Cuando empeza y cuando parar la profilaxisDocument Transcript
Clinical and Applied Thrombosis/Hemostasis Volume 16 Number 4The ‘‘Critical Thrombosis Period’’ in July/August 2010 394-405 # 2010 The Author(s) 10.1177/1076029609355151Major Orthopedic Surgery: When to http://cath.sagepub.comStart and When to Stop ProphylaxisDavid Warwick, MD, FRCS, FRCS (Orth), andNadia Rosencher, MDPatients undergoing major orthopedic surgery are at literature reflects the need to balance the improvedhigh venous thromboembolism (VTE) risk, with morbid efficacy of initiating prophylaxis close to the surgeryand potentially fatal consequences. Anticoagulant VTE with increased risk of perioperative bleeding. Evidenceprophylaxis reduces rates of postoperative deep vein from pathology, epidemiology, and clinical studies sug-thrombosis by up to 60% to 70% in these patients. gests the risk period for VTE begins at surgery andTherefore, pharmacological prophylaxis with low- extends well beyond hospitalization—a crucial issuemolecular-weight heparins (LMWHs), vitamin K when considering how long to give prophylaxis—and,antagonists, or fondaparinux is recommended by in the case of total hip arthroplasty, for at least 3current guidelines. However, there remains an ongoing months after surgery. Literature supports the greaterdebate regarding when to initiate and the optimal dura- use of ‘‘just-in-time’’ thromboprophylaxis initiation andtion for prophylaxis. Here, we discuss the mechanisms after-discharge continuation of optimal prophylaxis inunderlying thrombus formation in patients undergoing orthopedic surgery patients. Providing optimal throm-major orthopedic surgery, and we review the current boprophylaxis throughout the critical thrombosisliterature on the benefit-to-risk ratio associated with period where a patient is at VTE risk will ensure thepreoperative and postoperative initiation of thrombo- best reductions in VTE-related morbidity andprophylaxis and also the benefit-to-risk ratio in cases mortality.of neuraxial anesthesia. We also discuss the durationof postoperative VTE risk following major orthopedic Keywords: deep vein thrombosis; hip arthroplasty;surgery and assess the ‘‘critical thrombosis period’’ knee arthroplasty; prophylaxis; pulmonary embolism;when prophylaxis should be provided. Current venous thromboembolismIntroduction (HFS), between 40% and 60% of patients are at risk of subclinical deep vein thrombosis (DVT) and 4% toWithout prophylaxis, the frequency of venous throm- 10% develop pulmonary embolism (PE), of whichboembolism (VTE) after major orthopedic surgery is 5% might be fatal.1 High-risk orthopedic surgery canhigh.1 Following total hip arthroplasty (THA), total also predispose an individual to the development ofknee arthroplasty (TKA), or hip fracture surgery chronic venous insufficiency, although the risk of this sequela has not been quantified as comprehen- sively as the risk of postoperative VTE.From the Orthopaedic Surgery, University of Southampton,Hampshire, United Kingdom (DW); and Department of Anaes- Both international and US evidence–basedthesiology and Intensive Care, Groupe Hospitalier Cochin Port guidelines recommend the appropriate use of pro- ˆ ´ ´Royal, Assistance Publique – Hopitaux de Paris, Universite Rene phylaxis for the prevention of VTE following ortho-Descartes, Paris, France (NR). pedic surgery.1,2 Specifically, current guidanceAddress correspondence to: David Warwick, Orthopaedic from the American College of Chest PhysiciansSurgery, University of Southampton, Southampton, Hampshire,SO16 6UY, United Kingdom; e-mail: davidjwarwick@ (ACCP)1 and recently published International Con-btinternet.com. sensus guidelines2 strongly recommend prophylaxis394
The critical thrombosis period in major orthopedic surgery / Warwick and Rosencher 395 Table 1. Current Recommendations From the American College of Chest Physicians for Venous Thromboem- bolism Prophylaxis in Orthopedic Surgery Patients Thromboprophylaxis RegimenSurgery Type Recommendation Type Dose/InitiationElective hip Grade 1A LMWH Usual high-risk dose started 12 hours before surgery or replacement 12 to 24 hours after surgery or half the usual high-risk dose started 4 to 6 hours after surgery, increasing to the full usual high-risk dose the following day Fondaparinux 2.5 mg started 6 to 24 hours after surgery Adjusted-dose vitamin K INR target 2.5 (range 2.0 to 3.0) initiated preoperatively, antagonists or the evening of the day of surgery In patients with high Grade 1A Mechanical thromboprophylaxis When high bleeding risk decreases: pharmacologic bleeding risk with VFP or IPC thromboprophylaxis be substituted for or added to mechanical thromboprophylaxis (grade 1C)Elective knee Grade 1A LMWH Usual high-risk dose replacement Fondaparinux Adjusted-dose vitamin K INR target 2.5 (range 2.0-3.0) antagonists Grade 1B IPC (without anticoagulant) In patients with high Grade 1A IPC When high bleeding risk decreases: pharmacologic bleeding risk thromboprophylaxis be substituted for or added to Grade 1B VFP mechanical thromboprophylaxis (grade 1C)Hip fracture surgery Grade 1A Fondaparinux Grade 1B LMWH Grade 1B UFH Grade 1B Adjusted-dose vitamin K INR target 2.5 (range 2.0-3.0) antagonists In patients with high Grade 1A Optimal mechanical prophylaxis When high bleeding risk decreases: pharmacologic bleeding risk thromboprophylaxis be substituted for or added to mechanical thromboprophylaxis (grade 1C) When surgery likely Grade 1C LMWH to be delayed Grade 1C UFHNOTES: LMWH ¼ low-molecular-weight heparins; INR ¼ international normalized ratio; VFP ¼ venous foot pump; IPC ¼ inter-mittent pneumatic compression; UFH ¼ unfractionated heparin.with low-molecular-weight heparins (LMWHs), ‘‘critical thrombosis period’’ when patients are atvitamin K antagonists, or fondaparinux (Table 1). increased risk of developing VTE?There is clear evidence to show that the use of these There has been some debate in the literatureeffective prophylactic agents can reduce the rate of regarding the optimal timing for the initiation ofpostoperative DVT by 60% to 70%.1-3 Mechanical prophylaxis to maximize efficacy while minimizingmethods of prophylaxis, including graduated bleeding risk.4 For example, delaying the initiationcompression stockings (GCS) and intermittent of thromboprophylaxis with LMWHs (includingpneumatic compression, offer an alternative for enoxaparin, dalteparin, nadroparin, and tinza-patients in whom anticoagulant prophylaxis is con- parin) has been shown to result in suboptimaltraindicated, or they can be used as adjunct to antithrombotic effectiveness4,5; however, com-anticoagulant-based prophylaxis.1 mencing prophylaxis too soon after surgery has There are 2 important questions to consider been linked to an increased bleeding risk.6when planning VTE prophylaxis in major orthopedic Whatever the anticoagulant agent, the balancesurgery patients. First, when should anticoagulant between the benefits (prevention of VTE, a majorprophylaxis be initiated to balance efficacy with cause of perioperative morbidity and mortality)safety? And second, when should prophylaxis be and risks (major bleeding and epidural hematoma)stopped to ensure adequate risk reduction during the is the central consideration when deciding
