Prévention des thromboembolies veineuses dans un contexte ... · Prévention des thromboembolies...

Prévention des thromboembolies veineuses dans un contexte péri-

opératoire

François Lauzier, MD, MSc, FRCPC

Professeur adjoint Division de soins intensifs adultes Départements de médecine et d’anesthésiologie Centre de recherche du CHU de Québec Axe Santé des populations et pratiques optimales en santé Unité de traumatologie-médecine d�urgence-soins intensifs

6 février, 2014

Objectifs

• Revoir l’épidémiologie des maladies thromboemboliques durant la période post-opératoire pour différents types de chirurgie • Décrire l’efficacité et le risque d’une thromboprophylaxie pharmacologique dans différents types de chirurgie

Fardeau de la maladie

Sans thromboprophylaxie, le risque d’embolie pulmonaire fatale est de

< 1% si chirurgie générale 2-3% si PTH 4-7% si fracture de hanche

Les stratégies d’implantation de la thromboprophylaxie est une pratique organisationnelle requise pour l’accréditation des hôpitaux

Évaluation du risque thromboembolique

Localisation de la chirurgie Technique chirurgicale

Laparoscopie vs chirurgie ouverte Durée de la chirurgie

Facteurs spécifique au patient Âge ATCD personnel/familial Obésité Cancer Thrombophilie

Modèles prédictifs Quatre catégories

Très faible risque (0,5%) Risque modéré (3%) Faible risque (1,5%) Risque élevé (6 %)

Deux modèles Rogers

Aucune validation externe Compliqué Thromboprophylaxie?

Caprini Validation externe Compliqué Thromboprophylaxie Pas de gynéco

www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e243S

3.3.2 Baseline Risk, Risk Factors, and Risk Strat-ifi cation for Major Bleeding Complications: Few studies have examined the risk of bleeding in vas-cular surgery. Across three randomized trials of thromboprophylaxis, 109,111,115 the pooled weighted risk of major bleeding in the control (no prophylaxis) groups was 0.3% (95% CI, 0.2%-2.4%). However, an observational study reported that the incidence of life-threatening hemorrhage among 973 patients undergoing complex major vascular procedures was 1.8%, with most episodes of bleeding occurring intra-operatively and only 0.4% of patients experiencing severe bleeding postoperatively. 120 Because the base-line risk of bleeding is diffi cult to pinpoint in vascular surgery, we use the baseline risk from studies of gen-eral and abdominal-pelvic surgery (1.2%) and provide a list of risk factors as a guide ( Table 8 ).

3.4 Target Population: Plastic and Reconstructive Surgery

Because there have been no randomized controlled trials of thromboprophylaxis in plastic and recon-structive surgery, we applied indirect evidence about relative risks from trials in general and mixed surgical patients when making recommendations.

3.4.1 Baseline Risk, Risk Factors, and Risk Strati-fi cation for VTE: A retrospective study examined the 60-day risk of postoperative VTE in 1,126 patients who were at least at moderate risk for VTE (Caprini score, 3-4) and underwent plastic and reconstruc-tive surgery at one of fi ve tertiary-care facilities in the United States between 2006 and 2009. 4 All patients received mechanical prophylaxis with IPC.

vascular surgery patients (Appendix S1), most were limited by small samples, incomplete information about use of prophylaxis, and measurement of surro-gate outcomes (asymptomatic DVT).

Data from the British Million Women Study showed that the risk of symptomatic VTE in the 12 weeks following inpatient surgery is almost as high in vascu-lar surgery patients (one in 115) as it is in those who have surgery for cancer (one in 85). 33 Another study that used data from the California Discharge Data Set reported that the risk of symptomatic VTE within 91 days of vascular surgery was ! 1.7% for all the fol-lowing vascular procedures: peripheral vascular shunt or bypass, resection and replacement of abdominal aorta, above-knee amputation, aortoilliofemoral bypass or femoral-popliteal aneurysm resection with graft, and ligation and stripping of varicose veins. 75 The risk was slightly lower for patients who underwent below-knee amputation and arteriovenous fi stula placement (0.5%-0.9%), and it was lowest for carotid endarterectomy (0.2%). Use of prophylaxis was not described in either of these studies, so the risk of symptomatic VTE in the absence of prophylaxis is likely to be higher.

Risk factors for VTE in vascular surgery are not well established, although several studies have attempted to identify risk factors in this popula-tion, with little success. 117-119 However, vascular sur-gery patients comprised 16% of the retrospective cohort in a validation study of the Caprini model (V. Bahl, DMD, MPP, personal communication, November 29, 2010). Likewise, vascular patients comprised 18% of the sample in the Patient Safety in Surgery Study, 82 supporting the generalizability of both models to vascular surgery patients.

Table 7— Caprini Risk Assessment Model

1 Point 2 Points 3 Points 5 Points

Age 41-60 y Age 61-74 y Age ! 75 y Stroke ( , 1 mo)Minor surgery Arthroscopic surgery History of VTE Elective arthroplastyBMI . 25 kg/m 2 Major open surgery ( . 45 min) Family history of VTE Hip, pelvis, or leg fractureSwollen legs Laparoscopic surgery

( . 45 min)Factor V Leiden Acute spinal cord injury

( , 1 mo)Varicose veins Malignancy Prothrombin 20210APregnancy or postpartum Confi ned to bed ( . 72 h) Lupus anticoagulantHistory of unexplained or recurrent

spontaneous abortionImmobilizing plaster cast Anticardiolipin antibodies

Oral contraceptives or hormone replacement

Central venous access Elevated serum homocysteine

Sepsis ( , 1 mo) Heparin-induced thrombocytopeniaSerious lung disease, including

pneumonia ( , 1 mo)Other congenital or acquired thrombophilia

Abnormal pulmonary functionAcute myocardial infarctionCongestive heart failure ( , 1 mo)History of infl ammatory bowel diseaseMedical patient at bed rest

© 2012 American College of Chest Physicians at Bibliotheque De L Universite Laval on March 9, 2012chestjournal.chestpubs.orgDownloaded from

Très faible Faible Modéré Élevé

Chirurgie de reconstruction 0-2 3-4 5-6 7-8

Autres chirurgies 0 1-2 3-4 ≥ 5

Chirurgie thoracique, abdominale ou pelvienne

Risque d’événement

Risque de saignement Très faible Faible Modéré Élevé

Faible Ambulation

Jambières

HBPM ou HNF

HBPM ou HNF

Jambières Et Jambières

Et Jambières

Elevé Ambulation

Jambières Jambières Jambières Jambières

Qualité des données Élevée Modérée Faible Très faible

Évolution du risque post-opératoire

Indications for surgery

The postoperative risks of venous thromboembolismwere investigated according to indication for or type ofsurgery. The median lengths of (inpatient) hospital staywere five days after cancer surgery, eight days after hipor knee replacement, three days after fracture surgery,two days after other orthopaedic surgery, two days aftervascular surgery, four days after gynaecological sur-gery, four days after gastrointestinal surgery, and twodays after all other surgery. Figure 3 gives the relativerisks after inpatient surgery and figure 4 gives the corre-sponding relative risks after day case surgery. In the sixweeks after inpatient surgery the greatest relative riskwas that associated with joint replacement, at morethan 200 times the risk without surgery: relative risk220.6 (95% confidence interval 187.8 to 259.2). Therelative risks after surgery for cancer, fracture, and vas-cular conditions were also substantially increased: 91.6(73.9 to 113.4), 89.0 (65.5 to 121.0), and 87.0 (67.2 to112.5), respectively. The relative risks associated withother orthopaedic and gastrointestinal surgery werealso high: 57.3 (42.3 to 77.7) and 56.3 (39.4 to 80.4),respectively.The risk of venous thromboembolismdur-ing the six weeks after inpatient surgery for gynaecolo-gical and all other indications was still more than 20times that associated with no surgery: 22.7 (14.8 to34.9) and 36.0 (29.6 to 43.8), respectively.The highest relative risk for postoperative weeks

7-12 was after inpatient surgery for cancer (53.4, 40.0to 71.4). The relative risks after major joint

replacement and fracture surgery decreased rapidlyfrom those in the first six weeks to: 39.7 (27.3 to 57.8)and 39.8 (25.0 to 63.4), respectively. The relative risksafter inpatient surgery for vascular, gastrointestinal,and gynaecological conditions were all increasedmore than 10-fold (15.8 (8.5 to 29.3), 18.5 (9.9 to34.6), and 11.1 (5.9 to 20.6), respectively), and the rela-tive risk after other orthopaedic surgery and all otherinpatient surgery were still more than five times thatwithout surgery (5.6, 2.1 to 14.9 and 8.4, 5.6 to 12.6,respectively).The increased relative risk associated with inpatient

surgery for cancer was still evident 4-12 months aftersurgery (34.4, 29.3 to 40.2) and one year or more aftersurgery (6.1, 4.9 to 7.6). The overall relative risk afterinpatient surgery for non-cancer conditions was 3.3(2.8 to 3.9) 4-12 months after surgery and 1.7 (1.5 to1.9) one year or more after surgery.Few operations for joint replacement or fracture

were done as day cases so the risks associated withthese procedures could not be estimated. Cancerdominated the findings for day case surgery (fig 4),with relative risks of 80.4 (54.0 to 119.6) for the sixweeks after surgery, 47.7 (28.6 to 79.6) for the7-12 weeks after surgery, and 12.1 (7.9 to 18.7) for the4-12 months after surgery. Relative risks were morethan 20 during the first six weeks after day case vascu-lar surgery andother orthopaedic surgery (26.4, 17.2 to40.6 and 22.9, 14.4 to 36.5), and more than doubledafter other types of day case surgery: 2.5 (1.0 to 6.8)after gynaecological surgery, 5.3 (3.5 to 8.1) aftergastrointestinal surgery, and 6.2 (4.3 to 8.9) afterother surgery.Results for the separate outcomes of pulmonary

embolism and deep vein thrombosis showed similaroverall patterns in relation to operation type to themain venous thromboembolism analyses, althoughconfidence intervals werewider owing to smaller num-bers in each category (data not shown).

Event rates

The incidence rates are calculated using both hospitaladmissions and death records for venous thrombo-embolism. The incidence rate for venous thromboem-bolism during all time without surgery was 0.7 per

1 2 3 4 5 6 7 8 9 10 11 120

40

80

120

160

200

Weeks since inpatient surgery

Rela

tive

risk

(95%

CI)

Pulmonary embolismDeep vein thrombosis

Relative risk for time without surgery = 1

Fig 2 | Relative risks of pulmonary embolism and deep vein thrombosis by time since inpatientsurgery

Table 2 | Person years and number of women with incident venous thromboembolism, by time since surgery. Values arenumbers (percentages) unless stated otherwise

Time since surgery Person years (%)

Diagnosis on hospital admission or death record

Deep vein thrombosis orpulmonary embolism* Deep vein thrombosis† Pulmonary embolism‡

No surgery 5 136 506 (88) 3589 (63) 2248 (64) 1547 (62)

1-6 weeks after surgery 27 187 (0.5) 675 (12) 377 (11) 340 (14)

7-12 weeks after surgery 26 363 (0.5) 218 (4) 145 (4) 86 (3)

4-12 months after surgery 159 153 (3) 520 (9) 337 (10) 210 (8)

≥1 year after surgery 486 126 (8) 687 (12) 422 (12) 304 (12)

Numbers do not add up to total number of women with venous thromboembolism, and corresponding person years also varies slightly becausewomen are censored at different times in each analysis and some women have had admissions for both conditions.*Women with pulmonary embolism or deep vein thrombosis.†Women with pulmonary embolism.‡Women with deep vein thrombosis.

RESEARCH

page 4 of 8 BMJ | ONLINE FIRST | bmj.com

Sweetland S et coll. BMJ 2009

Durée prolongée (4 semaines) pour chirurgie oncologique abdomino-pelvienne

5 essais cliniques randomisés (1389 pts) Cancer (3) HBPM (5) Double-insu (3) Insu dans l’évaluation (2) Veinographie (5)

Résultats Diminution risque TPP Pas d’effet sur EP ou mortalité Aucun risque accru de saignement

Recommandation forte

Chirurgie cardiaque Risque de thromboembolie

Incertain, moins de 1 % (modéré), pas de données à l’ère de la prophylaxie universelle

Risque de saignement élevé Deux essais cliniques randomisés

Aucun comparant héparine vs. rien/mécanique

Recommandation faible Héparine si séjour compliqué Jambières si séjour non-compliqué

Craniotomie Risque de thromboembolie

4% (en général), 8% (néo primaire), 18% (métastase)

Risque de saignement 1%, mais conséquences +++

Trois revues systématiques (6 études, 1170 pts) Diminution risque TPP Augmentation non significative de saignement

Recommandation faible Héparine si néoplasie Jambières si pas de néoplasie

Chirurgie spinale Risque de thromboembolie

Faible si pas de néoplasie Modéré si néoplasie

Risque de saignement 0,5%, mais conséquences +++

Une revue systématique Population mixte, haut risque de biais

Recommandation faible Héparine si néoplasie ou approche antérieure & postérieure Jambières si pas de néoplasie

Arthroplastie ou fx hanche Risque de thromboembolie

Élevé

Risque de saignement Variable, conséquences moindres

Recommandation forte Début de la prophylaxie ± 12h plutôt que ± 4h

Recommandation faible Usage concomitant de jambières pneumatiques (18h/j) Thromboprophylaxie prolongée (35 jours)

Arthroplastie ou fracture de hanche Anciens agents comme

comparateur

HNF Warfarin ASA Fondaparinux

HBPM

! TPP = TPP ! TPP = TPP

= EP = EP = EP = EP

= saignement ! saignement = saignement = saignement


Arthroplastie ou fracture de hanche Nouveaux agents comme

comparateur

Rivaroxaban Dabigatran Apixaban Edoxaban

HBPM

" TPP = TPP " TPP " TPP

= EP = EP = EP = EP

= saignement = saignement = saignement = saignement


Arthroscopie ou trauma isolé du MI

Risque de thromboembolie Faible

Risque de saignement Faible

Revue systématique Arthroscopie (4 études, 529 patients) Trauma (5 études, 1568 patients)

Recommandation faible Pas de thromboprophylaxie

• Quantification du risque embolique • Quantification du risque hémorragique • Choix de l’agent

Arthroplastie (HBPM, anti-Xa ou anti-thrombine PO) Autres chirurgies (HBPM ou HNF)

• Traitement prolongé de 4 semaines Arthroplastie (HBPM, anti-Xa ou anti-thrombine PO) Chirurgie abdominale ou pelvienne majeure (HBPM)

Conclusions

Prévention de la maladie thromboembolique aux

soins intensifs



6 février, 2014

Objectifs • Revoir l’épidémiologie des maladies thromboemboliques à l’unité des soins intensifs • Décrire les limites et l’utilité des différentes stratégies diagnostiques • Comprendre l’utilité des différentes modalités prophylactiques pharmacologiques

Patients traumatisés

Geerts WH et coll. N Engl J Med 1994

The New England Journal of Medicine Downloaded from nejm.org at BIBLIOTHEQUE UNIV LAVAL SEC ACQ on June 18, 2012. For personal use only. No other uses without permission.

