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aDivision of General Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA bDivision of General Medicine, University of California—Davis, 4150 V Street/Suite 2400, To complete a comprehensive preoperative medical assessment prior to major surgery, the consultant must invariably address the issue of the pre-vention of postoperative thromboembolic complications. Venous throm-boembolism (VTE), a term encompassing deep vein thrombosis andpulmonary embolism (PE), is one of the most common postoperative com-plications. In a study from Olmsted County, Minnesota, surgery was asso-ciated with an over twentyfold increase in the odds of being diagnosed withVTE [1]. In an analysis of over 2 million inpatient surgical procedures per-formed in California, 0.8% of cases were diagnosed with symptomatic VTE,44% occurring during the hospitalization for surgery and the remainderwithin the first 3 months after surgery [2].
Overview of thromboembolism after surgery Certain procedures, such as craniotomy for brain malignancy, are associ- ated with a 3-month incidence of symptomatic VTE as high as 7.5% [3].
Because of the absence of reliable autopsy data, it is not clear how oftenfatal PE occurs after surgery. In a comprehensive study of patients under-going total hip arthroplasty, Seagroatt estimated an excess of 0.7 deathsfrom PE for every 1000 operations during the first 90 days after surgery, E-mail address: (R.H. White).
0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved.
PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 1 4 4 - X P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 compared with the ensuing 9-month period [4]. This compares with an esti-mated excess of 3.2 deaths/1000 from ischemic heart disease, 0.7 deaths/1000from stroke, and an overall excess mortality of 6.5 deaths/1000 total hipoperations. Thus, PE may account for 10% of all postoperative deaths fol-lowing total hip arthroplasty. Fatal PE accounts for approximately 3–4% ofall symptomatic VTE events [5]. For high-risk surgical procedures such astotal hip arthroplasty, this translates to a approximately 0.18–0.36% [6]. As discussed below, additional risk factorssuch as presence of a cancer, advanced age, and prolonged immobilizationare likely to be associated with an increase in the incidence of fatal PE.
The incidence of asymptomatic VTE is dramatically higher than that of symptomatic VTE, with asymptomatic VTE developing in 20–25% ofpatients after general surgery and 45–60% after orthopedic surgery involvingthe hip or knee [7]. Most clinical trials of thromboprophylaxis have eval-uated a surrogate end point, venographic evidence of thrombosis, or asymp-tomatic VTE, primarily because the low incidence of symptomatic VTEevents makes the sheer size and cost of conducting a sufficiently poweredstudy prohibitive. Unfortunately, the precise relationship between the surro-gate outcome of asymptomatic VTE and symptomatic VTE is not clear [8].
Most asymptomatic clots lyse spontaneously without treatment and they donot cause postphlebitic stasis or ulceration [9]. Fewer than one in eight veno-graphically defined clots progresses to symptomatic VTE, although a some-what higher proportion of proximal deep venous system clots becomesymptomatic compared with calf venous clots [7]. Relying on a one time‘‘snapshot’’ of thrombosis using venography does not reflect the dynamicnature of clot formation and dissolution, a process that varies over time. Forexample, in one study of patients who had a negative venogram 7–10 daysafter total hip arthroplasty, 20% had a demonstrable clot 21 days later [10].
Unfortunately, the vast majority of thromboprophylaxis studies assess effi-cacy based on the incidence of asymptomatic VTE at one point in time [7].
The most valuable studies of thromboprophylaxis are those that demon-strate a significant reduction in hard end points such as incidence of symp-tomatic VTE or fatal PE.
Implementing an optimal thromboprophylaxis regimen requires simulta- neous assessment of the risks of VTE and the risks of bleeding. After com-bining these estimates with evidence-based knowledge regarding the efficacyand safety of various thromboprophylaxis modalities, one can make anappropriate treatment recommendation. If any recommendations are goingto be followed, however, the consulting internist must also establish a work-ing relationship with the surgeon and reach an agreement about: (1) therelative risks of bleeding and thrombosis for each prophylaxis regimen, and(2) the optimal duration of prophylaxis.
P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 The risk of symptomatic VTE is directly related to: (1) the type of surgery being performed, (2) presence of other risk factors for VTE, (3) durationand extent of postoperative immobilization, and (4) use or nonuse of specificthromboprophylactic measures. Risk factors that have been shown to affectthe incidence of postoperative venous VTE are outlined in Table 1.
Essentially, all epidemiologic studies have shown that advancing age is a risk factor for incident VTE events, including postoperative VTE [1,11]. Theincidence of VTE developing after surgery among patients less than 40 yearsold is quite low but rises linearly with age [12].
Table 1Risk factors associated with venous thromboembolism (VTE) Polycythemia vera,essential thrombocytosis,paroxysmal nocturnalhemoglobinuria, others bowel disease,systemic lupuserythematosus, MI a Major: neurosurgery, abdominal, thoracic, vascular, or orthopedic surgery on lower Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; VTE, venous thromboembolism.
P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 Studies have shown that individuals with Asian/South Pacific Islander ethnicity have an approximately threefold lower risk of VTE, and this is alsotrue for postoperative VTE [13]. Whether this simply reflects the lower prev-alence of factor V Leiden and other thrombophilic disorders in this popula-tion is not known [14]. African Americans have a slightly higher relative riskof developing VTE compared with Caucasians, whereas Latinos appear tohave a modestly lower risk of developing VTE [13].
The particular surgical procedure is perhaps the strongest risk factor for developing VTE. We recently conducted a study of patients undergoing elec-tive and urgent surgery in California [2]. Neurosurgery involving entry intobrain or meningeal tissue and orthopedic surgery involving the hip (total orhemi-arthroplasty) was associated with the highest incidence of symptomaticVTE on the order of 6% and 3%, respectively. This compares with an incidenceof approximately 0.3% following laparoscopic cholecystectomy or appendec-tomy. Other procedures associated with a substantially increased risk of VTEinclude major vascular surgery involving the aorta, iliac or arteries of the leg,general surgery involving removal of a portion of the small or large bowel,radical cystectomy, gastric bypass for obesity, and kidney transplantation.
Surgical procedures associated with a very low risk of VTE include radicalneck dissection, inguinal hernia repair, laparoscopic cholecystectomy, tran-surethral resection of the prostate, and thyroid or parathyroid surgery.
Prior VTE, particularly within the past 6 months, is a major risk factor for developing postoperative VTE, with an over three-fold higher relativerisk [2]. This increased risk may reflect a higher propensity for a clot to formbecause of endothelial damage of the veins, or the presence of one or moreunderlying genetic or acquired thrombophilic conditions.
The interplay between thrombophilic disorders and postoperative VTE has been clarified in recent years. In a large study of asymptomatic carriersof either factor V Leiden or activated protein C resistance, the absolute riskof manifesting VTE by age 65 years was small, on the order of 5–10%, butthe relative risk of developing VTE was increased compared with noncar-riers (relative risk [RR] ¼ 3.3, CI 1.7–6.1), particularly after surgery(RR ¼ 5.1, confidence interval [CI] 2.2–11.8) [15]. Other studies have con-firmed these findings [16]. Based on these studies, it appears that the abso-lute risk of postoperative VTE among carriers is low (1 event per 100 P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 surgical procedures) and that patients should not be screened for inheritedthrombophilic disorders prior to surgery.
