Alex C. Spyropoulos, MD

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The BRIDGE trial: What the hospitalist should know

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In the United States, it is estimated that 2.7 to 6.1 million people have atrial fibrillation (AF).[1] This number is projected to increase to 12.1 million in 2030.[2] Despite the advent of direct oral anticoagulants (DOAC), roughly half of patients with AF on anticoagulation are treated with vitamin K antagonists (VKA), warfarin being the most widely used.[3]

Every year at least 250,000 individuals will require anticoagulation interruption for an elective procedure.[4] Clinicians, especially in hospitalized settings, are faced with the need to balance the risk of procedural bleeding with the potential for arterial thromboembolic (ATE) events. This is further complicated by warfarin's long half‐life (3660 hours).[5] The slow weaning off and restoration of warfarin's anticoagulant effect expose patients, in theory, to a higher risk of ATE in the perioperative period. Heparin bridging therapy with unfractionated heparin (UFH) or low‐molecular‐weight heparin (LMWH) was believed to be a solution to provide continuous anticoagulant effect during temporary interruption of warfarin. Perioperative bridging therapy remains widely used by hospitalists, despite uncertainties about whether it meets its premise of conferring a clinically meaningful reduction of ATE's risk that overweighs the likely higher incidence of major bleeding associated with its use over a no‐bridging strategy. Up until recently, no randomized clinical trials have evaluated the fundamental question of should we bridge. The landmark BRIDGE (Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation) trial published in August 2015 greatly contributed to answering this question.[6]

In this article we perform a narrative review of the literature on the perioperative anticoagulation management of patients with AF on chronic warfarin needing an elective procedure or surgery that led to the BRIDGE trial. We also examine the most recent 9th Edition Guidelines from the American College of Chest Physicians (ACCP) on perioperative management of anticoagulation in this population.[4] We then discuss in detail findings from the BRIDGE trial along with its implications for the hospitalist. Further, we suggest a practical treatment algorithm to the perioperative anticoagulation management of patients with AF on warfarin who are undergoing an elective procedure or surgery. We opt to focus on warfarin and to omit DOAC and antiplatelet therapies in our suggested practical approach. We lastly evaluate ongoing trials in this field.

RECENT STUDIES ON HEPARIN BRIDGING IN ATRIAL FIBRILLATION USING CONTROL GROUPS

In the last five years a body of evidence has progressively questioned the value of perioperative bridging therapy in preventing ATEs. The ORBIT‐AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) study examined data on oral anticoagulation (OAC) interruption among 2200 patients in the United States.[7] Patients who received bridging therapy accounted for 24% of interruptions and had a slightly higher CHADS₂ score than non‐bridged groups (2.53 vs 2.34, P = 0.004). Overall, no significant differences in the rate of stroke or systemic embolism were detected between the bridged and nonbridged groups (0.6% vs 0.3%, P = 0.3). In multivariate analysis, bridging was associated with an odds ratio (OR) of 3.84 of major bleeding within 30 days (P < 0.0001), along with a higher 30‐day composite incidence of myocardial infarction, stroke or systemic embolism, bleeding, hospitalization, or death (OR: 1.94, P = 0.0001). The increased adverse events with bridging therapy were independent of the baseline OAC (warfarin or dabigatran). Although the study argued against the routine use of bridging in AF patients, the authors could not exclude the potential impact of measured (CHADS₂) and unmeasured confounding variables.[7]

The open‐label RE‐LY (Randomized Evaluation of Long Term Anticoagulant Therapy With Dabigatran Etexilate) trial compared dabigatran to warfarin in nonvalvular AF. Its dataset provided prospective information on 1424 warfarin interruptions for an elective procedure or surgery. The interruptions, of which 27.5% were treated with bridging therapy, were analyzed in a substudy of the trial.[8] The CHADS₂ or CHA₂DS₂‐VASC scores were similar in the bridged and nonbridged warfarin groups. Relatively higher rates of major bleeding were observed in the bridged group (6.8% vs 1.6%, P < 0.001) with no statistically significant difference in stroke and systemic embolism (0.5% vs 0.2%, P = 0.32) compared to the nonbridged group. Paradoxically, bridging therapy was associated with a 6‐fold increase in the risk of any thromboembolic event among patients on warfarin (P = 0.007). As in the ORBIT‐AF study, it was difficult to determine whether this increase was secondary to unmeasured confounding variables associated with higher baseline risk of ATE.[8]

The problem of unmeasured variables was common to the previous studies of perioperative bridging therapy. The heterogeneity of event definitions, bridging regimens, and per‐protocol adherence rates were additional limitations to the studies' clinical implications, despite the consistency of a 3‐ to 4‐fold increase in the major bleeding risk among bridged patients with no accompanying protection against ATE. From this perspective, the absence of high‐quality data was the motivating force behind the BRIDGE trial.

THE BRIDGE TRIAL

The BRIDGE trial[6] attempted to answer a simple yet fundamental question: in patients with AF on warfarin who need temporary interruption for an elective procedure or surgery, is perioperative heparin bridging necessary?

Adult patients (18 years of age) were eligible for the study if they had chronic AF treated with warfarin for 3 months or more with a target International Normalized Ratio (INR) range of 2.0 to 3.0, CHADS₂ score 1, and were undergoing an elective invasive procedure or nonurgent surgery. The study excluded patients planned for a cardiac, intracranial, or intraspinal surgery. A history of stroke, ATE, or TIA in the preceding 3 months; a major bleed in the previous 6 weeks; or a mechanical heart valve precluded study participation. Further, those with a platelet count <100,000/mm[3] or creatinine clearance less than 30 mL per minute were also excluded.

Patients were randomly assigned to receive LMWH (dalteparin 100 IU/kg of body weight) or placebo subcutaneously twice daily in a double‐blind fashion. In all patients, warfarin was withheld 5 days before the invasive procedure or elective surgery and restarted within 24 hours afterward. The bridging arm received therapeutic‐dose LMWH starting 3 days before the procedure with matching placebo in the nonbridged arm. The last dose of LMWH or placebo was given around 24 hours before the procedure and then withheld. LMWH or placebo was restarted 12 to 24 hours after the procedure for defined low bleeding‐risk procedures and 48 to 72 hours for high bleeding‐risk procedures. The study drug was continued for 5 to 10 days and stopped when the INR was in the therapeutic range. The coprimary outcomes were ATE (stroke, TIA, or systemic embolism) and major bleeding using a standardized definition. These outcomes were assessed in the 30 days following the procedure.

Out of 1884 recruited patients in the United States and Canada, 934 patients were assigned to the bridging arm and 950 to the nonbridging arm. Study participants had a mean age of 71.7 years, a CHADS₂ score of 2.3, and 3 out of 4 were men. The 2 arms had similar baseline characteristics. Adherence to the study‐drug protocol was high, with an 86.5% rate of adherence before the procedure to 96.5% after the procedure. At 30 days, the rate of ATE in the bridging group (0.4%) was noninferior to the nonbridging one (0.3%) (95% confidence interval [CI]: 0.6 to 0.8; P value for noninferiority = 0.01). The mean CHADS₂ score in patients who sustained an ATE event was 2.6 (range, 14). The median time to an ATE event was 19.0 days (interquartile range [IQR], 6.023.0 days). The bridging group had a significantly higher rate of major bleeding compared to the nonbridging one (3.2% vs 1.3%, P = 0.005). The median time to a major bleeding event after a procedure was 7.0 days (IQR, 4.018.0 days). The 2 arms did not differ in their rates of venous thromboembolic (VTE) events and death in the study period. Yet, there was a significantly greater rate of minor bleeding in the bridging group (20.9% vs 12.0%, P < 0.001) and a trend toward more episodes of myocardial infarction in the bridging group as well (1.6% vs 0.8%, P = 0.10).

The BRIDGE trial was a proof of concept that the average AF patient may safely undergo commonly performed elective procedures or surgeries in which warfarin is simply withheld 5 days before and reinitiated within a day of the procedure without the need for periprocedural heparin bridging. Perioperative ATE rates, previously thought to be around 1%, have been overestimated. The ATE rate was low in the BRIDGE trial (0.4%), especially given a representative AF study population. The classical concern that warfarin interruption leads to a rebound hypercoagulable state was not supported by the trial.

The 9th Edition 2012 ACCP Guidelines on perioperative management of anticoagulation had suggested bridging in AF patients at high thrombotic risk and no bridging in the low risk group (Table 1).[4] For patients at moderate risk, the ACCP Guidelines called for an individualized assessment of risk versus benefits of bridging, a recommendation that was not based on high‐quality data. The BRIDGE trial findings are likely to change practice by providing level 1 evidence to forgo bridging in the vast majority of represented AF patients. For the hospitalist, this should greatly simplify periprocedural anticoagulant management for the AF patient on chronic warfarin in a hospitalized setting.

Table 1.ACCP Risk Stratification of Perioperative Thromboembolism
Risk Category	Mechanical Heart Valve	Atrial Fibrillation	Venous Thromboembolism
ACCP: American College of Chest Physicians, TIA: Transient Ischemic Attack, VTE: Venous Thromboembolism.
High	Mitral valve prosthesis	CHADS₂ score of 5 or 6	Recent (<3 month) VTE
High	Caged‐ball or tilting‐disc aortic valve prosthesis	Recent (<3 months) stroke or TIA	Severe thrombophilia
Recent (<6 months) stroke or TIA	Rheumatic valvular heart disease	Deficiency of protein C, protein S, or antithrombin
Recent (<6 months) stroke or TIA	Rheumatic valvular heart disease	Antiphospholipid antibodies
Multiple thrombophilias
Intermediate	Bileaflet aortic valve prosthesis with a major risk factor for stroke	CHADS₂ score of 3 or 4	VTE within past 312 months
Intermediate		CHADS₂ score of 3 or 4	Nonsevere thrombophilia
Recurrent VTE
Active cancer
Low	Bileaflet aortic valve prosthesis without a major risk factor for stroke	CHADS₂ score of 0 to 2 with no prior stroke or TIA	VTE >12 months previous

Limitations of the BRIDGE trial include the exclusion of surgeries that have an inherent high risk of postoperative thrombosis as well as bleeding, such as cardiac and vascular surgeries. Also, the trial had an under‐representation of patients with a CHADS₂ score of 5 or 6 and excluded those with a mechanical heart valve. Both of these groups carry a high risk of ATE. However, it would be expected that the increase in postprocedural bleed risk seen with therapeutic‐dose bridging therapy in the BRIDGE trial would only be magnified in high bleeding‐risk procedures, with either no effect on postoperative ATE risk reduction, or the potential to cause an increase in downstream ATE events by the withholding of anticoagulant therapy for a bleed event. The ongoing placebo‐controlled PERIOP‐2 trial (ClinicalTrials.gov no. NCT00432796)[9] utilizes a strategy of dose adaptation of bridging therapy based on procedural bleeding risk, rather than a strategy of changing the timing of reinitiation of bridging therapy seen in the BRIDGE trial. Though the bridging protocol adapted in PERIOP‐2 is used less often in clinical practice, the study is including patients with mechanical heart valves as well as following patients for a longer period of time compared to the BRIDGE trial (90 vs 30 postoperative days). This may elucidate the potential increase in downstream ATE events due to bleed events incurred by heparin bridging. The trial is planned to be completed in March 2017.

