A Systematic Analysis of VTE Prophylaxis in the Setting of Cancer

1
Innovation ? Investigation ? Application

• A Systematic Analysis of VTE Prophylaxis in the
  Setting of Cancer
• Linking Science and Evidence to Clinical
  Practice
• What Do Trials Teach?

Program Chairman Craig Kessler, MD MACP Director,
Division of Coagulation Lombardi Comprehensive
Cancer Center Georgetown University Medical
Center Washington, DC
2
VTE and Cancer Epidemiology

• Of all cases of VTE
• About 20 occur in cancer patients
• Annual incidence of VTE in cancer patients
  1/250
• Of all cancer patients
• 15 will have symptomatic VTE
• As many as 50 have VTE at autopsy
• Compared to patients without cancer
• Higher risk of first and recurrent VTE
• Higher risk of bleeding on anticoagulants
• Higher risk of dying

Lee AY, Levine MN. Circulation. 200310723
Suppl 1I17-I21
3
DVT and PE in Cancer Facts, Findings, and
Natural History

• VTE is the second leading cause of death in
  hospitalized cancer patients1,2
• The risk of VTE in cancer patients undergoing
  surgery is 3- to 5-fold higher than those without
  cancer2
• Up to 50 of cancer patients may have evidence of
  asymptomatic DVT/PE3
• Cancer patients with symptomatic DVT exhibit a
  high risk for recurrent DVT/PE that persists for
  many years4

1. Ambrus JL et al. J Med. 1975661-64
2. Donati MB. Haemostasis. 199424128-131
3. Johnson MJ et al. Clin Lab Haem. 19992151-54
4. Prandoni P et al. Ann Intern Med. 19961251-7

4
Clinical Features of VTE in Cancer

• VTE has significant negative impact on quality of
  life
• VTE may be the presenting sign of occult
  malignancy
• 10 with idiopathic VTE develop cancer within 2
  years
• 20 have recurrent idiopathic VTE
• 25 have bilateral DVT

Bura et. al., J Thromb Haemost 20042445-51
5
Thrombosis and SurvivalLikelihood of Death After
Hospitalization
Levitan N, et al. Medicine 199978285
6
Incidence of VTE and Colon Cancer Stage
White RH et al. Thrombosis Research 120 Suppl. 2
(2007) S29-40
7
Symptomatic VTE in Cancer Reduces Survival
Counterintuitively, Magnitude of Effect on
Survival is Greatest with Local Stage Disease
Cancer type Hazard ratio (95 CI) for death within one year, cases with VTE diagnosed in year 1 vs. no VTE, by stage Hazard ratio (95 CI) for death within one year, cases with VTE diagnosed in year 1 vs. no VTE, by stage Hazard ratio (95 CI) for death within one year, cases with VTE diagnosed in year 1 vs. no VTE, by stage
Cancer type Local Regional Remote
Prostate 5.6 (3.8-8.5) 4.7 (1.9-11.5) 2.8 (1.5-5.0)
Breast 6.6 (3.7-11.8) 2.4 (1.3-4.5) 1.8 (1.1-2.9)
Lung 3.1 (2.1-4.5) 2.9 (2.3-3.5) 2.5 (2.3-2.7)
Colon/rectum 3.2 (1.8-5.5) 2.2 (1.7-3.0) 2.0 (1.7-2.4)
Melanoma 14.4 (4.6-45.2) N/A 2.8 (1.5-5.3)
Non-Hodgkins lymphoma 3.2 (1.9-5.3) 2.0 (1.3-3.2) 2.3 (1.7-3.1)
Uterus 7.0 (3.4-14.2) 9.1 (4.8-17.2) 1.7 (1.0-3.0)
Bladder 3.2 (1.7-6.2) 3.3 (1.7-6.4) 3.3 (1.8-6.2)
Pancreas 2.3 (1.2-4.6) 3.8 (2.8-5.1) 2.3 (1.9-2.7)
Stomach 2.4 (1.1-5.1) 1.5 (1.0-2.1) 1.8 (1.4-2.3)
Ovary 11.3 (2.5-51.7) 4.8 (1.1-20.4) 2.3 (1.7-3.0)
Kidney 3.2 (1.2-8.8) 1.4 (0.6-3.2) 1.3 (0.9-2.0)
plt0.05 plt0.01) plt0.001)
R.H. White et al. Thombosis Research 120 Suppl. 2
(2007) S29-S40
8
VTE Associated with Accelerated Death in Breast
Cancer Does Symptomatic VTE Reflect Presence or
Emergence of Metastatic, Aggressive Cancer?
White, et al. Thromb Res,120 suppl. 2 (2007)
9
Recurrent Ovarian Cancer
7 symptomatic VTE (2.8-6.1 in primary ovarian
Cancer) 78 of VTE in ROC occur within 2 months
of second line chemo regimen cisplatin-related
Ascites is the only independent risk factor for
VTE (HR2.2)
Fotopoulou C et al. Thromb Res 2009
10
Hospital Mortality With or Without VTE
Mortality ()
N66,016
N20,591
N17,360
Khorana, JCO, 2006
11
Thrombosis Risk In Cancer

