www.thelancet.com/oncology Vol 10 October 2009 943
Nadroparin for the prevention of thromboembolic events
in ambulatory patients with metastatic or locally advanced
solid cancer receiving chemotherapy: a randomised,
placebo-controlled, double-blind study
Giancarlo Agnelli, Gualberto Gussoni, Carlo Bianchini, Melina Verso, Mario Mandalà, Luigi Cavanna, Sandro Barni, Roberto Labianca,
Franco Buzzi, Giovanni Scambia, Rodolfo Passalacqua, Sergio Ricci, Giampietro Gasparini, Vito Lorusso, Erminio Bonizzoni, Maurizio Tonato,
on behalf of the PROTECHT Investigators*
Background Clinical trials are needed to assess the clinical benefi t of antithrombotic prophylaxis in patients with
cancer who are receiving chemotherapy, since these patients are at an increased risk of developing a thromboembolism.
We did a trial to assess the clinical benefi t of the low-molecular-weight heparin nadroparin for the prophylaxis of
thromboembolic events in ambulatory patients receiving chemotherapy for metastatic or locally advanced solid
Methods Between October, 2003, and May, 2007, ambulatory patients with lung, gastrointestinal, pancreatic, breast,
ovarian, or head and neck cancer were randomly assigned in a double-blind manner to receive subcutaneous injections
of nadroparin (3800 IU anti-Xa once a day, n=779) or placebo (n=387), in a 2:1 ratio. Study treatment was given for the
duration of chemotherapy up to a maximum of 4 months. The primary study outcome was the composite of
symptomatic venous or arterial thromboembolic events, as assessed by an independent adjudication committee. All
randomised patients who received at least one dose of study treatment were included in the effi cacy and safety analyses
(modifi ed intention-to-treat population). The study is registered with ClinicalTrials.gov, NCT 00951574.
Findings 1150 patients were included in the primary effi cacy and safety analyses: 769 patients in the nadroparin group
and 381 patients in the placebo group. 15 (2·0%) of 769 patients treated with nadroparin and 15 (3·9%) of 381 patients
treated with placebo had a thromboembolic event (single-sided p=0·02). Five (0·7%) of 769 patients in the nadroparin
group and no patients in the placebo group had a major bleeding event (two-sided p=0·18). The incidences of minor
bleeding were 7·4% (57 of 769) with nadroparin and 7·9% (30 of 381) with placebo. There were 121 (15·7%) serious
adverse events in the nadroparin goup and 67 (17·6%) serious adverse events in the placebo group.
Interpretation Nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or
locally advanced cancer who are receiving chemotherapy. Future studies should focus on patients who are at a high
risk for thromboembolic events.
Funding Italfarmaco SpA, Milan, Italy.
Thromboembolic events are common in patients with
cancer,1,2 make patient management more complicated,
and are associated with increased mortality.3,4 Cancer cells
can promote the activation of blood coagulation directly
by generating thrombin, or indirectly by stimulating
endothelial cells and circulating mononuclear cells to
synthesise and express several procoagulant factors.5 The
risk of thromboembolic events in cancer patients varies
according to the type of malignancy and its disease stage,
and it is increased by surgical and non-surgical cancer
treatments.6 Cancer chemotherapy has been shown to both
amplify the prothrombotic eff ect of cancer cells5 and to
damage vessel walls directly, and is increasingly recognised
as a risk factor for thromboembolic complications.7,8
Thromboembolism is a frequent complication in
hospitalised and bedridden patients with cancer,9 but
fewer data are available for ambulatory patients with
cancer. A pivotal study by Levine and colleagues10 showed
warfarin prophylaxis was eff ective at reducing the risk of
thromboembolism in patients with advanced breast
cancer who were receiving chemotherapy. The clinical
benefi t was also assessed in patients with advanced lung
cancer.11 However, there is a paucity of evidence from
randomised studies regarding the clinical benefi t of
antithrombotic prophylaxis in patients with cancer who
are undergoing chemotherapy. Consequently, the most
recent guidelines of the American Society of Clinical
Oncology12 and the Conference on Antithrombotic
Therapy of the American College of Chest Physicians13
state that clinical trials are required before any
