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C LINICAL R EVIEW

Why Thrombosis Prophylaxis Fails

Joseph A. Caprini, MD, MS, FACS, RVT

Abstract never determined. One-third of these fatalities occurred

Thrombosis prophylaxis methods have been widely test- following hospital discharge, which presents a difficult
ed and found to be extremely effective for the prevention problem since resources are generally lacking for careful
of serious or fatal events known to be common in patients followup after discharge. It is uncommon to have autop-
undergoing surgery or who are medically ill. A common sies performed in these individuals due to cost and other
reason for failure occurs when physicians apply inade- issues. Unfortunately, without accurate necropsy data, the
quate measures due to a lack of awareness of the problem. true incidence of fatal PE or paradoxical stroke is difficult
Failure to perform individual risk assessment is another to determine. Heit et al developed an incidence-based
common reason for failure, since individuals may undergo model that included both hospital- and community-
a low-risk operation but have multiple risk factors dictat- acquired VTE events, as well as death from recognized and
ing a much more robust approach to prophylaxis than unrecognized VTE.
group recommendations dictate. The presence of ongoing A similar analysis of inpatients, using VTE criteria estab-
risk such as cancer or history of past venous thromboem- lished by the American College of Chest Physicians (ACCP)
bolism (VTE) may dictate the use of prophylaxis following estimated that more than 12 million patients are at risk for
hospital discharge. Failure to provide this coverage often VTE.2 A total of 7.7 million medical in-patients and 4.3
leads to serious or fatal events days or even weeks later. million surgical patients met ACCP guideline criteria for
The use of aspirin for prophylaxis after orthopedic surgery VTE risk, with VTE prophylaxis recommended.2 Although
is a weak, relatively ineffective approach to preventing the the risk of deep vein thrombosis (DVT) is thought to be
many faces of VTE, including clinical and asymptomatic most commonly associated with surgical patients, 50–70%
VTE, pulmonary hypertension, paradoxical stroke and the of symptomatic thromboembolic events and 70–80% of
post-thrombotic syndrome. Finally, failure to use combi- fatal PE occur in nonsurgical patients.3 Approximately
nation physical and pharmacologic methods together in 10% of all hospital deaths are due to PE. Patients in the
the highest-risk patients may lead to the development of medical intensive care unit (ICU) are at particularly high
VTE, which could be avoided with an appropriate combi- risk for DVT. During an 8-month screening study, DVT
nation approach. was detected by ultrasound in 33% of 100 patients admit-
ted to the medical ICU with an anticipated minimum stay
Background of 48 hours.4 It is unfortunate that these facts are not com-
Venous thromboembolism (VTE) is a serious and often mon knowledge among both physicians and the public.
fatal disease affecting approximately 900,000 individuals
in the United States each year, according to Heit et al.1 Inadequate prophylaxis due to lack of awareness
They estimate that 296,000 deaths from pulmonary Lack of awareness is a major reason for inappropriate or
embolism (PE) occur, including 34% who present as sud- weak thromboprophylaxis use in many hospitalized
den death. The inability of the clinician to help patients patients. Failure of an inadequate thromboprophylaxis mea-
who die without warning is a frustrating problem. Many sure such as aspirin is one example and is not recommend-
of these hospitalized patients had serious disease, and ed by Chest or the International Consensus Guidelines.5,6
without an autopsy, often the true cause of death was The American Academy of Orthopedic Surgeons created a
position statement that endorses the use of aspirin in some
orthopedic patients, but these changes lack robust evidence-
From the Division of Vascular Surgery, NorthShore University Health Sys- based guidelines documents.7
tem, Evanston, Illinois, Northwestern University Feinberg School of Medi-
cine, Chicago, Illinois, and the Robert R. McCormick School of
Bioengineering Northwestern University, Evanston, Illinois. Failure to perform individual risk assessment
The author discloses no conflicts of interest regarding the content herein. Another problem that affects the type and length of pro-
Manuscript submitted November 11, 2008, provisional acceptance given
January 12, 2009, final version accepted January 30, 2009. phylaxis and fosters development of VTE is the lack of
Address for correspondence: Joseph A. Caprini, MD, MS, FACS, Louis appropriate individual patient risk assessment. Many
Biegler Professor of Surgery, Division of Vascular Surgery, NorthShore Uni-
versity Health System, Coventry Road, Northfield, IL 60093. E-mail: jcapri- years ago, when there were no ultrasound, computed
[email protected] tomographic (CT) or magnetic resonance imaging (MRI)

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scanners, clinicians performed thorough history and phys-