• Primary Prophylaxis
• Medical Inpatients
• Surgery
• Radiotherapy
• Central Venous Catheters

12
Risk Factors for Cancer-Associated VTE

• Cancer
• Type
• Men prostate, colon, brain, lung
• Women breast, ovary, lung
• Stage
• Treatments
• Surgery
• 10-20 proximal DVT
• 4-10 clinically evident PE
• 0.2-5 fatal PE
• Chemotherapy
• Central venous catheters (4 generate clinically
  relevant VTE)
• Patient
• Prior VTE
• Comorbidities
• Genetic background

13
Medical Inpatients
Cancer and Thrombosis
14
Antithrombotic Therapy Choices
Pharmacologic (Prophylaxis Treatment)
Nonpharmacologic (Prophylaxis)
Low Molecular Weight Heparin (LMWH)
Intermittent Pneumatic Compression
Unfractionated Heparin (UH)
Elastic Stockings
Inferior Vena Cava Filter
Oral Anticoagulants
New Agents e.g. Fondaparinux,Direct anti-Xa
inhibitors,Direct anti-IIa, etc.?
15
Prophylaxis Studies in Medical Patients
Relative risk reduction 47
Relative risk reduction 63
Rate of VTE ()
Relative risk reduction 44
Placebo Enoxaparin MEDENOX Trial
Placebo Dalteparin PREVENT
Placebo Fondaparinux ARTEMIS
Francis, NEJM, 2007
16
ASCO Guidelines

• 1. SHOULD HOSPITALIZED PATIENTS WITH
• CANCER RECEIVE ANTICOAGULATION FOR
• VTE PROPHYLAXIS?
• Recommendation. Hospitalized patients with
  cancer should be considered candidates for VTE
  prophylaxis with anticoagulants in the absence of
  bleeding or other contraindications to
  anticoagulation.

Lyman GH et al. J Clin Oncol (25) 2007 34
5490-5505.
17
Surgical Patients
Cancer and Thrombosis
18
Incidence of VTE in Surgical Patients

• Cancer patients have 2-fold risk of
  post-operative DVT/PE and gt3-fold risk of fatal
  PE despite prophylaxis

No Cancer N16,954 Cancer N6124 P-value
Post-op VTE 0.61 1.26 lt0.0001
Non-fatal PE 0.27 0.54 lt0.0003
Autopsy PE 0.11 0.41 lt0.0001
Death 0.71 3.14 lt0.0001
Kakkar AK, et al. Thromb Haemost 2001 86 (suppl
1) OC1732
19
Natural History of VTE in Cancer Surgery The
_at_RISTOS Registry

• Web-Based Registry of Cancer Surgery
• Tracked 30-day incidence of VTE in 2373
  patients
• Type of surgery
• 52 General
• 29 Urological
• 19 Gynecologic
• 82 received in-hospital
  thromboprophylaxis
• 31 received post-discharge
  thromboprophylaxis
• Findings
• 2.1 incidence of clinically overt VTE (0.8
  fatal)
• Most events occur after hospital discharge
• Most common cause of 30-day post-op death

• Agnelli, Ann Surg 2006 243 89-95

20
Prophylaxis in Surgical Patients

• LMWH vs. UFH
• Abdominal or pelvic surgery for cancer (mostly
  colorectal)
• LMWH once daily vs. UFH tid for 710 days post-op
• DVT on venography at day 710 and symptomatic VTE

