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ORIGINAL ARTICLE
A phase II study of the oral factor Xa inhibitor LY517717 for
the prevention of venous thromboembolism after hip or knee
replacement
G. AGNELLI,* S. HAAS,J. S. GINSBERG,àK. A. KRUEGER,§ A. DMITRIENKO§ and J. T. BRANDT§
*Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy; Institute for Experimental Oncology and Therapy
Research, Technical University of Munich, Munich, Germany; àDepartment of Medicine, McMaster University, Hamilton, ON, Canada; and
§Global Medical Research and Development, Eli Lilly and Company, Indianapolis, IN, USA
To cite this article: Agnelli G, Haas S, Ginsberg JS, Krueger KA, Dmitrienko A, Brandt JT. A phase II study of the oral factor Xa inhibitor LY517717
for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 2007; 5: 746–53.
Summary. Background: LY517717 is an oral direct inhibitor of
activated factor X that is currently under clinical develop-
ment. Objectives: The aims of this proof-of-concept study in
patients undergoing total knee replacement (TKR) or total hip
replacement (THR) were to determine whether LY517717 can
safely reduce the risk of venous thromboembolism (VTE) and
to identify at least one dose of LY517717 that is non-inferior to
enoxaparin. Methods: In a double-blind, parallel-arm, dose-
ranging study, patients undergoing TKR or THR were
randomly allocated to receive once-daily oral LY517717 (25,
50, 75, 100, 125 or 150 mg), started 6–8 h after wound closure,
or s.c. enoxaparin, 40 mg, started in the evening before surgery.
The primary efficacy endpoint was the composite of deep
venous thrombosis (DVT), detected by mandatory bilateral
venography performed at the end of the study treatment
(between days 5 and 9), and objectively confirmed symptomatic
DVT and/or pulmonary embolism (PE), occurring during the
treatment period. The combination of major and minor
bleeding was the primary safety endpoint. Results: Five
hundred and seven patients received at least one dose of
LY517717 or enoxaparin (safety population). Three hundred
and ninety-one patients had evaluable bilateral venography or
experienced a clinical DVT and/or PE (primary efficacy
population). LY517717 treatment resulted in a dose-dependent
decrease in the incidence of thromboembolic events
(P= 0.0001). The incidences of VTE with 100, 125, and
150 mg of LY517717 were 19%, 19% and 16%, respectively,
compared to 21% with enoxaparin. The efficacies of 100-mg,
125-mg and 150-mg doses of LY517717 were non-inferior to
that of enoxaparin according to prespecified criteria. Bleeding
events were uncommon in both LY517717 and enoxaparin
patients. Conclusions: Doses of 100, 125 and 150 mg of
LY517717 are non-inferior to enoxaparin for the prevention
of VTE after TKR or THR, and are associated with similar low
rates of bleeding.
Keywords: deep vein thrombosis, factor Xa inhibitor, pulmon-
ary embolism, total hip replacement, total knee replacement,
venous thromboembolism.
Introduction
Anticoagulant agents currently used in clinical practice are
effective and relatively safe when properly used, but have
well-known limitations [1]. Low-molecular-weight heparins
(LMWHs) and fondaparinux require s.c. administration [2].
Coumarins are orally active but require laboratory monitor-
ing for dose initiation and adjustment, because of the
variability among patients in dose requirements, have a
narrow therapeutic window, are subject to drug and food
interactions, and require at least 3–5 days to achieve a
therapeutic effect [3]. These limitations indicate that there is
still an unmet need for an oral antithrombotic agent that is
as safe and effective as coumarins, but does not have its
limitations [1,4].
LY517717 difumarate (LY517717) is an orally available,
small-molecule (free base molecular mass 459 Da), highly
selective reversible inhibitor of factor Xa. The primary route
of elimination of LY517717 appears to be the gastrointestinal
tract. In contrast to indirect FXa inhibitors (e.g. fondapari-
nux), LY517717 directly inhibits FXa, not requiring anti-
thrombin as a cofactor. LY517717 showed antithrombotic
properties in experimental animals and a favorable pharma-
cokinetic profile in phase I studies (data on file, Eli Lilly
and Co.). In healthy volunteers, LY517717 showed an
Correspondence: Giancarlo Agnelli, Division of Internal and Vascular
Medicine-Stroke Unit, Ospedale S. Maria della Misericordia, Via G.