Table 1. A system of scoring that ical examinations. Today the trend is to provide prophy-
laxis by groups and not perform individual risk
involves eliciting from the patient all of assessment. This approach is endorsed by the current
the established risk factors that have Chest guidelines.5 However, the guidelines can truly only
been associated with developing a VTE apply to patients with the same characteristics as the clini-
(Table 2 allows for the prediction of risk cal trial population. Many patients we see in daily clinical
with the resulting score). practice would be excluded from those trials, but still
require care. The physician must tailor a plan of care based
Risk Factors (1 point)
• Age 40–59 years
on the unique risk of a particular patient by combining
• Minor surgery knowledge of the literature with clinical experience, logic
• Previous major surgery (1 month) and emotion (that is, the practice of medicine). One exam-
• Varicose veins ple would be a 43-year-old female who had repair of a rup-
• Inflammatory bowel disease tured Achilles tendon and postoperatively was placed in a
• Current leg swelling
• Obesity (BMI 30–40)
cast and was on crutches. She had active inflammatory
• Acute myocardial infarction (1 month) bowel disease (IBD) and was taking estrogen for birth con-
• Congestive heart failure (1 month) trol. She was given prophylaxis at the time of surgery, but
• Sepsis (1 month) anticoagulants were not recommended after discharge. Six
• Serious lung disease including pneumonia weeks later, while still in the cast, she developed a fatal PE.
(1 month)
• Chronic obstructive pulmonary disease (COPD)
She had received prophylaxis briefly, but because of her
• Leg plaster cast or brace multiple risk factors, the prophylaxis should probably
• Current bedrest have been continued. Unfortunately, there are no trials in
• Central venous or PICC line patients with her unique combination of risk factors, since
• Blood transfusion (1 month) no institutional review board would approve a study
• Oral contraceptives or hormonal replacement
therapy
where patients who were potentially “at risk” would be
• Pregnancy or postpartum (1 month) placed in a control group. Since she had seven risk factors
• History of unexplained stillborn infant, recurrent including leg injury, leg surgery, estrogens, leg cast, rela-
spontaneous abortion (3 or more), premature tive immobility, IBD and age over 40, her chance of devel-
birth with toxemia or growth-restricted infant oping VTE was nearly 100%.8 Such patients require
Risk Factors (2 points)
prophylaxis for the entire period they are at risk for VTE.9
• Age 60–74 years Guidelines indicate that patients with > 4 risk factors have
• Major surgery (> 60 minutes)* up to a 5% mortality risk without appropriate prophy-
• Arthroscopic surgery (> 60 minutes)* laxis.5 The administration of unfractionated heparin
• Laparoscopic surgery (> 60 minutes)* (UFH) or low-molecular-weight heparin (LMWH) pro-
• Previous malignancy
• Morbid obesity (BMI > 40)
phylaxis reduces the fatal PE rate to 0.15%.10 Hence, the
therapeutic plan for this patient would have been admin-
Risk Factors (3 points) istration of appropriate anticoagulation until she was
• Age ! 75 years walking normally. Had that been the case, she might still
• Major surgery (2–3 hours)* be alive, although she may have suffered a nonfatal event
• BMI > 50 (venous stasis syndrome)
• History of SVT, DVT/PE
requiring treatment.
• Family history of DVT/PE Prophylaxis that is inadequate often fails in the med-
• Present cancer or chemotherapy ically ill patient. An example would be a 78-year-old male
• Positive Factor V Leiden or prothrombin 20210A in the hospital on bedrest with pneumonia. The patient
• Hyperhomocysteinemia may have been given UFH 5,000 units twice daily or grad-
• Positive ACA antibodies/lupus anticoagulant
• Heparin-induced thrombocytopenia
uated compression stockings. However, both of these
• Other strategies in the medically ill population are associated with
a high failure rate, as patients develop VTE despite these
Risk Factors (5 points) measures.11 Individual risk assessment would place this
• Elective major lower-extremity arthroplasty patient at extreme risk. A lower dose of heparin or stock-
• Hip, pelvis, or leg fracture (< 1 month)
• Stroke (< I month)
ings alone are likely to fail, although technically it is pro-
• Multiple traumas ( < 1 month) phylaxis.11 However, giving heparin every 8 hours along
• Acute spinal cord injury/paralysis (< I month) with intermittent pneumatic compression (IPC) would be
• Major surgery lasting > 3 hours* justified. Studies have shown that UFH every 8 hours is
*Select only one from the surgery category more effective than every 12 hours, although the risk of
bleeding is higher.12 It has also been shown that combining

