Transcript Document

VTE and Cancer
The Science and Medicine of
Cancer and Thrombosis Management
VTE Prophylaxis
in the Cancer Patient
Scope, Trials, Guidelines and Solutions
Samuel Z. Goldhaber, MD
Professor of Medicine
Harvard Medical School
Cardiovascular Division
Director, Venous Thromboembolism Research Group
Brigham and Women’s Hospital
Boston, MA
Learning Objectives
VTE and Cancer
►
Epidemiology/ Scope of the Problem
►
Prophylaxis Paradigm Shift
►
Surgeon General’s Call To Action
►
Medicare’s “Never Events”
►
Prophylaxis Modalities
►
Electronic, Computerized Alerts
►
Human, Physician-to-Physician Alerts
►
Guidelines: NCCN, ASCO, ACCP
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Epidemiology:
Scope of the Problem
ICOPER Cumulative Mortality
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25
17.5%
Mortality (%)
20
15
10
5
0
7
14
30
60
Days From Diagnosis
Lancet 1999;353:1386-1389
90
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At-Risk for VTE
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► The high death rate from PE (exceeding
acute MI!) and the high frequency of
undiagnosed PE causing “sudden cardiac
death” emphasize the need for improved
preventive efforts.
► Failure to institute prophylaxis is a much
bigger problem with Medical Service
patients than Surgical Service patients.
At-Risk for VTE
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► Two quality improvement initiatives show
that among at-risk-for-VTE Medical
Service patients, Medical Oncology
patients are the least likely group to
receive VTE prophylaxis.
► 80% of omitted prophylaxis on Medical
Services occurred in Medical Oncology
patients.
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Annual At-Risk for VTE:
U.S. Hospitals
►
7.7 million Medical Service inpatients
►
3.4 million Surgical Service inpatients
►
Based upon ACCP guidelines for VTE
prophylaxis
Anderson FA Jr, et al. Am J Hematol; 2007; 82: 777-782
Outpatient and Inpatient VTE Are Linked
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►
74% of VTEs present in outpatients.
►
42% of outpatient VTE patients have
had recent surgery or hospitalization.
►
Only 40% had received VTE
prophylaxis.
Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475
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ENDORSE : WORLDWIDE
(Lancet 2008; 371: 387-394)
68,183 patients; 32 countries; 358 sites
First patient enrolled August 2, 2006;Last patient enrolled January 4, 2007
ENDORSE: 68,183 Patients
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52% at risk for VTE
(50% receive ACCP
recommended prophylaxis)
Surgical
64% at risk for VTE
59% receive ACCP
recommended
prophylaxis
Medical
42% at risk for VTE
40% receive ACCP
recommended
prophylaxis
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VTE Prophylaxis
Paradigm Shift
Cancer and Medical Conditions
in the Crosshairs
Ten Years Ago…
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►
Most Americans had not heard of DVT (deep
vein thrombosis) or PE (pulmonary embolism)
►
Virtually no awareness
►
Media attention was limited to featuring a few
celebrities who were stricken
►
No state or congressional resolutions
►
No patient advocacy
►
No Medicare input
VTE Awareness in 2009
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►
Growing interest in VTE’s public health threat
►
Known as the most preventable illness in hospitalized
patients
►
Publicity is increasing among health care
professionals and the public
►
Patient advocacy is a reality
►
Congress and most States have adopted months for
“Thrombosis Awareness”
►
Medicare has declared certain DVTs or PEs as “Never
Events” and will not reimburse
Old Prophylaxis Paradigm
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►
MD individualizes prophylaxis prescription
and ultimately has complete “yes” or “no”
authority to prescribe or withhold
prophylaxis
►
Hospital, government auditors, patients,
and families do not challenge the MD’s
decision to withhold prophylaxis. Instead,
they “defer to the physician’s medical
judgment”
New Prophylaxis Paradigm
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►
Hospital monitors VTE prophylaxis prescribing and insists
upon guideline-based practice
►
Electronic reminders and automated electronic orders
ultimately ensure appropriate prophylaxis for at-risk
patients
►
Hospital’s financial and medicolegal penalty for failure to
prophylax may be “passed on” to the responsible
attending physician
►
Cancer patients represent high-risk, “must prophylax”
subgroup
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SURGEON
GENERAL:
CALL TO
ACTION TO
PREVENT
DVT AND PE
September 15, 2008
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Medicare’s
“Never Events”
Medicare’s “Never Events”
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Medicare’s most recent strategy to reduce
medical errors is to withhold payment to
hospitals for treatment of serious
preventable illnesses or complications
termed “never events.” The initial 3 were:
1) Foreign object retained postop
2) Air embolism removing CVC
3) Blood transfusion incompatibility
Medicare’s “Never Events”
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► On October 1, 2008, Medicare added:
► DVT or pulmonary embolism occurring
after total knee or hip replacement.