Dottori #1, University of Perugia, Perugia, Italy.
Tel.: +39 075 578 2266; Fax: +39 075 578 2436; e-mail: agnellig@
unipg.it
Received 13 November 2006, accepted 22 January 2007
Journal of Thrombosis and Haemostasis,5: 746–753
2007 International Society on Thrombosis and Haemostasis
anticoagulant activity that peaked within 0.5–4 h following
oral administration and declined in a biphasic pattern with a
terminal half-life of approximately 27 h. These pharmacologic
features afford the drug the potential for safe and effective
once-daily dosing.
Clinical development of a novel antithrombotic agent
requires demonstration that it is safe and effective in relevant
populations. Often, initial phase II studies are performed in
patients undergoing total hip replacement (THR) or total knee
replacement (TKR), because these patients have a high
incidence of deep vein thrombosis (DVT) in the absence of
effective prophylaxis, and a residual, but significant, rate of
thrombosis with currently available agents [5,6]. These patients
are also at increased risk of bleeding, particularly with excessive
anticoagulation [7,8]. For these reasons, TKR and THR are
informative clinical settings in which to demonstrate the
efficacy and safety of an experimental antithrombotic agent.
The aims of this study were to determine whether LY517717
can safely reduce the risk of venous thromboembolism (VTE)
in patients undergoing TKR or THR surgery, and to identify
one or more dose regimens of LY517717 that is non-inferior to
enoxaparin.
Materials and methods
Patients
Patients between 18 and 75 years of age, weighing between
50 kg and 120 kg, and scheduled for elective primary unilateral
THR or TKR, were eligible for the study. Potentially eligible
patients were excluded if one or more of the following was
present: clinically significant bleeding disorder; baseline
International Normalized Ratio > 1.5 or platelet count
<100·10
9
/L; active peptic ulcer disease; recent stroke;
uncontrolled hypertension; intracranial tumor; brain or spinal
cord surgery; anticoagulant or thrombolytic therapy in the last
7 days; treatment with aspirin or any non-steroidal anti-
inflammatory drug (other than COX-2 inhibitors) within 48 h
of surgery; serum creatinine levels ‡2.0 mg/dL (177 lmol/L);
baseline aspartate aminotransferase (AST) or alanine amino-
transferase (ALT) ‡2 times the upper limit of normal or total
bilirubin outside of the normal range; hemoglobin
(Hbg) < 10 g/dL; female gender and childbearing potential;
or failure or inability to provide informed consent.
This study was approved by the respective institutional
review boards for each participating research center. Informed
consent was obtained from all participants.
Study design
This study was a multicenter, randomized, double-blind,
double-dummy, dose-escalation/parallel-arm, phase II clinical
trial (phase II study begun before July 2005). Patients were
screened for eligibility between 1 and 30 days prior to
scheduled surgery. Randomization was stratified by type of
surgical procedure (THR or TKR).
Treatment regimen
Initially, patients were randomized to one of the three lowest
doses of LY517717 (25, 50, or 75 mg) or enoxaparin. Higher
doses of LY517717 (100 and 125 mg) were to be introduced
into the study if the lowest doses were insufficiently effective
and did not cause excessive bleeding. A protocol amendment
allowedforfurtherdoseescalationupto200mg(Fig.1).
Oral LY517717 or its matching placebo was administered 6–
8 h after wound closure and then every morning, after
overnight fasting, at 07:00 ± 1 h. Patients were to continue
fasting for at least 1 h after the first dose and for at least 2 h
after subsequent doses. The requirement for fasting was based
on the results of the phase I study that showed some evidence of
a food effect. Thus, fasting was required to minimize the impact
of food on LY517717 adsorption. Enoxaparin (40 mg) or its
matching placebo was administered s.c. on the evening before
surgery and then every evening at 20:00 ± 2 h. Both treat-
ments were continued for a total of six to 10 doses.
Concomitant use of antiplatelet or anticoagulant agents
(other than study drugs), thrombolytic agents or non-steroidal
anti-inflammatory drugs (except COX-2 inhibitors) was
strongly discouraged during the treatment period. Indwelling
intrathecal or epidural catheters, intermittent pneumatic com-
pression devices and electrical/mechanical muscle stimulators
were also prohibited.