Presence of a lupus anticoagulant or anticardiolipin antibody in moder- ate or high titer among patients with no prior history of VTE is associatedwith a five to tenfold increase in the relative risk of developing VTE [17].
Patients with systemic lupus erythematosus plus either anticardiolipin anti-bodies or the lupus anticoagulant are probably at even higher risk for devel-oping postoperative VTE.
Presence of a malignancy is a potent risk factor that increases the risk of postoperative symptomatic VTE by at least twofold [2] and likely placessuch patients at increased risk for a longer period of time following the sur-gical procedure. Advanced clinical stage and pathology showing adenocar-cinoma are strongly associated with VTE [18].
Obesity, defined as a body mass index (BMI) over 30, appears to confer an increased risk of symptomatic VTE, at least in patients undergoing totalhip arthroplasty [5,19]. This may reflect a combination of greater physicalrestriction of venous outflow, higher right-sided cardiac filling pressures,decreased propulsion of blood because of reduced physical activity, or thepresence of an underlying inflammatory state associated with obesity [20].
Another factor may be inadequate thromboprophylaxis. For instance,although the dose of heparin or low molecular weight heparin (LMWH)for treatment of VTE is adjusted for weight, the recommended dose for pro-phylaxis is usually fixed, which could potentially result in under-dosing. Inaddition, mechanical prophylaxis using pneumatic compression may beineffective in obese individuals [19].
Congestive heart failure and chronic obstructive pulmonary disease (COPD) are associated with a higher incidence of VTE among hospitalizedmedical patients [21]. By extrapolation, it seems likely that these conditionsalso confer increased VTE risk in postoperative patients, with the mecha-nism being increased venous stasis.
Anything that leads to venous stasis likely increases the risk of VTE.
Conversely, early mobilization of patients has been associated with adecreased relative risk of developing postoperative VTE [19,22]. Conditionssuch as marked obesity, stroke with hemiparesis, and prolonged bed rest in P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 the hospital probably increase the risk of VTE by leading to increasedvenous stasis.
Risk factors for bleeding have not been specifically defined in a large cohort of surgical patients. Factors likely to contribute to the risk of post-operative bleeding include: the type of surgery, the underlying problem lead-ing to surgery (eg. cancer), the surgical technique, and other known bleedingrisk factors.
Widely appreciated bleeding risk factors during medical thromboprophy- laxis include a known bleeding disorder, use of antiplatelet agents or non-steroidal anti-inflammatory drugs (NSAIDs), previous gastrointestinalbleeding, cancer, and hepatic or renal insufficiency [23]. The relationshipbetween age and bleeding risk during anticoagulant therapy has been notedin some studies [24,25] but not in others [24,26].
The American College of Chest Physicians (ACCP) criteria for VTE risk stratification are widely endorsed (Table 2). Patients are categorized on thebasis of age, type of surgery, and presence or absence of additional throm-boembolic risk factors. The obvious deficiencies of this schema are: (1) the Table 2Risk stratification for thromboembolism after surgery Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism.
P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 absence of a precise definition of what constitutes major and nonmajor orminor surgery, and (2) absence of appropriate weighting of other knownVTE risk factors. Furthermore, there is nothing magical about the ages of40 or 60 that suddenly affects the risk of VTE. Nevertheless, it providessome estimates of the risk of developing clinical VTE.
Efficacy and safety of available prophylaxis Before making recommendations regarding perioperative VTE prophy- laxis, one must have a working knowledge of the efficacy and safety of thevarious thromboprophylaxis modalities. This information must be com-bined with an appreciation of individual patient characteristics, the typeof surgical procedure, and the preferences of the surgeon before an appro-priate recommendation can be made.
The Sixth ACCP Consensus Conference on Antithrombotic Therapy provides the most comprehensive evidence-based guidelines for the preven-tion of VTE in surgical patients [7]. Table 3 was adapted from the mostrecent literature and the ACCP review and outlines the appropriate regi-mens for various surgical procedures, including simple risk stratification.
Thromboprophylaxis methods can be broadly divided into nonpharmaco- logic and pharmacologic regimens. Nonpharmacologic interventions include:early ambulation, elastic stockings, intermittent pneumatic compression(IPC) devices, and inferior vena caval filters. Pharmacologic methods includeaspirin, unfractionated heparin, warfarin, LMWH, and synthetic pentasac-charides. We will also discuss newer agents including thrombin inhibitors andrecombinant hirudin as future potential options for prophylaxis.
Early ambulation should be a routine part of postoperative care for all patients, unless an absolute contraindication exits. The risks and benefitsof early ambulation are well established, especially among lower-extremityorthopedic surgery patients [27,28]. In total hip arthroplasty patients whobegan progressive weight bearing immediately after surgery, the rate ofultrasound-proven VTE was significantly less than in patients who delayedweight-bearing rehabilitation [29]. Early ambulation has also been shown tobe associated with a lower incidence of symptomatic thromboembolismafter hip arthroplasty [19]. In addition, early ambulation with physical ther-apy after hip fracture has been associated with an earlier return to the com-munity, shorter hospital length of stay, fewer complications, and a lower6-month mortality [30]. Early postoperative ambulation is acceptable asVTE prophylaxis for patients undergoing low-risk surgical procedures suchas general, gynecologic, and urologic surgery (Table 3). In practice, elasticstockings are often routinely used in these lowest-risk patients.
P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 Table 3Venous thromboembolism prophylaxis options in surgical patients a Pentasaccharide approved.
Abbreviations: A , acceptable for solo prophylaxis, with highest level of evidence; þ, combine with a nonpharmacologic method (ie, ES, IPC, or both); B, acceptable as analternative method of prophylaxis with less evidence compared to A; X, beneficial, butinadequate prophylaxis alone; ES, elastic stockings; IPC , intermittent pneumatic compression;LDUH , low-dose unfractionated heparin; LMWH , low molecular weight heparins; THA,total hip arthroplasty; TKA, total knee arthroplasty.
Risk definitionsGeneral surgery• Low risk: Minor procedure, <40 years of age, and no additional risk factors for VTE Minor procedure, but having additional VTE risk factorsMinor procedure between the ages 40 and 60 with no additional risk factorsMajor surgery, but < 40 years of age Minor procedure and over age 60 or additional VTE risk factorsMajor surgery over age 40 or with additional VTE risk factors • Very high risk: Major surgery with multiple VTE risk factorsGYN surgery:• Low risk: brief procedure for benign disease• Moderate risk: major surgery for benign disease, without additional VTE risk factors• High risk: extensive surgery for malignancyUrologic surgery:• Low risk: transurethral resection of the prostate or other low-risk urologic procedure• Moderate Risk: major, open urologic procedure• High risk: major procedure with additional VTE risk factors P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 Elastic stockings were first shown to reduce VTE events in 1952 [31].