Copyright © 1994 Massachusetts Medical Society. All rights reserved.

Facteurs de risque Âge

1,05 (1,03-1,06) Transfusion

1,74 (1,03-2,93) Chirurgie

2,30 (1,08-4,89) Fx fémur ou tibia

4,82 (2,79-8,33) Blessure médullaire

8,59 (2,92-25,28)

Patients médico-chirurgicaux

À l’admission 3 % ont une TPP proximale à l’échographie1,2

Avant l’ère de la thromboprophylaxie Le tiers développe une TPP proximale à l’échographie durant leur séjour3

À l’autopsie 7-27% d’embolie pulmonaire4

1Cook DJ et coll, Crit Care Med 2005

2PROTECT Investigators, N Engl J Med 2011 3Hirsh DR et coll, JAMA 1995

4McLeod AG et coll., Crit Care Clin 2011

21

Appendix Figure 4. This figure shows the numbers of proximal leg deep venous thromboses detected in the trial, by day from randomization.

PROXIMAL LEG DVT

0

5

10

15

20

25

1 11 21 31 41 51 61 71 81 91

Study Day

In ICU Post ICU

Moment du diagnostic chez les patients médico-chirurgicaux

PROTECT Investigators, N Engl J Med 2011

Facteurs de risque IMC (par 10 points d’augmentation) • TPP proximale:1,25 (1,06-1,46) • Embolie pulmonaire:1,37 (1,02-1,83) • Événements totaux :1,18 (1,04-1,35)

Statine • Embolie pulmonaire:0,46 (0,27-0,77)

Vasopresseurs ou inotropes • Embolie pulmonaire:1,84 (1,01-3,35)

Antécédent personnel ou familial • Événements totaux:1,64 (1,03-2,59)

Lim W et coll., soumis 2013

Patients médico-chirurgicaux

L’examen physique est non fiable

1Crowther et coll. J Crit Care 2005

Method 2 also lacked discriminatory power. Of 134 patientswith a score of 0, 10 (7%) had a DVT. The scores andproportions of patients with DVT for each were as follows:score 1, 10 (12%) of 83; score 2, 1 (6%) of 16; score 3, 1 (25%)of 4; and score 4, 2 (100%) of 2. As with method 1, patientswith a score in the bhighQ range (a score of 3 or more) had ahigh prevalence of deep venous thrombosis (3 of 6; 50%).However, once again, the scoring system lacked discrimina-tory power in that almost half of patients with DVT had a lowleg-specific risk score.

To further examine the test characteristics of thesemethods, patients with and without DVT were comparedusing an ROC. Using method 1, the AUC (where an idealtest would have an area of 1.0 and a test with no diagnosticutility would have an area of 0.5) was 0.57 (95% CI,0.33-0.78; P = .01) for the ipsilateral leg (Fig. 1). Similarly,using method 2, the AUC was 0.59 (95% CI, 0.42-0.75;P = .02) (Fig. 2). For low, moderate, and high pretestprobability scores, the likelihood ratios were, respectively,0.8 (95% CI, 0.6-1.1), 1.3 (95% CI, 0.6-2.7), and 9.0 (95%CI, 1.9-42.1) for method 1 and 0.7 (95% CI, 0.4-1.2),1.1 (95% CI 0.7-1.7), and 9.0 (95% CI, 1.9-42.1) for method2 (where 0 = low, 1-2 = medium, 3 or more = high).

6. Discussion

We found that 2 DVT scoring systems that have beenvalidated in symptomatic outpatients are not useful incritically ill medical-surgical patients. Thus, most patientsin both the risk classification and the risk scoring systemsexamined had a low probability of DVT, irrespective of itspresence, as diagnosed by ultrasonography. Given that anapproach to DVT screening must have a high sensitivity(low rate of false negatives), we conclude that physicalexamination is not useful to rule out a diagnosis of DVT inthe critically ill because most patients with this diagnosiswill not be detected using physical examination techniques.

Our results are concerning because they suggest that, inthe absence of a highly effective form of thromboprophy-laxis that is universally applied, routine screening forproximal DVT may be indicated in the critically ill be-cause it is the only way of detecting symptomless proximalDVT. Proximal DVTs in this population are associated withFig. 1 Receiver operating characteristic curve (method 1).

Fig. 2 Receiver operating characteristic curve (method 2).

Table 4 Clinical characteristics of critically ill cohort

Patient Characteristic Cases(n = 24)

Controls(n = 215)

P

Age (mean [SD]) 68.5 (13.8) 66.3 (15.4) .51Sex (n [%]) 10 (41.7) 86 (40.0) .87APACHE II

(mean [SD])

24.5 (7.4) 25.5 (8.4) .59

Medical admission(N [%])

19 (79.2) 184 (86.0) .37

Prior DVT orPE (n [%])

7 (29.2) 16 (7.4) .004

Duration of

mechanicalventilation (d[median, IQR])

17 (6, 27) 6 (3, 13) .002

ICU mortality (n [%]) 5 (20.8) 60 (27.9) .46

ICU LOS(median [IQR])

23.5 (11, 36.5) 9.0 (5, 17) b.001

Hospital

mortality (n [%])

11 (45.8) 81 (37.7) .44

SD indicates 1 SD; PE, pulmonary embolism; IQR, intraquartile range;

LOS, length of stay.

M.A. Crowther et al.338

Method 2 also lacked discriminatory power. Of 134 patientswith a score of 0, 10 (7%) had a DVT. The scores andproportions of patients with DVT for each were as follows:score 1, 10 (12%) of 83; score 2, 1 (6%) of 16; score 3, 1 (25%)of 4; and score 4, 2 (100%) of 2. As with method 1, patientswith a score in the bhighQ range (a score of 3 or more) had ahigh prevalence of deep venous thrombosis (3 of 6; 50%).However, once again, the scoring system lacked discrimina-tory power in that almost half of patients with DVT had a lowleg-specific risk score.

To further examine the test characteristics of thesemethods, patients with and without DVT were comparedusing an ROC. Using method 1, the AUC (where an idealtest would have an area of 1.0 and a test with no diagnosticutility would have an area of 0.5) was 0.57 (95% CI,0.33-0.78; P = .01) for the ipsilateral leg (Fig. 1). Similarly,using method 2, the AUC was 0.59 (95% CI, 0.42-0.75;P = .02) (Fig. 2). For low, moderate, and high pretestprobability scores, the likelihood ratios were, respectively,0.8 (95% CI, 0.6-1.1), 1.3 (95% CI, 0.6-2.7), and 9.0 (95%CI, 1.9-42.1) for method 1 and 0.7 (95% CI, 0.4-1.2),1.1 (95% CI 0.7-1.7), and 9.0 (95% CI, 1.9-42.1) for method2 (where 0 = low, 1-2 = medium, 3 or more = high).

6. Discussion

We found that 2 DVT scoring systems that have beenvalidated in symptomatic outpatients are not useful incritically ill medical-surgical patients. Thus, most patientsin both the risk classification and the risk scoring systemsexamined had a low probability of DVT, irrespective of itspresence, as diagnosed by ultrasonography. Given that anapproach to DVT screening must have a high sensitivity(low rate of false negatives), we conclude that physicalexamination is not useful to rule out a diagnosis of DVT inthe critically ill because most patients with this diagnosiswill not be detected using physical examination techniques.

Our results are concerning because they suggest that, inthe absence of a highly effective form of thromboprophy-laxis that is universally applied, routine screening forproximal DVT may be indicated in the critically ill be-cause it is the only way of detecting symptomless proximalDVT. Proximal DVTs in this population are associated withFig. 1 Receiver operating characteristic curve (method 1).

Fig. 2 Receiver operating characteristic curve (method 2).

Table 4 Clinical characteristics of critically ill cohort

Patient Characteristic Cases(n = 24)

Controls(n = 215)

P

Age (mean [SD]) 68.5 (13.8) 66.3 (15.4) .51Sex (n [%]) 10 (41.7) 86 (40.0) .87APACHE II

(mean [SD])

24.5 (7.4) 25.5 (8.4) .59

Medical admission(N [%])

19 (79.2) 184 (86.0) .37

Prior DVT orPE (n [%])

7 (29.2) 16 (7.4) .004

Duration of

mechanicalventilation (d[median, IQR])

17 (6, 27) 6 (3, 13) .002

ICU mortality (n [%]) 5 (20.8) 60 (27.9) .46

ICU LOS(median [IQR])

23.5 (11, 36.5) 9.0 (5, 17) b.001

Hospital

mortality (n [%])

11 (45.8) 81 (37.7) .44

SD indicates 1 SD; PE, pulmonary embolism; IQR, intraquartile range;

LOS, length of stay.

M.A. Crowther et al.338

Score de Wells Score de Wells modifié

Comment diagnostiquer?

Comment diagnostiquer? Échographie par compression

Sensibilité et spécificité de 95% Peu d’utilité du Doppler Peu d’utilité de variation du débit avec Valsalva

Simulation mathématique de 1000 patients médico-chirurgicaux

Thromboprophylaxie dans 85 % Incidence de 8,5 % de TPP

Gain clinique 3 épisodes d’embolie pulmonaire 2 épisodes de saignement majeur

Coût 223 801 $ par QALY (100 000 $ pour dialyse) 50 000 $ par QALY si incidence de 15 %

Dépistage systématique

Sud S et coll., Am J Resp Crit Care Med 2011

Échocardiographie Cinq signes

Signe de McCullen Thrombus dans l’oreillette droite Dilatation du ventricule droit Dysfonction ventriculaire droite Régurgitation tricuspidienne

30-40% des EP ont des signes à l’écho

Comment diagnostiquer?

Comment prévenir chez les patients médico-chirurgicaux?

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

10.1056/nejmoa1014475 nejm.org 1

original article

Dalteparin versus Unfractionated Heparin in Critically Ill Patients

The PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group

The members of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) writing committee (Deborah Cook, M.D., Maureen Meade, M.D., Gor-don Guyatt, M.D., Stephen Walter, Ph.D., Diane Heels-Ansdell, M.Sc., Theodore E. Warkentin, M.D., Nicole Zytaruk, R.N., and Mark Crowther, M.D., McMaster Uni-versity, Hamilton, ON, Canada; William Geerts, M.D., University of Toronto, Toron-to; D. Jamie Cooper, M.D., and Shirley Val-lance, R.N., Alfred Hospital, Melbourne, VIC, Australia; Ismael Qushmaq, M.D., King Faisal Specialist and Research Cen-ter, Jeddah, Saudi Arabia; Marcelo Rocha, M.D., Santa Casa Hospital, Porto Alegre, Brazil; Otavio Berwanger, M.D., Hospital do Coracao, São Paulo; and Nicholas E. Vlahakis, M.D., Mayo Clinic, Rochester, MN) assume responsibility for the integri-ty of this article. Address reprint requests to Dr. Cook at the Departments of Medi-cine and Clinical Epidemiology and Bio-statistics, McMaster University Health Sci-ences Center, Rm. 2C10, 1200 Main St. W., Hamilton, ON L8N 3Z5, Canada, or at [email protected].

This article (10.1056/NEJMoa1014475) was published on March 22, 2011, at NEJM.org.

N Engl J Med 2011.Copyright © 2011 Massachusetts Medical Society.

A bs tr ac t

BackgroundThe effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other out-comes are uncertain in critically ill patients.

MethodsIn this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalte-parin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed with-in 2 days after admission, twice weekly, and as clinically indicated. Additional test-ing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle.

ResultsThere was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P = 0.57). The proportion of patients with pulmonary emboli was significantly lower with dalte-parin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (haz-ard ratio, 0.51; 95% CI, 0.30 to 0.88; P = 0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P = 0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P = 0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced throm-bocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P = 0.046).

ConclusionsAmong critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Ca-nadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov num-ber, NCT00182143.)

The New England Journal of Medicine Downloaded from nejm.org at BIBLIOTHEQUE UNIV LAVAL SEC ACQ on March 22, 2011. For personal use only. No other uses without permission.


PROTECT Investigators. N Engl J Med 2011

The n

ew

en

gl

an

d jo

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ed

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was present in 3.5%

of those receiving dalteparin and 3.4%

of those receiving unfractionated hepa-rin. Throughout the trial, the rates of cointerven-tions w

ith drugs or devices that influence bleed-ing or throm

botic risk were sim

ilar in the two

groups (Table 2). Doses of a study drug w

ere m

issed on 3.3% of study days, and the use of a

nonstudy drug occurred on 1.0% of study days.

