Oral Thromboprophylaxis in Pelvic Trauma: A Standardized Protocol

The Journal of Emergency Medicine, Vol. 43, No. 4, pp. 612–617, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

doi:10.1016/j.jemermed.2011.09.006

Original Contributions

ORAL THROMBOPROPHYLAXIS IN PELVIC TRAUMA: A STANDARDIZED PROTOCOL Daniel Godoy Monzon, MD,* Kenneth V. Iserson, MD, MBA,† Alberto Cid, MD,‡ and Jorge A. Vazquez, MD* *Hospital Italiano de San Justo, ‘‘Centro Agustin Rocca’’ (HICAR), San Justo, Provincia de Buenos Aires, Argentina, †Arizona Bioethics Program, University of Arizona, Tucson, Arizona, and ‡Salud Ocupacional Integral (SOI) and Centro Medico Fitz Roy, Ciudad de Buenos Aires, Argentina Corresponding Address: Kenneth V. Iserson, MD, MBA, Arizona Bioethics Program, University of Arizona, 4930 N. Calle Faja, Tucson, AZ 85718

, Abstract—Background: Thromboprophylaxis for deep vein thrombosis (DVT) after lower-extremity trauma could include rivaroxaban, an oral medication that does not need laboratory monitoring. Objective: To assess rivaroxaban’s efficacy in preventing DVTs after pelvic trauma compared to its historical incidence. Materials and Methods: All patients admitted with pelvic fractures in a 12-month period followed a standardized thromboprophylaxis protocol: 1) rivaroxaban 10 mg/day within 24 h of injury or upon hemodynamic stability; 2) pre-operative, post-operative, and 30-day extremity ultrasound; 3) ventilation-perfusion scintigraphy for clinical signs of pulmonary embolus; and 4) a 45-, 90-, and 120-day re-evaluation. Rivaroxaban administration ceased the day of surgery and restarted 12 h postoperatively or upon hemodynamic stability, continuing for 30 days. Excluded patients had severe neurological or hepatosplenic injuries, heparin hypersensitivity, or hemodynamic instability. Results: Of 113 patients assessed, 84 patients (66 males), average age 46.6 years (range 19–69 years), were included. They had isolated pelvic trauma (n = 37), associated lower limb injuries (n = 47), average Injury Severity Score 21.4 (range 16–50), and average Glasgow Coma Scale score 13.6 (range 9–15). Patients receiving thromboprophylaxis soon after their fracture (n = 64) had a lower incidence of DVT than those receiving delayed thromboprophylaxis (n = 20) (p = 0.02). One patient (1.2%) died from a pulmonary embolus; 13 had asymptomatic below-the-knee DVTs. Rivaroxaban did not increase

intra- or post-operative bleeding in surgical wounds. Conclusions: DVT incidence after pelvic fractures is reduced by administering antithrombotics within 24 h of injury or, if the patient is hemodynamically unstable, 24 h after stabilization. Rivaroxaban is a safe and effective method of providing this thromboprophylaxis. Ó 2012 Elsevier Inc. , Keywords—rivaroxaban; deep vein thrombosis; thromboprophylaxis; pelvic trauma; lower-extremity trauma

INTRODUCTION The incidence of deep vein thrombosis (DVT) after pelvic trauma varies between 35% and 61% (1,2). Patients with pelvic trauma are at high risk of thromboembolic complications. Though effective methods of prophylaxis have yet to be accepted and adopted widely. A variety of thromboprophylactic regimes have been recommended in trauma patients (1,3–5). Low-dose or intermittent pneumatic compression devices alone are not always effective in preventing DVT (6–8). Although low-molecular-weight heparin agents have been shown to reduce the rate of DVT in patients with injury to the pelvis or lower limbs, they require parenteral administration (1,3,9,10). A new oral thromboprophylactic medication, rivaroxaban (XareltoÒ, Bayer AG, Manheim, Germany), was recently approved in Argentina for use in patients with

Reprints are not available from the authors.

RECEIVED: 6 May 2011; FINAL SUBMISSION RECEIVED: 12 September 2011; ACCEPTED: 18 September 2011 612