Their benefit is attributed to improved venous flow and reduced vessel walldamage caused by the passive venous dilation that occurs during surgery[32]. The relative risk reduction with stockings is estimated to be at least60% in general, neurologic, and gynecologic surgery [33–35]. Although thereis no direct evidence of benefit in the lowest-risk surgery patients, there issome indirect evidence of harm. This concern comes from the observationthat improperly fitted stockings may cause a ‘‘garter’’ effect that increasesvenous pressure below the knees and results in delayed venous emptying andan increased risk of VTE [36]. In a recent study of stocking use in orthopedichip and knee surgery patients, 54% were found to have a ‘‘reversed gra-dient,’’ and these patients experienced a significantly higher incidence ofVTE compared with patients who had correctly fitted stockings (25.6% ver-sus 6.1%) [37]. This potential adverse effect underscores the need for properfitting. Stockings should be applied preoperatively and continued through-out the hospital and rehabilitation period. There have been no controlledtrials of prolonged out-of-hospital prophylaxis using stockings. It is reason-able, however, to recommend prolonged prophylaxis with stockings inpatients who are relatively immobile after hospital discharge.
Although stockings reduce the risk of VTE in patients undergoing higher- risk general surgery [38], orthopedic surgery [39,40], neurologic surgery [35],and trauma surgery, there is very strong evidence that other modalities aremore effective. Therefore, stockings are not recommended as solo prophy-laxis but are recommended as an adjunct for all moderate or higher-riskpatients unless the patient’s anatomy precludes proper fitting.
Intermittent pneumatic compression devices There are two principal types of intermittent pneumatic compression (IPC) devices used to prevent VTE. The first provides sequential pneumatic com-pression of the leg, either to the level of the calf or thigh. The second is a‘‘foot-pump’’ device that compresses the venous plantar plexus of the foot.
Although the two devices have not been directly compared, they are consid-ered to be equivalent. Individual institutions, physicians, or nurses may havea preference based on ease of use or patient comfort. The mechanism of actioncausing the reduced incidence of VTE is unclear. The principal mechanism islikely a direct effect of pumping venous blood, thereby reducing stasis. It is alsopossible that there is promotion of clearance of prothrombotic clotting factors[41] and an increase in local plasminogen activators leading to enhanced fibri-nolysis [42]. More recent studies have not found enhanced fibrinolysis [43]. In acase-control study, White et al showed that use of IPCs was associated with astriking reduction in the incidence of symptomatic VTE after total hip arthro-plasty, but only among patients with a body mass index of less than 25 [19].
P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 These findings suggest that IPCs may not be effective in obese individuals, per-haps because of failure to transmit sufficient pressure to the deep veins.
IPC devices have an excellent safety profile, with no known complications except for patient discomfort and potential for skin breakdown. The pri-mary drawback of IPC devices is that they are only effective if used contin-uously while patients are nonambulatory. Although the precise number ofhours such devices need to be worn in order to be effective is not known,presumably the longer the better. In one randomized trial, IPC devices(worn for a median of 15 hours a day) were as effective as LMWH for VTEprevention after total hip replacement surgery [44]. As IPC devices have thepotential to reduce ambulation, nurses and other members of the health careteam must also be vigilant about encouraging patients to ambulate.
The efficacy of IPC devices has been evaluated after many different types of surgical procedures. They may be used as the primary prophylaxis modal-ity in many surgical settings, but the use of IPC is not recommended as theonly thromboprophylactic modality in: (1) highest-risk general surgerypatients [45], (2) high-risk urologic surgery patients [46], and (3) orthopedicsurgery patients undergoing hip or knee surgery [7] (Table 3). IPC devicesare the method of choice for VTE prophylaxis when patients are atincreased risk for bleeding with anticoagulants. They are used extensivelyin conjunction with pharmacologic methods because of a presumed ‘‘addi-tive’’ prophylactic effect suggested in some studies.
There are few studies that directly compare IPC devices with warfarin or LMWH [44,47,48]. A recent trial showed no difference between IPC devicesand LMWH for VTE prevention in women undergoing surgery for presumedgynecologic malignancy. Interestingly, there was no difference in the incidenceof bleeding between the groups [49]. Based on this study and others [50], thereis good evidence to support the use of IPC devices as solo thromboprophy-laxis in patients undergoing moderate to high-risk gynecologic surgery.
One potential unintended benefit of IPC devices is reduced bleeding at the surgical site, which has been suggested by several small studies [44,51,52]. Ina meta-analysis, IPC devices were found to have a 0.0% incidence of clini-cally important bleeding, which was no different from the control rate andsignificantly better than in the warfarin group (1.3%, P ¼ 0.6) or LMWHgroup (1.8%, P ¼ 0.02) [53]. A possible physiologic explanation for this find-ing relates to the aforementioned effects on the fibrinolytic and clotting cas-cades. Thus, there is good evidence that IPC devices do not increase the riskof clinically apparent bleeding and may actually decrease bleeding risk.
In summary, nonharmacologic VTE prophylaxis methods are widely used and very safe. Early ambulation should be a part of routine care forall postsurgical patients. If properly fitted, elastic stockings (ESs) haveessentially no adverse effects and may be appropriate for almost all surgicalpatients until full ambulation is achieved. IPC devices may be used as theprimary method in selected patients, and they likely have an additive effectwhen used in conjunction with pharmacologic methods. IPC is the method P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 of choice when anticoagulation is contraindicated, but efficacy may bereduced in patients who are obese or who have very large legs.
The currently accepted indications for inferior vena caval (IVC) filters include: (1) an absolute contraindication to anticoagulation, (2) life-threat-ening hemorrhage on anticoagulation, and (3) failure of adequate anticoag-ulation. When used appropriately, IVC filters are safe and effective inreducing the incidence of PE to 0.3–3.8% in patients with a contraindicationto anti-coagulation [54]. The risks of IVC filter placement include migrationof the filter, recurrent deep vein thrombosis (DVT), IVC thrombosis, andpostphlebitic syndrome.
In the perioperative period, the scenario that most commonly arises is when a patient needs urgent surgery after a recent (<4 weeks) diagnosisof acute VTE. In such a patient, the risk of acute recurrent thromboembo-lism is significantly higher in the first month of treatment than after 4 ormore weeks of treatment [55,56]. If anticoagulation therapy must be discon-tinued, placement of an IVC filter would be appropriate to prevent fatal PE.
Placement of a temporary retrievable filter such as the Gunther TulipTM(Cook Inc., Bloomington, IN) or Tempofilter (B. Braun Celsa, ChasseneuilCedex, France) would be preferred, so it can be removed once the contrain-dication for anticoagulation has passed [57,58].
To date, there has been only one controlled trial of IVC filter use in patients with acute DVT. Use of a filter was associated with a nonsignificantreduction in the incidence of fatal pulmonary embolism, but there was a sig-nificant increase in the incidence of subsequent recurrent deep vein throm-bosis [59]. Use of a prophylactic filter is not recommended simply becausea patient is undergoing a procedure associated with a high incidence ofvenous thromboembolism.
