A Year 2009 Update for
The Health System Pharmacist
The Pharmacologic Foundations of DVT
Prophylaxis in the Setting of Cancer
Program Co-Chairs
Samuel Z. Goldhaber, MD
Edith Nutescu, PharmD, FCCP
Clinical Associate Professor
Pharmacy Practice
Affiliate Faculty, Center for
Pharmacoeconomic Research
Director, Antithrombosis Center
The University of Illinois at Chicago
College of Pharmacy & Medical Center
Chicago, IL
Professor of Medicine
Harvard Medical School
Cardiovascular Division
Director, Venous Thromboembolism
Research Group
Brigham and Women’s Hospital
Boston, MA
Welcome and Program Overview
Jointly sponsored by the University of Florida College of Pharmacy and
CMEducation Resources, LLC.
Jointly sponsored by the University of Massachusetts Medical Center,
office of CME and CMEducation Resources, LLC
Commercial Support: Sponsored by an independent educational grant
from Eisai, Inc.
Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies
COI: Full faculty disclosures provided in syllabus and at the beginning
of the program
CEU Credit Designation Statement
The University of Florida College of Pharmacy is
accredited by the Accreditation Council for Pharmacy
Education as a provider of continuing pharmacy
education.
The University of Florida College of Pharmacy will mail
the Statements of Continuing Pharmacy Education
Credit within 4 weeks after the course.
To receive credit you must attend the sessions for
which you want credit and complete an evaluation form.
The College of Pharmacy will award 2 (two) continuing
pharmacy education credits (2.0 CEU’s) upon
completion of this program.
Program Educational Objectives
As a result of this session, attendees will be able to:
► List the recent trials, research, and expert analysis of issues focused on
thrombosis and cancer.
► Outline specific strategies for risk-directed prophylaxis against DVT in
at-risk patients with cancer.
► Describe dose anticoagulation therapy for patients requiring prophylaxis
in special patient populations.
► Outline steps for avoiding medication errors using anticoagulation in
cancer patients at risk for DVT.
► List the guidelines for DVT prophylaxis in cancer issued by the National
Comprehensive Cancer Network (NCCN), the American College of
Chest Physicians (ACCP), and the Surgeon General’s Report.
Program Faculty
Program Co-Chairs
Edith Nutescu, PharmD, FCCP
Distinguished Experts and Presenters
John Fanikos, RPh, MBA
Clinical Associate Professor, Pharmacy Practice
Affiliate Faculty, Center for Pharmacoeconomic
Research
Director, Antithrombosis Center
The University of Illinois at Chicago
College of Pharmacy & Medical Center
Chicago, IL
Assistant Director of Pharmacy
Brigham and Women’s Hospital
Assistant Clinical Professor of Pharmacy
Northeastern University
Massachusetts College of Pharmacy
Boston, MA
Karen Fiumara, PharmD
Samuel Z. Goldhaber, MD
Professor of Medicine
Harvard Medical School
Cardiovascular Division
Director, Venous Thromboembolism Research
Group
Brigham and Women’s Hospital
Boston, MA
Medication Safety Officer
Brigham and Women’s Hospital
Adjunct Assistant Professor of Pharmacy Practice
Massachusetts College of Pharmacy and Allied
Health Sciences
Adjunct Assistant Professor of Pharmacy Practice
Bouve’ College of Health Sciences Northeastern
University
Boston, MA
Faculty COI Financial Disclosures
Samuel Z. Goldhaber, MD
Grant/Research Support: AstraZeneca; Boehringer-Ingelheim; Eisai; GSK;
sanofi-aventis;
Consultant: Boehringer-Ingelheim; BMS; Eisai; Merck; Pfizer; sanofi-aventis
Edith Nutescu, PharmD
Speakers Bureau: Eisai Inc., GlaxoSmithKline, sanofi-aventis U.S.
Advisory Committees or Review Panels, Board Membership, etc.: Boehringer
Ingelheim Pharmaceuticals, Inc., Scios Inc.
Karen Fiumara, PharmD
Nothing to disclose
John Fanikos, RPh, MBA
Speakers Bureau and Consulting: Abbott Laboratories, Astra-Zeneca, Eisai
Pharmaceuticals, Genentech, GlaxoSmithKline, sanofi-aventis, The Medicines
Company
A Year 2009 Update for
The Health System Pharmacist
Cancer and Prevention of VTE
Landmark Advances and New Paradigms of Care
for the Health System Pharmacist
Program Co-Chair
Samuel Z. Goldhaber, MD
Professor of Medicine
Harvard Medical School
Cardiovascular Division
Director, Venous Thromboembolism Research Group
Brigham and Women’s Hospital
Boston, MA
VTE and Cancer—A Looming
National Healthcare Crisis
MISSION AND CHALLENGES
Recognizing cancer patients at risk for DVT and identifying
appropriate candidates for long-term prophylaxis and/or
treatment with approved and indicated therapies are
among the most important challenges encountered in
contemporary pharmacy and clinical practice.
