A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment
A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment
Seth Woodruff 0 1
Guillaume Feuge`re 0 1
Paula Abreu 0 1
Joseph Heissler 0 1
Marcia T. Ruiz 0 1
Frank Jen 0 1
0 Pfizer Inc , Kirkland, QC , Canada
1 & Seth Woodruff
Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of C6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance \60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for C5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced C1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal
Dalteparin; Low-molecular-weight heparin; Renal impairment; Thromboembolism; Vitamin K antagonist
Pfizer Inc, New York, NY, USA
renal function; however, anti-Xa monitoring could be
considered to further support safety in selected patients,
particularly those with very severe renal impairment.
Introduction
Patients with cancer experience a higher incidence of
venous thromboembolism (VTE; acute deep vein
thrombosis [DVT] and/or pulmonary embolism [PE]) than those
without cancer, ranging from 3.8–30.7 % [
1
], depending on
the cancer site [
2–4
], stage and grade [
5, 6
]. The risk of
VTE is partly attributable to the hypercoagulable state
induced by the cancer itself [4], and also can be
significantly increased by use of cancer interventions such as
chemotherapy, surgery, radiotherapy, hormonal therapy
and other targeted therapies [
4, 7–9
]. Therefore, patients
with cancer exhibit up to a sixfold higher risk of VTE than
those without cancer, particularly in patients with advanced
disease, hematological malignancies and certain types of
solid tumors, e.g. lung, brain and gastrointestinal tract [4].
Risk of VTE is highest following the cancer diagnosis and
when distant metastasis has occurred [
3
]. Development of
VTE in patients with cancer is associated with poor
prognosis and decreased survival [
4, 10
].
Standard treatment for VTE in patients with cancer is
long-term anticoagulant therapy [
9, 11, 12
]. Previously, this
included initial intravenous unfractionated heparin (UFH)
or initial subcutaneous high-dose low-molecular-weight
heparin (LMWH) overlapped and followed by an oral
vitamin K antagonist (VKA) administered for [3 months
[
13
]. However, dosing of VKA therapy requires
inconvenient, close laboratory monitoring [
14
], and VTE
recurrence rates in patients with cancer receiving this treatment
regimen are higher than in patients without cancer [
15
]. Use
of VKAs to treat VTE in patients with cancer also has
proved challenging because of patient nausea, vomiting and
anorexia, drug–drug interactions, poor venous access,
bleeding complications and difficulty in maintaining the
international normalized ratio (INR) within the targeted
therapeutic range [
9
].
Because of the insufficiencies associated with VKA
treatment, the CLOT study compared 6-month treatment
with dalteparin, a unique LMWH with mean molecular
weight of 6000 daltons, with initial dalteparin overlapped
with and followed by 6 months of VKA for both the acute
treatment and secondary prophylaxis of VTE in patients
diagnosed with cancer and symptomatic proximal DVT and/
or PE [
16
]. In summary, the results of the study showed a
52 % relative risk reduction of VTE recurrence over
6 months in the dalteparin-only arm compared with the VKA
arm (p = 0.002); no significant differences were observed
between groups in the incidence of major or minor bleeding
events. Furthermore, the risk ratio of dalteparin to VKA for
recurrent VTE (rVTE) remained statistically significant in
favor of dalteparin when the model was adjusted for other
factors found to be prognostic for VTE outcome (including
extent and type of tumor). Since the publication of the CLOT
study results, international guidelines have recommended
long-term treatment with high-dose LMWH (C6 months) as
standard care for the acute treatment and secondary
prophylaxis of VTE in patients with cancer [
9, 11, 17
].
Many patients with cancer also suffer from renal
impairment, which is clinically relevant because reduced renal
function can cause abnormalities in hemostasis, thereby
increasing the patient’s prothrombotic tendency and bleeding
risk [
18
]. In a French observational study of 4684 patients with
varying types of cancer, a majority (57.4 %) of patients had
abnormal creatinine clearance (CrCl; defined as\90 ml/min),
of which 37.6, 18.5 and 1.3 % had a CrCl of 60–89, 30–59 or
\30 ml/min, respectively [
19
]. Of note, in clinical practice,
the frequency of renal impairment in patients with cancer can
be underestimated if the diagnosis is based on serum
creatinine (SrCr) levels [
19
]. An observational study of patients
with cancer carried out at two French institutions reported that
while 29/316 (9.2 %) patients showed elevated SrCr levels
[
20
], 23 % of patients with normal SrCr (\110 lmol/l) had a
CrCl of \80 ml/min, with evidence of impaired renal
function. In addition to baseline renal impairment, cancer
treatment itself can lead to, or worsen, renal impairment because
such therapies can be nephrotoxic, particularly when used
sequentially or in combination [
21
].
