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Research

Original Investigation

Effect of Evolocumab or Ezetimibe Added to Moderate-


or High-Intensity Statin Therapy on LDL-C Lowering
in Patients With Hypercholesterolemia
The LAPLACE-2 Randomized Clinical Trial
Jennifer G. Robinson, MD, MPH: Bettina S. Nedergaard, MD, PhD; William J. Rogers, MD: Jonathan Fialkow, MD; Joel M. Neutel, MD:
David Ramstad, MD, MPH; Ransi Somaratne, MD, MBA; Jason C. Legg, PhD: Patrie Nelson, MPH, MBA; Rob Scott, MD; Scott M. Wasserman, MD;
Robert Weiss, MD; forthe LAPLACE-2 Investigators

Supplemental content at
IMPORTANCE In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, jama.com
reduced LDL-C levels in patients receiving statin therapy.

OBJECTIVE To evaluate the efficacy and tolerability of evolocumab when used in combination
with a moderate- vs high-intensity statin.

DESIGN, SETTING, AND PATIENTS Phase 3,12-week, randomized, double-blind, placebo- and
ezetimibe-controlled study conducted between January and December of 2013 in patients
with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries.

INTERVENTIONS Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps.


Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg],
simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg],
rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899)
were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with
placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin
patients only) when added to statin therapies.

MAIN OUTCOMES AND MEASURES Percent change from baseline in low-density lipoprotein
cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12.

RESULTS Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI,
65% to 84%) (every 2 weeks) and by 63% (95% Ci, 54% to 71%) to 75% (95% CI, 67% to 83%)
(monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-
treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity
statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/
dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a
baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-
intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89
to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C
from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse
events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated
patients, respectively. The most common adverse events in evolocumab-treated patients were Author Affiliations: Author
affiliations are listed at the end of this
back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%).
article.
Group Information: The LAPLACE-2
CONCLUSIONS AND RELEVANCE In this 12-week trial conducted among patients with primary Investigators are listed at the end of
hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or this article.
high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to Corresponding Author: Jennifer G.
evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. Robinson, MD, MPH, Departments of
Epidemiology and Medicine,
Prevention Intervention Center,
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01763866 College of Public Health, University
of Iowa, 145 N Riverside Dr,
S455 CPBH, Iowa City lA 52242
JAMA. 2O14;311(18):1870-1882. doi:10.1001/jama.2014.4030 (jennifer-g-robinson@uiowa.edu).

1870 jama.com
Evolocumab Plus Statin Therapy for LDL-C Lowering Original Investigation Research

S
tatin therapy reduces atherosclerotic cardiovascular dis- ing the efficacy and safety of evoloctimab in combination with
ease events in proportion to the magnitude of low-density background statin therapy in patients with primary hypercho-
lipoprotein cholesterol (LDL-C) lowering.' Based on an ex- lesterolemia and mixed dyslipidemia. Trial design and baseline
tensive body of evidence, statins are consideredfirst-linetherapy patient characteristics have been previously reported.'^
for reduction of atherosclerotic cardiovascular disease risk.^"^ An independent data monitoring committee reviewed ac-
The 2013 US cholesterol treatment guidelines recommend cumulating trial data provided by an independent biostatis-
high-intensity statin therapy (anticipated to lower LDL-C levels tical group external to Amgen. Deaths and suspected cardio-
by approximately >50%) for adults at high risk for atherosclerotic vascular events were adjudicated by an independent, blinded,
cardiovascular disease and moderate-intensity statin therapy (an- clinical events committee. All site personnel, patients, study
ticipated to lower LDL-C levels by 30%-<50%) if a high-intensity monitors and Amgen staff were blinded to subcutaneous in-
statin is not tolerated.^ Those with LDL-C levels of 190 mg/dL (4.9 vestigational product and oral ezetimibe or placebo.
mmol/L) or greater due to a genetic cholesterol disorder should
receive a high-intensity statin and may require nonstatin therapy Randomization and Intervention
to achieve additional LDL-C lowering. The addition of a nonsta- Patients meeting the inclusion criteria received a placebo in-
tin cholesterol-lowering drug also can be considered for pafients jection to determine tolerance for subcutaneous administra-
with a less than anticipated LDL-C lowering response or for those tion of study drug. Patients tolerating placebo injection dis-
unable to tolerate the recommended statin intensity. Outside the continued previous statin and ezetimibe use and were
United States, several guidelines recommend LDL-C goals of less randomized to 1 of 5 open-label, oral treatments vth a mod-
than 100 mg/dL (2.6 mmol/L) or less than 70 mg/dL (1.8 mmol/ erate-intensity statin (atorvastatin [10 mg], rosuvastatin [5 mg],
L) depending on the level of risk.^"^ Many patients receiving simvastatin [40 mg]) or high-intensity statin (atorvastatin [80
moderate- or high-intensity statin therapy are unable to achieve mg], rosuvastatin [40 mg]) (Figure 1 and Figure 2).
these recommended goals with statin therapy, and consideration After a 4-week lipid-stabilization period, patients taking
of nonstatin therapy for additional LDL-C lowering has been rosuvastatin or simvastatin during the lipid-stabilization phase
recommended.'*^^ were then randomized to 1 of 4 treatment groups: evo-
Proprotein convertase subdlisin/kexin type 9 (PCSK9) inhibi- locumab (140 mg, subcutaneous, every 2 weeks) or matching
tors reduce circulating LDL-C levels by preventing the degrada- placebo (subcutaneous, every 2 weeks), or evolocumab (420
tion of LDL-C receptors when bound to PCSK9.^ Evolocumab, a mg, subcutaneous, monthly) or matching placebo (subcuta-
fuUy human monoclonal antibody against PCSK9, showed robust neous, monthly) (Figures 1 and 2).'^
LDL-C lowering in phase 2 trials,'""'^ including a longer-term study Patients taking atorvastatin during the lipid-stabilization
of 52 weeks' duration,''' and was well tolerated. phase were then randomized to 1 of 6 treatment groups: evo-
The LAPLACE-2 (LDL-C Assessment with PCSK9 Mono- locumab (140 mg, subcutaneous, every 2 weeks) and placebo (oral,
clonal Antibody Inhibition Combined With Statin Therapy) daily), evolocumab (420 mg, subcutaneous, monthly) and placebo
study was designed to evaluate the efficacy and safety of evo- (oral, daily), placebo (subcutaneous, every 2 weeks) and placebo
locumab vs placebo or ezetimibe, the most commonly pre- (oral, daily) or ezetimibe (10 mg, oral, daily), or placebo (subcu-
scribed nonstatin therapy, in patients randomized to differ- taneous, monthly) and placebo (oral, daily) or ezetimibe (10 mg,
ent background moderate- and high-intensity statin therapies.'^ oral, day).'^ Ezetimibe was evaluated only in patients treated with
atorvastatin, the most commonly prescribed statin. Subcunta-
neous evolocumab and placebo were presented as a sterile,
preservative-free solution in a single-use, disposable, mechani-
METHODS cal prefiUed autoinjector pen for a fixed-dose, subcutaneous in-
Patients jection. Oral ezetimibe and placebo were provided as lO-mg tab-
Briefly, this study enrolled patients aged 18 to 80 years with a lets of identical size and color.
screening LDL-C level of 150 mg/dL or greater (to convert to No additional prescription lipid-modifying drugs were al-
mmol/L, multiply by 0.0259) (no statin at screening), 100 mg/dL lowed during the trial.
or greater (nonintensive statin at screening), or 80 mg/dL or
greater (intensive statin at screening) and fasting triglycride Efficacy and Safety Evaluations
levels of 400 mg/dL or less (to convert to mmol/L, multiply by Coprimary end points were the percent change from baseline
0.0113). At screening, intensive statin use was defined as daily in LDL-C level at the mean of weeks 10 and 12 and at week 12,
atorvastatin (40 mg or greater), rosuvastatin (20 mg or greater), The averaging of weeks 10 and 12 better reflects average LDL-C
simvastatin (80 mg), or any statin plus ezetimibe. Inclusion/ reduction with monthly dosing. Level of LDL-C was deter-
exclusion criteria focused on safety and conditions that could mined by the Friedewald formula, unless calculated LDL-C was
inuence efficacy.'^ The study was approved by the institu- less than 40 mg/dL or triglycride levels were greater than 400
tional review board at each site, and written informed con- mg/dL; then the LDL-C level was measured by preparative ul-
sent was obtained from all participants. tracentrifugation. Secondary end points included the mean at
weeks 10 and 12 and at week 12 for the change from baseline
Study Design and Oversight in LDL-C level, the percent change from baseline in addi-
LAPLACE-2 was a 12-week, randomized, double-blind, placebo- tional lipid parameters, and the proportion of patients achiev-
and ezetimibe-controlled, phase 3, multicenter study examin- ing LDL-C levels less than 70 mg/dL. Baseline lipid parameters

jama.com JAMA May 14,2014 Volume 311, Number 18 1871


Research Original Investigation Evolocumab Plus Statin Therapy for LDL-C Lowering

Figure 1. Trial Design and Patient Disposition, Atorvastatin Groups

3590 Patients screened for eligibility'"'S

Excluded
1428 Did not meet inclusion criteria or met exclusion criteria
561 Nonintensive statin and screening LDL-C <100 mg/dL
334 No statin and screening LDL-C <1SO mg/dL
a)
See Figure 2