PRACTICAL APPROACH TO PERIOPERATIVE MANAGEMENT OF WARFARIN ANTICOAGULATION IN ATRIAL FIBRILLATION

In Figure 1 we suggest a practical 3‐step framework for the perioperative anticoagulation management of patients on chronic warfarin for AF. First, if the planned invasive procedure or surgery falls under the minimal bleeding‐risk group in Table 2, we propose continuing warfarin in the perioperative period. Notably, implantation of a pacemaker or cardioverter‐defibrillator device is included in this group based on recently completed randomized trials in this patient group. In fact, the BRUISE CONTROL trial showed a markedly reduced incidence of device‐pocket hematoma when warfarin was continued in the perioperative period as compared to its temporary interruption and use of bridging (3.5% vs 16%, P < 0.001). Other surgical complications including ATE events were similar in the 2 groups.[10] The COMPARE trial demonstrated that warfarin can also be continued in the periprocedural period in patients undergoing catheter ablation of AF. Warfarin's continuation among 1584 AF patients who had this procedure was associated with significantly fewer thromboembolic events(0.25% vs 4.9%, P < 0.001) and minor bleeding complications (4.1% vs 22%, P < 0.001) compared to its temporary interruption and use of bridging.[11] We recognize that the clinical distinction between minimal and low bleeding risk can be difficult, yet the former is increasingly recognized as a group in which anticoagulation can be safely continued in the perioperative period.[12]

Table 2.Suggested Stratification of Procedural Bleeding Risk
Minimal Bleeding‐Risk Procedures	Low Bleeding‐Risk Procedures	High Bleeding‐Risk Procedures
*Level 1 evidence supports continuation of oral anticoagulation in perioperative period, as this approach results in significantly fewer pocket hematomas compared to temporary oral anticoagulation interruption and use of bridging therapy.[10, 11]
Implantation of pacemaker or cardioverter‐defibrillator device;* catheter ablation of atrial fibrillation*	Coronary angiography	Cardiac, intracranial, or spinal surgery; any major procedure lasting 45 minutes
Minor cutaneous excision (actinic keratosis, premalignant/malignant skin nevi, basal and squamous cell skin carcinoma)	Cutaneous or lymph node biopsy	Major surgery with extensive tissue resection; cancer surgery
Cataract surgery	Arthroscopy; surgery of hand, foot, or shoulder	Major orthopedic surgery
Minor dental procedure (cleaning, filling, extraction, endodontic, prosthetic)	Endoscopy/colonoscopy biopsy, laparoscopic cholecystectomy, hemorrhoidal surgery, abdominal hernia repair	Liver or spleen surgery, bowel resection, colonic polyp resection, percutaneous endoscopic gastrotomy placement, endoscopic retrograde cholangiopancreatography
	Bronchosopy	Nephrectomy, kidney biopsy, transurethral prostate resection, bladder resection, or tumor ablation

Suggested periprocedural management of warfarin anticoagulation in chronic atrial fibrillation based on the most recent clinical evidence. *Includes pacemaker and cardioverter‐defibrillator device implantation, and catheter ablation of atrial fibrillation as level 1 evidence indicates that they can be done without warfarin interruption (Table 2). **For patients with International Normalized Ratio (INR) target range of 2.5 to 3.5 and elderly patients, we suggest holding warfarin on day 6 (the procedure being on day 0). ***Especially valvular atrial fibrillation associated with (1) a mechanical heart valve, (2) a recent stroke or transient ischemic attack, or (3) severe rheumatic heart disease. There were few patients in BRIDGE with a CHADS2 score of 5 or 6. ****Therapeutic‐dose low‐molecular‐weight heparin (LMWH) may be stopped once INR ≥2.

Second, if the decision was made to hold warfarin, the next step is to estimate the patient's perioperative thrombotic risk based on the 9th Edition ACCP Guidelines shown in Table 1. Whereas patients may have additional comorbidities, a theoretical framework for an individual patient's ATE risk stratification as seen in the ACCP Guidelines is determined by the CHADS₂ score, a history of rheumatic heart disease, and a recent ATE event (within 3 months). In the low ATE risk group, recommendations from the ACCP,[4] the American Heart Association, and the American College of Cardiology[13] are in agreement against the use of perioperative bridging. Level 1 evidence from the BRIDGE trial now supports that bridging may be forgone in patients in the moderate ATE risk group and likely many patients in the high ATE risk group (although patients with a CHADS₂ score of 5 and 6 were under‐represented in the BRIDGE trial). In certain high ATE risk patient groups with AF, especially those with a recent ATE event, mechanical heart valves, or severe rheumatic heart disease, it may be prudent to bridge those patients with UFH/LMWH.

Third, assuming adequate hemostasis is achieved after the procedure, warfarin can be restarted within 24 hours at its usual maintenance dose regardless of bridging. For patients among whom bridging is chosen, we suggest that the timing of resumption of LMWH bridging be based on the procedural risk of bleeding (Table 2): 1‐day postprocedurally in the low bleeding‐risk groups or 2 to 3 days postprocedurally in the high bleeding‐risk groups. For the latter group, a stepwise use of prophylactic‐dose LMWH, especially after a major surgery for the prevention of VTE, may be resumed earlier at the discretion of the surgeon or interventionist. For both groups, therapeutic‐dose LMWH may be stopped once the INR is 2.

A number of challenges are associated with the proposed framework. Real‐world data show that nonindicated OAC interruptions and bridging are commonplace. This may defer the hospitalist's readiness to change practice.[7] Although the CHADS₂/CHA₂DS₂‐VASc scores are widely used to estimate the perioperative ATE risk, there is scant evidence from validation studies,[14, 15] whereas the CHADS₂ score has been used in guideline recommendations.[4] Also, as previously discussed, this framework excludes patients with a recent stroke or a mechanical heart valve, patients on warfarin for VTE, and patients on DOACs.

RETHINKING HEPARIN BRIDGING THERAPY IN NONATRIAL FIBRILLATION PATIENT GROUPS

There is now mounting recent evidence from over 12,000 patients that any heparin‐based bridging strategy does not reduce the risk of ATE events but confers an over 2‐ to 3‐fold increased risk of major bleeding.[16] Thus, in our view, the BRIDGE trial was a proof of concept that calls to question the premise of heparin bridging therapy in preventing ATE beyond the AF population. Retrospective studies provide evidence of the lack of treatment effect with heparin bridging even in perceived high thromboembolic risk populations, including those with mechanical heart valves and VTE (2 patient groups for whom there are currently no level 1 data on perioperative management of anticoagulation and bridging therapy).

In their systematic review and meta‐analysis, Siegal et al. evaluated periprocedural rates of bleeding and thromboembolic events in more than 12,000 patients on VKA based on whether they were bridged with control groups.[16] Thirty out of 34 studies reported the indication for anticoagulation, with AF being the most common (44%). Bridging was associated with an OR of 5.4 for overall bleeding (95% CI: 3.0 to 9.7) and an OR of 3.6 for major bleeding (95% CI: 1.5 to 8.5). ATE and VTE events were rare, with no statistically significant differences between the bridged (0.9%) and nonbridged patients (0.6%) (OR: 0.8, 95% CI: 0.42 to 1.54). The authors suggested that bridging might better be reserved to patients who are at high risk of thromboembolism. Nonetheless, the implications of the findings were limited by the poor quality of included studies and their heterogeneity in reporting outcomes, especially bleeding events.[16]

In a retrospective cohort study of 1777 patients who underwent mechanical heart valve replacement (56% aortic, 34% mitral, 9% combined aortic and mitral), 923 patients who received therapeutic‐dose bridging therapy in the immediate postvalve implantation period had a 2.5 to 3 times more major bleeding (5.4% vs 1.9%, P = 0.001) and a longer hospital stay compared to those who received prophylactic‐dose bridging anticoagulation. The two groups had comparable thromboembolic complications at 30 days (2%, P = 0.81).[17] Another study retrospectively analyzed data from 1178 patients on warfarin for prevention of secondary VTE who had anticoagulation interruption for an invasive procedure or surgery. About one‐third received bridging therapy, the majority with therapeutic‐dose LMWH. Of the bridged patients, 2.7% had a clinically relevant bleeding at 30 days compared to 0.2% in the nonbridged groups (P = 0.01). The incidence of a recurrent VTE was low across all thrombotic risk groups, with no differences between bridged and nonbridged patients (0.0% vs 0.2%, P = 0.56).[18]

There are a number of factors as to why heparin bridging appears ineffective in preventing periprocedural ATE events. It is possible that rebound hypercoagulability and a postoperative thrombotic state have been overestimated. Older analyses supporting postoperative ATE rates of 1.6% to 4.0% and a 10‐fold increased risk of ATE by major surgery are not supported by recent perioperative anticoagulant studies with control arms, including the BRIDGE trial, where the ATE event rate was closer to 0.5% to 1.0%.[6, 7, 8, 19] The mechanisms of perioperative ATE may be more related to other factors than anticoagulant‐related factors, such as the vascular milieu,[14] alterations in blood pressure,[20] improvements in surgical and anesthetic techniques (including increasing use of neuraxial anesthesia),[21] and earlier patient mobilization. Indeed, the occurrence of ATE events in the BRIDGE trial did not appear to be influenced by a patient's underlying CHADS₂ score (mean CHADS₂ score of 2.6). There is a growing body of evidence that suggests perioperative heparin bridging has the opposite effect to that assumed by its use: there are trends toward an increase in postoperative ATE events in patients who receive bridging therapy.[8]

In the BRIDGE trial, there was a trend toward an increase in myocardial infarction in the bridging arm. This can be explained by a number of factors, but the most obvious includes an increase in bleeding events as may be expected by the use of therapeutic‐dose heparin bridging over a no‐bridging approach, which then predisposes a patient to downstream ATE events after withholding of anticoagulant therapy. The median time to a major bleed in BRIDGE was 7 days, whereas the mean time to an ATE event was 19 days, suggesting that bleeding is front‐loaded and that withholding of anticoagulant therapy after a bleed event may potentially place a patient at risk for later ATE events. This is consistent with an earlier single‐arm prospective cohort study of 224 high ATE risk patients on warfarin who were treated with perioperative LMWH bridging therapy. Among patients who had a thromboembolic event in the 90 postoperative days, 75% (6 out of 8) had their warfarin therapy withdrawn or deferred because of bleeding.[22] Last, if prophylactic doses of heparin were used as bridging therapy, there is no evidence that this would be protective of ATE events, which is the premise of using heparin bridging. Both of these concepts will be assessed when results of the PERIOP‐2 trial are made available.

An emerging body of evidence suggests an unfavorable risk versus benefit balance of heparin bridging, regardless of the underlying thrombotic risk. Overall, if bridging therapy is effective in protecting against ATE (which has yet to be demonstrated), recent studies show that its number needed to treat (NNT) would be very large and far larger than its number needed to harm (NNH). If more patients undergoing high bleeding‐risk procedures were included in the BRIDGE trial, these effects of unfavorable NNT to NNH would be magnified. While awaiting more definite answers from future trials, we believe clinicians should be critical of heparin bridging. We also suggest that they reserve it for patients who are at a significantly high risk of ATE complications until uncertainties around its use are clarified.

CONCLUSION

The BRIDGE trial provided high‐quality evidence that routine perioperative heparin bridging of patients on chronic warfarin for AF needing an elective procedure or surgery is both unnecessary and harmful. The trial is practice changing for patients with AF, and its results will likely be implemented in future international guidelines on the topic, including those of the ACCP. The hospitalist should be aware that the current large body of evidence points to more harm than benefit associated with heparin bridging in preventing ATE for any patient group, including those at high risk of ATE. Ongoing and future trials may clarify the role of heparin bridgingif anyin patients on chronic warfarin at high risk of ATE, including those with mechanical heart valves.

Disclosures: Alex C. Spyropoulos, MD, has served as a consultant for Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Janssen. He also has served on advisory committees for Bristol‐Myers Squibb and Pfizer.

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References

Centers for Disease Control and Prevention. Atrial fibrillation fact sheet. Available at: http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm. Updated August 13, 2015. Accessed November 22, 2015.
Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112(8):1142–1147.
Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300–1305.e2.
Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e326S–e350S.
Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence‐based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):160S–198S.
Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015;373(9):823–833.
Steinberg BA, Peterson ED, Kim S, et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT‐AF). Circulation. 2015;131(5):488–494.
Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE‐LY trial. Thromb Haemost. 2015;113(3):625–632.
PERIOP 2—A Safety and Effectiveness Study of LMWH Bridging Therapy Versus Placebo Bridging Therapy for Patients on Long Term Warfarin and Require Temporary Interruption of Their Warfarin. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT00432796. Accessed December 9, 2015.
Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med. 2013;368(22):2084–2093.
Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation. 2014;129(25):2638–2644.
Bajkin BV, Vujkov SB, Milekic BR, Vuckovic BA. Risk factors for bleeding after oral surgery in patients who continued using oral anticoagulant therapy. J Am Dent Assoc. 2015;146(6):375–381.
Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(24):2215–2245.
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RECENT STUDIES ON HEPARIN BRIDGING IN ATRIAL FIBRILLATION USING CONTROL GROUPS

THE BRIDGE TRIAL

Table 1.ACCP Risk Stratification of Perioperative Thromboembolism
Risk Category	Mechanical Heart Valve	Atrial Fibrillation	Venous Thromboembolism
ACCP: American College of Chest Physicians, TIA: Transient Ischemic Attack, VTE: Venous Thromboembolism.
High	Mitral valve prosthesis	CHADS₂ score of 5 or 6	Recent (<3 month) VTE
High	Caged‐ball or tilting‐disc aortic valve prosthesis	Recent (<3 months) stroke or TIA	Severe thrombophilia
Recent (<6 months) stroke or TIA	Rheumatic valvular heart disease	Deficiency of protein C, protein S, or antithrombin
Recent (<6 months) stroke or TIA	Rheumatic valvular heart disease	Antiphospholipid antibodies
Multiple thrombophilias
Intermediate	Bileaflet aortic valve prosthesis with a major risk factor for stroke	CHADS₂ score of 3 or 4	VTE within past 312 months
Intermediate		CHADS₂ score of 3 or 4	Nonsevere thrombophilia
Recurrent VTE
Active cancer
Low	Bileaflet aortic valve prosthesis without a major risk factor for stroke	CHADS₂ score of 0 to 2 with no prior stroke or TIA	VTE >12 months previous

