Fragile Patients With Venous Thromboembolism, What did We
Learn From RIETE
Eugenio
Bucherini, Luis Manuel Hernndez-Blasco, Carmen Fernndez-Capitn, Alicia Lorenzo,
Aurora Villalobos, Raimundo Tirado, Isabelle Mah, Jana Hirmerova, Paolo
Prandoni, Manuel Monreal, And the RIETE Investigators, A full list of the RIETE
investigators is given in the appendix
Eugenio Bucherini, MD, Department of
Vascular Medicine. Azienda U.S.L. Di Ravenna C O.C. Di Faenza. Ravenna.
Italy
Luis
Manuel Hernndez-Blasco, Md. PhD, Department Of
Pneumonology, Hospital General Universitario De Alicante, Alicante, Spain
Carmen
Fernndez-Capitn, MD, PhD, Department Of
Internal Medicine, Hospital Universitario La Paz, Madrid, Spain.
Alicia
Lorenzo, MD, PhD, Department Of Internal Medicine,
Hospital Universitario La Paz, Madrid, Spain.
Aurora Villalobos, MD, PhD, Department Of
Internal Medicine. Hospital Regional Universitario De
Mlaga. Mlaga. Spain.
Raimundo Tirado, MD, Department Of
Internal Medicine, Hospital Infanta Margarita, Crdoba, Spain.
Isabelle Mah, MD, PhD,
Department Of Internal Medicine. Hôpital Louis Mourier. University Paris 7 (Aphp). Colombes. France.
Jana
Hirmerova, MD, PhD, Department Of Internal Medicine,
University Hospital Plzen, Plzen, Czech Republic
Paolo
Prandoni, MD, PhD, Department Of
Clinical Medicine, University Of Padua, Padua, Italy
Manuel
Monreal, MD, PhD, Department Of Internal Medicine,
Hospital De Badalona Germans Trias I Pujol, Universidad Catlica De Murcia,
Spain
Correspondence to: Manuel Monreal,
Professor, MD, PhD, Servicio de
Medicina Interna. Hospital Universitari Germans Trias i Pujol, 08916 Badalona
(Barcelona), Spain.
Email: mmonreal.germanstrias@gencat.cat
Telephone: +34 669675313
Received: April 9,
2015
Revised: May 7, 2015
Accepted: May 12, 2015
Published online: July 6, 2015
ABSTRACT
In recent years, a
number of new anticoagulants have been developed for the treatment of venous
thromboembolism (VTE), demonstrating significant reductions in major bleeding
compared with standard therapy. Subgroup analyses showed favourable results for
rivaroxaban in the so-called fragile patients (defined as those having
creatinine clearance levels 50 mL/min, age 75 years or body weight 50 kg) compared with standard therapy. However, the prevalence of
fragile patients with VTE in real life and their natural history during the
course of anticoagulation has not been thoroughly investigated. We used the
RIETE registry database to assess the proportion of fragile patients with VTE outside
clinical trials, and their natural history during the course of anticoagulant
therapy. We found that 43% of patients with VTE were fragile: 37% were aged 75 years, 4.0% weighed 50 kg, and 25% had CrCl levels 50 mL/min. During the course of anticoagulant
therapy, the rate of major bleeding was over 2-fold higher in fragile- than in
non-fragile patients: 6.6 (95% CI: 6.2-7.0) vs 2.3 (95% CI: 2.1-2.5)
bleeds per 100 patient-years, and their recurrence rate was similar: 3.5 (95%
CI: 3.2-3.8) vs 4.0 (95% CI: 3.7-4.2), respectively. Moreover, the rate
of fatal bleeding was over 4-fold higher: 1.4 (95% CI: 1.2-1.6) vs 0.4
(95% CI: 0.3-0.5) deaths per 100 patient-years, and the rate of fatal PE was
over 3-fold higher too: 2.5 (95% CI: 2.3-2.8) vs 0.7 (0.6-0.8),
respectively.
© 2015 ACT. All
rights reserved.