396 Clinical and Applied Thrombosis/Hemostasis / Vol. 16, No. 4, July/August 2010whether or not to provide anticoagulant prophy- of prophylaxis to cover the critical thrombosislaxis. This balance depends on the pharmacology period.of each agent and on the dosage, timing of admin-istration, the type of surgery, and patientcharacteristics. Pathological Drivers of VTE Associated Guidance on what constitutes an ‘‘optimal dura- With Orthopedic Surgerytion’’ of thromboprophylaxis after orthopedic surgeryis less clearly stated and continues to be a topic of Thrombosis formation begins during surgery in elec-debate.1,5,7-9 It is known that the risk of VTE contin- tive orthopedic surgery and perhaps earlier in theues long after patient discharge. Studies of large- case of hip fracture. For over a century, scientistsscale patient databases suggest that approximately and clinicians have recognized Virchow’s triad of50% to 75% of cases of surgery-related VTE manifest venous stasis, endothelial injury or damage, andafter a patient has been discharged from hospital.10-14 alterations to the constitution of the blood, whichFor example, a US study of postoperative throm- together predispose an individual to thrombi forma-boembolic events in over 19 000 primary THA tion.21 Such conditions prevail during major ortho-patients and over 24 000 primary TKA patients pedic surgery. There is often disruption to bloodfound that the diagnosis of VTE was made after hos- flow in the femoral vein and debris might be presentpital discharge in 76% of cases following THA and in a patient’s blood.22-24 Slow, turbulent blood flow47% of post-TKA cases. This corresponds to a med- in valve cusps creates local areas of stasis andian time to VTE diagnosis of 17 and 7 days postpro- encourages the development of thrombi.23 Duringcedure, respectively.10 Another European-based surgery, there is a significant reduction in bothprospective study looking at the annual incidence venous outflow and venous capacitance.24 Afterof DVT after almost 5000 joint operations noted that orthopedic surgery, DVT events are mostly concen-symptoms of DVT appeared on average 27 days after trated in the operated leg, emphasizing the role ofTHA, 36 days after surgery for hip fracture, and 17 stasis.25,26 Local tissue damage associated with sur-days after TKA.11 gery is also an important factor in proximal thrombo- Although 1 study of THA and TKA patients sug- sis,25 and it is recognized that surgical technique cangested that prophylaxis for 9 days with the LMWH affect both operative venous stasis and the risk ofenoxaparin was associated with a clinically accepta- thrombi formation.22,25,27 Femoral vein kinking, calfble incidence of symptomatic VTE and major bleed- vein distension, endothelial hypoxia, and vibrationing,7 other studies have demonstrated that extending during surgery, all contribute to endothelialLMWH prophylaxis for up to 35 days after THA damage.28offers significant reductions in the incidence of At the site of surgery, cell microaggregates areVTE.8,9,15,16 The potential for improving clinical formed which, together with bone marrow debris,outcomes by extending the period of thrombopro- embolize centrally. Some of this debris and microag-phylaxis after major orthopedic surgery has also been gregate formation can appear in the arterial side ofdescribed in patients receiving warfarin or the circulation as well. Symptoms can occur duringfondaparinux.17,18 Additionally, prolonged prophy- surgery itself—a phenomenon well known tolaxis of over 30 days with the novel anticoagulants anesthetists as a fall in PaO2, cardiovascular instabil-dabigatran and rivaroxaban has been shown to be ity, and lung shunts. Indeed, intraoperative deathwell tolerated.19,20 can occur. These microaggregates can obliterate Here, we evaluate the physiological and hema- small vessels within the brain leading to cognitivetological drivers of VTE, which lead to a prolonged changes and, within the heart, leading to myocardialhypercoagulable state in patients undergoing infarction.major orthopedic surgery, and the impact of these There is also substantial local and systemic acti-factors on the optimal timing of initiation and vation of coagulation during the operation. It hasduration of thromboprophylaxis. We review the been noted that after a fibrinolytic shutdown imme-current clinical and epidemiological evidence diately after surgery, activation of coagulationrelating to the risks and benefits of preoperative increases and leads to a prolonged hypercoagulableversus postoperative initiation of pharmacological state.28,29prophylaxis and prolonged-duration prophylaxis, Thus, the present day understanding is that sys-and evaluate what constitutes an optimal duration temic activation of coagulation, as well as
The critical thrombosis period in major orthopedic surgery / Warwick and Rosencher 397peripherally derived DVT, should be considered a undergoing elective THA found that preoperativetarget for prophylactic medication use. This is a initiation was associated with a reduced DVT inci-potent argument toward the use of chemical prophy- dence compared with postoperative initiationlaxis, rather than mechanical methods alone, which (10.0% vs 15.3%, respectively; P ¼ .02), with majorwould not influence the more systemic effects. bleeding also reduced in patients receiving preopera- tive prophylaxis (0.9% vs 3.5%, respectively; P ¼ .01).5 Additional reviews support the improved effi-When Should Prophylaxis Begin? cacy of initiating LMWH prophylaxis in orthopedic patients close to the time of surgery.4,30 A greaterThe ‘‘ideal’’ time for the initiation of thromboprophy- reduction in VTE risk was observed when half thelaxis should balance the optimal efficacy of the antith- usual dose of a LMWH was given to patients under-rombotic agent with the associated risk of bleeding. going elective total hip replacement close to the timeThe pathological drivers of VTE provide some founda- of surgery versus the full dose given either 12 hourstion for debating when is the best time to initiate preoperatively or 12 to 18 hours postoperatively.4 Aprophylaxis. Anticoagulant prophylaxis initiated preo- systematic review of studies of LMWH prophylaxisperatively and close to the time of surgery offers in patients undergoing THA, TKA, or HFS establishedpotential for the formation of fewer thrombi7 and can the risk of postoperative DVT, as confirmed by veno-increase the risk of intraoperative bleeding.30 graphy, according to the timing of prophylaxis.30 This Preoperative initiation of anticoagulant prophy- analysis found that postoperative DVT occurred inlaxis can also increase the risk of compressive neur- 19.2% of patients given LMWH 12 hours preopera-axial hematoma if regional anesthesia is used.31 tively, in 12.4% of patients given perioperative pro-Indeed, the general incidence of compressive spinal phylaxis, and in 14.4% of patients givenhematoma after neuraxial anesthesia is very low postoperative prophylaxis (started at least 12 hours(1 in 150 000 patients), but the incidence of hema- after surgery).30tomata increased to 1 in 3600 when analysis was Another theoretical benefit of preoperativerestricted to epidural anesthesia for TKA in women administration over postoperative administration isaged