Oral Thromboprophylaxis in Pelvic Trauma

lower limb fractures. In September 2008, both Health Canada and the European Commission approved rivaroxaban for the prevention of DVT in patients who have undergone elective total hip or knee replacement. The U.S. Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee has voted to recommend approval (11). Rivaroxaban is an oral, direct Factor Xa inhibitor with high oral bioavailability, a rapid onset of action, and predictable pharmacokinetics (half-life of 5–9 h) (12,13). It is excreted rapidly, mostly through the kidney (66%; 36% of the dose excreted unchanged), but also via the biliary/ fecal route (13). Single doses of rivaroxaban have pharmacodynamic effects that persist for 24 h and significantly inhibit peak and total amounts of thrombin generated for 24 h after administration (12,14). It has been shown to be as safe and effective in preventing DVTs as enoxaparin when administered after orthopedic surgery, and has been successfully used in a once-a-day dosage after total hip and knee replacement surgery (15,16). This led to the following study to assess rivaroxaban’s efficacy in preventing DVTs after major lower-extremity trauma. The study’s aim was to determine the use of thromboprophylactic therapy with this protocol, patient compliance and complications, and the incidence of DVT and pulmonary embolus (PE) in the treated patients. MATERIAL AND METHODS Between June 2009 and June 2010, all patients admitted to our trauma center with pelvic or acetabular fractures received a standardized protocol for DVT prophylaxis. Informed consent for inclusion in the study was obtained from patients or their surrogate decision-makers. The Institutional Review Board approved this study. Enrolled patients were evaluated with laboratory tests (complete blood count, hematocrit, electrolytes, liver and kidney function, coagulation). Vital signs (heart rate, respiratory rate, and mean arterial pressure), the Injury Severity Score (ISS), and Glasgow Coma Scale score (GCS) were recorded. Patients excluded from this study included those with the presence of a severe neurological injury (GCS # 8), spinal cord injury, identifiable hepatic or splenic injuries, a known hypersensitivity to heparin, and hemodynamic instability secondary to continued bleeding. Each study patient had an ultrasound evaluation for DVT of all lower-extremity veins from the groin to the foot at the time of admission, within 48 h after surgery, and 30 days post-surgery. The same imaging team for all patients identified the location and size of any thrombi. All patients with pelvic trauma were treated with a standardized protocol for thromboprophylaxis consisting of:

613

1) the administration of rivaroxaban (Xarelto, Bayer), 10 mg, orally once a day within 24 h of injury or upon the establishment of hemodynamic stability; 2) preoperative, post-operative, and 30-day investigation for DVT using duplex ultrasound; 3) a ventilation-perfusion scintigraphy (V/Q lung scan) if the patient showed clinical signs of PE; and 4) a clinical evaluation at 45, 90, and 120 days. All patients received treatment with rivaroxaban, with the last dose being given the day before surgery and restarted within 12 h after surgery or when hemodynamic stability was achieved post-operatively. Rivaroxaban prophylaxis was continued for 30 days post-operatively. After surgery, patients were mobilized within 48 h, depending on the complexity of their associated injuries. They generally walked short distances with partial weight-bearing. At the conclusion of the study, all patients were asked about their compliance with the medication and any post-hospitalization complications. RESULTS Of 113 patients initially assessed, 29 were excluded (Table 1); 84 patients (66 males [78.6%] and 18 females [21.4%]), average age 46.6 years (range 19–69 years) were included in the study group. Of these, 37 presented with isolated pelvic trauma, whereas 47 had associated injuries of their lower limbs (60%). The types of pelvic and acetabular fractures are shown in Table 2 (17,18). All subjects’ average ISS was 21.4 (range 16–50 points) and they had an average GCS of 13.6 (range 9– 15 points). The 65 patients that initially presented to our hospital had an average wait of 4.8 days until they had acetabular or lower-extremity surgery. The other 19 patients were transferred to us from other hospitals. They waited an average of 9.4 days after their injury for surgery due to delayed transfers (Mann-Whitney U test, p < 0.001). A delay of < 5 days post-injury is standard practice in Argentina. Of the 65 patients accepted directly into our institution, 57 (87.7%) started prophylaxis within 24 h; it was Table 1. Patients Excluded from the Study Reason for Exclusion Referred to another hospital (due to patient/family request or medical insurance requirements) Died on admission (due to multiple non-orthopedic injuries) Had proximal DVT on admission (2 had history of femoral intravenous catheter; thrombosis resolved after its withdrawal) GCS < 8 Total excluded

Number of Patients 8 5 7 9 24

DVT = deep vein thrombosis; GCS = Glasgow Coma Scale score.

614 Table 2. Types of Pelvic Fractures in Study Patients Pelvic fractures Type A fractures = 27. The pelvic ring was stable Type B fractures = 25. This is a partially stable fracture, such as occurs with ‘‘open-book’’ and ‘‘bucket-handle’’ fractures Type C = 10. These unstable fractures have a complete disruption of the posterior sacroiliac complex Acetabular fractures Type A fractures = 11. Partial articular fractures, involving only one of the two columns Type B fractures = 6. Partial articular fractures, involving a transverse component Type C fractures = 6. Complete articular fractures, involving both columns

delayed in eight cases (12.3%) due to hemodynamic instability. Of the 19 patients from other institutions, 5 (26.3%) started thromboprophylaxis with lowmolecular-weight heparin and 2 (10.5%) with heparin sodium. In 12 cases (18.5%), the patient did not receive thromboprophylaxis before transfer. At our institution, the average interval between injury and initial Doppler evaluation was 1.6 days (range 1–9 days). A proximal deep vein thrombosis without clinical manifestation was detected after surgery in 2 patients (2.4%). One patient (1.2%) died from a PE within the study period. Fourteen patients had below-the-knee DVT without symptomatic signs. Two patients had ventilation-perfusion scintigraphy and pulmonary angiography due to unexplained respiratory distress or hypoxic episodes. Only one of these tests demonstrated a pulmonary embolism. Six (7.1%) of the study patients

Figure 1. Flow diagram of study patients and results.

