PROFILAXIS*DE*LA*ETV*
EN*URGENCIAS*
Dr.$Pedro$Ruiz$Artacho$$
Servicio$de$Urgencias.$Hospital$Clínico$San$Carlos,$Madrid$$
Grupo$ETVCSEMES$
*
Arch Intern Med 2000;160:769-74.
Estudio sobre la Enfermedad Tromboembólica Venosa en España 2006
INCIDENCIA: 117,7 por 100.000 personas-año
ESPAÑA: 116-124/100.000 habitantes año
Tendencia CRECIENTE
MORTALIDAD ETEV (TEP): 10-30% a los 30 días
! MORBILIDAD
Recidiva ETEV (30% a los 10 años)
HT Pulmonar (1-5% a los 5 años)
Sd. Post-flebítico (40% a los 10 años)
Hemorragia (5-8% en primeros 6 meses)
Tiempo desde el evento ETEV (años)
% R
ec
id
iv
a E
TE
V a
cu
m
ul
ad
o
!edad, inmovilidad
!hospitalizaciones
!cirugía
!obesidad
Factores
Riesgo
!
Predictors of recurrence after deep
vein thrombosis and pulmonary
embolism: a population-based cohort
study.
•
Según*datos*del*Ministerio*de*Sanidad*en*
España*durante*el*año*2010*se*diagnosFcaron*
22,250*casos*de*TEP,*con*una*mortalidad*
3 grandes ensayos clínicos
de profilaxis en pacientes
médicos ingresados
MEDENOX
:
enoxaparina
20 ó 40 mg/día vs. placebo
(MM Samama et al, NEJM 341; 1999: 793-800)
PREVENT:
dalteparina
5000
IU/día vs. placebo
(A Leizorovicz et al, Circulation
2004;110: 874-879)
ARTEMIS:
fondaparinux
2.5 mg/día vs. placebo
Symptomatic deep venous thrombosis during anticoagulant prophylaxis.RR = relative risk.
Dentali F et al. Ann Intern Med 2007;146:278-288
Any pulmonary embolism during anticoagulant prophylaxis.RR = relative risk.
Dentali F et al. Ann Intern Med 2007;146:278-288
Fatal pulmonary embolism during anticoagulant prophylaxis.RR = relative risk.
Dentali F et al. Ann Intern Med 2007;146:278-288
Major bleeding during anticoagulant prophylaxis.RR = relative risks.
Dentali F et al. Ann Intern Med 2007;146:278-288
All-cause mortality during anticoagulant prophylaxis.RR = relative risk.
Dentali F et al. Ann Intern Med 2007;146:278-288
PROFILAXIS*EN*PACIENTES*MEDICOS*
•
36%*ETV:*hospitalización*en*los*3*meses*
previos.*
•
La*ETV*hospitalaria*representa*casi*dos*terceras*
partes*de*las*muertes*secundarias*a*ETV.*
•
Incidencia*de*ETV*en*pacientes*médicos:*
10X30%.*
•
EP*supone*el*10%*de*las*muertes*en*pacientes*
hospitalizados.*
•
72%*de*los*episodios*de*ETV*en*hospitalizados**
son*médicos.*
•
80%*de*las*EP*fatales*en*hospitalizados*son*
médicos.***
J Thromb Thrombolysis
2011; 32: 32-9.
J Thromb Haemost 2004; 2: 1892–8.
I N F O C U SThe outcome after treatment of venous thromboembolism
is different in surgical and acutely ill medical patients. Findings
from the RIETE registry
M . M O N R E A L , A . K . K A K K A R , * J . A . C A P R I N I , ! R . B A R B A , " F . U R E S A N D I , § R . V A L L E ,– C . S U A R E Z , * * R . O T E R O ! ! and T H E R I E T E I N V E S T I G A T O R S
Servicio de Medicina Interna, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; *Center for Surgical Sciences, St Bartholemew’s and the Royal London School of Medicine, London, UK; !Department of Surgery, Evanston Northwestern Healthcare, Evanston, IL, USA; "Servicio de Medicina Interna, Fundacio´ n Hospital Alcorco´n, Madrid, Spain; §Servicio de Neumologı´a, Hospital de Cruces, Bilbao, Spain;–Servicio de Medicina Interna, Hospital de Sierrallana, Cantabria, Spain; **Servicio de Medicina Interna, Hospital de la Princesa, Madrid, Spain; and !!Servicio de Neumologı´a, Hospital Virgen del Rocı´o, Sevilla, Spain
To cite this article: Monreal M, Kakkar AK, Caprini JA, Barba R, Uresandi F, Valle R, Suarez C, Otero R, the RIETE investigators. The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE registry. J Thromb Haemost 2004; 2: 1892–8.
See alsoAgeno W. Another good reason for not ignoring thromboprophylaxis in acutely ill medical patients. This issue, pp 1889–91.
Summary. Background: The history of venous thromboem-bolism (VTE), and the rationale for thromboprophylaxis in surgical patients are well understood. The situation is less clear for acutely ill medical patients. Objectives: To compare the clinical presentation of VTE and clinical outcomes of immobile acutely ill medical patients with surgical patients. Patients: RIETE (Registro Informatizado de la Enfermedad Trom-boEmbo´lica) is a Spanish registry of consecutively enrolled patients with objectively confirmed, symptomatic acute VTE. In this analysis, clinical characteristics of patients, details of anticoagulant therapy, and outcomes of all enrolled acutely ill medical patients with immobility‡ 4 days, and surgical patients are included. Results: Of 6160 patients enrolled up to December 2003, 756 (12%) were acutely ill medical patients with immobility‡ 4 days, and 884 (14%) were surgical patients who developed VTE within 2 months of surgical intervention. Only 28% of acutely ill medical patients had received throm-boprophylaxis, compared with 67% of surgical patients. During the 3-month follow-up period, both fatal pulmonary embolism (PE) and fatal bleeding occurred more frequently in acutely ill medical patients. Immobility in acutely ill medical patients,
cancer, and PE were associated with a significantly higher risk of fatal PE or bleeding. Conclusions: In patients treated for VTE, the incidences of fatal PE, fatal bleeding, and major bleeding were significantly higher in acutely ill medical patients compared with surgical patients. Given the low percentage of acutely ill medical patients who had received thromboprophylaxis, increasing its use appropriately may reduce the incidence of VTE and associated complications.
Keywords: low-molecular-weight heparin, medical patients, pulmonary embolism, registry, thromboprophylaxis, venous thrombosis.
The risk of venous thromboembolism (VTE) in surgical patients is well recognized and thromboprophylaxis is routinely recom-mended in surgery. However, clinical evidence shows that hospitalization of medical patients accounts for a comparable number of VTE events [1]. The incidence of VTE in general medical patients is in the range 10–30% [2]. Post-mortem studies indicate that up to 10% of deaths in hospitalized patients are related to pulmonary embolism (PE), and that only a quarter of these deaths occur following surgery [3,4]. This suggests that 75% of hospitalized patients suffering from PE have not had recent surgery, and that medical patients have a high risk of VTE. In addition to the published risk of VTE in medical patients, clinical evidence has demonstrated the benefits of providing medical patients with thromboprophylaxis [5–10]. The American College of Chest Physicians (ACCP) guidelines recommend that all hospitalized medical patients be assessed for the risk of VTE and that appropriate prophylaxis be utilized [2]. Despite these recommendations, in clinical practice the use of thromboprophylaxis in medical patients remains low [11–14].
A full list of RIETE investigators is given in the Appendix.