The median duration of exposure to a study drug

in both groups was 7 days (interquartile range,

4 to 12).

Ou

tcom

esThe prim

ary outcome of incident proxim

al leg deep-vein throm

bosis developed in 96 of 1873 pa-tients (5.1%

) assigned to receive dalteparin and in 109 of 1873 patients (5.8%

) receiving unfractionat-ed heparin (hazard ratio in the dalteparin group, 0.92; 95%

confidence interval [CI], 0.68 to 1.23; P = 0.57) (Table 3 and Fig. 1). Pulm

onary embolism

developed in significantly few

er patients assigned to receive dalteparin (24 patients, 1.3%

) than in those assigned to receive unfractionated heparin (43 patients, 2.3%

) (hazard ratio, 0.51; 95% CI, 0.30

to 0.88; P = 0.01) (Table 3, and Fig. 2 in the Supple-m

entary Appendix). The two groups did not differ

significantly with respect to the rates of other deep-

vein thromboses or any venous throm

boembolism

(Table 3, and Fig. 3 in the Supplem

entary Appen-dix). There w

as a trend toward a low

er rate of the com

posite outcome of any venous throm

boembo-

lism or death for patients assigned to receive dalte-

parin (530 patients, 28.3%) than for those assigned

to receive unfractionated heparin (589 patients, 31.4%

), but this difference was not significant

(hazard ratio, 0.89; 95% CI, 0.79 to 1.01; P = 0.07).

Catheter-related thrombosis occurred in 44

patients (2.3%) assigned to receive dalteparin and

in 39 patients (2.1%) assigned to receive unfrac-

tionated heparin (P = 0.51). The results of leg ul-trasonography w

ere indeterminate in 4 patients

(0.2%) assigned to receive dalteparin and 6 pa-

tients (0.3%) assigned to receive unfractionated

heparin (P = 0.52).M

ajor bleeding occurred in 103 patients (5.5%)

assigned to receive dalteparin and 105 patients (5.6%

) assigned to receive unfractionated heparin (hazard ratio, 1.00; 95%

CI, 0.75 to 1.34; P = 0.98) (Table 4). H

eparin-induced thrombocytopenia w

as confirm

ed in 5 patients (0.3%) assigned to receive

dalteparin and 12 patients (0.6%) assigned to re-

ceive unfractionated heparin (hazard ratio, 0.47;

Table 3. Venous Thromboembolic Outcomes.

Outcome Intention-to-Treat Analysis As-Treated Analysis

Dalteparin(N = 1873)

Unfractionated Heparin

(N = 1873)Hazard Ratio

(95% CI) P ValueDalteparin(N = 1827)

Unfractionated Heparin

(N = 1832)Hazard Ratio

(95% CI) P Value

no. (%) no. (%)

Deep-vein thrombosis

Proximal 96 (5.1) 109 (5.8) 0.92 (0.68–1.23) 0.57 94 (5.1) 108 (5.9) 0.91 (0.68–1.23) 0.54

Any 138 (7.4) 161 (8.6) 0.93 (0.72–1.19) 0.54 135 (7.4) 160 (8.7) 0.92 (0.72–1.19) 0.54

Pulmonary embolism

Any 24 (1.3) 43 (2.3) 0.51 (0.30–0.88) 0.01 22 (1.2) 42 (2.3) 0.48 (0.27–0.84) 0.01

Possible 1 (<0.1) 4 (0.2) 1 (<0.1) 4 (0.2)

Probable 5 (0.3) 11 (0.6) 4 (0.2) 10 (0.5)

Definite 18 (1.0) 28 (1.5) 17 (0.9) 28 (1.5)

Definite or probable 23 (1.2) 39 (2.1) 0.53 (0.30–0.92) 0.02 21 (1.1) 38 (2.1) 0.49 (0.28–0.88) 0.02

Any venous thromboembolism 154 (8.2) 186 (9.9) 0.87 (0.69–1.10) 0.24 150 (8.2) 184 (10.0) 0.87 (0.69–1.10) 0.24

Venous thromboembolism or death 530 (28.3) 589 (31.4) 0.89 (0.79–1.01) 0.07 511 (28.0) 575 (31.4) 0.89 (0.78–1.004) 0.06

The New

England Journal of Medicine

Dow

nloaded from nejm

.org at BIBLIOTH

EQU

E UN

IV LA

VA

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on March 22, 2011. For personal use only. N

o other uses without perm

ission. Copyright ©

2011 Massachusetts M

edical Society. All rights reserved.

PROTECT Investigators. N Engl J Med 2011


Alhazzani W et coll., Crit Care Med 2013

Alhazzani et al

2094 www.ccmjournal.org

PE by 50% with a number needed to prophylax of 52. Hepa-rin thromboprophylaxis did not influence the risk of major bleeding or mortality. Trials testing UFH used only bid dos-ing. Although there are no direct comparisons of bid versus tid

UFH in any population, indirect comparisons suggest that their effects are similar on thrombosis and bleeding (27). Compared with UFH, LMWH was associated with a 40% lower risk of PE with a number needed to prophylaxis with LMWH instead of

Figure 2. Low-molecular-weight heparin (LMWH) versus unfractionated heparin (UFH). DVT = deep vein thrombosis, M–H = Mantel-Haenszel. Squares represent single trial estimates whereas diamonds represent pooled trial effects.

Alhazzani et al

2094 www.ccmjournal.org

PE by 50% with a number needed to prophylax of 52. Hepa-rin thromboprophylaxis did not influence the risk of major bleeding or mortality. Trials testing UFH used only bid dos-ing. Although there are no direct comparisons of bid versus tid

UFH in any population, indirect comparisons suggest that their effects are similar on thrombosis and bleeding (27). Compared with UFH, LMWH was associated with a 40% lower risk of PE with a number needed to prophylaxis with LMWH instead of

Figure 2. Low-molecular-weight heparin (LMWH) versus unfractionated heparin (UFH). DVT = deep vein thrombosis, M–H = Mantel-Haenszel. Squares represent single trial estimates whereas diamonds represent pooled trial effects.


Mieux vaut prévenir que guérir

Factors independently associated with major bleeding

No baseline patient characteristic was independentlyassociated with the risk of major bleeding. We found sixsignificant time-dependent predictors of major bleeding(Table 4): prolonged aPTT, low platelet count, use oftherapeutic heparin, use of antiplatelet agents, use of renalreplacement therapy, and any surgical procedure. Similarresults were obtained when backwards-stepwise elimina-tion analyses were performed (data not shown). When weexamined all two-way interactions of predictors in themodel after backwards-stepwise elimination, we foundonly one significant interaction. The association betweenlower platelet count and major bleeding was stronger in

the absence of concomitant acetylsalicylic acid or clopi-dogrel (HR 1.25, 1.15–1.36) than with either drug (HR1.06, 0.96–1.17) (p value for interaction = 0.0095).Platelet counts were lower at the time of bleeding inpatients who did not receive antiplatelet agents comparedwith those who did [median 149 9 109/L (104–223 9109/L) versus 212 9 109/L (128–274 9 109/L), p =0.005]. There was no interaction between use of thera-peutic heparin and aPTT (p = 0.41), between use oftherapeutic heparin and renal replacement therapy(p = 0.54), or between renal replacement therapy anduse of antiplatelet agents (p = 0.38). Neither dalteparinnor unfractionated heparin thromboprophylaxis wasassociated with major bleeding. When we tested the

Table 1 Baselinecharacteristics Patient characteristics Patients with major

bleeding, n = 208Patients without majorbleeding, n = 3,538

p-Value

Age, mean (SD), years 63.4 (16.3) 61.3 (16.5) 0.08Female sex, n (%) 89 (42.8) 1,525 (43.3)a 0.89APACHE II score, mean (SD) 23.5 (7.6) 21.4 (7.8)b \0.001Body mass index, mean (SD), kg/m2 28.0 (7.3)c 28.3 (7.7)d 0.57Medical admission, n (%) 155 (74.5) 2,676 (75.6) 0.74Personal history of VTE, n (%) 9 (4.3) 111 (3.2)a 0.31Admitting diagnosis, n (%)Respiratory 71 (34.1) 1,630 (46.3) \0.001Sepsis 51 (24.5) 498 (14.2)Gastrointestinal 36 (17.3) 484 (13.8)Cardiovascular 17 (8.2) 319 (9.1)a

Neurologic 8 (3.8) 221 (6.3)Renal 6 (2.9) 59 (1.7)Metabolic 4 (1.9) 140 (4.0)Other—surgical 9 (4.3) 109 (3.1)Other—medical 6 (2.9) 59 (1.7)

History of malignancy, n (%) 8 (3.8) 142 (4.0)a 1.0Baseline life support, n (%)Mechanical ventilation 195 (93.8) 3,163 (90.0)e 0.09Vasopressors 121 (58.2) 1,556 (44.3)e \0.001Chronic dialysis 8 (3.8) 110 (3.1)a 0.54

This table presents the characteristics of enrolled patients according to major bleeding status. Due tosome missing data, denominators vary for some summary measures (an = 3,519; bn = 3,517;cn = 197; dn = 3,400; en = 3,516)SD standard deviation, APACHE Acute Physiology and Chronic Health Evaluation, VTE venousthromboembolism

Table 2 Sites of majorbleeding Site of bleeding Number of

patients, n (%)% of patients withmajor bleeding n = 208(95 % CI)

% of overall cohortn = 3,746 (95 % CI)

Gastrointestinal 108 51.9 (45.2–58.6) 2.9 (2.4–3.5)Surgical sitea 63 30.3 (24.4–36.8) 1.7 (1.3–2.1)Respiratory 33 15.9 (11.5–21.4) 0.9 (0.6–1.2)Retroperitoneal 17 8.2 (5.2–12.7) 0.5 (0.3–0.7)Intracranial 7 3.4 (1.6–6.8) 0.2 (0.1–0.4)Pericardial 3 1.4 (0.5–4.2) 0.1 (0.03–0.2)Other 20 9.6 (6.3–14.4) 0.5 (0.3–0.8)

This table presents the sites of major bleeding among 208 patients. Sites of bleeding are not mutuallyexclusivea 15 patients had major bleeding at central venous catheter insertion site

Lauzier F et coll., Intensive Care Med 2013


Table 3 Incidence of potentialrisk factors for bleeding All patients,

n = 3,724aPatients with majorbleeding, n = 208

Use of antiplatelet agents 1,244 (33.4) 80 (38.5)Acetylsalicylic acid 1,204 (32.3) 78 (37.5)Clopidogrel 194 (5.2) 10 (4.8)Concomitant therapy 154 (4.1) 8 (3.8)

Use of therapeutic heparin 144 (3.9) 13 (6.3)Renal replacement therapy 502 (13.5) 56 (26.9)ModalityIntermittent 334 (9.0) 31 (14.9)Continuous 258 (6.9) 26 (12.5)Sustained low-efficiency dialysis 36 (1.0) 4 (1.9)

Circuit anticoagulationUnfractionated heparin 289 (7.8) 22 (10.6)Saline flushes 251 (6.7) 21 (10.1)Citrate 160 (4.3) 19 (9.1)Danaparoid 7 (0.2) 1 (0.5)

Surgery 678 (18.2) 19 (9.1)Head and neck 366 (9.8) 10 (4.8)Thoracic 74 (2.0) 2 (1.0)Gastrointestinal 221 (5.9) 7 (3.4)Plastic 51 (1.4) 1 (0.5)Cardiac 17 (0.5) 0 (0.0)Vascular 14 (0.4) 0 (0.0)Orthopedic 15 (0.4) 0 (0.0)

This table presents therapeutic interventions and all surgical procedures in all patients in the secondcolumn. In the third column, among patients who had major bleeding, we present these interventions upto 3 days prior to major bleeding (or 7 days for use of antiplatelet agents)a Twenty-two patients had missing daily data. Therefore, 3,724 patients contributed to the risk factoranalysis

Table 4 Risk factors for majorbleeding Hazard ratio

(95 % CI)Adjustedp value

Baseline characteristicsAge (10 year increase) 0.99 (0.89–1.09) 0.77APACHE II (10 point increase) 1.04 (0.85–1.27) 0.70Medical admission 1.31 (0.88–1.93) 0.18End-stage renal disease 0.88 (0.41–1.88) 0.74

Time-dependent factorsLife supportInvasive mechanical ventilation 1.04 (0.65–1.67) 0.87Vasopressor infusion 1.27 (0.92–1.74) 0.14Any renal replacement therapy 1.75 (1.20–2.56) 0.004

Laboratory resultsHighest INR (0.5 unit increase) 1.03 (0.93–1.14) 0.58Highest aPTT (10 s increase) 1.10 (1.05–1.14) \0.001Lowest platelet count (50 9 109/L decrease) 1.16 (1.09–1.24) \0.001

Other interventionsSurgical procedure 1.64 (1.01–2.65) 0.045Stress ulcer prophylaxis 1.09 (0.66–1.82) 0.73Acetylsalicylic acid or clopidogrel 1.38 (1.02–1.88) 0.04Therapeutic heparin 3.26 (1.72–6.17) \0.001Prophylactic low-molecular-weight heparin 1.16 (0.78–1.73) 0.46Prophylactic unfractionated heparin 0.93 (0.62–1.39) 0.72Activated protein C 1.26 (0.50–3.17) 0.62

This table presents the independent risk factors for major bleeding using multivariable time-to-eventCox regression analysis. Time-dependent risk factors were considered in the preceding 3 days, or7 days in the case of acetylsalicylic acid or clopidogrel. All covariates were included in the modelAPACHE Acute Physiology and Chronic Health Evaluation, INR international normalized ratio, aPTTactivated partial thromboplastin time



assumption of nonproportional hazards, we did not findany significant interactions between time and any of thevariables.