► Medicare will not pay the incremental
cost to manage the complication. Nor
will the patient be responsible.
► The hospital will bear the additional
financial burden.
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Prophylaxis
Modalities
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VTE Prophylaxis in 19,958 Medical Patients/
9 Studies (Meta-Analysis)
►
62% reduction in fatal PE
►
57% reduction in fatal or nonfatal PE
►
53% reduction in DVT
Dentali F, et al. Ann Intern Med 2007; 146: 278-288
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VTE Prophylaxis in
Medical Patients is Cost-Effective
►
$1,264 per patient for LMWH
►
$2,245 for No Prophylaxis
Deitelzweig et al. Thromb Haemostas 2008; 100: 810-820
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Intermittent Pneumatic Compression
Meta-Analysis in Postop Patients
►
2,270 patients in 15 randomized trials
►
IPC devices reduced DVT risk by 60%
(Relative Risk 0.40, 95% CI 0.29-0.56,
p< 0.001)
Urbankova J. Thromb Haemost 2005; 94: 1181-5
Reversible Risk Factors
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1.
Nutrition: eat fruits, veggies, fish; less red
meat (Circulation 2007;115:188-195)
2.
Quit cigarettes
3.
Lose weight/ exercise
4.
Prevent DM/ metabolic syndrome
5.
Control hypertension
6.
Lower cholesterol
7.
Avoid air pollution
Arch Intern Med 2008; 168: 920-927)
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Statins Prevent
PE and DVT!
JUPITER
Total Venous Thromboembolism
0.025
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0.015
Placebo 60 / 8901
0.010
- 43 %
0.005
Rosuvastatin 34 / 8901
0.000
Cumulative Incidence
0.020
HR 0.57, 95%CI 0.37-0.86
P= 0.007
0
1
2
Rosuvastatin
Placebo
3
4
Follow-up (years)
Number at Risk
8,901
8,901
8,648
8,652
Glynn et al NEJM 2009
8,447
8,417
6,575
6,574
3,927
3,943
1,986
2,012
1,376
1,381
1,003
993
548
556
161
182
JUPITER
Venous Thromboembolism – Unprovoked vs Provoked
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HR 0.52, 95% CI 0.28-0.96
P= 0.03
Cumulative Incidence
0.010
0.015
Rosuvastatin
0.000
Rosuvastatin
Placebo
0.005
Placebo
0.000
0
Provoked Venous Thromboembolism
0.020
HR 0.61, 95% CI 0.35-1.09
P= 0.09
0.005
Cumulative Incidence
0.010
0.015
0.020
Unprovoked Venous Thromboembolism
1
2
Follow-up (years)
3
4
0
1
2
3
Follow-up (years)
Clear clinical benefit in the absence of any bleeding hazard
(hemorrhagic events: rosuvastatin 258, placebo 275, P=0.45)
Glynn et al NEJM 2009
4
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Electronic and “Human”
Prophylaxis Alerts
Implications for Cancer Patients
Randomization in ALERT Study
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VTE risk score > 4
No prophylaxis
N = 2,506
INTERVENTION:
Single alert
N = 1,255
Kucher N, et al. NEJM 2005;352:969-977
CONTROL
No computer alert
N = 1,251
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Primary End Point
%Freedom from DVT/ PE
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100
98
Intervention
96
94
Control
92
90
0
Number at risk
Intervention
1255
Control
1251
Kucher N, et al. NEJM 2005;352:969-977
30
60
Time (days)
977
976
900
893
90
853
839
Electronic Alerts
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Halve Rate of PE and Maintain Effectiveness
VTE Rate:
Pre-Alert 2005—3.3/1000
Post-Alert 2006—1.7/1000
Post-Alert 2007—1.7/1000
Thromb Haemost 2008; 100: 699-704
“Human” Physician Alert
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►
As we planned a multicenter randomized trial
applying the electronic alert strategy to a broad array
of hospitals across the U.S., we learned that
replication of our electronic alert was not feasible.