There are a variety of effective pharmacologic agents available for pre- venting VTE after surgery. We will briefly review the most widely usedagents: low-dose unfractionated heparin (LDUH), aspirin, warfarin, lowmolecular weight heparins (LMWH), and synthetic pentasaccharides.
LDUH is a very effective prophylactic agent that clearly reduces the inci- dence of fatal postoperative PE [46]. Many studies performed in the late1970s and 1980s documented the efficacy of subcutaneously administered P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 heparin [60,61] in doses of either 5000 international units (IU) every 12hours or 5000 IU every 8 hours, with the first dose being given 2 hours pre-operatively. Initiating prophylaxis postoperatively also appears to be effec-tive, although randomized trials of this approach are sorely needed [62].
Studies comparing LDUH with low-dose LMWH (40 mg enoxaparin orequivalent) in general surgery patients show equivalent efficacy with a mod-erate increase in the risk of bleeding associated with use of LDUH [63]. Useof LDUH is associated with a modestly higher incidence of bleeding com-pared with IPC devices [50]. Elastic stockings or IPC may provide additionalprotective effect when added to LDUH in higher-risk patients.
The risks of LDUH include excess bleeding and heparin-induced throm- bocytopenia (HIT). In a meta-analysis of thromboprophylaxis after totalhip arthroplasty, the incidence of bleeding associated with LDUH (usually7500 IU every 12 hours subcutaneously) was 2.6% (versus 0.3% in placebopatients) and 1.8% in patients treated with LMWH [53]. In a meta-analysisof general surgery trials, LDUH had a higher rate of minor bleeding(RR ¼ 1.3; P < .05), but a similar rate of major bleeding when comparedwith LMWH [64]. Another meta-analysis found increased bleeding compli-cations with LDUH versus low-dose LMWH after general surgery [63].
Thus, the major argument for using LMWH in place of LDUH amonggeneral surgery patients is a lower risk of bleeding [65].
LDUH, in addition to LMWH, is one of the recommended medical pro- phylactic agents for most general surgical procedures [7], as well as high-riskurologic or gynecologic surgery patients [50,66] with or without the additionof nonpharmacologic methods. Recommended dosages for LDUH are 5000IU subcutaneously every 12 hours for moderate-risk patients and 5000 IUevery 8 hours (or 7500 IU every 12 hours) for high-risk patients. LDUH(7500 IU every 12 hours subcutaneously) is less effective compared withLMWH (30 mg of enoxaparin q 12 hours subcutaneously or equivalent)in very high-risk orthopedic or neurosurgical [63,65] and is therefore not theprophylactic agent of choice for very high-risk procedures.
In summary, LDUH is a very effective drug for the prevention of VTE, and it is the drug of choice for many indications (Table 3). It is associated,however, with a modest increase in the incidence of bleeding and HIT com-pared with LMWH, and it must be given 2–3 times a day.
The use of aspirin as a thromboprophylactic agent is controversial. The Sixth ACCP Consensus Conference statement does not recommend aspirin P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 as sole prophylaxis for any surgical procedure (Table 3) [7]. There is someevidence from the recently conducted Pulmonary Embolism Prevention(PEP) trial that aspirin may have a beneficial effect in the subgroup ofpatients with hip fracture. Over 13,000 subjects with hip fracture in hospitalsall over the world were randomized to 160 mg of aspirin per day for 5 weeksor placebo and allowed to receive routine thromboprophylaxis prescribed bytheir physician [67]. There was a significant reduction in the incidence of PEdiagnosed during hospitalization in the aspirin group (0.7%) compared withplacebo (1.2%, P < 0.001) and an impressive 58% reduction in the incidenceof fatal PE (P ¼ 002, 18 in aspirin group, 43 in placebo). Aspirin preventedapproximately 4 fatal pulmonary emboli for every 1000 patients treated andresulted in 6 excess episodes of bleeding requiring transfusion.
The results of the PEP study suggest that aspirin may have a role for VTE prophylaxis among hip fracture patients. A potential role for aspirin may bepostdischarge prophylaxis in hip fracture patients if no other medical pro-phylactic agent is used. More studies are needed to evaluate the role of aspi-rin after other surgical procedures. The findings do provide an additionalrationale for using aspirin in postoperative patients who may benefit fromprimary or secondary prevention of cardiovascular events. Until furtherstudies are done, however, aspirin alone is not recommended as a principalthromboprophylactic agent in surgical patients.
The use of warfarin for VTE prophylaxis has been limited primarily to very high-risk patients with lower-extremity orthopedic and neurologic sur-gery. Warfarin has not been commonly used in general, gynecologic, andurologic surgery patients because of the proven efficacy of other availableagents, including IPC devices, LDUH, and LMWH (Table 3). Warfarinrequires more intensive monitoring, and the potential risk for bleeding hasbeen a concern. It is very useful among patients who require extendedthromboprophylaxis, which is necessary in certain very high-risk patients.
One of the major advantages of warfarin is that the onset of its anticoagu-lant effect is delayed for several days after starting treatment. This leads to alower incidence of bleeding complication, which surgeons appreciate, but ahigher incidence of asymptomatic thrombosis, particularly in calf veins. Alarge clinical study of patients undergoing total hip arthroplasty has shownthat the incidence of symptomatic VTE within a 3-month period of surgeryis comparable after 7–10 days of treatment with warfarin or enoxaparin [5].
Warfarin is recommended as one of the principal prophylactic agents among patients undergoing hip fracture repair, total hip arthroplasty(THA), and total knee arthroplasty (TKA) (Table 3). Numerous clinicaltrials [5,47,48] and meta-analyses [53,68,69] support the use of warfarinin patients undergoing such procedures. Warfarin can be initiated preop-eratively using a ‘‘two-stage’’ approach of starting with a very low dose of P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 warfarin 10–14 days preoperatively targeting an international normalizedratio (INR) of less than 1.5, and then increasing the dose postoperativelyto a target INR of 2.5. Alternatively, warfarin can be started the night beforesurgery or immediately after surgery. Such a regimen is perhaps associatedwith a lower risk of bleeding complications [70]. Many elderly patientsrequire very low doses of warfarin, particularly if they are acutely ill orrecovering from surgery because serum albumin levels are low and resultin higher levels of free warfarin. In general, an initial dose of 5.0 mg is rec-ommended, with a lower dose of 2.5 mg for patients over 75 years old [71].
Low molecular weight heparin and pentasaccharides In the United States, there are currently three available LMWH prepara- tions: dalteparin (FragminÒ, Kabi Vitram), enoxaparin (LovenoxÒ, Phar-mion Boulder, CO), and tinzaparin (InnohepÒ, Aventis, Bridgewater, NJ)(Table 4). The U.S. Food and Drug Administration (FDA) recently approveda very low molecular weight product, the pentasaccharide fondaparinux(ArixtraÒ, Organon Sanofi-Synthelabo UC, Westorange, NJ), for preventionof VTE. As with LMWH, its mechanism of action is inhibition of factor Xamediated by antithrombin [72]. Although there have been very few clinical tri-als that have directly compared LMWH preparations, they appear to be com-parable for prevention and treatment of VTE. The dose of each agent isdifferent, and FDA approval for VTE thromboprophylaxis is different foreach product (Table 4). None of these products are FDA-approved for theprevention of VTE associated with pregnancy, spinal cord injury, trauma,or neurosurgery.
