularly pre-existing diabetes, accounted for
this increase in risk (1.07, 0.85 to 1.37). There
were also no statistically significant increases in
any of the organ specific malformations assessed
after accounting for confounders. Results were
similar across a range of sensitivity analyses.
Conclusions
Our analysis did not find a significant teratogenic
effect from maternal use of statins in the first
trimester. However, these findings need to be
replicated in other large studies, and the long
term effects of in utero exposure to statins needs
to be assessed, before use of statins in
pregnancy can be considered safe.
Message
米国のメディケアデータ88万6996件を対象に、妊娠初期
のスタチン使用が産児の先天性奇形に与える影響をコ
ホート研究で検討。1152人が妊娠初期にスタチンを使用
していた。奇形有病率はスタチン使用者6.34％、非使用
者3.55％（相対リスク1.79）。交絡因子で調整後は1.07
だった。調整後、臓器特異的な奇形有病率にも増加はな
かった。
https://www.m3.com/clinical/journal/15304
ただし、補正しなければ有意にリスクが増えるのは「妊娠可能性があるのにス
タチンを用いているということ」自体がリスクなのであろう。
Propensity Score だと無作為化研究でなくても観察研究でそれに近い結果と
なるらしい。最初βブロッカーの研究が有名らしい（Lindenauer PK, et al:
Perioperative beta-blocker therapy and mortality after major
noncardiac surgery. N Engl J Med. 2005 Jul 28;353(4):349-61.）
sensitivity analysis 感応度分析
分析したいアウトプットをいくつかの変数（パラメータ）に分解し、その変数が変動したとき、ア
ウトプットにどの程度の影響を与えるかを調べる手法。
propensity score (PS) matching 傾向スコア
直感的に理解しやすい解析方法は、同じ治療割り当て確率の患者同士でペアを作って治療
群とコントロール群を比較する傾向スコアマッチング（プロペンシティスコアマッチング）
propensity score (PS) matching法です。このように傾向スコアの近い症例同士をペアにす
るマッチング方法をcaliper matchingと呼び、症例1例に対してコントロール1例を割り当てる
1:1マッチングが一般的です。

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