PRACTICAL APPROACH TO PERIOPERATIVE MANAGEMENT OF WARFARIN ANTICOAGULATION IN ATRIAL FIBRILLATION

Table 2.Suggested Stratification of Procedural Bleeding Risk
Minimal Bleeding‐Risk Procedures	Low Bleeding‐Risk Procedures	High Bleeding‐Risk Procedures
*Level 1 evidence supports continuation of oral anticoagulation in perioperative period, as this approach results in significantly fewer pocket hematomas compared to temporary oral anticoagulation interruption and use of bridging therapy.[10, 11]
Implantation of pacemaker or cardioverter‐defibrillator device;* catheter ablation of atrial fibrillation*	Coronary angiography	Cardiac, intracranial, or spinal surgery; any major procedure lasting 45 minutes
Minor cutaneous excision (actinic keratosis, premalignant/malignant skin nevi, basal and squamous cell skin carcinoma)	Cutaneous or lymph node biopsy	Major surgery with extensive tissue resection; cancer surgery
Cataract surgery	Arthroscopy; surgery of hand, foot, or shoulder	Major orthopedic surgery
Minor dental procedure (cleaning, filling, extraction, endodontic, prosthetic)	Endoscopy/colonoscopy biopsy, laparoscopic cholecystectomy, hemorrhoidal surgery, abdominal hernia repair	Liver or spleen surgery, bowel resection, colonic polyp resection, percutaneous endoscopic gastrotomy placement, endoscopic retrograde cholangiopancreatography
	Bronchosopy	Nephrectomy, kidney biopsy, transurethral prostate resection, bladder resection, or tumor ablation

RETHINKING HEPARIN BRIDGING THERAPY IN NONATRIAL FIBRILLATION PATIENT GROUPS

CONCLUSION

RECENT STUDIES ON HEPARIN BRIDGING IN ATRIAL FIBRILLATION USING CONTROL GROUPS

THE BRIDGE TRIAL

Table 1.ACCP Risk Stratification of Perioperative Thromboembolism
Risk Category	Mechanical Heart Valve	Atrial Fibrillation	Venous Thromboembolism
ACCP: American College of Chest Physicians, TIA: Transient Ischemic Attack, VTE: Venous Thromboembolism.
High	Mitral valve prosthesis	CHADS₂ score of 5 or 6	Recent (<3 month) VTE
High	Caged‐ball or tilting‐disc aortic valve prosthesis	Recent (<3 months) stroke or TIA	Severe thrombophilia
Recent (<6 months) stroke or TIA	Rheumatic valvular heart disease	Deficiency of protein C, protein S, or antithrombin
Recent (<6 months) stroke or TIA	Rheumatic valvular heart disease	Antiphospholipid antibodies
Multiple thrombophilias
Intermediate	Bileaflet aortic valve prosthesis with a major risk factor for stroke	CHADS₂ score of 3 or 4	VTE within past 312 months
Intermediate		CHADS₂ score of 3 or 4	Nonsevere thrombophilia
Recurrent VTE
Active cancer
Low	Bileaflet aortic valve prosthesis without a major risk factor for stroke	CHADS₂ score of 0 to 2 with no prior stroke or TIA	VTE >12 months previous

PRACTICAL APPROACH TO PERIOPERATIVE MANAGEMENT OF WARFARIN ANTICOAGULATION IN ATRIAL FIBRILLATION

Table 2.Suggested Stratification of Procedural Bleeding Risk
Minimal Bleeding‐Risk Procedures	Low Bleeding‐Risk Procedures	High Bleeding‐Risk Procedures
*Level 1 evidence supports continuation of oral anticoagulation in perioperative period, as this approach results in significantly fewer pocket hematomas compared to temporary oral anticoagulation interruption and use of bridging therapy.[10, 11]
Implantation of pacemaker or cardioverter‐defibrillator device;* catheter ablation of atrial fibrillation*	Coronary angiography	Cardiac, intracranial, or spinal surgery; any major procedure lasting 45 minutes
Minor cutaneous excision (actinic keratosis, premalignant/malignant skin nevi, basal and squamous cell skin carcinoma)	Cutaneous or lymph node biopsy	Major surgery with extensive tissue resection; cancer surgery
Cataract surgery	Arthroscopy; surgery of hand, foot, or shoulder	Major orthopedic surgery
Minor dental procedure (cleaning, filling, extraction, endodontic, prosthetic)	Endoscopy/colonoscopy biopsy, laparoscopic cholecystectomy, hemorrhoidal surgery, abdominal hernia repair	Liver or spleen surgery, bowel resection, colonic polyp resection, percutaneous endoscopic gastrotomy placement, endoscopic retrograde cholangiopancreatography
	Bronchosopy	Nephrectomy, kidney biopsy, transurethral prostate resection, bladder resection, or tumor ablation

RETHINKING HEPARIN BRIDGING THERAPY IN NONATRIAL FIBRILLATION PATIENT GROUPS

CONCLUSION

References

Centers for Disease Control and Prevention. Atrial fibrillation fact sheet. Available at: http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm. Updated August 13, 2015. Accessed November 22, 2015.
Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112(8):1142–1147.
Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300–1305.e2.
Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e326S–e350S.
Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence‐based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):160S–198S.
Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015;373(9):823–833.
Steinberg BA, Peterson ED, Kim S, et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT‐AF). Circulation. 2015;131(5):488–494.
Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE‐LY trial. Thromb Haemost. 2015;113(3):625–632.
PERIOP 2—A Safety and Effectiveness Study of LMWH Bridging Therapy Versus Placebo Bridging Therapy for Patients on Long Term Warfarin and Require Temporary Interruption of Their Warfarin. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT00432796. Accessed December 9, 2015.
Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med. 2013;368(22):2084–2093.
Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation. 2014;129(25):2638–2644.
Bajkin BV, Vujkov SB, Milekic BR, Vuckovic BA. Risk factors for bleeding after oral surgery in patients who continued using oral anticoagulant therapy. J Am Dent Assoc. 2015;146(6):375–381.
Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(24):2215–2245.
Kaatz S, Douketis JD, Zhou H, Gage BF, White RH. Risk of stroke after surgery in patients with and without chronic atrial fibrillation. J Thromb Haemost. 2010;8(5):884–890.
Daniels PR. Peri‐procedural management of patients taking oral anticoagulants. BMJ. 2015;351:h2391.
Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta‐analysis of bleeding and thromboembolic rates. Circulation. 2012;126(13):1630–1639.
Mathew JG, Spyropoulos AC, Yusuf A, et al. Efficacy and safety of early parenteral anticoagulation as a bridge to warfarin after mechanical valve replacement. Thromb Haemost. 2014;112(6):1120–1128.
Clark NP, Witt DM, Davies LE, et al. Bleeding, recurrent venous thromboembolism, and mortality risks during warfarin interruption for invasive procedures. JAMA Intern Med. 2015;175(7):1163–1168.
Dunn AS, Turpie AG. Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med. 2003;163(8):901–908.
Cheung CC, Martyn A, Campbell N, et al. Predictors of intraoperative hypotension and bradycardia. Am J Med. 2015;128(5):532–538.
Selim M. Perioperative stroke. N Engl J Med. 2007;356(7):706–713.
Kovacs MJ, Kearon C, Rodger M, et al. Single‐arm study of bridging therapy with low‐molecular‐weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin. Circulation. 2004;110(12):1658–1663.

References

Centers for Disease Control and Prevention. Atrial fibrillation fact sheet. Available at: http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_atrial_fibrillation.htm. Updated August 13, 2015. Accessed November 22, 2015.
Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112(8):1142–1147.
Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300–1305.e2.
Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(2 suppl):e326S–e350S.
Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence‐based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):160S–198S.
Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015;373(9):823–833.
Steinberg BA, Peterson ED, Kim S, et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT‐AF). Circulation. 2015;131(5):488–494.
Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE‐LY trial. Thromb Haemost. 2015;113(3):625–632.
PERIOP 2—A Safety and Effectiveness Study of LMWH Bridging Therapy Versus Placebo Bridging Therapy for Patients on Long Term Warfarin and Require Temporary Interruption of Their Warfarin. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT00432796. Accessed December 9, 2015.
Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med. 2013;368(22):2084–2093.
Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation. 2014;129(25):2638–2644.
Bajkin BV, Vujkov SB, Milekic BR, Vuckovic BA. Risk factors for bleeding after oral surgery in patients who continued using oral anticoagulant therapy. J Am Dent Assoc. 2015;146(6):375–381.
Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(24):2215–2245.
Kaatz S, Douketis JD, Zhou H, Gage BF, White RH. Risk of stroke after surgery in patients with and without chronic atrial fibrillation. J Thromb Haemost. 2010;8(5):884–890.
Daniels PR. Peri‐procedural management of patients taking oral anticoagulants. BMJ. 2015;351:h2391.
Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta‐analysis of bleeding and thromboembolic rates. Circulation. 2012;126(13):1630–1639.
Mathew JG, Spyropoulos AC, Yusuf A, et al. Efficacy and safety of early parenteral anticoagulation as a bridge to warfarin after mechanical valve replacement. Thromb Haemost. 2014;112(6):1120–1128.
Clark NP, Witt DM, Davies LE, et al. Bleeding, recurrent venous thromboembolism, and mortality risks during warfarin interruption for invasive procedures. JAMA Intern Med. 2015;175(7):1163–1168.
Dunn AS, Turpie AG. Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med. 2003;163(8):901–908.
Cheung CC, Martyn A, Campbell N, et al. Predictors of intraoperative hypotension and bradycardia. Am J Med. 2015;128(5):532–538.
Selim M. Perioperative stroke. N Engl J Med. 2007;356(7):706–713.
Kovacs MJ, Kearon C, Rodger M, et al. Single‐arm study of bridging therapy with low‐molecular‐weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin. Circulation. 2004;110(12):1658–1663.

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Address for correspondence and reprint requests: Bassel Nazha, MD, MPH, Department of Medicine, Staten Island University Hospital–Northwell Health, 475 Seaview Avenue, Staten Island, NY 10305; Telephone: 718‐226‐6205; Fax: 718‐226‐8695; E‐mail: bnazha@northwell.edu

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In reply: VTE prevention in major orthopedic surgery

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Alpesh N. Amin, MD

Editor's Note: This letter concerns an article in a Cleveland Clinic Journal of Medicine supplement (Preventing Venous Thromboembolism Throughout the Continuum of Care) distributed to only a portion of the Journal's regular readership, owing to the terms of the grant supporting the supplement.

In Reply: We appreciate the comments by Drs. Fishmann and Boyd, but we strongly disagree with their suggestion that aspirin monotherapy is an appropriate option for the prevention of venous thromboembolism (VTE) following major orthopedic surgery.

As discussed in our original article,¹ multiple large-scale clinical trials in patients undergoing elective hip arthroplasty, knee arthroplasty, or hip fracture surgery have demonstrated the thromboprophylactic efficacy of warfarin, unfractionated heparin, low-molecular-weight heparin (LMWH), fondaparinux, and oral direct thrombin inhibitors. The relative risk reduction with these agents has been greater than 50% in most studies. In contrast, in a large meta-analysis of VTE prophylaxis following total hip replacement, which included data from 56 randomized trials published between 1966 and 1993, aspirin was not beneficial in preventing DVT.¹⁴

The largest prospective randomized trial comparing aspirin with placebo for VTE prevention was conducted between 1992 and 1998 among 17,444 patients in five countries.⁵ It involved 13,356 patients requiring hip fracture surgery and 4,088 patients requiring elective hip arthroplasty. Patients were randomized to receive aspirin 160 mg/day or placebo for 35 days. However, additional forms of VTE prophylaxis were allowed if deemed necessary by the clinician. In fact, 26% of patients received LMWH in addition to aspirin, and dual therapy was probably more common in those patients at highest thromboembolic risk. As such, the 36% relative risk reduction in VTE ascribed to aspirin should be viewed with caution. Further, this is a smaller risk reduction than that observed in trials of other anticoagulant agents.

A large, well-designed, randomized clinical trial comparing aspirin to LMWH or fondaparinux remains to be conducted.

Dr. Fishmann cites a small study of patients undergoing knee arthroplasty who received spinal anesthesia and intermittent calf compression devices.⁷ In this underpowered study, 275 patients were randomized to receive aspirin 325 mg twice daily or enoxaparin 30 mg twice daily for 3 weeks. The overall DVT rates were 14.1% in the enoxaparin group vs 17.8% in the aspirin group (P = .27).⁷ Patients who received aspirin had significantly more postoperative drainage than those randomized to enoxaparin. In addition, the protocol for scheduling enoxaparin 48 hours postoperatively is not consistent with recommendations of the American College of Chest Physicians (ACCP) and may have reduced the efficacy of enoxaparin.

The other evidence in support of aspirin cited by Dr. Fishmann includes an editorial,⁹ an uncontrolled retrospective analysis,⁸ a single-center retrospective review,¹⁰ and a review article.⁶ Although there is evidence that the use of aspirin is probably associated with a modest reduction in postoperative VTE risk, it has been unequivocally surpassed in efficacy by other anticoagulants.

Both the latest (2004) ACCP guidelines on VTE² and the 2006 International Consensus Statement on VTE prevention and treatment¹⁵ advise against aspirin monotherapy as VTE prophylaxis in any patient groups. It is likely that the upcoming 2008 ACCP guidelines will also advocate against using aspirin as well.