The newest agent, fondaparinux, has been compared with enoxaparin after hip arthroplasty [72], knee arthroplasty [73], and hip fracture surgery[74]. In these studies, fondaparinux was associated with a significantly lower Table 4Current FDA approved indications for use of LMWH/pentasaccharide P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 incidence of venographically documented thrombi, but with no difference inthe incidence of symptomatic VTE events. For example, following kneearthroplasty, the incidence of venographically defined thrombosis was12.5% eleven days after surgery in the fondaparinux group and 27.8% in theenoxaparin group [73]. The incidence of symptomatic VTE was 0.5% in eachgroup. Differences in the dose and timing of the administration of fondapar-inux and the comparison drug, enoxaparin, make it difficult to know if theapparent efficacy is caused by the drug, the dose, or earlier administration ofthe drug. In this study of knee arthroplasty patients, there was an increase inthe incidence of major bleeding in the fondaparinux group (P < 0.009) [72].
If the postmarketing experience of surgeons suggests that the incidence ofbleeding is acceptably low, use of this agent may become widespread.
Among general and urologic surgery patients, some surgeons prefer LMWH as there is evidence indicating a modestly lower incidence of bleed-ing compared with LDUH [53,61,63,65,75]. Although LDUH is rec-ommended for most patients undergoing general surgery, LMWH isapproved for general surgical patients. It can be used in patients in all VTEprophylaxis categories, with the exception of low-risk patients who do notwarrant pharmacologic prophylaxis [61,65].
In gynecologic surgery, use of LMWH is considered a second-line agent, as there is considerable evidence supporting the use of IPC devices orLDUH in moderate and high-risk patients, as noted above. In neurosurgery,IPC is the prophylaxis modality of choice because of the minimal risk ofbleeding. LMWH is effective in preventing VTE, however, and safe whencompared with placebo in terms of bleeding complications [76]. In traumasurgery, LMWH has become the agent of choice if the risk of bleeding isjudged to be low [77]. But if bleeding risk is significant, elastic stockingsand/or IPC devices are preferred in this high-risk group.
A large number of clinical trials have evaluated the efficacy of enoxaparin after major orthopedic surgery. It has been shown to be more effective thanLDUH with equivalent safety after THA [53,77–79] and TKA [80]. LMWHappears to be comparable to warfarin when administered for comparableperiods of time [5], although some studies have shown lower rates of veno-graphically proven VTE with LMWH, particularly after total knee arthro-plasty [81]. Dosing recommendations for LMWH and fondaparinux areshown in Table 5. Tinzaparin has been directly compared with enoxaparinafter THA, and it appears that these two agents are comparable [82].
Bleeding is the primary complication associated with pharmacologic pro- phylaxis. As noted above, LMWH has similar efficacy as LDUH, with a lower P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 Table 5Acceptable dosing of low molecular weight heparins and pentasaccharide preoperatively or 4500IU once daily startedpreoperatively Abbreviation: IU, international unit.
reported incidence of clinically important bleeding [53,61,63,65,75,78].
When compared with IPC devices, however, the zincidence of bleedingcomplications is equivalent or higher in LMWH-treated patients. In a 1996survey of U.K. orthopedists, 48% of those who had used LMWH disconti-nued use because of perceived excessive bleeding, and of those who continuedusing LMWH, 88% witnessed excessive bruising, and 53% reported woundbleeding and hematomas [81]. Because of the perceived risk of bleeding asso-ciated with the use of LMWH after orthopedic surgery, agreement must bereached with the surgeon prior to recommending these agents.
An important complication of LMWH is the potential for epidural/spinal hematoma when administered prior to removal of an epidural catheterplaced for anesthesia and/or analgesia. This was initially reported in 1997after several reports of hematoma development following concurrent useof enoxaparin prophylaxis and regional epidural or spinal anesthesia or spi-nal puncture [83]. Subsequent guidelines for use of LMWH and regionalanesthesia have been developed and include [7,84]: (1) regional anesthesiashould be avoided in patients with an abnormal bleeding history or thosereceiving drugs that affect hemostasis; (2) spinal needle insertion shouldbe delayed for 10–12 hours after the initial LMWH prophylaxis dose, andregional anesthesia should be avoided in patients with a hemorrhagic aspi-rate during spinal needle placement; (3) single-dose anesthetic is preferableto continuous epidural anesthesia; (4) in patients receiving continuous epi-dural anesthesia, the epidural catheter should be left indwelling overnight P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 and removed the next day; (5) subsequent LMWH doses should be delayedfor at least 2 hours after spinal needle placement or catheter removal; and(6) if LMWH prophylaxis is started postoperatively, the initial dose shouldbe delayed at least 2 hours after catheter removal.
Adjusted dose unfractionated heparin (ADH) has been utilized and studied [85]. Its use in practice and clinical trials, however, has all but dis-appeared since the emergence of LMWH. Although there is evidence to sup-port its use in some surgical procedures for VTE prophylaxis, it is morecumbersome than other effective methods and, therefore, was not includedin Table 4 and our review.
Direct thrombin inhibitors are a new class of anticoagulant drugs in var- ious stages of development and testing. Desirudin, the recombinant form ofhirudin, was tested for VTE prophylaxis after THA and was found to havea similar safety profile as enoxaparin, and was more effective in preventingVTE [86]. Lepirudin (RefludanÒ, Berlex, Montville, NJ), another form ofrecombinant hirudin, has been approved for the treatment of HIT. Argatro-banÒ, (Glaxo Smith Klein Research triangle Park, NC) is another thrombininhibitor that has been approved for the treat of HIT. The newest of theclass, ximelagatran, an oral thrombin inhibitor, was recently tested in aphase 2 dose-finding trial compared with enoxaparin. When given afterTKA surgery, ximelagatran (Exanta Astrozeneca Wilmington, DE) had asimilar safety and efficacy profile as enoxaparin [87].
These and other agents will continue to be developed in an effort to dis- cover the optimal VTE prophylaxis in surgical patients in terms of safetyand efficacy.
In most patients, it is appropriate to initiate VTE prophylaxis as soon as the risk of developing thrombosis begins. For trauma patients, this meansas soon as they are hospitalized. For elective surgery patients, it is as soon asthey are taken to the operating room. For recently immobilized patients, itmay be prior to admission to the hospital.
Stockings and IPC devices should be initiated preoperatively as soon as the risk of immobility increases, then continued during the procedure andthroughout the hospital stay. If aspirin is part of the VTE prophylaxis regi-men, it should be started preoperatively [67]. Warfarin can be started at alow-dose 10–14 days preoperatively, or at a therapeutic dose on the nightprior to surgery. For LMWH, the optimal timing to maximize efficacy andminimize bleeding is not yet clear (Table 5). Options include initiatingLMWH 12 hours preoperatively, immediately prior to surgery, as soonas hemostasis is achieved after surgery, or 12–24 hours postoperatively.