365 Randomized to rosuvastatin


139 Intensive statin and screening LDL-C <80 mg/dL (5 mg/d, oral)
42 Screening triglycrides >400 mg/dL
352 Other
95 Meteligibility criteria but did not enroll 366 Randomized to rosuvastatin
i (40 mg/d, oral)
_

2067 Randomized to receive statin in ^ - ^ 364 Randomized to simvastatin


tipid stabilization phase (40 mg/d, oral)

485 Randomized to atorvastatin f'' 487 Randomized to atorvastatin


(10 mg/d, oral) (80 mg/d, oral)

43 Excluded 47 Excluded
5 Never received statin 4 Never received statin
38 Discontinued statin j , i ,/,, , 43 Discontinued statin
and ended study and ended study
'LJJ

(^442 Randomized to study drug _J

56 Randomized to receive 55 Randomized to receive 56 Randomized to receive 55 Randomized to receive 110 Randomized to receive 110 Randomized to
placebo (subcutaneous. placebo (subcutaneous. placebo (subcutaneous. placebo (subcutaneous. evolocumab (140 mg. receive evolocumab
every 2 wk) + placebo monthly) + placebo every2 wl<) + ezetimlbe monthly)+ ezetlmihe subcutaneous, every (420 mg, monthly) ;
(oral, daily) (oral, daily) (10 mg/d, oral) (10 mg/d, oral) 2 wl<) +placebo + placebo(oraL daily)!
56 Received study 54 Received study 56 Received study 55 Received study (oral, daily) 110 Received study
drug as randomized drug as randomized drug as randomized drug as randomized 110 Received study drug as
1 Not given oral drug as randomized |
study drug randomized
,1
6 Discontinued study drug 5 Discontinued study drug 14 Discontinued study drug 2 Discontinued study drug 6 Discontinued study drug 10 Discontinued study drug.
3 Subcutaneous 3 Subcutaneous 8 Subcutaneous 1 Subcutaneous 4 Subcutaneous 5 Subcutaneous
1 Adverse event 2 Adverse event 1 Adverse event (adverse event) 2 Adverse event 2 Adverse event
1 Participant request 1 Participant request 6 Participant request 1 Oral (adverse event) 1 Participant request 2 Participant request
1 Other 2 Oral (adverse events) 1 Other 1 Other 1 Other
3 Oral 6 Oral 2 Oral 5 Oral
1 Adverse event 1 Adverse event 1 Adverse event 3 Adverse event
1 Participant request 5 Participant request 1 Participant request 1 Participant requests!
1 Other 1 Other j

56 Included in efficacy 55 Included in efficacy 56 Included in efficacy 55 Included in efficacy 110 Included in efficacy 110 Included in efficacy ]
and safety analyses and safety analyses and safety analyses and safety analyses and safety analyses and safety analyses i

C 440 Randomized to study drut


"
55 Rafrdomized to receive ' ' 55 Randomized to receive ' '5S Randomized to receive 54 Randomized to receive '110 Randomlzeij to receive ' 110 Randomi2ed to
placebo (subcutaneous. placebo (subcutaneous. placebo (subcutaneous. placebo (subcutaneous. evolocumab (140 mg. receive evolocumab
every 2 wk) + placebo monthly) + placebo every 2 wk) + ezetimibe monthlyjtezetimibe subcutaneous, every (420 mg, monthly)
(oral, daily) (oral, daily) (10 mg/d, oral) (10 mg/d, oral) 2 wk) + placebo + placebo(oraL daily);
55 Received study 55 Received study 56 Received study 54 Received study (oral, daily) 110 Received study
drug as randomized drug as randomized drug as randomized drug as randomized 109 Received study drug as ;
drug as randomized
randomized '
1 Not given
subcutaneous
study drug
(excluded from
analyses)
1 Not given oral
study drug

12 Discontinued study drug' 5 Discontinued study drug 5 Discontinued study drug 7 Discontinued study drug 12 Discontinued study drug 10 Discontinued study druS
6 Subcutaneous 2 Subcutaneous(other) 2 Subcutaneous 3 Subcutaneous 6 Subcutaneous 5 Subcutaneous ;
1 Adverse event 3 Oral 1 Adverse event 1 Adverse event 2 Adverse event 1 Adverse event '
4 Participant request 2 Adverse event 1 Physician decision 2 Participant request 2 Participant request 1 Sponsor decision^
1 Other 1 Other 3 Oral 4 Oral (participant 2 Other 3 Other
6 Oral 2 Adverse event request) 6 Oral 5 Oral
2 Adverse event 1 Physician decision 4 Adverse event 2 Adverse event '
3 Partie pant request 1 Participant request 1 Physician decision ,
1 Lost to follow-up 1 Other 1 Sponsor decision' '
1 Other ,i

55 Included in efficacy 55 Included in efficacy 56 Included in efficacy 54 Included in efficacy 109 Included in efficacy 110 Included in efficacy j
and safety analyses and safety analyses and safety analyses and safety analyses and safety analyses and safety analyses ],
1 Excluded (not given
subcutaneous study
drug)

' Sponsor decision because of other reason.

1872 JAMA May 14,2014 Volume 311, Number 18 jama,com


Evolocumab Plus Statin Therapy for LDL-C Lowering Original Investigation Research

Figure 2. Trial Design and Patient Disposition, Rosuvastatin and Simvastatin Groups

Continued From Figure 1


365 Randomized to rosuvastatin
(5 mg/d, oral)

21 Excluded
2 Never received statin
L 19 Discontinued statin and ended study

144 Randomized to study drug'

58 Randomized to receive placebo 57 Randomized to receive placebo 114 Randomized to receive evolocumb 115 Randomized to receive evolocumab
(subcutaneous, every 2 wk) (subcutaneous, monthly) (140 mg, every 2 wk) (420 mg, monthly)
58 Received study drug as 57 Received study drug as 113 Received study drug as 115 Received study drug as
randomized randomized randomized randomized
1 Not given subcutaneous study
drug (excluded from analyses)

3 Discontinued study drug 1 Discontinued study drug 8 Discontinued study drug 6 Discontinued study drug
1 Adverse event (other) 6 Adverse event 2 Adverse event
1 Participant request 2 Participant request 3 Subject request
1 Lost to follow-up 1 Other

58 Included in efficacy and safety 57 Included in efficacy and safety 113 Included in efficacy and safety 115 Included in efficacy and safety
analyses analyses analyses analyses
1 Excluded (not given subcutaneous
study drug)

366 Randomized to rosuvastatin '


(40 mg/d, oral)

r
31 Excluded
2 Never received statin
I 29 Discontinued statin and ended study

Randomized to study drug

56 Randomized to receive placebo 56 Randomized to receive placebo 111 Randomized to receive evolocumb 112 Randomized to receive evolocumab
(subcutaneous, every 2 wk) (subcutaneous, monthly) (140 mg, every 2 wk) (420 mg, monthly)
56 Received study drug as 55 Received study drug as 111 Received study drug as 112 Received study drug as
randomized randomized randomized randomized
1 Not given subcutaneous study
drug (excluded from analyses)

2 Discontinued study drug 2 Discontinued study drug 3 Discontinued study drug 3 Discontinued study drug
1 Adverse event 1 Adverse event 1 Participant request 1 Adverse event
1 Other 1 Participant request 1 Sponsor decision^ 2 Participant request
1 Lost to follow-up

56 Included in efficacy and safety 55 Included in efficacy and safety 111 included in efficacy and safety 112 Included in efficacy and safety
analyses analyses analyses analyses
1 Excluded (not given
subcutaneous study drug)

364 Randomized to simvastatin


(40 mg/d, oral)

26 Excluded
*; 2 Never received statin
t. 24 Discontinued statin and ended study

Randomized to study dru^

56 Randomized to receive placebo 55 Randomized to receive placebo 112 Randomized to receive evolocumab 115 Randomized to receive evolocumab
(subcutaneous, every 2 wk) (subcutaneous, monthly) (140m9, every2wk) (420 mg, monthly)
56 Received study drug as 55 Received study drug as 112 Received study drug as 115 Received study drug as
randomized randomized randomized randomized

3 Discontinued study drug 4 Discontinued study drug 3 Discontinued study drug 3 Discontinued study drug
2 Adverse event 1 Adverse event 2 Adverse event 1 Adverse event
1 Participant request 2 Participant request 1 Participant request 1 Participant request
1 Physician decision 1 Lost to follow-up

56 Included in efficacy and safety 55 Included in efficacy and safety 112 Included in efficacy and safety 115 Included in efficacy and safety
analyses analyses analyses analyses

' Patient removed from study because of eligibility deviation (participated in previous evolocumab study).