►
Therefore, we crafted a strategy that employed a
“human” rather than electronic alerting system.
►
The physician alert consisted of a direct page from a
hospital staff member to the Attending Physician.
►
The primary end point was reduction in symptomatic
VTE within 90 days of randomization.
Physician Alert: Results
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►
2493 patients (82% on Medical Services) from 25 study
sites were randomized to the intervention (n=1238) versus
the control group (n=1255).
►
Patients whose physicians were alerted were more than
twice as likely to receive VTE prophylaxis (46.0% versus
20.6%, p<0.0001).
►
The symptomatic VTE rate was lower in the intervention
group (2.7% versus 3.4%; hazard ratio, 0.79; 95%
confidence interval, 0.50 to 1.25), but the difference did
not achieve statistical significance.
►
Major bleeding at 30 days in the alert group was similar to
the control group.
Physician Alert: Results
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Freedom from Primary Endpoint
100%
98%
96%
Wilcoxon P-value: 0.307; Long-Rank P-value: 0.309
94%
92%
0
7
90%
Human Alert
14
21
28
35 42
49
No Alert
56
63
70
77
84
Time after initial enrollment (days)
Piazza G. Circulation 2009;119: 2196-2201
90
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Current Status of ASCO and
NCCN Guidelines for VTE
Prophylaxis in Cancer Patients
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ASCO Guidelines
Hospitalized Patients with Cancer
Role of VTE Prophylaxis
Evidence
Patients with cancer should be
considered candidates for VTE
prophylaxis with anticoagulants
(UFH, LMWH, or fondaparinux) in
the absence of bleeding or other
contraindications to anticoagulation
Multiple RCTs of hospitalized
medical patients with subgroups of
patients with cancer. The 8th ACCP
guidelines strongly recommend
(1A) prophylaxis with either lowdose heparin or LMWH for
bedridden patients with active
cancer.
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Ambulatory Patients with Cancer Without VTE
Receiving Systemic Chemotherapy
Role of VTE Prophylaxis
Evidence
Routine prophylaxis with an
antithrombotic agents is not
recommended except as noted below
Routine prophylaxis in ambulatory
patients receiving chemotherapy is not
recommended due to conflicting trials,
potential bleeding, the need for
laboratory monitoring and dose
adjustment, and the relatively low
incidence of VTE.
LMWH or adjusted dose warfarin (INR
~ 1.5) is recommended in myeloma
patients on thalidomide or
lenalidomide plus chemotherapy or
dexamethasone
This recommendation is based on
nonrandomized trial data and
extrapolation from studies of
postoperative prophylaxis in
orthopedic surgery and a trial of
adjusted-dose warfarin in breast
cancer
Patients with Cancer Undergoing Surgery
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Role of VTE Prophylaxis
Evidence
All patients undergoing major surgical
intervention for malignant disease
should be considered for
thromboprophylaxis with low- dose
UFH, LMWH, or fondaparinux starting
as early as possible for at least 7-10
days unless contraindicated.
RCTs of UFH and those comparing
the effects of LMWH and UFH on DVT
rates on patients with cancer indicate
broadly similar prophylactic efficacies
for these two agents
Mechanical methods may be added to
anticoagulation in very high risk
patients but should not be used alone
unless anticoagulation in
contraindicated.
A Cochrane review of 19 studies
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Patients with Cancer
Undergoing Surgery (continued)
Role of VTE Prophylaxis
Evidence
LMWH for up to 4 weeks may be
considered after major
abdominal/pelvic surgery with residual
malignant disease, obesity, and a
previous history of VTE
Recent RCTs suggest that prolonging
prophylaxis up to 4 weeks is more
effective than short-course
prophylaxis in reducing postoperative
VTE.