The clinical practice in North America tends to be to dose LMWH P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 postoperatively, whereas in European countries it is begun preoperatively.
There is data to support both regimens; however, a 1999 meta-analysis byHull et al found that LMWH initiated preoperatively was associated withlower rates of venographically proven VTE and lower rates of major bleed-ing [88]. The timing of pharmacologic prophylaxis should always be clarifiedwith the anesthesia team, particularly if spinal or epidural anesthesia (oranalgesia) is planned. The use of preprinted orders, computer reminders,or practice guidelines may be an effective method for prompting appropriateVTE prophylaxis [89].
The optimal duration of thromboprophylaxis is not known. In the 1970s and 1980s when hospitalizations were longer, patients were given thrombo-prophylaxis for their 7–10 day stay in the hospital. As the duration of hos-pitalization decreased in the 1990s, the duration of thromboprophylaxis alsodecreased. Early studies looking for asymptomatic VTE after hospital dis-charge noted a high incidence of asymptomatic thrombosis [90], and thisprompted many more studies, both in orthopedic surgery and after somegeneral surgical procedures [91–93].
A 1998 Danish trial evaluated extended thromboprophylaxis with tinza- parin in 118 patients who had undergone major abdominal and noncardiacthoracic surgery. At 4 weeks, there was no difference in the rate of veno-graphic DVT in the control group (10%) and the placebo (5.2%) groups[94]; however, the study had low power. In a larger study, Bergqvist et alfound that extended duration prophylaxis (27–31 days) with enoxaparin,40 mg/day, led to a significant (P ¼ 0.02) reduction (4.8%) in the asympto-matic VTE after abdominal or pelvic surgery for cancer compared with con-trol patients (12%) who were treated for only 6–10 days [95]. The cost ofextended thromboprophylaxis using enoxaparin (40 mg/day, $$16.00) ordalteparin (5000 IU/day, $$12.00) in the United States is significant [23].
A cost-effectiveness analysis from 1996 concluded that prolonged DVT pro-phylaxis in general surgery patients could prevent out-of-hospital DVT, butat a marginal cost that was deemed inappropriate for routine use [96].
There is evidence that extended prophylaxis is important for patients undergoing lower-extremity orthopedic surgery, particularly total hiparthroplasty. A recent meta-analysis of eight hip arthroplasty studies andtwo knee arthroplasty studies found that extended prophylaxis using LDUHor LMWH significantly reduced the frequency of symptomatic and asympto-matic VTE [97]. Extended prophylaxis for 30–42 days was associated with a P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 significantly lower incidence of symptomatic VTE (1.3%) than placebo(3.3%), or one fewer symptomatic VTE for every 50 patients treated. A casecontrol study also found that extended prophylaxis with warfarin was asso-ciated with absence of VTE [19]. Extended prophylaxis is associated with amodest increase in the risk of minor bleeding compared with placebo(3.7% versus 2.5%), or one more minor bleed for each 83 patients treated[97]. Extended prophylaxis does not appear to benefit patients who undergototal knee arthroplasty [92]. Knee arthroplasty patients develop symptomaticVTE early after surgery, with few additional cases diagnosed 3 or more weeksafter the day of surgery, whereas symptomatic VTE is frequently diagnosedin hip arthroplasty patients up to 2 months after the day of surgery [98].
The only procedure for which there is strong evidence in favor of extended prophylaxis is total hip arthroplasty, and, although the most opti-mal duration of prophylaxis after this procedure is not known, 4–6 weeksappears reasonable. Existing evidence to support extended prophylaxis afterhip fracture and total knee arthroplasty is weak, and more studies areneeded to determine the optimal duration of thromboprophylaxis. Never-theless, because the length of hospitalization after surgery is becoming soshort, some extenuation in the duration of prophylaxis is certainly logical.
Because of cost and safety concerns, it would be reasonable and appropriateto risk-stratify patients and recommend extended prophylaxis for the high-er-risk patients. Unfortunately, there is not a validated risk stratificationtool available at this time. The risk factors that are probably most importantare: obesity (BMI > 30) and sedentary lifestyle, being bed- or wheelchair-bound, and a history of prior VTE [19]. Patients who have active cancermay also be excellent candidates for extended prophylaxis, but the optimalduration of prophylaxis is unknown. Continued use of well-fitted elasticstockings after patients are discharged from the hospital is reasonable,although there is no evidence to support this recommendation. Finally, itis reasonable to consider aspirin prophylaxis, particularly in patients whohave risk factors that would warrant prophylaxis for cardiovascular disease.
If extended prophylaxis is recommended, the two logical choices are LMWH (enoxaparin 40 mg or dalteparin 5000 IU) or warfarin (targetINR ¼ 2.5). Three different cost-effectiveness studies suggest the differencein cost between warfarin and LMWH is small, but these conclusions arehighly dependent on the cost of the drug and cost of monitoring [99–101].
Given the high price of LMWH in the United States, warfarin is currentlycheaper and more cost-effective than LMWH [102].
This is a controversial topic. As noted earlier, most VTE events (includ- ing PE) are asymptomatic. Thus, screening using venous ultrasound imaging P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 is most likely to detect asymptomatic thrombi that are unlikely to becomesymptomatic. In addition, venous ultrasound is less accurate when used inasymptomatic individuals than in symptomatic individuals. In one random-ized study of patients undergoing total hip or knee arthroplasty whoreceived warfarin prophylaxis, screening with ultrasound did not reduce theincidence of symptomatic VTE but lead to treatment of 2.5 times morepatients, one of whom developed a major bleeding complication [103]. Otherstudies have concluded that screening ultrasound testing is not cost-effectiveand not warranted [104–106].
Perioperative management of patients on long-term oral anticoagulation Indications for long-term oral anticoagulation therapy (OAT) include prevention of systemic embolization in patients with prosthetic heart valvesor atrial fibrillation (AF), as well as primary or secondary prevention ofVTE. Other potential indications for chronic OAT include mitral stenosis,left ventricular aneurysm, severe left ventricular systolic dysfunction, coro-nary artery disease, previous inferior vena cava (IVC) filter placement, andpresence of synthetic peripheral arterial bypass grafts. There is a paucity ofclinical data available on the perioperative management of patients on long-term OAT, and experts’ recommendations vary widely [55,107–109]. Peri-operative management of patients on chronic OAT must be individualized,balancing the risks of thromboembolism if OAT is interrupted versus therisk of bleeding if such therapy is continued. Options for perioperative anti-coagulation include the following regimens: (1) continue OAT and performsurgery with the patient fully anticoagulated; (2) discontinue OAT preoper-atively, give prophylactic subcutaneous heparin perioperatively during hos-pitalization, and reinstitute OAT as soon as possible postoperatively; and(3) discontinue OAT preoperatively and administer ‘‘bridging therapy’’ withfull-dose intravenous heparin or LMWH during the time that the INR issubtherapeutic. The risk of thromboembolism in patients who temporarilydiscontinue OAT depends on the particular indication and other patient-specific factors, which are discussed below.