Key words: Venous thromboembolism; Real life; Registry;
Anticoagulant therapy and outcome
Bucherini E,
Hernndez-Blasco LM, Fernndez-Capitn C, Lorenzo A, Villalobos A, Tirado R,
Mah I, Hirmerova J, Prandoni P, Monreal M. Fragile Patients With Venous
Thromboembolism, What did We Learn From RIETE. International
Journal of Hematology Research 2015; 1(2): 35-39 Available from: URL:
http://www.ghrnet.org/index.php/ijhr/article/view/1153
Introduction
The benefits of
anticoagulant therapy in patients with acute venous thromboembolism (VTE) are
well established. In recent years, a number of direct oral anticoagulants
(DOACs) have been developed for the treatment of VTE, demonstrating
non-inferiority compared with standard therapy, and most showed significant
reductions in major bleeding[1-5].
Hence, direct factor Xa inhibitors apixaban and rivaroxaban, and direct
thrombin inhibitor dabigatran etexilate have been approved for use in the
European Union for the treatment of patients with deep vein thrombosis (DVT) or
pulmonary embolism (PE), and for prevention of recurrent DVT and PE. Another
direct factor Xa inhibitor, edoxaban, is currently being evaluated by the
regulatory agencies in Europe for both indications.
In a systematic review of
registration-track trials of the DOACs in the treatment of VTE, we reported a
potential benefit of the new compounds in terms of major bleeding rate and
corresponding case-fatality rate (CFR) in comparison with standard therapy, and
a similar CFR of recurrent VTE[6,7]. The use of DOACs was associated
with a lower rate of major bleeding and critical bleeding (including
intracranial bleeding) and a trend towards a lower CFR of bleeding compared
with standard therapy. In sensitivity analyses, these results were consistent
under different assumptions, thus supporting the robustness of the data.
Subgroup analyses from these
randomized clinical trials have delivered further promising results. For
example, data from the EINSTEIN DVT and PE trials showed favourable results for
rivaroxaban in the so-called fragile patients (defined as those having
creatinine clearance levels 50 mL/min, age 75 years or body weight 50 kg) compared with standard therapy,
where the rate of VTE recurrences was 2.7% and 3.8%, respectively (hazard ratio
[HR]: 0.68; 95% CI 0.39-1.18) and the rate of major bleeding was 1.3% and 4.5%,
respectively (HR: 0.27; 95% CI 0.13-0.54)[8]. Thus, fragile patients
with VTE might be ideal candidates for long-term therapy with rivaroxaban since
their bleeding rate with rivaroxaban was much lower than the rate in those
receiving standard therapy. However, the prevalence of fragile patients with
VTE outside clinical trials and their natural history during the course of
anticoagulant therapy has not been thoroughly investigated. This article will
review available information on the natural history of VTE in fragile- and
non-fragile patients outside clinical trials.
VTE
patients in real world
A large proportion of VTE patients were not recruited into randomized
clinical trials involving DOACs owing to the presence of a number of exclusion
criteria, e.g. renal insufficiency, high bleeding risk, concomitant therapies,
pregnancy, recent thrombolytic therapy or recent trauma/major surgery[9].
Hence, clinical information is limited in patient subgroups, e.g. fragile
patients or patients with renal impairment or cancer, who may be at higher risk
of bleeding and/or VTE.
The Registro
Informatizado de Enfermedad TromboEmblica (RIETE Registry) is an ongoing,
international (Spain, Italy, France, Israel, Portugal, Germany, Switzerland,
Belgium, Czech Republic, Republic of Macedonia, Greece, Canada, United States,
Brazil, Venezuela, Argentina and Ecuador), prospective registry of consecutive
patients with acute VTE designed to gather and analyze data on treatment
patterns and outcomes in patients with acute VTE[10-13]. It started
in Spain in 2001, and 6 years later the database was translated into English
with the aim to expand the Registry to other countries, ultimately allowing
physicians worldwide to use the database. It is aimed to improve the treatment
of VTE through a better understanding of patient demographics, management, and
in-hospital and post-discharge outcomes.