older than 70 years.32 Both US and European protection against the systemic activation of coagula-guidelines allow a clearance of 12 hours after tion, which is initiated during surgery. Clinical trialsLMWH injection for a neuraxial puncture, thus and meta-analyses comparing preoperative againstpreoperative injection can be done 12 hours before postoperative administration have used venographicsurgery.33,34 Alternatively, prophylaxis may be surrogate endpoints considering only peripheral veinstarted after surgery in case of neuraxial puncture.35 manifestations of thrombosis. At present, therefore,Indeed, puncture can be difficult with many there are no data on this important aspect of theattempts or may result in a bloody puncture. There- pathophysiology of thrombus formation and whetherfore, the risk of bleeding with a compressive epidural prophylaxis can influence it.hematoma could outweigh the still-debated potentialbenefits of preoperative initiation. Postoperative initiation of anticoagulant prophy- Timing of Prophylaxis Initiation tolaxis avoids increasing the risk of bleeding during Achieve Peak Efficacyprocedures but might not protect against the forma-tion of perioperative thrombi. Current clinical guide- The peak efficacy of both LMWHs and other antith-lines suggest either preoperative or postoperative rombotic agents depends on the timing of the firstanticoagulant prophylaxis,1 with practices varying injection.4,5,30 A meta-analysis of studies directlyby region. For example, LMWH prophylaxis is gener- comparing VTE prophylaxis with fondaparinux orally initiated up to 12 hours preoperatively (40 mg LMWH (enoxaparin) reported that fondaparinuxonce daily) in Europe in accordance with regimens started 6 hours postoperatively was more effectiveapproved by the regulatory authorities, whereas in in reducing VTE risk.36 However, in 2 of the 4 stud-North America it is mostly initiated 12 to 24 hours ies in this meta-analysis, the first dose of enoxaparin(30 mg twice daily) postoperatively.4 was not administered until 12 hours after surgery, A meta-analysis of 6 trials of LMWHs comparing whereas in the other 2 studies enoxaparin was initi-the effectiveness of preoperative versus postoperative ated 12 hours before surgery. Thus, the pooled datainitiation of LMWH prophylaxis in patients in this meta-analysis combine the results of
398 Clinical and Applied Thrombosis/Hemostasis / Vol. 16, No. 4, July/August 20102 different approaches to the timing and use of States between January 1998 and December 2000LMWH, and in our opinion do not allow a true reported an incidence of major bleeding of 2.6%, andor consistent comparison of these agents as throm- data from randomized clinical trials have demon-boprophylactic agents. Furthermore, recently strated little or no increase in the rates of clinicallyreported clinical trials comparing new oral agents important bleeding with prophylactic doses ofand enoxaparin have also used different timing guideline-recommended thromboprophylacticapproaches.19,20 Ideally, future studies comparing agents. 1,39 However, the definition of perioperativeanticoagulants in this setting should be made with bleeding is vague and there is no consistent assess-therapies initiated at the same time points or at opti- ment in different trials. Significant bleeding wouldmal time points for both regimens, according to be regarded as that leading to a degraded surgicalthe time to reach maximum concentration for outcome (wound dehiscence, infection, and delayedeach drug.37 hospital discharge), anesthetic risk (in particular, It is likely that if a single dose of prophylactic intraspinal bleeding associated with neuraxial block-agent is provided too far in advance of surgery, the ade), or general effect (retroperitoneal, cerebral, oranticoagulant effect may have declined by the time intestinal bleeding). After neuraxial anesthesia, thisof the surgical insult. The ideal time to begin risk of bleeding is rare but can lead to paraplegia.administering an LMWH for peak efficacy is Even if the complication is less catastrophic, afterbetween 2 hours before and 8 hours after surgery.4 lumbar plexus block, some compressive hematoma‘‘Just in time’’ LMWH prophylaxis, given 4 to 6 can occur also but with only femoral nerve compres-hours after surgery, is as effective as preoperative sion.40-42LMWH given 2 hours before surgery,4 with no rela- Current ACCP guidelines acknowledge that thetive increase in the risk of perioperative bleeding. evidence supports both the preoperative and theHowever, the risk of bleeding and neuraxial com- postoperative initiation of LMWH prophylaxis inpressive hematoma in elderly patients increases if patients undergoing elective hip replacement (gradeprophylaxis is initiated too close to the start of 1A recommendations; Table 1).1 In clinical practice,surgery (ie, between À2 and þ4 hours of sur- we believe that mechanical methods of prophylaxis,gery).4,30 It would seem prudent, therefore, to delay as recommended in the ACCP guidelines, could haverestarting anticoagulant medications until a stable a role in covering the perioperative period until it isclot has been established; hemostasis of small decided safe for an individual patient to receivevessels should be at least 8 hours.31,38 However, antithrombotic prophylaxis (grade 1C in patients atthis does not mean waiting 8 hours in each patient bleeding risk, grade 2A as adjunct to chemoprophy-because the onset time (tmax) of most anticoagu- laxis).1 However, the lack of protection provided bylants is substantial. Instead, it is recommended mechanical prophylactic methods against the sys-waiting for 8 hours minus tmax. The result of this temic activation of thrombin must be remembered.strategy is that a total of 8 hours will have elapsed The mechanical method is an addition to, ratherbefore peak anticoagulation is reestablished. In than substitute for, chemical methods. Sole use ofpractice, the longer the tmax the shorter the delay mechanical prophylaxis methods should only be con-before anticoagulant reinitiation. For example, if sidered for patients with contraindications tothe tmax is 4 hours (as it is for LMWH), the safety anticoagulants.1delay would be 4 hours; but if the tmax is only 1 hour In summary, the timing of initiation of pharma-(as it is for unfractionated heparin), the safety delay cological prophylaxis should, according to theshould be at least 7 hours.31 This safety delay time guidelines,1 be based on risk-to-benefit considera-is confirmed by the decrease of major bleeding in tions for each patient. This should consider bothfondaparinux studies when initiation of the drug is an individual patient’s relative risk of bleeding com-done 6 to 8 hours after the end of surgery.36 plications versus their risk factors for VTE, both of which should be established prior to surgery. In general, it should be assumed that the more effica-The Impact of Bleeding in Major cious a compound is against thrombosis, the greaterOrthopedic Surgery the risk of bleeding; that risk can be mitigated by giving the compound further away from theA large-scale database including 23 518 patients who moment of surgery (or reducing dose) but at theunderwent major orthopedic surgery in the United cost of decreased efficacy.