recommendations can be made about the use of
antithrombotic prophylaxis in ambulatory patients
receiving chemotherapy for cancer, although the
Lancet Oncol 2009; 10: 943–49
September 1, 2009
See Refl ection and Reaction
*For full list of investigators see
Internal and Vascular
University of Perugia, Perugia,
Italy (Prof G Agnelli MD,
M Verso MD); Protecht Clinical
Project Leader, Milan, Italy
(G Gussoni MD); Scientifi c
Milan, Italy (C Bianchini MD);
Medical Oncology Unit,
Oncology and Hematology
Department, Ospedali Riuniti,
(M Mandalà MD,
R Labianca MD); Hematology
and Oncology Department,
Piacenza, Italy (L Cavanna MD);
Department, Consorzio degli
Ospedali di Treviglio e
Caravaggio, Treviglio, Italy
(S Barni MD); Medical
Ospedaliera “S Maria”, Terni,
Italy (F Buzzi MD);
University, Rome, Italy
(Prof G Scambia MD); Medical
Azienda Istituti Ospitalieri,
(R Passalacqua MD); Oncology
Department, University of
Pisa, Pisa, Italy (S Ricci MD);
Oncology Department, San
Filippo Neri Hospital, Rome,
Italy (G Gasparini MD);
Ospedale “V Fazzi”, Lecce, Italy
(V Lorusso); Institute of
Medical Statistics and
Biometry, University of Milan,
www.thelancet.com/oncology Vol 10 October 2009
guidelines do recommend antithrombotic prophylaxis in
hospitalised and bedridden patients with cancer.
The PROTECHT (PROphylaxis of ThromboEmbolism
during CHemoTherapy) was a randomised, placebo-
controlled, multicentre study aimed at assessing the
effi cacy of the low-molecular-weight heparin nadroparin
for the prophylaxis of thromboembolic events in
ambulatory patients receiving
metastatic or locally advanced solid cancer.
Ambulatory patients older than 18 years of age who were
receiving chemotherapy for metastatic or locally advanced
lung, gastrointestinal (stomach, colon, or rectum),
pancreatic, breast, ovarian, or head and neck cancer were
recruited to the study at 62 centres across Italy between
October, 2003, and May, 2007.
Patients on adjuvant or neoadjuvant chemotherapy
were excluded from the study. Other exclusion criteria
were: objectively confi rmed venous or arterial thrombo-
embolism in the past 3 months; antithrombotic treatment
for any indication; life expectancy of less than 3 months;
Eastern Cooperative Oncology Group score greater
than 2; active bleeding or bleeding requiring
hospitalisation or transfusion or surgical intervention in
the past 4 weeks; intracranial bleeding in the past
6 months; high risk of bleeding (international normalised
ratio or activated partial thromboplastin time ratio
above 1·3, or platelet count lower than 50×10⁹/L); known
active gastric or duodenal ulcer; known cerebral
metastasis; severe and uncontrolled hypertension; renal
impairment (creatinine concentration >0·025 mg/mL);
substantial liver insuffi ciency; and known hypersensitivity
to heparin and derivates.
The study was done in accordance with the provisions
of the Declaration of Helsinki and local regulations. The
protocol was approved by the institutional review board
at each study centre, and written informed consent was
obtained from all patients before randomisation.
Eligible patients were randomly assigned to receive either
subcutaneous injections of nadroparin (3800 IU anti-Xa
once a day) or placebo in a 2:1 ratio. The 2:1 randomisation
ratio was chosen to minimise the number of patients
exposed to parenteral placebo. The dose of low-molecular-
weight heparin was chosen as recommended for the
prophylaxis of venous thrombo embolism in high-risk
Study treatment was started on the same day as
chemotherapy (the fi rst cycle or a new course), and was
given for the duration of chemotherapy or up to a
maximum of 120 days (±10 days). If the duration of
chemotherapy was less than 4 months, study treatment
was given after the last cycle of chemotherapy for a period
of time equal to the duration of the last cycle. Antiplatelet
agents, oral anticoagulants, fi brinolytic agents, un-
fractionated heparin or low-molecular-weight heparin
other than nadroparin were not allowed during the study
period. The administration of non-steroidal anti-
infl ammatory drugs was allowed with caution if considered
necessary, and was monitored closely. Paracetamol was
recommended as the fi rst step for analgesic or anti-
infl ammatory treatment. All concomitant therapies were
fully reported in case-report forms along with their daily
dosage, duration, and reason for administration.