Reduced renal function also can impact the clinical
outcomes of patients treated with anticoagulants because
renal impairment can limit the elimination of these agents,
potentially leading to bioaccumulation, and therefore, to
adverse bleeding events. Of note, because of different
pharmacokinetic profiles, the risk of bioaccumulation
differs between classes of agents and between agents within
the same class (e.g. LMWHs) [
22
]. For example, while
UFH is cleared in a dose-dependent manner by the hepatic
reticuloendothelial system, LMWHs primarily undergo
renal elimination [
23
]. As a result, depending on dose and
duration of treatment, LMWHs, as a class, which include
bemiparin, dalteparin, danaparoid, enoxaparin, nadroparin
and tinzaparin, can accumulate in patients with reduced
renal function more than UFH [
14, 22, 23
]. However,
LMWHs with higher mean molecular weights (e.g.
dalteparin or tinzaparin—which was removed from the US
market in 2011) undergo less renal (and more hepatic)
elimination than LMWHs with lower mean molecular
weights (e.g. bemiparin, enoxaparin or nadroparin). As a
result, the risk of bioaccumulation of dalteparin or
tinzaparin in patients with renal impairment is lower than that of
LMWHs with lower mean molecular weights [
24, 25
].
Standard treatment for VTE in patients with cancer is
long-term therapy with a LMWH. However, many of these
patients have, or will develop, renal impairment, thereby
increasing the risk of anticoagulant bioaccumulation that
could lead to life-threatening adverse bleeding events.
Because the risk of bioaccumulation owing to renal
impairment differs significantly between LMWH agents,
there is a critical need to have prospective published
evidence on long-term use of specific LMWHs in patients
with cancer, VTE and renal impairment to help guide
treatment choices. The current analysis aims to address that
gap for dalteparin. The exclusion criterion for the CLOT
trial related to renal function was SrCr level [39 the upper
limit of normal (ULN; 3.6 mg/dl). Consequently, a
significant number of patients with some degree of renal
impairment, as defined by CrCl, were enrolled in the study.
In this post hoc subanalysis of CLOT, we evaluated the
efficacy and safety of long-term high-dose dalteparin
(therapeutic doses of 150–200 IU/kg/d as opposed to low
prophylactic doses of 2500–5000 IU/d used for primary
VTE prophylaxis) versus VKA in patients with cancer,
VTE and normal/mild (CrCl C 60 ml/min), moderate
(30 B CrCl \ 60 ml/min) or severe (CrCl \ 30 ml/min)
renal impairment at baseline.
Methods
Study design and population
CLOT was an international, multicenter, open-label,
randomized clinical trial of 676 patients presenting with
cancer and VTE. A detailed description of the study design,
population, treatment regimens and outcome measures has
previously been published [
16
].
Per protocol, patients underwent 6-month treatment with
dalteparin alone, or initial dalteparin overlapped with and
followed by a VKA (i.e. warfarin or acenocoumarol).
Those patients randomly assigned to dalteparin received
once-daily subcutaneous injections of dalteparin 200 IU/kg
(maximum daily dose 18,000 IU) for 1 month, followed by
injections of *150 IU/kg for the remaining 5 months.
Those in the VKA group received once-daily VKA for
6 months, with initial overlapping subcutaneous dalteparin
200 IU/kg once daily for C5 days until INR was 2.0–3.0
for 2 consecutive days. Thereafter, laboratory monitoring
of the INR was performed at each clinical assessment, once
every 2 weeks or more frequently when clinically
indicated, to adjust the oral anticoagulant dose. The INR level
in the oral anticoagulant group was measured frequently to
enhance the likelihood that patients were adequately
treated. Using linear interpolation over time, it was estimated
that the INR was in the therapeutic range 46 % of the time,
below the range 30 % of the time, and above the range
24 % of the time.
