Clinical trial NCT01573169
Conditions: Hemorrhagic Stroke Venous Thromboembolism Deep Venous Thrombosis
Keywords: hemorrhagic stroke venous thromboembolism prevention
Sponsor: University Of Perugia
Start date: 2012-05-01; Completion date: 2020-03-01
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with cerebral hemorrhage (ICH) have a high risk of venous thromboembolism. Intermittent pneumatic compression combined with elastic stockings have been shown to be superior to elastic stockings alone in reducing the rate of asymptomatic deep vein thrombosis after ICH in a randomized trial (4.7% vs. 15.9%). Graduated compression stockings alone are ineffective in preventing deep vein thrombosis in patients with ischemic or hemorrhagic stroke. Less clear is the role of anticoagulation in the prevention of venous thromboembolism in patients with ICH because the use of anticoagulants may cause an enlargement of the hematoma. In a multicenter, randomized trial, the investigators will assess the efficacy and safety of enoxaparin in the prevention of venous thromboembolism in patients with spontaneous intracerebral hemorrhage. Enoxaparin (40 mg once daily) or standard therapy (graduated compression stockings and/or intermittent pneumatic compression and/or early mobilization) will be given subcutaneously for not less than 10 days beginning after 72 hours from stroke onset.

Detailed description:

Arms: arm 1: enoxaparin 0.4 ml subcutaneous per day arm 2: Graduated compression stockings and/or intermittent pneumatic compression and/or early mobilization
Interventions: intervention 1: Enoxaparin intervention 2: Graduated compression stockings and/or intermittent pneumatic compression and/or early mobilization
Intervention descriptions: intervention 1: enoxaparin 0.4 ml sc per day for 10 days started 72 hours after the stroke intervention 2: placebo standard therapy

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
1 
COVER LETTER 
 
 
1st June, 2011 
 
PREVENTIHS STUDY 
PREvention of VENous Thromboembolism In Hemorrhagic Stroke patients 
 
NCT01573169


 
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PREVENTIHS STUDY 
PREvention of VENous Thromboembolism In Hemorrhagic Stroke patients 
 
Introduction 
Venous thromboembolism (VTE) is a common life-threatening complication in 
patients with stroke. In these patients, an average incidence of asymptomatic 
deep-vein thrombosis (DVT) of 50% has been reported (1). Additionally, 
pulmonary embolism (PE) has been reported to occur in 2% of patients with 
stroke (2) and 5% of early deaths after stroke is reported to be due to PE (3). 
Prospective trials have shown that both unfractionated heparin and low 
molecular weight heparin are effective in reducing VTE and PE in ischemic stroke 
patients (4). Current guidelines recommend the use of these agents in ischemic 
stroke patients with risk factors for VTE (5). The role of anticoagulants for the 
prevention of VTE in acute hemorrhagic stroke is uncertain and anticoagulant 
agents have not gained wide acceptance because of concern about possible 
increases in hematoma enlargement. To support this, a  recent meta-analysis  
has   indicated  that in patients with hemorrhagic stroke, early anticoagulation is 
associated with a significant reduction in PE and a non-significant reduction in 
mortality, with the trade-off of a non-significant increase in hematoma 
enlargement (6). These meta-analysis results cannot be reliably applied to clinical 
practice due to the low quality of the studies included. 
 
Objectives 
In this multicenter, randomized trial, the use of standard treatment alone 
(compression stockings and /or intermittent pneumatic compression and /or 
early mobilization) will be compared with the use of standard treatment plus the 


 
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administration of the low molecular weight heparin enoxaparin for the prevention 
of VTE in patients with acute hemorrhagic stroke. Enoxaparin will be started 
after 72 hours from stroke onset and will be continued for 10 days. The principal 
outcome measures will be symptomatic, objectively confirmed VTE or 
asymptomatic DVT (proximal and/or distal) as assessed by ultrasound 
examination. Because the use of anticoagulants in patients with hemorrhagic 
stroke could be associated with a high risk of re-bleeding, the safety of 
enoxaparin in this clinical setting will also be assessed. 
 