Correspondence: M. Monreal, Servicio de Medicina Interna, Hospital Universitari Germans Trias i Pujol, 08916 Badalona (Barcelona), Spain.
Tel.: +34 93 465 1200; Fax: +34 93 395 2229; e-mail: mmonreal@ ns.hugtip.scs.es
Received 15 June 2004, accepted 23 July 2004
Journal of Thrombosis and Haemostasis, 2: 1892–1898
! 2004 International Society on Thrombosis and Haemostasis
strong stimulus for VTE, whereas acutely ill medical patients
may be at risk for extended durations. Differences in
charac-teristics of VTE might explain the observed differences in
presentation of VTE. However, further studies are needed to
confirm this hypothesis. A more severe presentation and, thus,
a less favorable prognosis of VTE may have resulted in the
poorer outcomes of acutely ill medical patients compared with
surgical patients.
Although a number of variables (age > 65 years, acute
medical illness with immobility
‡ 4 days, PE, chronic heart
failure, abnormal creatinine levels, use of corticosteroids, and
cancer) were found to be associated with increased risk of death
due to bleeding or PE, the multivariate analysis confirmed that
acutely ill medical patients with immobility
‡ 4 days, PE
diagnosis on admission, and cancer were the only variables
independently associated with a significantly increased risk of
either fatal PE or fatal bleeding.
VTE treatment received by the patients was not included in
the univariate or the multivariate analyses. Since no
experi-mental protocol was imposed, and the dose and the duration of
VTE treatment varied between participating centers, no firm
Table 3 Baseline characteristics of immobile acutely ill medical patients vs. surgical patients at enrollment following symptomatic venous thrombo-embolism (VTE) diagnosis
Acutely ill medical patients, n (%) (n¼ 756) Surgical patients, n (%) (n¼ 884) Odds ratio (95% CI) P-value Baseline characteristics Sex (male) 375 (50) 385 (44) 1.3 (1.1, 1.6) 0.014 Age > 65 years 542 (72) 488 (55) 2.1 (1.7, 2.5) < 0.001 Outpatients 440 (60) 480 (56) 1.2 (0.9, 1.4) NS Underlying conditions
Chronic lung disease 155 (25) 62 (9) 3.3 (2.4, 4.5) < 0.001 Chronic heart failure 111 (18) 35 (5) 4.0 (2.7, 6.0) < 0.001 Abnormal creatinine levels 165 (22) 57 (6) 4.1 (2.9, 5.6) < 0.001 Recent major bleeding 63 (8) 47 (5) 1.6 (1.1, 2.4) 0.015 Associated treatments
NSAIDs 59 (9) 104 (15) 0.6 (0.4, 0.9) 0.004 Antiplatelet drugs 124 (20) 63 (9) 2.2 (1.8, 3.5) < 0.001 Corticosteroids 132 (21) 67 (9) 2.6 (1.9, 3.5) < 0.001 Other risk factors for VTE
Cancer 171 (23) 214 (24) 0.9 (0.7, 1.2) NS Previous VTE 77 (10) 91 (10) 1.0 (0.7, 1.4) NS Leg varicosities 142 (19) 148 (17) 1.0 (0.8, 1.3) NS VTE characteristics DVT 412 (55) 526 (59) 0.8 (0.7, 0.99) 0.041 Upper extremity* 10 (2.5) 30 (6) 0.4 (0.2, 0.8) 0.013 Lower extremity, proximal* 354 (88) 368 (71) 2.9 (2.1, 4.2) < 0.001 Lower extremity, distal* 40 (10) 122 (24) 0.4 (0.2, 0.5) < 0.001 PE 344 (46) 358 (41) 1.2 (1.0–1.5) 0.041 Arterial PO2 < 60 mmHg! 159 (54) 117 (40) 1.8 (1.3–2.4) 0.001 Systolic BP < 90 mmHg! 22 (6) 13 (4) 1.8 (0.9–3.3) NS Heart rate > 120 bpm! 55 (17) 44 (13) 1.4 (0.9–2.1) NS VTE treatment Initial therapy: LMWH 675 (89) 785 (89) 1.1 (0.8–1.4) NS Initial therapy: UFH 77 (10) 96 (11) 0.9 (0.7–1.3) NS Long-term therapy: AVK" 461 (61) 614 (70) 0.7 (0.6–0.8) < 0.001 Long-term therapy: LMWH" 225 (30) 245 (28) 1.1 (0.9–1.4) NS AVK, Antivitamin K drugs; BP, blood pressure; CI, confidence interval; DVT, deep vein thrombosis; LMWH, low-molecular-weight heparin; NS, not significant; NSAIDs, non-steroidal anti-inflammatory drugs; PE, pulmonary embolism; UFH, unfractionated heparin. *Percentages calculated based on number of patients with DVT.!Percentages calculated based on total number of patients with PE. "Some patients did not receive long-term treatment because they died during initial therapy.
Table 4 Clinical outcomes of immobile acutely ill medical patients vs. surgical patients at 3 months after presentation with symptomatic venous thromboembolism (VTE) Acutely ill medical patients, n (%) (n¼ 756) Surgical patients, n (%) (n¼ 884) Odds ratio (95% CI) P-value Recurrent VTE 25 (3.3) 25 (2.8) 1.2 (0.7, 2.1) NS Major bleeding 44 (5.8) 18 (2.0) 3.0 (1.7, 5.2) < 0.001 Minor bleeding 36 (4.8) 35 (4.0) 1.2 (0.8, 1.9) NS Overall mortality 182 (24.1) 70 (7.9) 3.7 (2.7, 4.9) < 0.001 Fatal PE 27 (3.6) 8 (0.9) 4.1 (1.8, 9.0) < 0.001 Fatal bleeding 15 (2.0) 2 (0.2) 8.9 (2.0, 39) < 0.001 CI, Confidence interval; NS, not significant; PE, pulmonary embolism.
1896 M. Monreal et al
! 2004 International Society on Thrombosis and Haemostasis
conclusions can be drawn relating clinical outcomes to types or
duration of VTE treatment received by the patients.
Overall mortality was significantly higher in immobile
acutely ill medical patients than in surgical patients. This could
be due to the nature of their specific underlying conditions. In
this analysis, the incidences of fatal PE and fatal bleeding were
chosen as the primary outcome measures. Overall mortality
was not used as the major measure of outcome, because the
acutely ill medical patients could have a higher mortality rate
due to the nature of their specific disease or their underlying
medical conditions.
In this analysis, we compared the clinical outcomes of
surgical patients with symptomatic VTE with those of acutely
ill medical patients with immobility
‡ 4 days and symptomatic
VTE. Acutely ill medical patients with immobility < 4 days
and VTE were not included in this analysis and may have had
different outcomes compared with those that had immobility
‡ 4 days.
Although RIETE (http://www.riete.org) started as a Spanish
initiative in March 2001, it is now open to physicians in other
countries, thus becoming an international registry. In contrast
to a randomized controlled trial, no experimental intervention
is imposed: management is determined entirely by the treating
physicians. Data captured and reported in the registry therefore
reflect
!real-world" practices and outcomes in the treatment of
VTE. The main objective of the registry is to provide online
information to help physicians evaluate treatment options,
particularly for those patient groups that are not included in
clinical trials, thereby aiding patient management and
dissem-inating information on good clinical practice. A limitation of
this registry is that, although not expected to change the results
of this analysis, it may influence management of patients by
participating physicians.
