original article
The
new england journal
of
medicine
n engl j med 370;18 nejm.org may 1, 2014
1702
Darapladib for Preventing Ischemic Events
in Stable Coronary Heart Disease
The STABILITY Investigators*
The authors and their affiliations are list-
ed in the Appendix. Address reprint re-
quests to Dr. Harvey D. White at Green
Lane Cardiovascular Service, Auckland
City Hospital, Private Bag 92024, Victoria
St. W., Auckland 1142, New Zealand, or
at harveyw@adhb.govt.nz.
* The investigators in the Stabilization of
Atherosclerotic Plaque by Initiation of
Darapladib Therapy (STABILITY) trial
are listed in the Supplementary Appen-
dix, available at NEJM.org.
This article was published on March 30,
2014, and updated on May 1, 2014, at
NEJM.org.
N Engl J Med 2014;370:1702-11.
DOI: 10.1056/NEJMoa1315878
Copyright © 2014 Massachusetts Medical Society.
ABSTRACT
Background
Elevated lipoprotein-associated phospholipase A
2
activity promotes the develop-
ment of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme
are associated with an increased risk of coronary events. Darapladib is a selective
oral inhibitor of lipoprotein-associated phospholipase A
2
.
Methods
In a double-blind trial, we randomly assigned 15,828 patients with stable coronary
heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo.
The primary end point was a composite of cardiovascular death, myocardial infarc-
tion, or stroke. Secondary end points included the components of the primary end
point as well as major coronary events (death from coronary heart disease, myocar-
dial infarction, or urgent coronary revascularization for myocardial ischemia) and total
coronary events (death from coronary heart disease, myocardial infarction, hospital-
ization for unstable angina, or any coronary revascularization).
Results
During a median follow-up period of 3.7 years, the primary end point occurred in
769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%)
in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence
interval [CI], 0.85 to 1.03; P = 0.20). There were also no significant between-group
differences in the rates of the individual components of the primary end point or in
all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major
coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P = 0.045)
and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98;
P = 0.02).
Conclusions
In patients with stable coronary heart disease, darapladib did not significantly re-
duce the risk of the primary composite end point of cardiovascular death, myocardial
infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov
number, NCT00799903.)
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Darapladib in Stable Coronary Heart Disease
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1703
A
therosclerotic lesions in humans
— in particular, vulnerable
1
and ruptured
plaques — are characterized by inflamma-
tory activity and a high expression of lipoprotein-
associated phospholipase A
2
.
2,3
In atherosclerotic
plaques, lipoprotein-associated phospholipase A
2
increases the production of proinflammatory and
proapoptotic mediators.
4-8
In a meta-analysis of
individual records from 79,036 participants in 32
prospective studies, there was a continuous asso-
ciation between lipoprotein-associated phospho-
lipase A
2
activity and the risk of coronary heart
disease, with a relative increase in risk of 1.10
(95% confidence interval [CI], 1.05 to 1.16) for
each 1-SD increase in lipoprotein-associated phos-
pholipase A
2
activity, after adjustment for conven-
tional risk factors.
9
Darapladib is a potent and reversible oral in-
hibitor of lipoprotein-associated phospholipase
A
2
.
10
In a swine model of atherosclerosis, dara-
pladib reduced levels of lipoprotein-associated
phospholipase A
2
in plaque, reduced the necrotic
core area, and inhibited the development of le-
sions in coronary arteries.
11
Darapladib has also
been shown to reduce lipoprotein-associated phos-
pholipase A
2
activity in human carotid plaque.
12
In the Integrated Biomarker and Imaging Study 2
(IBIS-2) involving patients with coronary heart
disease, darapladib, as compared with placebo,
halted the progression in the volume of the
necrotic core of coronary-artery plaques (a second-
ary end point), as determined by intravascular
ultrasonographic virtual histologic analysis dur-
ing a 12-month period.
13
These findings suggest
that darapladib could reduce the risk of events
associated with coronary heart disease by alter-
ing the composition of atherosclerotic plaques to
a less vulnerable state.
1
In the Stabilization of
Atherosclerotic Plaque by Initiation of Darap-
ladib Therapy (STABILITY) trial, we evaluated
the clinical efficacy and safety of darapladib in
patients with chronic coronary heart disease.
Methods
Study Design and Oversight
The study design has been described previously.
14
The trial was sponsored by GlaxoSmithKline. The
executive and steering committees designed the
study and supervised its conduct. (A complete list
of committee members is provided in the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org.) In each country, the study
was approved by national regulatory authorities
and by local ethics committees or institutional
review boards, according to local regulations.