Dose modification, including temporary interruption of
treatment, was permitted when clinically indicated (i.e. if
patients experienced transient thrombocytopenia or
significant renal impairment: defined as SrCr level [39 ULN).
Full dose was then reinstated once it could be resumed
safely. In patients treated with dalteparin who developed
significant renal impairment, the treatment dose was
adjusted to maintain an anti-Xa therapeutic level of 1 IU/ml
(range 0.5–1.5 IU/ml). If the steady-state anti-Xa level,
measured 4–6 h after the last dalteparin injection, was below
or above the therapeutic range, the dalteparin dose was
altered by switching to the next highest or lowest prefilled
syringe formulation dose, respectively—dalteparin was
supplied as 1 mL single-dose syringes containing 5000,
7500, 10,000, 12,500, 15,000 or 18,000 IU anti-factor
Xa—and the anti-Xa measurement was repeated after 3–4
new doses. This dose adjustment was repeated until the
target anti-Xa therapeutic level was achieved. For those
patients developing significant renal impairment while
receiving VKA, no dose adjustment was made. During
scheduled clinical assessments at baseline, days 7–10 and
months 1, 3 and 6, blood samples were taken for CrCl
measurements, and used to assess changes in renal function
status over the course of the study.
The present post hoc analysis divided patients enrolled
in CLOT into subgroups of those with normal renal
function (CrCl C 60 ml/min), and those with renal impairment
at baseline, (CrCl \ 60 ml/min), calculated using the
Cockcroft–Gault formula [
26
]. For this analysis, patients
with renal impairment were further classified as having
either moderate (30 B CrCl \ 60 ml/min) or severe renal
impairment (CrCl \ 30 ml/min). Patients with normal
renal function at baseline who developed renal impairment
during the course of CLOT were excluded from this
analysis.
Outcome measures
The primary efficacy outcome was the rate of rVTE (i.e.
the first episode of objectively documented, symptomatic,
recurrent DVT or PE) in the intention-to-treat population.
Secondary safety outcomes included clinically overt
bleeding (any and major) and death in the as-treated
population. Diagnostic criteria for rVTE and bleeding events
have been described in detail elsewhere [
16
]. Briefly, rVTE
was defined by ultrasonography or venography outcomes,
and bleeding event severity was determined by its
association with death, the site at which it occurred, requirements
for blood transfusion, and impact on hemoglobin level
[
16
].
Statistical analysis
Baseline demographic and clinical characteristics of
patients with renal impairment at study entry were
summarized in frequency tables, with descriptive statistics used
for quantitative variables. VTE recurrence and bleeding
events were summarized by both frequency and proportion.
A two-sided log-rank test was used to compare treatment
effects of dalteparin and VKA on the risk of VTE
recurrence and bleeding events. Significance was set at the 5 %
level, and hazard ratios (HRs) and 95 % confidence
intervals (CIs) were provided. Cox proportional hazard
regression models were used to assess treatment effects on
events.
Descriptive statistics and graphics were used to
summarize changes in CrCl from baseline to lowest level
during treatment, as well as any change in dalteparin
dosing.
Results
Study population
Baseline demographic and clinical characteristics of
patients stratified by renal function and treatment group are
shown in Table 1. Overall, 162/676 (24 %) of patients in
CLOT had renal impairment at baseline (dalteparin arm,
74; VKA arm, 88). Most of these patients had moderate
impairment (dalteparin, 65/74 [88 %]; VKA, 82/88
[93 %]); only a small number of patients had severe renal
impairment (dalteparin, 9/74 [12 %]; VKA, 6/88 [7 %]).
Patients with renal impairment tended to be older and
female, and weighed less than those with normal renal
function; however, differences in these variables were
anticipated because in addition to SrCr, they were used to
calculate CrCl and therefore to determine patient renal
function. Patients with renal impairment were well
matched for age, body weight, SrCr and CrCl between the two
treatment arms. Most patients had an Eastern Cooperative
Oncology Group status score of 1 or 2, with the distribution
of status scores being comparable among the four
subgroups. An additional 91 patients in CLOT developed renal
impairment at some point during treatment but were not
included in this analysis.