Lastly, the most recent guideline from the American Academy of Orthopaedic Surgeons advocating aspirin as monotherapy¹¹ is based on the assumption that the major important clinical end point in the orthopedic surgery patient is clinical pulmonary embolism, an end point that was not included as a lone primary end point in any of the modern randomized controlled studies in major orthopedic surgery. This represents a flawed logic for the development of evidence-based guideline recommendations, and this recommendation has not been advocated by well-respected bodies such as the ACCP and the international groups that developed the International Consensus Statement. Furthermore, if this practice is going to be advocated by the American Academy of Orthopaedic Surgeons, then large rigorously designed randomized trials must be conducted to compare aspirin to currently available anticoagulants, and the type of joint surgery should be clearly defined.

References

Deitelzweig SB, McKean SC, Amin AN, Brotman DJ, Jaffer AK, Spyropoulos AC. Prevention of venous thromboembolism in the orthopedic surgery patient. Cleve Clin J Med 2008; 75(suppl 3):S27–S36.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl):338S–400S.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 suppl):132S–175S.
Zimlich RH, Fulbright BM, Friedman RJ. Current status of anticoagulation therapy after total hip and total knee arthroplasty. J Am Acad Orthop Surg 1996; 4:54–62.
PEP Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Berend KR, Lombardi AV. Multimodal venous thromboembolic disease prevention for patients undergoing primary or revision total joint arthroplasty: the role of aspirin. Am J Orthop 2006; 35:24–29.
Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006; 21(6 suppl 2):139–143.
Lotke PA, Lonner JH. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res 2006; 452:175–180.
Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians—are they appropriate for orthopaedic surgery? J Arthroplasty 2005; 20:273–274.
Dorr LD, Gendelman V, Maheshwari AV, Boutary M, Wan Z, Long WT. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007; 89:2648–2657.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty: Summary of Recommendations. http://www.aaos.org/Research/guidelines/PE_summary.pdf. Accessed April 16, 2008.
Parvizi J, Ghanem E, Joshi A, Sharkey PF, Hozack WJ, Rothman RH. Does “excessive” anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007; 22(6 suppl 2):24–28.
Bern M, Deshmukh RV, Nelson R, et al. Low-dose warfarin coupled with lower leg compression is effective prophylaxis against thromboembolic disease after hip arthroplasty. J Arthroplasty 2007; 22:644–650.
Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271:1780–1785.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.

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Steven B. Deitelzweig, MD
Ochsner Health System, New Orleans, LA

Alpesh N. Amin, MD
University of California, Irvine

Daniel J. Brotman, MD
Johns Hopkins Hospital, Baltimore, MD

Sylvia C. McKean, MD
Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Lovelace Medical Center, Albuquerque, NM

Amir K. Jaffer, MD
University of Miami, Miami, FL

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Steven B. Deitelzweig, MD
Ochsner Health System, New Orleans, LA

Alpesh N. Amin, MD
University of California, Irvine

Daniel J. Brotman, MD
Johns Hopkins Hospital, Baltimore, MD

Sylvia C. McKean, MD
Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Lovelace Medical Center, Albuquerque, NM

Amir K. Jaffer, MD
University of Miami, Miami, FL

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Steven B. Deitelzweig, MD
Ochsner Health System, New Orleans, LA

Alpesh N. Amin, MD
University of California, Irvine

Daniel J. Brotman, MD
Johns Hopkins Hospital, Baltimore, MD

Sylvia C. McKean, MD
Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Lovelace Medical Center, Albuquerque, NM

Amir K. Jaffer, MD
University of Miami, Miami, FL

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A large, well-designed, randomized clinical trial comparing aspirin to LMWH or fondaparinux remains to be conducted.

References

Deitelzweig SB, McKean SC, Amin AN, Brotman DJ, Jaffer AK, Spyropoulos AC. Prevention of venous thromboembolism in the orthopedic surgery patient. Cleve Clin J Med 2008; 75(suppl 3):S27–S36.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl):338S–400S.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 suppl):132S–175S.
Zimlich RH, Fulbright BM, Friedman RJ. Current status of anticoagulation therapy after total hip and total knee arthroplasty. J Am Acad Orthop Surg 1996; 4:54–62.
PEP Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Berend KR, Lombardi AV. Multimodal venous thromboembolic disease prevention for patients undergoing primary or revision total joint arthroplasty: the role of aspirin. Am J Orthop 2006; 35:24–29.
Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006; 21(6 suppl 2):139–143.
Lotke PA, Lonner JH. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res 2006; 452:175–180.
Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians—are they appropriate for orthopaedic surgery? J Arthroplasty 2005; 20:273–274.
Dorr LD, Gendelman V, Maheshwari AV, Boutary M, Wan Z, Long WT. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007; 89:2648–2657.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty: Summary of Recommendations. http://www.aaos.org/Research/guidelines/PE_summary.pdf. Accessed April 16, 2008.
Parvizi J, Ghanem E, Joshi A, Sharkey PF, Hozack WJ, Rothman RH. Does “excessive” anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007; 22(6 suppl 2):24–28.
Bern M, Deshmukh RV, Nelson R, et al. Low-dose warfarin coupled with lower leg compression is effective prophylaxis against thromboembolic disease after hip arthroplasty. J Arthroplasty 2007; 22:644–650.
Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271:1780–1785.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.

References

Deitelzweig SB, McKean SC, Amin AN, Brotman DJ, Jaffer AK, Spyropoulos AC. Prevention of venous thromboembolism in the orthopedic surgery patient. Cleve Clin J Med 2008; 75(suppl 3):S27–S36.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl):338S–400S.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 suppl):132S–175S.
Zimlich RH, Fulbright BM, Friedman RJ. Current status of anticoagulation therapy after total hip and total knee arthroplasty. J Am Acad Orthop Surg 1996; 4:54–62.
PEP Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302.
Berend KR, Lombardi AV. Multimodal venous thromboembolic disease prevention for patients undergoing primary or revision total joint arthroplasty: the role of aspirin. Am J Orthop 2006; 35:24–29.
Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J Arthroplasty 2006; 21(6 suppl 2):139–143.
Lotke PA, Lonner JH. The benefit of aspirin chemoprophylaxis for thromboembolism after total knee arthroplasty. Clin Orthop Relat Res 2006; 452:175–180.
Callaghan JJ, Dorr LD, Engh GA, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians—are they appropriate for orthopaedic surgery? J Arthroplasty 2005; 20:273–274.
Dorr LD, Gendelman V, Maheshwari AV, Boutary M, Wan Z, Long WT. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007; 89:2648–2657.
American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty: Summary of Recommendations. http://www.aaos.org/Research/guidelines/PE_summary.pdf. Accessed April 16, 2008.
Parvizi J, Ghanem E, Joshi A, Sharkey PF, Hozack WJ, Rothman RH. Does “excessive” anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007; 22(6 suppl 2):24–28.
Bern M, Deshmukh RV, Nelson R, et al. Low-dose warfarin coupled with lower leg compression is effective prophylaxis against thromboembolic disease after hip arthroplasty. J Arthroplasty 2007; 22:644–650.
Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271:1780–1785.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.

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Prevention of venous thromboembolism in the hospitalized medical patient

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The need for prophylaxis of venous thromboembolism (VTE) in hospitalized acutely ill medical patients is well established. Without prophylaxis, hospitalized medical patients develop VTE at a rate of 5% to 15%.^1–3 Moreover, pulmonary embolism (PE) occurs more frequently in hospitalized medical patients than in nonmedical patients, and is a leading cause of sudden death in hospitalized medical patients.^4,5 Without appropriate prophylaxis, 1 in 20 hospitalized medical patients may suffer a fatal PE.⁴

PROPHYLAXIS IN MEDICAL PATIENTS: UNDERUSED AND OFTEN INAPPROPRIATE

Despite these risks and the clear indications for VTE prophylaxis in hospitalized medical patients, prophylaxis of VTE is omitted more often in these patients than in hospitalized surgical patients.⁵ Even when prophylaxis is given, it is often used inappropriately in the medical population. So concludes a recent analysis of data from 196,104 patients with acute medical conditions who were discharged from 227 US hospitals from January 2002 to September 2005.⁶ Criteria for inclusion in the analysis were patient age of 40 years or older, a hospital stay of 6 days or greater, and an absence of contraindications to anticoagulation. Appropriate prophylaxis was defined in accordance with the Sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy.⁷

The analysis revealed an overall VTE prophylaxis rate of 61.8%, but the rate of appropriate prophylaxis was only 33.9%, meaning that two-thirds of discharged patients did not receive prophylaxis in accordance with ACCP guidelines. When temporal trends were analyzed according to groups based on patients’ diagnosis at admission (acute myocardial infarction, severe lung disease, ischemic stroke, cancer, heart failure, or trauma), the rate of appropriate prophylaxis remained essentially flat from the beginning to the end of the study period for virtually all diagnosis groups.⁶

Similar findings have emerged from the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE), an ongoing international registry of acutely ill medical patients.⁸ Data from the first 15,156 patients, enrolled from July 2002 through September 2006, reveal that 50% of patients received pharmacologic and/or mechanical VTE prophylaxis in the hospital, and only 60% of patients who met established criteria for VTE prophylaxis actually received it.

Analysis of the US portion of the IMPROVE data shows that 54% of the US patient sample received some form of VTE prophylaxis; 22% of US patients received intermittent pneumatic compression, 21% received unfractionated heparin (UFH), 14% received low-molecular-weight heparin (LMWH), and 3% wore compression stockings.⁸ Thus, despite a paucity of data supporting a benefit of intermittent pneumatic compression in this population,⁹ it was the most frequently used form of prophylaxis in US patients.

CLINICAL TRIALS OF PHARMACOLOGIC PROPHYLAXIS IN MEDICAL PATIENTS

Figure 1. Rates of venous thromboembolism (VTE) in three large double-blind, placebo-controlled studies of pharmacologic prophylaxis of VTE in high-risk hospitalized medical patients.

The evidence in support of pharmacologic prophylaxis of VTE in high-risk hospitalized medical patients is considerable. Three large double-blind, placebo-controlled trials of anticoagulants currently available in the United States have been reported in this patient population (Figure 1).^1–3

The Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial1 randomized 1,102 hospitalized patients to one of two doses of the LMWH enoxaparin (20 mg or 40 mg once daily subcutaneously) or placebo for 6 to 14 days. Compared with placebo, the 40-mg dose of enoxaparin was associated with a 63% reduction in risk of VTE over 3 months of follow-up (P < .001) (Figure 1).

The Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT)2 was a multicenter, randomized, double-blind study comparing the LMWH dalteparin (5,000 IU daily given subcutaneously for 14 days) with placebo in 3,706 acutely ill medical patients. Over 90 days of follow-up, the risk of VTE was reduced by 44% in patients assigned to dalteparin compared with those assigned to placebo (P = .0015) (Figure 1).

The Arixtra for Thromboembolism Prevention in a Medical Indications Study (ARTEMIS)3 randomized 849 medical patients 60 years or older to 6 to 14 days of therapy with the selective factor Xa inhibitor fondaparinux (2.5 mg once daily subcutaneously) or placebo. Compared with the placebo group, fondaparinux recipients had a 47% lower risk of developing VTE by day 15 (P = .029) (Figure 1).

Fewer events and fatal PEs, but no effect on all-cause mortality

A recent meta-analysis by Dentali et al¹⁰ further demonstrates the efficacy of anticoagulant therapy for preventing symptomatic VTE in hospitalized medical patients. This analysis included several other trials in addition to the three reviewed above,^1–3 for a total of nine randomized studies (seven of which were dou-ble-blind) comprising 19,958 patients. Across the nine studies, anticoagulant prophylaxis was clearly superior to placebo in preventing fatal PE (relative risk, 0.38 [95% CI, 0.21 to 0.69]). There was a strong trend toward a reduction in symptomatic deep vein thrombosis (DVT) with prophylaxis but no effect on all-cause mortality. The meta-analysis also provided reassurance that prophylaxis does not increase the rate of major bleeding.

HOW DO THE PROPHYLAXIS OPTIONS STACK UP?

What the ACCP recommends

Current ACCP guidelines recommend the use of either LMWH or low-dose UFH (5,000 U subcutaneously two or three times daily) as a Grade 1A recommendation for VTE prophylaxis in patients with medical conditions and risk factors for VTE.⁹ This represents the guidelines’ highest level of recommendation, ie, one that is based on randomized controlled trials (RCTs) without important limitations. In contrast, the 2006 International Consensus Statement, developed as a collaborative effort among expert bodies on VTE, specified a more narrow dosing recommendation for UFH in this patient population (5,000 U three times daily, not twice daily) as well as specifying 40 mg once daily as the recommended dose of enoxaparin and 5,000 IU once daily as the recommended dose of dalteparin.¹¹

For medical patients with risk factors for VTE who have a contraindication to anticoagulant prophylaxis, the ACCP guidelines recommend the use of graduated compression stockings or intermittent pneumatic compression devices as a Grade 1C+ recommendation (“no RCTs but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies”⁹).

Current ACCP guidelines do not address the use of fondaparinux in their recommendations for VTE prophylaxis in medical patients.