In conclusion, our data from a large, prospective series of
consecutively enrolled patients indicate that immobile acutely
ill medical patients with VTE may have a significantly poorer
clinical outcome, in terms of the incidence of fatal PE and
bleeding complications, than surgical patients with VTE. The
poorer outcome of acutely ill medical patients could be due to a
more severe presentation of VTE, coexisting underlying
conditions, or associated therapies in this patient group. Given
the low percentage of immobile acutely ill medical patients who
received thromboprophylaxis and then presented with VTE
compared with surgical patients, and the published evidence on
the benefits of thromboprophylaxis at preventing VTE [5–8],
increasing the use of thromboprophylaxis may reduce the
Table 5 Fatal pulmonary embolism (PE), fatal bleeding, or both, in various subgroups of acutely ill medical patients with symptomatic venous thromboembolism (VTE)
Reason for immobility n
Fatal PE, n (%) Fatal bleeding, n (%) Fatal PE or bleeding, n (%) Acute infection 210 3 (1.4) 2 (1.0) 5 (2.4) Acute stroke 98 5 (5.1) 1 (1.0) 6 (6.1) Cancer 97 5 (5.2) 8 (8.2) 13 (13.4) Heart failure 75 4 (5.3) 1 (1.3) 5 (6.7) Chronic lung disease 70 4 (5.7) 1 (1.4) 5 (7.1) Ischemic heart disease 26 1 (3.8) 0 (0) 1 (3.8) Other reasons 180 5 (2.8) 2 (1.1) 7 (3.9) Total
Acutely ill medical patients 756 27 (3.6)* 15 (2.0)* 42 (5.6)* Surgical patients 884 8 (0.9) 2 (0.2) 10 (1.1) *P < 0.001 compared with surgical patients.
Table 6 Univariate analysis on the risk of either fatal pulmonary embolism (PE) or fatal bleeding
Odds ratio (95% CI) P-value Baseline characteristics Sex (male) 0.9 (0.5–1.6) NS Age > 65 years 3.4 (1.6–7.2) 0.002 Outpatients 0.5 (0.3–0.8) 0.007 Acutely ill medical patients
with immobility‡ 4 days
5.1 (2.6–10.3) < 0.001 Underlying conditions
Chronic lung disease 1.2 (0.6–2.6) NS Chronic heart failure 2.3 (1.1–4.8) 0.019 Abnormal creatinine levels 3.3 (1.8–6.0) < 0.001 Recent major bleeding 1.9 (0.8–4.5) NS Associated treatments
NSAID intake 1.7 (0.8–3.7) NS Antiplatelet drugs 1.7 (0.8–3.5) NS Corticosteroids 2.0 (1.0–4.1) 0.045 Other risk factors for VTE
Cancer 3.2 (1.8–5.5) < 0.001 Previous VTE 0.2 (0.02–1.2) NS Leg varicosities 0.3 (0.1–0.9) 0.047 VTE characteristics DVT 0.3 (0.2–0.6) < 0.001 PE 2.8 (1.6–5.1) < 0.001 Arterial PO2 < 60 mmHg 1.9 (0.9–3.9) NS Systolic BP < 90 mmHg 1.9 (0.5–6.4) NS Heart rate > 120 beats min)1 1.3 (0.5–3.2) NS BP, Blood pressure; CI, confidence interval; DVT, deep vein throm-bosis; NS, not significant; NSAID, non-steroidal anti-inflammatory drugs; VTE, venous thromboembolism.
Table 7 Multivariate logistic regression analysis of the risk of either fatal pulmonary embolism (PE) or fatal bleeding
Odds ratio
(95% CI) P-value Baseline characteristics
Age > 65 years 1.8 (0.8–4.2) NS Acutely ill medical patients
with immobility‡ 4 days
3.4 (1.6–7.3) 0.002 Outpatients 0.5 (0.3–1.0) NS Underlying conditions
Chronic heart failure 1.3 (0.6–-3.2) NS Abnormal creatinine levels 1.7 (0.8–3.5) NS Other risk factors for VTE
Cancer 3.6 (1.8–7.2) < 0.001 Leg varicosities 1.7 (0.8–3.5) NS VTE characteristics
PE 3.3 (1.6–6.7) 0.001 CI, Confidence interval; NS, not significant; VTE, venous thrombo-embolism.
VTE outcome in medical vs. surgical patients
1897
¿*SE*SIGUEN*LAS*RECOMENDACIONES*DE*
LAS*GUÍAS*EN*LA*PROFILAXIS*DE*
PACIENTES*MÉDICOS?*(PRETEMED*2007,*
ACCP*2004/2008/2012)*
Emergencias 2012; 24: 19-27
agudos intercurrentes que aunque no
reque-rían ingreso, sí los confinaba en el domicilio con
movilidad disminuida. Todos estos estudios se
en-cuentran recogidos en la Tabla 6.
Las razones de la no instauración de
trombo-profilaxis no han sido suficientemente analizadas.
Algunos estudios previos que analizan la
adecua-ción de la tromboprofilaxis en pacientes
hospitali-zados
20,21han investigado las razones de la
inade-cuación y han encontrado que los pacientes de
menor edad, con estancias hospitalarias más
pro-longadas y sin antecedentes previos de ETV
reci-ben menos profilaxis. Un estudio multicéntrico
americano más reciente
22no ha hallado relación
entre ninguna de las indicaciones o las
contraindi-caciones para la tromboprofilaxis, lo que sugiere
un conocimiento inadecuado de las guías de
prác-tica clínica actuales. De hecho, tras una
interven-ción educativa utilizando guías de práctica clínica,
se registró una mejor adecuación de la
trombo-profilaxis
23. A la vista de los factores que se
aso-cian a la no instauración de tromboprofilaxis en el
presente estudio, se podría concluir que entre los
pacientes que se marchan de los SUH sin
trombo-profilaxis requiriéndola están, por una parte,
aquéllos con movilidad normal y, por otra,
aqué-llos con edad avanzada, demencia y
pluripatolo-gía. En el primero de los casos es curioso advertir
como la movilidad normal sigue siendo un factor
que genera una percepción de riesgo disminuido.
Llama poderosamente la atención el segundo
per-fil de pacientes, cuando precisamente es el que
con seguridad, de ingresar, lo haría con
trombo-profilaxis. Se puede hipotetizar que el urgenciólogo
utiliza criterios de eficiencia en los que se
confron-ta el coste de la tromboprofilaxis farmacológica
con los costes derivados del sangrado atribuible a
la misma (en un tipo de paciente con alto riesgo
para ello) o del tratamiento del acontecimiento
tromboembólico. Este hecho podría explicarse
porque la ETV es vista como una complicación,
mientras que el sangrado es considerado una
ya-trogenia.
El presente estudio tiene limitaciones
impor-tantes. En primer lugar, al facilitarse un método
de medición de riesgo y una recomendación de
tromboprofilaxis, se pudo generar un sesgo en la
indicación de la misma. Sin embargo, los datos
obtenidos distan mucho de sugerir un impacto de
este hecho en los resultados finales del estudio. En
segundo lugar, no se ha evaluado el riesgo
hemo-rrágico (aunque la contraindicación para la
anti-coagulación formaba parte de los criterios de
ex-clusión) por lo que se desconoce su impacto en la
no instauración de tromboprofilaxis.
Independientemente de estas limitaciones, el
estudio responde a los objetivos planteados. Y
más allá de ello, implica una gran posibilidad de
mejora. Las sociedades científicas y los
investiga-dores deben continuar esforzándose en difundir la
importancia de la valoración del riesgo de la
en-fermedad tromboembólica en pacientes con
pato-logía médica, tanto para los procesos agudos
co-mo para los crónicos con co-morbilidades asociadas.