In contrast to
randomized controlled trials, there was no imposed experimental intervention in
RIETE: the management was determined solely by physicians. Thus, it provides
data on patients with VTE outside clinical trials with an unselected patient
population. It can, therefore, help to identify practices for providing
treatment to patients, and factors associated with better or worse patient
outcomes. Data from RIETE are hypothesis-generating and provide feedback from
real-world clinical situations which may be of help when designing new
randomized clinical studies. Patients were managed according to the clinical
practice of each participating hospital (i.e., there is no standardization of
treatment). The drug, dose and duration of anticoagulant therapy were recorded.
During each visit, any signs or symptoms suggesting VTE recurrences, bleeding
complications, and any other adverse events were noted. After initial
diagnosis, patients were followed-up for at least 3 months.
VTE
patients weighing <50 kg
The influence of extreme body weight on the natural history of VTE
during the course of anticoagulant therapy had not been consistently studied.
As of August 2004, 8845 patients with acute VTE were enrolled from 94
participating centres[14]. Of these, 169 (1.9%) weighed <50 kg,
8382 (95%) weighed 50-100 kg and 294 (3.3%) weighed >100 kg. Patients
weighing <50 kg received higher doses of low-molecular-weight heparin (LMWH)
than those weighing 50-100 kg (20851 vs 18136 IU/kg/day) and had a
higher rate of bleeding complications during the first 15 days of therapy: five
patients (3.0%) had major bleeding and nine patients (5.3%) had minor bleeding,
compared with 1.3% and 2.6%, respectively in patients weighing 50-100 kg (odds
ratio [OR]: 2.2; 95% CI 1.2-4.0). They also had a higher mortality (7.7% vs
3.0%; OR: 2.7; 95% CI: 1.5-4.7). The use of high doses of LMWH (>200
IU/kg/day) in over 50% of patients weighing <50 kg may have contributed to
this significant increase in the bleeding rate.
In another
study, we examined the association between body mass index (BMI) and mortality
during the first 3 months of therapy[15]. As of March 2006, there
were 10,114 patients enrolled in RIETE. Of these, 153 (1.5%) were underweight
(BMI <18.5) 2,882 (28%) normal weight (BMI: 18.5-24.9), 4,327 (43%)
overweight (BMI: 25.0-30.0) and 2,752 (27%) were obese (BMI: >30.0).
Underweight patients were significantly younger and more likely had cancer,
immobilization or renal insufficiency compared with those with normal weight.
During the first 3 months of therapy, their rates of major bleeding were 7.2% vs
2.7%, fatal bleeding were 2.0% vs 0.6% and all-cause death were 28% vs
12%, respectively. On multivariate analysis, the relative risk for death after
adjusting for confounding variables including age, cancer or renal
insufficiency in patients with underweight was: 2.1 (95% CI: 1.5-2.7) compared
with patients with normal weight.
Renal insufficiency
Patients with renal insufficiency are often excluded from clinical
trials of anticoagulant therapy, which means that treatment regimens based on
the results from clinical trials may not be suitable for these patients.
Moreover, the influence of renal insufficiency on the risk of bleeding
complications, a factor which can lead to physicians withholding anticoagulant
therapy, is not clear. Of 10526 patients enrolled in 2005, 88% had creatinine
clearance (CrCl) levels >60 mL/min, 6.7% had 30-60 mL/min, and 5.6% had CrCl
<30 mL/min[15]. Patients with CrCl levels <30 mL/min were more
often female and significantly older than patients with CrCl >60 mL/min.
They more likely had recent immobility or chronic heart failure, and less
likely had recent surgery. Most patients in all 3 subgroups were initially
treated with LMWH, but those with CrCl levels <30 mL/min more likely
received unfractionated heparin (UFH) (8.8%) than those with CrCl levels >60
mL/min (6.1%). The rate of fatal PE during the first 15 days was 1.0%, 2.6%,
and 6.6%, respectively. Major bleeding appeared in 1.0%, 4.0% and 5.4%,
respectively. Fatal bleeding occurred in 0.2%, 0.3%, and 1.2%, respectively.