Efficacy assessments
The primary efficacy endpoint of the study was the composite
of DVT, detected by mandatory bilateral venography per-
formed at the end of the study treatment period (between days
5 and 9), and objectively confirmed symptomatic DVT and/or
pulmonary embolism (PE), occurring during the treatment
period.
Patients underwent bilateral contrast venography of the
lower limbs within 12 h of the last dose of the oral study, using
a standard technique [9]. Visualization of the entire proximal
and distal deep venous system of the lower extremities or the
presence of a DVT was required for venography to be
adjudicated as adequate. A DVT was defined as a filling defect
at least partially surrounded by contrast medium visible in two
or more views.
Patients were monitored daily during the study treatment
period. Patients with suspected DVT or PE underwent
Fig. 1. Modified dose-escalation, parallel-arm design; total enrollment 511
patients.
VTE prevention with LY517717 747
2007 International Society on Thrombosis and Haemostasis
appropriate diagnostic testing. Symptomatic patients who had
DVT or PE ruled out were encouraged to undergo bilateral
venography as per protocol, at the end of study drug
administration.
The study included a follow-up visit (on study day 30 ± 7).
Extended prophylaxis following completion of study drug was
permitted at the discretion of the investigator.
Safety assessments
The combination of major and minor bleeding events was the
primary safety endpoint of this study. Patients were assessed
for unusual or unexpected bleeding during the treatment period
and at the follow-up visit (on study day 30 ± 7). Any patient
who experienced unusual or unexpected bleeding underwent
evaluation using appropriate testing. Bleeding was defined as
major if it was clinically overt and: led to death; involved a
critical site (e.g. intracranial, retroperitoneal, intraocular or
pericardial bleeding); was associated with a bleeding in-
dex ‡2.0 [bleeding index = units of red blood cells trans-
fused + prebleed Hgb)postbleed Hgb); or required surgical
intervention. Clinically overt bleeding that did not fulfill the
criteria for major bleeding was classified as minor bleeding.
Other safety parameters evaluated during the study included
serious and non-serious adverse events, standard laboratory
evaluations (including hepatic enzymes), vital signs, and
electrocardiography measurements.
Independent central adjudication committee
All venograms and suspected symptomatic episodes of DVT
and PE as well as all suspected bleeding events were adjudicated
by a blinded independent central adjudication committee. The
adjudicated results were used in all primary analyses.
Assessment committee
The assessment committee was independent, and monitored
efficacy and safety data in an unblinded fashion. Major
bleeding and serious adverse event data were monitored in a
continuous fashion by the assessment committee chair and
were reviewed during two planned interim analyses by the full
assessment committee. Efficacy data were reviewed during two
planned interim analyses by the full assessment committee, and
recommendations regarding dose continuation or cessation
were made.
Statistical analysis
It was estimated that a sample size of 70 patients per treatment
group would give the study 80% power of declaring non-
inferiority between a dose of LY517717 and enoxaparin, using
a one-sided 90% confidence interval (CI) with a non-inferiority
margin of 0.14. This calculation assumed that the underlying
VTE rates for the LY517717 doses and enoxaparin were both
18%. The non-inferiority margin was defined as the midpoint
between the expected active therapy response (18%) and
placebo response (45%) in this patient population. Eighty-five
patients per treatment group (510 patients in total) were
planned to be enrolled in the study to allow for an estimated
17% rate of non-evaluability (because bilateral venography
was non-evaluable or the patient dropped out of the study).
The primary efficacy analysis was a comparison of the
proportions of patients experiencing a VTE event (DVT and/or
PE) detected on bilateral venography or on clinical assessment
through the treatment period in the LY517717 and enoxaparin
arms. Asymptotic one-sided 90% CIs were computed for each
dose-control comparison to perform the non-inferiority assess-
ments. The primary efficacy analysis was carried out in the per-
protocol population, which excluded patients with protocol
violations that could potentially impact on efficacy, including
violations in the duration and timing of study drug dosing,
concomitant medication use, and adherence to fasting guide-
lines. No adjustments were made to the CIs to correct for
multiple testing.