Además, estamentos de ámbito sanitario como el
NICE (National Institute for Health and Clinical
Ex-cellence) consideran la tromboprofilaxis
farmacoló-gica una práctica coste efectiva
24.
T
ROMBOPROFILAXIS EN LOS SERVICIOS DE URGENCIAS HOSPITALARIOS DE PACIENTES CON PATOLOGÍA MÉDICA QUE NO REQUIEREN INGRESO
Emergencias 2012; 24: 19-27
25
Tabla 6. Características diferenciales entre algunos de los estudios previos
Estudio
N
% pacientes con indicación
% pacientes con indicación
EER utilizada
de tromboprofilaxis
de tromboprofilaxis que la recibieron
ETAPE 2006
1516.532 (ambulatorios)
43,5
35
A criterio investigador
AT-HOME 2007
141.210 (ambulatorios)
83
87
Hass
IMPROVE 2007
5USA
3.410 (hospitalizados)
52
33
ACCP
Otros países
11.746 (hospitalizados)
43
47
ACCP
Jones et al. 2007
184.732 (hospitalizados)
9
36
Kucher
Levine et al. 2007
17254 (hospitalizados)
79
32
Caprini’s Risk Assessment
ENDORSE 2008
637.356* (hospitalizados)
41,5
39,5
ACCP
Lawall H, et al. 2011
167.271 (ambulatorios)
82,8
90,8-97,3
Hass/Cohen
AVAIL ME Extensión 2011
191.615* (hospitalizados)
87,7
24
ACCP
URGENTV
2.280 (ambulatorios)
81,1
57,9
PRETEMED
EER: escala de estratificación del riesgo; ACCP: American College of Chest Physicians. *Pacientes médicos.
Tabla 5. Desarrollo de acontecimientos tromboembólicos en
el mes posterior a recibir el alta del SUH
Riesgo moderado-alto Riesgo bajo
(PRETEMED ! 4) (PRETEMED " 3)
n = 1850
n = 430
Pacientes con seguimiento
[n (%)]
887 (47,9)
178 (41,4)
Pacientes con ETV
[n (%)]
28 (3,1)
8 (4,5)
Pacientes con ETV y
tromboprofilaxis [n (%)]
9 (32,1)
–
Pacientes con ETV
sin tromboprofilaxis [n (%)]
19 (67,9)
–
SUH: servicio de urgencias hospitalario; ETV: enfermedad
tromboembólica venosa.
Emergencias 2012; 24: 19-27
trumento de medición del riesgo y recomendación
de tromboprofilaxis, este desconocimiento no
ten-dría que ser el factor determinante.
Los estudios realizados desde la perspectiva de
urgencias de pacientes que requieren
hospitaliza-ción muestran, asimismo, porcentajes de
trombo-profilaxis inferiores a los observados en el presente
estudio
15,16. Sin embargo, los estudios realizados
en el ámbito ambulatorio muestran porcentajes
de tromboprofilaxis en pacientes de riesgo muy
superiores
17-19. Este hecho diferencial podría
expli-carse por el propio diseño de los estudios, en el
que se sugiere al médico tratante la necesidad de
instaurar la tromboprofilaxis; facultativo que es,
además, el mismo que realiza todo el seguimiento
del paciente. En el presente estudio, aunque el
in-vestigador también disponía de una guía de
cál-culo del riesgo y recomendación de
tromboprofi-laxis, no era el facultativo responsable del
segui-miento posterior del paciente. Además, el perfil
de los pacientes incluidos en este último tipo de
estudios es bastante más homogéneo que el que
se recoge en el presente estudio, al tratarse de
pacientes añosos, pluripatológicos, con procesos
S. Jiménez Hernández et al.
24
Emergencias 2012; 24: 19-27
Especificidad
Área bajo la curva: 0,786
IC 95%: 0,764-0,808
1,0
0,8
0,6
0,4
0,2
0,0
Figura 2. Curva ROC de los factores asociados a la no
instau-ración de tromboprofilaxis al alta del servicio de urgencias
hospitalario.
Tabla 3. Diferencias entre los pacientes con riesgo tromboembólico moderado-alto según la instauración o no de tromboprofilaxis
Total
Tromboprofilaxis
No tromboprofilaxis
p
n = 1.850
n = 1.071
n = 779
Sexo varón [n (%)]
1.012 (54,7)
573 (56,6)
439 (43.4)
0,2
Edad (m ± DS)
69,9 ± 15,5
68,1 ± 16,3
72,5 ± 14,1
< 0,001
Índice de masa corporal (m ± DS)
26,9 ± 4,6
27,2 ± 4,7
26,5 ± 4,3
< 0,01
Obesidad, IMC > 28 [m (%)]
659 (37,6)
434 (62,4)
262 (37,6)
< 0,05
Centro [n (%)]
Público
1.806 (97,6)
1.031 (57,1)
775 (42,9)
< 0,001
Privado
44 (2,4)
40 (90,9)
4 (9,1)
Procedencia [n (%)]
Domicilio
1.153 (62,3)
659 (61,5)
494 (63,4)
0,5
Urgencias extrahospitalarias
303 (16,4)
182 (17,0)
121 (15,5)
Atención Primaria
317 (17,1)
179 (16,7)
138 (17,7)
Centro de especialidades
52 (2,8)
34 (3,2)
18 (2,3)
Otro hospital
25 (1,4)
17 (1,6)
8 (1,0)
Diabetes [n (%)]
750 (40,5)
427 (40,7)
323 (41,6)
0,6
Hipertensión arterial [n (%)]
1.146 (61,9)
654 (62,5)
492 (63,5)
0,6
Dislipemia [n (%)]
711 (38,4)
411 (40,3)
300 (40,0)
0,9
Arritmia [n (%)]
318 (17,2)
180 (17,3)
138 (18,2)
0,6
Cardiopatía isquémica [n (%)]
404 (21,8)
225 (21,6)
179 (23,6)
0,3
Enfermedad ulcerosa péptica [n (%)]
108 (5,8)
51 (4,9)
57 (7,5)
< 0,001
Enfermedad hepática [n (%)]
96 (5,3)
58 (5,6)
38 (5,0)
0,6
Insuficiencia renal [n (%)]
245 (13,2)
130 (12,5)
115 (15)
0,1
Enfermedad neurodegenerativa [n (%)]
201 (10,9)
102 (9,8)
99 (12,8)
< 0,05
Enfermedad vascular cerebral [n (%)]
250 (13,5)
147 (14,8)
103 (14,7)
0,9
Estancia en urgencias > 12 h
1.075 (58,1)
592 (55,3)
483 (62,1)
< 0,001
Movilidad prevista al alta
Encamamiento > 50% >3 días
461 (24,9)
362 (33,8)
99 (12,7)
< 0,001
Movilidad reducida
844 (45,6)
553 (51,6)
291 (37,4)
< 0,001
Cama/aseo/cama*
306 (36,3)
208 (37,6)
98 (33,7)
0,2
Cama/sillón/cama*
538 (63,7)
345 (62,4)
193 (66,3)
0,2
Movilidad normal
545 (29,4)
156 (14,6)
389 (49,9)
< 0,001
*Porcentajes calculados sobre el grupo de pacientes con movilidad reducida.
Tabla 4. Factores asociados de forma independiente a la no
instauración de tromboprofilaxis al alta del SUH
OR
IC 95%
p
Encamamiento no previsto al alta
19,7
13,9-28,1
< 0,0005
Movilidad reducida no prevista al alta
6,8
5,2-8,9
< 0,0005
Enfermedad neurodegenerativa
1,7
1,2-2,5
0,003
Estancia > 12 horas
1,3
1,1-1,8
0,007
Edad (por año)
1,03 1,02-1,04
< 0,0005
SUH: servicio de urgencias hospitalario.