D. G. Monzon et al.

died during hospitalization, including 5 that succumbed to sepsis and multi-organ failure unrelated to their orthopedic disorders. Non-symptomatic DVT diagnosed by Doppler indicated a significant difference between those who received some form of thromboprophylaxis within 24 h of injury (6/64; 9.4%) compared to those receiving delayed treatment (8/20; 40%; p < 0.001 Fisher’s exact test) (Figure 1). There were no significant differences in the two groups’ ISS on arrival at our hospital (p = 0.742; NS), or between men and women included as study subjects (p = 0.832; NS). All study patients adhered to the treatment protocol. There were no significant complications, such as medication intolerance, increased bleeding, a need for wound revision, or post-operative transfusion. There were no complications, such as prolonged wound oozing, excessive bruising, or bleeding, associated with the use of rivaroxaban. Oral administration was satisfactory for the patients and their caretakers. During follow-up assessments at 45, 90, and 120 days, neither the physical examination nor patient/caregiver reports exhibited clinical manifestations of DVT. DISCUSSION Venographic studies have shown that proximal DVT (high risk for PE) affects 25%–35% of patients with pelvic trauma. Symptomatic PE occurs in 2%–10% of these patients and is fatal in 0.5%–2% (1,2,19,20). In our study,

Oral Thromboprophylaxis in Pelvic Trauma

pre-operative ultrasound demonstrated a DVT in 7 patients (6.2%), who were excluded from the study. This incidence is similar to the expected rates of presentation (1–3). Pre-operative ultrasound Doppler screening is a simple, very accurate, inexpensive, widely available technique (21–24). Our findings show that rivaroxaban is well tolerated by patients and requires no formal anticoagulation level monitoring, does not increase intra- or post-operative bleeding in surgical wounds, and decreased the incidence of symptomatic and asymptomatic DVT. There was a lower incidence of DVT in patients who received thromboprophylaxis at the time of the injury than those who received delayed thromboprophylaxis (9.4%/45%; p = 0.02). In our study, there was no association between the presentation of post-operative DVT and either the time to surgery or the ISS. Using our protocol is simple and non-invasive (7,21– 23,25). It is also economical because rivaroxaban has also been shown to be more cost-effective than enoxaparin after lower-extremity surgery (25). A fundamental aspect of our protocol is the use of ultrasound evaluation for DVT pre-operatively and, if possible, upon patient arrival, especially if the patient is initially seen > 3 days after injury (26). Based on this, we believe that thromboprophylaxis should be initiated early in appropriate cases, even if the patient will be transferred to another center where surgery can be performed (27). Specifically, our study strongly suggests that to reduce the incidence of symptomatic DVT after pelvic and lower-extremity injury needing surgery, antithrombotics should be administered within 24 h of injury—as early as in the emergency department—or, if the patient is hemodynamically unstable, delayed until 24 h after the patient’s condition has stabilized. Rivaroxaban is a safe, effective, and welltolerated method of providing this thromboprophylaxis. Limitations This relatively small study included patients that arrived at the study institution primarily and those that were transferred. All data were captured for the transferred patients. Although accepting transferred patients represents a norm for tertiary care hospitals, the study may have been cleaner if a large enough sample had presented initially to the study hospital. In addition, the study drug, rivaroxaban, is still in the approval process in some countries (including the United States), so it is not yet available. CONCLUSION The incidence of DVTs after pelvic fractures is reduced by administering antithrombotics within 24 h of injury