Getting a handle on bleeding risk

Patient characteristics that exclude pharmacologic thromboprophylaxis due to bleeding risk are generally limited to active bleeding or coagulopathy, as demonstrated by a platelet count less than 50,000 cells/µL or an international normalized ratio greater than 1.5. Additionally, bleeding risk should be carefully assessed if an invasive procedure is planned during a patient’s hospital stay.

It is worth noting that the anticoagulant doses used for VTE prophylaxis are a fraction of those used for treatment of VTE. Thus, if a patient would be treated with full-dose anticoagulation if VTE developed, then that patient should be eligible for VTE prophylaxis.

Because the use of mechanical forms of prophylaxis in medical patients is not truly evidence-based, mechanical prophylaxis should be reserved for medical patients who have a contraindication to anticoagulants, or for use in combination with anticoagulants in patients at very high risk of VTE.

UFH vs LMWH

Two meta-analyses have compared UFH with LMWH for VTE prevention in medical patients.12,13 In a recent analysis that included 10 trials directly comparing the two therapies, 14 trials comparing UFH with control, and 11 trials comparing LMWH with control, Wein et al found a lower risk of DVT with LMWH than with UFH (relative risk, 0.68 [95% CI, 0.52 to 0.88]) but no difference between the therapies in mortality or bleeding risk.¹² In an earlier and smaller analysis, Mismetti et al found no significant differences between UFH and LMWH in preventing DVT or death but did find a significant reduction in major bleeding episodes with LMWH versus three-times-daily UFH (52% relative reduction; P = .049).¹³

Randomized trials also reveal that enoxaparin 40 mg once daily is as efficacious as UFH 5,000 U three times daily for VTE prevention in medical patients.^14,15 The above analysis by Wein et al¹² and an additional meta-analysis by King and colleagues¹⁶ found that three-times-daily dosing of UFH is more efficacious than twice-daily dosing of UFH, but at the expense of more bleeding, including major bleeding.

Economic considerations

Because of differences in drug acquisition costs between UFH and the LMWH agents, several economic evaluations have compared the use of these therapies for prophylaxis in medical patients at risk of VTE.

In an analysis of hospital costs for medical patients receiving VTE prophylaxis from more than 330 US hospitals for the period 2001–2004, Burleigh et al found that mean total hospital costs were higher for patients who received UFH than for those who received LMWH ($7,615 vs $6,866) even though mean drug costs were higher for LMWH ($791 vs $569 for UFH).¹⁷ A reduction in hospital length of stay appeared to contribute to the overall savings with LMWH; other contributors may have included costs associated with heparin-induced thrombocytopenia (HIT) in UFH recipients or the extra nursing time required for administering UFH in two or three daily doses.

Leykum et al used a decision analysis model to estimate the economic effect of substituting enoxaparin for UFH in hospitalized medical patients for whom VTE prophylaxis is indicated.¹⁸ Cost data were based on Medicare reimbursement rates as well as drug and laboratory costs for a multi-institutional health system. The model assumed HIT incidence rates of 2.7% with UFH and 0.3% with enoxaparin. It also assumed the cost of a daily dose to be $4 for UFH versus $84 for enoxaparin. From the payer perspective, the model showed that substituting enoxaparin for UFH would reduce the overall cost of care by $28.61 per day on a per-patient basis, despite enoxaparin’s higher acquisition cost, and would save $4,550 per quality-adjusted life-year by reducing the incidence of HIT.

Another cost analysis confirms the association between HIT and increased hospital costs. Creekmore et al retrospectively analyzed data from 10,121 adult medical patients who received VTE prophylaxis at the University of Utah Hospital in Salt Lake City from August 2000 to November 2004.¹⁹ They found that an admission during which HIT developed incurred a mean cost of $56,364, compared with $15,231 for an admission without HIT. Because LMWH was associated with a lower incidence of HIT compared with UFH (0.084% vs 0.51%, respectively), LMWH reduced the incremental cost of VTE prophylaxis by $13.88 per patient compared with UFH.

THE EXCLAIM TRIAL: IS THERE A ROLE FOR EXTENDED PROPHYLAXIS?

Although the previously discussed studies have clearly demonstrated the benefit of in-hospital VTE prophylaxis for acutely ill medical patients, none has rigorously examined extended-duration out-of-hospital prophylaxis in these patients. This represents an important gap in the literature, since a substantial proportion of VTE develops in the outpatient setting within 3 months of a hospitalization, and most outpatient VTE episodes occur within 1 month of a preceding hospitalization.²⁰

To begin to fill this gap, the Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) trial was conducted to compare extended-duration LMWH prophylaxis with a standard LMWH prophylaxis regimen in acutely ill medical patients using a prospective, multicenter, randomized, double-blind, placebo-controlled design.²¹

Patients and study design

Patients were eligible for enrollment if they were aged 40 years or older and had recent immobilization (≤ 3 days), a predefined acute medical illness, and either level 1 mobility (total bed rest or sedentary state) or level 2 mobility (level 1 with bathroom privileges). The predefined acute medical illnesses consisted of New York Heart Association class III/IV heart failure, acute respiratory insufficiency, or other acute medical conditions, including post-acute ischemic stroke, acute infection without septic shock, and active cancer.

All patients received open-label enoxaparin 40 mg subcutaneously once daily for 10 ± 4 days, after which they were randomized to either enoxaparin 40 mg subcutaneously once daily or placebo for an additional 28 ± 4 days.

The primary efficacy end point was the incidence of VTE events, defined as asymptomatic DVT documented by mandatory ultrasonography at the end of the double-blind treatment period (28 ± 4 days) or as symptomatic DVT, symptomatic PE, or fatal PE at any time during the double-blind period. Symptomatic DVT was confirmed by objective tests; PE was confirmed by ventilation-perfusion scan, computed tomography, angiography, or autopsy.

Secondary efficacy end points were mortality at the end of the double-blind period, at 3 months, and at 6 months, as well as the incidence of VTE at 3 months.

The primary safety outcome measure was the incidence of major hemorrhage during the double-blind period; secondary safety measures were rates of major and minor hemorrhage, minor hemorrhage, HIT, and serious adverse events.

Population amended at planned interim analysis

After approximately half of the patients were enrolled, a planned and blinded interim analysis for futility concluded that the study was unlikely to show a statistically significant advantage of enoxaparin over placebo. The trial’s steering committee followed the suggestion of its data safety monitoring board to redefine the inclusion criteria to refocus enrollment on patients with a high risk of VTE. A blinded analysis was performed to identify this subgroup.

The resulting amended inclusion criteria were the same as above except that level 2 mobility had to be accompanied by at least one of three additional high-risk criteria: (1) age greater than 75 years, (2) history of prior VTE, or (3) diagnosis of cancer.

The trial’s main exclusion criteria were evidence of active bleeding, a contraindication to anticoagulation, receipt of prophylactic LMWH or UFH more than 72 hours prior to enrollment, treatment with an oral anticoagulant within 72 hours of enrollment, major surgery within the prior 3 months, cerebral stroke with bleeding, and persistent renal failure (creatinine clearance < 30 mL/min).

Results

The amended study population included 5,105 patients, 5,049 of whom received open-label enoxaparin. Of this group, 2,013 were randomized to active extended prophylaxis with enoxparain and 2,027 to placebo. Baseline characteristics, including level of mobility, were similar between the two groups.

Efficacy. As detailed in Table 1, VTE events occurred at a statistically significantly higher rate in the placebo arm than in the extended-duration enoxaparin arm, as did asymptomatic proximal DVT and symptomatic VTE. Rates of PE and fatal PE were also lower with enoxaparin than with placebo, but the number of events was so small that the betweengroup differences were not statistically significant.

The efficacy of extended prophylaxis with enoxaparin was enduring, as the cumulative incidence of VTE events at day 90 was significantly lower in enoxaparin recipients than in placebo recipients (3.0% vs 5.2%; relative reduction of 42%; P = .0115).

There was no difference in all-cause mortality at 6 months between the enoxaparin and placebo groups (10.1% vs 8.9%, respectively; P = .179).

Safety. Major hemorrhage was significantly more frequent in the enoxaparin arm, occurring in 0.60% of enoxaparin recipients compared with 0.15% of placebo recipients (P = .019). Minor bleeding was also more common with enoxaparin (5.20% vs 3.70%; P = .024).

Conclusions

The EXCLAIM trial found that an extended-duration (38-day) enoxaparin regimen significantly reduced the overall incidence of VTE relative to a 10-day enoxaparin regimen in acutely ill medical patients with reduced mobility. At the same time, the extended regimen was associated with a significant increase in the rate of major bleeding, although the incidence of major bleeding was low. The investigators concluded that the net clinical effect of extended-duration prophylaxis with enoxaparin is favorable, as only 46 patients would need to be treated to prevent one VTE event, whereas 224 patients would need to be treated to result in one major bleeding event.²¹

For this reason, it is reasonable to consider extended prophylaxis for hospitalized medical patients after identifying these patients’ risk factors. In keeping with the trial’s amended inclusion criteria, patients older than age 75 and those with cancer or prior VTE should receive special consideration for extended prophylaxis.

RECOMMENDED APPROACH TO VTE PREVENTION IN HOSPITALIZED MEDICAL PATIENTS

Figure 2. Algorithm for VTE prophylaxis in the hospitalized medical patient.

Given the wide gap between the evidence reviewed above and current practice worldwide,^8,22,23 we propose the algorithm presented in Figure 2 for the prevention of VTE in hospitalized medical patients. Our recommended approach is guided by the principles below:

All hospitalized medical patients should be screened at the time of admission, and patients at risk for VTE should receive prophylaxis.
All patients with reduced mobility and one or more other risk factors for VTE are candidates for prophylaxis.
Patients should be reassessed daily for the development of VTE risk factors during their hospitalization if risk factors are absent on admission.
If screening or reassessment reveals any VTE risk factors, pharmacologic prophylaxis is the mainstay of therapy. If exclusion criteria for pharmacologic prophylaxis are present, mechanical prophylaxis with graduated compression stockings and intermittent compression devices should be used. For very high-risk medical patients without a contraindication to anticoagulants, combination prophylaxis with both an anticoagulant and mechanical devices is preferred.
In this patient population, LMWH agents are preferred as pharmacologic prophylaxis over UFH and over fondaparinux (which is not currently approved by the US Food and Drug Administration for this population).
If UFH is to be used in this patient population, 5,000 U three times daily is the preferred dosage.
Extended pharmacologic prophylaxis should be considered in patients older than age 75 and in patients with a cancer diagnosis or a prior VTE episode.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

Dr. Jaffer: Dr. Spyropoulos, are there any guidelines, other than those from the ACCP, that speak to VTE prophylaxis in hospitalized medical patients? If so, what are their take-home messages and how do they differ from the ACCP guidelines?

Dr. Spyropoulos: I was part of the group that developed the International Consensus Statement (ICS) published in International Angiology in 2006,¹¹ which is more recent than the latest ACCP guidelines, which were published in 2004. The ICS drew on much of the same data that the ACCP did, but we did an updated review of clinical trials.

For VTE prophylaxis in hospitalized medical patients, the ICS recommendations are more specific with regard to the type, dose, and dosing frequency of anticoagulant agents. First, they specify doses for both LMWH agents in this patient setting: 40 mg once daily for enoxaparin, and 5,000 IU once daily for dalteparin.

The ICS document also states that if UFH is the choice for prophylaxis, a regimen of 5,000 U three times daily should be considered. In the past year alone, two analyses suggest that three-times-daily dosing of UFH in medical patients provides superior efficacy to twice-daily dosing, although perhaps at the expense of more bleeding episodes.^12,16 It is important to remember that no large placebo-controlled trial supports the efficacy of a UFH regimen of 5,000 U twice daily in this population.

Finally, the ICS document states that fondaparinux 2.5 mg once daily is a viable option for prophylaxis in medical patients, based on the ARTEMIS trial,³ even though this represents an off-label use.

Dr. Jaffer: Real-world use of VTE prophylaxis is far from optimal, especially in medical patients, and this is partly a result of system-of-care issues. I’d like to conclude by asking each of my colleagues to offer your perspectives on how your own institutions have improved their systems of care to promote better use of VTE prophylaxis and what lessons might be shared with others. Dr. McKean, you work at Brigham and Women’s Hospital, which recently reported impressive results with an electronic alert system designed to increase clinicians’ consideration of VTE risk assessment and use of prophylaxis.²⁴ Please tell us about that study and the alert system.

Dr. McKean: Despite many educational initiatives at Brigham and Women’s Hospital, there were still some patients at high risk for VTE who were not receiving appropriate prophylaxis. What Dr. Samuel Goldhaber and his colleagues wanted to determine was whether changing the system of care could result in a reduced incidence of VTE.²⁴ They devised a computer software program linked to the patient database that used eight common risk factors to determine each hospitalized patient’s risk profile for VTE. Each risk factor was weighted according to a point scale, with major risk factors (cancer, prior VTE, or hypercoagulability) assigned 3 points, the intermediate risk factor of surgery assigned 2 points, and minor risk factors (advanced age, obesity, immobility, or use of hormone replacement therapy or oral contraceptives) assigned 1 point. For patients with a total risk score of 4 or greater, the computer screen generates a color-coded VTE risk alert that requires the physician to acknowledge the alert and choose one of three options: order prophylaxis as appropriate, review a 60-page document on the computer to learn more about prophylaxis, or do nothing.