Data were collected and managed by Glaxo-
SmithKline. Unblinded interim analyses of the
ongoing trial, including four efficacy analyses
(two prespecified and two unplanned) and semi-
annual safety analyses, were conducted at the
University of Wisconsin–Madison and reviewed
by an independent data and safety monitoring
committee. The final analyses of trial data were
performed by GlaxoSmithKline. Final statistical
analyses of key efficacy and safety measures,
including those presented in this article, were
independently verified by the Duke Clinical Re-
search Institute.
The first draft of the manuscript was written
by the first author. The executive and steering
committees contributed to subsequent drafts of
the manuscript and approved the submission of
the final manuscript for publication. The study’s
cochairs had full access to all data, verified their
accuracy, and vouch for the fidelity of the study
to the protocol, available at NEJM.org.
Study Population
Patients were eligible to participate in the study
if they had coronary heart disease, as documented
by at least one of the following: previous myocar-
dial infarction, previous percutaneous coronary
intervention (PCI) or coronary-artery bypass graft-
ing (CABG), or multivessel coronary artery dis-
ease. In addition, at least one of the following
additional predictors of cardiovascular risk was
required: an age of 60 years or older, diabetes
requiring pharmacotherapy, a high-density lipo-
protein (HDL) cholesterol level of less than 40 mg
per deciliter (1.03 mmol per liter), status as a
smoker of five or more cigarettes per day at study
entry or within 3 months before screening, mod-
erate renal dysfunction, or polyvascular arterial
disease. Exclusion criteria were planned PCI or
CABG or another major surgical procedure, cur-
rent liver disease, severe renal impairment, a his-
tory of nephrectomy or kidney transplantation,
current New York Heart Association class III or
IV heart failure, or severe asthma that was poorly
controlled with standard medical therapy. Details
of the inclusion and exclusion criteria are pro-
vided in the Supplementary Appendix. All patients
provided written informed consent.
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Study Procedures and Follow-up
After baseline assessments were performed, pa-
tients were randomly assigned, with the use of an
interactive voice-response system, to receive either
a once-daily oral dose of darapladib (160 mg) or
matching placebo to be taken with food and
swallowed whole. The assigned dose of darap-
ladib was expected to lower plasma levels of lipo-
protein-associated phospholipase A
2
by approxi-
mately 60%.
13
Patients were instructed to return for clinic
visits 1, 3, and 6 months after randomization
and thereafter every 6 months for the duration
of the study. In addition, patients were followed
up by telephone beginning at 9 months and then
every 6 months thereafter until the end of the
study.
Investigators were strongly encouraged to treat
patients according to international guidelines
for secondary prevention of coronary heart dis-
ease. All patients were to receive long-term treat-
ment with platelet-inhibitor therapy and statin
therapy unless such therapy was not indicated
according to guidelines, was contraindicated, or
resulted in unacceptable side effects. Metrics of
standard of care were monitored by the study
leaders and provided to all investigators every
6 months, which allowed the investigators to
compare the standard of care at their sites with
national and international standards at other sites
participating in this study. In addition, the im-
portance of adherence to standard-of-care med-
ications was reinforced over the duration of the
trial and at periodic meetings with investigators.
Patients were instructed to continue taking
the study drug until the day before their end-of-
treatment visit. Patients who permanently dis-
continued a study drug before the end of the
study were contacted by telephone for an assess-
ment of clinical outcomes. At the end of the
study, all patients were asked to return to the
clinic within a 3-month period for their final
study visit. Final survival status was sought for
patients who were lost to follow-up or withdrew
consent.
Study End Points
The primary end point was a composite of cardio-
vascular death, myocardial infarction, or stroke.
Secondary end points included major coronary
events (a composite of death from coronary heart
disease, myocardial infarction, or urgent coro-
nary revascularization for myocardial ischemia);
total coronary events (a composite of death from
coronary heart disease, myocardial infarction,
hospitalization for unstable angina, or any coro-
nary revascularization procedure); the individual
components of the primary end point; a compos-
ite of all-cause mortality, myocardial infarction,
or stroke; and all-cause mortality. Definitions of
the primary and secondary end points are pro-
vided in the Supplementary Appendix.
Laboratory Testing
All laboratory tests were performed at central
laboratories (Quest Diagnostics Clinical Labora-
tories). The estimated glomerular filtration rate
(GFR) was calculated with the use of the Modifi-
cation of Diet in Renal Disease method.