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Research Original Investigation Evolocumab Plus Statin Therapy for LDL-C Lowering

were measured after the lipid-stabilization period and before of the coprimary end points, a protocol-prespecified first set of
administration of the first dose of study drug. cosecondary end points were tested at a significance level of .005
Key safety end points included incidence of adverse events, using a Hochberg adjustment. Additional testing on a second pre-
serious adverse events, and antievolocumab antibodies. Safety specified set of cosecondary end points was conducted using a
laboratory studies included measurement of transaminase, bil- Hochberg adjustment vth the remainder of the significance level
irubin, and creatine kinase levels. Adjudicated cardiovascular not spent from the prior tests.
events included cardiovascular death, myocardial infarction, hos- Subgroup analyses were conducted using the same model and
pitalization for unstable angina, coronary revascularization, included the stratificadon factors age (<65 years, >65 years), race,
stroke, and hospitazation for heart failure. Neurocognitive events region, baseline LDL-C level (split by median), screening LDL-C
were not prespecified as key safety end points in the protocol but level (<13O mg/dL, >13O mg/dL), body mass index (<25,25-<30,
were documented if reported at clinical visits; no formal assess- >30), glucose tolerance status, hypertension, smoking status, hav-
ments of cognitive function were performed. ing 2 or more baseline coronary heart disease risk factors, fam-
ily history of premature coronary heart disease, baseline PCSK9
Stati5tical Analyses level (split by median), baseline triglycride level (spUt by median:
Efficacy and safety analyses were conducted for all patients ran- <15O mg/dL, >15O mg/dL, <200 mg/dL, >2OO mg/dL), and National
domized to invesrigational product and who received at least l Cholesterol Education Program high risk. Interaction tests were
dose of study drug. For coprimary and secondary efficacy end conducted using the subgroup analyses to help identify possible
points within each dose frequency and statin dose cohort, a patient factors with differing treatment effects.
repeated-measures linear effects model was used, which included Descriptive statistics were used to summarize results of the
stratification factor(s) (study entry stafin intensity and simvasta- safety analyses.'^ Adverse events were coded using the most
tin contraindicated concomitant medication group for patients recent version of MedDRA (MedDRA MSSO) (version 16.1). All
randomized to simvastatin), treatment, visit, and treatment by statistical analyses were performed using SAS version 9.3 (SAS
visit terms. There was no imputation of missing data because the Institute Inc).
repeated-measures model accounts for missing data. A patient
was determined to have achieved an LDL-C level less than 70 mg/
dL if a postbaseline LDL-C value was less than 70 mg/dL. If the
value was missing, the patient was considered to have not Results
achieved the target LDL-C level. Mean achievement of LDL-C less Patient Characteristics
than 70 mg/dL at weeks 10 and 12 was defined using the mean of Patients were recruited from 198 study sites in Australia, Belgium,
nonmissing LDL-C values at those 2 time points. Achievement end Canada, the Czech Republic, Dermiark, France, Germany, Hong
points were assessed using Cochran-Mantel-Haenszel tests ac- Kong, Hungary, Italy, the Netherlands, Russia, Spain, Sweden,
counting for the stratification factor(s). Switzerland, the United Kingdom, and the United States. The first
Comparisons were made between evolocumab and each patient was screened on January 15,2013; the last patient com-
matched dose frequency (every 2 weeks; monthly) compara- pleted the study on December 4, 2013. Of 3590 participants
tor within a statin dose cohort. Significance testing was 2-sided. screened at 164 sites, 1899 were randomized to 1 of 24 different
Because the study was designed to assess the efficacy of each study-drug treatment groups and included in efficacy and safety
evolocumab regimen given each statin dose cohort, a total sig- analyses (Figures 1 and 2). In total, 1896 patients received at least
nificance level of .05 was allocated for comparisons between 1 dose of study drug; 3 patients did not receive any study drug and
treatment and control within each dose frequency and statin were subsequently excluded from all analyses (Figures 1 and 2).
cohort. The significance level was split to .01 vs placebo and In total, 1826 patients (96%) completed the study.
.04 vs ezetimibe within each atorvastatin dose cohort and dose Approximately 50% to 60% of the LDL-C measurements
frequency, because of lower assumed power vs ezetimibe. The in the overall evolocumab group were measured by ultracen-
significance level split led to similar power calculations vs pla- trifugation in parients treated with a moderate-intensity stat-
cebo and vs ezetimibe for atorvastatin dose cohorts. in; approximately 70% to 80% were measured by ultracentri-
The overall sample size was chosen to ensure a sufficient fugation in the high-intensity statin groups. The majority
safety database size. However, power calculations were con- (>90%) of ultracentrifugation LDL-C values were provided be-
ducted to verify sufficient power given the planned alloca- cause calculated LDL-C was less than 40 mg/dL.
tion of 100 patients to each evolocumab treatment group and Prior to enrollment, intensive statin therapy was used by 29%
50 patients to each control treatment group. The lowest cal- of patients, nonintensive statin by 41%, and 30% were using no
culated power for any coprimary end point test was 92% for statin. In the total treatment population, the mean age was 60 (SD,
testing vs ezetimibe in either atorvastatin dose cohort. This cal- 10) years, 46% were women, 23% had coronary artery disease, 10%
culation assumed a treatment effect of 16.5% vs ezetimibe with had other atherosclerotic cardiovascular disease, and 16% had dia-
a common SD of 23% (10% of patients missing all data). betes meUitus. Following the lipid stabilization period, the mean
To control for testing multiple primary and secondly end LDL-C level was 109.1 (SD, 41.I) mg/dL (Table 1).'=^ A detailed de-
points within each dose frequency and statin dose cohort, test- scription of patient baseline characteristics by treatment group
ing was conducted sequentially and withP-value adjustments.*" is provided in eTables 1 and 2 in Supplement). At the time of ran-
Testing was first conducted for the coprimary end points of per- domization to study drug, mean LDL-C levels were 109 to 127 mg/
cent change from baseline in LDL-C. Given statistical significance dL in the moderate-intensity statin groups (atorvastatin [10 mg].

1874 JAMA May 14,2014 Volume 311, Number 18 jama.com


Evolocumab Plus Statin Therapy for LDL-C Lowering Original Investigation Research

Tablet Baseline Characteristics

Overall
Placebo Ezetimibe Evolocumab
Characteristic (n = 558) (n = 221) (n = 1117)
Age, mean (SD), y 59.9 (10.2) 60.8(9.3) 59.6 (9.9)
Women, No. (%) 267 (47.8) 109 (49.3) 492 (44.0)
Race, No. (%)
White 531 (95.1) 204 (92.3) 1047 (93.7)
Black or African American 16 (2.9) 10 (4.5) 49 (4.4)
Abbreviations: ApoB, apolipoprotein
Other= 11 (2.0) 7 (3.2) 21 (1.9) B: HDL-C, high-density lipoprotein
Cardiac risk factors. No. (%) cholesterol; IQR, interquartile range;
LDL-C, low-density lipoprotein
Coronary artery disease 123 (22.0) 38(17.2) 266 (23.8) cholesterol: Lp(a), lipoprotein(a);
Peripheral arterial disease or cerebrovascular 55 (9.9) 19 (8.6) 124(11.1) PCSK9, proprotein convertase
disease subtilisin/kexin type 9; VLDL-C,very
Type 2 diabetes mellitus 74(13.3) 44 (19.9) 175 (15.7) low-density lipoprotein cholesterol.
Baseline lipid parameters, mean (SD), mg/dL*" SI conversion factors: To convert
LDL-C 107.7 (40.2) 109.4 (37.3) 109.7 (42.3) LDL-C, total cholesterol, HDL-C, and
NonHDL-C values to mmol/L,
Total cholesterol 187.9 (44.3) 188.2 (43.3) 190.4 (47.5) multiply by 0.0259; triglycride
HDL-C 54.5 (16.5) 51.8 (14.8) 53.4(15.7) values to mmol/L, multiply by 0.0113.
. Non-HDL-C 133.5 (43.4) 136.4 (41.7) 137.0(46.5) ' Other includes American Indian or
VLDL-C, median (Ql, Q3) 23.0(17.0,30.0) 25.0(18.0,32.0) Alaska Native, Asian, Native
23.0(17.0,32.0)
Hawaiian or Other Pacific Islander,
ApoB 87.8(25.1) 90.1 (25.0) 89.5 (26.9) or Mixed Race.
Triglycrides, median (Ql, Q3) 114.0(85.0,154.0) 123.0(89.0,158.0) 116.0(86.0,160.0) ^ Baseline was measured after the
Lp(a), median (Ql, Q3), nmol/L 34.0(12.0, 149.0) 34.5(10.0,178.0) 34.5(11.0,164.0) lipid stabilization period and before
administration of first dose of study
Free PCSK9, mean (SD), ng/mL 352.7 (114.4) 351.2(112.3) 355.1 (110.6)
drug.

Figure 3. Mean Percent Change From Baseline in LDL-C at the Mean of Weeks 10 and 12

Placebo (every 2 wl<) 9 Placebo (monthly)


A Ezetimibe (daily) + placebo (every 2 wk) A Ezetimibe (daily) + placebo (monthly)
Evolocumab (every 2 wk) D Evolocumab (monthly)

20-
10
0
II -10-
0) o
-20-
-30-
-40
-50-
-60-
-70
Atorvastatin (80 mg) Rosuvastatin (40 mg) Atorvastatin (10 mg) Rosuvastatin (5 mg) Simvastatin (40 mg)
J
High-Intensity Statin Moderate-Intensity Statin
Participants, No. 56 55 55 54 109 110 56 55 111112 56 55 56 55 110 110 58 57 113 115 56 55 112 115

Baseline was measured after the lipid-stabilization period and prior to administration of first dose of study drug. Error bars indicate 95% confidence intervals. To
convert low-density lipoprotein cholesterol (LDL-C) values to mmot/L, multiply by 0.0259.

rosuvastatin [5 mg], and simvastatin [40 mg]), and 77 to 103 mg/ Supplement), and at week 12 (eFigure 1 and eTable 5 in
dL in the high-intensity statin groups (atorvastatin [80 mg] and Supplement). The mean of week 10 and 12 results are pre-
rosuvastatin [40 mg]). sented below, with week-12 results available in the eAppen-
dix in Supplement.
LDL-C Reduction At the mean of weeks 10 and 12, percent reduction from
Significant lowering of LDL-C occurred in all evolocumab- basehne in LDL-C was 59% to 66% with every-2-weeks dosing
treated statin groups at the mean of weeks 10 and 12 and 62% to 65% with monthly dosing (Tables 2 and 3). These
(Figure 3; Table 2, Table 3, Table 4; eTable 3 and eTable 4 in reductions corresponded to changes vs placebo of 66% to 75%

jama.com JAMA May 14,2014 Volume 311, Number 18


Research Original Investigation Evolocumab Plus Statin Therapy for LDL-C Lowering