Comorbidity Connection
COMORBIDITY
CONNECTION
SUBSPECIALIST
STAKEHOLDERS
CAP
UTI
Cancer
Heart Failure
ABE/COPD
Respiratory Failure
Myeloproliferative Disorder
Thrombophilia
Surgery
History of DVT
Other
Infectious diseases
Oncology
PHARMACISTS
Cardiology
Pulmonary medicine
Hematology
Oncology/hematology
Interventional Radiology
Hospitalist
Surgeons
EM
PCP
Epidemiology of First-Time VTE
Variable
Finding
Seasonal Variation
Possibly more common in winter and less
common in summer
Risk Factors
25% to 50% “idiopathic”
15%-25% associated with cancer
20% following surgery (3 months)
Recurrent VTE
6-month incidence, 7%;
Higher rate in patients with cancer
Recurrent PE more likely after PE than
after DVT
Death After Treated VTE
30-day incidence 6% after incident DVT
30-day incidence 12% after PE
Death strongly associated with cancer,
age, and cardiovascular disease
White R. Circulation. 2003;107:I-4 –I-8.)
Epidemiology of VTE
► One major risk factor for VTE is ethnicity, with a
significantly higher incidence among Caucasians
and African Americans than among Hispanic
persons and Asian-Pacific Islanders.
► Overall, about 25% to 50% of patient with first-time
VTE have an idiopathic condition, without a readily
identifiable risk factor.
► Early mortality after VTE is strongly associated with
presentation as PE, advanced age, cancer, and
underlying cardiovascular disease.
White R. Circulation. 2003;107:I-4 –I-8.)
Comorbidity Connection
Overview
Comorbidity
Connection
Acute Medical Illness and VTE
Multivariate Logistic Regression Model
for Definite Venous Thromboembolism (VTE)
Risk Factor
Odds Ratio
(95% CI)
X2
Age > 75 years
Cancer
Previous VTE
1.03 (1.00-1.06)
1.62 (0.93-2.75)
2.06 (1.10-3.69)
0.0001
0.08
0.02
Acute infectious
disease
1.74 (1.12-2.75)
0.02
Alikhan R, Cohen A, et al. Arch Intern Med. 2004;164:963-968
Comorbid Condition and DVT Risk
► Hospitalization for surgery (24%) and for medical illness
(22%) accounted for a similar proportion of the cases, while
nursing home residence accounted for 13%.
► The individual attributable risk estimates for malignant
neoplasm, trauma, congestive heart failure, central venous
catheter or pacemaker placement, neurological disease with
extremity paresis, and superficial vein thrombosis were 18%,
12%, 10%, 9%, 7%, and 5%, respectively.
► Together, the 8 risk factors accounted for 74% of disease
occurrence
Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Arch Intern
Med. 2002 Jun 10;162(11):1245-8. Relative impact of risk factors for deep vein thrombosis and pulmonary
embolism: a population-based study
VTE Recurrence
Predictors of First Overall VTE Recurrence
Baseline Characteristic
Hazard Ratio
(95% CI)
Age
1.17 (1.11-1.24)
Body Mass Index
1.24 (1.04-1.7)
Neurologic disease with extremity
paresis
1.87 (1.28-2.73)
Malignant neoplasm
With chemotherapy
Without chemotherapy
Heit J, Mohr D, et al. Arch Intern Med. 2000;160:761-768
4.24 (2.58-6.95)
2.21 (1.60-3.06)
ICOPER Cumulative Mortality
25
17.5%
Mortality (%)
20
15
10
5
0
7
14
30
60
Days From Diagnosis
Lancet 1999;353:1386-1389
90
Stages of Chronic Venous Insufficiency
1.
Varicose veins
2.
Ankle/ leg edema
3.
Stasis dermatitis
4.
Lipodermatosclerosis
5.
Venous stasis ulcer
Progression of Chronic Venous Insufficiency
From UpToDate 2006
Rising VTE Incidence in
Hospitalized Patients
Stein PD et al. Am J Cardiol 2005; 95: 1525-1526
DVT Registry (N=5,451):
Top 5 Medical Comorbidities
1. Hypertension
2. Immobility
3. Cancer
4. Obesity (BMI > 30)
5. Cigarette Smoking
Am J Cardiol 2004; 93: 259-262
Implementation
Implementation of VTE prophylaxis
continues to be problematic, despite
detailed North American and European
Consensus guidelines.
SURGEON
GENERAL:
CALL TO
ACTION TO
PREVENT DVT
AND PE
September 15, 2008
Surgeon General’s Call to Action
42-Page Document
►
Issued September 15, 2008
►
Endorsed by Secretary, HHS
►
Endorsed by Director, NHLBI
►
Foreword by Acting Surgeon General, Steven K.