Sensibilidad
0,2
0,4
0,6
0,8
1,0
19-27-C20-12554.EME-ORIGINAL-Jimenez_C10-12346.EME ORIGINAL-Fernandez 25/01/12 12:51 Página 24
trumento de medición del riesgo y recomendación
de tromboprofilaxis, este desconocimiento no
ten-dría que ser el factor determinante.
Los estudios realizados desde la perspectiva de
urgencias de pacientes que requieren
hospitaliza-ción muestran, asimismo, porcentajes de
trombo-profilaxis inferiores a los observados en el presente
estudio
15,16. Sin embargo, los estudios realizados
en el ámbito ambulatorio muestran porcentajes
de tromboprofilaxis en pacientes de riesgo muy
superiores
17-19. Este hecho diferencial podría
expli-carse por el propio diseño de los estudios, en el
que se sugiere al médico tratante la necesidad de
instaurar la tromboprofilaxis; facultativo que es,
además, el mismo que realiza todo el seguimiento
del paciente. En el presente estudio, aunque el
in-vestigador también disponía de una guía de
cál-culo del riesgo y recomendación de
tromboprofi-laxis, no era el facultativo responsable del
segui-miento posterior del paciente. Además, el perfil
de los pacientes incluidos en este último tipo de
estudios es bastante más homogéneo que el que
se recoge en el presente estudio, al tratarse de
pacientes añosos, pluripatológicos, con procesos
S. Jiménez Hernández et al.
24
Emergencias 2012; 24: 19-27
Especificidad
Área bajo la curva: 0,786
IC 95%: 0,764-0,808
1,0
0,8
0,6
0,4
0,2
0,0
Figura 2. Curva ROC de los factores asociados a la no
instau-ración de tromboprofilaxis al alta del servicio de urgencias
hospitalario.
Tabla 3. Diferencias entre los pacientes con riesgo tromboembólico moderado-alto según la instauración o no de tromboprofilaxis
Total
Tromboprofilaxis
No tromboprofilaxis
p
n = 1.850
n = 1.071
n = 779
Sexo varón [n (%)]
1.012 (54,7)
573 (56,6)
439 (43.4)
0,2
Edad (m ± DS)
69,9 ± 15,5
68,1 ± 16,3
72,5 ± 14,1
< 0,001
Índice de masa corporal (m ± DS)
26,9 ± 4,6
27,2 ± 4,7
26,5 ± 4,3
< 0,01
Obesidad, IMC > 28 [m (%)]
659 (37,6)
434 (62,4)
262 (37,6)
< 0,05
Centro [n (%)]
Público
1.806 (97,6)
1.031 (57,1)
775 (42,9)
< 0,001
Privado
44 (2,4)
40 (90,9)
4 (9,1)
Procedencia [n (%)]
Domicilio
1.153 (62,3)
659 (61,5)
494 (63,4)
0,5
Urgencias extrahospitalarias
303 (16,4)
182 (17,0)
121 (15,5)
Atención Primaria
317 (17,1)
179 (16,7)
138 (17,7)
Centro de especialidades
52 (2,8)
34 (3,2)
18 (2,3)
Otro hospital
25 (1,4)
17 (1,6)
8 (1,0)
Diabetes [n (%)]
750 (40,5)
427 (40,7)
323 (41,6)
0,6
Hipertensión arterial [n (%)]
1.146 (61,9)
654 (62,5)
492 (63,5)
0,6
Dislipemia [n (%)]
711 (38,4)
411 (40,3)
300 (40,0)
0,9
Arritmia [n (%)]
318 (17,2)
180 (17,3)
138 (18,2)
0,6
Cardiopatía isquémica [n (%)]
404 (21,8)
225 (21,6)
179 (23,6)
0,3
Enfermedad ulcerosa péptica [n (%)]
108 (5,8)
51 (4,9)
57 (7,5)
< 0,001
Enfermedad hepática [n (%)]
96 (5,3)
58 (5,6)
38 (5,0)
0,6
Insuficiencia renal [n (%)]
245 (13,2)
130 (12,5)
115 (15)
0,1
Enfermedad neurodegenerativa [n (%)]
201 (10,9)
102 (9,8)
99 (12,8)
< 0,05
Enfermedad vascular cerebral [n (%)]
250 (13,5)
147 (14,8)
103 (14,7)
0,9
Estancia en urgencias > 12 h
1.075 (58,1)
592 (55,3)
483 (62,1)
< 0,001
Movilidad prevista al alta
Encamamiento > 50% >3 días
461 (24,9)
362 (33,8)
99 (12,7)
< 0,001
Movilidad reducida
844 (45,6)
553 (51,6)
291 (37,4)
< 0,001
Cama/aseo/cama*
306 (36,3)
208 (37,6)
98 (33,7)
0,2
Cama/sillón/cama*
538 (63,7)
345 (62,4)
193 (66,3)
0,2
Movilidad normal
545 (29,4)
156 (14,6)
389 (49,9)
< 0,001
*Porcentajes calculados sobre el grupo de pacientes con movilidad reducida.
Tabla 4. Factores asociados de forma independiente a la no
instauración de tromboprofilaxis al alta del SUH
OR
IC 95%
p
Encamamiento no previsto al alta
19,7
13,9-28,1
< 0,0005
Movilidad reducida no prevista al alta
6,8
5,2-8,9
< 0,0005
Enfermedad neurodegenerativa
1,7
1,2-2,5
0,003
Estancia > 12 horas
1,3
1,1-1,8
0,007
Edad (por año)
1,03 1,02-1,04
< 0,0005
SUH: servicio de urgencias hospitalario.
Sensibilidad
0,2
0,4
0,6
0,8
1,0
Tromboprofilaxis en los servicios de urgencias hospitalarios de pacientes con patología médica
que requieren ingreso: estudio
PROTESU
Jiménez S, Ruiz-Artacho P, et al.
Estudio MULTICÉNTRICO (7 hospitales): Dic 2011- Julio 2012.
610 pacientes
Tabla*1.*Perfil*de*pacientes**PROTESU
$
Total*
N=*610*
Edad*−*años*(media,*DS)*
69,6*(17,2)*
Sexo*femenino*−*no.*(%)*
342*(56,1)*
MOTIVO*DE*INGRESO*
Infección*respiratoria*−**no.*(%)*
262*(43,0)*
ACCP
378 p (62%)
PRETEMED
268 p (44%)
TP: 47,7%
58,6%
Mortalidad intrahospitalaria: 6,6%
ETV mortal: 2 pac. sin tromboprofilaxis.
Tabla*2.*Variables*asociadas*con*la*NO*tromboprofilaxis
$
OR*
IC*95%*
p*
Factor*de*riesgo*hemorragia*
12,7*
4,3X37,5*
<0,001*
Ingreso*desde*primera*visita*
9,1*
0,9X93,5**
0,008*
Ingreso*desde*unidad*de*observación*
18,6*
1,6X205,1**
0,008*
Enfermedad*hematológica*
4,9*
0,9X26,7*
0,051*
Infección*del*tracto*urinario*
2,5*
0,9X6,9**
0,075*
OR:*Odds*RaFo;*IC*95%:*intervalo*de*confianza*del*95%.**
*
Barthel*<20,*ictus,*obesidad*y*consumo*de*tabaco*se*asociaron*con*mayor*tromboprofilaxis.*
AUC 0,765 (0,706-0,823).