The study found that hospitalized patients who were randomized to treatment under the computer alert system were significantly more likely to receive VTE prophylaxis and significantly less likely to develop VTE than were patients randomized to a control group. The alert system reduced the risk of DVT or PE at 90 days by 41% in patients considered to be at high risk. It was particularly interesting that the incidence of VTE was lower in the intervention group even when physicians chose not to use prophylaxis, which suggests that simply having this alert system in place improved outcomes, perhaps by raising awareness of the risk of VTE.²⁴

Additional studies are needed to better understand physicians’ behavior and determine why they seem to have a disproportionate fear of the risk of bleeding relative to the risk of clotting, including fatal PE, because that is really the heart of the matter. When patients are not given prophylaxis, often it is because of fear of bleeding. It is not clear, however, why some of these patients did not receive mechanical devices as an alternative form of prophylaxis, but this seems to be the case worldwide, as shown recently by the multinational ENDORSE study.²² Meanwhile, as we await studies to better understand physician perceptions and behaviors regarding prophylaxis, we need to work hard to change the system of care.

Dr. Deitelzweig: Over the past couple of years, the Ochsner Clinic has grown from a one-hospital teaching organization to a seven-hospital system with a mix of closed and open medical staff. The challenge is how to take a process that worked well in the one center, where appropriate prophylaxis was used about 90% of the time, and transfer it to the other centers in the larger system. We have endorsed several types of performance tools, such as the change-acceleration processes used by General Electric. The aim is to share a vision of heightening awareness. To do that, we have worked to mobilize the key stakeholders, at least half of them, to build algorithms that they all will endorse. It is easier said than done, however, and we have found it essential to involve both physicians and non-physician colleagues from pharmacy and nursing who have political and organizational clout.

Dr. Brotman: At Johns Hopkins, I took a bit more draconian approach to this issue because I thought that hospitalists often knew that they should be using VTE prophylaxis but sometimes weren’t, and I am not convinced that clinicians always look at prompts. So we came up with a system that incorporates both billing and documentation simultaneously. We put a hard stop on users’ documentation so that they could not sign off on a note or bill for their care until they checked off the kind of VTE prophylaxis they were using. Since hospitalists ultimately care about billing for their work, this system has at least ensured that everybody has considered and documented VTE prophylaxis on a daily basis. There are other hard stops that can be implemented in computer order-entry systems as well, and we are considering ways to roll them out on a broader scale.

However, all of these systems can have problems because patient situations change from day to day. For instance, VTE prophylaxis is not necessarily indicated in a 38-year-old ambulatory patient who comes in with a sickle cell crisis, but you will need to reconsider if the patient ends up in acute chest syndrome in the intensive care unit. I do not yet have a good way to ensure that this is being done on a daily basis with all patients.

Dr. Amin: At the University of California, Irvine, we implemented an electronic alert system, but we locked users in so that they could not complete their admission orders until they answered questions about VTE prevention. This practice increased our VTE prophylaxis rates tremendously. Because we are a level I trauma center, we allow users to bypass the screens one time, but the next time they log in, even to get a simple lab result, they have to answer the questions about VTE prevention.

With any system you develop, you also have to continue with the education process, because clinicians sometimes get into bad habits or simply forget things.

Dr. Spyropolous: At Lovelace Medical Center, we didn’t have the sophistication of an electronic order-entry system, but we had an experienced clinical pharmacist (the director of inpatient pharmacy) who helped to develop and champion VTE prevention guidelines that have then been used throughout the system in close conjunction with our hospitalists’ rounds. This system has been used successfully for the past 7 years.

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Author and Disclosure Information

Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Alpesh N. Amin, MD, MBA
Professor and Chief, Division of General Internal Medicine; Executive Director, Hospitalist Program; Vice Chair for Clinical Affairs & Quality, Department of Medicine, University of California, Irvine, Irvine, CA

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Alex C. Spyropoulos, MD
Chair, Clinical Thrombosis Center, Lovelace Medical Center; Clinical Associate Professor of Medicine/Associate Professor of Pharmacy, University of New Mexico Health Sciences Center/College of Pharmacy, Albuquerque, NM

Correspondence: Amir K. Jaffer, MD, Chief, Division of Hospital Medicine, Leonard M. Miller School of Medicine, University of Miami, 1120 NW 14th Street, 933 CRB (C216), Miami, FL 33136; ajaffer@med.miami.edu

Dr. Jaffer reported that he has received consulting fees and honoraria for teaching/speaking from Sanofi-Aventis, consulting fees and research grant support from AstraZeneca, and consulting fees from Roche Diagnostics and Boehringer Ingelheim; he also serves on the governing board of the Society for Perioperative Assessment and Quality Improvement (SPAQI) and the board of directors of the Anticoagulation Forum.

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

Drs. Deitelzweig and McKean each reported that they have received honoraria for teaching/speaking from Sanofi-Aventis. Dr. Spyropoulos reported that he has received consulting fees from Sanofi-Aventis, Eisai, and Boehringer Ingelheim.

Each author received an honorarium for participating in the roundtable that formed the basis of this supplement. The honoraria were paid by the Cleveland Clinic Center for Continuing Education from the educational grant from Sanofi-Aventis underwriting this supplement. Sanofi-Aventis had no input on the content of the roundtable or this supplement.

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Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

Author and Disclosure Information

Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

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PROPHYLAXIS IN MEDICAL PATIENTS: UNDERUSED AND OFTEN INAPPROPRIATE

CLINICAL TRIALS OF PHARMACOLOGIC PROPHYLAXIS IN MEDICAL PATIENTS

Fewer events and fatal PEs, but no effect on all-cause mortality

HOW DO THE PROPHYLAXIS OPTIONS STACK UP?

What the ACCP recommends

Current ACCP guidelines do not address the use of fondaparinux in their recommendations for VTE prophylaxis in medical patients.

Getting a handle on bleeding risk

UFH vs LMWH

Economic considerations

THE EXCLAIM TRIAL: IS THERE A ROLE FOR EXTENDED PROPHYLAXIS?

Patients and study design

Secondary efficacy end points were mortality at the end of the double-blind period, at 3 months, and at 6 months, as well as the incidence of VTE at 3 months.

Population amended at planned interim analysis

Results

There was no difference in all-cause mortality at 6 months between the enoxaparin and placebo groups (10.1% vs 8.9%, respectively; P = .179).

Conclusions

RECOMMENDED APPROACH TO VTE PREVENTION IN HOSPITALIZED MEDICAL PATIENTS

All hospitalized medical patients should be screened at the time of admission, and patients at risk for VTE should receive prophylaxis.
All patients with reduced mobility and one or more other risk factors for VTE are candidates for prophylaxis.
Patients should be reassessed daily for the development of VTE risk factors during their hospitalization if risk factors are absent on admission.
If screening or reassessment reveals any VTE risk factors, pharmacologic prophylaxis is the mainstay of therapy. If exclusion criteria for pharmacologic prophylaxis are present, mechanical prophylaxis with graduated compression stockings and intermittent compression devices should be used. For very high-risk medical patients without a contraindication to anticoagulants, combination prophylaxis with both an anticoagulant and mechanical devices is preferred.
In this patient population, LMWH agents are preferred as pharmacologic prophylaxis over UFH and over fondaparinux (which is not currently approved by the US Food and Drug Administration for this population).
If UFH is to be used in this patient population, 5,000 U three times daily is the preferred dosage.
Extended pharmacologic prophylaxis should be considered in patients older than age 75 and in patients with a cancer diagnosis or a prior VTE episode.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

With any system you develop, you also have to continue with the education process, because clinicians sometimes get into bad habits or simply forget things.

PROPHYLAXIS IN MEDICAL PATIENTS: UNDERUSED AND OFTEN INAPPROPRIATE

CLINICAL TRIALS OF PHARMACOLOGIC PROPHYLAXIS IN MEDICAL PATIENTS

Fewer events and fatal PEs, but no effect on all-cause mortality

HOW DO THE PROPHYLAXIS OPTIONS STACK UP?

What the ACCP recommends

Current ACCP guidelines do not address the use of fondaparinux in their recommendations for VTE prophylaxis in medical patients.

Getting a handle on bleeding risk

UFH vs LMWH

Economic considerations

THE EXCLAIM TRIAL: IS THERE A ROLE FOR EXTENDED PROPHYLAXIS?

Patients and study design

Secondary efficacy end points were mortality at the end of the double-blind period, at 3 months, and at 6 months, as well as the incidence of VTE at 3 months.

Population amended at planned interim analysis

Results

There was no difference in all-cause mortality at 6 months between the enoxaparin and placebo groups (10.1% vs 8.9%, respectively; P = .179).

Conclusions

RECOMMENDED APPROACH TO VTE PREVENTION IN HOSPITALIZED MEDICAL PATIENTS

All hospitalized medical patients should be screened at the time of admission, and patients at risk for VTE should receive prophylaxis.
All patients with reduced mobility and one or more other risk factors for VTE are candidates for prophylaxis.
Patients should be reassessed daily for the development of VTE risk factors during their hospitalization if risk factors are absent on admission.
If screening or reassessment reveals any VTE risk factors, pharmacologic prophylaxis is the mainstay of therapy. If exclusion criteria for pharmacologic prophylaxis are present, mechanical prophylaxis with graduated compression stockings and intermittent compression devices should be used. For very high-risk medical patients without a contraindication to anticoagulants, combination prophylaxis with both an anticoagulant and mechanical devices is preferred.
In this patient population, LMWH agents are preferred as pharmacologic prophylaxis over UFH and over fondaparinux (which is not currently approved by the US Food and Drug Administration for this population).
If UFH is to be used in this patient population, 5,000 U three times daily is the preferred dosage.
Extended pharmacologic prophylaxis should be considered in patients older than age 75 and in patients with a cancer diagnosis or a prior VTE episode.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

With any system you develop, you also have to continue with the education process, because clinicians sometimes get into bad habits or simply forget things.

References

Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thrombo-embolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341:793–800.
Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110:874–879.
Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332:325–329.
Baglin TP, White K, Charles A. Fatal pulmonary embolism in hos-pitalised medical patients. J Clin Pathol 1997; 50:609–610.
Piazza G, Seddighzadeh A, Goldhaber SZ. Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent. Chest 2007; 132:554–561.
Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost 2007; 5:1610–1616.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 Suppl):132S–175S.
Tapson VF, Decousus H, Pini M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132:936–945.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thrombo-embolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl):338S–400S.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146:278–288.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.
Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; 167:1476–1486.
Mismetti P, Laporte-Simitsidis S, Tardy B, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83:14–19.
Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis 1996; 26(Suppl 2):49–56.
Kleber FX, Witt C, Vogel G, et al; the PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145:614–621.
King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a meta-analysis. Chest 2007; 131:507–516.
Burleigh E, Wang C, Foster D, et al. Thromboprophylaxis in medically ill patients at risk for venous thromboembolism. Am J Health Syst Pharm 2006; 63(20 Suppl 6):S23–S29.
Leykum L, Pugh J, Diuguid D, Papadopoulos K. Cost utility of substituting enoxaparin for unfractionated heparin for prophylaxis of venous thrombosis in the hospitalized medical patient. J Hosp Med 2006; 1:168–176.
Creekmore FM, Oderda GM, Pendleton RC, Brixner DI. Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism. Pharmacotherapy 2006; 26:1438–1445.
Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007; 167:1471–1475.
Hull RD, Schellong SM Tapson VF, et al. Extended-duration venous thromboembolism (VTE) prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. Presentation at: International Society on Thrombosis and Haemo-stasis XXIst Congress; July 6–12, 2007; Geneva, Switzerland.
Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371:387–394.
Kahn SR, Panju A, Geerts W, et al; CURVE study investigators. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res 2007; 119:145–155.
Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent thromboembolism among hospitalized patients. N Engl J Med 2005; 352:969–977.
Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151:933–938.
Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 2001; 54:810–816.
Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367:1075–1079.
Alikhan R, Cohen AT, Combe S, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Firbinolysis 2003; 14:341–346.
Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107(23 Suppl 1):I9–I16.
Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update. Thromb Res 2006; 118:165–176.
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710–2715.
Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105:225–231.
Douketis J, Cook D, Zytaruk N, et al. Dalteparin thromboprophylaxis in critically ill patients with severe renal insufficiency: the DIRECT study [abstract]. J Thromb Haemost 2007; 5(Suppl 2): P-S-680.
Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002; 12:19–24.