The primary effi cacy outcome was the composite of
symptomatic deep-vein thrombosis of lower or upper
limbs, pulmonary embolism, visceral or cerebral venous
thrombosis, acute myocardial infarction, ischaemic
stroke, acute peripheral arterial thromboembolism, and
unexplained death of possible thromboembolic origin
occurring during the study treatment plus 10 days. The
secondary effi cacy outcomes were asymptomatic
thromboembolic events incidentally diagnosed, survival
at the end of study treatment and at 12 months, superfi cial
thrombophlebitis of the lower limbs, response to
chemotherapy and, for patients with central venous
catheters, central-venous-catheter-related complications
of possible thrombotic origin. In a subgroup of patients,
biological markers of activation of blood coagulation
were collected before and at the end of study treatment;
the results of these assays will be reported elsewhere.
Major bleeding that occurred between randomisation
and 48 h after the last injection of the study drug was the
main safety outcome. A bleeding event was defi ned as
major if it was fatal or clinically overt and associated with
a decrease in haemoglobin concentration of at least
0·02 g/mL over a 48-h period, or with transfusion of two
or more units of whole blood or red cells, or occurred in a
critical organ (brain, spine, pericardium, retroperitoneum,
or eye), or required an invasive intervention.14 All other
overt bleeding events were considered to be minor.
All study outcomes were assessed by a central
independent adjudication committee whose members
were unaware of patients’ study-group allocation. The
adjudication committee reviewed all cases of death that
occurred during the study period.
Patients were seen regularly at their scheduled
chemotherapy visits. Additional study visits were done at
the occurrence of clinically suspected thromboembolic
events. If patients had symptoms of venous or arterial
diagnostic work-up. Patients were followed up for survival
at 12 months after study inclusion.
A data and safety monitoring board was responsible for
the assessment of safety and effi cacy during the course of
this clinical trial. This was done at pre-specifi ed meetings
to review interim analyses.
underwent confi rmative
Randomisation and masking
The randomisation list was generated by an independent
statistician who used a standard permuted block of six
Milan, Italy (E Bonizzoni PhD);
and Regional Cancer Center,
Perugia, Italy (M Tonato MD)
Prof Giancarlo Agnelli, Internal
and Vascular Medicine—Stroke
Unit, University of Perugia,
www.thelancet.com/oncology Vol 10 October 2009 945
without stratifi cation. The list was generated with SAS
version 8.2. The allocation sequence was available online
to the investigators using the Hypernet web-based
system. At the time the investigator accessed the
web-based system with personal codes (user ID and
password) and requested the treatment allocation for a
new patient who fulfi lled the eligibility criteria, the
system assigned the next free number in accordance
with the randomisation sequence. Patients and
investigators did not know whether study drug or placebo
was being given, since pre-fi lled syringes were used
which were identical in appearance. Treatment
assignments were masked from all study personnel and
participants for the duration of the study. The planned
interim analysis was done by an independent data and
safety monitoring board to maintain the masking of
treatment assignments from the people involved in the
trial. For the fi nal analysis, the treatment code was
opened after the database was locked.