Dosing and treatment duration
A summary of the average dalteparin dose administered to
patients in each of the three renal function subgroups
during month 1 and months 2–6 is presented in Fig. 1. As
shown, the distributions of the received dalteparin doses
were comparable between renal function subgroups during
months 2–6, with median doses near the dose levels
prespecified in the protocol and no differences between
subgroups. Irrespective of renal function at baseline, the
majority ([84 %) of patients received dalteparin at C90 %
of the prescribed levels. During month 1, the mean doses
received by patients with normal renal function, moderate
renal impairment and severe renal impairment were: 190.6,
196.0 and 193.3 IU/kg, respectively; during months 2–6,
the mean doses were 160.3, 157.2 and 159.5 IU/kg,
respectively. Each of these six mean doses was within the
5 % range of the dosages specified in the CLOT study
treatment protocol.
Distribution of dalteparin doses seen in patients with
renal impairment was similar to that for patients with
normal renal function, i.e. there was no systematic
reduction of dalteparin dosage in patients with renal impairment
(including patients with severe impairment). Among the 74
dalteparin-treated patients with renal insufficiency at
baseline, only 1 patient had a temporary dose reduction
owing to increased anti-Xa levels. Similarly, of the 91/676
(13 %) patients in CLOT who developed renal impairment
during the course of the study, 2/91 (2 %) had dose
reductions owing to increased anti-Xa levels.
VTE recurrence
Overall, 2/74 (2.7 %) dalteparin-treated patients with renal
impairment (moderate impairment, 2) and 15/88 (17.0 %)
VKA-treated patients with renal impairment (moderate
impairment, 14; severe impairment, 1) in the
intention-totreat population, experienced C1 adjudicated symptomatic
rVTE during the 6-month study period (cox proportional
hazard model: HR [95 % CI], 0.15 [0.03–0.65] in favor of
dalteparin; p = 0.01; Table 2). A Kaplan–Meier curve
showing time to first rVTE during the 6-month study
period for patients with renal impairment is presented in Fig. 2
(p value calculated using log-rank test).
Cox proportional hazard models were used to evaluate
the potential influence of baseline renal function on the
likelihood of VTE recurrence. Specifically, both numerical
CrCl values and a derived indicator variable (based on a
CrCl less than or greater than 60 ml/min) were used as
renal function indices and as possible explanatory variables
in two Cox models calculated with or without prognostic
variables. Prognostic variables included extent of tumor
(nonmetastatic vs. metastatic), type of tumor
(gastrointestinal vs. breast, lung vs. breast, genitourinary vs. breast,
hematological vs. breast, other vs. breast), current smoking
status (smoker vs. nonsmoker) and age at study entry.
Neither the numerical CrCl value nor the derived indicator
value was found in either Cox model to influence the
treatment effect of dalteparin versus VKA on VTE
recurrence.
Bleeding events
First instances of any bleeding or major bleeding were
determined in the as-treated population according to
treatment and renal function status (Tables 2, 3).
Dalteparin
VKA
0
25
Patients at risk, n (events)
Dalteparin 74 (1) 70 (1)
VKA 88 (9) 76 (3)
50
The proportion of patients with renal impairment at
baseline in the as-treated population experiencing C1 bleeding
episode was higher in the VKA treatment arm than in the
dalteparin treatment arm (21/87 [24.1 %] vs. 15/74
[20.3 %]; Table 2); however, the between-group difference
in cumulative probability of any bleeding event was not
statistically significant (p = 0.47).
The rate of any bleeding increased as renal function
declined in both treatment groups (Table 3). Among
astreated patients with moderate renal impairment, bleeding
events were experienced by 10/65 (15.4 %) of those treated
with dalteparin and 18/81 (22.2 %) of those treated with
VKA. In patients with severe renal impairment, bleeding
events were experienced by 5/9 (55.6 %) of those receiving
dalteparin and 3/6 (50.0 %) of those receiving VKA.
Major bleeding
Dalteparin was associated with a numerically higher
incidence of C1 adjudicated major bleeding event compared
with VKA, but the between-group difference in cumulative
probability of such an event was not statistically significant
(p = 0.65; Table 2). Specifically, incidence of a major
bleeding event in as-treated patients with moderate renal
impairment was 5/65 (7.7 %) in patients treated with
dalteparin and 5/81 (6.2 %) in patients treated with VKA.