Planned secondary efficacy analyses explored the incidence of
VTE subtypes, including venography-detected and clinically
detected DVT, proximal or distal DVT or PE, as well as the
composite of proximal DVT or PE (major VTE). All secondary
efficacy analyses were carried out in the same way as determin-
ation of the primary endpoint; however, no attempt was made
to declare non-inferiority on the basis of the secondary efficacy
measures. These secondary analyses were carried out in the per-
protocol and intent-to-treat populations. The intent-to-treat set
followed the intention-to-treat principle, and included patients
who received at least one dose of LY517717 or enoxaparin, and
had evaluable bilateral venography or experienced an objec-
tively confirmed clinical VTE. In addition, the relationship
between the percentage of per-protocol patients experiencing
any postoperative VTE throughout the treatment period and
LY517717 dose was modeled using a logistic regression model
with the dose as an independent variable (this analysis was
restricted to the patients who received LY517717). The Wald
chi-square test was carried out with respect to the dose term to
assess the significance of the dose-dependent decrease in the
incidence of thromboembolic events [10].
The primary safety analyses were based on the intent-to-treat
set throughout the treatment period. The intent-to-treat set for
safety included all patients who received at least one dose of
LY517717 or enoxaparin. The percentage of patients who
experienced a major or minor bleeding event was summarized
using a logistic model similar to the primary efficacy parameter.
No attempt was made to declare non-inferiority.
In order to minimize the number of patients exposed to
ineffective doses of LY517717 and to optimize the efficiency of
the study, an adaptive design with two interim analyses and
continuous monitoring of the study outcomes by the assess-
ment committee chair was utilized. Insufficient effectiveness
was to be declared if the lower limit of the 95% CI for the point
estimate of the VTE rate was >15%. Randomization ratios
were adjusted across the three enrollment phases to achieve
numerical balance across treatment groups.
748 G. Agnelli et al
2007 International Society on Thrombosis and Haemostasis
Results
Study groups
The first interim analysis was performed after 131 patients were
enrolled in the study. On the basis of lack of efficacy and
absence of excessive bleeding with the 25-, 50- and 75-mg doses,
the assessment committee recommended discontinuation of
these doses and initiation of enrollment to the 100- and 125-mg
groups. The second interim analysis was performed after an
additional 176 patients were enrolled into the study. Following
review of this interim data, the assessment committee recom-
mended continuation of the 100- and 125-mg groups and
addition of a 150-mg group. Fig. 1 shows the dose-escalation
process resulting from the interim analyses.
Overall, between December 2003 and April 2005, 511
patients were randomized in eight countries and 31 centers
(Fig. 2). Of these, four patients did not receive any study drug,
and 10 did not undergo surgery. Of the 497 remaining patients,
391 (79%) had evaluable bilateral venography or experienced
objectively confirmed symptomatic VTE. After exclusion of the
patients with significant protocol violations, 361 patients were
included in the per-protocol population. The most frequent
reasons for exclusion from the per-protocol population were
receiving fewer than five doses of study drug, using a prohibited
concomitant medication, and fasting violations. The safety full
analysis set included 507 patients. Demographic and surgical
characteristics were similar across treatment groups (Table 1).
The median treatment duration was 8 days.
No statistically significant differences concerning the use of
general or neuraxial anesthesia were observed throughout the
treatment groups. Among the enoxaparin patients, 26.7%
underwent general anesthesia and 71.1% neuraxial anesthesia.
Among the patients assigned to one of the six LY517717 doses,
the proportion of patients who underwent general or neuraxial
anesthesia ranged from 18.8% (25 mg) to 34.4% (75 mg) and
511 randomized
420 randomized to
LY517717
Three not treated
417 treated with at least
one dose of study drug
(safety)
409 underwent surgery
One not treated
90 treated with at least
one dose of study drug
(safety)
88 underwent surgery
72 (79%) in efficacy
Intent-to-treat set
318 (76%) in efficacy
Intent-to-treat set
294 (70%) evaluable for
primary efficacy (per-
protocol population)
66 (73%) evaluable for
primary efficacy (per-
protocol population)
16 Not evaluable for any VTE event
12 Venography not done
Four venography not evaluable
91 Not evaluable for any VTE event
41 Venography not done
50 Venography not evaluable
Six excluded from per-protocol
population
Zero received less than 5 doses of
study drug
Two used prohibited concomitant
medication
Three violated study drug tasting
requirement
One other
24 excluded from per-protocol
population
Three received less than 5 doses of
study drug
Nine used prohibited concomitant
medication
Three violated study drug tasting
requirement
Nine other
91 randomized to
enoxaparin
Fig. 2. Trial profile. VTE, venous thromboembolism.