Clinical outcomes related to major bleeding

When compared with patients who did not have majorbleeding, patients who had major bleeding had longermedian duration of mechanical ventilation, and longerICU and hospital length of stay, and received significantlymore red blood cell and frozen plasma transfusions(Table 5). Most transfused patients received leukode-pleted blood products, as universal leukodepletion wasimplemented in Canada and the UK since 1999 and inAustralia since 2008 and 86.6 % of patients enrolled werefrom those countries. Among patients with major bleed-ing who died, the median time from the first day ofbleeding to death was 11 (5–25) days. After adjustmentfor baseline characteristics, patients who had majorbleeding were significantly more likely to be transfusedand had significantly higher ICU mortality (HR 1.64,1.27–2.10) and hospital mortality (HR 2.09, 1.69–2.57)(Table 6).

Discussion

In medical–surgical critically ill patients, we observed anincidence of major bleeding of approximately 6 %. Wealso found that prolonged aPTT, lower platelet count,treatment with therapeutic heparin, antiplatelet agents,renal replacement therapy, and surgery were indepen-dently associated with major bleeding. Neither baselinecharacteristics nor type of heparin thromboprophylaxispredicted major bleeding. When adjusting for other con-founders, major bleeding was associated with greatertransfusion of blood products, and a twofold increasedrisk of ICU and hospital mortality.

Our findings are consistent with the 5.2 % (95 % CI3.6–7.6 %) major bleeding rate found in a single-centerobservational study of consecutive unselected medical–surgical ICU patients, all of whom received prophylacticunfractionated heparin [8], and similar to a 7.2 % (95 %CI 4.0–12.8 %) major bleeding rate found in a multicenterobservational study in which all medical–surgical ICUpatients received prophylactic low-molecular-weightheparin [12]. Our results differ from those of a multi-center observational study of non-critically ill medicalpatients [13], which found a 1.2 % major bleeding

Table 5 Blood products transfused, duration of mechanical ventilation, and ICU and hospital length of stay

Patients with majorbleeding, n = 208

Patients without majorbleeding, n = 3,538a

Unadjustedp value

Units of red blood cells transfused (ever),b median (25th–75th) 8 (4–15), n = 193 2 (1–4), n = 1,034 \0.001Units of platelets transfused (ever),b median (25th–75th) 5 (2.5–11.5), n = 52 5 (2–6), n = 61 0.15Units of frozen plasma transfused (ever),b median (25th–75th) 6 (2–11), n = 91 3 (2–5), n = 190 \0.001Units of cryoprecipitate transfused (ever),b median (25th–75th) 7 (3–10), n = 20 5 (5–10), n = 3 0.89Duration of invasive mechanical ventilation (days), median (25th–75th) 16.5 (10–30) 5 (2–10) \0.001Duration of ICU stay (days), median (25th–75th) 23 (15–39) 9 (6–15) \0.001Duration of hospital stay (days), median (25th–75th) 36 (21–66) 21 (12–38) \0.001

This table presents unadjusted comparison of the amount of bloodproducts transfused per patient and duration of mechanical venti-lation, and ICU and hospital stay in patients who had majorbleeding and patients without major bleeding

a n = 3,516 who have daily data for transfusionb Per patient who had transfusions

Table 6 Multivariable analysis of transfusion of blood products and mortality

Patients with majorbleeding, n = 208

Patients without majorbleeding, n = 3,538a

Adjustedb hazardratio (95 % CI)

Adjustedb

p value

Red blood cell transfusion (ever), n (%) 193 (92.8) 1,034 (29.4) 8.54 (6.70–10.89) \0.001Platelet transfusion (ever), n (%) 52 (25.0) 61 (1.7) 18.61 (11.71–29.57) \0.001Frozen plasma transfusion (ever), n (%) 91 (43.8) 190 (5.4) 15.81 (11.27–22.18) \0.001Cryoprecipitate transfusion (ever), n (%) 20 (9.6) 3 (0.1) 97.20 (31.59–299.05) \0.001ICU mortality, n (%) 82 (39.4) 506 (14.3) 1.64 (1.27–2.10) \0.001Hospital mortality, n (%) 106 (51.0) 767 (21.7) 2.09 (1.69–2.57) \0.001

This table presents the outcomes associated with major bleedingICU intensive care unita n = 3,516 who have daily data for transfusion and ventilationinformation

b Adjusted for age, APACHE II score, baseline use of inotropes/vasopressors, and baseline mechanical ventilation (invasive ornoninvasive). All covariates were included in the models


Que faisons-nous?

Lauzier et coll., Crit Care 2014, sous presse

Patients (N=1935)

Patient-Days (N=12756)

Prophylactic Anticoagulants LMWH 535 (27.6) 2687 (21.1)

UFH 1044 (54.0) 5504 (43.1) Therapeutic Anticoagulants 390 (20.2) 1693 (13.3)

UFH 284 (14.7) 1210 (9.5) LMWH 35 (1.8) 119 (0.9)

Coumadin 94 (4.9) 324 (2.5) Danaparoid 5 (0.3) 7 (0.05)

Other* 52 (2.7) 168 (1.3) Any of the above 1619 (83.7) 9589 (75.2)

Patients médico-chirurgicaux •  28 centres nord-américains •  Novembre 2011

HNF ou HBPM?

Lauzier et coll., Crit Care 2014, sous presse

Évaluation pharmaco-économique de PROTECT

Daltéparine plus rentable • Même si le coût moyen est de 8,13$/jour • Même si le coût augmenterait à 183 $/jour • Aucun seuil minimal pour lequel l’HNF serait plus rentable

Fowler R et coll., soumis 2013

editorials

n engl j med 358;23 www.nejm.org june 5, 2008 2507

Figure 1. Activation of the Contact System by a Polyanion Such as Oversulfated Chondroitin Sulfate (OSCS), a Heparin Contaminant.

The most common disaccharide units of heparin and the OSCS contaminant are shown with their high negative charge densities. Fac-tors XII and XI, high-molecular-weight kininogen, and prekallikrein — members of the contact system — circulate in the blood as inac-tive precursor molecules. Although the physiologic activation of this system occurs on cell surfaces and perhaps in connective tissue, activation also occurs on exposure to a negatively charged membrane or polymer and on exposure to certain microbial surfaces. Both dextran sulfate and OSCS, for example, facilitate the autocatalytic activation of factor XII to XIIa, which then activates the transformation of factor XI to factor XIa and plasma prekallikrein to plasma kallikrein. Factor XIa can activate the intrinsic coagulation system, whereas plasma kallikrein catalyzes the conversion of high-molecular-weight kininogen to bradykinin. C1 inhibitor is the principal regulator of these proteases, whereas other serine protease inhibitors such as α2-macroglobulin and α1-antitrypsin play lesser roles. Factor XIIa and plasma kallikrein also might activate plasminogen to plasmin (not shown); plasmin, like plasma kallikrein, has the ability in vitro to gen-erate anaphylatoxins from C5 and C3.

The New England Journal of Medicine Downloaded from nejm.org at BIBLIOTHEQUE UNIV LAVAL SEC ACQ on September 29, 2013. For personal use only. No other uses without permission.


Douketis J et coll., Arch Intern Med 2008

effect from drug bioaccumulation. In support of this con-clusion, no patient had bioaccumulation (trough anti-Xalevel !0.40 IU/mL) and trough anti-Xa levels were un-detectable ("0.10 IU/mL) or minimal (0.10-0.20 IU/mL) in 99% of measurements. Furthermore, dalteparinhad a “rapid rise and gradual fall to baseline” pharma-codynamic profile, typical of drugs that do not bioaccu-mulate. Finally, dalteparin prophylaxis was unlikely tocontribute to major bleeding, since all patients with suchbleeding had undetectable ("0.10 IU/mL) or minimal(0.10-0.18 IU/mL) trough anti-Xa levels, and an asso-ciation between detectable trough anticoagulant levelsand major bleeding was lacking (hazard ratio, 0.76; 95%CI, 0.15-3.81). Taken together, these findings challengethe premise that DVT prophylaxis with LMWHs shouldbe avoided in patients with renal insufficiency, includ-ing patients with severe renal insufficiency.

We also evaluated clinical outcomes relevant to pa-tients who are receiving DVT prophylaxis, since pa-tients with renal insufficiency are at high risk for bothDVT and bleeding.28,29 The incidence of proximal leg DVT(approximately 5%) is consistent with findings from pre-vious studies in critically ill patients who received DVTprophylaxis.3 However, 6 of 7 cases of DVT occurred inassociation with a central vein catheter, which suggeststhe need for careful clinical monitoring and, possibly,screening for DVT in such patients. The incidence of ma-jor bleeding (approximately 7%) is considerably higherthan that reported in other DVT prophylaxis trials1 butlikely reflects the disease burden in critically ill patients

and is consistent with findings from other studies as-sessing bleeding rates in such patients who receive anti-coagulants.3

Our study is novel in that it assessed bioaccumulationand the pharmacodynamics of LMWH exclusively in pa-tients with severe renal insufficiency. Our findings are con-sistent with a pilot study involving 19 critically ill patientswith moderate to severe renal insufficiency (creatinine clear-ance "50 mL/min), in which we found no detectable troughanticoagulant effect (anti-Xa level "0.10 IU/mL) 23 hoursafter administration of dalteparin sodium, 5000 IU oncedaily.12 Although LMWHs have been widely studied for theprevention and treatment of DVT and in patients with anacute coronary syndrome, these trials excluded patients withsevere renal insufficiency.1,30,31

Others have investigated the potential for dalteparinbioaccumulation in patients with renal insufficiency. Kaniand associates32 studied 10 critically ill patients with mod-erate to severe renal insufficiency (mean creatinine clear-ance, 29.5 mL/min) who received dalteparin sodium, 5000IU once daily, and had undergone serial anti-Xa testing.Although there was no dalteparin bioaccumulation, theclinical applicability of this study is limited because pa-tients received only one dose of dalteparin. Tincani andassociates33 assessed DVT prophylaxis with dalteparin in109 elderly patients (mean age, 83 years) with renal in-sufficiency. Although there was no evidence of daltepa-rin bioaccumulation after 6 days of treatment, only 24patients had severe renal insufficiency, and selected pa-tients received a lower dose of dalteparin sodium (2500

Table 2. Trough Anti-Xa Levels According to the Duration of Dalteparin Treatment

Variable

Study Day (From Date of Study Enrollment) of Trough Anti-Xa Measurements

1-3 4-6 7-9 10-12 !12

Proportion of all trough anti-Xa levels #0.10 IU/mL,No./total No. (%)

13/67 (19.4) 26/149 (17.4) 19/55 (34.6) 11/63 (17.5) 24/93 (25.8)

Proportion of patients with at least 1 trough anti-Xalevel #0.10 IU/mL, No./total No. (%)

13/63 (20.6) 25/103 (24.3) 19/54 (35.2) 11/48 (22.9) 16/37 (43.2)

Trough anti-Xa levels #0.10 IU/mL, median (IQR) 0.10 (0.10-0.13) 0.10 (0.10-0.14) 0.10 (0.10-0.13) 0.10 (0.10-0.12) 0.11 (0.10-0.13)

Abbreviation: IQR, interquartile range.

Table 3. Serial Anti-Xa Levels at 0, 1, 2, 4, 8, 12, 20, and 24 Hours After a Targeted 3, 10, and 17 Days of Dalteparin Treatmenta

Hours After DalteparinAdministration

Median (IQR) Anti-Factor Xa Levels

After 3 Days ofDalteparin Prophylaxis

(n=102)

After 10 Days ofDalteparin Prophylaxis

(n=46)

After 17 Days ofDalteparinProphylaxis

(n=15)

0 (Before treatment) "0.06 ("0.06-"0.06) "0.06 ("0.06-"0.06) "0.06 ("0.06-0.08)1 0.16 (0.10-0.26) 0.20 (0.11-0.29) 0.23 (0.19-0.25)2 0.28 (0.19-0.40) 0.29 (0.18-0.39) 0.32 (0.25-0.38)4 0.29 (0.20-0.42) 0.35 (0.24-0.43) 0.34 (0.27-0.45)8 0.19 (0.11-0.30) 0.23 (0.09-0.31) 0.17 (0.10-0.27)12 0.09 ("0.06-0.15) 0.11 ("0.06-0.18) 0.10 ("0.06-0.29)20 "0.06 ("0.06-0.06) "0.06 ("0.06-0.06) "0.06 ("0.06-0.11)24 "0.06 ("0.06-"0.06) "0.06 ("0.06-"0.06) "0.06 ("0.06-0.06)

Abbreviation: IQR, interquartile range.aThe lower limit of detection was an anti-Xa level lower than 0.06 IU/mL.

(REPRINTED) ARCH INTERN MED/ VOL 168 (NO. 16), SEP 8, 2008 WWW.ARCHINTERNMED.COM1809

©2008 American Medical Association. All rights reserved. at University Laval, on February 19, 2010 www.archinternmed.comDownloaded from

Daltéparine 5000 unités sous-cut die Clairance moyenne 18,9 ml/min Post-op chez 21%

Comment prévenir chez les insuffisants rénaux?

LOW-DOSE HEPARIN VS. LOW-MOLECULAR-WEIGHT HEPARIN TO PREVENT VENOUS THROMBOEMBOLISM

Volume 335 Number 10

!

703

ed outcomes were available for 244 patients. The recruitment ofpatients was discontinued after this formal review.