The critical thrombosis period in major orthopedic surgery / Warwick and Rosencher 399 or is elective in nature. For example, in patients with femoral fractures, it has been shown using whole blood thromboelastography that a hypercoagulable state persists for at least 6 weeks after surgical repair.29 Additional studies comparing venous blood flow in fractured versus nonfractured legs found that disturbed venous outflow persisted in fractured legs for as long as 42 days after surgery (Figure 1).24 Epidemiological Studies Other evidence for a protracted period of VTE risk after orthopedic surgery comes from studies show- ing, as described above, that the discontinuation of prophylaxis a week after THA is associated with rebound hypercoagulability persisting for 5 weeks of follow-up.28 Epidemiological studies have identified that VTE risk persists for prolonged periods after major ortho-Figure 1. Venous output pattern following surgery (mean + pedic surgery.48,49 This is evident in the late emer- standard error of mean) comparing fractured versus gence of symptomatic VTE and deaths after normal nonfractured legs.24 Values at day 0 are preopera- venography or cessation of prophylaxis. For example, tive recordings. Only patients with preoperative the Norwegian Arthroplasty Register, providing a measurements were included in the postoperative 10-year follow-up data for 39 543 THA patients, days. noted a higher mortality rate among THA patients in the first 60 postoperative days, than in the generalWhat Is the Optimal Duration of population.50 The continuing burden of VTE afterProphylaxis? surgery has also been highlighted by a study of DVT and PE incidence among 19 586 THA and 24 059Historically, the timing of prophylaxis and assess- TKA patients in a US discharge database.51 The cumu-ment of VTE risk following major orthopedic surgery lative incidence of DVT or PE within 3 months ofhave closely mirrored the usual period of hospitaliza- surgery was 2.8% and 2.1% following THA and TKA,tion, which was 10 to 14 days.2,9,43-46 However, the respectively. The diagnosis was made after dischargephysiological and hematological disturbances associ- in 76% of THA and 47% of TKA cases and at a medianated with major orthopedic surgery persist for longer time of 17 and 7 days after surgery, respectively.than this period, depending on the type of surgery The majority of these patients received in-hospitaland any patient-related factors determining individ- VTE prophylaxis, with only 32% receiving outpatientual VTE risk.1 prophylaxis. This suggests that more intense, earlier prophylaxis might be needed following TKA and more prolonged prophylaxis might be required follow- ing THA to reduce the risk of late VTE.51 Physiological Studies According to the UK National Total HipFemoral blood flow (capacitance and outflow) is sig- Replacement Outcome study—documenting out-nificantly reduced for at least 6 weeks after THA47 comes after primary THA in 13 343 patients in acompared with a period of 6 days of altered hemody- health service setting over 1 year—VTE is the mostnamics after TKA.26 Furthermore, in THA patients common complication following surgery.52 The hos-there are 2 timings for the onset of DVT, with peaks pital readmission rate within 12 months of THA wasin incidence about 4 days after surgery and 13 days 17%, with almost a third of readmissions resultingafter surgery.27 It has also been shown that venous from complications of THA. The most commonfunction and the subsequent development of DVT complication was VTE, with rates higher than thoseare affected by whether surgery follows a fracture for dislocation, urinary tract infections, wound
400 Clinical and Applied Thrombosis/Hemostasis / Vol. 16, No. 4, July/August 2010 Table 2. Median Time After Surgery to Presenta- tion of Objectively Confirmed Venous Throm- boembolism Following Major Orthopedic Proceduresa Median Time, Days Pulmonary Deep Vein Embolism ThrombosisSurgery Diagnosis DiagnosisHip fracture 17 24Total hip arthroplasty 34 21Total knee 12 20 arthroplastya Data from a study of 5607 patients all of whom receivedlow-molecular-weight heparin prophylaxis while in hospital3complications, and perioperative fracture; fatal PEoccurred at a rate of 0.1%. The risk of PE in THA and TKA patients is highand sustained, despite the use of prophylaxis forapproximately 10 days.53 In a prospective registry of4000 patients from a single center, the overall inci-dence of confirmed PE was 1.3% after in-hospitalLMWH prophylaxis lasting 10 days following jointsurgery. After major hip surgery, the incidence ofPE was raised for at least 2 to 3 months. Additional support for prolonged and differingVTE risk periods following THA and TKA is pro-vided by a recent observational study reportingdata collected over 13 years.3 In over 5000 Figure 2. The time course of prophylaxis use (any type) versuspatients, all of whom had received in-hospital the cumulative incidence of venous thromboembo-LMWH prophylaxis, the cumulative incidence of lism (VTE) following (A) total hip arthroplasty (n ¼symptomatic VTE was 2.7% within 6 months fol- 6639) or (B) total knee arthroplasty (n ¼ 8236).14lowing surgery (1.1% PE, 1.5% DVT, and 0.6% *Compared with prophylaxis use on the day whenboth). In 70% of cases, VTE was diagnosed after most patients received it.discharge. After surgery for hip fracture, DVT andPE occurred at a median of 24 and 17 days, was discontinued, with equivalent rates of VTErespectively. Deep vein thrombosis and PE between both groups 3 months after hospital dis-occurred at a median of 21 and 34 days, respec- charge.54 A prospective study11 of 4840 patientstively, following THA, and 20 and 12 days, respec- given routine prophylaxis for 10 days noted that thetively, following TKA. The cumulative risk of VTE annual incidence of DVT following major orthopediclasted for up to 3 months after hip surgery and for procedures was 2.1%. More recently, data from the1 month after knee surgery (Table 2).3 GLobal Orthopaedic Registry (GLORY) concerning A number of studies have identified that the ben- VTE incidence in 6639 THA and 8326 TKA patientsefits of prophylaxis could be lost when medication is showed that 75% of VTE after THA and 57% afterdiscontinued too soon after orthopedic surgery. In- TKA occurred following discharge.14 In this registry,patient prophylaxis with enoxaparin for a mean of over a quarter of all patients (26% of THA and 27%7.3 days afforded significantly greater protection of TKA patients) were not receiving prophylaxis 7from VTE than adjusted-dose warfarin during hospi- days after surgery, highlighting the discrepancytalization in a group of over 3000 THA patients (P ¼ between the risk of VTE and the administration of.0083). However, the benefits were lost once therapy prophylaxis (Figure 2).14