Methods 
Study population 
The study will be designed as a multicentre, prospective, randomised, open, 
blinded endpoint clinical trial. Consecutive bedridden patients (a score of 3 or 4 
per item 6 of the NIHSS or the impossibility to maintain  an upright position such 
as in the case of ataxia in patients with hemorrhagic cerebellar stroke) 18 years of 
age or older with primary intracerebral hemorrhage on CT scan or patients with 
intracranial hemorrhage during treatment with oral anticoagulants (after 
reversal), will be assessed for eligibility. 
Exclusion criteria will include: intracranial hemorrhage due to vascular 
malformation, bleeding disorders (defined by a prothrombin time more than 30% 
longer than the control value or a platelet count of less than 100,000 per cubic 
millimetre), renal failure defined as a clearance of creatinine  less than 30, severe 
hepatic failure, known neoplastic disease, pregnancy, necessity of therapeutic 
anticoagulant or antiplatelet agents for concomitant disease, participation in 


 
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other ongoing clinical trials or patient refusal to consent. The study protocol will 
be approved by  the local ethics committees of the participating hospitals. 
 
Study design and interventions   
Patients will be randomized 72 h after the onset of symptoms after having 
undergone a brain CT scan which will be considered the baseline examination. 
This CT must exclude a re-bleeding compared to the CT at admission. In the face 
of re-bleeding, patients will be excluded from randomization. Re-bleeding will be 
defined as an increase of 10% in the basal volume measured by standardized and 
validated criteria (9). 
Patients will be randomized over the phone using a random list of numbers 
(even numbers – treatment A; odd numbers – treatment B) to receive enoxaparin 
0.4 ml die plus standard therapy (group A) or standard therapy alone (group B).  
Treatment with enoxaparin is scheduled to last 10±2 days. A venous eco-Color-
Doppler examination with a compression test will be performed bilaterally on the 
lower limbs 10±2 days following the start of treatment. This exam will evaluate 
the following three points: the common femoral vein at the groin, superficial 
femoral vein at the mid-thigh and the popliteal vein at the popliteal fossa up until 
the trifurcation. 
Included patients will be visited on a daily basis during their hospital stay 
in order to monitor any complications as well as check for symptoms and signs of 
venous thromboembolism. An ultrasound exam of the lower limbs will be 
performed expediently on any patient having clinical signs of  suspected deep 
venous thrombosis. If this exam results being negative, the patient will undergo a 
second ultrasound exam according to the timetable set out in the protocol. An 


 
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ultrasound exam of the lower limbs and a CT thoracic angiography will be 
performed expediently on any patient having clinical signs of pulmonary 
embolism. If these exams result being negative, the patient will undergo a second 
ultrasound exam according to the timetable set out in the protocol. 
A positive result from either the CT thoracic angiography or an ultrasound 
exam will necessitate a treatment with heparin (unfractioned or at a low 
molecular weight), warfarin or vena cava filter according to clinical need. Brain 
CT scan will be performed 10±2 days from the start of treatment or whenever 
there is a worsening of the clinical condition, defined as an increase of 4 points or 
more on the NIHSS score. Treatment with heparin will be suspended whenever 
CT shows an increase of at least 10% in the volume of cerebral hemorrhage, 
notwithstanding clinical condition. Lesion volume will be measured with the 
methodology elaborated by Broderick et al. (9). Antithrombotic treatment different 
from that which is planned by the protocol during the treatment period will be 
forbidden except in the case of clinical need (i.e. diagnosis of venous 
thromboembolism). Follow-ups at 30 and 90 days after cerebral hemorrhage will 
be performed either in-clinic or over the phone in order to monitor for any clinical 
signs of venous thromboembolism or re-bleeding. All deaths will be recorded.  
The final follow-up, at 90 days, will be carried out over the phone by an 
independent physician blinded to the treatment received. After the treatment 
period outlined in the protocol (10±2 days), the treating physician will be able to 
determine future therapy.  
In the event of positive ecographs, patients can be treated with heparin 
(unfractioned or low molecular weight heparin), warfarin or vena cava filter, 
according to necessity. 


 
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Neuroradiological exams as well as pulmonary angio-CTs will be evaluated 
by the study coordinating centre (University of Perugia) blinded to the clinical 
condition of the patients. 
Venous thrombo-embolic and intra- and extra-cranial hemorrhagic events 
will be judged blindly on the type of treatment received by the following 
physicians from the University of Perugia: Giancarlo Agnelli, Andrea Alberti, 
Cecilia Becattini, Valeria Caso, Francesco Guercini e Michele Venti. 
The study will be divided into 3 sections: I. Patients 1-120; II. Patients 121-
240; III. Patients 241-406. 
Given the complexity of the study, a data safety monitoring board (DSMB) 
will be responsible for evaluating the progress of the study after the closure of 
section I. The second evaluation will performed by the DSMB after the closure of 
section II. The DSMB will be composed of three independent and external 
physicians, one of which is a statistician, to the coordinating centre:  Gualtiero 
Palareti, University of Bologna, Gian Paolo Reboldi, University of Perugia and 
Leandro Provinciali, University of Ancona. 
 