Risk of bleeding depends on the operative procedure and characteristics of the individual patient. Patient-related factors include: a prior history ofbleeding problems, concurrent use of antiplatelet agents (aspirin, NSAIDs,etc.), age >65, and acquired conditions associated with increased bleeding,such as chronic renal or liver disease and cancer. Bleeding risk is highlydependent on the type of surgery, the vascularity of the tissues, and the abil-ity of the surgeon to control bleeding either by compression or other phys-ical means (packing, cautery, topical coagulants) [110]. Guidelines forperioperative management of anticoagulation can be developed accordingto the patient’s risk of bleeding.
P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 Management of patients at low risk for bleeding complications Procedures that appear to be associated with a low risk of bleeding despite OAT include cataract extraction [111,112], laparoscopic cholecys-tectomy [113], dermatologic procedures [114], and possibly transurethralresection of the prostate [115]. In general, patients who undergo theselow-bleeding risk procedures may either continue OAT or have the intensityof OAT reduced to ‘‘low’’ therapeutic levels (ie, an INR of approximately2.0) [108]. Delayed bleeding after colonoscopic polypectomy is not unusualand may be associated with OAT [116,117], so that many endoscopists rec-ommend discontinuation of OAT if polypectomy is to be performed.
Although many dentists recommend temporary interruption of OAT pri- or to tooth extractions and other dental procedures, a recent review foundthat serious bleeding is distinctly unusual when OAT is continued duringtooth extraction, or during gingival and alveolar surgery [118]. Tranexamicacid mouthwash, a local fibrinolytic agent, has been shown to decreasebleeding in patients who undergo oral surgery while continuing to take OAT[119]. Most experts recommend that outpatient dental procedures be per-formed without discontinuing OAT or by slightly lowering the INR (toapproximately 2.5) [110,118]. A recent prospective cohort study of 104patients with a tilting disk or a bileaflet mechanical heart valve demon-strated that temporarily interrupting therapeutic OAT prior to tooth extrac-tion and immediately restarting the normal daily dose of warfarin on theevening after surgery was both safe and effective [120]. There were 2 minorbleeding complications (treated with local measures) and no thromboem-bolic complications reported after 3 months, even though 40% of thepatients had atrial fibrillation, a marker of high thromboembolic risk. Theauthors discontinued warfarin 2 days prior to the procedure if the INR wastherapeutic (2.0–4.5) at the time, resulting in a mean procedural INR of 1.87.
Management of patients with high risk for bleeding complications Neurosurgery in particular and almost all other major surgical procedures are considered high risk for bleeding [121], necessitating the transient discon-tinuation of OAT. Options include temporary discontinuation of OAT with-out ‘‘bridging’’ anticoagulation, or the use of perioperative bridging therapy.
Whether or not bridging therapy should be used depends on underlyingpatient-specific risk factors for thromboembolism if OAT is stopped.
Aside from the dental literature [118,120], there is very little clinical trial data available to inform the clinician about the risk of thromboembolism P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 during transient cessation of OAT for surgery or other procedures. Riskestimates must be extrapolated from epidemiologic studies of patients at riskfor thromboembolism (prosthetic heart valves, atrial fibrillation [AF]) butwho are not receiving OAT for a variety of reasons including gastrointesti-nal bleeding [122,123]. Such data suggest that patients at high risk forthromboembolism while not taking OAT include those with: mechanicalprosthetic heart valves [124], AF, prior stroke or multiple stroke risk factors[125,126], and recent (<1 month) acute venous thromboembolism [55,56].
Using this epidemiologic data, estimates of the daily thromboembolic risk[55,108] among patients in whom OAT is discontinued range from 0.2–1%with VTE < 3 months and 0.04% with VTE > 3 months [56,127], 0.02%with mechanical prosthetic valves [124], and 0.003–0.05% with atrial fibrilla-tion [125]. It should be kept in mind that these estimates may not apply topatients who temporarily interrupt anticoagulation to undergo surgery.
There is also a possibility of a rebound hypercoagulable state following thecessation of OAT [128,129]. Some authors also feel that patients with inher-ited or acquired hypercoagulable states and recent or life-threatening throm-bosis are also at high risk if OAT is interrupted [108].
Venous thromboembolism and atrial fibrillation As mentioned above, there have been no clinical trials that have addressed the perioperative anticoagulation management of patients witheither AF or VTE. Such patients may be managed as outlined in Table 6,with patients deemed at highest thromboembolic risk being treated withbridging therapy using either intravenous heparin or subcutaneous LMWH.
The stroke risk in patients with AF increases with age (particularly if age isgreater than 75 years), prior transient ischemic attack (TIA)/stroke or sys-temic embolus, hypertension, diabetes, reduced left ventricular function,prosthetic valves, and rheumatic mitral valve disease [125]. In patients withnonvalvular AF, those with previous TIA or stroke have the highest risk ofrecurrence (13%/year) [125,126] and should probably be given bridging ther-apy. VTE recurs commonly in the first 3 months after an acute event[56,130], and recurrence rates may be as high as 40% at 1-month withoutanticoagulation therapy [155]. Therefore, many experts recommend bridgingtherapy in patients who have had VTE in the preceding 3 months. In the firstmonth after the diagnosis of acute VTE, full-dose anticoagulation withLMWH or intravenous heparin is recommended as bridging therapy. If aprocedure is to be performed more than 1 month after acute VTE, someexperts recommend that these patients be bridged with lower, prophylacticdoses of LMWH (enoxaparin 40 mg or dalteparin 5000 IU). Patients withhistory of VTE occurring greater than 3 months earlier may be managedby simply interrupting OAT, without bridging therapy. Remember, prophy-lactic LDUH or LMWH is indicated in the perioperative period for manysurgical procedures and should be administered to most hospitalized P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 Table 6Suggested anticoagulation regimens for patients on chronic OAT undergoing noncardiacsurgery Continue OAT at usual dose or reduce dose to achieve INR in the low therapeutic range (target INR ¼ 2.0) Discontinue OAT 4–5 days prior to surgery [154], operate when INR 1.5; resume normal daily dosage on day of surgery if possible. Administerprophylactic dose SC heparin perioperativelyif clinically indicated.
Discontinue OAT 3–5 days prior to surgery; start IV heparin (target APTT 2.0–3.0 Â control) when INR falls below 2.0; stop heparin 6 h prior to surgery; restart subscataneous heparin prophylaxsisand oral anticoagulation as soon as possible; stopheparin when INR becomes therapeutic on 2consecutive daysb.
a TE risk factors include: atrial fibrillation, previous embolism, caged-ball valves, Bjork- Shiley single tilting disk valves, severe left ventricular dysfunction, and a hypercoagulable state(eg, surgery for cancer).
b Low-molecular-weight heparin in currently being investigated as an alternative agent, but is not approved for use with mechanical prosthetic valves. Treatment doses not clear, butexperts suggest: enoxaparin 1 mg/kg q 12 h, dalteparin 100 IU/kg q 12 h, or tinzaparin 175 IU/kg q day.