Table 2. Efficacy at the Mean of Weeks 10 and 12, High-Intensity Statin Groups

Atorvastatin (80 mg) Rosuvastatin (40 mg)


Evolocumab +
Placebo + Placebo Ezetimibe1 + Placebo Placebo Placebo Evolocumab
Every Daily Every
2wk Monthly + Every Daily 2wk Monthly Every Every
+ Daily + Daily 2wk + iVlonthly + Daily + Daily 2wk Monthly 2wk Monthly
LDL-C, mg/dL' (n = 55) (n = 55) (n = 56) (n = 54) (n = 109) (n = 110) (n = 56) (n = 55) (n = 111) (n = 112)
Day-1 (post LS period), mean (SD)'' 100.3 94.7 98.7 92.3 94.2 93.8 77.4 102.9 88.5 88.5
(36.2) (31.9) (34.0) (19.3) (34.8) (32.3) (20.9) (49.3) (31.5) (31.3)
Achieved at mean of wl< 10 and 12, 109.5 100.1 85.6 72.1 35.3 34.8 81.6 96.6 37.5 33.0
mean (SD)'' (45.7) (37.0) (66.7) (26.2) (21.2) (31.4) (27.5) (45.9) (27.0) (28.3)
Change from baseline to mean 11.0 5.5 -13.0 -21.3 -58.8 -60.1 3.4 -4.8 -52.3 -55.3
of wl< 10 and 12, mean (95% CI) (1.1 to (-1.7 to (-22.7 to (-28.6 to (-65.7 to (-65.3 to (-2.5 to (-13.0 to (-56.6 to (-61.0 to
21.0) 12.8) -3.3) -14.0) -51.9) -54.9) 9.4) 3.4) -48.0) -49.6)
LS mean % change from baseline 13.1 9.8 -16.9 -21.3 -61.8 -65.1 6.6 0 -59.1 -62.9
to mean wi< 10 and 12, (5.3 to (3.1 to (-24.5 to (-28.0 to (-67.3 to (-69.8 to (0.4 to (-7.0 to (-63.5 to (-67.8 to
mean(95%Ci)'= 21.0) 16.5) -9.2) -14.5) -56.3) -60.3) 12.7) 6.9) -54.7) -58.1)
<70 mg/dL at mean of weeks 10 13.7 9.3 50.9 62.3 94.4 92.5 38.9 28.8 93.5 94.5
and 12,% (95% CI) (6.8 to (4.0 to (38.1 to (48.8 to (88.4 to (85.9 to (27.0 to (18.3 to (87.1 to (88.6 to
25.7) 19.9) 63.6) 74.1) 97.4) 96.2) 52.2) 42.3) 96.8) 97.5)

Abbreviations: LDL-C, low-density lipoprotein cholesterol; LS, lipid stabilization. via ultracentrifugation when calculated LDL-C was less than 40 mg/dL
SI conversion factor: To convert LDL-C values to mmol/L, multiply by (1.0 mmol/L) or triglycride levels were greater than 400 mg/dL (3.9 mmol/L).
0.0259. '' Observed values.
" LDL-C was determined by the Friedewald formula with reflexive testing ^ Coprimary end point.

Table 3. Efficacy at the Mean of Weeks 10 and 12, Moderate-Intensity Statin Groups

Atorvastatin (10 mg) Simvastatin (40 mg) Rosuvastatin (5 mg]I


Ezetimihe + Evolocumab +
Placebo + Placebo Placebo Placebo Placebo Evolocumah Placebo Evolocumab
Every Daily Every Every Every Every Every
2wk Monthly + Every Daily 2wk Monthly 2wk Monthly 2wk Monthly 2wk Monthly 2wk Monthly
LDL-C, mg/dL= + Daily + Daily 2wk + Monthly + Daily + Daily (n = 56) (n=55) (n=112) (n=115) (n=58) (n=57) (n=113) (n=115)
Day-1 123.0 123.7 126.8 119.3 124.2 126.1 110.3 108.6 114.9 123.7 115.6 119.9 118.7 122.9
(post LS period), (46.6) (47.9) (49.6) (28.1) (43.4) (50.4) (28.0) (30.9) (34.5) (48.5) (39.8) (39.1) (40.9) (42.0)
mean (SD)''
Achieved at mean 126.2 123.6 95.0 94.2 47.9 46.6 111.8 114.4 39.0 48.4 121.6 121.5 48.9 43.3
of wk 10 and 12, (41.6) (51.4) (36.7) (29.8) (28.1) (25.5) (27.9) (40.7) (18.2) (42.8) (44.4) (39.7) (38.9) (25.3)
mean (SD)*"
Change from 6.8 -0.4 -32.4 -25.1 -76.8 -80.1 -5.7 1.7 -83.8 -78.4 6.5 0.1 -68.9 -77.8 '
baseline to mean (-0.4 to (-9.1 to (-39.9 (-33.6 to (-82.0 (-86.1 to (-15.9 (-11.0 to (-92.7 (-88.5 to (-0.4 to (-8.2 to (-73.9 (-83.6 to
wklOand 12, 14.1) 8.2) to -16.6) to -74.1) to 4.5) 14.5) to -68.3) 13.3) 8.4) to -71.9) 1
mean (95% CI) -24.9) -71.5) -75.0) -64.0)
LS mean % 8.5 0.4 -23.9 -19.0 -61.4 -62.5 3.3 6.0 -66.2 -62.4 7.6 2.8 -59.3 -63.8 '
change from (4.1 to (-4.8 to (-28.5 (-24.0 to (-64.6 (-66.1 to (-3.4 to (-3.5 to (-72.0 (-70.0 to (2.8 to (-2.1 to (-62.8 (-67.3 t o '
baseline to mean 13.0) 5.5) to -13.9) to -58.9) 10.0) 15.5) to -54.9) 12.3) 7.7) to -60.3)
wk 10 and 12, -19.3) -58.2) -60.4) -55.9)
mean (95% Cl)'
<70atmeanof 5.7 5.6 20.0 16.7 88.1 85.8 1.9 3.9 93.6 88.5 7.0 5.3 88.7 89.9
wk 10 and 12, % (1.9 to (1.9 to (11.2 to (9.0 to (80.7 to (78.0 to (0.3 to (1.1 to (87.3 to (81.3 to (2.8 to (1.8 to (81.2 to (82.8 to
(95% CI) 15.4) 15.1) 33.0) 28.7) 92.9) 91.2) 9.8) 13.2) 96.9) 93.2) 16.7) 14.4) 93.4) 94.3)

Abbreviations: LDL-C, low-density lipoprotein cholesterol; LS, lipid stabilization. ultracentrifugation when calculated LDL-C was less than 40 mg/dL (1.0
SI conversion factor: To convert LDL-C values to mmol/L, multiply by mmol/L) or triglycride levels were greater than 400 mg/dL (3.9 mmol/L).
0.0259. ''Observed values.
' LDL-C was determined by the Friedewald formula with reflexive testing via ' Coprimary end point.

for every-2-weeks dosing and 63% to 75% for monthly dosing ezetimibe both significant [P < .001]; Tables 2,3, and 4; eTables
(Table 4 and eTable 6 in Supplement). Percent reductions were 1, 3, and 6 in Supplement; Figures 3 and 4). The addition of
similar across the statin groups for evolocumab administered monthly evolocumab reduced LDL-C values by 62% to 65%
every 2 weeks and monthly. from baseline (treatment differences vs placebo and ezeti-
In patients treated with atorvastatin (10 mg or 80 mg), the mibe both significant [P < .001]).
addition of ezetimibe resulted in reductions in LDL-C values For patients receiving a moderate-intensity statin, evo-
of 17% to 24% from baseline (eTables 1 and 3 in Supplement; locumab administered every 2 weeks reduced LDL-C values from
Figure 3 and Figure 4) compared with the addition of evo- a baseline mean of 115 to 124 mg/dL to an on-treatment mean of
locumab administered every 2 weeks, which reduced LDL-C 39 to 49 mg/dL, and 88% to 94% achieved an LDL-C level less
values by 61% to 62% (treatment differences vs placebo and than 70 mg/dL (Table 3, eTables 3 and 4 in Supplement; Figure 4);

1876 JAMA May 14,2014 Volume 311, Number 18 jama.com


Evolocumab Plus Statin Therapy for LDL-C Lowering Original Investigation Research

Table 4. Treatment Difference (vs Placebo or Ezetimibe) at the Mean of Weeks 10 and 12 and at Week 12

Mean (95% CI)'