EP
N=1113
Ingreso 3 meses previos
N=182 (16,4%)
SIN ingreso previo
N=931
Ingreso MÉDICO
N=124 (68,1%)
Ingreso QUIRÚRGICO
N= 58 (31,2%)
***********Mortalidad*
INTRAhospitalaria*
FACTORES
ASOCIADOS
(Tipo ingreso)
Enero 2008- Diciembre 2010
Resultados a corto plazo del embolismo pulmonar agudo sintomático tras un ingreso previo
médico o quirúrgico.
Ruiz-Artacho P, Pérez C, Marín N, González del Castillo J, Calvo E, Martín-Sánchez FJ.
**********Diferencias*PERFIL*
Tabla*1.*Perfil*de*pacientes**ETV*con*ingreso*previo*Médico*Vs*Quirúrgico*
$
Total*
N=*182*
Médico*
N=124*
Quirúrgico*
N=58*
p*
Edad*−*años*(media,*DS)*
73,2*(13,6)*
75,0*(12,2)*
69,2*(15,5)*
0,007*
Sexo*femenino*−*no.*(%)*
110*(60,4)*
80*(64,5)*
30*(51,7)*
0,100*
ANTECEDENTES*PERSONALES*
Cáncer*acFvo*−**no.*(%)*
74*(40,7)*
55**(44,4)*
19*(32,8)*
0,138*
Hipertensión*arterial−**no.*(%)*
114*(62,6)*
81*(65,3)*
33*(56,9)*
0,274*
Diabetes*Mellitus−**no.*(%)*
37*(20,3)*
28*(22,6)*
9*(15,5)*
0,270*
Consumo*de*tabaco−**no.*(%)*
18*(9,9)*
14*(11,3)*
4*(6,9)*
0,355*
Insuficiencia*cardíaca*congesFva−**no.*
(%)*
23*(12,6)*
19*(15,3)*
4*(6,9)*
0,111*
Cardiopaoa*isquémica−**no.*(%)*
34*(18,7)*
27*(21,8)*
7*(12,1)*
0,118*
Ictus−**no.*(%)**
13*(7,1)*
12*(9,7)*
1**(1,7)*
0,065*
EPOC−**no.*(%)*
22*(12,1)*
19*(15,3)*
3*(5,2)*
0,054*
Insuficiencia*renal*crónica−**no.*(%)*
28*(15,4)*
22*(17,7)*
6*(10,3)*
0,197*
Demencia−**no.*(%)*
16*(8,8)*
12*(9,7)*
4*(6,9)*
0,779*
ETV:*enfermedad*tromboembólica*venosa;*DS:*desviación*estándar;*ACCP:*American*College*of*Chest*Physicians;*RI:*rango*intercuarolico.*PESI:*Pulmonary* Embolism*Severity*Index.*ESCALA DE RIESGO PRONÓSTICO PESI
simplificada
Puntos
•
Edad > 85 años
•
Historia de cáncer
•
Historia de insuficiencia cardíaca o EPOC
•
Frecuencia cardíaca
≥
110/min
•
TAS < 100 mmHg
•
Saturación de Oxígeno < 90%
1
1
1
1
1
1
BAJO RIESGO: 0 puntos
Mortalidad precoz <2%
ALTO RIESGO
≥*1*punto*
Am J Respir Crit Care Med 2005; 172: 1041-1046.
Arch Intern Med 2010; 170: 1383-1389.
Tabla*1.*Perfil*de*pacientes**ETV*con*ingreso*previo*Médico*Vs*Quirúrgico*
$
Total*
N=*182*
Médico*
N=124*
Quirúrgico*
N=58*
p*
Escala*PESI*simplificada**
PESI*alto*(≥1)*−*no.*(%)*
150*(82,4)* 111*(89,5)*
39*(67,2)*
<0,001*
Tensión*arterial*sistólica*
123,4*(24,9)*
121,7*
(24,6)*
126,9*(25,4)*
0,236*
Frecuencia*cardíaca*(media,*DS)*
93,4*(22,7)* 94,3*(24,1)* 91,3*(19,4)*
0,470*
Saturación*oxígeno*(media,*DS)*
89,8*(8,2)*
88,6*(9,1)*
92,4*(4,8)*
0,003*
Frecuencia*respiratoria*(media,*DS)*
22,2*(7,0)*
22,9*(7,1)*
19,9*(6,5)*
0,298*
Estancia*hospitalaria*(días)−*mediana*
(RI)*
(7,0X23,0)*
12,5*
(7,0X23,0)*
14*
(7,0X20,8)*
10,5*
0,425*
Tiempo*hasta*el*ingreso*previo*(días)*
(mediana,*RI)*
(17,0X50,3)*
32,0*
(18,3X57,5
31,5*
)*
32,0*
(14,5X44,3)*
0,163
*
Mortalidad*al*mes−*no.*(%)*
30*(16,5)*
27*(21,8)*
3*(5,2)*
0,005*
Mortalidad*intrahospitalaria−*no.*(%)*
35*(19,2)*
31*(25,0)*
4*(6,9)*
0,004*
ETV:*enfermedad*tromboembólica*venosa;*DS:*desviación*estándar;*ACCP:*American*College*of*Chest*Physicians;*RI:*rango*intercuarolico.*PESI:*
Pulmonary*Embolism*Severity*Index.*
FACTORES*DE*RIESGO*DE*ETV*(Ingreso*previo)*
Total*
N=*182*
Médico*
N=124*
Quirúrgico*
N=58*
p*
Cáncer*acFvo*−**no.*(%)*
74*(40,7)*
55**(44,4)*
19*(32,8)*
0,138*
ETV*previa*−*no.*(%)*
28*(15,4)*
22*(17,7)*
6*(10,3)*
0,197*
Trombofilia**conocida*−*no.*(%)*
1*(0,5))*
1*(0,8)*
0*
1,000*
Movilidad*reducida*−*no.*(%)*
29*(15,9)*
15*(12,1)*
14*(24,1)*
0,039*
Trauma*o*cirugía*reciente*(mes*
previo)*−*no.*(%)*
54*(29,7)*
1*(0,8)*
53*(91,4)*
<0,001*
Edad*>=*70*años*−*no.*(%)*
129*(70,9)*
91*(74,2)*
37*(63,8)*
0,150*
Fracaso*cardiorrespiratorio*−*no.*
(%)*
50*(27,5)*
48*(38,7)*
2*(3,4)*
<0,001*
Obesidad*−*no.*(%)*
17*(9,3)*
13*(10,5)*
4*(6,9)*
0,438*
Tratamiento*hormonal*−*no.*(%)*
0*
0*
0*
X*
Riesgo*ETV*alto*(ACCP≥4)*−*no.*(%)*
93*(51,1)*
59*(47,6)*
34*(58,6)*
0,165*
Tromboprofilaxis*recibida*−*no.*(%)* 26*(28,0)*
12*(20,3)*
14*(41,2)*
0,031*
Tabla*2.*Efecto*del*ingreso*previo*médico*sobre*la*mortalidad*intrahospitaria
$
OR*
IC*95%*
p*
Ingreso*previo*médico*
3,34*
1,08X10,31*
0,020*
Cardiopaoa*isquémica*
3,35*
1,37X8,21*
0,009*
PESI*simplificada*
9,11*
1,12X73,84*
0,006*
OR:*Odds*RaFo;*IC*95%:*intervalo*de*confianza*del*95%.**
Controlado*por:*Edad,*Cáncer,*PESI*simplificada,*Cardiopaoa*isquémica,*ICC*y*Saturación*basal*de*O2*
%
%
Se#
recomienda%
profilaxis#con#
HBPM%%
%
>%4%
#Se#
sugiere
#
profilaxis#con#
HBPM%
4%
Considerar#el#uso#de#
medidas%físicas
%
1?3%
Recomendación#
Riesgo#
ajustado
##
Cálculo%del%riesgo%Ajustado%(RA)
%
RA=%
Procesos%precipitantes%(rojo)%+%Otras%circunstancias%de%riesgo%(verde)%
%%
Esta%fórmula%sólo%se%puede%aplicar%si%al%menos%un%proceso%rojo%(desencadenante)%o%un%
proceso%asociado%con%peso%≥%2%%
Factores*de*riesgo*de*ETEV*en*pacientes*
médicos*hospitalizados*
FACTOR$DE$RIESGO$
PUNTUACIÓN$
Cáncer*acFvo*
3*
ETEV*previa*(excepto*
superficial)*
Mobilidad*reducida*
Trombofilia*
Cirugía*o*trauma*(≤*1mes)*
2*
Edad*≥*70*años*
1*
Insuficiencia*respiratoria*o*
cardíaca*
IAM*o*Ictus*
Infección*aguda/E.*
reumatológica*
Obesidad*(IMC*≥*30)*
Tratamiento*hormonal*
ALTO RIESGO
≥ 4 puntos
11 % ETEV
Factores*de*riesgo*independientes*de*
hemorragia*en*pacientes*médicos*hospitalizados*
FACTOR$DE$RIESGO$
OR$
Ulcus*gastroduodenal*acFvo*
4,15*
Hemorragia*previa*(3*meses)*
3,64*
Plaquetas*<*50.000*
3,37*