Incidence of major bleeding events in as-treated patients
with severe renal impairment was 2/9 (22.2 %) with
dalteparin and 1/6 (16.7 %) with VKA (Table 3); there were
few major bleeding events seen in patients with moderate
or severe renal impairment in either treatment group.
Death rates
The overall death rate among patients with renal
impairment during the 6-month study period was 79/162
(48.8 %). The death rate in dalteparin-treated patients was
36/74 (48.6 %) and was 43/88 (48.9 %) in VKA-treated
patients.
Change in renal function status
Change in renal function status during treatment in the
intention-to-treat population is summarized in Table 4.
Results indicate that 79 % of patients treated with
dalteparin and 75 % of patients treated with VKA who had
normal renal function at baseline maintained this status
during the treatment period, while 75 % of
dalteparintreated patients and 79 % of VKA-treated patients with
moderate renal impairment at baseline either maintained or
improved their renal function during the treatment period
(Table 4).
CrCl at baseline and at its lowest point during treatment
is shown for the intention-to-treat population in Fig. 3.
VTE venous thromboembolism, CrCl creatinine clearance, VKA vitamin K antagonist, ITT intention-to-treat, AST as-treated
a Normal: CrCl C 60 ml/min; moderate impairment: 30 B CrCl \ 60 ml/min; severe impairment: CrCl \ 30 ml/min
b ITT population
c AST population, 3 patients less
Most measured CrCl values were below the line of identity
and the slopes of the regression lines were \1, indicating
that most patients with or without renal impairment at
baseline experienced a decrease in CrCl level during
treatment. However, this change in CrCl was not
sufficiently large enough to change the classification of renal
function (e.g. normal, moderate impairment, severe
impairment) assigned to most patients. The regression lines
for dalteparin and VKA were similar, thereby indicating
that change in renal function was comparable between
treatment groups and that stability of renal function over
the course of the study was similar.
Discussion
In this post hoc analysis of prespecified endpoints, patients
with cancer who had both acute VTE and impaired renal
function at baseline demonstrated an 86.5 % relative risk
reduction of developing rVTE when treated with dalteparin
versus VKA. In the dalteparin arm, VTE recurrence event
rates decreased as baseline renal function declined from
normal to moderate or severe (although the number of
patients in the severe group was small), while VTE
recurrence event rates remained stable as renal function
declined in the VKA arm. In both treatment groups, rates of
ITT intention-to-treat, CrCl creatinine clearance, VKA vitamin K antagonist
a Normal: CrCl C 60 ml/min; moderate impairment: 30 B CrCl \ 60 ml/min; severe impairment: CrCl \ 30 ml/min
CrCl missing
Normal
Moderate impairment
Severe impairment
)
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100
150
200
250
Baseline CrCl (ml/min)
Fig. 3 Lowest creatinine clearance (CrCl) during treatment versus
baseline CrCl in patients given dalteparin (F) or vitamin K antagonist
(VKA [O]; intention-to-treat population). The solid black diagonal
line is the line of identity (y = x). Linear regression lines, i.e. the
solid blue diagonal line for patients receiving VKA and the solid red
diagonal line for those receiving dalteparin, have been added to
indicate trends. The black dashed lines signify CrCl 30 ml/min and
CrCl 60 ml/min
any bleeding were higher in patients with renal impairment
(moderate or severe) than in patients with normal renal
function, respectively (20.3 and 11.8 % for dalteparin; 24.1
and 16.5 % for VKA).
Overall, the post hoc efficacy findings in patients with
moderate and severe renal impairment were consistent with
those described for the full CLOT study population where
dalteparin reduced the cumulative risk of rVTE at
6 months by 52 % versus VKA, without increasing risk of
bleeding [
16
]. In general, safety findings were similar
between patients with renal impairment and those
comprising the entire CLOT study population. Namely, there
were no significant differences in rates of any bleeding
event or major bleeding events between dalteparin and
VKA treatment groups [
16
]. A higher death rate of 49 %
was observed among patients with renal impairment,
compared with 40 % among all patients in CLOT.
Comparable safety findings were recently reported for
dalteparin from the DALTECAN study, a single-arm
12-month safety study modeled after CLOT that also
included patients with renal impairment [
27
].