High-Intensity Statin Moderate-Intensity Statin
Rosuvastatin Simvastatin Rosuvastatin
Atorvastatin (80 mg) (40 mg) Atorvastatin (10 mg) (40 mg) (5mg)
vs Placebo vs Ezetimibe vs Placebo vs Placebo vs Ezetimibe vs Placebo vs Placebo
Every Every Every Every Every Every Every
LDL-C 2wk Monthly 2 wk Monthly 2 wk Monthly 2 wk Monthly 2 wk Monthly 2 wk Monthly 2 wk Monthly
-76,3 -70,5 -47,2 -38,9 -68,3 -55,0 -71,4 -59,2 -39,6 -41,1 -70,6 -60,4 -68,2 -64,5
change (-86,9 (-79,8 to (-57,5 (-48,2 to (-77,0 (-65,3 to (-77,6 (-65,9 to (-45,8 (-47,8 to (-76,7 (-69,1 to (-74,7 (-70,8 to
atwkl2 to -61,2) to -29,6) to -44,7) to -52,4) to -34,4) to -51,7) to -58,1)
-65,7) -36,9) -59,6) -65,3) -33,4) -64,4) -61,7)
-74,9 -74,8 -44,9 -43,8 -65,7 -62,9 -70,0 -62,8 -37,5 -43,5 -69,4 -68,5 -66,9 -66,6
change (-84,5 (-83,0 to (-54,3 (-52,1 to (-73,2 (-71,4 to (-75,4 (-69,1 to (-43,0 (-49,7 to (-74,9 (-76,7 to (-72,7 (-72,6 to
at mean to -66,6) to -35,6) to -54,5) to -56,6) to -37,3) to -60,2) to -60,6)
ofwklO -65,4) -35,6) -58,1) -64,5) -32,0) -64,0) -61,1)
and 12
Change -71,7 -61,8 -49,0 -35,3 -57,2 -44,6 -85,5 -75,8 -46,8 -51,7 -79,0 -71,9 -77,1 -75,8
atwk (-84,4 (-71,6 to (-61,5 (-45,2 to (-65,1 (-55,9 to (-95,2 (-86,8 to (-56,6 (-62,6 to (-87,5 (-83,8 to (-86,2 (-86,3 to
12, to -52,0) to -25,5) to -33,4) to -64,9) to -40,9) to -60,0) to -65,3)
mg/dL -59,0) -36,6) -49,4) -75,9) -37,1) -70,4) -67,9)
Change -69,9 -65,6 -45,8 -38,8 -55,8 -50,6 -83,6 -79,7 -44,4 -55,0 -78,1 -80,1 -75,4 -77,9
at mean (-81,9 (-74,5 to (-57,7 (-47,8 to (-63,1 (-60,6 to (-92,6 (-90,2 to (-53,4 (-65,4 to (-86,2 (-91,7 to (-83,9 (-88,0 to
OfwklO to -56,7) to -29,9) to -40,6) to -69,2) to -44,6) to -68,6) to -67,8)
and 12, -57,8) -33,9) -48,4) -74,6) -35,3) -70,0) -67,0)
mg/dL
Abbreviation: LDL-C, low-density lipoprotein cholesterol,
SI conversion factor: To convert LDL-C values to mmol/L, multiply by 0,0259,
' Adjusted P < ,05 for all treatment differences.

24.5% of these patients achieved an LDL-C value less than 25 86% to 94% of evolocumab-treated patients receiving back-
mg/dL on 2 consecutive occasions. In patients treated with ground atorvastatin therapy (Figure 4).
monthly evolocumab added to a moderate-intensity statin, Evolocumab administered every 2 weeks and monthly was
LDL-C values were reduced from a baseline mean of 123 to 126 effective in all prespecifled subgroups relative to placebo and
mg/dL to an on-treatment mean of 43 to 48 mg/dL, and 86% to ezetimibe, with no notable differences observed between sub-
90% of patients achieved an LDL-C value less than 70 mg/dL; an groups. An additional sensitivity analysis of the coprimary end
LDL-C value less than 25 mg/dL on 2 consecutive occasions was points was conducted using only calculated LDL-C concen-
achieved by 17.9% of these patients. trations to support the results obtained using the reflexive ap-
For patients receiving a high-intensity statin, evo- proach (eTables 7 and 8 in Supplement). Use of calculated
locumab administered every 2 weeks reduced LDL-C values LDL-C can return falsely low values when calculated LDL-C
from a baseline mean of 89 to 94 mg/dL to an on-treatment concentrations are less than 40 mg/dL or triglycride levels are
mean of 35 to 38 mg/dL, and 94% achieved an LDL-C value less high,'^ thereby resulting in a larger estimated treatment dif-
than 70 mg/dL (Table 2; eTables 3 and 4 in Supplement; ference in LDL-C percent reduction than that calculated from
Figure 4); 42.3% of these patients achieved an LDL-C value less ultracentrifugation LDL-C values.
than 25 mg/dL on 2 consecutive occasions. In patients treated
with monthly evolocumab added to a high-intensity statin, evo- Other Lipids
locumab reduced LDL-C values from a baseline mean of 89 to Evolocumab administered every 2 weeks and monthly
94 mg/dL to an on-treatment mean of 33 to 35 mg/dL, and 93% resulted in significant reductions in non-high-density lipo-
to 95% achieved an LDL-C level less than 70 mg/dL; 42.3% of protein cholesterol (non-HDL-C), apolipoprotein B, and lipo-
patients achieved LDL-C levels less than 25 mg/dL on 2 con- protein(a) for all statin groups (eTables 3 and 5 and eFigures 2
secutive occasions. In pairwise comparisons between moder- and 3 in Supplement). For evolocumab every-2-weeks dos-
ate- and high-intensity statins, mean differences between treat- ing, reductions at the mean of weeks 10 and 12 in non-HDL-C
ment groups receiving evolocumab every 2 weeks ranged from ranged from 52% to 59% (58%-65% vs placebo), reductions in
1.5 (95% CI, 7.7 to -4.7) to 12.6 (95% CI, -6.0 to 19.3) mg/dL, and apolipoprotein B from 47% to 56% (5l%-59% vs placebo), and
for monthly evolocumab ranged from 8.6 (95% CI, 0.9 to 16.2) reductions in lipoprotein(a) from 24% to 39% (2l%-36% vs pla-
to 15.4 (95% CI, -5.8 to 24.9) (Figure 4). cebo). For monthly dosing, percent reductions in non-
In atorvastatin-treated patients, the addition of ezeti- HDL-C, apohpoprotein B, and lipoprotein(a) were compa-
mibe resulted in achievement of an LDL-C level less than 70 rable to those achieved with every-2-weeks dosing. At the mean
mg/dL in 17% to 20% of patients receiving moderate- of weeks 10 and 12, triglycride levels were reduced by 12% in
intensity statins and 51% to 62% of those receiving high- patients receiving evolocumab every 2 weeks (l2%-23% vs pla-
intensity statins (eTables 3 and 4 in Supplement; Figure 4). In cebo) and by 6% to 16% in patients receiving evolocumab
contrast, an LDL-C level less than 70 mg/dL was achieved by monthly (14%-3O% vs placebo) (eTable 3 in Supplement). Lev-

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Research Original Investigation Evolocumab Plus Statin Therapy for LDL-C Lowering

Figure 4, Summary Statistics for Baseline, and Mean of Weel<s 10 and 12 LDL-C Values

Moderate-intensity statin
250-1

150

100 - 100 mg/dL

\ 70 mg/dL
it
^ 5o^
- 25 mg/dL

Atorvastatin (10 mg) Rosuvastatin (5 mg) Simvastatin (40 mg)

Participants, 442 56 55 56 55 110 110 343 58 57 113 115 338 56 55 112 115
No,
Baseline (after lipid stabilization phase)
High-intensity statin
2501 Placebo (every 2 wk)
Placebo (monthly)
Ezetimibe (dally) * placebo (every 2 wk)
i 200^
Ezetimibe (daily) + placebo (monthy)
Evolocumab (every 2 wk)
> 150^
Evolocumab (monthly)

o 100- 100 mg/dL

70 mg/dL Horizontal dashed lines represent


11 low-density lipoprotein cholesterol
(LDL-C) goals/levels of interest.
- 25 mg/dL
s Boxes indicate 50th and 70th
o percentiles; error bars indicate 5th
Atorvastatin (80 mg) Rosuvastatin (40 mg)
and 95th percentiles. Within boxes,
Participants, 439 55 55 56 54 109 110 334 56 55 111112 dots and horizontal lines indicate
No. mean and median achieved LDL-C
levels, respectively.

els of HDL-C were modestly increased by 5% to 10% across both patients, and 2.3% of placebo-treated patients (Table 5).
the every-2-weeks and the monthly dose groups (4%-io% vs Elevations in aspartate aminotransferase/alanine amino-
placebo at the mean of weeks 10 and 12) (eTables 3 and 6 and transferase levels greater than 3 times the upper limit of nor-
eEigure 2 in Supplement). Baseline PSCKg levels were higher mal were uncommon, and creatine kinase elevations greater
in the high-intensity statin groups than in the moderate- than 5 times the upper limit of normal were rare among
intensity statin groups. Reductions in PSCK9 levels were com- treatment groups. During the 12-week treatment period,
parable in the high-intensity and moderate-intensity statin positively adjudicated cardiovascular events occurred in 5
groups for every-2-weeks dosing (up to 52% for high intensity evolocumab-treated patients (0.4%), 2 ezetimibe-treated
vs up to 57% for moderate intensity at the mean of weeks 10 patients (0.9%), and 2 placebo-treated patients (0.4%)
and 12), For monthly dosing, PCSK9 levels were reduced more (Table 5). One death was reported during the study in a
in the moderate-intensity statin groups (up to 33%) than in the patient receiving rosuvastatin and subcutaneous placebo
high-intensity statin groups (up to 16%) (eTable 5 in Supple- (Table 5). Neurocognitive adverse events were reported in 1
ment). evolocumab-treated patient (0.1%), 3 ezetimibe-treated
patients (1.4%), and 0 placebo-treated patients (Table 5).
Tolerability and Safety Injection site reactions were reported in 1.3% of
Adverse events occurred in 36% of evolocumab-treated evolocumab-treated patients, 0,9% of ezetimibe-treated
patients, 40% of ezetimibe-treated patients, and 39% of patients, and 1.4% of placebo-treated patients (Table 5). Prior
placebo-treated patients (Table 5; eTables 9 and 10 in to study drug administration, 3 evolocumab-treated patients
Supplement). Musculoskeletal symptoms or headache were tested positive for binding antibodies. Of these, 1 patient in
the most common adverse events (Table 5). Adverse events the evolocumab (420 mg monthly) (simvastatin [40 mg]
resulting in study drug discontinuation were 1.9%, 1.8%, background) group had detectable binding antibodies at the
and 2.2% in the evolocumab, ezetimibe, and placebo end of study; no new cases of binding antibodies posttreat-
groups. Serious adverse events were reported in 2.1% of ment were reported. Neutralizing antibodies were not
evolocumab-treated patients, 0,9% of ezetimibe-treated detected.