References

Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thrombo-embolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341:793–800.
Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110:874–879.
Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332:325–329.
Baglin TP, White K, Charles A. Fatal pulmonary embolism in hos-pitalised medical patients. J Clin Pathol 1997; 50:609–610.
Piazza G, Seddighzadeh A, Goldhaber SZ. Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent. Chest 2007; 132:554–561.
Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost 2007; 5:1610–1616.
Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(1 Suppl):132S–175S.
Tapson VF, Decousus H, Pini M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132:936–945.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thrombo-embolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl):338S–400S.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146:278–288.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence). Int Angiol 2006; 25:101–161.
Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; 167:1476–1486.
Mismetti P, Laporte-Simitsidis S, Tardy B, et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83:14–19.
Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis 1996; 26(Suppl 2):49–56.
Kleber FX, Witt C, Vogel G, et al; the PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145:614–621.
King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a meta-analysis. Chest 2007; 131:507–516.
Burleigh E, Wang C, Foster D, et al. Thromboprophylaxis in medically ill patients at risk for venous thromboembolism. Am J Health Syst Pharm 2006; 63(20 Suppl 6):S23–S29.
Leykum L, Pugh J, Diuguid D, Papadopoulos K. Cost utility of substituting enoxaparin for unfractionated heparin for prophylaxis of venous thrombosis in the hospitalized medical patient. J Hosp Med 2006; 1:168–176.
Creekmore FM, Oderda GM, Pendleton RC, Brixner DI. Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism. Pharmacotherapy 2006; 26:1438–1445.
Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med 2007; 167:1471–1475.
Hull RD, Schellong SM Tapson VF, et al. Extended-duration venous thromboembolism (VTE) prophylaxis in acutely ill medical patients with recent reduced mobility: the EXCLAIM study. Presentation at: International Society on Thrombosis and Haemo-stasis XXIst Congress; July 6–12, 2007; Geneva, Switzerland.
Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371:387–394.
Kahn SR, Panju A, Geerts W, et al; CURVE study investigators. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res 2007; 119:145–155.
Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent thromboembolism among hospitalized patients. N Engl J Med 2005; 352:969–977.
Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151:933–938.
Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 2001; 54:810–816.
Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367:1075–1079.
Alikhan R, Cohen AT, Combe S, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Firbinolysis 2003; 14:341–346.
Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107(23 Suppl 1):I9–I16.
Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update. Thromb Res 2006; 118:165–176.
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710–2715.
Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105:225–231.
Douketis J, Cook D, Zytaruk N, et al. Dalteparin thromboprophylaxis in critically ill patients with severe renal insufficiency: the DIRECT study [abstract]. J Thromb Haemost 2007; 5(Suppl 2): P-S-680.
Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg 2002; 12:19–24.

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Prevention of venous thromboembolism in the cancer surgery patient

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Venous thromboembolism (VTE) is a major complication of cancer, occurring in 4% to 20% of patients,¹ and is one of the leading causes of death in cancer patients, although these figures are believed to be underestimates, given the low autopsy rates among cancer patients.² In hospitalized cancer patients specifically, VTE is the second leading cause of death.^3,4 The risk of VTE in cancer patients undergoing surgery is three to five times greater than that in surgical patients without cancer.⁴ Moreover, cancer patients with symptomatic deep vein thrombosis (DVT) exhibit a high risk of recurrent VTE that may persist for many years after the index event.⁵

VTE PREVENTION POSES PARTICULAR CHALLENGES IN CANCER PATIENTS

Until recently, data on VTE prevention specific to cancer patients have been sparse. Cancer patients have represented only a small subset (< 20%) of participants in most of the largest clinical trials of VTE prophylaxis. Until the past 2 or 3 years, clinicians largely have had to extrapolate their approach to VTE prophylaxis in cancer patients from data in patients without cancer, bearing in mind that cancer patients are among the populations at highest risk of developing VTE.

High rates of VTE, even with prophylaxis

What has been clear is that VTE prevention is a formidable challenge in this population, even when thromboprophylaxis is used. Despite thromboprophylaxis, cancer patients undergoing surgery have twice the risk of VTE and nonfatal pulmonary embolism (PE) and three times the risk of fatal PE compared with other surgical patients (Table 1).^6,7

Further insights have come from the @RISTOS project, a Web-based prospective registry of patients undergoing general, urologic, or gynecologic surgery for cancer at multiple centers in Italy.⁸ Of the 2,372 patients tracked in this study, 82% received in-hospital VTE prophylaxis and 31% received prophylaxis following discharge. Despite this relatively high frequency of prophylaxis, however, the incidence of clinically overt VTE was 2.1% and the incidence of fatal VTE was 0.8%. Notably, most VTE events occurred after hospital discharge, and VTE was the most common cause of 30-day postoperative death in this registry.

RISK FACTORS: CANCER TYPE AND TREATMENT LOOM LARGE

Both the type and stage of a patient’s cancer are important in assessing the risk of VTE. For men, cancers of the prostate, colon, brain, and lung have been associated with an increased risk of VTE. Among women, cancers of the breast, ovary, and lung have been especially implicated as risk factors for VTE.^9,10

The type of cancer therapy also influences VTE risk:

Surgery. Among patients who undergo cancer-related surgery, the rate of proximal DVT is 10% to 20%, the rate of clinically evident PE is 4% to 10%, and the incidence of fatal PE is 0.2% to 5%.^8,11
Systemic treatments, including chemotherapy and hormone therapy, are also associated with an increased risk of VTE.^12–15
Central venous catheters. Approximately 4% of cancer patients who have central venous catheters placed develop clinically relevant VTE.^16,17

In addition to the above risks related to cancer treatments, the following have been identified as risk factors for VTE in surgical oncology patients:

Age greater than 40 years (risk also increases steeply after age 60 and again after age 75)
Cancer procoagulants
Thrombophilia
Length and complications of cancer surgery (ie, often involving tissue trauma and immobilization)
Debilitation and slow recovery.

Another risk factor worth noting is perioperative transfusion, as illustrated in a recent study of 14,104 adults undergoing colorectal cancer resection.¹⁸ The overall incidence of VTE in these patients was 1.0%, and the risk of death was nearly four times as great in patients who developed VTE as in those who did not. Notably, the need for transfusion was a marker of increased risk of VTE, particularly in women: women who received perioperative transfusions had almost double the risk of developing VTE compared with women who did not receive transfusions (P = .004).

CLINICAL TRIALS OF PROPHYLAXIS IN CANCER SURGERY PATIENTS

LMWH vs UFH for in-hospital prophylaxis

Two large randomized, double-blind trials have compared low-molecular-weight heparin (LMWH) with low-dose unfractionated heparin (UFH) for VTE prophylaxis in surgical patients with cancer—the Enoxaparin and Cancer (ENOXACAN) study¹⁹ and the Canadian Colorectal Surgery DVT Prophylaxis Trial.²⁰ Patients in these studies underwent surgery for abdominal or pelvic cancer (mostly colorectal cancer). Both studies compared 40 mg of the LMWH enoxaparin given once daily with 5,000 U of UFH given three times daily for 7 to 10 days postoperatively. Outcome measures were the presence of DVT determined by venography on day 7 to 10 and the incidence of symptomatic VTE. Rates of VTE were statistically equivalent between the two treatment arms in both ENOXACAN (14.7% with LMWH vs 18.2% with UFH) and the Canadian Colorectal Surgery study (9.4% with both therapies), as were rates of major bleeding (4.1% with LMWH vs 2.9% with UFH in ENOXACAN; 2.7% with LMWH vs 1.5% with UFH in the Canadian study).

These findings are consistent with a 2001 meta-analysis by Mismetti et al of all available randomized trials comparing LMWH with placebo or with UFH for VTE prophylaxis in general surgery.²¹ This analysis found no differences in rates of asymptomatic DVT, clinical PE, clinical thromboembolism, death, major hemorrhage, total hemorrhage, wound hematoma, or need for transfusion between LMWH and UFH in patients undergoing either cancer-related surgery or surgery not related to cancer.

Fondaparinux for in-hospital prophylaxis

Subgroup analysis of the large randomized trial known as PEGASUS²² sheds some light on the efficacy of the factor Xa inhibitor fondaparinux relative to LMWH for thromboprophylaxis in cancer surgery patients. PEGASUS compared fondaparinux 2.5 mg once daily with the LMWH dalteparin 5,000 IU once daily for 5 to 9 days in patients undergoing high-risk abdominal surgery. Among the study’s 1,408 patients undergoing surgery for cancer, rates of VTE were 4.7% in the fondaparinux group compared with 7.7% in the LMWH group, a relative risk reduction of 38.6% with fondaparinux (95% CI, 6.7% to 59.6%). In contrast, in the rest of the PEGASUS population (patients undergoing abdominal surgery for reasons other than cancer), LMWH was nonsignificantly more efficacious at preventing VTE than was fondaparinux. Rates of major bleeding in this cancer subgroup were comparable between the two treatments.

Extended prophylaxis

Two additional randomized trials have evaluated extended prophylaxis with LMWH in surgical cancer patients—ENOXACAN II²³ and the Fragmin After Major Abdominal Surgery (FAME) study.²⁴

In ENOXACAN II, patients undergoing surgery for abdominal or pelvic cancer first received 6 to 10 days of prophylaxis with enoxaparin 40 mg once daily and then were randomized in a double-blind fashion to an additional 21 days of enoxaparin or placebo.²³ Among 332 patients in the intent-to-treat analysis, the rate of VTE at the end of the double-blind phase was reduced from 12.0% with placebo to 4.8% with extended-duration enoxaparin (P = .02), an effect that was maintained at 3-month follow-up (P = .01). There was no significant difference between the two groups in rates of major bleeding events or any bleeding events.

In FAME, patients received 5,000 IU of dalteparin once daily for 1 week following major abdominal surgery and then were randomized in open-label fashion to either placebo or extended prophylaxis with dalteparin for 3 more weeks; a subanalysis examined outcomes in the 198 FAME participants whose abdominal surgery was for cancer.²⁴ Among these 198 cancer surgery patients, the rate of venography-documented VTE at 4 weeks was reduced from 19.6% with placebo to 8.8% with extended-duration dalteparin, a relative reduction of 55% (P = .03). The rate of proximal DVT was reduced from 10.4% to 2.2% with extended prophylaxis, a relative reduction of 79% (P = .02).

The number needed to treat with extended LMWH prophylaxis to prevent one VTE event was 14 in ENOXACAN II²³ and 9 in the FAME subanalysis of cancer surgery patients.²⁴

New systematic review of relevant trials

Leonardi et al recently published a systematic review of 26 randomized controlled trials of DVT prophylaxis in 7,639 cancer surgery patients.²⁵ They found the overall incidence of DVT to be 12.7% in those who received pharmacologic prophylaxis compared with 35.2% in controls. They also found high-dose LMWH therapy (> 3,400 U daily) to be associated with a significantly lower incidence of DVT than low-dose LMWH therapy (≤ 3,400 U daily) (7.9% vs 14.5%, respectively; P < .01). No differences were demonstrated between LMWH and UFH in preventing DVT, DVT location, or bleeding. Bleeding complications requiring discontinuation of pharmacologic prophylaxis occurred in 3% of patients overall.

Implications of HIT

The sequelae of heparin-induced thrombocytopenia (HIT) can have major consequences for cancer surgery patients. The incidence of HIT is markedly lower with LMWH than with UFH, as demonstrated in a nested case-control study by Creekmore et al.²⁶ These researchers also found that the average cost of an admission during which HIT developed was nearly four times as great as the average cost of an admission during which UFH or LMWH was given without development of HIT ($56,364 vs $15,231; P < .001).

EVIDENCE IN SPECIFIC ONCOLOGIC POPULATIONS

Most of the patients in the trials reviewed above underwent abdominal surgery for malignancy. Although studies of VTE prophylaxis in patients undergoing nonabdominal cancer surgery are relatively few, some data are available for a few other specific oncologic populations, as reviewed below.

Surgery for gynecologic cancer

There is a paucity of randomized controlled trials or prospective observational studies on VTE and its prevention in the gynecologic cancer surgery population. Based on small historical studies, the postoperative risk of VTE in this population varies from 12% to 35%.^27,28 Twice-daily administration of UFH 5,000 U appears to be ineffective as VTE prophylaxis in this population, but increasing the frequency to three times daily reduces VTE risk by 50% to 60% compared with placebo. Once-daily LMWH is comparable to three-times-daily UFH in efficacy and safety in this population.

A systematic Cochrane review of eight randomized controlled trials in patients undergoing major gynecologic surgery revealed that heparin prophylaxis (either UFH or LMWH) reduces the risk of DVT by 70% compared with no prophylaxis, with an identical risk reduction specifically among women with malignancy (odds ratio, 0.30; 95% CI, 0.10 to 0.89).²⁹ This review found no evidence that anticoagulation reduces the risk of PE following major gynecologic surgery. LMWH and UFH were similar in efficacy for preventing DVT and had a comparable risk of bleeding complications.

Surgery for urologic cancer

The risk of VTE and the benefits of thromboprophylaxis also are poorly studied in patients undergoing surgery for urologic cancer.