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W H Y T H R O M B O S I S P R O P H Y L A X I S FA I L S

observational study of 2,373 surgical patients to evaluate

Table 2. The elicited score (see Table 1)
3,15 the incidence of clinically overt VTE and to identify risk
can be used to predict the risk of an indi- factors for VTE. Thirty percent of patients received post-
vidual patient having a clinically evident, discharge VTE prophylaxis compared to 81.8% during
imaging-proven VTE during or following hospitalization. In the study, 40% of VTE and PE events
occurred more than 21 days after surgery, leading
discharge
researchers to conclude that there is a need to extend
Score Incidence Risk Prophylaxis antithrombotic prophylaxis beyond hospital discharge and
of DVT* Level the conventional perioperative period.23
0–1 0.00% Low No specific
measures Inadequate prophylaxis following major
2 0.70% Moderate Physical or orthopedic surgery
pharmacologic
Although there have been advances in understanding the
3–4 0.97% High Pharmacologic
incidence, pathophysiology and benefits of VTE prophy-
5 or more† 1.94% Highest Physical +
pharmacologic laxis post major orthopedic surgery, and guidelines for
prophylaxis have been established, there remains a portion
*
Clinically evident, imaging-proven VTE. of the total hip replacement (THR), total knee replacement
†
Out-of-hospital pharmacologic prophylaxis may be
appropriate. (TKR), and hip fracture repair (HFR) population that does
not receive adequate VTE prophylaxis. To establish a bet-
ter understanding of the current practices of prophylaxis
IPC with anticoagulants increases efficacy without increas- implementation, Stratton et al performed a retrospective
ing bleeding in the medically ill patient.13 review of the medical charts of 1,907 patients from 10
We use a system of scoring that involves eliciting from teaching or community-based hospitals. These patients
the patient all of the established risk factors that have been were randomly selected from the patient population that
associated with developing a VTE (Table 1). Each factor is underwent high-risk major abdominal surgery, TKR, THR
weighted according to the likelihood of that factor causing or HFR from January 1996 to February 1997. The per-
a VTE.14 The resulting score can be used to predict the risk centage of patients who received Grade A VTE prophy-
of an individual patient having a clinically evident, imag- laxis in accordance with recommendations of the ACCP
ing-proven VTE during or following discharge (Table 2). guidelines was 84.3% in the THR group, 45.2% in the
Data from the National Surgical Quality Improvement HFR group and 76% in the TKR group. In the THR, HFR
Project (NSQIP) sponsored by the American College of and TKR groups, 8.4%, 46.4% and 22.6% of patients,
Surgeons have validated this concept.15 The system is wide- respectively, received some form of prophylaxis. However,
ly used and several investigators have employed this con- the prophylaxis given did not comply with ACCP guide-
cept of scoring in different clinical settings.16-21 The method lines. Only 7.3%, 8.4% and 1.5% in the THR, HFR and
is far from perfect, but provides a guide to the clinician. In TKR groups, respectively, received no prophylaxis what-
some cases where the incidence of post-discharge VTE is soever. Prophylactic therapies prescribed at discharge were
high, continued prophylaxis following discharge can be most common in the TKR group (70.2%). Patients in the
justified and help prevent thrombosis. THR and HFR groups were only given prophylactic ther-
apy approximately 50% of the time.24
Failure to provide extended prophylaxis In their meta-analysis of randomized trials, Eikelboom
Medical patients with ongoing risk benefit from extend- et al found a significant reduction in the incidence of
ed prophylaxis, as was shown in a multicenter, prospective, asymptomatic DVT among THR or TKR patients
randomized, double-blind, placebo-controlled clinical trial in receiving extended-duration prophylaxis with LMWH
5,049 patients that compared extended-duration (28 days) or UFH (9.6% of treated patients vs. 19.6% of controls;
prophylaxis with LMWH and the standard regimen of p " 0.001)25 The authors concluded that among patients
LMWH given during hospitalization. The rates of all VTE undergoing THR or TKR, extended-duration prophy-
events and symptomatic or asymptomatic events were sig- laxis significantly reduces the frequency of symptomatic
nificantly reduced with extended prophylaxis versus stan- VTE. The reduction in risk is equivalent to about 20
dard-duration prophylaxis. Major bleeding occurred in 12 symptomatic events per 1,000 patients treated. Geerts et
patients receiving extended LMWH and in 3 patients al reviewed studies of the incidence of symptomatic
receiving the short-duration prophylaxis (0.6% vs. 0.1%; DVT or PE in patients undergoing THR or TKR who
p = 0.0192).22 Studies in surgical patients have also received extended prophylaxis with LMWH or war-
revealed that failure to provide extended prophylaxis to farin. Symptomatic DVT/PE occurred in 1–3% of
those at risk results in a significant late incidence of patients and fatal PE in < 1% of patients receiving
VTE. Agnelli and colleagues undertook a prospective extended prophylaxis.3