Risks of treatments and procedures. 
Risks include intra and extracranial hemorrhagic complications associated 
with heparin use and/or complications such as ulcers and subcutaneous 
hematomas due to the use of elastic stockings. There are no anticipated risks due 
to diagnostic procedures, given that all of the exams outlined in the protocol will  
be usually performed in clinical practice.  
 
 


 
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Risk-benefit evaluation 
Patients with ICH have a reported risk of ~ 20% for thromboembolic 
complications. The use of prophylactic heparin, where it has been tested on 
cancer, orthopedic and neurosurgery patients, has reduced the incidences of 
these events and their respective mortality rates and hospital stays. These studies 
have also reported an increase in ICH in patients treated with heparin compared 
to placebo. Whereas, at the end of follow-up, a net benefit, which was statistically 
significant, remained for those patients treated with heparin compared to those 
on placebo. 
 
End-points 
The primary endpoint of this study will be made up of either: 1) 
symptomatic venous thromboembolism objectively documented as 
proximal/distal DVT or pulmonary embolism or 2) asymptomatic proximal/distal 
DVT documented by ultrasound at the end of follow-up. Diagnostic criteria which 
has already been validated will be utilized (10). 
 
Secondary end-points: 
1. The number of symptomatic and asymptomatic intracranial bleedings as 
described above in Methods; 
2. The number of extracranial bleedings will be divided into two groups: major 
and minor. Major bleedings will be defined as 1) presence in critical organ 
sites including the retroperitoneal and intraocular spaces, 2) a reduction of 
2 or more gr/dL of hemoglobin or the need to carry out a transfusion of 2 
or more units of concentrate red blood cells or 3) fatal bleeding. Medical 


 
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intervention, including any interruption of study treatment, will be 
considered clinically relevant but not a major bleeding for all the events 
that do not satisfy the above described criteria. All other bleedings will be 
considered minor;  
3. The combined end-point of disability (modifed Rankin Scale ≥ 3) and 
mortality for any cause at 90 days;  
4. Mortality alone at 90 days. 
For each endpoint event, centres will be required to submit adequate 
documentation which will be evaluated by the Adjudication Committee. 
 
Statistical analysis 
The primary and secondary endpoints will be evaluated with an intention to 
treat analysis that will include all the randomized patients in both groups which 
will be treated or not, depending on the randomized group. Differences between 
the two groups will be calculated using  the Chi-square test. The odds ratio, as 
well as relative risk will be calculated with confidence intervals. All predefined 
endpoints will be assessed without adjusting for confounding factors. Post-hoc 
analysis (logistic regression) will be carried out, in the face off any possible un-
matching between the two groups, by adjusting for the confounding factors. 
Logistic regression analysis will be performed by including all the variables and 
then retaining those having a statistical significance of p<0.1.  
The same statistical analyses will be carried out on the per protocol 
population; that is, those patients that are randomized and assessed for type of 
treatment actually administered. 


 
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Sample size was calculated on the basis of an expected incidence of TVE 
equal to ~ 20% of non-treated patients, and ~ 10% of enoxaparin treated patients. 
Both groups will need approximately 203 patients each, in order to evidence a 
statistical difference of 50% with an alpha-value equal to 0.05 and a beta value of 
0.20. The study will be multi-centered with an expected 20 Italian centers 
participating over a 2-year enrollment period.  
 
Treatment of data 
Data results will be published within 12 months of the study’s termination. The 
principal investigator grants to every participating researcher the right to utilize 
all of the data and results for teaching and lecture purposes as well as scientific 
publications. 
 
Ethics 
The study will be carried out in accordance with the Helsinki and GCP 
declarations, as well as with local governing laws.  
 
References 
1. Davenport RJ, Tennis MS, Wellwood I, Warlow CP. Complications following 
acute stroke. Stroke 1996; 27: 415-420. 
2. Kelly J, Rudd A, Lewis R, Hunt BJ. Venous thromboembolism after acute 
stroke. Stroke 2001; 32: 262-267. 
3. Antiplatelets Trialist’s Collaboration. Collaborative overview of randomized 
trials of antiplatelet therapy (III). Reduction in venous thrombosis and 