15
Safety Monitoring and Adjudication
Investigators were responsible for detecting, docu-
menting, and reporting adverse events and serious
adverse events. Information on adverse events
was collected from the time the randomized reg-
imens were started until 35 days after the last
dose of a study drug was taken or at the next
follow-up visit, whichever occurred later. Serious
adverse events that were assessed as being related
to a study drug or related to study participation
were recorded up to and including any follow-up
contact. The occurrence of cancers and of gastro-
intestinal polyps or neoplasms was recorded
until the end of the study, including during the
period after discontinuation of the study drug,
since 2-year carcinogenicity studies in rodents
had suggested that darapladib was associated
with the development of jejunal adenomas or ad-
enocarcinomas in male mice and rats. Other ad-
verse events of special interest included asthma,
anaphylaxis, diarrhea, and odor-related events,
because in previous studies,
13
darapladib had
been associated with an unpleasant odor of skin,
urine, or feces.
Suspected primary and secondary end points
were evaluated by an independent clinical-events
committee whose members were unaware of the
study-group assignments. Gastrointestinal neo-
plasms and cancers were adjudicated by a sepa-
rate committee in a blinded fashion.
Statistical Analysis
We anticipated an annual event rate for the pri-
mary end point of 4% in the placebo group. We
then estimated that 1500 events would be re-
quired for the study to have a power of 90% to
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Darapladib in Stable Coronary Heart Disease
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1705
detect a relative-risk reduction of 15.5% in the
rate of the primary end point in the darapladib
group, as compared with the placebo group.
All patients who underwent randomization
were included in the intention-to-treat analyses.
Time-to-event analyses were performed with the
use of Kaplan–Meier estimates for the primary
and secondary end points. Hazard ratios and
95% confidence intervals were estimated with
the use of Cox proportional-hazards models.
The effect of treatment on the primary end
point was estimated with the use of hazard
ratios and adjusted 95.1% confidence intervals,
with a two-sided P value of 0.049 indicating sta-
tistical significance after adjustment for the four
interim analyses conducted by the data and
safety monitoring committee. For secondary and
other end points, no adjustments were made
for multiple testing. Nominal significance re-
fers to an unadjusted P value of less than 0.05
in which the type I error was not controlled at
the 5% level.
The consistency of effects on efficacy end
points was prespecified to be explored in 35 sub-
groups, without adjustment for multiple com-
parisons. The analyses of safety data focused on
adverse events, laboratory data, and vital signs
and included all patients who received at least
one dose of a study drug. Baseline and on-
treatment lipoprotein-associated phospholipase
A
2
levels are not yet available and thus are not
reported here.
Results
Study Patients
From December 2008 through April 2010, we en-
rolled 15,828 patients at 663 centers in 39 coun-
tries (Fig. 1). A total of 7924 patients were ran-
domly assigned to the darapladib group, and
7904 were assigned to the placebo group. The
median age of the patients was 65 years; 81%
were men, 78% were white, 20% were current or
recent smokers, and 34% had diabetes mellitus
requiring pharmacotherapy (Table 1, and Table S1
in the Supplementary Appendix). The median low-
density lipoprotein (LDL) cholesterol level at base-
line was 79.9 mg per deciliter (2.07 mmol per liter).
Follow-up, Adherence, and Background
Therapy
The median duration of follow-up for the primary
end point was 3.7 years (interquartile range,
3.5 to 3.8). The median duration of study-drug
exposure was 3.5 years in the darapladib group
and 3.6 years in the placebo group. We were able
to ascertain vital status for 99.3% of the patients
(15,722 of 15,828) and for 99.6% of the total pos-
sible follow-up time. For the analysis of the pri-
mary end point, complete follow-up was obtained
in 96.5% of patients and for 97.7% of total follow-
up time (Fig. S1 in the Supplementary Appendix).
The percentage of patients with at least 80% ad-
herence to treatment, as determined on the basis
of pill counts, was 89.3% in the darapladib group
and 91.3% in the placebo group.