Thus, patients with severe renal insufficiency had an increased rate of both
fatal PE and fatal bleeding, but the risk of fatal PE far exceeded that of
fatal bleeding. In fact, the rate of fatal PE was over 5-fold higher that of
fatal bleeding in all three groups, but patients with CrCl levels <30 mL/min
had a 6-7 times greater mortality due to PE or bleeding than those with normal
function.
In another
study, we assessed the 3-month outcome in VTE patients with CrCl levels <30
mL/min[16]. In March 2007, 1037 of 18251 (5.7%) patients enrolled in
RIETE had CrCl levels <30 mL/min at baseline. During the 3-month study
period, these patients had an increased incidence of fatal bleeding, fatal PE,
and overall death compared to those with CrCl levels >30 mL/min. Of 579
patients initially presenting with PE, 52 (9.0%) died of the initial PE event,
13 (2.2%) died of recurrent PE and 9 (1.6%) died of bleeding. During the first
15 days of therapy their 10% incidence of fatal PE was 10-fold higher than
their 1.0% of fatal bleeding. From day 16 to 90, their 1.0% rate of fatal PE
was non-significantly higher than their 0.5% rate of fatal bleeding. However,
of 458 patients with CrCl levels <30 mL/min initially presenting with DVT
alone, 14 (3.1%) had fatal bleeding and only one patient (0.2%) died of PE.
These findings revealed the existence of major differences in outcome of VTE
patients with severe renal insufficiency, according to their initial VTE
presentation. In those initially presenting with PE, the rate of fatal PE was
7-fold higher than the rate of fatal bleeding, while in those initially
presenting with DVT the rate of fatal bleeding was 10-fold higher than the rate
of fatal PE.
Finally, in a
third study, we evaluated the 15-day outcome in 38531 patients and used
propensity score matching to compare patients treated with UFH with those
treated with LMWH in 3 groups stratified by CrCl levels at baseline: >60
mL/min, 30 to 60 mL/min, or <30 mL/min[17]. Propensity
score-matched groups showed an increased 15-day mortality for UFH compared with
LMWH [4.5% vs 2.4% (p<0.001), 5.4% vs 5.8% (p=NS)
and 15% vs 8.1% (p=0.02)], an increased rate of fatal PE [2.8% vs
1.2% (p<0.001) 3.2% vs 2.5% (p=NS), and 5.7% vs
2.4% (p<0.02)], and a similar rate of fatal bleeding (0.3% vs 0.3%,
0.7% vs 0.7%, and 0.5% vs 0.0%). Multivariate analysis confirmed
that patients treated with UFH were at increased risk for all-cause death (OR:
1.8; 95% CI, 1.3-2.4) and fatal PE (OR: 2.3; 95% CI, 1.5-3.6) compared with
those receiving LMWH.
Elderly people
Some patients with VTE are often excluded from randomized clinical
trials of anticoagulant treatment because of existing conditions (such as renal
insufficiency, short life expectancy, long-term immobility, or because of
contraindications to therapy). These conditions occur more often in elderly
patients. Moreover, the influence of advanced age on the risk of bleeding, a
factor which can lead to physicians withholding anticoagulant therapy, is not
clear. Up to September 2005, 2,890 (22%) of 13,011 patients in RIETE were aged 80 years[19]. Most patients in both subgroups (93% and 90%,
respectively) were initially treated with LMWH. As for long-term therapy, 34%
of patients aged 80 years, and 25% of those <80
years received LMWH.
During the
first 3 months of anticoagulant therapy, 106 patients (3.7%) aged 80 years and 107 (1.1%) aged <80 years (1.1%) died of PE (OR: 3.6;
95% CI: 2.7-4.7). Eighty-three patients aged 80 years (2.9%)
died of their initial PE and 23 (0.8%) died of recurrent PE. Fatal bleeding
occurred in 0.8% and 0.4%, respectively (OR: 2.0; 95% CI: 1.2-3.4). In other
words, 50% of all patients with fatal PE and 36% of those with fatal bleeding
were aged 80 years old. Moreover, in patients aged 80 years the 3.4%
rate of major bleeding exceeded the 2.1% rate of VTE recurrences. However, the
3.7% rate of fatal PE clearly outweighed the 0.8% rate of fatal bleeding.