Galson, MD, MPH (RADM, U.S. Public Health
Service)
Call to Action for VTE
Foreword
►
Dr. Galson’s 1st Call To Action
►
> 350,000-600,000 Americans suffer VTE
annually
►
> 100,000 U.S. deaths per year
►
Negative impact on QOL of survivors
►
“Must disseminate info widely” to “address gap”
because we’re not applying knowledge
systematically
Call to Action for VTE
I.
Major Public Health Problem
II.
Reducing VTE Risk
III.
Gaps in Application, Awareness of
Evidence
IV.
Public Health Response
V.
Catalyst for Action
Symposium Themes
1.
Cancer rates are increasing as heart
disease Rx improves and as cancer Rx
improves.
2.
Cancer increases VTE risk.
3.
VTE is preventable (immunize!)
4.
VTE prophylaxis may slow cancer
5.
Increased emphasis on prophylaxis: OSG,
NCCN, ASCO, ACCP, NATF
6.
Facilitate prophylaxis with alerts.
A Year 2009 Update for
The Health System Pharmacist
Cancer and Prevention of VTE
Landmark Advances and New Paradigms of Care
for the Health System Pharmacist
Edith Nutescu, PharmD, FCCP
Clinical Associate Professor
Pharmacy Practice
Affiliate Faculty, Center for
Pharmacoeconomic Research
Director, Antithrombosis Center
The University of Illinois at Chicago
College of Pharmacy & Medical Center
Chicago, IL
Peculiar Relationship
Between Cancer and Thrombosis
Hypercoagulation/
thrombosis
may indicate
Occult Cancer
may cause
Cancer
Hypercoagulation/
thrombosis
Thromboembolism in Malignancy
1.
2.
3.
4.
►
15% of cancer patients develop venous or arterial
thrombosis1
►
Annual incidence of VTE in all patients: 117 in 100,0002
►
Cancer increases risk of thrombosis 4.1-fold3
►
Chemotherapy increases risk of thrombosis 6.5-fold3
►
Annual incidence of VTE in patients with cancer: 1 in 2004
Green KB, Silverstein RL. Hematol Oncol Clin North Am. 1996;10:499-530.
Silverstein MD et al. Arch Intern Med. 1998;158:585-593
Heit JA et al. Arch Intern Med. 2000;160:809-815
Lee AYY, Levine MN. Circulation. 2003;107(23 Suppl 1):I17-21.
Factors That May Affect Risk for
Cancer-Associated VTE
Patient-related factors
Treatment-related factors
►
Older age
►
Recent surgery
►
Comorbidities
►
Hospitalization
►
Chemotherapy
►
Hormonal therapy
Cancer-related factors
►
Antiangiogenic agents
► Site of cancer
► Advanced stage
► Initial period after diagnosis
►
Erythropoiesis-stimulating agents
Biological factors (biomarkers)
► Elevated pre-chemotherapy platelet
count
► D-dimer
► Tissue factor expression by tumor
cells
Rao MV, et al., In Khorana AA, Francis CW, eds. 2007
Risk of Inpatient VTE by
Type of Cancer
Rate of VTE, %
14
n=3550 n=68 n=326 n=43
n=51
n=55 n=127 n=95
12.10
12
9.50
10
8
6
n=53
8.96
7.00
7.41
6.75
7.64
5.37
4
2
0
In hospitalized neutropenic cancer patients
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
6.50
Risk of Inpatient VTE by
Type of Cancer
7
Rate of VTE, %
6
N=3550
n=641
n=79
n=262
n=204
5.79
5.37
5
n=650
5.01
4.39
3.87
4
3.93
3
2
1
0
All
Leukemia
NHL
Hodgkin’s
Myeloma
In hospitalized neutropenic cancer patients
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
Breast
Patients With Cancer Represent
About 20% of All DVT and PE
Patients with cancer:
approximately 19.8%
All DVT and PE
Heit JA. et al. Arch Intern Med 2002;162:1245-1248.
VTE, Cancer, and Survival
N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer
1.00
Probability of
Death
DVT/PE and Malignant Disease
0.80
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0
20
Levitan N, et al. Medicine 1999;78:285
40
60
80 100 120
Number of Days
140 160
180
VTE and Inpatient Mortality
Mortality, %
No Venous Thromboembolism
20
18
16
14
12
10
8
6
4
2
0
Venous Thromboembolism
16.13
14.85
10.59
7.98
All
(n=66,016)
Nonmetastatic
Cancer
(n=20,591)
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
16.41
8.67
Metastatic
Cancer
(n=17,360)
Prophylaxis Rates in Hospitalized Patients
Amin A et al. J Thromb Haemost. 2007; 5:1610-6.
Patients Receiving
Appropriate DVT Prophylaxis,
%
Thromboprophylaxis Is Underutilized
in Non-surgical Patients With Cancer
Premiere Perspective™ database: 72,391
discharges from 225 hospitals between
January 2002 and September 2005
Amin AN et al. J Clin Oncol. 2007;25 (suppl):Abstract 9047.