15,828 Patients underwent randomization
7924 Were assigned to receive
darapladib
7912 Received darapladib
12 Did not receive darapladib
7904 Were assigned to receive
placebo
7890 Received placebo
14 Did not receive placebo
7924 Were included in the analysis
7641 Had known cardiovascular
end-point status at the end
of the study
283 Had unknown cardiovascular
end-point status at the end
of the study
7877 Had known vital status at the
end of the study
47 Had unknown vital status
at the end of the study
7904 Were included in the analysis
7628 Had known cardiovascular
end-point status at the end
of the study
276 Had unknown cardiovascular
end-point status at the end
of the study
7845 Had known vital status at the
end of the study
59 Had unknown vital status
at the end of the study
7646 Completed the study
278 Withdrew from the study
175 Withdrew consent
80 Were lost to follow-up
23 Participated at investigative
site that closed
5322 Were taking darapladib at the
end of the study
2590 Discontinued darapladib
1569 Had adverse event
47 Had protocol deviation
55 Were lost to follow-up
895 Decided to stop or proxy
decision
7 Stopped owing to sponsor
decision
17 Participated at investigative
site that closed
7631 Completed the study
273 Withdrew from the study
179 Withdrew consent
69 Were lost to follow-up
25 Participated at investigative
site that closed
5774 Were taking placebo at the
end of the study
2116 Discontinued placebo
1067 Had adverse event
50 Had protocol deviation
49 Were lost to follow-up
918 Decided to stop or proxy
decision
13 Stopped owing to sponsor
decision
19 Participated at investigative
site that closed
Figure 1. Randomization and Follow-up.
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The use of guideline-recommended treatments
for secondary prevention was high. At trial close-
out, 90% of the patients were taking aspirin,
96% statins, 79% beta-blockers, 54% angiotensin-
converting–enzyme inhibitors, and 26% angio-
tensin II–receptor blockers. The median LDL cho-
lesterol level at the end of the study was 78.0 mg
per deciliter (2.02 mmol per liter) in the darap-
Table 1. Characteristics of the Patients at Baseline.*
Characteristic Placebo (N = 7904) Darapladib (N = 7924)
Age
Median (IQR) — yr 65.0 (59.0–71.0) 65.0 (59.0–71.0)
<65 yr — no. (%) 3893 (49.3) 3808 (48.1)
65–74 yr — no. (%) 2938 (37.2) 3022 (38.1)
≥75 yr — no. (%) 1073 (13.6) 1094 (13.8)
Female sex — no. (%) 1506 (19.1) 1461 (18.4)
Race or ethnic group — no. (%)†
White 6174 (78.1) 6232 (78.6)
Black 191 (2.4) 175 (2.2)
Central, South, or Southeast Asian 598 (7.6) 592 (7.5)
East Asian or Japanese 766 (9.7) 758 (9.6)
Other 175 (2.2) 167 (2.1)
Region of enrollment — no. (%)
North America
All 2016 (25.5) 2007 (25.3)
United States 1555 (19.7) 1547 (19.5)
South America 597 (7.6) 602 (7.6)
Western Europe 1980 (25.1) 2006 (25.3)
Eastern Europe 1764 (22.3) 1767 (22.3)
Asia or Pacific Rim 1547 (19.6) 1542 (19.5)
Cardiovascular risk factors
Diabetes requiring pharmacotherapy — no. (%) 2687 (34.0) 2664 (33.6)
High-density lipoprotein cholesterol
Median (IQR) — mg/dl 44.4 (38.6–52.9) 44.8 (38.6–53.7)
<40 mg/dl — no. (%) 2786 (35.2) 2646 (33.4)
Smoker — no. (%)‡ 1656 (21.0) 1572 (19.8)
Renal dysfunction — no. (%)§ 2374 (30.0) 2410 (30.4)
Polyvascular disease — no. (%) 1187 (15.0) 1185 (15.0)
Qualifying diagnosis of coronary heart disease — no. (%)
Previous myocardial infarction 4642 (58.7) 4681 (59.1)
Previous coronary revascularization 5911 (74.8) 5952 (75.1)
Percutaneous coronary intervention 3978 (50.3) 3987 (50.3)
Coronary-artery bypass grafting 2592 (32.8) 2644 (33.4)
Multivessel disease 1191 (15.1) 1199 (15.1)
* There was no significant difference between the two groups, except among patients who had a high-density lipoprotein
cholesterol level of less than 40 mg per deciliter (P = 0.01). Percentages may not total 100 because of rounding. To convert
the values for cholesterol to millimoles per liter, multiply by 0.02586. IQR denotes interquartile range.
† Race or ethnic group was self-reported.
‡ Smokers included both current smokers of five or more cigarettes per day and those who were smokers within 3 months
before screening.
§ Renal dysfunction was defined as an estimated glomerular filtration rate of 30 to 59 ml per minute per 1.73 m
2
of body-
surface area (moderate kidney disease) or a urine albumin-to-creatinine ratio of 30 or more (as measured in milligrams of
albumin and grams of creatinine).
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