Another large randomized trial modeled after CLOT but
evaluating a different LMWH (tinzaparin) versus VKA,
also was recently published [
28
]. In this study, known as
CATCH, 900 patients with active cancer and VTE were
randomized to tinzaparin 175 IU/kg once daily for
6 months or to tinzaparin 175 IU/kg once daily for
5–10 days followed by warfarin for 6 months [
28
].
Overall, in contrast to CLOT, the results reported no significant
reduction in a composite measure of rVTE, overall
mortality or major bleeding events following 6-month
treatment with tinzaparin [
28
]. A subanalysis of CATCH
directly investigated the impact of renal impairment on
rVTE or clinically relevant bleeding (CRB) incidences;
among 129 patients with CrCl \ 60 ml/min, 14 %
developed rVTE and 20 % had CRB. Of 733 patients with
normal renal function, 8 % developed rVTE, while 15 %
had CRB. For those patients with CrCl \ 60 ml/min, no
statistically significant differences were observed in rVTE
and CRB incidences between the tinzaparin and warfarin
treatment arms [
29
].
This post hoc analysis of CLOT and the subanalysis of
CATCH are the earliest studies reporting long-term 6-month
use of specific LMWHs to treat VTE in patients with active
cancer and renal impairment. These two analyses provide
evidence suggesting that both dalteparin and tinzaparin,
although different agents, have safety profiles similar to
VKA in this indication and patient cohort. In these two
studies, bleeding events were markedly increased when
anticoagulant treatment (LWMH or VKA) was administered
to patients with renal impairment (compared with patients
with normal renal function), but when LMWH treatment was
compared with VKA, there was no evidence of excess
bleeding (as would be expected should bioaccumulation be
occurring). Intriguingly, this post hoc analysis of CLOT
documented a larger and statistically significant reduction in
rVTE with dalteparin in renally impaired patients than was
previously demonstrated in the entire CLOT study
population. The subanalysis of CATCH, however, reported
similar rates of rVTE with tinzaparin and VKA in renally
impaired patients, and these rates are almost twofold higher
than observed in the entire CATCH study population. The
difference in efficacy observed between dalteparin and
tinzaparin versus VKA in this indication is unexplained and
could be due to chance, or because of differences in
pharmacodynamics that become clinically relevant in the
hypercoagulable state induced by cancer, and/or because of
study design variations.
In terms of dosing, the mean dalteparin dose received by
patients within the three renal subgroups (normal, moderate
impairment, severe impairment) fell within ±5 % of the
range specified in the CLOT study protocol. Specifically,
the protocol defined the month 1 dose to be 200 IU/kg per
day, an amount designed to provide therapeutic levels of
anticoagulation for acute VTE at a time when recurrence
rates are highest in patients with cancer [
15
]. To reduce
risk of bleeding complications during months 2–6, the dose
was reduced to approximately 75–83 % of the initial daily
dose (i.e. about 150 IU/kg per day), without regard to renal
function and in the absence of serum anti-Xa monitoring.
Dalteparin dose modification or interruption was, however,
permitted if patients experienced transient
thrombocytopenia or significant renal impairment. Importantly, we
found no systematic or widespread reduction of dalteparin
dosage in patients with renal impairment, even in those
with CrCl \ 30 ml/min. Indeed, elevated anti-Xa levels led
to a reduction in the dose of dalteparin in only 1/74 patients
enrolled with a baseline CrCl \ 60 ml/min.
Of note, not every hospital or clinic has ready access to
anti-Xa monitoring tests. Based on previously published
data, current American Society of Clinical Oncology
guidelines do advise that if anti-Xa monitoring is
unavailable for patients with moderate to severe renal impairment,
then UFH and VKAs are safer options for initial and
longterm treatment, respectively [
17
]. Similarly, current
National Comprehensive Cancer Network guidelines,
which highlight that only limited data are available to
support the clinical relevance of anti-Xa monitoring,
recommend generally limiting the use of LMWHs in patients
with renal insufficiency, rather than close monitoring [
30
].