Study N Design Regimens
ENOXACAN 1 631 double-blind enoxaparin vs. UFH
Canadian Colorectal DVT Prophylaxis 2 475 double-blind enoxaparin vs. UFH
1. ENOXACAN Study Group. Br J Surg
1997841099103 2. McLeod R, et al. Ann Surg
2001233438-444
21
Prophylaxis in Surgical Patients
Canadian Colorectal DVT Prophylaxis Trial
16.9
P0.052
13.9
N234
Incidence of Outcome Event
N241
1.5 2.7
VTE Major Bleeding (Cancer)
(All)
McLeod R, et al. Ann Surg 2001233438-444
22
Extended Prophylaxis inSurgical Patients
12.0
ENOXACAN II
P0.02
Incidence of Outcome Event
N167
5.1
4.8
N165
3.6
1.8
NNT 14
0 0.4
0.6
VTE Prox Any Major
DVT Bleeding Bleeding
Bergqvist D, et al. (for the ENOXACAN II
investigators) N Engl J Med 2002346975-980
23
Major Abdominal Surgery FAME InvestigatorsDaltep
arin Extended

• A multicenter, prospective, assessor-blinded,
  open-label, randomized trial Dalteparin
  administered for 28 days after major abdominal
  surgery compared to 7 days of treatment
• RESULTS Cumulative incidence of VTE was reduced
  from 16.3 with short-term thromboprophylaxis
  (29/178 patients) to 7.3 after prolonged
  thromboprophylaxis (12/165) (relative risk
  reduction 55 95 confidence interval 15-76
  P0.012).
• CONCLUSIONS 4-week administration of dalteparin,
  5000 IU once daily, after major abdominal surgery
  significantly reduces the rate of VTE, without
  increasing the risk of bleeding, compared with 1
  week of thromboprophylaxis.

Rasmussen, J Thromb Haemost. 2006
Nov4(11)2384-90. Epub 2006 Aug 1.
24
ASCO Guidelines VTE Prophylaxis

• All patients undergoing major surgical
  intervention for malignant disease should be
  considered for prophylaxis.
• Patients undergoing laparotomy, laparoscopy, or
  thoracotomy lasting gt 30 min should receive
  pharmacologic prophylaxis.
• Prophylaxis should be continued at least 7 10
  days post-op. Prolonged prophylaxis for up to 4
  weeks may be considered in patients undergoing
  major surgery for cancer with high-risk features.

Lyman GH et al. J Clin Oncol (25) 2007 34
5490-5505.
25
Central Venous Catheters

• Thrombosis is a potential complication of central
  venous catheters, including these events
• Fibrin sheath formation
• Superficial phlebitis
• Ball-valve clot
• Deep vein thrombosis (DVT)