The critical thrombosis period in major orthopedic surgery / Warwick and Rosencher 401 and almost 70% received LMWH for 4 weeks after surgery. The rate of symptomatic VTE (confirmed by ultrasound or venography) was 1.34% after 3 months. This is in the lower range reported in the lit- erature for patients with hip fracture (1% to 9%).61-63 Data from randomized clinical trials show a trend toward fewer symptomatic VTE events with extended-duration prophylaxis in patients who have undergone elective total knee replacement58; although this difference did not reach statistical significance. A meta-analysis of prophylaxis studies also supports the hypothesis that extended-durationFigure 3. Rates of symptomatic venous thromboembolism prophylaxis is of benefit compared with standard (VTE) following total hip arthroplasty from studies duration prophylaxis in TKA patients, with VTE comparing in-hospital prophylaxis with prolonged incidences of 0% versus 1.4%, respectively (odds (5 week) prophylaxis.6,8,9,15,57-59 ratio, 0.74; 95% confidence interval, 0.26-2.15).64 In summary, there is evidence to suggest that altered blood flow and hypercoagulability persist for Radiological Studies weeks after major orthopedic surgery and that theIn our opinion, additional radiological evidence for cumulative risk of VTE continues for about 3 monthsthe extended risk of VTE is convincing. Orthopedic after surgery. There is also a growing tendency topatients are still at risk of late VTE, even when dis- continue prophylaxis beyond the period of hospitali-charged due to negative ultrasound or venography zation. Indeed, French guidelines recommend 42results.7,44,45 For example, an overview of published days of prophylaxis following hip replacement.35studies, in which more than 4000 orthopedic This commentary has a limitation as some arti-patients were discharged after pharmacological pro- cles only report incidences of symptomatic VTE atphylaxis, showed that in 68.1% of patients who were long-term follow-up, but not asymptomatic VTEvenographically negative, there were 30 reported events that may also result in long-term morbidityepisodes of symptomatic VTE after hospital dis- or even a fatal PE. This can lead to an underestima-charge.45 Imaging studies over recent decades have tion of postoperative VTE risk, and especially post-also suggested that VTE risk extends beyond the discharge risk.period during which orthopedic patients typicallyreceive prophylaxis.27,43,55,56 Indeed, most of thesestudies suggest that short periods of prophylaxis, Conclusionslasting 7 to 10 days, often serve simply to delay theinterval between surgical operation and onset of The ‘‘critical thrombosis period’’ associated withDVT, rather than preventing VTE entirely. The liter- major orthopedic surgery begins at the time of sur-ature suggests that 20% to 30% of THA patients gery and persists beyond the assumed limits of hospi-develop venographically confirmed DVT 4 to 5 weeks tal stay and the standard assessments made toafter surgery despite having had a normal day-10 or determine a patient’s risk of VTE. Thrombosis for-day-7 venogram at the end of their prophylactic mation begins during (or even before in hip fracture)therapy and hospital stay.8,9,15,57 Data from several surgery due to prevailing conditions that includestudies show that prolonging prophylaxis for up to endothelial injury, disruption in blood flow, venous5 weeks after hospital stay for THA can reduce the stasis, and alterations in coagulability. It follows thatincidence of postdischarge VTE, both symptomatic efforts to prevent the formation of thrombi shouldand venographic (Figure 3).6,8,9,15,17,18,57-59 begin as early as possible. Current guidelines advise Real-world data from the ESCORTE study of that the timing of initiation of pharmacological pro-approximately 7000 prospectively enrolled hip frac- phylaxis is a clinical decision that should considerture patients are also supportive of a lower incidence the trade-off between the risk of VTE and the bleed-of VTE associated with prolonged prophylaxis.60 ing risks associated with antithrombotic therapy.1Approximately 98% of hip fracture patients in this For agents such as the LMWHs, the current clinicalobservational study received perioperative LMWH guidelines note that prophylaxis can be initiated