Clots and Cancer—A Looming
National Healthcare Crisis
MISSION AND CHALLENGES
Recognizing cancer patients at risk for DVT and
identifying patients who are appropriate
candidates for long-term prophylaxis and/or
treatment with approved and indicated therapies
are among the most important and difficult
challenges encountered in contemporary
pharmacy and clinical practice.
Clotting, Cancer, and Controversies
A Systematic Analysis of VTE Prophylaxis
in the Setting of Cancer
Linking Science and Evidence to Clinical Practice—What Do
Trials Teach the Health System Pharmacist?
Program Co-Chairman
Samuel Z. Goldhaber, MD
Professor of Medicine
Harvard Medical School
Cardiovascular Division
Director, Venous Thromboembolism Research Group
Brigham and Women’s Hospital
Boston, MA
VTE and Cancer: Epidemiology
►
Of all cases of VTE:
●
●
►
Of all cancer patients:
●
●
►
About 20% occur in cancer patients
Annual incidence of VTE in cancer
patients ≈ 1/250
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. 2003;107:23 Suppl 1:I17-I21
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 3to 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. 1975;6:61-64
2. Donati MB. Haemostasis. 1994;24:128-131
3. Johnson MJ et al. Clin Lab Haem. 1999;21:51-54
4. Prandoni P et al. Ann Intern Med. 1996;125:1-7
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 2004;2:445-51
Thrombosis and Survival
Likelihood of Death After Hospitalization
1.00
Probability of
Death
DVT/PE and Malignant Disease
0.80
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0
20 40
60
80 100 120140 160 180
Number of Days
Levitan N, et al. Medicine 1999;78:285
Mortality (%)
Hospital Mortality With or Without VTE
N=66,016
Khorana, JCO, 2006
N=20,591
N=17,360
Rate of VTE (%)
Trends in VTE in Hospitalized Cancer Patients
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
P<0.0001
1995
1996
1997
VTE- patients on chemotherapy
Khorana AA et al. Cancer. 2007.
1998
1999
2000
2001
VTE-all patients
PE-all patients
2002
2003
DVT-all patients
Thrombosis Risk In Cancer
Primary Prophylaxis
►
Medical Inpatients
►
Surgery
►
Radiotherapy
►
Central Venous Catheters
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
VTE Risk And Cancer Type
“Solid And Liquid Malignancies”
Relative Risk of VTE Ranged From 1.02 to 4.34
Relative Risk of VTE in
Cancer Patients
4.5
4
3.5
3
2.5
2
1.5
1
Stein PD, et al. Am J Med 2006; 119: 60-68
Bladder
Cervix
Breast
Leukemia
Liver
Ovary
Colon
Kidney
Rectal
Prostate
Esophagus
Lung
Uterus
Lymphoma
Stomach
Myeloprol
Brain
Pancreas
0.5
Cancer and Thrombosis
Medical Inpatients
Thromboembolism in Hospitalized
Neutropenic Cancer Patients
►Retrospective cohort study of
discharges using the University Health
System Consortium
►66,106 adult neutropenic cancer
patients between 1995 and 2002 at
115 centers
Khorana, JCO, 2006
Neutropenic Patients: Results
►8% had thrombosis
►5.4% venous and 1.5% arterial in 1st hospitalization
►Predictors of thrombosis
●
●
●
Age over 55
Site (lung, GI, gynecologic, brain)
Comorbidities (infection, pulmonary and renal
disease, obesity)
Khorana, JCO, 2006
Predictors of VTE in
Hospitalized Cancer Patients
Characteristic
OR
P Value
Site of Cancer
Lung
Stomach
Pancreas
Endometrium/cervix
Brain
1.3
1.6
2.8
2
2.2
<0.001
0.0035
<0.001
<0.001
<0.001
Age 65 y
1.1
0.005
Arterial thromboembolism
1.4
0.008
Comorbidities (lung/renal disease,
infection, obesity)
1.3-1.6
<0.001
Khorana AA et al. J Clin Oncol. 2006;24:484-490.
Antithrombotic Therapy: Choices
Nonpharmacologic
(Prophylaxis)
Intermittent
Pneumatic
Compression
Elastic
Stockings
Inferior
Vena Cava
Filter
Pharmacologic
(Prophylaxis & Treatment)
Unfractionated
Heparin (UH)
Low Molecular
Weight
Heparin
(LMWH)
Oral
Anticoagulants
New Agents: e.g.
Fondaparinux,
Direct anti-Xa inhibitors,
Direct anti-IIa, etc.?
Rate of VTE (%)
Prophylaxis Studies in Medical Patients
Relative
risk
reduction
63%
Relative
risk
reduction
44%
Placebo Enoxaparin Placebo Dalteparin
MEDENOX Trial
Francis, NEJM, 2007
PREVENT
Relative
risk
reduction
47%
Placebo Fondaparinux
ARTEMIS
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.