Geerts W, et al. Chest Jun 2008 381S453S
26
Prophylaxis for Venous Catheters

• Placebo-Controlled Trials

Study Regimen N CRT ()
Reichardt 2002 Dalteparin 5000 U daily placebo 285 140 11 (3.7) 5 (3.4)
Couban 2002 Warfarin 1mg daily placebo 130 125 6 (4.6) 5 (4.0)
ETHICS 2004 Enoxaparin 40 mg daily placebo 155 155 22 (14.2) 28 (18.1)
symptomatic outcomes routine venography at 6 weeks symptomatic outcomes routine venography at 6 weeks symptomatic outcomes routine venography at 6 weeks symptomatic outcomes routine venography at 6 weeks
Reichardt P, et al. Proc ASCO 200221369a
Couban S, et al, Blood 2002100703a Agnelli G,
et al. Proc ASCO 200423730
27
WARP Prophylactic Warfarin Does Not Reduce
Catheter-Associated Thrombosis in CA
Thrombotic Events Warfarin evaluation Warfarin evaluation Warfarin evaluation Dose evaluation Dose evaluation Dose evaluation
Thrombotic Events No warfarin (n404) Warfarin (n408) Relative risk (95 CI, p value) Fixed-dose warfarin (n471) Dose-adjusted warfarin (n473) Relative risk (95 CI, p value)
Catheter-related thrombotic events 24 (6) 24 (6) 0.99 (0.57-1.72, 0.98) 34 (7) 13 (3) 0.38 (0.20-0.71,0.002)
No catheter-related event 370 (92) 372 (91) - 433 (92) 448 (95) -
Not known 10 (2) 12 (3) 4 (lt1) 12 (3)
All thrombotic events 38 (9) 30 (7) 0.78 (0.50-1.24), 0.30 37 (8) 26 (6) 0.70 (0.43-1.14, 0.15)
Young AM et al. Lancet 2009373567
28
WARP Prophylactic Warfarin Does Not Reduce
Catheter-Associated Thrombosis in CA
Bleeding and Raised INR Warfarin evaluation Warfarin evaluation Warfarin evaluation Dose evaluation Dose evaluation Dose evaluation
Bleeding and Raised INR No warfarin (n404) Warfarin (n408) Relative risk (95 CI, p value) Fixed-dose warfarin (n471) Dose-adjusted warfarin (n473) Relative risk (95 CI, p value)
Major bleeding and no reported raised INR 1 (lt1) 3 (lt1) - 5 (1) 7 (1) -
Major bleeding and raised INR 0 4 (lt1) - 2 (lt1) 9 (2) -
Total major bleeding 1 (lt1) 7 (2) 6.93 (0.85-56.08, 0.07) 7 (1) 16 (3) 2.28 (0.95-5.48, 0.09)
Moderate and severe raised INR and no major bleeding 0 3 (lt1) - 1 (lt1) 12 (3) -
Minor bleeding 1 (lt1) 14 (3) - 21 (4) 24 (5) -
Young AM et al. Lancet 2009373567
29
WARP Prophylactic Warfarin Does Not Reduce
Catheter-Associated Thrombosis in CA
Combined thrombosis and major bleeding events Warfarin evaluation Warfarin evaluation Warfarin evaluation Dose evaluation Dose evaluation Dose evaluation
Combined thrombosis and major bleeding events No warfarin (n404) Warfarin (n408) Relative risk (95 CI, p value) Fixed-dose warfarin (n471) Dose-adjusted warfarin (n473) Relative risk (95 CI, p value)
Total catheter-related thrombosis and major bleeding events 25 (6) 31 (8) 1.23 (0.83-1.52, 0.51) 41 (9) 29 (6) 0.84 (0.74-2.04, 0.17)
All thrombotic and major bleeding events 39 (10) 37 (9) 0.94 (0.61-1.44, 0.87) 44 (9) 42 (9) 0.95 (0.64-1.42, 0.89)
Young AM et al. Lancet 2009373567
30
Central Venous Catheters Warfarin

• Tolerability of Low-Dose Warfarin
• 95 cancer patients receiving FU-based infusion
  chemotherapy and 1 mg warfarin daily
• INR measured at baseline and four time points
• 10 of all recorded INRs gt1.5
• Patients with elevated INR
• 2.02.9 6
• 3.04.9 19
• gt5.0 7

Masci et al. J Clin Oncol. 200321736-739
31
Influence of Thrombophilia on Thrombotic
Complications of CVADs in Cancer
In 10 studies involving more than 1250 cancer
patients with CVADs vs CA controls The
attributable risk of catheter associated
thrombosis conferred by
CA FVL OR5.18 (95 confidence
interval 3.0-8.8) CA G20210A OR3.95 (95
confidence interval 1.5-10.6)
FVL 13.5 G20210A 3.6
Dentali F et al. JTH 2007 5(Suppl 2)P-S-564
32
8th ACCP Consensus Guidelines
No routine prophylaxis to prevent thrombosis
secondary to central venous catheters, including
LMWH (2B) and fixed-dose warfarin (1B) Revised
2009 NCCN guidelines diverge from this philosophy

Chest Jun 2008 454S545S
33
Primary Prophylaxis in Cancer Radiotherapy The
Ambulatory Patient

• No recommendations from ACCP
• No data from randomized trials (RCTs)
• Weak data from observational studies in high risk
  tumors (e.g. brain tumors mucin-secreting
  adenocarcinomas Colorectal, pancreatic, lung,
  renal cell, ovarian)
• Recommendations extrapolated from other groups of
  patients if additional risk factors present
  (e.g., hemiparesis in brain tumors, etc.)