402 Clinical and Applied Thrombosis/Hemostasis / Vol. 16, No. 4, July/August 2010either before or immediately after surgery; whereas evidence and case for VTE prevention and stronglyfor newer agents the current advice is begin prophy- advocate use of thromboprophylaxis, yet do notlaxis 6 to 8 hours after surgery. In practice, many provide strong recommendations on when to initi-surgeons seek to adopt a ‘‘just in time’’ approach ate prophylaxis or the optimal duration for effec-to prophylaxis, where initiation of prophylaxis tive prophylaxis. Both pathophysiological andoccurs several hours after surgery at a time when clinical evidence suggests that the risks begin ear-the patient’s bleeding risk is deemed to be suffi- lier and extend for longer than the period duringciently low (the precise time when pharmacological which most patients are provided with VTE pro-prophylaxis is administered will depend on the phylaxis. The issue for an individual patient is topatient’s individual risk of bleeding), while ensuring ensure that prophylaxis is given and continues forthe earliest possible antithrombotic activity against the known duration of risk of venous thrombosis.surgery-related thrombosis. The use of mechanical By adopting a ‘‘just-in-time’’ approach to themethods of prophylaxis to cover the delayed initia- initiation of thromboprophylaxis with LMWH,tion of anticoagulant prophylaxis may be that is, starting therapy at a safe time before orconsidered. after surgery, and by continuing with effective Investigations of the pathophysiology of thromboprophylaxis beyond hospital discharge forsurgery-related thrombosis and hematological up to 5 weeks after major orthopedic surgery, itchanges that occur during the postoperative period could be possible to further reduce the burdenhighlight that VTE risk continues well beyond the of VTE disease associated with otherwisefirst few days after surgical injury. Evidence from life-enhancing surgery.epidemiological studies, analyses of patient data-bases, radiological investigations, and clinical trialsattest to a period of risk of postoperative VTEextending for a considerable time after major ortho- Acknowledgmentspedic procedures. The duration of risk is particu-larly prolonged in THA and HFS, persisting for at We acknowledge the professional writing support ofleast 5 weeks after surgery. Dr Tim Norris and Dr Rachel Spice from Elsevier Increasingly, patients undergoing major ortho- and support from sanofi-aventis. The manuscriptpedic surgery are discharged earlier than in the was reviewed by sanofi-aventis prior to its sub-past. The trend toward more frequent use of mini- mission but the content was not influenced. Themally invasive procedures and financial pressures opinions expressed are those of the authors and nofor early patient discharge is resulting in hospital other party.stays of 3 to 4 days becoming common. Thus, unlesssteps are taken to ensure patients receive effectiveprophylaxis for an adequate duration, they willremain at risk of a potentially fatal VTE event or a Declaration of Conflicting Interestssymptomatic DVT or PE event following hospitaldischarge. Improvements in the implementation David Warwick has received honoraria for lecturesand quality of VTE prophylaxis are advocated by or consulting from sanofi-aventis, Orthofix, Boehrin-various government and professional organizations, ger-Ingelheim, Novamedix, Bayer. Nadia Rosencherfor example, the Surgical Care Improvement Proj- has received honoraria for lectures or consultingect in the United States and the Venous Throm- from Bayer, Boehringer Ingelheim, BMS, Glaxoboembolism in Hospitalized Patients Expert Smith Kline.Working Group in the United Kingdom.65,66 Theseinitiatives are important in reducing the risk of mor-tality and morbidity in patients undergoing majororthopedic surgery. Funding In summary, there is a wealth of evidence thatthe ‘‘critical thrombosis period’’ associated with Editorial support has seen funded by sanofi-aventis.major orthopedic surgery begins at the time of The authors or any of their associated institutionssurgery and extends for at least 5 to 6 weeks after have received no financial or any other compensa-surgery. Current clinical guidelines present the tion for this work.
The critical thrombosis period in major orthopedic surgery / Warwick and Rosencher 403References 11. Dahl OE, Gudmundsen TE, Haukeland L. Late occur- ring clinical deep vein thrombosis in joint-operated 1. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of patients. Acta Orthop Scand. 2000;71(1):47-50. venous thromboembolism: American College of Chest 12. White RH, Zhou H, Romano PS. Incidence of sympto- Physicians Evidence-Based Clinical Practice Guidelines matic venous thromboembolism after different elective (8th Edition). Chest. 2008;133(suppl):381S-453S. or urgent surgical procedures. Thromb Haemost. 2. Cardiovascular Disease Educational and Research 2003;90(3):446-455. Trust; Cyprus Cardiovascular Disease Educational and 13. Oster G, Ollendorf DA, Vera-Llonch M, Hagiwara M, Research Trust; European Venous Forum; Interna- Berger A, Edelsberg J. Economic consequences of tional Surgical Thrombosis Forum; International Union venous thromboembolism following major orthopaedic ´ of Angiology; Union Internationale de Phlebologie. Pre- surgery. Ann Pharmacother. 2004;38(3):377-382. vention and treatment of venous thromboembolism. 14. Warwick D, Friedman RJ, Agnelli G, et al. Insufficient International Consensus Statement (guidelines accord- duration of venous thromboembolism prophylaxis after ing to scientific evidence). Int Angiol. 2006;25(2): total hip or knee replacement when compared with the 101-161. time course of thromboembolic events: findings from the ˚ 3. Bjørnara BT, Gudmundsen TE, Dahl OE. Frequency and Global Orthopaedic Registry. J Bone Joint Surg Br. timing of clinical venous thromboembolism after major 2007;89(10):799-807. joint surgery. J Bone Joint Surg Br. 2006;88(3):386-391. 15. Dahl OE, Andreassen G, Aspelin T, et al. Prolonged 4. Hull RD, Pineo GF, Stein PD, et al. Timing of initial thromboprophylaxis following hip replacement sur- administration of low-molecular-weight heparin prophy- gery–results of a double-blind, prospective, randomised, laxis against deep vein thrombosis in patients following placebo-controlled study with dalteparin (Fragmin). elective hip arthroplasty: a systematic review. Arch Thromb Haemost. 1997;77(1):26-31. Intern Med. 2001;161(16):1952-1960. 