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Extended therapy as a means of prophylaxis: further proof that many VTE events can occur weeks
Evidence-based guidelines after discharge.
Evidence-based medicine guidelines based on veno- Abdominal surgical patients with cancer form another
graphic endpoints recommend in-hospital prophylaxis important group where the value of out-of-hospital pro-
with LMWH in patients undergoing elective hip surgery. phylaxis has been demonstrated using venography.
Emerging data suggest that out-of-hospital use may offer Bergqvist evaluated 332 patients undergoing surgery for
additional protection; however, uncertainty remains about cancer who received enoxaparin for 6–10 days after
the risk-benefit ratio. To provide clinicians with a practical surgery and then were randomized to enoxaparin or place-
pathway for translating clinical research into practice, a bo for another 21 days.2 The incidence of all VTE events at
systematic review of trials comparing extended out-of-hos- 21 days was 12.0% with placebo and 4.8% with enoxa-
pital LMWH prophylaxis versus placebo was conducted. parin (p = 0.02), and this benefit persisted to 3 months (p
Compared with placebo, extended out-of-hospital prophy- = 0.01). No differences were observed in the incidence of
laxis decreased the frequency of all episodes of DVT (place- bleeding or complications.32 Rasmussen reported the
bo rate, 150/666 patients [22.5%]; relative risk [RR], 0.41; results of a multicenter randomized trial of short-term ver-
95% confidence interval [CI], 0.32–0.54; p < 0.001), prox- sus long-term dalteparin thromboprophylaxis after major
imal venous thrombosis (placebo rate, 76/678 patients abdominal surgery in 590 patients. The venographic inci-
[11.2%]; RR, 0.31; CI, 0.20–0.47; p < 0.001), and symp- dence of VTE was reduced from 16.3% with short-term
tomatic VTE (placebo rate, 36/862 patients [4.2%]; RR, thromboprophylaxis (29/178 patients) to 7.3% after pro-
0.36; CI, 0.20–0.67; p = 0.001). Major bleeding was rare, longed thromboprophylaxis (12/165) (RRR 55%; 95%
occurring in only 1 patient in the placebo group. Extended CI, 15–76; p = 0.012). Bleeding events were not increased
LMWH prophylaxis showed consistent effectiveness and with prolonged compared to short-term thromboprophy-
safety in the trials (regardless of study variations in clinical laxis.33 Thus, we have another study with a different
practice and length of hospital stay) for venographic DVT LMWH that shows the value of prolonged prophylaxis
and symptomatic VTE.26–29 These findings support the need after major abdominal surgery in patients with cancer.
for extended out-of-hospital prophylaxis in patients under-
going hip arthroplasty surgery. These observations under- Combination prophylaxis for the highest-risk
score the relation between venographic and symptomatic patients
VTE events. This evidence, along with numerous other stud- The value of combining IPC with anticoagulants has
ies, has convinced us to treat the highest-risk patients with a been known for over 25 years since the results of Maxwell
thrombosis prophylaxis regime that has been shown to be Borow were first published. This careful investigator was
superior both clinically and venographically. significantly ahead of his time. The following is a quote
In an excellent study examining the efficacy of fonda- from his studies in surgical patients. “Worldwide statistics
parinux for thromboprophylaxis in high-risk hip fracture reveal that 25 to 40 percent of patients who are over the
patients, patients received fondaparinux 2.5 mg for 7 days age of 40 years and operated on for 1 or more hours will
following surgery; 656 patients were randomized double- develop a deep venous thrombosis (DVT). The studies
blind to receive placebo or continue the fondaparinux reg- reviewed in this paper were performed to evaluate several
imen for 21 additional days. Primary efficacy was VTE modalities and compare their effectiveness in preventing
based on bilateral venography. Total VTE was 1.4% for DVT in postoperative patients. In the first study, five
extended prophylaxis and 35% for short-term prophylax- modalities plus a control group were evaluated in 562
is (p = 0.001), with a relative risk reduction (RRR) of patients from five surgical specialties. The incidence of
96%.30 The authors reported that although there was a DVT in the control group was 35 percent. Though most of
trend toward more major bleeding in the fondaparinux the pharmacologic agents were effective in reducing the
group than in the placebo group (p = 0.06), there were no incidence of DVT, the antistasis devices (gradient elastic
differences between the two groups in the incidence of clin- stockings and intermittent pneumatic compression) were
ically relevant bleeding (leading to death, reoperation or most effective. The purpose of the second study was to
critical organ bleeding). They further concluded that evaluate the effectiveness of combining a pharmacologic
extended prophylaxis with fondaparinux for 3 weeks after drug with an antistasis modality. Deep venous thrombosis
hip-fracture surgery reduced the risk of VTE by 96% and was virtually eliminated in this group of 328 patients. There
was well tolerated. The patients who received the drug over was only a 1.5 percent incidence of DVT in the treated pop-
the short term experienced an 8.3% incidence of positive ulation as compared to a 26.8 percent incidence in the con-
venograms done 7–10 days postoperatively.31 If the trol group. Thus, it seems that combining one antistasis and
venogram was delayed for 28–35 days, the venographic one pharmacologic agent greatly reduces the incidence of
incidence of DVT was 35%. What a dramatic illustra- lower extremity thrombi. I-125 fibrinogen scanning was the
tion of the value of extended prophylaxis in the very- most sensitive test in detecting DVT and had an accuracy of
high risk orthopedic patient! These studies also provide 97 percent.”34 It is fascinating that in 2007 the APOLLO