In another
study, we used the RIETE Registry data to assess the risk of fatal PE and fatal
bleeding in 16,199 patients with lower limb DVT (without symptomatic PE at the
time of inclusion) during the three months after diagnosis, with patients
categorized according to age[20]. During the first 3 months of
anticoagulant therapy, there were 31 fatal PE events (0.19%) and 83 fatal
bleeds (0.51%). During the first 7 days of therapy, the rate of fatal PE was
similar to the rate of fatal bleeding (12 vs 14 deaths, respectively;
OR: 0.86; 95% CI: 0.39-1.87). However, from Day 8 to Day 90 the rate of fatal
bleeding was greater than the rate of fatal PE (69 vs 19 deaths; OR:
3.64; 95% CI: 2.22-6.20). The higher frequency of fatal bleeding compared to
fatal PE from Day 8 to Day 90 appeared to be confined to patients aged 60 years. On multivariate analysis, the patients age was independently
associated with an increased risk for death from bleeding during the first 3
months: every 10 years the odds ratio increased by 1.37 (95% CI: 1.12-1.67).
Fragile patients and bleeding
Up to February 2015, there were 54,939 patients with acute VTE in
RIETE. Of these, 20,558 (37%) were aged 75 years, 2,194
(4.0%) weighed 50 kg, 13,736 (25%) had CrCl levels
50 mL/min, and 23,866 (43%) were fragile (Table 1)[21].
During the course of anticoagulant therapy, the rate of major bleeding was over
2-fold higher in fragile- than in non-fragile patients: 6.6 (95% CI: 6.2-7.0) vs
2.3 (95% CI: 2.1-2.5) bleeds per 100 patient-years, and their recurrence rate
was similar: 3.5 (95% CI: 3.2-3.8) vs 4.0 (95% CI: 3.7-4.2), respectively.
Moreover, the rate of fatal bleeding was over 4-fold higher: 1.4 (95% CI:
1.2-1.6) vs. 0.4 (95% CI: 0.3-0.5) deaths per 100 patient-years, and the rate
of fatal PE was over 3-fold higher too: 2.5 (95% CI: 2.3-2.8) vs 0.7
(0.6-0.8), respectively.
Discussion
In real world practice, over 40% of patients with acute symptomatic VTE
were fragile (i.e., weighed 50 kg, had CrCl levels 50 mL/min or were aged 75 years). During the course of
anticoagulant therapy they had an over 2-fold higher rate of major bleeding
complications than non-fragile patients. Since rivaroxaban seemed to be (in
post-hoc analyses) equally effective and safer than standard therapy in this
patient population, our data may help to identify the ideal candidates for
long-term therapy with this new compound.
Certainly,
RIETE has a number of limitations. First, patients are not treated with a
standardized anticoagulant regimen; treatment varies with local practice, and
is likely to be influenced by a physicians assessment of a patients risk of
bleeding. Second, to fulfil the definition of fatal PE in RIETE, patients must
first experience an objectively confirmed PE event, followed by death within 10
days. Thus, all sudden unexplained deaths that are usually considered as
likely fatal recurrent PE are not considered, and the rate of fatal PE may
have been underestimated, especially after hospital discharge. Third, RIETE is
an ongoing observational registry (and not a randomized controlled trial), and
the data are hypothesis-generating. Thus, we should be extremely cautious
before suggesting changes in treatment strategies based on uncontrolled
registry data. Finally, there is no external adjudication of the events, which
are merely reported by the authors. Strengths of the registry include that a
large number of consecutive unselected patients were enrolled, and a large
number of variables were considered.