Cancer and Thrombosis
Surgical Patients
Incidence of VTE in Surgical Patients
►
Cancer patients have 2-fold risk of post-operative DVT/PE
and >3-fold risk of fatal PE despite prophylaxis:
No Cancer
Cancer
N=16,954
N=6124
Post-op VTE
0.61%
1.26%
<0.0001
Non-fatal PE
0.27%
0.54%
<0.0003
Autopsy PE
0.11%
0.41%
<0.0001
Death
0.71%
3.14%
<0.0001
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
P-value
Natural History of VTE in Cancer Surgery:
The @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
Prophylaxis in Surgical Patients
LMWH vs. UFH
►
Abdominal or pelvic surgery for cancer (mostly colorectal)
►
LMWH once daily vs. UFH tid for 7–10 days post-op
►
DVT on venography at day 7–10 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 1997;84:1099–103
2. McLeod R, et al. Ann Surg 2001;233:438-444
Prophylaxis in Surgical Patients
Incidence of Outcome Event
16.9%
P=0.052
13.9%
Canadian
Colorectal DVT
Prophylaxis Trial
N=234
N=241
1.5% 2.7%
VTE
(Cancer)
McLeod R, et al. Ann Surg 2001;233:438-444
Major Bleeding
(All)
Incidence of Outcome Event
Extended Prophylaxis in
Surgical Patients
12.0%
ENOXACAN II
P=0.02
N=167
5.1%
4.8%
N=165
3.6%
1.8%
0.6%
VTE
Prox
DVT
0% 0.4%
NNT = 14
Any
Major
Bleeding Bleeding
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
Major Abdominal Surgery: FAME
Investigators—Dalteparin 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; P=0.012).
►
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 Nov;4(11):2384-90. Epub 2006 Aug 1.
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 > 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.
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: 381S–453S
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
Reichardt P, et al. Proc ASCO 2002;21:369a; Couban S, et al, Blood 2002;100:703a; Agnelli G, et
al. Proc ASCO 2004;23:730
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 >1.5
►
Patients with elevated INR
2.0–2.9
6%
3.0–4.9
19%
>5.0
7%
Masci et al. J Clin Oncol. 2003;21:736-739
Prophylaxis for Central Venous
Access Devices
Summary
►
Recent studies demonstrate a low
incidence of symptomatic catheter-related
thrombosis (~4%)
►
Routine prophylaxis is not warranted to
prevent catheter-related thrombosis, but
catheter patency rates/infections have not
been studied
►
Low-dose LMWH and fixed-dose warfarin
have not been shown to be effective for
preventing symptomatic and asymptomatic
thrombosis
8th ACCP Consensus Guidelines
No routine prophylaxis to prevent
thrombosis secondary to central
venous catheters, including LMWH
(2B) and fixed-dose warfarin (1B)
Chest Jun 2008: 454S–545S
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; mucinsecreting 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.)
Cancer and Thrombosis
Ambulatory Chemotherapy
Patients
Risk Factors for VTE in
Medical Oncology Patients
► Tumor
●
Ovary, brain, pancreas, lung, colon
► Stage,
●
►
grade, and extent of cancer
Metastatic disease, venous stasis due to
bulky disease
Type of antineoplastic treatment
●
►
type
Multiagent regimens, hormones,
anti-VEGF, radiation
Miscellaneous VTE risk factors
●
Previous VTE, hospitalization, immobility,
infection, thrombophilia
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. 2001;86:452-463
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-Hodgkin’s lymphomas w/ chemo
3%
Hodgkin’s disease w/ chemo
6%
Advanced cancer (1-year survival=12%)
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 2000;30:72. Lee & Levine. Circulation 2003;107:I17
Primary VTE Prophylaxis
►Recommended for hospitalized
cancer patients
►Not recommended or generally used
for outpatients
●
●
Very little data
Heterogeneous
Need for risk stratification
Ambulatory Cancer plus Chemotherapy
Study Methods
► Prospective observational study of
ambulatory cancer patients initiating a new
chemotherapy regimen, and followed for a
maximum of 4 cycles
► 115 U.S. centers participated
► Patients enrolled between March, 2002 and
August, 2004 who had completed at least
one cycle of chemotherapy were included in
this analysis
Khorana, Cancer, 2005
Ambulatory Cancer plus Chemotherapy
Study Methods
► VTE events were recorded during mid-cycle or new-cycle
visits
► Symptomatic VTE was a clinical diagnosis made by the
treating clinician
► Statistical analysis
●
●