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15. Bahl V, Hu H, Henke PK, et al. A validation study of a retrospective venous

trial reported a 1.5% incidence of DVT in patients receiving thromboembolism risk scoring method. Submitted for publication 2009.
IPC plus fondaparinux.35 This study was performed in 16. McLafferty RB, Lohr JM, Caprini JA, et al. Results of the national pilot
screening program for venous disease by the American Venous Forum. J
abdominal surgery patients, and included both gallbladder Vasc Surg 2007;45:142–148.
and hernia operative procedures. Forty percent of the 17. McLafferty R, Passman M, Caprini J. Increasing awareness about venous
patients had cancer, and the comparator was IPC and a disease: The American Venous Forum expands the National Venous Screen-
ing Program. J Vasc Surg 2008;48:394–399.
saline placebo-blinded injection. Ramos, in 1996, reported 18. Osborne NH, Wakefield TW, Henke PK. Venous thromboembolism in can-
on a consecutive group of 2,500 cardiac surgery patients cer patients undergoing major surgery. Ann Surg Oncol
2008;15:3567–3578.
undergoing coronary artery bypass over a 10-year period. 19. Seruya MS, Venturi ML, Iorio ML, et al. Efficacy and safety of venous
He found that the incidence of proven PE was 1.4% in the thromboembolism prophylaxis in highest risk plastic surgery patients. J
Plastic Reconstr Surg 2008;122:1701–1708.
UFH plus IPC group compared to heparin alone (4%). This 20. Zakai NA, Wright J, Cushman M. Risk factors for venous thrombosis in
represented a 62% reduction in PE that was highly statisti- medical inpatients: Validation of a thrombosis risk score.[see comment]. J
cally significant (p < 0.001).36 Failure of clinicians to employ Thromb Haem 2004;2:2156–2161.
21. O’shaunnessey D. Evaluating the performance of a previously reported risk
combined prophylaxis in the highest-risk patients is, in our score to predict venous thromboembolism. A verity registry study. Blood
opinion, a significant reason for failure of prophylaxis. 2006;108:716.
22. Hull R. Extended duration of anticoagulation in the medically ill. XXIST
Congress of the International Society on Thrombosis and Haemostasis.
Conclusion Geneva, Switzerland 2007:s001.
There are many reasons for the failure of prophylaxis to 23. Agnelli G, Bolis G, Capussotti L, et al. A clinical outcome-based prospec-
tive study on venous thromboembolism after cancer surgery: The @RISTOS
prevent a VTE event. One essential ingredient for success project. [see comment]. Ann Surgery 2006;243:89–95.
is to perform a careful history and physical on every 24. Stratton MAP, Anderson FAP, Bussey HIP, et al. Prevention of venous
thromboembolism: Adherence to the 1995 American College of Chest
patient to assess their unique risks for thrombosis. It is also Physicians consensus guidelines for surgical patients. Arch Intern Med
essential to use appropriate prophylaxis alone or in com- 2000;160:334–340.
25. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis
bination for the entire period the patient is at thrombotic against venous thromboembolism after total hip or knee replacement: A
risk. The use of out-of-hospital prophylaxis in many situ- meta-analysis of the randomised trials. [see comment]. Lancet
ations is important to reduce the overall morbidity and 2001;358:9–15.
26. Bergqvist D, Benoni G, Bjorgell O, et al. Low-molecular-weight heparin
mortality of this serious disease. (enoxaparin) as prophylaxis against venous thromboembolism after total
hip replacement.[see comment]. N Engl J Med 1996;335:696–700.
27. Planes A, Vochelle N, Mazas F, et al. The use of enoxaparine in preventing
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