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Treatment of Patients with Established
VTE to Prevent Recurrence
Role of VTE Prophylaxis
LMWH is the preferred approach for the initial
5-10 days in cancer patient with established
VTE.
LMWH for at least 6 months is preferred for
long-term anticoagulant therapy. Vitamin K
antagonists with a targeted INR of 2-3 are
acceptable when LMWH is not available. The
CLOT study demonstrated a relative risk
reduction of 49% with LMWH vs. a vitamin K
antagonist. Dalteparin sodium approved by the
FDA for extended treatment of symptomatic
VTE to reduce the risk of recurrence of VTE in
patients with cancer (FDA 2007)
Evidence
LMWH for 3-6 months is
more effective than vitamin K
antagonists given for a
similar duration for
preventing recurrent VTE.
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Treatment of Patients with Established
VTE to Prevent Recurrence (continued)
Role of VTE Prophylaxis
Evidence
In the absence of clinical trials,
benefits and risks of continuing LMWH
Anticoagulation for an indefinite period
beyond 6 months is a clinical
should be considered for patients with
judgment in the individual patient.
active cancer (metastatic disease,
Caution is urged in elderly patients
continuing chemotherapy)
and those with intracranial
malignancy.
Inferior vena cava filters are reserved
for those with contraindications to
anticoagulation or PE despite
adequate long-term LMWH.
Consensus recommendations due to
lack of date in cancer-specific
populations
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Anticoagulants in the Absence of
Established VTE to Improve Survival
Role of VTE Prophylaxis
Anticoagulants are not currently
recommended to improve survival in
patients with cancer without VTE.
Evidence
RCTs and meta-analysis of warfarin,
UFH and LMWH have reported
encouraging but variable results
generally showing clinical benefit only
in subgroup analyses.
Summary of the Guidelines Updates
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Summary of Major Changes in the
1.2009 Version of the Venous
Thromboembolic Disease Guidelines
Changes in 2009 NCCN Guidelines
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►
Stage 1 Immediate:
“Stage 1 Immediate: Concomitant with diagnosis or while diagnosis
and risk assessment (heparin phase)” changed to “Stage 1
Immediate: At diagnosis or during diagnostic evaluation”
►
Low –molecular-weight-heparin: New footnote “6” was added that
states, “Although each of the low molecular weight heparins
(LMWH), have been studies in randomized control trials in cancer
patients, dalteparin’s efficacy in this population is supported by the
highest quality evidence and it is the only LMWH approved by the
FDA for this indication.”
►
Unfractionated heparin (IV): target aPTT range changed from “2.02.9 x control) to “2.0-2.5 x control…” (Also for VTE-H) in these
patients.
Changes in 2009 NCCN Guidelines
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Stage 3 Chronic:
► “Third bullet: “Consider indefinite anticoagulation….”
changed to “Recommend indefinite anticoagulation….”
► Fourth bullet: “For catheter associated thrombosis,
anticoagulate as long as catheter is in place and for at
least 3 months after catheter removal”.
Changes in 2009 NCCN Guidelines
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►
6Although
each of the low molecular weight heparins
(LMWH) have been studied in randomized controlled
trials in cancer patients, dalteparin’s efficacy in this
population is supported by the highest quality evidence
and is the only LMWH approved by the FDA for this
indication.
Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight
heparin versus a coumarin for the prevention of recurrent venous
thromboembolism on patients with cancer. New Eng J Med 2003;349(2):
146-153.
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(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
► The NCCN panel recommends VTE thromboprophylaxis for all
hospitalized patients with cancer who do not have
contraindications to such therapy, and the panel also
emphasized that an increased level of clinical suspicion of
VTE should be maintained for cancer patients. Following
hospital discharge, it is recommended that patients at high-risk
of VTE (e.g. cancer surgery patients) continue to receive VTE
prophylaxis for up to 4 weeks post-operation. Careful
evaluation and follow-up of cancer patients in whom VTE is
suspected and prompt treatment and follow-up for patients
diagnosed with VTE is recommended after the cancer status
of the patient is assessed and the risks and benefits of
treatment are considered.