RESULTS

During the study period, there were 1076 admis-sions to our trauma unit. A total of 698 patientswere excluded for the following reasons: intracranialbleeding (220 patients); discharge likely within sev-en days (202); an estimated Injury Severity Scorebelow 9 (145); uncontrolled bleeding at the time ofpotential randomization (47); survival likely to beless than seven days (29); a need for therapeutic an-ticoagulation (13); inability to undergo venographybecause of leg amputation (12), severe foot injury(9), allergy to contrast material (7), or pregnancy(4); and a delayed transfer to our center (10). Eight-een patients or their surrogate family members re-fused to participate in the trial, and consent couldnot be obtained from 16.

One hundred seventy-three patients were ran-domly assigned to receive low-dose heparin, and171 were assigned to receive enoxaparin. Thirteenrandomized patients did not complete the study.Three patients assigned to heparin withdrew theirconsent; two more were given full doses of antico-agulants (one to preserve an arterial graft and theother, whose condition was too unstable for the pa-tient to be studied, to treat a suspected pulmonaryembolism); and an additional two were too ill to un-dergo venography. One patient assigned to enox-aparin withdrew her consent; two others died (oneof multisystem organ failure and the other of cardiacarrest), neither of whom had pulmonary embolismat autopsy; another patient underwent craniotomybecause of a tumor; and two patients were with-drawn from the study because of bleeding. Venog-raphy was nondiagnostic (either venous access inboth legs could not be achieved or the venogramwas inadequate at the time of adjudication) in 30patients assigned to heparin and 36 patients as-signed to enoxaparin. A total of 265 patients com-pleted the study and had adequate assessments ofoutcome. There were no significant differences be-tween the treatment groups with regard to any dem-ographic variables or injury characteristics (Table 1).In particular, the predicted risks of deep-vein throm-bosis if the patients had received no prophylaxiswere 55 percent in the heparin group and 54 per-cent in the enoxaparin group (P

!

0.69). Venogra-phy was performed in both groups a mean (

"

SD)of 11.9

"

2.3 days after randomization.

Deep-Vein Thrombosis

The overall rates of deep-vein thrombosis, as shownin Table 2, were 44.1 percent (60 of 136 patients) inthe heparin group and 31.0 percent (40 of 129 pa-tients) in the enoxaparin group (relative risk reduc-tion with enoxaparin, 30 percent; 95 percent confi-

*P

#

0.1 for all the characteristics shown. Plus–minus values are means

"

SD.†Some patients had injuries at more than one site.‡Each patient’s maximal mobility on each study day was scored on a five-

point scale described elsewhere.

1

§Data shown refer to each patient’s stay at the study center. When a pa-tient was hospitalized for more than 60 days, the stay was considered tohave lasted 60 days.

¶This assessment was made by the method described in the Appendix.

T

ABLE

1.

C

LINICAL

C

HARACTERISTICS

OF

THE

265 S

TUDY

P

ATIENTS

WITH

A

DEQUATE

V

ENOGRAPHY

.*

C

HARACTERISTIC

L

OSE

-D

OSE

H

EPARIN

(N

"

136)E

NOXAPARIN

(N

"

129)

Age — yr 37.0

"

16.5 39.1

"

16.8Male sex — no. of patients (%) 99 (72.8) 93 (72.1)Cause of injury — no. of patients (%)

Motor vehicle accidentPedestrian accidentFallViolenceOther

95 (69.9)15 (11.0)8 (5.9)

11 (8.1)7 (5.1)

84 (65.1)18 (14.0)7 (5.4)9 (7.0)

11 (8.5)Site of major injury — no. of patients (%)†

HeadFace, chest, or abdomenSpineLower limb (orthopedic injury)

6 (4.4)53 (39.0)24 (17.6)75 (55.1)

7 (5.4)47 (36.4)16 (12.4)69 (53.5)

Specific injury — no. of patients (%)†Spinal cord injuryPelvic fractureFemoral fractureTibial fracture

15 (11.0)25 (18.4)29 (21.3)27 (19.9)

8 (6.2)23 (17.8)24 (18.6)20 (15.5)

Injury Severity Score 22.7

"

9.0 23.1

"

8.3Surgery performed — no. of patients (%) 119 (87.5) 107 (82.9)Blood transfusion in first 24 hr — no. of

patients (%)48 (35.3) 55 (42.6)

Maximal mobility — mean of daily scores‡ 2.4

"

1.0 2.4

"

1.0Hospital stay — days§ 23.5

"

13.8 26.0

"

15.4Predicted risk of deep-vein thrombosis¶ 54.7

"

26.3 53.5

"

25.4

*One patient with proved pulmonary embolism was considered to haveproximal deep-vein thrombosis for the purposes of this comparison.

T

ABLE

2.

R

ATES

OF

T

HROMBOSIS

IN

THE

S

TUDY

P

ATIENTS

, B

OTH

O

VERALL

AND

A

CCORDING

TO

THE

P

RESENCE

OR

A

BSENCE

OF

L

EG

F

RACTURE

.

G

ROUP

AND

O

UTCOME

L

OW

-D

OSE

H

EPARIN

ENOXAPARIN

no. with event/no. studied (%)

All patientsAll deep-vein thrombosisProximal-vein thrombosis

60/136 (44.1)20/136 (14.7)

40/129 (31.0)8/129 (6.2)*

Patients with leg fracturesAll deep-vein thrombosisProximal-vein thrombosis

43/88 (48.9)16/88 (18.2)

31/80 (38.8)4/80 (5.0)

Patients without leg fracturesAll deep-vein thrombosisProximal-vein thrombosis

17/48 (35.4)4/48 (8.3)

9/49 (18.4)4/49 (8.2)*

The New England Journal of Medicine Downloaded from nejm.org at BIBLIOTHEQUE UNIV LAVAL SEC ACQ on June 18, 2012. For personal use only. No other uses without permission.


Geerts WH et coll. N Engl J Med 1996

Comment prévenir chez les polytraumatisés?

• Dépistage systématique Pas recommandé

• Prévention Patients médico-chirurgicaux • HBPM (daltéparine 5000 unités sc die)

Même si insuffisance rénale Traumatologie • HBPM (énoxaparine 30 mg sc bid) • Jambières lorsque HBPM contre-indiqué

Conclusions

Maladie thromboembolique et moyens non

pharmacologiques



6 février, 2014

Objectifs • Réviser les indications et l’utilité des moyens non-pharmacologiques pour la prévention des maladies thromboemboliques pour des patients de soins aigus

Filtres pour la prévention primaire en traumatologie

Revue systématique d’études observationnelles Cohortes historiques Pas de thromboprophylaxie dans le groupe contrôle !des embolies pulmonaires (pas d’effet sur TPP)

Rajasekhar J et coll. J Thromb Thrombolysis 2011

developed. A subsequent study by Rogers et al. [16]

reported approximately 6% insertions site thrombosis and

3% tilt complication rate.Three studies reported IVCF patency rates while no

studies reported retrieval rates. At mean follow-up of

32 months, Rosenthal et al. [17] noted 100% patency ratesof IVCFs. Both studies by Rogers and co workers [9, 16]

published 100% 30 day patency rate and over 90% 1-year

and 2-year patency rate.

Discussion

Practice patterns regarding the placement of pIVCFs in

trauma patients vary. The 2002 EAST guidelines cite ret-rospective data, expert opinion, or case report to support

the use of pIVCFs in high-risk trauma patients while 2008

ACCP guidelines recommend against the use of pIVCFs intrauma patients [2, 3]. However, in performing this sys-

tematic review and meta-analysis we note that even among

the higher quality observational cohort studies, the primarylimitation of these older studies is the inconsistent use of

appropriate pharmacologic prophylaxis. Practice patterns

have changed with respect to pharmacologic prophylaxis in2010. The current standard of practice for pharmacologic

prophylaxis in trauma patients is low-molecular weight

heparin, typically enoxaparin 30 mg subcutaneously twicedaily, based on two randomized controlled trails published

in 1996 [33, 34]. In this review, more than half of the

studies were published in the era prior to 1996 whenLMWH was not the standard of VTE prophylaxis. Only

one study was published recently in 2009 and even in this

study, prophylaxis was not standardized (LMWH, UFH, orCoumadin) [18].

With these limitations in mind, we performed a meta-

analysis to weigh the results of the pooled data based onboth contemporary and previous studies used to develop

the EAST and ACCP guidelines. Such an analysis may add

to the interpretation of the collective body of literature.

There was a statistically significant decrease in PE withpIVCF placement among the cohort studies (OR 0.21, 95%

CI 0.09–0.49). This illustrates how the pooled data may

provide a different result since, individually, nearly all ofthe cohort studies did not show significance. The exception

was the cohort study by Rodriguez et al. which demon-

strated a significant reduction in PE incidence in the IVCFgroup compared with a control group without IVCF (2.5%

versus 17%) matched for mechanism of injury and risk

factors for PE [7]. The risk of DVTs among the pIVCFgroup is less clear. There were only two cohort studies that

met our criteria for meta-analysis. There was a trend

towards an increased incidence of DVTs, OR 1.6 (95% CI0.76–3.37) in the IVCF group.

There are several limitations of this study. While the

methodological quality of observational studies is subopti-mal when compared to randomized controlled studies, the

number of published meta-analyses of observational studies

has increased [35]. Meta-analysis of observational studiescan be a useful adjunct to a systematic review, when gen-

eralizations have been made on a collective body of existing

studies. Some aspects of power, heterogeneity, and bias canbe addressed with stringent methods such as those employed

by the MOOSE criteria [19]. The MOOSE methodology has

been accepted by epidemiologists as an alternative whenthere is a lack of randomized controlled trials, yet there is an

abundance of observational studies of similar design.

As mentioned previously, most studies were publishedprior to the era that LMWH was established as the standard

of pharmacologic prophylaxis. More recent studies may

have employed pharmacologic prophylaxis but this waseither not documented or not standardized in terms of

dose, time of initiation, or length of extended prophylaxis

[5, 7, 15, 18]. This variation could account for why oursensitivity analysis showed that lack of pharmacologic

Fig. 2 Cohort studies reportingPE

Fig. 3 Cohort studies reportingDVT

44 A. Rajasekhar et al.

123

1 seul essai clinique randomisé de 34 patients Étude pilote Patients à haut risque

Obèse Blessé médullaire Fx bassin ou MI bilatéral

Thromboprophylaxie pharmacologique permise 90% à l’inclusion dans l’étude

Pas d’événement thromboembolique dans les deux groupes

Rajasekhar J et coll. J Trauma 2011

Filtres pour la prévention primaire en traumatologie

Jambières vs rien si haut risque de saignement Jambières + bas compressifs vs bas compressifs Haut risque de saignement HIP: 35% TCC: 25% Trauma: 10 %

Vignon P et coll. Intensive Care Med 2013

Compliance with GCS was poor in eight patients(2.0 %, one in the GCS group and seven in theIPC ? GCS group). Tolerance of GCS was poor in 13patients (3.3 %) in both groups with no differencebetween groups. The reported adverse effects (noneserious) were mild cutaneous injuries (n = 8) or dis-comfort (sweating, warmth, and tight GCS).Compliance with IPC was poor in 14 patients (7.0 %)in the IPC ? GCS group. Tolerance of IPC was poor in12 patients (6.0 %) and early removal of IPC wasnecessary in seven patients. The most frequent reasonsfor discontinuation of IPC were discomfort, noise andrestlessness. No serious adverse event was reportedwith IPC. By day 6, 15 deaths were related to fatalhemorrhage with no difference between the groups: 7(3.4 %) in the IPC ? GCS group and 8 (4 %) in theGCS group (p = 0.78). Nonfatal major hemorrhage wasobserved in 22 patients: 10 (4.9 %) in the IPC ? GCSgroup and 12 (5.9 %) in the GCS group (p = 0.65). Byday 30, 58 patients (29 %) in the GCS group and 61patients (30 %) in the IPC ? GCS group had died(p = 0.79). By day 90, 68 patients (34 %) in the GCSgroup and 69 patients (34 %) in the IPC ? GCS grouphad died (p = 0.97).

Discussion

In this first randomized trial specifically designed toevaluate the potential benefit of two distinct mechanicaldevices in ICU patients with a high risk of bleeding, wefound no significant difference in the incidence of VTEbetween those receiving IPC together with GCS and thosereceiving GCS alone.

For critically ill patients who are at high risk ofbleeding, current guidelines recommend the optimal useof mechanical thromboprophylaxis with GCS and/or IPCto prevent VTE at least until the bleeding risk decreases[17]. However, little is known about the efficacy andsafety of mechanical prophylaxis methods in ICU patients[21]. From a physiological point of view, the dynamiccompression produced by IPC is assumed to be more

efficient than the static compression produced by theGCS. In addition, IPC is thought to have a fibrinolyticaction, primarily by increasing tissue plasminogen acti-vator and decreasing plasminogen activator inhibitor [22].Despite these theoretical advantages, the addition of IPCprovided no additional benefit compared to GCS alone inour ICU patients with a high risk of bleeding. Neverthe-less, the lack of statistical power of the present study(54 % when calculated a posteriori) did not allow us toconfidently rule out a potential beneficial effect of IPC forthe prevention of VTE in this specific clinical setting.