1878 JAMA May 14,2014 Volume 311, Number 18 jama.com


Evolocumab Plus Statin Therapy for LDL-C Lowering Original Investigation Research

Table 5. Summary of Overall Safety

No. (%)
Any
Any Atorvastatin -i- Statin -1-
Statin + Placebo Ezetlmibe Evolocumab
(n = 558) (n = 221) (n = 1117)
Adverse events' 219(39.2) 89 (40.3) 406 (36.3)
Most common adverse events (top 5 in
evolocumab)
Abbreviations: ALT/AST, alanine
Back pain 14 (2.5) 7 (3.2) 20(1.8) aminotransferase/aspartate
Arthralgia 9 (1.6) 4(1.8) 19 (1.7) aminotransferase; CK, creatine
kinase; NA, not applicable; ULN,
Headache 15 (2.7) 5 (2.3) 19(1.7)
upper limit of normal.
Muscle spasms 6(1.1) 6 (2.7) 17 (1.5)
' Adverse events are those occurring
Pain in extremity 7(1.3) 3 (1.4) 17 (1.5) between the first dose of study drug
Adverse events leading to study drug 12 (2.2) 4 (1.8) 21(1.9) and the end of study.
discontinuation *= One patient died after the end of
Serious adverse events 13 (2.3) 2 (0.9) 23(2.1) study and contributes to the
Deaths 1 (0.2) 0" 0 positive cardiovascular events
count.
Potential injection site reactions' 8(1.4) 2 (0.9) 15 (1.3)
' Reported using high-level group
Any postbaseline
terms, including injection site rash,
CK>5xLN 2 (0.4) 0 1 (0.1) inflammation, pruritus, reaction,
CK>10xULN 0 0 0 and urticaria.

ALT/AST >3xULN 6(1.1) 3 (1.4) 4 (0.4) '' Searched high-level group terms:
deliria (including confusion);
Total bilirubin>2xULN 0 0 0 cognitive and attention disorders
Positively adjudicated cardiovascular events 2 (0.4) 2 (0.9) 5 (0.4) and disturbances; dementia and
Neurocognitive adverse events'" amnestic conditions; disturbances
0 3 (1.4) 1 (0.1)
in thinking and perception; mental
Disturbance in attention 0 1 (0.5) 0 impairment disorders.
Cognitive disorder 0 1 (0.5) 0 " Binding antibody was present at
Disorientation 0 1 (0.5) 1 (0.1) baseline and at the end of study. No
neutralizing antibodies were
Any postbaseline binding evolocumab antibodies NA NA 1 io,ir detected.

With the addition of ev(


Discussion therapy (e!ither moderate or hi]
94%) achieved LDL-C levels less than 70 mg/dL at the mean
This 12-week trial examined the safety, tolerability, and LDL- of weeks 10 and 12 and at week 12. In contrast, 17% to 62% of
C-lowering efficacy of a PCSK9 inhibitor compared with pla- patients receiving background moderate- or high-intensity
cebo and ezetimibe in patients with hypercholesterolemia ran- statin therapy with ezetimibe achieved LDL-C levels less than
domized to receive background statin therapy. The statins used 70 mg/dL at the mean of weeks 10 and 12 and at week 12.
in the study include the 3 most commonly prescribed statins LAPLACE-2 is to our knowledge the first study to dem-
globally at doses consistent with the moderate- and high- onstrate that the addition of evolocumab results in similar
intensity statin therapy recommended in the 2013 American percent reductions in LDL-C and achieved LDL-C levels
College of Cardiology/American Heart Association (ACC/ regardless of stable baseline statin type, dose, or intensity,
AHA) guidelines.^ Compared with placebo, evolocumab ad- across 3 commonly prescribed statins and a broad range of
minstered every 2 weeks (66%-75%) and monthly evo- doses. The similarity of achieved LDL-C levels may refiect
locumab (63% [when added to moderate- or high-intensity greater up-regulation of PCSK9 levels with high-intensity
statin therapy] to 75%) provided clinically equivalent percent statin therapy, as was observed in other evolocumab
reductions in levels of LDL-C when added to moderate- or high- studies.'^ In this study, patients receiving a moderate-
intensity statin therapy. The additional LDL-C lowering with intensity statin and treated with evolocumab had slightly
evolocumab (140 mg every 2 weeks or 420 mg monthly) (up greater mean percent reductions in PCSK9 levels than those
to 66% reduction) was significantly greater than that ob- receiving a high-intensity statin. The difference in PCSK9
served with ezetimibe (10 mg/d) (up to 24% reduction). Evo- percent reduction between patients receiving every-2-weeks
locumab was well tolerated, with comparable rates of ad- and monthly dosing may have been infiuenced by the timing
verse events vs placebo and ezetimibe over the 12-week of PCSK9 measurement. The week-12 measurement occurred
treatment period. Neurocognitive events were uncommon in 4 weeks after the last evolocumab dose in the monthly dos-
this study, and data from an ongoing, longer-term evo- ing group and 2 weeks after the last dose in the every-2-
locumab extension study reported 1% or less incidence of these weeks group, allowing greater time for PCKS9 levels to
events in patients receiving evolocumab.^"* recover before measurement in the monthly groups. This

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Research Original Investigation Evolocumab Plus Statin Therapy for LDL-C Lowering

effect appears more pronounced when combined with ceiving a high-intensity statin.^^-^'* Therefore, the results of car-
enhanced PCSK9 expression in the intensive statin groups. diovascular outcomes trials will be essential for establishing
According to the 2013 ACC/AHA Cholesterol Guidelines, the net benefit (in terms of the further reduction in CVD events
nonstatin therapy may be considered for individuals with se- vs the excess of adverse events) from the additional LDL-C low-
vere hypercholesterolemia, those who are at higher risk but ering achieved with evolocumab.
unable to tolerate high-intensity statin therapy, or those in need For the third question, about 18% to 25% (moderate-
of additional LDL-C lowering.^ Nonstatin LDL-C-lowering intensity statin) and 42% (high-intensity statin) of patients in
therapies that have been shown to reduce atherosclerotic car- the LAPLACE-2 trial had achieved LDL-C levels less than 25
diovascular disease (CVD) events in randomized, controlled mg/dL on at least 2 consecutive occasions. A longer-term, open-
trials are preferred. Atherosclerotic CVD outcomes trials are cur- label study has shown that evolocumab added to background
rently under way for both ezetimibe and evolocumab.^-^^ atorvastatin therapy was safe and effective,- similar rates of ad-
The evolocumab outcomes trial is evaluating the effects verse effects in patients with LDL-C levels less than 25 mg/dL
of evolocumab added to moderate- or high-intensity statins and less than 50 mg/dL or 50 mg/dL or greater have been ob-
on reduction in atherosclerotic CVD events.^' Results of this served to date in that trial.^ Safety continues to be carefully
trial will answer at least 3 important questions: (1) Does addi- monitored in other ongoing studies in the evolocumab devel-
tional lowering of LDL-C with evolocumab reduce atheroscle- opment program.
rotic cardiovascular disease events more than observed with Limitations of LAPLACE-2 include the 12-week treatment
maximal statin therapy? (2) What is the relationship between duration for the assessment of safety, tolerability, and athero-
the magnitude of LDL-C lowering and the relative reduction sclerotic CVD outcomes, the lack of formal neurocognitive as-
in atherosclerotic cardiovascular disease risk in the lower ranges sessments, the small sample sizes in some groups, and the ab-
of LDL-C (linear, curvilinear, a threshold, or other)? and (3) Is sence of information on untreated LDL-C levels prior to
long-term exposure to very low LDL-C safe? prestudy statin therapy. The trial was also designed prior to
For the second question, LAPLACE-2 provides informa- the publication of the 2013 ACC/AHA guidelines, so study par-
tion on the expected magnitude of LDL-C lowering that may ticipants were not identified based on the 4 statin benefit
be observed when evolocumab is added to moderate- and high- groups defined in these guidelines. The study was also not de-
intensity statin therapy. The Cholesterol Treatment Trialists signed to determine whether patients taking nonintensive
individual meta-analysis of statin trials reported a 22% reduc- statin therapy at baseline had a history of statin intolerance.
tion in major CVD events for each 39-mg/dL reduction in LDL-C
level.' This estimate was based largely on trials of moderate-
intensity statin therapy. However, high-intensity atorva-
statin (80 mg) has been shown to reduce CVD events more than Conclusions
moderate-intensity statins (atorvastatin [10 mg], pravastatin In this 12-week trial conducted among patients with primary
[40 mg], or simvastatin [20-40 mg]) in individuals with coro- hypercholesterolemia and mixed dyslipidemia, evolocumab
nary heart disease.^'^'^^ Nonetheless, a different relationship added to moderate- or high-intensity statin therapy resulted
between LDL-C lowering and CVD event reduction may exist in additional LDL-C lowering. Further studies are needed to
when additional LDL-C lowering occurs in individuals who evaluate the longer-term clinical outcomes and safety of this
have LDL-C levels less than 100 mg/dL or who are already re- approach for LDL-C lowering.