The risk of VTE varies with the type of urologic surgery and the method used to diagnose VTE. For instance, patients undergoing radical retropubic prostatectomy have been reported to develop DVT at rates of 1% to 3%, PE at rates of 1% to 3%, and fatal PE at a rate of 0.6%, whereas the incidences of these events are somewhat higher in patients undergoing cystectomy: 8% for DVT, 2% to 4% for PE, and 2% for fatal PE. Radiologic diagnosis of thromboembolism in pelvic surgery patients has yielded higher incidences, with DVT rates of 21% to 51% and PE rates of 11% to 22%.³⁰

Small studies suggest that prophylaxis with either low-dose UFH or LMWH is both effective in reducing VTE risk and safe in urologic cancer surgery patients, although pharmacologic prophylaxis poses a possible increased risk of pelvic hematoma and lymphocele formation in this population.³⁰

Neurosurgery

Most neurosurgical procedures are performed for malignancies. The risk of venography-confirmed VTE in patients undergoing neurosurgery is approximately 30% to 40%.^31,32 Likewise, the risks of intracranial or intraspinal hemorrhage in these patients are high. For this reason, mechanical methods of VTE prophylaxis are preferred in these patients. The use of anticoagulant prophylaxis remains controversial in this setting, although more recent data suggest that it might be safer than previously recognized.

A meta-analysis of studies of pharmacologic prophylaxis of VTE in neurosurgery included three randomized controlled trials that compared LMWH, with or without mechanical prophylaxis, to placebo plus mechanical prophylaxis or placebo alone in a total of 922 neurosurgery patients.³³ As detailed in Table 2, the analysis demonstrated statistically significant reductions in the risks of VTE and proximal DVT in favor of LMWH, with a statistically significant doubling in the risk of any bleeding and a nonsignificant 70% increase in the risk of major bleeding with LMWH therapy. The number needed to treat to prevent 1 proximal DVT was 16, while the number needed to treat to cause 1 major bleeding event was 115. A risk-benefit analysis showed that the use of LMWH in neurosurgery patients was associated with 1 major nonfatal bleeding event for every 7 proximal DVTs prevented. When a fourth randomized trial was included in the analysis, comparing UFH 5,000 U three times daily with no prophylaxis, rates of VTE and bleeding events remained similar to those for the LMWH trials alone.

GUIDELINES FOR VTE PROPHYLAXIS IN THE CANCER SURGERY PATIENT

American College of Chest Physicians

The American College of Chest Physicians’ Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy makes a number of recommendations regarding VTE prevention in patients undergoing surgery for cancer, as outlined in Table 3.³⁴

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) recently published clinical practice guidelines on venous thromboembolic disease in cancer patients.³⁵ The defined at-risk population for these guidelines is the adult cancer inpatient with a diagnosis of (or clinical suspicion for) cancer. The guidelines recommend prophylactic anticoagulation (category 1 recommendation) with or without a sequential compression device as initial prophylaxis, unless the patient has a relative contraindication to anticoagulation, in which case mechanical prophylaxis (sequential compression device or graduated compression stockings) is recommended. (A category 1 recommendation indicates “uniform NCCN consensus, based on high-level evidence.”)

The NCCN guidelines include a specific recommended risk-factor assessment, which includes noting the patient’s age (VTE risk increases beginning at age 40 and then steeply again at age 75), any prior VTE, the presence of familial thrombophilia or active cancer, the use of medications associated with increased VTE risk (chemotherapy, exogenous estrogen compounds, and thalidomide or lenalidomide), and a number of other risk factors for VTE as outlined in the prior two articles in this supplement. The NCCN guidelines explicitly call for assessment of modifiable risk factors for VTE (ie, smoking or other tobacco use, obesity, and a low level of activity or lack of exercise) and call for active patient education on these factors.

American Society of Clinical Oncology

The American Society of Clinical Oncology (ASCO) recently released guidelines on VTE prevention and treatment in patients with cancer;¹ their key recommendations for prevention are summarized in Table 4. Notable differences from the recommendations of the Seventh ACCP Conference are the ASCO guidelines’ inclusion of fondaparinux among recommended prophylactic options for this population and more explicit recommendations on the prophylactic use of LMWH. Also, for treatment of cancer patients with established VTE, ASCO specifies that LMWH is the preferred anticoagulant for both initial and continuing treatment.

Our recommended algorithm

Figure 1. Algorithm for VTE prophylaxis in the patient undergoing major surgery for cancer.

Drawing from the above formal society guidelines and the published literature, we recommend the algorithm in Figure 1 as a practical approach to VTE prevention in patients undergoing major surgery for cancer.

LINGERING CHALLENGE OF UNDERUTILIZATION

Despite this consensus on ways to reduce thromboembolic risk in this population and the clear evidence of the benefit of VTE prophylaxis in patients with cancer, data from several registries confirm a persistently low utilization of prophylaxis in patients with cancer.^36–38 The global Fundamental Research in Oncology and Thrombosis (FRONTLINE) study surveyed 3,891 clinicians who treat cancer patients regarding their practices with respect to VTE in those patients.36 The survey found that only 52% of respondents routinely used thromboprophylaxis for their surgical patients with cancer. More striking, however, was the finding that most respondents routinely considered thrombo-prophylaxis in only 5% of their medical oncology patients. These data are echoed by findings of other retrospective medical record reviews in patients undergoing major abdominal or abdominothoracic surgery (in many cases for cancer), with VTE prophylaxis rates ranging from 38% to 75%.^37,38

SUMMARY

Patients undergoing surgery for cancer have an increased risk of VTE and fatal PE, even when thromboprophylaxis is used. Nevertheless, prophylaxis with either LMWH or UFH does reduce venographic VTE event rates in these patients. If UFH is chosen for prophylaxis, a three-times-daily regimen should be used in this population. In specific surgical cancer populations, especially those undergoing abdominal surgery, out-of-hospital prophylaxis with once-daily LMWH is warranted. Current registries reveal that compliance with established guidelines for VTE prophylaxis in this population is low.

DISCUSSION: ADDITIONAL PERSPECTIVES FROM THE AUTHORS

Dr. Jaffer: Dr. Amin, based on your study on thrombo-prophylaxis rates in US medical centers, will you comment on rates of prophylaxis for cancer surgery patients?

Dr. Amin: The overall study included approximately 200,000 medical patients and about 80,000 surgical patients enrolled over more than a 3-year period between 2002 and 2005.^39,40 Our goal was to assess rates of prophylaxis and, when it was provided, whether it was appropriate (in terms of type, dosage, and duration) based on the ACCP guidelines. A subanalysis assessed medical cancer patients and surgical cancer patients separately. Medical cancer patients received thromboprophylaxis 56% of the time but received appropriate prophylaxis only 28% of the time. Among surgical cancer patients, appropriate prophylaxis was given only about 24% of the time for those undergoing gynecologic surgery and about 12% of the time for those undergoing neurosurgery. These percentages are consistent with data from other national registries, such as the IMPROVE registry, which documented prophylaxis rates on the order of 45% in medical patients with cancer.⁴¹ We also analyzed the data according to individual practitioners and found that medical oncologists use prophylaxis about 25% of the time, which is relatively consistent with other providers, such as internists and surgeons.

So there is a huge opportunity to improve rates of prophylaxis for this group of patients that national guidelines say are at high risk. Why is prophylaxis so underutilized in the cancer population? One factor may be a misperception about the risk of bleeding with anticoagulants. Yet several studies have shown that the rate of bleeding from prophylaxis is extremely low, whether LMWH or UFH is used, so more awareness of actual bleeding risk is needed. Another factor is the obvious focus among internists and oncologists on treating the patient, with perhaps a reduced consideration of prophylaxis and prevention. A third factor may be a concern about thrombocytopenia. However, in our study of prophylaxis rates in US medical centers, we excluded patients who had thrombocytopenia, yet rates of prophylaxis were still low. Nothing in the literature indicates that anticoagulants cannot be used in patients with platelet counts of 50,000 to 150,000 cells/µL or higher, so this suggests that we need to do more education.

Dr. Jaffer: Dr. Brotman, can you tell us more about how clinicians in practice should use prophylaxis in their neurosurgery patients, such as those undergoing craniotomy or spine surgery for cancer? What is the safest and most efficacious way to prevent DVT in these patients?

Dr. Brotman: First, it’s important to recognize that some sort of prophylaxis needs to be used. Neurosurgery patients are at an extremely high risk for thromboembolic events, and such events are often fatal in these patients. Having said that, the jury is still out on whether the prophylaxis in these patients should be compression devices or anticoagulation. This gives physicians some latitude in their decisions. They can decide not to use pharmacologic prophylaxis so long as they use pneumatic compression devices consistently, perhaps even starting during the operation and certainly throughout hospitalization when the patient is immobilized.

Certainly, the concerns about using full-dose anticoagulation in the immediate postoperative setting in neurosurgery patients are valid. Yet these patients are at very high risk for thromboembolic events, and if we take too cautious an approach to prophylaxis in the immediate perioperative setting, more patients are going to have thromboembolic events, at which point management decisions become much more difficult. The risk of intracranial bleeding with anticoagulation to treat a patient who develops a DVT at postoperative day 10 will certainly be higher than it would have been with lower-dose perioperative prophylactic anticoagulation. Plus, if you put in a filter at that point, the outcomes tend to be poor. Therefore, I believe there is some degree of risk that we should be willing to take with regard to perioperative bleeding, even in neurosurgery patients.

Dr. McKean: I’d like to make a point about combination prophylaxis. At many institutions, compression stockings and sequential compression devices are used preoperatively and intraoperatively, and then pharmacologic prophylaxis—for example, twice-daily UFH—is used postoperatively. There is concern that these patients are hypercoagulable, and most clinicians believe that mechanical prophylaxis alone, even with sequential compression devices plus compression stockings, is not aggressive enough in these high-risk patients.

Dr. Jaffer: Dr. Spyropoulos, what is the optimal duration of pharmacologic prophylaxis for cancer surgery patients?

Dr. Spyropoulos: First let’s consider in-hospital prophylaxis. The supportive data for in-hospital prophylaxis are strong, and the duration of therapy used in the major in-hospital prophylaxis trials was 7 to 10 days. With regard to extended prophylaxis, we have at least two moderately sized randomized controlled trials, ENOXACAN II²³ and the substudy of FAME,²⁴ that demonstrated that extending prophylaxis with LMWH at doses of 3,400 U once daily (5,000 IU of dalteparin; 40 mg of enoxaparin) reduces VTE risk at postoperative day 30. Also, recent data from the @RISTOS registry show that in cancer surgery patients, especially those having abdominal or pelvic procedures, the leading cause of 30-day mortality was VTE.⁸ This registry also shows that despite prophylaxis, the rate of symptomatic VTE can be as high as 2%, with the rate of fatal VTE approaching 1%. Thus, in cancer patients undergoing abdominal or pelvic surgery, physicians should strongly consider prophylaxis of up to 30 days’ duration.

Dr. Jaffer: One striking finding from the @RISTOS registry was that 40% of VTE events in these cancer surgery patients occurred after postoperative day 21. This really underscores the need to consider prophylaxis for at least 4 weeks in these patients in real-world practice.

Dr. Brotman: The other striking finding from that registry was that the in-hospital prophylaxis rate was quite high, about 80%, and the rate of extended prophylaxis approached 35%. These are rates that are rarely achieved in clinical practice. Yet despite these high levels of prophylaxis, patients in this registry still had a high incidence of morbidity and mortality from VTE. This suggests that we need to improve our out-of-hospital VTE prevention paradigms.

Dr. Jaffer: Dr. Deitelzweig, oncologists and internists are often unsure about whether their ambulatory cancer patients who are receiving chemotherapy should be on any form of prophylaxis. What is your opinion?

Dr. Deitelzweig: That question comes up regularly because these patients are encountered across many medical specialties. At this point, all of the large organizations, including ASCO and NCCN, are advocating that prophylaxis is not indicated for such patients.

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Author and Disclosure Information

Daniel J. Brotman, MD
Director, Hospitalist Program; Associate Professor of Medicine, Johns Hopkins Hospital, Baltimore, MD

Steven B. Deitelzweig, MD
Vice President of Medical Affairs; Chairman, Department of Hospital Medicine, Ochsner Health System, New Orleans, LA

Amir K. Jaffer, MD
Associate Professor of Medicine; Chief, Division of Hospital Medicine, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL

Sylvia C. McKean, MD
Medical Director, BWH/Faulkner Hospitalist Service; Associate Professor of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA

Correspondence: Alex C. Spyropoulos, MD, Chair, Clinical Thrombosis Center, Lovelace Medical Center, 500 Walter Street NE, Suite 301, Albuquerque, NM 87108; alex.spyropoulos@lovelace.com

Dr. Spyropoulos reported that he has received consulting fees from Sanofi-Aventis, Eisai, and Boehringer Ingelheim.

Dr. Brotman reported that he has no financial relationships with commercial interests that are relevant to this article.

Dr. Amin reported that he has received research funding and honoraria for speaking from Sanofi-Aventis, Eisai, and GlaxoSmithKline.

Drs. Deitelzweig and McKean each reported that they have received honoraria for teaching/speaking from Sanofi-Aventis.

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