Table 1 Baseline characteristics of all treated patients
Characteristic
LY517717 Enoxaparin
25 mg 50 mg 75 mg 100 mg 125 mg 150 mg 40 mg
N32 34 32 106 110 103 90
Age, mean (range) years 63.4 (44–75) 62.4 (33–75) 64.4 (45–74) 62.4 (31–75) 61.6 (32–75) 62.1 (33–75) 63.5 (42–75)
Female sex, n(%) 22 (68.8) 19 (55.9) 21 (65.6) 56 (52.8) 53 (48.2) 54 (52.4) 52 (57.8)
BMI, mean (SD) kg/m
2
28.0 (4.4) 28.7 (4.1) 29.4 (5.4) 28.8 (4.5) 29.3 (4.6) 29.7 (4.3) 29.0 (4.4)
THR, n(%) 19 (59.4) 19 (55.9) 17 (53.1) 63 (59.4) 71 (64.5) 59 (57.3) 52 (57.8)
N, number of patients treated; n, number of patients; BMI, body mass index; SD, standard deviation; THR, total hip replacement.
VTE prevention with LY517717 749
2007 International Society on Thrombosis and Haemostasis
from 62.5% (75 mg) to 81.3% (25 mg), respectively. Overall,
six LY517717 patients received combined anesthesia: one in the
100-mg group, two in the 125-mg group, and three in the
150-mg group.
Efficacy
In the per-protocol population throughout the treatment
period, administration of LY517717 resulted in a statistically
significant dose-dependent decrease in the incidence of throm-
boembolic events (P= 0.0001) (Table 2). Doses ranging
between 25 and 75 mg were ineffective. The incidences of
VTE with 100, 125 and 150 mg of LY517717 were 19%, 19%
and 16%, respectively, compared to 21% in the enoxaparin
group. The 100-mg, 125-mg and 150-mg doses of LY517717
were non-inferior to enoxaparin (upper limits for the 90% CI
of the absolute differences 0.13, 0.05 and 0.01, respectively).
None of the patients included in the per-protocol analysis
had a symptomatic VTE during the study treatment period.
Two patients excluded from the per-protocol analysis had
confirmed PE during the treatment period. One patient,
randomized to the 125-mg group, developed symptoms of a
PE on the day of surgery, and the diagnosis was confirmed on
day 4. This patient did not receive any doses of active study
drug during the study. The second patient, randomized to the
75-mg group, developed symptoms of PE and took the last
study drug dose on day 3. The diagnosis of PE was
subsequently confirmed on day 4. It is possible that this patient
might have experienced PE while on the study drug. Had this
patient been included in the per-protocol population analysis,
Table 2 Incidence of venous thromboembolic events during the treatment period*
Characteristic
LY517717 Enoxaparin
25 mg 50 mg 75 mg 100 mg 125 mg 150 mg 40 mg
Total population
Any VTE – n/N(%) 11/26 (42.3) 8/20 (40) 12/22 (54.6) 13/69 (18.8) 15/80 (18.8) 12/77 (15.6) 14/66 (21.2)
(95% CI) (26.4–58.2) (22.0–58.0) (37.1–72.0) (11.1–26.6) (11.6–25.9) (8.8–22.4) (12.9–29.5)
Proximal DVT or PE – n/N(%) 0/28 (0) 3/21 (14.3) 6/22 (27.3) 5/77 (6.5) 2/81 (2.5) 0/84 (0) 3/65 (4.6)
(95% CI) NA (1.7–26.9) (11.7–42.9) (1.9–11.1) (0–5.3) NA (0.3–8.9)
Distal DVT – n/N(%) 11/26 (42.3) 5/20 (25) 6/22 (27.3) 8/69 (11.6) 13/80 (16.3) 12/77 (15.6) 11/66 (16.7)
(95% CI) (26.4–58.2) (9.1–40.9) (11.7–42.9) (5.3–17.9) (9.5–23.0) (8.8–22.4) (9.1–24.2)
Total hip replacement
Any VTE – n/N(%) 4/15 (26.7) 2/10 (20) 6/14 (42.9) 4/45 (8.9) 6/57 (10.5) 3/47 (6.4) 6/38 (15.8)