This low statistical power may be explained by thelow incidence of VTE observed in the GCS group(9.2 %), when compared to an expected 15 % rate. In aprevious randomized clinical trial that evaluatedIPC ? GCS versus GCS alone in patients with intrace-rebral hemorrhage, we found a 15.9 % incidence of VTEin the GCS group using systematic CUS on day 10 [19].In the present trial, the incidence of VTE in a similarpopulation subset (patients with intracranial hemorrhagein the GCS group, n = 103) was 12.6 %. In an observa-tional study performed in 100 medical ICU patients,lower limb Doppler ultrasonography performed twice-weekly and 1 week after ICU discharge detected a DVTin 33 % of patients who were receiving a mechanicalprophylaxis [6]. A prospective study using twice-weeklyleg ultrasonography identified a proximal DVT in 25 of261 patients (10 %) during their ICU stay [3]. Takentogether, these results led us to initially expect a 15 %incidence of VTE in the GCS group, including asymp-tomatic distal and proximal DVT. The lower incidence ofVTE observed in the control group of the present studymay be related to a lower risk of thrombosis in criticallyill patients at high risk of bleeding when compared to thatof the general ICU population.

Early CUS evaluation on day 6 presumably con-tributed to the fairly low incidence of observed VTE inthe present study. In previous trials, VTE endpointswere generally evaluated on day 10 or later. Never-theless, in studies that screened regularly for DVT inICU patients, DVT were identified in the first days ofICU stay. In a study by Hirsch et al., 23 of 33 DVT(70 %) were detected during the first CUS [6].

Table 2 Venous thromboembolic events by day 6

Outcome IPC ? GCS group,n/N (%)

GCS group,n/N (%)

Relative risk 95 % confidence interval p value

Fatal pulmonary embolism 0/204 0/202 –Symptomatic pulmonary embolism 0/204 1/202 –Symptomatic deep vein thrombosis 0/204 0/202 –Asymptomatic distal deep vein thrombosis 6/179 (3.4) 12/183 (6.6) 0.51 0.2–1.33 0.17Asymptomatic proximal deep vein thrombosis 4/179 (2.2) 4/183 (2.2) 1.02 0.26–4.03 0.975Primary endpoint on day 6 10/179 (5.6) 17/184 (9.2) 0.60 0.28–1.28 0.191

Analysis 2.1. Comparison 2 Mechanical prophylaxis vs No prophylaxis, Outcome 1 DVT.

Review: Thromboprophylaxis for trauma patients

Comparison: 2 Mechanical prophylaxis vs No prophylaxis

Outcome: 1 DVT

Study or subgroup Mechanical No prophylaxis Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Knudson 1994 group I 4/32 2/64 3.5 % 4.00 [ 0.77, 20.69 ]

Knudson 1994 group III 0/26 5/39 11.6 % 0.13 [ 0.01, 2.34 ]

Velmahos 2005 7/26 6/21 17.4 % 0.94 [ 0.37, 2.38 ]

Fisher 1995 4/145 12/159 30.1 % 0.37 [ 0.12, 1.11 ]

Dennis 1993 8/281 10/114 37.4 % 0.32 [ 0.13, 0.80 ]

Total (95% CI) 510 397 100.0 % 0.55 [ 0.34, 0.90 ]Total events: 23 (Mechanical), 35 (No prophylaxis)

Heterogeneity: Chi2 = 9.66, df = 4 (P = 0.05); I2 =59%

Test for overall effect: Z = 2.40 (P = 0.016)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours Mechanical prophylaxis Favours No prophylaxis

43Thromboprophylaxis for trauma patients (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Barrera LM et coll. Cochrane Database Sys Rev 2013

Jambières vs rien en traumato

Clots 3. Lancet 2013

Articles

522 www.thelancet.com Vol 382 August 10, 2013

who were initially immobile (unpublished data from the Scottish Stroke Care Audit).20 This suggests that our results have external validity and would apply to about half of all patients who had had a stroke admitted to hospital. Our pre specifi ed decision to increase our sample size to take account of the overall primary event rate ensured that the trial had adequate power (>90%) to detect a 4% absolute diff erence in risk of proximal DVT. Central randomisation, mainly masked assessment of

our primary outcome, low losses to follow-up and intention-to-treat analysis have minimised bias.

The trial has some limitations: moderate adherence to IPC; imperfect masking of the technicians (because of some patients attending the CDU wearing the IPC, which could bias detection of our primary outcome); no masking of caregivers (which might bias their use of background treatment and assessment of some of the secondary outcomes); no masking of patients; some scheduled CDUs

IPC (n=1438) No IPC (n=1438) Absolute risk diff erence (95% CI)

Risk ratio (95% CI)* Odds ratio (95% CI) p value

Dead by 6 months 320 (22·3%) 361 (25·1%) –2·9 (–6·0 to 0·3) 0·87 (0·75 to 1·00) 0·85 (0·70 to 1·01) 0·059

Any DVT 240 (16·7%) 312 (21·7%) –5·0 (–7·9 to –2·1) 0·76 (0·64 to 0·89) 0·72 (0·60 to 0·87) 0·001

Any symptomatic DVT 77 (5·4%) 101 (7·0%) –1·7 (–3·4 to 0·1) 0·76 (0·56 to 1·01) 0·75 (0·55 to 1·02) 0·061

Any confi rmed PE 42 (2·9%) 49 (3·4%) –0·5 (–1·8 to 0·8) 0·86 (0·57 to 1·29) 0·86 (0·56 to 1·30) 0·463

Any death, DVT, or PE 526 (36·6%) 626 (43·5%) –7·0 (–10·5 to –3·4) 0·83 (0·75 to 0·92) 0·74 (0·63 to 0·86) <0·0001

Odds ratios and risk ratios are adjusted for factors included in our minimisation algorithm, as specifi ed in the statistical analysis plan. IPC=intermittent pneumatic compression. DVT=deep vein thrombosis. PE=pulmonary embolism. *Risk ratios were not prespecifi ed in our statistical analysis plan but are presented to enhance interpretation of results.

Table 4: All deaths and venous thromboembolic events (including those in fi rst 30 days) during the 6-month follow-up

Figure 4: Frequency of the primary outcome by allocated treatment in the prespecifi ed subgroups The graph show the point estimates of the OR (adjusted for baseline factors) for every subgroup as a square (whose size is proportional to the amount of information) and the horizontal lines depict the 95% CIs. The open diamond indicates the adjusted ORs with 95% CIs for all patients enrolled. The vertical line, at the OR of unity corresponds to the line of no eff ect. OR values of less than unity correspond to a reduction in the primary outcome with IPC. p values are for the interaction between the treatment eff ect and the subgroup. Patients who died without previous DVT (n=323) and those without either CDU (n=41) are excluded from the denominators, which are therefore diff erent to the total number allocated to each treatment group. IPC=intermittent pneumatic compression. DVT=deep vein thrombosis. CDU=compression duplex ultrasound. OR=odds ratio.

Delay: onset to randomisation0–1 day≥2 daysDelay: onset to randomisation0–2 days≥3 daysHeparin, warfarin, or alteplase usedYesNoCan lift both legs off bedYesNoProbability of favourable outcome0–0·150·16–1·0High risk of DVTYesNoStroke due to haemorrhageYesNoType of sleevesOriginalComfortAll

p value

52/550 (9·5%) 70/717 (9·8%)

94/967 (9·7%) 28/300 (9·3%)

38/306 (12·4%) 84/958 (8·8%)

84/807 (10·4%) 38/460 (8·3%)

82/765 (10·7%) 40/502 (8·0%)

104/981 (10·6%) 18/286 (6·3%)

11/163 (6·7%) 111/1104 (10·1%)

70/735 (9·5%) 52/532 (9·8%) 122/1267 (9·6%)

IPC n/N (%)

70/536 (13·1%) 104/709 (14·7%)

129/926 (13·9%) 45/319 (14·1%)

54/313 (17·3%) 120/932 (12·9%)

131/792 (16·5%) 43/453 (9·5%)

117/730 (16·0%) 57/515 (11·1%)

153/946 (16·2%) 21/299 (7·0%)

27/159 (17·0%) 147/1086 (13·5%)

95/727 (13·1%) 79/518 (15·3%) 174/1245 (14·0%)

No IPC n/N (%)

0·572

0·758

0·897

0·164

0·793

0·294

0·057

0·510

OR (95% CI)

Favours IPC Favours no IPC

10·1 10

0·001

0·71 (0·48–1·04)0·61 (0·44–0·85)

0·67 (0·51–0·89)0·61 (0·37–1·01)

0·68 (0·43–1·06)0·65 (0·48–0·87)

0·84 (0·53–1·34)0·58 (0·43–0·78)

0·64 (0·47–0·86)0·69 (0·45–1·05)

0·61 (0·47–0·80)0·87 (0·45–1·67)

0·36 (0·17–0·75)0·72 (0·55–0·93)

0·70 (0·51–0·98)0·60 (0·41–0·87)0·65 (0·51–0·84)

Jambières vs rien en ACV

Jambières vs prophylaxie pharmacologique en traumato

Analysis 3.1. Comparison 3 Pharmacological prophylaxis vs Mechanical prophylaxis, Outcome 1 DVT.


Comparison: 3 Pharmacological prophylaxis vs Mechanical prophylaxis

Outcome: 1 DVT

Study or subgroup Pharmacologycal Mechanical Risk Ratio Weight Risk Ratio


Ginzburg 2003 1/218 6/224 24.5 % 0.17 [ 0.02, 1.41 ]

Knudson 1992 3/37 5/76 13.5 % 1.23 [ 0.31, 4.88 ]

Knudson 1994 group I 1/44 4/32 19.1 % 0.18 [ 0.02, 1.55 ]

Knudson 1996 1/120 2/82 9.8 % 0.34 [ 0.03, 3.71 ]

Kurtoglu 2004 3/60 4/60 16.5 % 0.75 [ 0.18, 3.21 ]

Yanar 2007 2/40 4/40 16.5 % 0.50 [ 0.10, 2.58 ]

Total (95% CI) 519 514 100.0 % 0.48 [ 0.25, 0.95 ]Total events: 11 (Pharmacologycal), 25 (Mechanical)

Heterogeneity: Chi2 = 3.94, df = 5 (P = 0.56); I2 =0.0%



0.01 0.1 1 10 100

Favours pharmacologycal Favours mechanical




Analysis 5.1. Comparison 5 Mechanical + pharmacological prophylaxis vs Pharmacological, Outcome 1 DVT.


Comparison: 5 Mechanical + pharmacological prophylaxis vs Pharmacological

Outcome: 1 DVT

Study or subgroup

Mechanical pluspharmacologycal

prophylaxis Pharmacologycal Risk Ratio Weight Risk Ratio


Fuchs 2005 4/111 29/116 64.8 % 0.14 [ 0.05, 0.40 ]

Stannard 2006 9/103 13/97 30.6 % 0.65 [ 0.29, 1.46 ]

Yanar 2007 2/40 2/40 4.6 % 1.00 [ 0.15, 6.76 ]

Total (95% CI) 254 253 100.0 % 0.34 [ 0.19, 0.60 ]Total events: 15 (Mechanical plus pharmacologycal prophylaxis), 44 (Pharmacologycal)

Heterogeneity: Chi2 = 6.52, df = 2 (P = 0.04); I2 =69%



0.01 0.1 1 10 100

Favours mechanical + phar Favours pharmacologycal



Traumatologie


Jambières seules vs jambières +pharmaco en traumato

Filtre Jamais en prévention primaire

Jambières Alternative si contre-indication à une thromboprophylaxie pharmacologique Effet additif très incertain à la thromboprophylaxie pharmacologique

Conclusions

Traitement aigu de la maladie

thromboembolique



6 février, 2014

Objectifs • Revoir l’épidémiologie des maladies thromboemboliques à l’unité des soins intensifs • Décrire les limites et l’utilité des différentes stratégies diagnostiques • Comprendre l’utilité des différentes modalités prophylactiques • Réviser les modalités thérapeutiques

Quand commencer le traitement?


Table 6—[Section 2.5.1] Summary of Findings: LMWH vs IV UFH for Initial Anticoagulation of Acute VTE74

OutcomesNo. of Participants (Studies),

Follow-upQuality of the Evidence

(GRADE)Relative Effect

(95% CI)

Anticipated Absolute Effects

Risk With IV UFHRisk Difference With

LMWH (95% CI)

All-cause mortality

7,908 (17 studies), 3 mo Lowa,b due to risk of bias, publication bias

RR 0.79 (0.66-0.95) 46 per 1,000c 10 fewer per 1,000 (from 2 fewer to 16 fewer)

Recurrent VTE 7,976 (17 studies), 3 mo Lowa,b due to risk of bias, publication bias

RR 0.72 (0.58-0.89) 55 per 1,000c 15 fewer per ,1000 (from 6 fewer to 23 fewer)

Major bleeding 6,910 (20 studies), 3 mo Lowa,b,d due to risk of bias, publication bias

RR 0.67 (0.45-1) 15 per 1,000c 5 fewer per 1,000 (from 8 fewer to 0 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOf the 20 trials, allocation was concealed in nine and was unclear whether concealed in the remaining 11. In 18 trials, outcome assessors were blinded. Seven trials did not have any postrandomization exclusions or losses to follow-up. Ten trials reported the number of participants lost to follow-up, which ranged from 1.0% to 12.7%. One trial did not report the drop-outs.bInverted funnel plot very suggestive of publication bias. Many of the included studies are of small size, and all were funded by industry.cEvent rate corresponds to the median event rate in the included studies.dCI includes values suggesting signifi cant benefi t and no effect.

fi ve of these studies 83-87 that had unconfounded com-parisons. This evidence suggests that LMWH once daily and twice daily are associated with similar mor-tality, recurrent VTE, and major bleeding. However, the quality of the evidence is low because of impre-cision and inconsistency. The sixth study that used a lower total daily dose of LMWH with once-daily compared with twice-daily administration (enox-aparin 1.5 mg/kg once daily vs 1.0 mg/kg bid; enox-aparin 2 mg/kg once daily is not used) suggested that outcomes might be inferior with this once-daily regimen. 85

fondaparinux and LMWH are equivalent and that fondaparinux shares the advantages that LMWH has over SC UFH (section 2.5). This recommendation does not take into account difference in purchase cost between SC UFH and fondaparinux and is based on low-quality evidence.