Edad*≥*85*años*
2,96*
Insuf.*HepáFca**(INR*>*1,5)*
2,18*
Insuf.*Renal*(CCl<30*mL/min)*
2,14*
Ingreso*en*UCI*
2,10*
Catéter*venoso*central*
1,85*
Enfermedad*reumáFca*
1,78*
Cáncer*acFvo*
1,78*
Sexo*masculino*
1,48*
Tromboprofilaxis en los servicios de urgencias hospitalarios de pacientes con patología médica
que requieren ingreso: estudio
PROTESU
Jiménez S, Ruiz-Artacho P, et al.
Datos preliminares: pendiente publicación.
Concordancia*ACCPXPRETEMED
$
PRETEMED*
BAJO*
ALTO*
ACCP*
BAJO*
30,5%*
6%*
ALTO*
25,3%*
38,1%*
CONCORDANCIA: 68,6%
DISCORDANCIA: 31,3%
Índice Kappa 0,392 p<0,001
63,4%
44,1%
Incidencia*ETV*según*riesgo*(3*MESES)
$
ACCP*
BAJO*
1,7%*
ALTO*
3,2%*
PRETEMED*
BAJO*
2,5%*
ALTO*
3,1%*
ETV : 16 pacientes
8 con TP
8 sin TP
5 de ALTO RIESGO según ACCP
1 de ALTO RIESGO según PRETEMED
CONCLUSIONES
- Discordancia entre las escalas utilizadas en los SU.
- ACCP clasifica mejor (mayor incidencia de ETV en alto riesgo y menor en bajo riesgo).
Estudio*EXCLAIM*
hours after the double-blind treatment period, as
deter-mined by central adjudication with blinding to treatment
assignment (Appendix 2). Secondary safety end points
were the incidence of major and minor hemorrhagic
com-plications, serious adverse events, and thrombocytopenia.
We assessed safety end points and mortality in all
ran-domly assigned patients who received at least 1 dose of
study medication (safety population).
Hemorrhages were considered to be major if they were
overt and associated with death; a decrease in hemoglobin
level of at least 30 g/L or a transfusion of at least 2 units of
packed red blood cells or whole blood; surgical
interven-tion; or retroperitoneal, intracranial, or intraocular
bleed-ing. In a post hoc analysis, we used a more stringent
threshold hemoglobin decrease of 20 g/L, as used in other
trials, to further assess major bleeding events.
Minor hemorrhages were those that were overt and
did not meet the criteria for a major hemorrhage. These
included epistaxis lasting more than 5 minutes or requiring
intervention, ecchymosis or hematoma larger than 5 cm,
hematuria not associated with urinary catheter trauma,
subconjunctival or gastrointestinal hemorrhage, or wound
hematoma. We obtained platelet counts at the end of both
the open-label and double-blind treatment phases.
We defined adverse events as new illness, worsening of
preexisting illness, study medication effects (including
comparator), or a combination of these. Serious adverse
events were those that resulted in death or persistent or
substantial disability or incapability, were life-threatening
or considered an important medical event, or required
in-patient hospitalization or prolongation of existing
hospital-ization. Bleeding events and VTE were considered serious
adverse events if they met the above criteria.
Trial Monitoring and Amendment
An independent data safety monitoring board (DSMB)
(Appendix 1) conducted interim analyses of adjudicated
efficacy and safety outcomes when 25%, 50%, and 75% of
the target enrollment (4044 patients) had been recruited.
For the final interim analysis, adjudicated efficacy data
were available for 3056 of 3685 patients with evaluable
ultrasonograms and adjudicated safety data were available
for 4060 patients.
The final interim efficacy analysis found
lower-than-assumed VTE rates, with no statistically significant
differ-ence between treatment groups (37 of 1526 [2.4%] in the
enoxaparin group vs. 50 of 1530 (3.3%) in the placebo
group; P ! 0.16) after unblinding and an 8.67% chance of
finding such a significant difference. The interim safety
analysis also found a statistically significant increase in
ma-jor hemorrhages associated with 1 treatment group (13 of
2020 [0.64%] in the enoxaparin group vs. 6 of 2040
[0.29%] in the placebo group; P ! 0.05) after unblinding.
On the basis of these analyses, the DSMB recommended
that the study as designed be terminated. The DSMB also
highlighted that event rates in patients with level 1
immo-Table 2.
Incidence of Primary Efficacy and Safety Outcomes
End Point Preamendment* Postamendment
Extended-Duration
Enoxaparin,n/N (%) Placebo, n/N
(%) Absolute RiskDifference (CI),%† Extended-DurationEnoxaparin, n/N (%) Placebo, n/N
(%) Absolute RiskDifference (CI),%† VTE‡§ All 45/1818 (2.5) 78/1867 (4.2) "1.70 ("2.86 to "0.55) 16/667 (2.4) 22/643 (3.4) "1.02 ("2.85 to 0.80) Level 1 12/496 (2.4) 30/488 (6.1) "3.73 ("6.25 to "1.20) 13/574 (2.3) 17/552 (3.1) "0.81 ("2.70 to 1.07) Level 2 33/1313 (2.5) 47/1368 (3.4) "0.92 ("2.21 to 0.36) 3/92 (3.3) 5/91 (5.5) "2.23 ("8.16 to 3.69) High-risk! 18/519 (3.5) 31/561 (5.5) "2.05 ("4.51 to 0.41) 3/77 (3.9) 5/80 (6.3) "2.35 ("9.20 to 4.49) Low-risk¶ 15/794 (1.9) 16/807 (2.0) "0.09 ("1.44 to 1.26) 0/15 (0.0) 0/11 (0.0) –
Major bleeding events**
All 19/2159 (0.9) 10/2176 (0.5) 0.42 ("0.07 to 0.91) 6/816 (0.7) 0/812 (0.0) 0.74 (0.15 to 1.32) Level 1 5/590 (0.8) 2/589 (0.3) 0.51 ("0.37 to 1.38) 4/702 (0.6) 0/692 (0.0) 0.57 (0.01 to 1.13) Level 2 14/1559 (0.9) 8/1576 (0.5) 0.39 ("0.19 to 0.98) 2/113 (1.8) 0/120 (0.0) 1.77 ("0.66 to 4.20)
High-risk! 4/627 (0.6) 3/640 (0.5) 0.17 ("0.65 to 0.99) 2/94 (2.1) 0/106 (0.0) 2.13 ("0.79 to 5.04) Low-risk¶ 10/932 (1.1) 5/936 (0.5) 0.54 ("0.27 to 1.35) 0/19 (0.0) 0/14 (0.0) 0.00 (0.00 to 0.00)
VTE ! venous thromboembolism.