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(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
Stage 1 Immediate: At diagnosis or during diagnostic
evaluation:
► Low-molecular-weight heparin (LMWH)
•
•
•
Dalteparin (200 units/kg subcutaneous daily)
Enoxaparin (1 mg/kg subcutaneous every 12 hours)
Tinzaparin (175 units/kg subcutaneous daily)
►
Fondaparinux (5 mg [<50 kg]; 7.5 mg [50-100 kg]; 10 mg [> 100 kg]
subcutaneous daily
► Unfractionated heparin (IV) (80 units/kg load, then 18
units/kg per hour, target aPTT of 2.0-2.5 x control or per
hospital SOP)
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(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
► Additional VTE risk factors for surgical oncology patients
with a previous episode of VTE include anesthesia times
longer than 2 hours, advanced stage disease, bed rest, >
4 days and patients age 60 years or older. Extended
prophylaxis out to 4 weeks post-surgery was associated
with a greater than 50% reduction in venographic VTE
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(VTE-D): Therapeutic Anticoagulation
Treatment for VenousThromboembolism
Stage 2 Acute: Short term, during transition to chronic
phase:
► LMWH (category 1) is preferred as monotherapy without
warfarin in patients with proximal DVT or PE and
prevention of recurrent VTE in patients with advanced or
metastatic cancer
► If UFH or factor Xa antagonist, transition to LMWH or
warfarin
► Warfarin (2.5-5 mg every day initially, subsequent dosing
based on INR value; target INR 2.0-3.0)
Therapeutic Anticoagulation Failure
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Therapeutic
INR
Patient
on
warfarin
Switch to heparin
(LMWH
preferred) or
fondaparinux
Check
INR
Subtherapeutic
INR
Increase warfarin
dose and treat with
parenteral agent until
INR target achieved
or consider switching
to heparin (LMWH
preferred) or
fondaparinux
Therapeutic Anticoagulation Failure
VTE and Cancer
Therapeutic
aPTT
Patient
on
heparin
Increase dose of heparin
or Switch to LMWH
or Switch to fondaparinux
and Consider placement
of IVC filter
and Consider HIT
Check
aPTT
levels
Subtherapeutic
aPTT
Increase dose of
heparin to reach
therapeutic level
Improving VTE Prophylaxis in Cancer
VTE and Cancer
► “Immunize”
cancer patients with LMWH
unless MD “opts out”—analogous to flu
vaccine or pneumonia vaccine
► Pay attention to the Continuum of Care
and to VTE risk at the time of Discharge—
Order discharge LMWH
► Withhold payments to hospitals when DVT/
PE develops after total hip or knee
replacement—Medicare began this
practice in October 2008
Conclusions
VTE and Cancer
1.
VTE prophylaxis has enjoyed a paradigm shift. Gone are
the days when the imperial physician reigned unchallenged
on VTE prophylaxis decisions. Hospitals and Medicare are
scrutinizing implementation of prophylaxis.
2.
Hospital-acquired VTE is not supposed to happen any
longer. Medicare is declaring some VTEs “Never Events”
and will not reimburse hospitals for additional treatment.
3.
Effective VTE prophylaxis in cancer patients usually
requires anticoagulation with LMWH but when bleeding risk
is too high, use mechanical measures.
4.
DVT prophylaxis in cancer patients is under-utilized and
requires increased vigilance and prophylaxis-focused
intervention
Conclusions
VTE and Cancer
5.
DVT prophylaxis following cancer surgery for four
weeks is recommended; longer periods may be
necessary depending on risk assessment
6. DVT prophylaxis following established DVT in cancer
for at least 6 months is recommended and for longer,
indefinite periods with active cancer and/or
chemotherapy.
7. Heart healthy lifestyle and statins reduce VTE risk
8. Electronic, computerized alerts can reduce symptomatic
VTE by at least 40%.
9. When “human” alerts are used, symptomatic VTE is
reduced by about 20%.
10. PE/ DVT patients with cancer warrant LMWH
monotherapy.