ARTICLE INFORMATION Acquisition, analysis, or interpretatior) of data: studies sponsored by Amgen, Sanofi, and Pfizer and
Author Affiliations: Department of Epidemiology, Robinson, Nedergaard, Rogers, Fialkow, Neutel, receiving research grants during the past year from
College of Public Health, University of Iowa, Iowa Ramstad, Somaratne, Legg, Nelson, Scott, Amgen, Sanofi, Regeneron, Pfizer, Genentech,
City (Robinson); Department of Medicine, College Wasserman, Weiss. Hoffman-Laroche, Eli Lilly, and Merck. Dr Fialkow
of Public Health, University of Iowa, Iowa City Drafting of the manuscript: Robinson, Somaratne, reported serving as principal investigator for
(Robinson): Center for Clinical and Basic Research, Legg, Wasserman. studies sponsored by Amgen and serving on
Aalborg, Denmark (Nedergaard); Division of Critical revision of the manuscript for important speakers bureaus for Pfizer, Bristol Myers Squibb,
Cardiovascular Disease, University of Alabama intellectual content: Robinson, Nedergaard, Rogers, and Amarin Pharmaceuticals. Dr Nedergaard
Medical Center, Birmingham (Rogers); Department Fialkow, Neutel, Ramstad, Somaratne, Legg, reported serving as principal investigator for
of Medicine, Herbert Wertheim College of Nelson, Scott, Wasserman, Weiss. studies sponsored by Amgen. Dr Neutel reported
Medicine, Florida International University, Miami Statistical analysis: Legg. serving as principal investigator for multiple clinical
(Fialkow); Orange County Research Center, Tustin, Obtained funding: Somaratne, Scott, Wasserman. trials and serving on speakers bureaus for multiple
California (Neutel); Hampton Roads Center for Study supervision: Somaratne, Scott, Wasserman. companies. Dr Ramstad reported serving as
Clinical Research, Suffolk, Virginia (Ramstad); principal investigator for studies sponsored by
Conflict of Interest Disclosures: All authors have
Amgen Inc, Thousand Oaks, California (Somaratne, Amgen, Pfizer, Bristol-Myers Squibb, Novartis,
completed and submitted the ICMJE Form for
Legg, Nelson, Scott, Wasserman); Maine Research GlaxoSmithKline, Takeda, Dailchi-Sankyo, Arete
Disclosure of Potential Conflicts of Interest. Dr
Associates, Auburn (Weiss). Therapeutics, Akros, Forest Research Institute, Lilly,
Robinson reported that her institution has received
Shire-Novartis, Hoffman-LaRoche, Aventis, and
Author Contributions: Dr Robinson had full access research grants from Amarin, Amgen, AstraZeneca,
NovoNordisk. Dr Rogers reported serving as
to all of the data in the study and takes Daiichi-Sankyo, Espertan, Genentech/Hoffman La
principal investigator for studies sponsored by
responsibility for the integrity of the data and the Roche, Glaxc-Smith Kline, Merck,
Amgen and Sanofi. Drs Somaratne. Legg, Scott, and
accuracy of the data analysis. Regeneron/Sanofi, and Zinfandei/Takeda; and
Wasserman and Mr Nelson, all Amgen employees,
Study concept and design: Somaratne, Legg, reported serving as a consultant for Amgen,
reported owning Amgen stock/stock options.
Nelson, Scott, Wasserman. Hoffman LaRoche, Pfizer, and Sanofi. Dr Weiss
reported serving as a principal investigator for

1880 JAMA May 14,2014 Volume 311, Number 18 jama.com


Evolocumab Plus Statin Therapy for LDL-C Lowering Original Investigation Research