Once- vs Twice-Daily Administration of LMWH for Initial Treatment of DVT: Two meta-analyses 80,81 summarized six studies comparing once-daily and twice-daily administrations of the same LMWH. 82-87 Table 8 and Table S8 summarize the fi ndings of

Table 5—[Section 2.5.1] Summary of Findings: LMWH vs SC UFH for Initial Anticoagulation of Acute VTE70,71,76,77

OutcomesNo. of Participants (Studies),

Follow-upQuality of the Evidence

(GRADE)Relative Effect

(95% CI)


Risk With SC UFHRisk Difference With

LMWH (95% CI)

All-cause mortality

1,566 (3 studies), 3 mo Moderatea,b due to imprecision

RR 1.1 (0.68-1.76) 33 per 1,000c 3 more per 1,000 (from 11 fewer to 25 more)

Recurrent VTE 1,563 (3 studies), 3 mo Moderatea,b due to imprecision

RR 0.87 (0.52-1.45) 42 per 1,000c 5 fewer per 1,000 (from 20 fewer to 19 more)

Major bleeding 1,634 (4 studies), 3 mo Moderatea,b due to imprecision

RR 1.27 (0.56-2.9) 16 per 1,000c 4 more per 1,000 (from 7 fewer to 30 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. SC 5 subcutaneous. See Table 1 and 3 legends for expansion of abbreviations.aIn the two largest trials (Prandoni et al,70 Kearon et al;71 87% of patients), allocation was concealed, outcome adjudicators and data analysts were concealed, analysis was intention to treat, and there were no losses to follow-up.bPrecision judged from the perspective of whether SC heparin is noninferior to LMWH. The total number of events and the total number of participants were relatively low.cEvent rate corresponds to the median event rate in the included studies.


Kearon Cet coll. CHEST 2012

HNF ou HBPM?

Filtres pour la prévention secondaire Indications Contre-indication à l’anticoagulothérapie Échec de l’anticoagulothérapie Fragilité hémodynamique

Recommandation forte Si pas d’anticoagulothérapie (2.13.2 et 5.9.2)

Filtres pour la prévention secondaire Utilité à court, moyen et long-terme

1 essai clinique randomisé de 400 patients Filtre + ATC vs ATC

1Decousus H et coll. N Engl J Med 1998 2PREPIC study group, Circulation 2005

12 jours1 2 ans1 8 ans2

TPP = ! (20 vs 8) ! (57 vs 41)

EP " (2 vs 9) = " (9 vs 24)

Mortalité = = =

Filtres pour la prévention secondaire Temporaire?

8,5 % des filtres sont retirés

Complications majeures (1%) Migration Rupture et saignement rétropéritonéal

Sarosiek s et coll. JAMA Intern Med 2013

Pour améliorer l’hémodynamie Diminution de la pression artère pulmonaire moyenne

4,4 mmHg Amélioration de la fonction ventriculaire droite

RC 3,1

Pour diminuer la charge thrombotique résiduelle

Aucune évidence

Dong C et coll. CHEST 2012

Pourquoi thrombolyser?

Qui est à risque de mourir d’une embolie pulmonaire?

Si non traitée • 30 %

Si traitée • Globalement, 5 %

Si arrêt cardiaque • 70 %

Si choc nécessitant des vasopresseurs • 30 %

Si pas d’hypotension •  2 %

Dong C et coll. CHEST 2012

Dysfonction ventriculaire droite et décès

Sanchez O et coll. Eur Heart J 2008

of RV dysfunction for predicting death was 2.5 (95% CI 1.2–5.5)with no heterogeneity. The pooled unadjusted relative risk forthe two spiral CT studies was 2.3 (95% CI 0.9–5.98).

For echocardiography and spiral CT, the pooled sensitivity,specificity, positive and negative predictive values are summarizedin Table 2.

Cardiac biomarkersTable 1 and Figure 3 summarize the characteristics of the eightstudies evaluating one or several cardiac biomarkers and thepooled unadjusted relative risk for mortality. Six studies assessedone biomarker15,16,19– 21,23 and two studies assessed two differentbiomarkers in the same patients.14,22 BNP was evaluated in fivestudies16,19 – 22 and pro-BNP in two studies.14,23 Cardiactroponin-T was evaluated in three studies.15,22,23 Two studiesdescribed potential confounding factors in detail.14,16 The patientswere recruited in the emergency department in one study,15 andwere admitted to cardiology departments in the other seven

studies.14,16,19– 23 All studies provided the method for biomarkerdetermination, the manufacturer, the name of the kit and time tomeasurement which ranged from 0 to 4 h after admission. Thethreshold used for the biological dosage was reported for sevenof the 10 evaluations (Table 1). The threshold value was definedaccording to ROC curve analysis in five studies.15,16,19,20,23 Thethreshold values varied from 0.08 to 0.49 ng/mL for BNP, from0.6 to 7.6 ng/mL for pro-BNP and from 0.01 to 0.07 ng/mL fortroponin-T. The pooled unadjusted relative risk for predictingin-hospital or 30-day death was 9.5 (95% CI 3.1–28.6) for BNP,5.7 (95% CI 2.2–15.1) for pro-BNP and 8.3 (95% CI 3.6–19.3)for troponin-T. No statistical heterogeneity was observed for anyof these biomarkers (I2 ¼ 0).

Some adjustment for confounders was reported in three studiesfor all-cause mortality.14,20,23 In one study, the prognostic value ofpro-BNP on in-hospital mortality was still statistically significantafter adjustment for pulse, oximetry, age, blood pressure, RV/LVratio, and tricuspid valve pressure gradient [OR (odds ratio) for

Figure 2 Prognostic value of right ventricular dysfunction for mortality in patients with pulmonary embolism without shock. The outcomewas in-hospital mortality for all studies, except two: (*) 40-day mortality and (†) 90-day mortality.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 2 Pooled diagnostic indexes for echocardiography, computed tomography, brain natriuretic peptide (BNP),pro-BNP, and cardiac troponin

Test

Echocardiography Computed tomography BNP Pro-BNP Cardiac troponin

Sensitivity (%) (95% CI) 70 (46–86) 65 (35–85) 88 (65–96) 93 (14–100) 81 (23–100)

Specificity (%) (95% CI) 57 (47–66) 56 (39–71) 70 (64–75) 58 (14–92) 84 (77–90)

Negative predictive value (%) (95% CI) 60 (55–65) 58 (51–65) 76 (73–79) 81 (65–97) 73 (68–78)

Positive predictive value (%) (95% CI) 58 (53–63) 57 (49–64) 67 (64–70) 63 (50–76) 75 (69–80)

95% CI, 95% confidence interval.

O. Sanchez et al1574

Sanchez O et coll. Eur Heart J 2008

Biomarqueurs et décès

Thrombus oreillette droite Pas un facteur de risque indépendant1

Thrombophlébite2

1Rorbicki A et coll. J Am Coll Cardiol 2003 2Jimenez D et coll., Am J Resp Crit Care Med 2010

remained an independent predictor of recurrent VTE whenpatients with nondiagnostic _V/ _Q scans or negative contrast-enhanced helical chest CT scans (n 5 28) were excluded fromthe analysis (adjusted HR, 4.93; 95% CI, 1.89 to 12.89; P 50.001).

External Validation in the RIETE Registry

Compared with the 707 patients in the original study cohort, the4,476 eligible patients from the RIETE validation cohort weresignificantly more likely to have immobilization for 4 days ormore, chronic pulmonary disease, and symptoms or signs ofDVT and PE at the time of presentation (Table 6). Hypoxemia

was significantly more prevalent among patients in the RIETEcohort compared with the study cohort. However, patients inthe RIETE cohort had a lower prevalence of cancer comparedwith patients in the study cohort. In the RIETE cohort,concomitant DVT was detected in 62.6% of patients (2,803 of4,476 patients; 62.6%; 95% CI, 61.2 to 64.0%), compared withthe 51.2% of patients in the study cohort (362 of 707 patients;51.2%; 95% CI, 47.5 to 54.9%; absolute risk difference, 11.4%;95% CI, 7.5 to 15.4%).

Of the 4,476 patients included in the RIETE validationcohort, 697 (697 of 4,476 patients; 15.6%; 95% CI, 14.5 to16.7%) patients died, compared with 10.9% (77 of 707 patients;

Figure 2. Mortality of patients with acutesymptomatic pulmonary embolism, strat-ified by the presence or absence of con-comitant deep vein thrombosis at thetime of pulmonary embolism diagnosis.DVT 5 deep vein thrombosis; PE 5 pul-monary embolism. Log-rank P , 0.001.

TABLE 3. UNADJUSTED AND ADJUSTED HAZARD RATIOS FOR OVERALL MORTALITY IN PATIENTSWITH ACUTE SYMPTOMATIC PULMONARY EMBOLISM

Risk Factor Unadjusted HR (95% CI) P Value Adjusted HR (95% CI) P Value

Age, per year 1.01 (0.99–1.02) 0.22 — —Male sex 1.43 (0.91–2.24) 0.12 — —COPD 0.93 (0.38–2.31) 0.88 — —Presence of DVT 2.48 (1.51–4.07) ,0.001 2.05 (1.24–3.38) 0.005SBP ,100 mm Hg 1.25 (0.57–2.71) 0.58 — —Dyspnea 0.99 (0.61–1.63) 0.98 — —Chest pain 0.86 (0.55–1.36) 0.53 — —Syncope 0.58 (0.25–1.34) 0.20 — —Cancer* 3.70 (2.37–5.78) ,0.001 3.69 (2.32–5.85) ,0.001Immobilization† 1.58 (0.99–2.53) 0.06 1.96 (1.20–3.20) 0.007DVT signs or symptoms 1.74 (1.10–2.76) 0.02 — —Insertion of an IVC filter 3.20 (1.17–8.74) 0.02 — —Suboptimal quality of oral anticoagulation‡ — —

Definition of abbreviations: CI 5 confidence interval; COPD 5 chronic obstructive pulmonary disease; DVT 5 deep veinthrombosis; HR 5 hazard ratio; IVC 5 inferior vena cava; SBP 5 systolic blood pressure.

Patients evaluated, n 5 707, with 77 deaths. Analysis was performed using final model chi square 5 52.62; P , 0.001.* Active or under treatment in the last year.† Immobilized patients are defined in this analysis as nonsurgical patients who had been immobilized (i.e., total bed rest with

bathroom privileges) for 4 days or more in the month before PE diagnosis.‡ Thirty percent or more of all measured INR values were less than 2.0.

Jimenez, Aujesky, Dıaz, et al.: Prognostic Significance of DVT 987

Localisation du thrombus et décès


5.6.2.2. In patients with acute PE, when a throm-bolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter (Grade 2C) .

5.6.3 Initial Anticoagulant Therapy in Patients Treated With Thrombolytic Therapy: Trials that evaluated thrombolysis for PE used IV UFH in

conjunction with thrombolytic therapy ( Table 30 , Tables S40-S42), and no randomized trials have com-pared different regimens of IV UFH in this setting. IV UFH should be given in full therapeutic doses 1,3 before thrombolytic therapy is administered, and it is acceptable to either continue or suspend the UFH infusion during administration of thrombo-lytic therapy (these two practices have never been

Table 30—[Section 5.6.1] Summary of Findings: Systemic Thrombolytic Therapy vs Anticoagulation Alone in Patients With Acute PEa-d,273,309,310,314,315

OutcomesNo. of Participants

(Studies), Follow-upQuality of the

Evidence (GRADE)Relative Effect

(95% CI)


Risk With No Systemically Administered

Thrombolytic Therapy

Risk Difference With Systemically Administered

Thrombolytic Therapy (95% CI)

Mortality 847 (12 studies), 30 d

Lowe-h due to risk of bias and imprecision

RR 0.7 (0.37-1.31)

Lowi,j

11 per 1,000 3 fewer per 1,000 (from 7 fewer to 3 more)

Highi,j


Recurrent PE 801 (9 studies), 30 d

Lowe-h due to risk of bias and imprecision

RR 0.7 (0.4-1.21)


Major bleeding 847 (12 studies), 10 d

Moderatee,f,h,k due to risk of bias and imprecision

RR 1.63 (1-2.68)l

Lowm

1 per 1,000 1 more per 1000 (from 0 more to 2 more)

Highm

62 per 1,000 39 more per 1,000 (from 0 more to 104 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOne study included exclusively patients with hemodynamic compromise (shock), six excluded them, whereas the rest either included a number of such patients or did not specify related eligibility criteria. Of studies not restricted to patients with hemodynamic compromise (n 5 11), only three were clearly restricted to patients with right ventricular dysfunction; the rest either did not specify related eligibility criteria or included both patients with and without right ventricular dysfunction. As a result, it was not possible to perform reliable categorization of studies to conduct subgroup analyses based on the presence or absence of right ventricular dysfunction or hemodynamic compromise.bStudies included patients at low risk for bleeding.cIncluded studies that used different thrombolytic agents with varying doses and durations of administration; no statistical heterogeneity was noted.dThrombolysis was in addition to anticoagulation (most of the studies used heparin followed by warfarin; three studies used warfarin only).eReport of methodologic quality was poor in most studies. Of the 12 eligible studies, allocation was concealed in fi ve, three were single blind (outcome assessor), six were double blind, and three were not blinded. Most studies did not report on missing outcome data. None of the studies were stopped early for benefi t. For the increase in bleeding with thrombolytic therapy, quality of evidence is increased from low to moderate because there is high quality evidence of this association in patients with myocardial infarction and the indirectness of this evidence to patients with PE is minor.fI2 5 0%.gCI includes values suggesting both benefi t and no effect or harm; small number of events.hInverted funnel plots suggestive of possible publication bias in favor of thrombolytics.iRecurrent PE stratifi cation based on the simplifi ed Pulmonary Embolism Severity Index validated in the RIETE (RegistroInformatizado de la Enfermedad Tromboembólica) cohort.262

jSome studies suggested that the baseline risk of mortality in patients with hemodynamic instability is as high as 30%.274 In that case, the absolute number of deaths associated with thrombolytics would be 90 fewer per 1,000 (from 189 fewer to 93 more).kCI includes values suggesting both harm and no effect; small number of events.lMajor bleeding risk stratifi cation derived from the RIETE cohort.30 The median risk of bleeding over the fi rst 10 d reported in the eligible trials was 3.1%. In that case, the absolute number of major bleeding events with thrombolysis would be 20 more per 1,000 (from 0 more to 52 more).mIndirect evidence from studies of thrombolysis for myocardial infarction and acute stroke provide more precise estimates of increase major bleeding with thrombolytics use.