34
Risk Factors for VTE inMedical Oncology Patients

• Tumor type
• Ovary, brain, pancreas, lung, colon
• Stage, grade, and extent of cancer
• Metastatic disease, venous stasis due to bulky
  disease
• Type of antineoplastic treatment
• Multiagent regimens, hormones,anti-VEGF,
  radiation
• Miscellaneous VTE risk factors
• Previous VTE, hospitalization, immobility,
  infection, thrombophilia

35
Independent Risk Factors for DVT/PE
Risk Factor/Characteristic O.R.
Recent surgery with institutionalization 21.72
Trauma 12.69
Institutionalization without recent surgery 7.98
Malignancy with chemotherapy 6.53
Prior CVAD or pacemaker 5.55
Prior superficial vein thrombosis 4.32
Malignancy without chemotherapy 4.05
Neurologic disease w/ extremity paresis 3.04
Serious liver disease 0.10
Heit JA et al. Thromb Haemost. 200186452-463
36
VTE Incidence In Various Tumors
Oncology Setting VTE Incidence
Breast cancer (Stage I II) w/o further treatment 0.2
Breast cancer (Stage I II) w/ chemo 2
Breast cancer (Stage IV) w/ chemo 8
Non-Hodgkins lymphomas w/ chemo 3
Hodgkins disease w/ chemo 6
Advanced cancer (1-year survival12) 9
High-grade glioma 26
Multiple myeloma (thalidomide chemo) 28
Renal cell carcinoma 43
Solid tumors (anti-VEGF chemo) 47
Wilms tumor (cavoatrial extension) 4
Otten, et al. Haemostasis 20003072. Lee
Levine. Circulation 2003107I17
37
Primary VTE Prophylaxis

• Recommended for hospitalized cancer patients
• Not universally recommended for outpatients, but
  there are exceptions
• New data for certain agents
• Heterogeneous population

Need for risk stratification
38
VTE Risk with Bevacizumab in Colorectal Cancer
Approaches Risk of Antiangiogenesis in Myeloma
All-Grade Venous Thromboembolism, No./Total No. All-Grade Venous Thromboembolism, No./Total No.
Tumor Type No. of Studies Bevacizumab Control Incidence (95 CI), RR (95 CI)
Overall 6 155/1196 107/1083 11.9 (6.8-19.9) 1.29 (1.03-1.63)
Colorectal cancer 3 108/564 85/532 19.1 (16.1-22.6) 1.19 (0.92-1.55)
NSCLC 1 10/66 3/32 14.9 (8.2-25.5) 1.59 (0.47-5.37)
Breast cancer 1 17/229 12/215 7.3 (4.6-11.5) 1.30 (0.64-2.67)
Renal cell carcinoma 1 20/337 6/304 3.0 (1.6-5.5) 3.00 (1.23-7.33)
Naluri SR et al. JAMA. 20083002277
39
Bevacizumab Increases Risk of Symptomatic VTE by
33 vs Controls
Naluri SR et al. JAMA. 20083002277
40
Incidence of VTE USA and Canada Greater than
Israel, Australia, and Europe

• rEPO used more in USA and Canada
• LDex 23 VTE with EPO vs 5 w/o EPO
• Placebo Dex 7 VTE with EPO vs 1 without EPO

Multivariate Analysis of the Risk of Thrombosis
Associated with Lenalidomide plus High-Dose
Dexamethasone and Concomitant Erythropoietin for
the Treatment of Multiple Myeloma
Treatment Odds Ratio P Value (95
CI) Lenalidomide plus 3.51 (1.77-6.97) lt0.001 Hig
h-dose dexamethasone Concomitant erythropoietin
3.21 (1.72-6.01) lt0.001
Knight N Engl J Med.2006,3542079
41
Oral Anticoagulant Therapyin Cancer Patients
Problematic

• Warfarin therapy is complicated by
• Difficulty maintaining tight therapeutic control,
  due to anorexia, vomiting, drug interactions,
  etc.
• Frequent interruptions for thrombocytopenia and
  procedures
• Difficulty in venous access for monitoring
• Increased risk of both recurrence and bleeding
• Is it reasonable to substitute long-term LMWH for
  warfarin ? When? How? Why?