* Data include outcomes that were not fully adjudicated at the time of interim analysis. The analysis using adjudicated data only found no significant difference between groups. See “Trial Monitoring and Amendment” in the Methods section for further details.
† For VTE end points in the total population, we report 95.8% CIs (P # 0.042) because of the ! adjustment for the interim analysis. For all other end points, we report 95% CIs (P # 0.050).
‡ Assessed in the efficacy population (4995 patients). We excluded 21 patients from the immobility subgroups (20 preamendment [9 in the enoxaparin group and 11 in the placebo group] and 1 postamendment [from the enoxaparin group]) because of missing immobility-level data or absence of immobility-level classification.
§ One patient included in the placebo group of the preamendment and total populations experienced a VTE but had missing immobility-level data or absence of immobility-level classification.
!Patients with level 2 immobility and "1 of the following VTE risk factors: age $75 y, history of VTE, or active or previous cancer. ¶ Patients with level 2 immobility and none of the additional specified risk factors for VTE.
** Post hoc analysis performed by using a threshold hemoglobin decrease of "20 g/L for a major bleeding event. Assessed in the safety population (5963 patients), except for 22 patients (21 preamendment [10 from the enoxaparin group and 11 from the placebo group] and 1 postamendment [from the enoxaparin group]) whom we excluded because of missing immobility-level data or absence of immobility-level classification. Appendix Table 3 (available at www.annals.org) describes the types of major bleeding events we observed.
Article
Extended-Duration Venous Thromboembolism Prophylaxis in Medical Patients
EXCLAIM*
•
La$enoxaparina$frente$a$placebo:$$
–
Disminuye$el$riesgo$de$ETEV$(4.2$vs$2.5%)$
–
Aumenta$el$riesgo$de$hemorragia,$
principalmente$menores$(mayor:$0.9$vs$0.5%)$
–
No$diferencias$en$mortalidad$a$los$3$y$6$meses$
•
Beneficio/Riesgo:$$
•
Nivel$1$inmovilidad$(total)$
•
Mujeres$
•
Mayores$de$75$años$
NUEVOS*ACO*
•
Inhibidores*de*la*trombina*(DABIGATRAN):*
–
Aprobado*su*uso*Profilaxis*en*Cirugía*Ortopédica.*
–
No*estudios*en*pacientes*médicos.*
•
Inhibidores*directos*del*factor*Xa:*
–
RIVAROXABAN*(
Estudio$MAGELLAN
)*
–
APIXABAN*(
Estudio$ADOPT
)*
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 368;6 nejm.org february 7, 2013 513
original article
Rivaroxaban for Thromboprophylaxis
in Acutely Ill Medical Patients
Alexander T. Cohen, M.D., Theodore E. Spiro, M.D., Harry R. Büller, M.D., Lloyd Haskell, M.D., Dayi Hu, M.D., Russell Hull, M.B., B.S.,
Alexandre Mebazaa, M.D., Geno Merli, M.D., Sebastian Schellong, M.D., Alex C. Spyropoulos, M.D., and Victor Tapson, M.D.,
for the MAGELLAN Investigators*
From King’s College Hospital, London (A.T.C.); Bayer HealthCare Pharmaceuti-cals, Montville (T.E.S.), and Janssen Re-search and Development, Raritan (L.H.) — both in New Jersey; Academic Medical Center, Amsterdam (H.R.B.); People’s Hospital of Peking University, Beijing (D.H.); Foothills Hospital, Calgary, AB, Canada (R.H.); University Paris Diderot, pôle de recherche et d’enseignement su-périeur Sorbonne Paris Cite and Hôpital Lariboisière, Paris (A.M.); Thomas Jeffer-son Medical Center, Philadelphia (G.M.); Dresden-Friedrichstadt Hospital, Dresden, Germany (S.S.); Hofstra North Shore– Long Island Jewish School of Medicine, Manhasset, NY (A.C.S.); and Duke Uni-versity Medical Center, Durham, NC (V.T.). Address reprint requests to Dr. Co-hen at Vascular Medicine, Department of Vascular Surgery, King’s College Hospi-tal, London SE5 9RS, United Kingdom, or at alexander.cohen@kcl.ac.uk.
*The investigators participating in the Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembo-lism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin (MAGELLAN) and the study committees are listed in the Sup-plementary Appendix, available at NEJM.org.
N Engl J Med 2013;368:513-23. DOI: 10.1056/NEJMoa1111096
Copyright © 2013 Massachusetts Medical Society.
A b s t r a c t
Background
The clinically appropriate duration of thromboprophylaxis in hospitalized patients with acute medical illnesses is unknown. In this multicenter, randomized, double-blind trial, we evaluated the efficacy and safety of oral rivaroxaban administered for an extended period, as compared with subcutaneous enoxaparin administered for a standard period, followed by placebo.
Methods
We randomly assigned patients 40 years of age or older who were hospitalized for an acute medical illness to receive subcutaneous enoxaparin, 40 mg once daily, for 10±4 days and oral placebo for 35±4 days or to receive subcutaneous placebo for 10±4 days and oral rivaroxaban, 10 mg once daily, for 35±4 days. The primary ef-ficacy outcomes were the composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 10 (noninferiority test) and up to day 35 (supe-riority test). The principal safety outcome was the composite of major or clinically relevant nonmajor bleeding.
Results
A total of 8101 patients underwent randomization. A primary efficacy outcome event occurred in 78 of 2938 patients (2.7%) receiving rivaroxaban and 82 of 2993 patients (2.7%) receiving enoxaparin at day 10 (relative risk with rivaroxaban, 0.97; 95% confidence interval [CI], 0.71 to 1.31; P = 0.003 for noninferiority) and in 131 of 2967 patients (4.4%) who received rivaroxaban and 175 of 3057 patients (5.7%) who received enoxaparin followed by placebo at day 35 (relative risk, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). A principal safety outcome event occurred in 111 of 3997 patients (2.8%) in the rivaroxaban group and 49 of 4001 patients (1.2%) in the enoxaparin group at day 10 (P<0.001) and in 164 patients (4.1%) and 67 patients (1.7%) in the respective groups at day 35 (P<0.001).
Conclusions
In acutely ill medical patients, rivaroxaban was noninferior to enoxaparin for stan-dard-duration thromboprophylaxis. Extended-duration rivaroxaban reduced the risk of venous thromboembolism. Rivaroxaban was associated with an increased risk of bleeding. (Funded by Bayer HealthCare Pharmaceuticals and Janssen Research and Development; MAGELLAN ClinicalTrials.gov number, NCT00571649.)
The New England Journal of Medicine
Downloaded from nejm.org at HOSPITAL UNIV PUERTA DE HIERRO on February 24, 2013. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
Rivaroxaban in Acutely Ill Medical Patients
n engl j med 368;6 nejm.org february 7, 2013