Kearon C et coll. CHEST 2012


Konstantinides S et coll. N Engl J Med 2002

1146

·

N Engl J Med, Vol. 347, No. 15

·

October 10, 2002

·

www.nejm.org

The New England Journal of Medicine

stay was 16.7±8.4 days (range, 2 to 70). The mortal-ity rate was low in both treatment groups. Four pa-tients in the heparin-plus-alteplase group died, twofrom pulmonary embolism and two from underlyingdisease. Three patients in the heparin-plus-placebogroup died, two from pulmonary embolism and onefrom a bleeding complication. Although the mortalityrate in the two groups was similar, the rate of escala-tion of treatment because of clinical deterioration wasmuch higher in the heparin-plus-placebo group thanin the heparin-plus-alteplase group. For example, sec-ondary (rescue) thrombolysis was performed rough-ly three times as often in the heparin-plus-placebogroup as in the heparin-plus-alteplase group (Table 2).In the heparin-plus-placebo group, the indications forsecondary thrombolysis were cardiogenic shock (in4 patients), arterial hypotension requiring catechola-mine infusion (in 4), and worsening symptoms andrespiratory failure (in 24 patients, 3 of whom under-went endotracheal intubation and mechanical ventila-tion). In the heparin-plus-alteplase group, nine pa-tients underwent additional thrombolysis, one becauseof arterial hypotension and the remaining eight be-cause of worsening symptoms; one of the latter pa-tients underwent endotracheal intubation). Overall,

the incidence of the primary end point (death or es-calation of treatment) was significantly greater in theheparin-plus-placebo group than in the heparin-plus-alteplase group (34 patients [24.6 percent] vs. 13 pa-tients [11.0 percent], P=0.006).

In accord with these data, the probability of 30-day event-free survival according to Kaplan–Meieranalysis was significantly higher in the group of pa-tients treated with heparin plus alteplase than in thosetreated with heparin plus placebo (P=0.005 by thelog-rank test) (Fig. 1). Further analysis with use ofthe proportional-hazards model confirmed that treat-ment with heparin plus placebo predicted an unfavor-able in-hospital outcome: the relative risk of the pri-mary end point with heparin plus placebo as comparedwith heparin plus alteplase was 2.63 (P=0.006) (Ta-ble 3). As shown in Figure 2, the favorable outcomeof the patients assigned to heparin plus alteplase wasnot due to greater effectiveness of heparin anticoag-ulation in this group than in the other group, sincethe activated partial-thromboplastin time reached sim-ilar levels in the two treatment groups between 12and 48 hours after randomization. Of the other base-line variables tested in the proportional-hazards mod-el, age older than 70 years, female sex, and the pres-

*The numbers shown are based on calculations for the intention-to-treat population.†P values were calculated with the use of Fisher’s exact test (two-sided).‡Recurrence of pulmonary embolism had to be confirmed by ventilation–perfusion lung scanning,

spiral computed tomography, or pulmonary angiography.§Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or a drop in the hemoglobin

concentration by at least 4 g per deciliter, with or without the need for red-cell transfusion.¶Hemorrhagic or ischemic stroke had to be confirmed by computed tomography or magnetic res-

onance imaging.

T

ABLE

2.

I

N

-H

OSPITAL

C

LINICAL

E

VENTS

.*

E

VENT

H

EPARIN

PLUS

A

LTEPLASE

(N=118)

H

EPARIN

PLUS

P

LACEBO

(N=138) P V

ALUE

†

no. (%)

Primary end point

13 (11.0) 34 (24.6) 0.006Death from all causes 4 (3.4) 3 (2.2) 0.71Escalation of treatment 12 (10.2) 34 (24.6) 0.004

Catecholamine infusion (for persistent hypotension or shock)

3 (2.5) 8 (5.8) 0.33

Secondary thrombolysis 9 (7.6) 32 (23.2) 0.001Endotracheal intubation 3 (2.5) 3 (2.2) 0.85Cardiopulmonary resuscitation 0 1 (0.7) 1.0Embolectomy or thrombus fragmentation 0 1 (0.7) 1.0

Secondary end points

Recurrent pulmonary embolism‡ 4 (3.4) 4 (2.9) 0.89Major bleeding§ 1 (0.8) 5 (3.6) 0.29

Fatal bleeding 0 1 (0.7) 1.0Hemorrhagic stroke¶ 0 0 —

Ischemic stroke¶ 0 1 (0.7) 1.0

Copyright © 2002 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at MCMASTER UNIVERSITY HEALTH SCI LIB on January 8, 2007 .


Embolectomie par cathéter?

• Aucun essai clinique randomisé • Revue systématique de séries de cas1 • 594 patients • Succès clinique 86 %

• Recommandation 2C2 • Seulement si hypotension et contre-indication à la thrombolyse ou échec à la thrombolyse

1Kuo WT et coll. J Vasc Interv Radiol 2009

2Kearon C et coll. CHEST 2012

Et le patient qui vient de coder? T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;25 www.nejm.org december 18, 2008 2651

original article

Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest

Bernd W. Böttiger, M.D., Hans-Richard Arntz, M.D., Douglas A. Chamberlain, M.D., Erich Bluhmki, Ph.D., Ann Belmans, M.Sc.,

Thierry Danays, M.D., Pierre A. Carli, M.D., Jennifer A. Adgey, M.D., Christoph Bode, M.D., and Volker Wenzel, M.D., M.Sc.,

for the TROICA Trial Investigators and the European Resuscitation Council Study Group*

From the University of Cologne, Cologne, and the University of Heidelberg, Heidel-berg — both in Germany (B.W.B.); Charité, Benjamin Franklin Medical Center, Berlin (H.-R.A.); the Prehospital Emergency Re-search Unit, School of Medicine, Cardiff University, Cardiff, United Kingdom (D.A.C.); Boehringer Ingelheim, Biberach, Germany (E.B.); the Biostatistical Center, Catholic University of Leuven, Leuven, Belgium (A.B.); Boehringer Ingelheim, Reims, France (T.D.); Service d’Aide Médicale d’Urgence de Paris, Hôpital Necker–Enfants Mal-ades, Paris (P.A.C.); the Regional Medical Cardiology Centre, Royal Victoria Hospital, Belfast, United Kingdom (J.A.A.); Albert-Ludwig-University, Freiburg, Germany (C.B.); and Innsbruck Medical University, Innsbruck, Austria (V.W.). Address reprint requests to Dr. Böttiger at the Depart-ment of Anesthesiology and Postopera-tive Intensive Care Medicine, University of Cologne, Kerpener Str. 62, Cologne D-50937, Germany, or at [email protected].

*The investigators in the Thrombolysis in Cardiac Arrest (TROICA) trial are listed in the Appendix.

N Engl J Med 2008;359:2651-62.Copyright © 2008 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDApproximately 70% of persons who have an out-of-hospital cardiac arrest have under-lying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival.

METHODSIn a double-blind, multicenter trial, we randomly assigned adult patients with wit-nessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardio-pulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome.

RESULTSAfter blinded review of data from the first 443 patients, the data and safety moni-toring board recommended discontinuation of enrollment of asystolic patients be-cause of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenec-teplase was administered to 525 patients and placebo to 525 patients; the two treat-ment groups had similar clinical profiles. We did not detect any significant differ-ences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P = 0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P = 0.67), return of spontaneous circulation (55.0% vs. 54.6%, P = 0.96), 24-hour survival (30.6% vs. 33.3%, P = 0.39), survival to hospital discharge (15.1% vs. 17.5%, P = 0.33), or neuro-logic outcome (P = 0.69). There were more intracranial hemorrhages in the tenecte-plase group.

CONCLUSIONSWhen tenecteplase was used without adjunctive antithrombotic therapy during ad-vanced life support for out-of-hospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.)

Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at BIBLIOTHEQUE UNIVERSITE LAVAL on December 18, 2008 .

Bottiger BW et coll. N Engl J Med 2008

Bottiger BW et coll. N Engl J Med 2008

Thrombolysis During Cardiopulmonary Resuscitation

n engl j med 359;25 www.nejm.org december 18, 2008 2657

respects with regard to clinical profile, event in-tervals, and concomitant medications before and during cardiopulmonary resuscitation (Tables 1, 2, and 3). The mean age of the patients was 65 years, and 21.1% were women. The median time from collapse to administration of study drug was 18 minutes. Acute myocardial infarction was the as-sumed cause of cardiac arrest in a larger propor-tion of the tenecteplase group than of the placebo group; this was the only baseline characteristic for which there was a statistically significant differ-ence between the two treatment groups (Table 3).

FOLLOW-UPProtocol violations with regard to inclusion or ex-clusion criteria (mostly violations of timelines) oc-curred in 86 patients in the tenecteplase group (16.4%) and 74 patients in the placebo group (14.1%, P = 0.34). Treatment assignment was unblinded in 33 patients who had received tenecteplase (6.3%) and in 22 who had received placebo (4.2%, P = 0.17). Unblinding was generally performed for safety rea-sons. Sixteen patients who subsequently underwent a percutaneous coronary intervention were believed to need a glycoprotein IIb/IIIa inhibitor, the treat-ing investigator decided to use open-label throm-bolytic treatment in 9 patients with prolonged unsuccessful cardiopulmonary resuscitation or suspected pulmonary embolism, 7 patients had bleeding complications, and 23 patients received unblinded treatment for other reasons.

Complete follow-up data were available for 1032 study patients. The relatives of 18 deceased pa-tients were unwilling to give consent for the pa-tients’ data to be used. For 11 of these patients, permission to use their 30-day survival status was obtained, and for the remaining 7 patients, the missing primary end point was imputed to be “death.” No patient was lost to 30-day follow-up.

OUTCOMESAt 30 days, 77 of 525 patients in the tenecteplase group (14.7%) and 89 of 525 patients in the placebo group (17.0%) were alive (relative risk of survival, 0.87; 95% confidence interval, 0.65 to 1.15; P = 0.36). Thus, we did not detect a significant difference be-tween the two treatment groups in the primary end point (Table 4 and Fig. 1). There were also no sta-tistically significant differences in any of the sec-ondary end points, including return of sponta-neous circulation, hospital admission, 24-hour survival, survival to hospital discharge, and neu-

rologic outcome (Table 4). Subgroup analysis did not reveal any significant differences between groups in the primary end point, except for those patients who received cardiopulmonary resuscita-tion from a bystander (Fig. 2).

Intracranial hemorrhage occurred with signifi-cantly greater frequency in the tenecteplase group (14 of 518 [2.7%]) than in the placebo group (2 of 514 [0.4%], P = 0.006). Four patients with intracra-nial hemorrhage (all in the tenecteplase group) were symptomatic (Table 4) (P = 0.13).

A separate analysis was performed excluding the 223 patients with asystole who had been in-cluded in the trial before the decision of the data and safety monitoring board to stop further en-rollment of such patients. The results were similar to those of the primary analysis (see the Supple-mentary Appendix, available with the full text of this article at www.nejm.org).

Discussion

We evaluated the potential benefit of thrombolytic therapy during cardiopulmonary resuscitation for out-of-hospital cardiac arrest. There were no sig-nificant differences between the tenecteplase and placebo groups in the efficacy end points that we evaluated, including the primary end point of 30-day survival and the secondary end points of return of spontaneous circulation, hospital admis-

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Figure 1. Kaplan–Meier Survival Curves.

At 30 days, there was no significant difference in survival between the tenecteplase and placebo groups (relative risk of survival, 0.87; 95% confi-dence interval, 0.65 to 1.15; P = 0.36). The total number of patients is 1050.

Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at BIBLIOTHEQUE UNIVERSITE LAVAL on December 18, 2008 .

Et le patient qui vient de coder?

• Choix de l’héparine pour le traitement HBPM

Si faible risque de saignement/interventions

• Thrombolyse Patients hémodynamiquement instables Jamais chez les patients stables

Conclusions

Thrombose sur cathéter Cathéter central inséré en périphérie

12 études comparatives (0 ECR, 4 prospectives)

Risque accru de thrombose (RC 2,55; 1,54-4,23) Pas de risque accru d’embolie pulmonaire 52 études observationnelles Incidence plus important chez Patients de soins intensifs (13,9%; 7,7%-20,1%) Cancer (6,7%; 4,7%-8,6%)

Incidence pas affectée par Thromboprophylaxie Thrombose asx vs sx

Konstantinides S et coll. Lancet 2013

Thrombose sur cathéter Recommandations

Ne pas retirer si fonctionne et toujours utile (faible) Anticoagulation si axillaire

Ad 3 mois après le retrait (forte) À long-terme si cancer (faible)

Anticoagulation si brachiale Et symptomatique (faible) Et cathéter demeure en place (faible)

Prévention des thromboembolies veineuses dans un contexte ... · Prévention des thromboembolies...

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