Some limitations of this exploratory post hoc analysis
are evident. First, patients with SrCr [ 3.6 mg/dl were
excluded from CLOT, thus limiting enrollment of patients
with severe renal insufficiency. Indeed, only 15 patients
enrolled in the two treatment arms had severe renal
impairment (i.e. CrCl \ 30 ml/min). However, the
prevalence of severe renal insufficiency in patients with cancer
has been shown to be low [
19
]. Second, CLOT did not
stratify patients by the presence or severity of renal
impairment, nor was it powered to detect
between-treatment differences for most subgroups. However, a review of
baseline characteristics of patients with CrCl \ 60 ml/min
demonstrated reasonable comparability between the
dalteparin and VKA subgroups, thus permitting a statistical
analysis of the treatment effects of dalteparin versus VKA
on efficacy and safety endpoints in this subpopulation.
Despite these limitations, a review of currently available
published literature indicated that CLOT offered the largest
safety and efficacy database of patients with cancer and
renal impairment who were given long-term ([30 days)
VKA and LMWH therapy.
We omitted 91 patients from our statistical analyses who
developed renal impairment during the course of CLOT
because heterogeneity in the cause, duration and course of
renal function in patients who developed renal dysfunction
during the study would have invalidated comparisons
between patients with and without renal impairment. Those
patients who transitioned from normal to impaired renal
status were not a statistically well-defined subpopulation, i.e.
their status was based on an outcome (change in renal
function) that occurred at variable times during treatment.
Moreover, the combined population of patients with renal
impairment—those identified at baseline plus those who
became impaired during treatment—was not truly
randomized between treatment arms, further making any
comparisons statistically invalid.
Efficacy and safety data from this post hoc analysis
provide useful information to clinicians considering use of
dalteparin to prevent rVTE in patients with cancer and
renal impairment. However, the results cannot be
extrapolated to other LMWHs because the pharmacokinetic and
pharmacodynamic profiles of LMWHs clearly differ [
31
].
This reflects differences in manufacturing processes [
32
]
and also mean molecular weight [
24
], which is considered
to determine the extent to which LMWHs undergo renal
elimination [
25
].
Given the findings of the current analysis, a
pharmacoeconomic analysis is planned to test the hypothesis that
dalteparin may be both cost effective and cost saving when
used in patients with cancer and renal impairment. This
analysis builds on a study by Dranitsaris et al. that used
health care resource data collected during CLOT to conduct
a patient-level economic analysis from a Canadian health
care perspective. The investigators reported that secondary
prophylaxis with dalteparin as an alternative to VKA in
patients with cancer was economically attractive [
33
].
Conclusions
In this post hoc analysis of patients with active cancer and
acute VTE, high-dose long-term treatment with dalteparin
significantly reduced the risk of rVTE in patients with renal
impairment and had a comparable safety profile versus
VKA. These findings, which are specific for dalteparin, are
consistent with results reported previously from both the
full CLOT study [
16
], which evaluated clinical outcomes
with dalteparin and VKA in a large cohort of patients with
active cancer and VTE who were treated for 6 months, and
DALTECAN, a 12-month safety study [
27
].
No evidence emerged from this analysis to support
dosing of dalteparin in patients with renal impairment other
than with the dosages recommended in the CLOT study
protocol. Baseline renal impairment leading to elevated
anti-Xa levels was an exceptionally rare reason for dose
reduction during dalteparin treatment. However, bleeding
events were more common in the presence of renal
insufficiency, particularly in patients with severe renal
impairment. Therefore, in line with American College of Chest
Physicians recommendations, clinicians who select
dalteparin for the treatment of VTE in patients with cancer
and renal impairment should continue to consider
monitoring steady-state anti-Xa levels [
22
].
Acknowledgments This study was funded by Pfizer. Editorial
support for the development of this manuscript was provided by Tina
Morley, Michelle Jenvey, PhD, and Katy Beck, PhD, of Engage
Scientific Solutions and was funded by Pfizer. The authors wish to
thank the study investigators and study participants for their
assistance in conducting this study. They also would like to thank Liang
Chen, Anna Polli, Paul Glue, Rebecca Shi and Kannan Raghavan for
their contributions to manuscript development.
Compliance with ethical standards
Conflicts of interest Seth Woodruff, Guillaume Feuge`re, Paula
Abreu, Joseph Heissler, Marcia T. Ruiz and Frank Jen are full-time
employees of Pfizer and hold stock and/or stock options in Pfizer.
Ethical approval All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards.
Informed consent Informed consent was obtained from all
individual participants included in the study.
Animal rights statement This article does not contain any studies
with animals performed by any of the authors.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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