Odds ratios to estimate relative risk
Multivariate logistic regression to adjust for other risk factors
Khorana, Cancer, 2005
Incidence of VTE
Rate of VTE (%)
3.0%
2.5%
2.0%
1.5%
1.0%
0.5%
0.0%
Baseline
Cycle 1
Cycle 2
Cycle 3
VTE / 2.4 months
VTE/month
VTE /cycle
Cumulative rate
(95% CI)
1.93%
0.8%
0.7%
2.2% (1.7-2.8)
Khorana, Cancer, 2005
VTE (%) / 2.4 months
Risk Factors: Site of Cancer
12
10
8
6
4
2
0
Site of Cancer
Khorana, Cancer, 2005
Incidence of Venous Thromboembolism By
Quartiles of Pre-chemotherapy Platelet Count
Incidence Of VTE Over 2.4
Months(%)
5.0%
p for trend=0.005
4.5%
4.0%
3.5%
3.0%
2.5%
2.0%
1.5%
1.0%
0.5%
0.0%
<217
217-270
270-337
Pre-chemotherapy Platelet Count/mm
Khorana, Cancer, 2005
>337
3 (x1000)
Risk Factors: Multivariate Analysis
Characteristic
OR
Site of Cancer
P value
0.03
Upper GI
3.88
0.0076
Lung
1.86
0.05
Lymphoma
Pre-chemotherapy platelet count >
350,000/mm3
Hgb < 10g/dL or use of red cell growth
factor
Use of white cell growth factor in highrisk sites
1.5
0.32
2.81
0.0002
1.83
0.03
2.09
0.008
Khorana, Cancer, 2005
Predictive Model
Patient Characteristic
Score
Site of Cancer
Very high risk (stomach, pancreas)
2
High risk (lung, lymphoma, gynecologic, GU
excluding prostate)
1
Platelet count > 350,000/mm3
1
Hgb < 10g/dL or use of ESA
1
Leukocyte count > 11,000/mm3
1
BMI > 35
1
Khorana AA et al. JTH Suppl Abs O-T-002
Incidence of VTE Over 2.4 Months
Predictive Model
Actual Incidence
Estimated Incidence
95 % Confidence Limits
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
0
1
2
3
4
Risk Score
0
1
2
3
4
N
1,352
974
476
160
33
VTE(%) /2.4 mos.
0.8
1.8
2.7
6.3
13.2
Predictive Model Validation
Rate of VTE over 2.5 mos (%)
8%
7.1%
7%
Development cohort
6%
Validation cohort
6.7%
5%
4%
3%
1.8% 2.0%
2%
1%
0.8%
0.3%
0%
n=734 n=374
Risk
Low (0)
Khorana AA et al. JTH Suppl Abs O-T-002
n=1627 n=842
Intermediate(1-2)
n=340 n=149
High(>3)
Oral Anticoagulant Therapy
in 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?
CLOT: Landmark Cancer/VTE Trial
Dalteparin
Dalteparin
CANCER PATIENTS WITH
Randomization
ACUTE DVT or PE
[N = 677]
►
►
Dalteparin
Oral Anticoagulant
Primary Endpoints: Recurrent VTE and Bleeding
Secondary Endpoint: Survival
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Landmark CLOT Cancer Trial
Probability of Recurrent VTE, %
Reduction in Recurrent VTE
25
Recurrent VTE
Risk reduction = 52%
p-value = 0.0017
20
OAC
15
10
Dalteparin
5
0
0
Lee, Levine, Kakkar, Rickles et.al. N
Engl J Med, 2003;349:146
30
60
90
120
150
Days Post Randomization
180
210
Bleeding Events in CLOT
Dalteparin
OAC
N=338
N=335
Major bleed
19 ( 5.6%)
12 ( 3.6%)
0.27
Any bleed
46 (13.6%)
62 (18.5%)
0.093
* Fisher’s exact test
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
P-value*
Treatment of Cancer-Associated VTE
Study
Design
Length of
Therapy
(Months)
N
Recurrent
Major
Death
VTE
Bleeding
(%)
(%)
(%)
6
4
NS
39 NS
41
0.09
7
16
0.09
11 0.03
23
0.03
6
8
NS
23 NS
22
CLOT Trial
(Lee 2003)
Dalteparin
OAC
6
336
336
9
17
0.002
CANTHENOX
(Meyer 2002)
Enoxaparin
OAC
3
67
71
11
21
LITE
(Hull ISTH 2003)
Tinzaparin
OAC
3
80
87
6
11
ONCENOX
(Deitcher ISTH
2003)
Enox (Low)
Enox (High)
OAC
6
32
36
34
3.4
3.1
6.7
NS
NS
NR
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
recommendation—ACCP)
►
NOTE: Dalteparin is only LMWH approved (May,
2007) for both the treatment and secondary
prevention of VTE in cancer
►
Oral anticoagulant therapy to follow for as long as
cancer is active (Grade 1C recommendation—ACCP)
Chest Jun 2008: 454S–545S
CLOT 12-month Mortality
All Patients
Probability of Survival, %
100
90
80
70
Dalteparin
60
OAC
50
40
30
20
10
0
HR 0.94 P-value = 0.40
0
30 60 90 120
180
240
300
Days Post Randomization
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
360
Anti-Tumor Effects of LMWH
CLOT 12-month Mortality
Patients Without Metastases (N=150)
Probability of Survival, %
100
Dalteparin
90
80
70
OAC
60
50
40
30
20
10
HR = 0.50 P-value = 0.03
0
0
30 60 90 120 150 180
240
300
Days Post Randomization
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
360
LMWH for Small Cell Lung Cancer
Turkish Study
►
84 patients randomized: Chemo +/- LMWH (18 weeks)
►
Patients balanced for age, gender, stage, smoking history,
ECOG performance status
Chemotherapy
plus 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 2004;2:1266.