It was assumed that 8% of patients in the placebo group
would have a primary effi cacy outcome,7 compared with
4% of patients in the nadroparin group. Using the
one-sided Pampallona-Tsiatis group sequential design
with a shape parameter of 0, type I error rate of 0·05 and
type II error rate of 0·20, a total sample size of
1080 patients randomised in a 2:1 allocation ratio was
estimated, considering the normal approximation to the
binomial proportion (Z-pooled statistic), and two interim
analyses at a third and two-thirds of the total enrolment.15
At each interim analysis, the study could be stopped for
effi cacy or futility, as well as for safety issues. A sequential
design with predefi ned interim analyses was used to
minimise the exposure of patients to the parenteral
All randomised patients who received at least one dose
of the study treatment were included in the effi cacy and
safety analyses. The empirical error spending approach15
for both α and β spending was used to approximate the
planned Pampallona-Tsiatis boundaries during the
interim and fi nal analyses while allowing, under specifi ed
conditions, the accommodation of irregular or
unscheduled interim looks or the elimination of planned
analyses. Consistent with the sequential nature of the
trial, the stage-wise ordering approach was used to
compute the fi nal p-value and the point estimate of the
treatment diff erence with associated one-sided 95% CI at
the end of the study. Patients’ characteristics were
compared by means of the χ² test or the Student’s t test as
appropriate. Cumulative rates for thromboembolic events
were estimated by the Kaplan–Meier method. Secondary
effi cacy and safety analyses were performed only on the
fi nal study data set.
The software program East version 5.1 was used to plan
and perform the interim and fi nal analyses; SAS version
9.1 was used for all other analyses.
The study was registered at the Drug Agency (AIFA) of
the Italian Ministry of Health with the code DS/Sele/01,
May 2003. The study is registered at ClinicalTrials.gov,
Role of the funding source
The study was designed and supervised by a steering
committee. Data were collected and analysed by
Hyperphar Group, Milan, Italy. The sponsor gave advice
on the preparation of the protocol and the interpretation
of the results. The sponsor had no role in data collection
and data analysis. All authors had access to all data.
The corresponding author had fi nal responsibility for the
decision to submit the manuscript for publication.
Between October, 2003, and May, 2007, 1166 patients
were recruited to the study at 62 study centres in Italy.
1150 patients received at least one dose of the study
treatment and were included in the effi cacy and safety
analyses (fi gure 1). Patient characteristics, thrombo-
embolic risk factors, cancer site, and chemotherapy
regimens were well balanced between the two treatment
groups (tables 1 and 2).
The median duration of follow-up was 111 and 113 days
in the nadroparin and placebo groups, respectively.
766 (66·6%) of 1150 patients completed the study
treatment as defi ned by the protocol: 496 (64·5%)
of 769 patients in the nadroparin group and 270 (70·9%)
of 381 patients in the placebo group. The main reasons
for not completing the study are shown in fi gure 1.
1166 patients enrolled
779 assigned to nadroparin treatment
10 (1·3%) not treated
6 consent withdrawal
1 venous/arterial thromboembolism
1 protocol deviation
6 (1·6%) not treated
4 consent withdrawal
1 venous/arterial thromboembolism
1 protocol deviation
273 (35·5%) discontinued treatment
57 consent withdrawal
11 protocol deviation
12 lost to follow-up
101 adverse events
18 disease progression
15 best interest of patient
111 (29·1%) discontinued treatment
27 consent withdrawal
6 protocol deviation
5 lost to follow-up
33 adverse events
12 disease progression
4 best interest of patient
387 assigned to placebo
769 as treated population 381 as treated population
496 completed treatment270 completed treatment
Figure 1: Trial profi le
www.thelancet.com/oncology Vol 10 October 2009
Adverse events were the cause of not completing the
study in 13·1% (101 of 769 patients) and 8·7% (33 of 381
patients) in the nadroparin and placebo group,
Only one of the two planned interim analyses was done.
The second interim analysis was omitted because its
results would not have been available before the conclusion
of patient enrolment. For this reason, the steering
committee accepted the opportunity off ered by the fl exible
monitoring approach to spend all the remaining type I
and type II error rates in the fi nal analysis.
At the interim analysis, which was done with 394 patients,
the Z-pooled statistic comparing the nadroparin and
placebo groups was 1·80. This value crossed neither the
lower boundary for accepting the null hypothesis (–0·02),
nor the upper boundary for rejecting the null hypothesis
(2·74), so the trial was allowed to continue.