(95% CI) (7.9–45.5) (0–40.8) (21.1–64.6) (1.9–15.9) (3.8–17.2) (0.5–12.3) (6.1–25.5)
Proximal DVT or PE – n/N(%) 0/17 (0) 1/11 (9.1) 4/14 (28.6) 1/50 (2) 1/57 (1.8) 0/52 (0) 1/39 (2.6)
(95%CI) NA (0–23.4) (8.7–48.4) (0–5.3) (0–4.6) NA (0–6.7)
Distal DVT – n/N(%) 4/15 (26.7) 1/10 (10) 2/14 (14.3) 3/45 (6.7) 5/57 (8.8) 3/47 (6.4) 5/38 (13.2)
(95% CI) (7.9–45.5) (0–25.6) (0–29.7) (0.6–12.8) (2.6–14.9) (0.5–12.3) (4.1–22.2)
Total knee replacement
Any VTE – n/N(%) 7/11 (63.6) 6/10 (60) 6/8 (75) 9/24 (37.5) 9/23 (39.1) 9/30 (30) 8/28 (28.6)
(95% CI) (39.8–87.5) (34.5–85.5) (49.8–100) (21.3–53.8) (22.4–55.9) (16.2–43.8) (14.5–42.6)
Proximal DVT or PE – n/N(%) 0/11 (0) 2/10 (20) 2/8 (25) 4/27 (14.8) 1/24 (4.2) 0/32 (0) 2/26 (7.7)
(95% CI) NA (0–40.8) (0–50.2) (3.6–26.1) (0–10.9) NA (0–16.3)
Distal DVT – n/N(%) 7/11 (63.6) 4/10 (40) 4/8 (50) 5/24 (20.8) 8/23 (34.8) 9/30 (30) 6/28 (21.4)
(95% CI) (39.8–87.5) (14.5–65.5) (20.9–79.1) (7.2–34.5) (18.5–51.1) (16.2–43.8) (8.7–34.2)
VTE, venous thromboembolism; DVT, deep venous thrombosis; PE, pulmonary embolism; n, number of patients; CI, confidence interval; NA, not
applicable; *per protocol population.
Table 3 Bleed-related safety during the treatment period
Characteristic
LY517717 Enoxaparin
25 mg 50 mg 75 mg 100 mg 125 mg 150 mg 40 mg
Safety (N) 32 34 32 106 110 103 90
Bleeding events [% (95% CI)] 0 (NA) 0 (NA) 0 (NA) 0.9 (0–2.5) 0 (NA) 1.0 (0–2.6) 2.2 (0–4.8)
Major bleeds [% (95% CI)] 0 (NA) 0 (NA) 0 (NA) 0.9 (0–2.5) 0 (NA) 0 (NA) 0 (NA)
Mean transfusion volume (mL) 418.9 429.1 441 370.6 357.9 353.8 444.1
Proportion with transfusion (%) 65.6 61.8 68.8 53.8 50 48.5 61.1
Mean Hgb reduction (g/dL) 3.5 3.8 2.8* 3.8 3.7 3.8 3.8
Mean bleeding index
4.0 4.1 3.2* 3.8 3.8 3.9 4.1
*P< 0.05 for comparison to enoxaparin.
Bleeding index = units of red blood cells transfused + change in hemoglobin.
CI, confidence interval; Hgb, hemoglobin.
750 G. Agnelli et al
2007 International Society on Thrombosis and Haemostasis
the incidence of PE and proximal DVT in the 75-mg group
would have been 30.4% for the pooled population and 33.3%
for the TKR subpopulation. Inclusion or exclusion of this
subject in the per-protocol population has no impact on the
conclusions of the study.
Among the per-protocol population, one PE (150-mg group
on day 21) and one proximal DVT (100-mg group on day 20)
were confirmed during the follow-up period.
Safety
The bleeding events during the treatment period are shown in
Table 3. One major bleeding event occurred during study drug
administration, and two major bleeding events were observed
during the follow-up period (125-mg group on day 28, and
enoxaparin group on day 8). One patient in the 100-mg group
developed a thigh hematoma on day 2 that required transfu-
sion. There was one intracranial hemorrhage, which occurred
on day 28 in the 125-mg group in a patient who suffered major
head trauma. The patient was receiving prophylaxis with
enoxaparin at the time of the trauma. The third major bleeding
event was a surgical site hematoma occurring in a patient
randomized to enoxaparin and requiring surgical evacuation
on day 8. There were no bleeding-related deaths.