615

or, if the patient is hemodynamically unstable, 24 h after stabilization. Rivaroxaban is a safe and effective method of providing this thromboprophylaxis. As of 2011, it has been approved for use in more than 60 countries. REFERENCES 1. Montgomery KD, Geerts WH, Potter HG, Helfet DL. Thromboembolic complications in patients with pelvic trauma. Clin Orthop 1996;329:68–87. 2. Geerts WH, Code KI, Jay RM, et al. A prospective study of venous thromboembolism after major trauma. N Engl J Med 1993;331: 1601–6. 3. Fishmann AJ, Greeno RA, Brooks LR, Matta JM. Prevention of deep vein thrombosis and pulmonary embolism in acetabular and pelvic fracture surgery. Clin Orthop 1994;305:133–7. 4. Rosenthal D, McKinsey JF, Levy AM, et al. Use of the Greenfield filter in patients with major trauma. Cardiovasc Surg 1994;2:52–5. 5. Rogers FB, Cipolle MD, Velmahos G, et al. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group. J Trauma 2002;53:142–64. 6. Fisher CG, Blachut PA, Salvian AJ, et al. Effectiveness of pneumatic leg compression devices for the prevention of thromboembolic disease in orthopaedic trauma patients: a prospective, randomized study of compression alone versus no prophylaxis. J Orthop Trauma 1995;9:1–7. 7. Knudson MM, Lewis FR, Clinton A, et al. Prevention of venous thromboembolism in trauma patients. J Trauma 1994;37:480–7. 8. Velmahos GC, Kern J, Chan L, et al. Prevention of venous thromboembolism after injury: an evidence-based report – Part I: analysis of risk factors and evaluation of the role of vena cava filters. J Trauma 2000;49:132–9. 9. Knudson MM, Morabito D, Paiement GD, Shackleford S. Use of low molecular weight heparin in preventing thromboembolism in trauma patients. J Trauma 1996;41:446–59. 10. Geerts H, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335:701–7. 11. FDA advisory committee recommends rivaroxaban for approval. HemOnc Today: Clinical News in Oncology and Hematology, March 20, 2009. Available at: www.hemonctoday.com/article. aspx?rid=38043. Accessed March 22, 2011. 12. Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–21. 13. Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873–80. 14. Harder S, Graff J, Hentig NV, et al. Effects of BAY 59-7939, an oral, direct Factor Xa inhibitor, on thrombin generation in healthy volunteers [Abstract PO078]. Pathophysiol Haemost Thromb 2004; 33(Suppl 2):97. 15. Eriksson BI, Borris L, Dahl OE, et al. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4:121–8. 16. Kakkar K, Muehlhofer E, Dierig C, et al. Thromboprophylaxis after total hip replacement. Circulation 2006;114:2374–81. 17. Tile M. Acute pelvic fractures: I. Causation and classification. J Am Acad Orthop Surg 1996;4:143–51. 18. Letournel E. Acetabulum fractures: classification and management. Clin Orthop Relat Res 1980;151:81–106. 19. Buerger PM, Peoples JB, Lemmon GW, McCarthy MC. Risk of pulmonary emboli in patients with pelvic fractures. Am Surg 1993;59: 505–8.

616 20. Spencer JD, Lalanadham T. The mortality of patients with minor fractures of the pelvis. Injury 1985;16:321–3. 21. White RH, Goulet JA, Bray TJ, et al. Deep-vein thrombosis after fracture of the pelvis: assessment with serial duplex-ultrasound screening. J Bone Joint Surg Am 1990;72:495–500. 22. Gruen GS, McClain EJ, Gruen RJ. The diagnosis of deep vein thrombosis in the multiply injured patient with pelvic ring or acetabular fractures. Orthopedics 1995;18:253–7. 23. Wells PS, Lensing AW, Davidson BL, et al. Accuracy of ultrasound for the diagnosis of deep venous thrombosis in asymptomatic patients after orthopedic surgery: a meta-analysis. Ann Intern Med 1995;122:47–53.

D. G. Monzon et al. 24. Diamantopoulos A, Lees M, Wells PS, et al. Cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of postsurgical venous thromboembolism in Canada. Thromb Haemost 2010;104: 760–70. 25. Cipolle MD, Wojcik R, Seislove E, et al. The role of surveillance duplex scanning in preventing venous thromboembolism in trauma patients. J Trauma 2002;52:453–62. 26. Montgomery KD, Geerts WH, Potter HG, Helfet DL. Practical management of venous thromboembolism following pelvic fractures. Orthop Clin North Am 1997;28:397–404. 27. Ward DA, Bircher MD. The early management of pelvic and acetabular fractures. Injury 1996;27(Suppl 1):S-A24–8.

Oral Thromboprophylaxis in Pelvic Trauma

ARTICLE SUMMARY 1. Why is this topic important? Post-trauma deep vein thromboses (DVTs) represent a significant patient risk. Emergency physicians can lower this risk by initiating oral thromboprophylaxis. 2. What does this study attempt to show? Early use of rivaroxaban lowers DVT risk after fractures in the pelvic region without causing increased bleeding. 3. What are the key findings? Oral rivaroxaban reduces DVTs in patients with fractures in the pelvic area without increasing operative or post-operative bleeding. The earlier it can be initiated, the lower the risk for developing a DVT. 4. How is patient care impacted? Well tolerated, this oral anticoagulant reduces personnel and laboratory costs while decreasing a significant post-traumatic complication.

617