At the fi nal analysis, 15 of the 769 patients treated with
nadroparin (2·0%) and 15 of the 381 patients treated
with placebo (3·9%) were judged to have had a
thromboembolic event (table 3). The null hypothesis was
rejected as the fi nal Z score was 2·0, and therefore crossed
the upper boundary of 1·62 with a fi nal one-sided p value
of 0·02, point estimate of treatment diff erence of 2·00%
and associated one-sided 95% CI of 0·303%. The time
course of the thromboembolic events is shown in fi gure 2.
Venous thromboembolism accounted for 22 events, with
rates of 1·4% (11 of 769 patients) in the nadroparin group
and 2·9% (11 of 381 patients) in the placebo group,
respectively. Of note, 14 thromboembolic events occurred
in patients with lung cancer: 3·5% (seven of 199) in
patients treated with nadroparin and 8·8% (seven of 80)
in patients treated with placebo (one-sided p value=0·07
at post-hoc analysis.)
Six (0·8%) of 769 patients in the nadroparin group and
four (1·0%) of 381 patients in the placebo group were
incidentally diagnosed with an asymptomatic thrombo-
embolic event. These events were not counted in the
primary analysis. Superfi cial thrombophlebitis occurred
in 1·3% (10 of 769) of patients in the nadroparin group
and 1·6% (six of 381) of patients in the placebo group. No
diff erence was found in complete or partial response to
chemotherapy, which was reported in 20·5% (158 of 769)
of patients in the nadroparin group and 23·6% (90 of 381)
of patients in the placebo group. The proportion of
patients with a central venous catheter was 41·9%
(322 of 769) in the nadroparin group and 38·6% (147 of
381) in the placebo group (table 1). Among these patients,
central-venous-catheter-related complications of possible
throm botic origin occurred in 1·6% (fi ve of 322) of
patients in the nadroparin group and 2·0% (three of 147)
of patients in the placebo group.
Five of 769 patients in the nadroparin group (0·7%)
and none in the placebo group had major bleeding
(p=0·18, two-sided test). One 58-year-old man with
small-cell lung carcinoma developed haemoptysis and
died as a result; one 75-year-old man with head and neck
cancer developed melaena and recovered; one 68-year-old
man with lung adenocarcinoma developed haemoptysis
and recovered; one 74-year-old man with pancreatic
cancer developed melaena and recovered; and one
81-year-old woman with rectal cancer developed
intracranial bleeding and recovered. The incidence of
minor bleeding was similar in the two treatment groups:
77 events in 57 (7·4%) of 769 patients given nadroparin,
and 38 events in 30 (7·9%) of 381 patients given placebo.
A serious adverse event, comprehensive or major
bleeding, was reported in 121 (15·7%) of 769 patients
given nadroparin and 67 (17·6%) of 381 patients given
placebo. Serious adverse events were considered to be
Mean age (years; SD)
Mean body mass index (kg/m2; SD)
Recent cancer surgery*
Previous venous thromboembolism
Previous cancer surgery
Previous hormone therapy
Central venous catheter
Data are n (%) unless otherwise stated. *In the past 3 months. †At least 7 days in
the last 4 weeks.
Table 1: Baseline characteristics and risk factors for thromboembolic
events by treatment group
Head and neck
Anthracyclines (and related)
Nitrogen mustard analogues
Data are n (%).
Table 2: Cancer site and chemotherapy by treatment group
www.thelancet.com/oncology Vol 10 October 2009 947
related to the study treatment by the investigators in
1·2% (nine of 769) of patients given nadroparin and in
1·6% (six of 381) of patients given placebo (table 4).
33 (4·3%) of 769 patients in the nadroparin group and
16 (4·2%) of 381 patients in the placebo group had died
by the end of the study treatment. Overall, 48 of these
deaths were judged to be related to disease progression,
and one death in the nadroparin group to severe
haemoptysis in a patient with lung cancer. 1 year after
randomisation, 488 patients had died: 333 (43·3%) of
769 patients in the nadroparin group and 155 (40·7%)
of 381 patients in the placebo group.