In view of the low rate of bleeding events, additional
bleeding-related measures were carefully assessed to further
quantify the risk of bleeding associated with LY517717 (Table
3). There were no statistically significant differences between
LY517717 doses and enoxaparin in the volume of blood
transfusions throughout the treatment period. The proportion
of patients requiring any blood transfusion during the treat-
ment period was statistically significantly lower in the 125-mg
and the 150-mg groups than in the enoxaparin group.
Transfusion requirements tended to be lower with the higher
doses of LY517717 as compared to enoxaparin.
Other safety measures
There were no statistically significant differences among
treatment groups or between any dose of LY517717 and
enoxaparin in the percentage of patients with 3-, 5- and tenfold
elevation above the upper limit of normal for ALT or AST
during the treatment period (Table 4).
One patient randomized to enoxaparin had a serious adverse
event of pneumonia that resulted in death on day 36. None of
the serious adverse events was considered to be related to study
drug or procedures.
Discussion
The results of this study are the first to show that LY517717 is an
efficacious oral antithrombotic agent in humans, and that, at the
doses used in this study, the drug does not appear to cause
excessive bleeding. Administration of LY517717 resulted in a
dose-dependent decrease in the incidence of thromboembolic
events. A range of once-daily doses (100–150 mg) showed
efficacy and safety that were comparable to those of enoxaparin.
The lack of excessive bleeding with the highest dose regimens
supports evaluation of higher doses to determine whether
greater efficacy can be achieved without an increase in bleeding.
The results of our study are consistent with the efficacy
achieved in the same clinical setting with other FXa inhibitors,
both injectable (fondaparinux) and oral [BAY 59-7939 (now
rivaroxaban) and razaxaban], providing further evidence that
FXa is a reasonable target for novel anticoagulant agents [11–
17].
LY517717 was shown to be effective in the prevention of
VTE after both THR and TKR. Both types of major
orthopedic surgery have become appropriate models for
dose-ranging trials investigating new anticoagulants. Differ-
ences between THR and TKR populations include a higher
overall DVT rate after TKR and a higher proportion of
proximal DVT after THR,as well as different patterns of
bleeding [5,11,15,18,19]. Despite these differences, the recom-
mended dosages of conventional antithrombotic therapy for
these two patient populations have been identical. Combining
TKR and THR patient populations allows a more extensive
initial evaluation in two different postoperative settings.
LY517717 and enoxaparin were initiated at different times
relative to the surgical procedure in this study. LY517717 was
first administered 6–8 h postoperatively, whereas enoxaparin
was administered the night before surgery. In theory, this
Table 4 Proportion of patients with elevated hepatic enzymes
Characteristic
LY517717 Enoxaparin
25 mg 50 mg 75 mg 100 mg 125 mg 150 mg 40 mg
Safety (N) 32 34 32 106 110 103 90
ALT
3·ULN (%) 6.3 6.3 3.2 3.8 0.9 2.9 5.6
5·ULN (%) 6.3 3.1 3.2 1.9 0 1 3.4
10 ·ULN (%) 0 0 0 0 0 0 1.1
AST
3·ULN (%) 9.4 6.3 6.5 2.8 1.8 2.9 6.7
5·ULN (%) 6.3 3.1 0 1.9 0.9 1.9 2.2
10 ·ULN (%) 3.1 3.1 0 0.9 0 0 0
N, number of patients; ALT, alanine aminotransferase; AST, aspartate aminotransferase;
ULN, upper limit of normal.
VTE prevention with LY517717 751
2007 International Society on Thrombosis and Haemostasis
should have put LY517717 at a disadvantage in terms of
efficacy, and perhaps at an advantage in terms of bleeding
[5,20]. However, postoperative administration of LY517717
proved to be safe and efficacious. In view of the increasing use
of spinal anesthesia, postoperative administration of anti-
thrombotic prophylaxis has potential advantages, particularly
in North America, where antithrombotic prophylaxis is rarely
given preoperatively.