Rate of Appropriate Prophylaxis, %
VTE Prophylaxis Is Underused
in Patients With Cancer
Cancer:
FRONTLINE Survey1—
3891 Clinician
Respondents
Cancer:
Surgical
Major
Surgery2
Major
Abdominothoracic
Surgery (Elderly)3
Medical
Inpatients4
Confirmed DVT
(Inpatients)5
Cancer:
Medical
1. Kakkar AK et al. Oncologist. 2003;8:381-388
4. Rahim SA et al. Thromb Res. 2003;111:215-219
2. Stratton MA et al. Arch Intern Med. 2000;160:334-340
3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
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
Clotting, Cancer, and Clinical Strategies
Venous Thromboembolism (VTE)
Prophylaxis in the
Cancer Patient and Beyond
Guidelines and Implications for Clinical Practice
John Fanikos, RPh, MBA
Assistant Director of Pharmacy
Brigham and Women’s Hospital
Assistant Clinical Professor of Pharmacy
Northeastern University
Massachusetts College of Pharmacy
Boston, MA
Outline of Presentation
►
Guidelines for VTE prevention
►
Performance to date
►
Opportunities for improvement
►
Guidelines for VTE Treatment
►
Performance to date
Prophylaxis Rates in Hospitalized Patients
Amin A et al. J Thromb Haemost. 2007; 5:1610-6.
VTE, Cancer, and Survival
N = 1,211,944 Medicare admissions with cancer vs 8,177,634 without cancer
1.00
Probability of
Death
DVT/PE and Malignant Disease
0.80
0.60
Malignant Disease
0.40
DVT/PE Only
0.20
Nonmalignant Disease
0.00
0
20
Levitan N, et al. Medicine 1999;78:285
40
60
80 100 120
Number of Days
140 160
180
Time Distribution of VTE Events
Following Cancer Surgery
@RISTOS Registry: prospective cohort N=2373
12
10
VTE Events
8
6
4
2
0
1-5 d
Agnelli G et al. Ann Surg 2006; 243:89-95.
6-10 d
11-15 d
16-20 d
21-25 d
26-30 d
> 30 d
• www.nccn.org
• NCCN Clinical Practice Guidelines in
Oncology™
• “…The panel of experts includes medical
and surgical oncologists, hematologists,
cardiologists, internists, radiologists. And a
pharmacist.”
• www.asco.org
•Recommendations for VTE Prophylaxis &
Treatment in Patients with Cancer
2004 ACCP Recommendations
Cancer patients undergoing surgical procedures receive prophylaxis that is
appropriate for their current risk state (Grade 1A)
●
General, Gynecologic, Urologic Surgery
• Low Dose Unfractionated Heparin 5,000 units TID
• LMWH > 3,400 units Daily
– Dalteparin 5,000 units
– Enoxaparin 40 mg
– Tinzaparin 4,500 units
• GCS and/or IPC
Cancer patients with an acute medical illness receive prophylaxis
that is appropriate for their current risk state (Grade 1A)
• Low Dose Unfractionated Heparin
• LMWH
Contraindication to anticoagulant prophylaxis (Grade 1C+)
• GCS or IPC
1A is the highest possible grade
Indicates that benefits outweigh risks, burdens, and costs,
with consistent RCT level of evidence
Geerts WH et al. Chest. 2004;126(suppl):338S-400S
NCCN Practice Guidelines in VTE Disease
At Risk Population
►
►
►
►
►
►
►
►
►
►
►
►
►
►
Adult patient
Diagnosis or
clinical
suspicion of
cancer
Inpatient
Relative contraindication to
anticoagulation
treatment
RISK FACTOR ASSESSMENT
Age
Prior VTE
Familial thrombophilia
Active cancer
Trauma
Major surgical procedures
Acute or chronic medical illness requiring
hospitalization or prolonged bed rest
Central venous catheter/IV catheter
Congestive heart failure
Pregnancy
Regional bulky lymphadenopathy with
extrinsic vascular compression
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
Initial Prophylaxis
Continue
Prophylaxis
After
Modifiable
risk factors: Lifestyle,
Discharge
?