Abbreviations: AF, atrial fibrillation; APTT, activated partial thromboplastin time; INR, International Normalized Ratio; OAT, oral anticoagulation therapy; SC, subcutaneous; TE,thromboembolic; VTE, venous thromboembolism.
patients not receiving bridging therapy. Discontinuation of OAT for majorsurgery is not an indication for IVC filter placement and should be avoidedin this setting because several studies have documented an increased long-term risk of lower extremity DVT [56,59]. Patients being treated with OATfor mitral stenosis, coronary artery disease, left ventricular dilatation, pre-vious IVC filter placement, and synthetic arterial bypass grafts can probablybe managed with temporary interruption of therapy [110].
Several clinical studies of the management of patients with mechanical prosthetic valves have been published and may help to risk stratify thesepatients. In such patients, OAT is usually given to prevent arterial embolism(stroke, myocardial infarction) and prosthetic valve thrombosis, which areboth potentially lethal complications. A retrospective study of 159 patientswith mostly caged-ball (Starr-Edwards) prostheses undergoing 180 noncar-diac procedures at the Mayo Clinic in Rochester, Minnesota, reported a lowincidence of thromboembolism with discontinuation of OAT for an averageof 3 days preoperatively and 3 days postoperatively [131]. Katholi P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 performed the only prospective study, a small nonrandomized cohort of 39patients with older generation caged-ball aortic valves and caged-disk mitralvalves undergoing noncardiac procedures. No thromboemboli occurred in18 aortic valve patients undergoing 19 procedures who had OAT discontin-ued 3–5 days preoperatively and resumed 2 days postoperatively. Similarly,no thromboemboli were observed in 21 mitral valve patients undergoing 26procedures who had rapid reversal of OAT using vitamin K [132]. A recentretrospective study of 235 patients with newer generation, bileaflet mechan-ical valves undergoing major noncardiac operations demonstrated a veryhigh thromboembolic complication rate for tilting disk mitral valves despitebridging therapy being administered to most patients. Thromboembolicevent rates were lowest for bileaflet aortic valves (0.7%). In a multivariateanalysis, thromboembolic events were associated with surgery for malig-nancy and tilting disk mitral valves [133].
These studies and others suggest that the following factors are associated with a high risk for thromboembolic complications: all mitral prostheses,single tilting disk or Bjork-Shiley valves, double-position prosthetic valves,atrial fibrillation, severe left ventricular dysfunction, previous embolic event[134], and a hypercoagulable state (eg, cancer) [107,109,124]. It appears thatOAT can be temporarily interrupted without bridging therapy in patientswith isolated mechanical aortic valve prostheses who have none of the aboverisk factors. Patients with mitral prostheses or other embolic risk factorsshould receive bridging therapy (Table 6). Most authors also recommendthat patients on chronic OAT receive prophylactic subcutaneous LDUHor LMWH any time their INR falls to below 2.0 [109,110]. Aspirin is oftenprescribed to patients with mechanical valves as an adjunct to OAT for pre-vention of systemic embolization [135,136]; it should be discontinuedapproximately 1 week prior to major surgery and resumed as soon asdeemed safe by the surgeon [107].
Bridging therapy with low molecular weight heparins LWMH is currently being investigated as a less costly alternative for bridging therapy because of the potential to avoid hospitalization prior tomajor surgery [137]. LMWH is not FDA-pproved for use in patients withmechanical heart valves, although there is preliminary data suggesting thatenoxaparin [138] and dalteparin [139] may be safe alternatives for bridgingtherapy during minor surgical procedures. Other preliminary studies havereported excess bleeding events in patients undergoing noncardiac surgery[140]. A recent small trial of 24 patients undergoing 26 procedures using sub-cutaneous dalteparin (200 anti-Xa IU/kg/day subcutaneously for an averageof 5 days) for patients with high thromboembolic risk resulted in only 2minor bleeding complications and 1 transient ischemic attack but avoided2 days of hospitalization preoperatively [141]. Other LMWH regimens thathave been used for bridging therapy include: dalteparin (100 anti-Xa IU/kg P. Kaboli et al / Med Clin N Am 87 (2003) 77–110 SC q 12 h), enoxaparin (1 mg/kg SC q12 h or 1.5 mg/kg once daily), andtinzaparin (175 anti-Xa IU/kg SC once daily). Some experts recommend thefollowing bridging regimen: start LMWH on the day the INR is anticipatedto fall below 2.0, give the last preoperative dose on the morning prior to sur-gery; reinstitute OAT on the evening after surgery; restart LMWH at least24–48 hours after the procedure (or when risk of postoperative bleedingbecomes sufficiently low); and continue LMWH until the INR is therapeuticon 2 consecutive days [110]. The safety, efficacy, and optimal dosing regi-mens for LMWH as bridging therapy remain speculative and should be sub-stantiated by further clinical studies.
Recommending and implementing a postoperative thromboprophylaxisregimen In order to implement a thromboprophylaxis regimen successfully, con- sulting internists must balance the bleeding risk of using prophylactic agentssuch as heparin, LMWH, and warfarin against the risk of thromboembo-lism associated with the operative procedure. VTE risks and the effect ofprophylaxis can be estimated from the literature, although clinical data onbleeding risks are much more limited. Bleeding complications such aswound hematomas tend to be very troublesome for surgeons, particularlywhen such bleeding may be harmful or even catastrophic [eg, central ner-vous system (CNS) surgery]. On the other hand, VTE is a major cause ofmorbidity and mortality, including over 150,000 deaths from PE each yearin the United States [142], making this disorder the most common prevent-able cause of hospital death. Because internists care for large numbers ofpatients with VTE (but very few bleeding complications) and surgeons dealwith bleeding complications (but very few VTE complications), it can bevery difficult to reach consensus on the relative harms of a VTE versus awound hematoma.
Regardless, internists should recommend effective thromboembolic regi- mens but recognize the potential harms caused by such recommendations.
We strongly recommend direct consultation with the primary surgeon todetermine the risk/benefit ratio of each thromboprophylaxis regimen. It isinappropriate to recommend intensive thromboprophylaxis when it is clearthat the surgeon opposes this strategy and will obviously not follow yourrecommendation. Consensus must be reached before the time of surgery,and decisions based on a review of the available evidence.
Multi-disciplinary approaches include development of local guidelines that are endorsed by all interested parties (administration, internists, sur-geons, anesthesia team, pharmacists, and nurses) under the umbrella of aclinical pathway for postoperative VTE prevention. Other important con-siderations include the availability and cost of the various options, whetheror not the patient’s insurance covers the prophylactic agent, and of course,whether or not the risk/benefit ratio is acceptable to the patient.
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Study 1: culture and perceived social similarity

Men as Cultural Ideals: How Culture Shapes Gender Stereotypes Amy J. C. Cuddy, Harvard Business School Susan Crotty, Dubai School of Government Michael I. Norton, Harvard Business School Dubai School of Government Working Paper 10-07 Men as Cultural Ideals: How Culture Shapes Gender Stereotypes Amy J. C. Cuddy, Harvard Business School Susan Crotty, Dubai School of Government

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