 
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pulmonary embolism by antiplatelet prophylaxis among surgical and 
medical patients. BMJ 1994; 308: 235-246. 
4. Kamphuisen PW, Agnelli G. What is the optimal pharmacological 
prophylaxis for the prevention of deep venous thrombosis and pulmonary 
embolism in patients with acute ischemic stroke. Thromb Res 2006; May 2 
(epub ahead of print). 
5. Adams HP jr, Del Zoppo G, Alberts MJ et al. Guidelines for the early 
management of adults with ischemic stroke. Circulation 2007; 115: e478-
e534.  
6. Paciaroni M, Agnelli G, Venti M, Alberti A, Acciarresi M, Caso V. Efficacy 
and Safety of Anticoagulants in the prevention of venous thrombo-
embolismin in patients with acute cerebral hemorrhage. A Meta-Analysis of 
Controlled Studies. J Thromb Haemost. 2011 Feb 16 


 
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Informed Consent Form  
 
I, the underwritten  ………………………………………………………………….  
 
Born in …………………………………………………………………….. on …………………..……………… 
 
 
Express my desire to participate in the study entitled:  
“PREvention of VENous Thromboembolism In Hemorrhagic Stroke patients.  
Cod: PREVENTIHS STUDY  
 
With regard to this study, I have been informed of the following: 
 
1. The study has been approved by Regional Ethics Committee; 
2. The objectives and the potential side effects have been clearly explained by the 
investigators of the study,  
3. My consensus is valuntary; 
4. I am aware that the results of the study can be or not my favour;  
5. I have understood the possible side effects I could encounter. This has been clearly 
outlined in the accompanying leaflet, that I have read.   
6. I consent to the investigators any data collected on my clinical course regarding the 
disease for the purpose of this study. 
7. I comprehend that, although the results of the study are planned to be published, my 
name will never result.  
8. I understand that I can drop out of the study and/or suspend the prescribed treatment at 
any moment, without the risk of compromising any future treatments. 
9. For any issues that could be attributed to the prescribed treatment of the study, I can 
contact the following investigators: …………………………. at the telephone number………………; 
10. I consent/do not consent to inform my General Practitioner regarding my participation in 
this clinical trial.  
 
 
Name and Surname of the patient (or of the legal representative):  
printed …………………………….. 
 
 
Signature of the patient (or of the legal representative) 
………………………………               
 Date ………………... 
 
 
 
 
 


 
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I, Dr. ……………………………………………………………...…………., have thoroughly explained the project 
of the research and the type of procedure to follow. After having accepted my explanations, 
the patient expressed without prejudice his/her consent to participate in the study.  
 
 
      Signature …………………………………………………..       Date ………………. 
 
 


 
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Results 
The study was prematurely stopped after the randomization of 73 patients due to the low 
recruitment rate and the consequent inability to close the study in the anticipated time 
frame. The study was carried out between May 1, 2016, and March 30, 2020: thirty-eight 
patients were randomized in the enoxaparin group and 35 in the control group.  
The primary end point, any VTE at 10 days, was 15.8% (6/38 patients) in the enoxaparin 
group and 20.0% (7/35 patients) in the control group (ITT: adjusted RR 0.97 [95% CI 
0.26–3.57]). The secondary end point, the prevalence of DVT (proximal and distal) and PE 
at 90 days was 18.4% (7/38 patients) in the enoxaparin group and 25.7% (9/35 patients) 
in the control group (ITT: RR 0.72 [95% CI 0.30–1.72]). Overall, 1/38 of the enoxaparin 
(2.6%) and 3/35 of the standard therapy (8.6%) patients had severe bleedings (ITT: RR 
0.31 [95% CI 0.03–2.82]). Thirteen patients died during the 90-day study period: 7 in the 
enoxaparin group (18.4%) and 6 in the standard therapy group (17.1%) (ITT: RR 1.07 
[95% CI 0.40–2.89]). 
 
Full paper citation 
Paciaroni M, Agnelli G, Alberti A, Becattini C, Guercini F, Martini G, Tassi R, Marotta G, 
Venti M, Acciarresi M, Mosconi MG, Marcheselli S, Fratticci L, D'Amore C, Ageno W, 
Versino M, De Lodovici ML, Carimati F, Pezzini A, Padovani A, Corea F, Scoditti U, Denti 
L, Tassinari T, Silvestrelli G, Ciccone A, Caso V. PREvention of VENous 
Thromboembolism in Hemorrhagic Stroke Patients – PREVENTIHS Study: A Randomized 
Controlled Trial and a Systematic Review and Meta-Analysis. Eur Neurol. 2020 Nov 13:1-
10. doi: 10.1159/000511574. Epub ahead of print. PMID: 33190135.