A modified dose-escalation design was used, taking advant-
age of two interim analyses and the continuous monitoring of
study outcomes by the assessment committee chair. This design
has the advantages of minimizing the number of patients
exposed to non-efficacious doses and of maximizing the
number of patients allocated to the efficacious doses. This
allowed evaluation and early discontinuation of ineffective
doses while minimizing the risk of exposure to doses that might
be associated with excessive bleeding. In fact, the three lower-
dose arms of LY517717 were discontinued on the basis of a
lack of efficacy as documented by adjudicated venography. No
dose arm had to be prematurely stopped because of excessive
bleeding.
Population drift is a potential limitation of any dose
escalation study. This can also occur with the partially parallel
modified dose-escalation design utilized in this study, and the
possibility of drift in the rate of VTE over time should be
considered when interpreting the data. In order to assess this
risk, enoxaparin VTE rates over time were assessed, and no
statistically significant changes were observed (data not
shown).
As in the large majority of proof-of-concept studies on the
prevention of VTE after major orthopedic surgery, the
experimental design of our study included a 6–10-day period
of treatment [5,8,11,15,21]. Given the current trend in favor of
extended prophylaxis following THR, the clinical benefit seen
in this study should be confirmed in studies including 4–
6 weeks of study drug administration following THR [5,19,21–
23]. Currently available prophylactic agents include LMWHs
and fondaparinux, which require s.c. injection, and warfarin,
which requires laboratory monitoring. Because LY517717 is
suitable for oral administration, perhaps without the need for
laboratory monitoring, it has the potential to simplify extended
prophylaxis in high-risk patients.
The low rate of bleeding events seen in this study raises
the possibility of under-reporting of this event. However,
several other objective measures of bleeding were evaluated,
including the proportion of patients requiring transfusion,
volume of transfusion, change in Hgb, and bleeding index.
These assessments were consistent with the results for
clinical bleeding events, and support the conclusion that
LY517717 was not associated with greater blood loss than
enoxaparin.
There was no evidence or signal of liver toxicity when
LY517717 was administered over a period of 6–10 days. The
short duration of therapy limits the interpretation of the liver
toxicity data obtained in this study. Liver toxicity should be
carefully evaluated in studies with longer durations of
LY517717 administration.
In conclusion, this phase II proof-of-concept study demon-
strated the safety and efficacy of LY517717 for the prevention
of VTE following THR or TKR in comparison to enoxaparin,
the current standard of care in many institutions. Effective and
safe doses of LY517717 were identified. LY517717 deserves
further evaluation in studies on the prevention of VTE after
major orthopedic surgery as well as in other clinical indications
requiring prolonged anticoagulant therapy.
Study group members and participating research centers
Australia: R. Baker (Perth), A. Gallus (Adelaide), M.
Horsley (Camperdown), and H. Salem (Melbourne). Austria:
J. Grohs (Vienna), J. Hochreiter (Linz), H. Niessner (Wr.
Neustadt), and R. Windhager (Graz). Belgium: P.-P. Caste-
leyn (Brussels). Czech Republic: R. Ditmar (Olomouc), R.
Kasparek (Ostrava-Poruba), I. Kofranek (Prague), M. Krbec
(Brno), J. Kubes (Pardubice), and T. Trc (Prague). Germany:
A. Halder (Kremmen) and U. Hoffman (Mannheim).
Hungary: L. Bucsi (Sze
´kesfehe
´rva
´r), G. Do
´sa (Gyula), T.
Me
´sza
´ros (Szeged), and K. To
´th (Kecskeme
´t).Italy:P.Parise
(Gubbio), M. Silingardi (Reggio Emilia), and L. Spotorno
(Milano). Poland: J. Blacha (Lublin), J. Majewski (Piekary
Slaskie), T. Niedzwiedzki (Krakow), J. Skowronski (Bialy-
stok), M. Synder (Lodz), E. Szymkowiak (Bydgoszoz), and
A. Wall (Wroclaw).
Acknowledgements
We are grateful to the chairman of the independent central
adjudication committee C. Kearon, and to the other committee
members from the Henderson Research Center, McMaster
University, Hamilton, Ontario. We thank A. Bedding for his
input into the statistical design of the study. We thank F.
Niethard for his support in achieving regulatory approval of
this study in Germany.
Disclosure of Conflict of Interests
G. Agnelli, S. Haas and J.S. Ginsberg state that they have no
conflict of interest. K.A. Krueger, A. Dmitrienko and J.T.
Brandt are employees of Eli Lilly and Company and own stock
and hold stock options in Eli Lilly and Company.
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