Funding/Support: This trial was funded by Amgen Villeneuve, Montpellier cedex 05); Michael Joubert Budget Health care institution Altay Regional
Inc. which was responsible for the design and (Centre Hospitalier Universitaire de Caen - Hpital Cardiology Dispensary, Barnaul); Elena Demchenko
conduct of the study as well as data collection and Cte de Nacre, Caen Cedex 9); Jacques Mansourati (Almazov Federal Heart, Blood and Endocrinology
interpretation, management, and analysis. (Centre Hospitalier Universitaire de Brest-Hpital Center, Saint-Petersburg); Mikhail Kotelnikov
de la Cavale Blanche, Brest Cedex 2); Vincent (Clinical Hospital MSCh GUVD, Moscow); Alexander
LAPLACE-2 Investigators: Australia: Andrew
Probst (Centre Hospitalier Universitaire de Nantes, Litvin (FSBI Russian Cardiology Research and
Hamilton (Heart and Vascular Research Centre,
Hpital Nord Lannec, Nantes Cedex 1); Bruno Production Complex MOH and SD of RF, Moscow);
Fullarton, South Australia); Ronald Lehman
Verges (Centre Hospitalier Universitaire de Yury Lukyanov (SBEI of HPS Saint Petersburg State
(Adelaide Medical Research, Ashford, South
Dijon-Hpital du Bocage, Dijon). Germany: Medical University n a Acad i P Pavlov MOH and SD
Australia); Joseph Proietto (Heidelberg Repatriation
Elizaveta Degtyareva (Synexus Clinical Research of RF, Saint Petersburg); Yury Shvarts (Clinical
Hospital, Heidelberg Heights. Victoria); Leon
GmbH, Leipzig); Andreas Frster (Gemeinschaft- Hospital named after V I Razumovskiy, Saratov);
Simons (Associate Professor, Simons Private
spraxis fr Innere Medizin und Kardiologie, Berlin); AndreySusekov (FSBI Russian Cardiology Research
Rooms, Sydney, New South Wales). Belgium:
Thomas Horacek (Forschungszentrum Ruhr, and Production Complex MQH and SD of RF,
Jean-Paul Bous (Cabinet Medical Docteur Jean-Paul
Witten); Christian Kasperk (Universittsklinikum Moscow); Tatiana Treshkur (FSBI Federal centre of
Bous sprlu, Chne); Koenraad Cornelli
Heidelberg, Heidelberg); Ernst Kohler heart, blood and endocrinology n a V A Almazova
(Huisartsenpraktijk Die Prince, Oostende); Luc De
(Gemeinschaftspraxis Dres Senftleber/Kohler, MOH and SD of RF, Saint Petersburg); Polina
Munck (Dokter De Munck ebvba, Vilvoorde);
Messkirch); Ulrich Laufs (Universittsklinikum des Yakhontova (SBHI of Novosibirsk Region
Vantroyen (Huisartsenpraktijk Hygeia bv cvba,
Saarlandes, Homburg); Gudrun Meissner (Synexus Novosibirsk regional clinical cardiology dispensary,
Hasselt); Lode Vermeersch (Dokter Lode
Clinical Research GmbH, Magdeburg); Isabelle Novosibirsk). Spain: Juan Francisco Ascaso Gimilio
Vermeersch Algemene Geneeskunde bvba,
Schenkenberger (Klinische Forschung Berlin GbR, (Hospital Clinico Universitario de Valencia, Valencia,
Tremelo); Geert Vileyn (Huisartsenpraktijk Vileyn
Berlin); Janna Stoessel (Synexus Clinical Research Comunidad Valenciana); Esteban Jodar Gimeno
bvba, Blankenberge). Canada; Ronald Akhras
GmbH, Berlin [Hellersdorf]); Dietmar Trenk (Hospital Quiron Madrid, Pozueio de Alarcon,
(Centre Medical Acadie, Montreal, Quebec); James
(Universittsherzzentrum Freiburg-Bad Krozingen, Madrid); Pedro Mezquita Raya (Clnica San Pedro,
Cha (Dr James Cha, Oshawa, Ontario); Raja
Bad Krozingen); Karl Winkler (Universittsklinikum Almeria, Andaluca); Jesus Millan Nuez-Cortes
Chehayeb (ViaCar Recherche Clinique Incorporated,
Freiburg, Freiburg). Hong Kong: Edith Ming Chu (Hospital General Universitario Gregorio Maranon,
Longueuil. Quebec); Martyn Chilvers (Sarnia
Lau (Center for Health and Medical Research, Hong Madrid, Madrid); Jose Maria Mostaza Prieto
Institute of Clinicai Research. Sarnia, Ontario);
Kong); Chun Yip Yeung (University of Hong Kong, (Hospital Carlos III, Madrid, Madrid); Xavier Pinto
Ronald Collette (Dr Ronald Collette. Burnaby, British
Queen Mary Hospital, Hong Kong). Hungary: Saia (Ciutat Sanitaria i Universitaria de Beilvitge,
Columbia); Anthony Dowell (Dynamik Research
Laszio Bajnok (Pecsi Tudomanyegyetem Altalanos LHospitalet de Llobregat, Catalua); Emilio Ros
Incorporated, Pointe-Claire, Quebec); Peter
Orvosi Kar, Pecs); Emil Bod (Grof Tisza Istvan (Hospital Clinic i Provincial de Barcelona, Barcelona,
Dzongowski (Milestone Research, London,
Korhaz, Berettyoujfalu); Eleonora Harcsa (Markhot Catalua). Sweden: Bertil Borgencrantz
Ontario); Anii Gupta (Dr Anil l< Gupta Medicine
Ferenc Qktatokorhaz es Rendelointezet, Eger); (Lkargruppen i rebro, rebro); Peter Bosson
Professional Corporation, Toronto, Ontario); Frank
Jozsef Lippai (Jaszberenyi Szent Erzsebet itorhaz, (ProbarE Lund, Lund); Dan Curiac (Sahigrenska
Halperin (Kelowna Cardiology Research Limited.
Jaszbereny); Attiia Mohacsi (Pharma4 Trial Kft, Universitetssjukhuset, Gteborg); Georg Dahln
Kelowna, British Columbia); Randy Hart (White Hills
Gyongyos); Attila Palinkas (Csongrad Megyei (Vrdcentralen Silentzvgen, Uddevalla); Charlotte
Medical Clinic, St. John's, New Brunswick); Kenneth
Egeszsegugyi Eilato Kozpont Hodmezovasarhely- Delavaran (ProbarE Soina, Stockholm); Carl-Johan
Heaton (Devonshire Clinical Research Incorporated,
Mako, Hodmezovasarhely); Ferenc Poor (Karolina Lind holm (Capio Cityklinii<en, Lund). Switzerland:
Woodstock. New Brunswick); Sam Henein (SKDS
Korhaz Rendelointezet, Mosonmagyarovar); Imre Michel Burnier (Centre Hospitalier Universitaire
Research Incorporated, Newmarket, Ontario);
Szakal (Selye Janos Korhaz, Komarom); Zsuzsanna Vaudois, Lausanne); Franz Eberli (Stadtspital
Subodh Kanani (Dr Subodh Kanani, Toronto.
Sziegl (Bajai Szent Rokus Korhaz, Baja). Italy: Triemli, Zurich); Augusto Gallino (Ospedale
Ontario); Jan Kornder (Surrey Memorial Hospitai,
Claudio Borghi (Azienda Ospedaliero Universitaria Regionale di Bellinzona e Valli, Bellinzona); Francois
Surrey, British Columbia); Andre Lamy (Hamilton
di Bologna PolidinicoSOrsola Malpighi, Bologna); Mach (Hpitaux Universitaires de Geneve, Geneva
Health Sciences Hamilton General Hospital,
Marco Bucci (Fondazione Universita Gabriele d 14); Hans Rickli (Kantonsspital St Gallen, St Gallen);
Hamilton, Ontario); Michael OMahony (London
Annunzio, Chieti); Luigi Cattin (Azienda Ospedaliero Fritz Widmer (Kantonsspital Muensteriingen,
Road Diagnostic Clinic and Medical Centre, Sarnia,
Universitaria Qspedali Riuniti di Trieste, Trieste); Muensterlingen). United Kingdom: Essam Eidin
Ontario); A. Shekhar Pandey (Cambridge Cardiac
Arcangelo lannuzzi (Azienda Qspedaliera di Rilievo Ahmed Abdulhakim (Synexus Merseyside Clinical
Care Centre, Cambridge. Ontario); Georges
Nazionale Antonio Cardareili, Napoli); Roberto Research Centre, Liverpool); Lawrence Adler (The
Sabe-Affaki (Medialpha Research Centre. Lachine,
Miccoii (Ospedale di Cisanello, Pisa); Angeiina Circle Practice, Harrow); Mark Blagden (Avondale
Quebec); Francois St Maurice (ViaCar Recherche
Passaro (Azienda Ospedaliero Universitaria di Surgery, Chesterfield); Ryan D'Costa (Pinderfields
Clinique Incorporated. Brossard, Quebec). Czech
Ferrara Nuovo Ospedale S Anna, Ferrara); Paolo Hospital, Wakefield); Richard Falk (South Axholme
Republic: Vera Adamkova (Institut klinicke a
Pintus (Azienda Ospedaliera Brotzu, Cagliari); Practice, Doncaster); Michael Fisher (The Royal
experimentaini mediciny, Praha 4); Ondrej Cermak
Matteo Pirro (Ospedale Santa Maria della Liverpool University Hospital, Liverpool); Hana
(Nemocnice Siany, Siany); Richard Ceska
Misericordia Universit degli Studi di Perugia; Hassanin (Synexus Lancashire Ciinical Research
(Vseobecna fakuitni nemocnice v Praze, Praha 2);
Perugia); Cesare Sirtori (Azienda Ospedaliera Centre, Chorley); Veronika Horvathova (Synexus
Petr Frana (Centrum pro zdravi sro, Brno); Tomas
Ospedale Niguarda Ca Granda, Milano); Sabina Scotland Clinical Research Centre, Glasgow);
Hala (CCBR Pardubice, Pardubice); Ivana Kellnerova
Zambn (Azienda Ospedaliera Universitaria di Jerome Kerrane (Layton Medical Centre,
(Svitavska nemocnice as, Svitavy); Martina
Padova, Padova). The Netherlands: Jacqueline De Blackpool); Judith Mackay (Synexus Thames Valley
Machkova (CCBR Czech Prague sro, Praha 3); Jirina
Graaf (Universitair Medisch Centrum St Radboud, Clinical Research Centre, Reading); Terry
Petrzelkova (CCBR Czech Brno sro, Brno); Stepan
Nijmegen); Servaes Donders (Martini Ziekenhuis, McCormack (Whitby Group Practice, Whitby); Carol
Pojsl (Mestska nemocnice v Litomericich,
Groningen); Bernard Imholz (TweeSteden McKinnon (Castlemilk Group Practice, Glasgow);
Litomerice); Vera Stankova (Kardiologicka poradna
ziekenhuis, iocatie Waalwijk, Waalwijk); Franoise Babatunde Oyesile (Synexus Midlands Clinical
Kladno sro. Kladno); Jan Vaclavik (Fakuitni
Klessens-Godfroy (Sint Franciscus Gasthuis, Research Centre, Birmingham); Irina Pavel-Knox
nemocnice Olomouc, Olomouc); Jiri Zemanek
Rotterdam); Adriaan i<ooy (Bethesda Diabetes (Synexus Manchester Clinicai Research Centre,
(Poliklinika Moravske Budejovice sro, Moravske
Research Center, Hoogeveen); Erik Stroes Manchester); Handrean Soran (Central Manchester
Budejovice). Denmark: Annesofie Krogsaa (Centre
(Academisch Medisch Centrum, Amsterdam); University Hospitals NHS Trust, Manchester);
for Clinical and Basic Research Ballerup, Ballerup);
Rudolf Van Leendert (Albert Schweitzer Ziekenhuis Hawys Thomas (Synexus Wales Clinical Research
Bettina Storgaard Nedergaard (Center for Clinical
Locatie Zwijndrecht, Zwijndrecht); Peter Viergever Centre, Cardiff). United States: William Abraham
and Basic Research Aalborg, Aalborg); Susanne
(Gemini Ziekenhuis, Den Helder); Hieronymus (Radiant Research Ine, Tucson, Arizona); Stephen
Wermuth (Center for Clinicai and Basic Research
Vincent (Sint Antonius Ziekenhuis, locatie Aronoff (Research Institute of Dallas, Dallas, Texas);
Vejie, Vejie). France: Sylvaine Clavel (Hpital
Nieuwegein, Nieuwegein). Russia: Olga Barbarash Keith Atassi (Northwest Indiana Cardiovascuiar
Fondation Htel-Dieu du Creusot, Le Creusot); Aron
(FSBi Scientific Research Institute of Complex Physicians PC, Valparaiso); Vivek Awasty (Awasty
Ariel Cohen (Hpitai Saint Antoine, Paris cedex 12);
Issues of Cardiovascular Diseases of SB of RAMS, Research Network LLC, Marion, Ohio); Kimberly
Jean-iVIarc Davy (Centre Hospitalier Rgional
Kemerovo); Galina Chumakova (Regional State Bailey (The Christ Hospital, Cincinnati, Ohio); Scott
Universitaire de Montpellier, Hpital Arnaud de

jama.com JAMA May 14,2014 Volume 311, Number 18 1881


Research Original Investigation Evolocumab Plus Statin Therapy for LDL-C Lowering

Baron (Capitol Interventional Cardiology, Additional Contributions: We acknowledge Wei 12, Sullivan D, Olsson AG, Scott R, et al. Effect of a
Carmichael, California); Robert Bear (Cardiovascular Cui, MS, and Ying Xiang, MS, of Amgen Inc for monoclonal antibody to PCSK9 on low-density
Consultants, Giendale, Arizona); Barry Bertolet programming support and Annalise M, Nawrocki, iipoprotein cholesterol levels in statin-intolerant
(Cardiology Associates of North Mississippi, PhD, of Amgen Inc for providing editorial support. patients, JAMA. 2O12;3O8(23):2497-25O6,
Tupelo); Ravi Bhagwat (Cardiology Associates of These persons received no compensation apart
13, Raal F, Scott R, Somaratne R, et al. Low-density
Northwest Indiana LLC, Hammond); Nancy Coburn from usual salary for their contributions,
lipoprotein cholesterol-lowering effects of AMG
(Advanced Clinical Research, Carmichael,
145, a monoclonal antibody to proprotein
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