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PROFILAXIS*DE*LA*ETV*

EN*URGENCIAS*

Dr.$Pedro$Ruiz$Artacho$$

Servicio$de$Urgencias.$Hospital$Clínico$San$Carlos,$Madrid$$

Grupo$ETVCSEMES$

*

(2)

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.

(3)

• 

Según*datos*del*Ministerio*de*Sanidad*en*

España*durante*el*año*2010*se*diagnosFcaron*

22,250*casos*de*TEP,*con*una*mortalidad*

(4)
(5)
(6)

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

(7)
(8)

Symptomatic deep venous thrombosis during anticoagulant prophylaxis.RR = relative risk.

Dentali F et al. Ann Intern Med 2007;146:278-288

(9)

Any pulmonary embolism during anticoagulant prophylaxis.RR = relative risk.

Dentali F et al. Ann Intern Med 2007;146:278-288

(10)

Fatal pulmonary embolism during anticoagulant prophylaxis.RR = relative risk.

Dentali F et al. Ann Intern Med 2007;146:278-288

(11)

Major bleeding during anticoagulant prophylaxis.RR = relative risks.

Dentali F et al. Ann Intern Med 2007;146:278-288

(12)

All-cause mortality during anticoagulant prophylaxis.RR = relative risk.

Dentali F et al. Ann Intern Med 2007;146:278-288

(13)
(14)

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.

(15)

J Thromb Haemost 2004; 2: 1892–8.

I N F O C U S

The 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

(16)

¿*SE*SIGUEN*LAS*RECOMENDACIONES*DE*

LAS*GUÍAS*EN*LA*PROFILAXIS*DE*

PACIENTES*MÉDICOS?*(PRETEMED*2007,*

ACCP*2004/2008/2012)*

(17)

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

20,21

han 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

22

no 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

15

16.532 (ambulatorios)

43,5

35

A criterio investigador

AT-HOME 2007

14

1.210 (ambulatorios)

83

87

Hass

IMPROVE 2007

5

USA

3.410 (hospitalizados)

52

33

ACCP

Otros países

11.746 (hospitalizados)

43

47

ACCP

Jones et al. 2007

18

4.732 (hospitalizados)

9

36

Kucher

Levine et al. 2007

17

254 (hospitalizados)

79

32

Caprini’s Risk Assessment

ENDORSE 2008

6

37.356* (hospitalizados)

41,5

39,5

ACCP

Lawall H, et al. 2011

16

7.271 (ambulatorios)

82,8

90,8-97,3

Hass/Cohen

AVAIL ME Extensión 2011

19

1.615* (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.

(18)

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

(19)

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.

(20)

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.*

(21)

AUC 0,765 (0,706-0,823).

(22)

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*

(23)

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.*

(24)

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.

(25)

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.*

(26)

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*

(27)

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*

(28)
(29)
(30)

%

%

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%%

(31)
(32)

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

(33)

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*

(34)

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%

(35)

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).

(36)
(37)

Estudio*EXCLAIM*

(38)

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

(39)

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$

(40)
(41)

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

)*

(42)

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.

(43)

Rivaroxaban in Acutely Ill Medical Patients

n engl j med 368;6 nejm.org february 7, 2013

519

patients (2.8%) who were receiving rivaroxaban

as compared with 49 of 4001 patients (1.2%) who

were receiving enoxaparin (relative risk, 2.3; 95%

CI, 1.63 to 3.17; P<0.001), and fatal bleeding

oc-curred in 5 patients in the rivaroxaban group and

in 1 patient in the enoxaparin group. Between

day 1 and day 35, an episode of clinically relevant

bleeding occurred in 164 of 3997 patients (4.1%)

in the group that received extended-duration

riva-roxaban as compared with 67 of 4001 patients

(1.7%) in the group that received enoxaparin

fol-lowed by placebo (relative risk, 2.5; 95% CI, 1.85 to

3.25; P<0.001). There was no evidence of

hetero-geneity according to subgroup with respect to

clinically relevant bleeding at day 35 (Fig. S2 in

the Supplementary Appendix). Fatal bleeding

oc-curred in 7 patients in the group that received

extended-duration rivaroxaban and in 1 patient in

the group that received enoxaparin followed by

placebo. The seven fatal bleeding events involved

pulmonary bleeding (in 3 patients), intracranial

bleeding (in 2 patients), and retroperitoneal and

gastrointestinal bleeding (each in 1 patient). In

the enoxaparin group there was one death due to

tracheal bleeding.

The adverse-event profiles and the incidence of

any cardiovascular event were similar up to day

35 in the group that received extended-duration

rivaroxaban and the group that received

enoxa-parin followed by placebo (Table 4). Over the

total study period, alanine aminotransferase

el-evations greater than three times the upper

limit of the normal range with a concurrent

el-evation in the bilirubin level that was greater

than two times the upper limit of the normal

range occurred in 7 of 3364 patients (0.2%) in

the rivaroxaban group and 7 of 3382 patients

(0.2%) in the enoxaparin group (measurements

were not available for approximately 16% of the

patients). The incidence of death from any cause

over the entire study period was similar in the

two groups.

Net Clinical Benefit or Harm

By day 10, an event of the primary efficacy

out-come or major or clinically relevant nonmajor

bleeding (the measure of net clinical benefit or

harm) had occurred in 216 of 3266 patients

(6.6%) in the rivaroxaban group, as compared

with 151 of 3291 patients (4.6%) in the

enoxapa-rin group (relative risk, 1.44; 95% CI, 1.18 to

1.77; P<0.001) (Table 3). By day 35, an event of

this composite outcome had occurred in 286 of

3042 patients (9.4%) in the group that received

extended-duration rivaroxaban, as compared with

240 of 3082 patients (7.8%) in the group that

re-ceived enoxaparin followed by placebo (relative

risk, 1.21; 95% CI, 1.03 to 1.43; P = 0.02) (Table 3).

Table 2.

Rates of the Composite Primary Efficacy Outcome and Its Components.

Outcome

Day 10

Day 35

Rivaroxaban

(N = 2938)

Enoxaparin

(N = 2993)

Relative Risk

(95% CI)*

P Value†

Rivaroxaban

(N = 2967)

Enoxaparin–

Placebo

(N = 3057)

Relative Risk

(95% CI)*

P Value†

no. (%)

no. (%)

Composite primary efficacy

outcome

78 (2.7)

82 (2.7)

0.97 (0.71– 1.31)

0.003

131 (4.4)

175 (5.7) 0.77 (0.62– 0.96)

0.02

Asymptomatic proximal DVT

71 (2.4)

71 (2.4)

103 (3.5)

133 (4.4)

Symptomatic proximal or

distal DVT

7 (0.2)

6 (0.2)

13 (0.4)

15 (0.5)

Symptomatic nonfatal

pulmonary embolism

6 (0.2)

2 (<0.1)

10 (0.3)

14 (0.5)

VTE-related death

3 (0.1)

6 (0.2)

19 (0.6)

30 (1.0)

* Two-sided 95% confidence intervals (CI) for weighted relative risks were calculated with the use of asymptotic methods, with weights based

on sample sizes per stratum of geographic region.

† The P values were calculated on the basis of the normal approximation. The P value for the day 10 analysis is a one-sided P value for

nonin-feriority, calculated in the per-protocol population; the P value for the day 35 analysis is a two-sided P value for superiority, calculated in the

modified intention-to-treat population.

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.

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