16. Lassen MR, Borris LC, Anderson BS, et al. Efficacy and 5. Hull RD, Brant RF, Pineo GF, Stein PD, Raskob GE, safety of prolonged thromboprophylaxis with a low mole- Valentine KA. Preoperative vs postoperative initiation cular weight heparin (dalteparin) after total hip arthro- of low-molecular-weight heparin prophylaxis against plasty–the Danish Prolonged Prophylaxis (DaPP) venous thromboembolism in patients undergoing elec- Study. Thromb Res. 1998;89(6):281-287. tive hip replacement. Arch Intern Med. 1999;159(2): 17. Prandoni P, Bruchi O, Sabbion P, et al. Prolonged 137-141. thromboprophyalxis with oral anticoagulants after total 6. Hull RD, Pineo GF, Francis C, et al. Low-molecular- hip arthroplasty: a prospective controlled randomized weight heparin prophylaxis using dalteparin extended study. Arch Intern Med. 2002;162(17):1966-1971. out-of-hospital vs in-hospital warfarin/out-of-hospital 18. Eriksson BI, Lassen MR;. PENTasaccharide in HIp- placebo in hip arthroplasty patients: a double-blind, ran- FRActure Surgery Plus Investigators. Duration of pro- domized comparison. North American Fragmin Trial phylaxis against venous thromboembolism with fonda- Investigators. Arch Intern Med. 2000;160(14): parinux after hip fracture surgery: a multicenter, 2208-2215. randomized, placebo-controlled, double-blind study. 7. Leclerc JR, Gent M, Hirsch J, Geerts WH, Ginsberg JS. Arch Intern Med. 2003;163(11):1337-1342. The incidence of symptomatic venous thromboembolism 19. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran during and after prophylaxis with enoxaparin: a multi- etexilate versus enoxaparin for prevention of venous institutional cohort study of patients who underwent hip thromboembolism after total hip replacement: a rando- or knee arthroplasty. Canadian Collaborative Group. mised, double-blind, non-inferiority trial. Lancet. Arch Intern Med. 1998;158(8):873-878. 2007;370(15):949-956. 8. Planes A, Vochelle N, Darmon JY, Fagola M, 20. Kakkar AK, Brenner B, Dahl OE, et al. Extended dura- Bellaud M, Huet Y. Risk of deep-venous thrombosis tion rivaroxaban versus short-term enoxaparin for the after hospital discharge in patients having undergone prevention of venous thromboembolism after total hip total hip replacement: double-blind randomised com- arthroplasty: a double-blind, randomised controlled parison of enoxaparin versus placebo. Lancet. trial. Lancet. 2008;372(9632):31-39. 1996;348(9022):224-228. 21. Dickson BC. Venous thrombosis: on the history of Virch- ¨ 9. Bergqvist D, Benoni G, Bjorgell O, et al. Low-molecular- ow’s triad. UTMJ. 2004;81:166-171. weight heparin (enoxaparin) as prophylaxis against 22. Warwick D, Martin AG, Glew D, Bannister GC. Mea- venous thromboembolism after total hip replacement. surement of femoral vein blood flow during total hip N Engl J Med. 1996;335(10):696-700. replacement. Duplex ultrasound imaging with and with-10. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. out the use of a foot pump. J Bone Joint Surg Br. Incidence and time course of thromboembolic outcomes 1994;76(6):918-921. following total hip or knee arthroplasty. Arch Intern 23. Dahl OE, Aspelin T, Lyberg T. The role of bone trauma- Med. 1998;158(14):1525-1531. tization in the initiation of proximal deep vein
404 Clinical and Applied Thrombosis/Hemostasis / Vol. 16, No. 4, July/August 2010 thrombosis during cemented hip replacement surgery in considerations related to timing of administration. Am J pigs. Blood Coagul Fibrinolysis. 1995;6(8):709-717. Cardiovasc Drugs. 2007;7(1):1-15.24. Wilson D, Cooke EA, McNally MA. Altered venous func- 38. Bouma BN, Mosnier LO. Thrombin activatable fibrino- tion and deep venous thrombosis following proximal lysis inhibitor (TAFI) – how does thrombin regulate fibri- femoral fracture. Injury. 2002;33(1):33-39. nolysis? Ann Med. 2006;38(6):378-388.25. Planes A, Vochelle N, Fagola M. Total hip replacement 39. Vera-Llonch M, Hagiwara M, Oster G. Clinical and and deep vein thrombosis. A venographic and necropsy economic consequences of bleeding following major study. J Bone Joint Surg Br. 1990;72(1):9-13. orthopedic surgery. Thromb Res. 2006;117(5):569-577.26. McNally MA, Bahadur R, Cooke EA, Mollan RA. 40. Aveline C, Bonnet F. Delayed retroperitoneal haema- Venous haemodynamics in both legs after total knee toma after failed lumbar plexus block. Br J Anaesth. replacement. J Bone Joint Surg Br. 1997;79(4):633-637. 2004;93(4):589-591.27. Sikorski JM, Hampson WG, Staddon GE. The natural 41. Hsu DT. Delayed retroperitoneal haematoma after failed history and aetiology of deep vein thrombosis after total lumbar plexus block. Br J Anaesth. 2005;94(3):395. hip replacement. J Bone Joint Surg Br. 1981;63-B(2): 42. Weller RS, Gerancher JC, Crews JC, Wade KL. Exten- 171-177. sive retroperitoneal hematoma without neurologic defi-28. Dahl OE, Aspelin T, Arnesan H, et al. Increased activa- cit in two patients who underwent lumbar plexus block tion of coagulation and formation of late deep venous and were later anticoagulated. Anesthesiology. 2003;98: thrombosis following discontinuation of thrombopro- 581-585. phylaxis after hip replacement surgery. Thromb Res. 43. Hampson WG, Harris FC, Lucas HK, et al. Failure of 1995;80(4):299-306. low-dose heparin to prevent deep-vein thrombosis after29. Wilson D, Cooke EA, McNally MA. Changes in coagul- hip-replacement arthroplasty. Lancet. 1974;2(7884): ability as measured by thrombelastography following 795-797. surgery for proximal femoral fracture. Injury. 44. Robinson KS, Anderson DR, Gross M, et al. Ultrasono- 2002;32(10):765-770. graphic screening before hospital discharge for deep30. ¨ Strebel N, Prins M, Agnelli G, Buller HR. Preoperative venous thrombosis after arthroplasty: the post- or postoperative start of prophylaxis for venous throm- arthroplasty screening study. A randomized, controlled boembolism with low-molecular-weight heparin in elec- trial. Ann Intern Med. 1997;127(6):439-445. tive hip surgery? Arch Intern Med. 2002;162(13): 45. Ricotta S, Iorio A, Parise P, Nenci GG, Agnelli G. Post 1451-1456. discharge clinically overt venous thromboembolism in31. Rosencher N, Bonnet MP, Sessler DI. Selected new orthopaedic surgery patients with negative venogra- antithrombotic agents and neuraxial anaesthesia for phy—an overview analysis. Thromb Haemost. major orthopaedic surgery: management strategies. 