Coordinator of
the RIETE Registry:
Dr. Manuel
Monreal (Spain)
RIETE Steering Committee Members:
Dr. Herv Decousus (France)
Dr. Paolo
Prandoni (Italy)
Dr. Benjamin Brenner (Israel)
RIETE National
Coordinators:
Dr. Raquel
Barba (Spain)
Dr. Pierpaolo
Di Micco (Italy)
Dr. Laurent
Bertoletti (France)
Dr. Sebastian Schellong (Germany)
Dr. Inna
Tzoran (Israel)
Dr. Abilio
Reis (Portugal)
Dr. Marijan
Bosevski (R.Macedonia)
Dr. Henri
Bounameaux (Switzerland)
Dr. Radovan
Malý (Czech Republic)
Dr. Philip
Wells (Canada)
Dr. Manolis
Papadakis (Greece)
RIETE Registry
Coordinating Center:
S & H
Medical Science Service
APPENDIX
Members of the RIETE Group: SPAIN:
Adarraga MD, Arcelus JI, Auguet T, Ballaz A, Barba R, Barrn M, Barrn-Andrs
B, Bascuñana J, Blanco-Molina A, Casado I, Castejn-Pina N, de Miguel J, del
Molino F, del Toro J, Daz JA, Espuis M, Falg C, Fernndez-Capitn C, Font L,
Gallego P, Garca-Bragado F, Gmez V, Gonzlez J, Grau E, Guijarro R, Guirado
L, Gutirrez J, Hernndez-Blasco L, Hernndez-Huerta S, Jara-Palomares L, Jaras
MJ, Jimnez D, Lacruz B, Lecumberri R, Lobo JL, Lpez-Jimnez L, Lpez-Reyes R,
Lpez-Sez JB, Lorente MA, Lorenzo A, Madridano O, Maestre A, Marchena PJ,
Martn-Antorn JM, Martn-Martos F, Monreal M, Morales MV, Nauffal D, Nieto JA,
Nñez MJ, Ochoa-Urizar FP, Otero R, Pagn B, Pedrajas JM, Prez G, Peris ML,
Pons I, Porras JA, Riera-Mestre A, Rivas A, Rodrguez-Dvila MA, Rosa V,
Ruiz-Gimnez N, Sampriz A, Snchez R, Sanz O, Soler S, Suriñach JM, Tiberio G,
Tirado R, Tolosa C, Trujillo-Santos J, Uresandi F, Valero B, Valle R, Vela J,
Vidal G, Villalobos A, Villalta J, BELGIUM: Vanassche T, Verhamme P, CANADA:
Wells P, CZECH REPUBLIC: Hirmerova J, Malý R, ECUADOR: Salgado E, FRANCE:
Bertoletti L, Bura-Riviere A, Farge-Bancel D, Hij A, Mah I, Merah A, Moustafa
F, GERMANY: Schellong S, GREECE: Babalis D, Papadakis M, Tzinieris I, ISRAEL:
Braester A, Brenner B, Tzoran I,
ITALY: Apollonio A, Barillari G, Bucherini E, Ciammaichella M, Di Micco P,
D'Onofrio P, Ferrazzi P, Lodigiani C, Maida R, Mastroiacovo D, Pace F, Pesavento
R, Pinelli M, Piovella C, Prandoni P, Rota L, Tiraferri E, Tonello D, Tufano A,
Vison A, Zalunardo B, LATVIA: Belovs A, Skride A, PORTUGAL: Pipa S, Ribeiro
JL, Sousa MS, REPUBLIC OF MACEDONIA: Bosevski M, SWITZERLAND: Alatri A,
Bounameaux H, Calanca L, Mazzolai L.
ACKNOWLEDGEMENTS
We express our gratitude to Sanofi Spain for supporting this Registry
with an unrestricted educational grant. We also express our gratitude to Bayer
Pharma AG for supporting this Registry. Bayer Pharma AGs support was limited
to the part of RIETE outside Spain, which accounts for a 22.2% of the total
patients included in the RIETE Registry. We also thank the RIETE Registry
Coordinating Center, S & H Medical Science Service, for their quality
control data, logistic and administrative support and Prof. Salvador Ortiz,
Universidad Autnoma de Madrid and Statistical advisor at S&H Medical
Science Service for the statistical analyses in this manuscript.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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Peer reviewer: Stavros
K. Kakkos, MD, PhD, RVT, Department of Vascular Surgery, University of Patras
Medical School, Patras, 26504, Greece.
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