42
CLOT Landmark Cancer/VTE Trial
Dalteparin
Dalteparin
CANCER PATIENTS WITH ACUTE DVT or PE
Randomization
Dalteparin
Oral Anticoagulant
N 677

• Primary Endpoints Recurrent VTE and Bleeding
• Secondary Endpoint Survival

Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,
2003349146
43
Landmark CLOT Cancer Trial Reduction in Recurrent
VTE
Recurrent VTE

• Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,
  2003349146

44
Bleeding Events in CLOT
Dalteparin N338 OAC N335 P-value
Major bleed 19 ( 5.6) 12 ( 3.6) 0.27
Any bleed 46 (13.6) 62 (18.5) 0.093
Fishers exact test

• Lee, Levine, Kakkar, Rickles et.al. N Engl J Med,
  2003349146

45
Treatment of Cancer-Associated VTE
Study Design Length of Therapy (Months) N Recurrent VTE () Major Bleeding () Death ()
CLOT Trial (Lee 2003) Dalteparin OAC 6 336 336 9 17 6 4 39 41
CANTHENOX (Meyer 2002) Enoxaparin OAC 3 67 71 11 21 7 16 11 23
LITE (Hull ISTH 2003) Tinzaparin OAC 3 80 87 6 11 6 8 23 22
ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC 6 32 36 34 3.4 3.1 6.7
NS
NS
0.002
0.09
0.09
0.03
NS
0.03
NS
NR
NS
NS
46
Treatment and 2 Prevention of VTE in Cancer
Bottom Line
New Development

• New standard of care is LMWH at therapeutic doses
  for a minimum of 3-6 months (Grade 1A
  recommendationACCP)
• NOTE Dalteparin is only LMWH approved (May,
  2007) for both the treatment and secondary
  prevention of VTE in cancer (NCCN preferred
  agent)
• Oral anticoagulant therapy to follow for as long
  as cancer is active (Grade 1C recommendationACCP)

Chest Jun 2008 454S545S
47
CLOT 12-month Mortality All Patients
Lee AY et al. J Clin Oncol. 2005 232123-9.
48
Anti-Tumor Effects of LMWH CLOT 12-month Mortality
Patients Without Metastases (N150)
Dalteparin
OAC
Probability of Survival,
HR 0.50 P-value 0.03
0
30
60
90
120
150
180
240
300
360
Days Post Randomization
Lee AY et al. J Clin Oncol. 2005 232123-9.
49
LMWH Influences Survival of Patients with
Advanced Solid Tumor Malignancies
6 wks LMWH immediately post diagnosis of CA-no
initial chemo
gt6 mos anticipated survival
lt6 mos anticipated survival

• Klerk, C. P.W. et al. J Clin Oncol 232130-2135
  2005

50
LMWH for Small Cell Lung CancerTurkish Study

• 84 patients randomized Chemo /- LMWH (18 weeks)
• Patients balanced for age, gender, stage, smoking
  history, ECOG performance status

Chemotherapyplus Dalteparin Chemo alone P-value
1-y overall survival, 51.3 29.5 0.01
2-y overall survival, 17.2 0.0 0.01
Median survival, m 13.0 8.0 0.01
CEV cyclophosphamide, epirubicin, vincristine
LMWH Dalteparin, 5000 units daily
Altinbas et al. J Thromb Haemost 200421266.
51
VTE Prophylaxis Is Underused in Patients With
Cancer
Cancer FRONTLINE Survey1 3891 Clinician
Respondents
Major Surgery2
Cancer Surgical
Major Abdominothoracic Surgery (Elderly)3
Confirmed DVT (Inpatients)5
Rate of Appropriate Prophylaxis,
Medical Inpatients4
Cancer Medical
1. Kakkar AK et al. Oncologist.
20038381-388 2. Stratton MA et al. Arch Intern
Med. 2000160334-340 3. Bratzler DW et al. Arch
Intern Med. 19981581909-1912
4. Rahim SA et al. Thromb Res. 2003111215-219 5.
Goldhaber SZ et al. Am J Cardiol. 200493259-262
52
Conclusions and Summary

• Risk factors for VTE in the setting of cancer
  have been well characterized solid tumors,
  chemotherapy, surgery, thrombocytopenia
• Long-term secondary prevention with LMWH has been
  shown to produce better outcomes than warfarin
• Guidelines and landmark trials support
  administration of LMWH in at risk patients
• Cancer patients are under-prophylaxed for VTE
• Health system pharmacists can play a pivotal role
  in improving clinical outcomes in this patient
  population