This study shows that the low-molecular-weight heparin
nadroparin almost halves the absolute rate of thrombo-
embolic complications in ambulatory patients receiving
chemotherapy for cancer (from 3·9% to 2·0%). This
reduction in symptomatic outcomes is consistent with
reductions attributable to low-molecular-weight heparin
in the prevention of venous thromboembolism in several
other clinical settings.13 The antithrombotic eff ect was
most evident for deep-vein thrombosis and pulmonary
embolism, and was most apparent in patients with lung
or gastrointestinal cancer.
In this study, the event rate in untreated patients was
lower than expected compared with the rates seen in
observational studies.1,2 This might be explained by the
fact that this trial was designed in the absence of reliable
data on the incidence of thromboembolic events during
intervention studies in ambulatory patients receiving
chemotherapy. It is not uncommon to observe a lower
event rate in randomised clinical trials than in other
experimental settings.16 Most of the thromboembolic
events occurred in patients with lung and gastrointestinal
cancer, and the rate was unexpectedly low in patients
with breast and ovarian cancer. A recently developed
predictive model for chemotherapy-associated thrombosis
could be used to identify high-risk patients.17 Moreover,
the median treatment duration in our study was less than
4 months, which could have precluded the observation of
thromboembolic events that occurred after that period,
especially in some types of cancer.18,19
Although less common than venous thrombo-
embolism, the rate of arterial complications in cancer
patients is not negligible. For this reason, and for the
clinical relevance of arterial events, we included both
venous and arterial complications as study endpoints.
However, in our study the contribution of arterial events
to the overall rate of thromboembolism was limited,
possibly owing to the exclusion of patients chronically
receiving antithrombotic or anticoagulant treatments.
As a further fi nding, the proportion of patients with
central venous catheters and the rate of central-venous-
catheter-related thromboses were well balanced in the
two treatment groups, and therefore did not signifi cantly
aff ect study outcomes.
More patients who received nadroparin experienced a
major bleeding event than did those who received
placebo. However, the study was not powered to assess a
diff erence in the bleeding rate between the two treatment
groups. The rate of minor bleeding events was similar in
the two groups, and this is somewhat reassuring, as
minor bleeding is considered to be a surrogate for major
bleeding. Overall, the rate of bleeding was low and
Overall thromboembolic events
Visceral venous thrombosis
Stroke and peripheral thrombosis
Thromboembolic event by cancer site
Data are n (%).
Table 3: Thromboembolic events by treatment group and cancer site
Rate of thromboembolic events
0 3060 90
Figure 2: Cumulative hazard of thromboembolic events by treatment
Serious adverse events (SAE)
SAE related to investigational drug
Type of SAE*
Data are n (%). *Serious adverse events with an incidence of more than 0·5% in at
least one of the treatment groups were reported.
Table 4: Serious adverse events by treatment group
www.thelancet.com/oncology Vol 10 October 2009
consistent with that seen in other studies of long-term
prophylaxis comparing low-molecular-weight heparin
with placebo in patients with cancer.20,21
It has recently been claimed that low-molecular-weight
heparin can prolong survival in patients with cancer,22–26
but no eff ect on patient survival was noted here. This lack
of eff ect on survival could be due to several factors. First,
the duration of treatment in our study was shorter than
that of the trials focused on survival. Second, the dose of
low-molecular-weight heparin was lower than the doses
that have shown a favourable eff ect in terms of survival.
And third, this study included patients with metastatic or
locally advanced disease, whereas most of the benefi t from
low-molecular-weight heparin noted in the survival studies
has been seen in patients with less advanced disease.
Preventing thromboembolic complications in patients
with cancer has a substantial eff ect on patient care.