1996;76(6):887-892. Anaesthesia. 2007;62(11):1154-1160. 46. Warwick D, Samama MM. The contrast between veno-32. Moen V, Dahlgren N, Irestedt L. Severe neurological graphic and clinical endpoints in trials of thrombopro- complications after central neuraxial blockades in Swe- phylaxis in hip replacement. J Bone Joint Surg Br. den 1990-1999. Anesthesiology. 2004;101(4):950-959. 2000;82(4):480-482.33. Horlocker T, Wedel DJ, Benzon HT, et al. Regional 47. McNally MA, Mollan RA. Total hip replacement, lower anesthesia in the anticoagulated patient: defining the limb blood flow and venous thrombogenesis. J Bone Joint risks (the second ASRA Consensus Conference on Neur- Surg Br. 1993;75(4):640-644. axial Anesthesia and Anticoagulation). Reg Anesth Pain 48. Warwick D, Williams MH, Bannister GC. Death and Med. 2003;28(3):172-197. thromboembolic disease after total hip replacement. A34. Tryba M. European practice guidelines: thromboembo- series of 1162 cases with no routine chemical prophy- lism prophylaxis and regional anesthesia. Reg Anesth laxis. J Bone Joint Surg Br. 1995;77(1):6-10. Pain Med. 1998;23(6 Suppl 2):178-182. 49. Warwick DJ, Whitehouse S. Symptomatic venous35. Samama CM, Albaladejo P, Benhamou D, et al. Venous thromboembolism after total knee replacement. J Bone thromboembolism prevention in surgery and obstetrics: Joint Surg Br. 1997;79(5):780-786. clinical practice guidelines. Eur J Anaesthesiol. 50. Lie SA, Engesaeter LB, Havelin LI, Gjessing HK, 2006;23(2):95-116. Vollset SE. Mortality after total hip replacement: 0-10-36. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fonda- year follow-up of 39,543 patients in the Norwegian parinux vs enoxaparin for the prevention of venous Arthroplasty Register. Acta Orthop Scand. 2000;71(1): thromboembolism in major orthopaedic surgery: a 19-27. meta-analysis of 4 randomized double-blind studies. 51. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Arch Intern Med. 2002;162(16):1833-1840. Incidence and time course of thromboembolic outcomes37. Tribout B, Colin-Mercier F. New versus established following total hip or knee arthroplasty. Arch Intern drugs in venous thromboprophylaxis: efficacy and safety Med. 1998;158(14):1525-1531.
The critical thrombosis period in major orthopedic surgery / Warwick and Rosencher 40552. A Joint Report from The Royal College of Surgeons of 59. Heit JA. Low-molecular-weight heparin: the optimal England and the British Orthopaedic Association. duration of prophylaxis against postoperative venous National Total Hip Replacement Outcome Study. Final thromboembolism after total hip or knee replacement. Report to the Department of Health. Revised June Thromb Res. 2001;101(1):V163-V173. 2000. http://www.rcseng. ac.uk/publications/docs/ 60. Rosencher N, Vielpeau C, Emmerich J, Fagnani F, hip_replacement.html/attachment_download/pdffile. Samama CM. the ESCORTE group. Venous throm- Accessed April 17, 2009. boembolism and mortality after hip fracture surgery: the ˚53. Dahl OE, Gudmundsen TE, Bjørnara BT, Solheim DM. ESCORTE study. J Thromb Haemost. 2005;3(9): Risk of clinical pulmonary embolism after joint surgery 2006-2014. in patients receiving low-molecular-weight heparin pro- 61. Perez JV, Warwick DJ, Case CP, Bannister GC. Death phylaxis in hospital: a 10-year prospective register of after proximal femoral fracture–an autopsy study. Injury. 3,954 patients. Acta Orthop Scand. 2003;74(3): 1995;26(4):237-240. 299-304. 62. Todd CJ, Freeman CJ, Camilleri-Ferrante C, et al. Dif-54. Colwell CW Jr, Collis DK, Paulson R, et al. Comparison ferences in mortality after fracture of hip: the east of enoxaparin and warfarin for the prevention of venous Anglian audit. BMJ. 1995;310(6984):904-908. thromboembolic disease after total hip arthroplasty. Eva- 63. Lawrence VA, Hilsenbeck SG, Noveck H, Poses RM, luation during hospitalization and three months after Carson JL. Medical complications and outcomes after discharge. J Bone Joint Surg Am. 1999;81(7):932-940. hip fracture repair. Arch Intern Med. 2002;162(18):55. Mannucci PM, Citterio LE, Panajotopoulos N. Low- 2053-2057. dose heparin and deep-vein thrombosis after total hip 64. Eikelboom JW, Quinlan DJ, Douketis JD. Extended- replacement. Thromb Haemost. 1976;36(1):157-164. duration prophylaxis against venous thromboembolism56. Trowbridge A, Boese CK, Woodruff B, Brindley HH Sr, after total hip or knee replacement: a meta-analysis of Lowry WE, Spiro TE. Incidence of posthospitalization the randomised trials. Lancet. 2001;358(9275):9-15. proximal deep venous thrombosis after total hip arthro- 65. The Surgical Care Improvement Project. MedQIC. plasty. A pilot study. Clin Orthop Relat Res. 1994;299: Oklahoma City, OK. Scip Project Information. 203-208. www.medqic.org/dcs/ContentServer?cid¼1122904930457. Lassen MR, Borris LC, Anderson BS, et al. Efficacy and 22&pagename¼Medqic%2FContent%2FParentShellTe safety of prolonged thromboprophylaxis with a low mole- mplate&parentName¼Topic&c¼MQParents. Accessed cular weight heparin (dalteparin) after total hip arthro- April 17, 2009. plasty–the Danish Prolonged Prophylaxis (DaPP) 66. DH/CMO. Report of the independent expert working Study. Thromb Res. 1998;89(6):281-287. group on the prevention of venous thromboembolism58. Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enox- in hospitalised patients, March 2007. http://www.dh.gov aparin therapy to prevent venous thromboembolism .uk/en/Publicationsandstatistics/Publications/Publicatio after primary hip or knee replacement. Enoxaparin Clin- nsPolicyAndGuidance/DH_073944? IdcService¼GET_ ical Trial Group. J Bone Joint Surg Am. 2001;83-A(3): FILE&dID¼138346&Rendition¼Web. Accessed April 336-345. 17, 2009.For reprints and permissions queries, please visit SAGE’s Web site at http://www.sagepub.com/journalsPermissions.nav.