Thromboembolic events can cause the interruption of
chemotherapy and increase
Thromboembolic complications require anticoagulant
treatment that is particularly complicated in patients with
cancer. Additionally, the rate of recurrence and bleeding
is particularly high in patients with cancer and venous
To our knowledge, this is the fi rst study since the pivotal
trial of Levine and colleagues,10 published 15 years ago, to
show that antithrombotic prophylaxis during chemo-
therapy can have signifi cant favourable eff ects in
ambulatory patients with cancer. The study by Levine and
colleagues showed that warfarin had a clinical benefi t in
patients with advanced breast cancer. However, despite
that result, warfarin is not currently used for this
indication because treatment with this agent is
particularly problematic in patients with cancer due to
monitoring diffi culties and drug interaction.28 These
issues might be made easier to deal with by using a
This study supports the concept that thromboembolic
events can be prevented in ambulatory patients with
cancer receiving chemotherapy. This has potential
implications for future therapeutic scenarios. There is
increasing evidence that the new angiogenesis inhibitors
are associated with a particularly high risk of arterial and
venous thromboembolic complications.30–32 Furthermore,
the availability of new oral antithrombotic agents that do
not require monitoring and do not cause signifi cant drug
interactions could optimise our results by extending the
use and duration of antithrombotic prophylaxis, once
proved eff ective.
This study has several limitations. First, the duration of
study treatment might have been too short to fully explore
the clinical benefi t of antithrombotic prophylaxis. Ethical
concerns related to the use of a parenteral placebo were
the main reason for choosing 4 months as the maximum
study treatment duration. Furthermore, vascular mortality
did not seem to contribute to the composite study outcome.
This fi nding is not consistent with the concept that
vascular mortality is the second cause of death in patients
with cancer. Of note, patients in this study were ambulatory,
and most of them died at home from disease progression.
Therefore, the exact cause of death was diffi cult to assess.
However, this study also has several methodological
strengths. This was a double-blind and placebo-controlled
study that had confi rmed symptomatic clinical events as
study outcomes. Furthermore, all the study outcomes
were assessed by an independent adjudication committee,
whose members were unaware of the patients’ study
group allocation. Almost 99% of the randomised patients
were included in the effi cacy and safety analysis.
The heterogeneity of the study population concerning
the sites of cancer and the chemotherapy regimens could
be seen both as a limitation and a strength of the study.
On the one hand, this heterogeneity might have caused
the dilution of a benefi cial eff ect from antithrombotic
prophylaxis. On the other hand, the heterogeneity of
study population allowed the burden of thromboembolic
complications and the benefi t of the intervention in
diff erent types of cancer to be estimated.
In conclusion, nadroparin reduces the incidence of
thromboembolic events in ambulatory patients with
metastatic or locally advanced cancer receiving
chemotherapy. Future studies should focus on patients at
high risk for thromboembolism, such as patients with
lung cancer or patients identifi ed through the use of
scores that have recently been proposed to optimise
patient risk stratifi cation.17
GA, GG, CB, MV, EB, and MT were responsible for the design of the
study. EB planned and reviewed the statistical analysis. All authors
contributed to the writing of the paper and vouch for the accuracy and
completeness of the data and analysis.
Confl icts of interest
CB is the scientifi c director of Italfarmaco. All other authors declared
that they had no confl icts of interest.
We are indebted to Katherine Brandt for her editorial assistance; to
colleagues at Hyperphar Group, Milan, Italy; to the nursing staff of the
participating study centres for their enthusiastic cooperation; and to the
patients included in the study for their trust and support.
1 Blom JW, Vanderschoot JP, Oostindiër MJ, et al. Incidence of
venous thrombosis in a large cohort of 66329 cancer patients:
results of a record linkage study. J Thromb Haemost 2006; 4: 529–35.
2 Chew HK, Wun T, Harvey D, et al. Incidence of venous
thromboembolism and its eff ect on survival among patients with
common cancers. Arch Intern Med 2006; 166: 458–64.
3 Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of
cancers associated with venous thromboembolism. N Engl J Med
2000; 343: 1846–50.
4 Stein PD, Beemath A, Meyers FA, Kayali F, Skaf E, Olson RE.
Pulmonary embolism as a cause of death in patients who died with
cancer. Am J Med 2006; 119: 163–65.
5 Bick RL. Cancer-associated thrombosis. N Engl J Med 2003;
6 Falanga A. The incidence and risk of venous thromboembolism
associated with cancer and non-surgical treatment. Cancer Invest
2009; 27: 472–73.
7 Otten HM, Mathijssen J, ten Cate H, et al. Symptomatic venous
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