smoking, tobacco, obesity,
Prophylactic anticoagulation
therapy (category 1) + sequential
compression device (SCD)
Mechanical prophylaxis (options)
- SCD
- Graduated compression stockings
activity level/exercise
►
►
►
AGENTS ASSOCIATED
WITH INCREASED RISK
Chemotherapy
Exogenous estrogen
compounds
- HRT
- Oral contraceptives
- Tamoxifen/Raloxifene
- Diethystilbestrol
Thalidomide/lenalidomide
NCCN Practice Guidelines
in VTE Disease
Inpatient Prophylactic Anticoagulation Therapy
► LMWH
- Dalteparin 5,000 units subcutaneous daily
- Enoxaparin 40 mg subcutaneous daily
- Tinzaparin 4,500 units (fixed dose) subcutaneous daily or
75 units/kg subcutaneous daily
► Pentasaccharide
- Fondaparinux 2.5 mg subcutaneous daily
► Unfractionated heparin 5,000 units subcutaneous 3
times daily
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
NCCN Practice Guidelines
in VTE Disease
Relative Contraindications to Prophylactic or
Therapeutic Anticoagulation
►
►
►
►
►
►
►
►
►
Recent CNS bleed, intracranial or spinal lesion at high risk for bleeding
Active bleeding (major): more than 2 units transfused in 24 hours
Chronic, clinically significant measurable bleeding > 48 hours
Thrombocytopenia (platelets < 50,000/mcL)
Severe platelet dysfunction (uremia, medications, dysplastic
hematopoiesis)
Recent major operation at high risk for bleeding
Underlying coagulopathy
Clotting factor abnormalities
- Elevated PT or aPTT (excluding lupus inhibitors)
- Spinal anesthesia/lumbar puncture
High risk for falls
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
►
Should hospitalized patients with cancer
receive anticoagulation for VTE
prophylaxis ?
●
“Hospitalized patients with cancer should be
considered candidates for VTE prophylaxis in
the absence of bleeding or other
contraindications to anticoagulation”
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
Incidence and Relative Risk of High-Grade VTE
with Bevacizumab
Tumor Type No.
Studies
Overall
13
Bevacizumab
Control
Incidence
RR
235/3795
134/3167
6.3
1.38
Colo-rectal
4
96/1315
50/1128
7.3
1.56
NSCLC
4
78/1228
41/862
6.6
1.24
Breast
Cancer
Renal Cell
2
20/594
13/561
3.9
1.47
1
7/337
2/304
2.0
2.86
Mesothelioma
1
9/53
5/55
17.0
1.89
Pancreatic
Cancer
1
24/268
23/257
9.0
1.00
SR Nalluri et al. JAMA 2008;300(19):2277-2285
►
Should ambulatory patients with cancer
receive anticoagulation for VTE
prophylaxis during systemic
chemotherapy?
●
“Routine prophylaxis is not recommended.”
●
“Patients receiving thalidomide or lenalidomide
with chemotherapy or dexamethasone are at high
risk for thrombosis and warrant prophylaxis.”
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
►
Should hospitalized patients with cancer
undergoing surgery receive perioperative VTE
prophylaxis ?
●
All patients should be considered for
thromboprophylaxis.
Procedures greater than 30 minutes should receive
pharmacologic prophylaxis.
Mechanical methods should not be used as
monotherapy.
Prophylaxis should continue for at least 7-10 days
post-op. Prolonged prophylaxis may be considered
for cancer with high risk features.
●
●
●
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
Compliance With ACCP VTE
Prophylaxis Guidelines Is Poor
Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group
62,012
70,000
At risk for DVT/PE
35,124
Received compliant care
Number of patients
10,000
9175
5,000
2324
1388
52.4%
15.3%
12.7%
Orthopedic
Surgery
At-risk Medical
Conditions
General
Surgery
9.9%
6.7%
0
Urologic
Surgery
Gynecologic
Surgery
Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based
on the 6th American College of Chest Physicians (ACCP) guidelines.
HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76
Reasons for Inadequate Duration
of VTE Prophylaxis
At-Risk Medical
(n=5,994)
Abdominal Surgery
(n=3,240)
Urologic surgery
(n=158)
Gynecologic surgery
(n=163)
Neurosurgery
(n=250)
Started Late
Started late &
Ended Early
Ended Early
1,347 (22.5)
2,961 (49.4)
1,686 (28.1)
824 (25.4)
1,764 (54.4)
652 (20.1)
18 (11.4)
73 (46.2)
67 (42.4)
13 (8.0)
43 (26.4)
107 (65.6)
66 (26.4)
125 (50.0)
59 (23.6)
HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76
Predictors of the
Use of Thromboprophylaxis
Effect
Odds Ratio (95% CI)
Malignancy
0.40
Others
0.58
Infection
0.83
Bleeding Risk
0.91
Gender
Hospital Size
0.92
0.93
Age
1.00
LOS
1.05
Cardiovascular Disease
1.06
Internal Medicine
1.33
Respiratory
1.35
AMC
Duration of Immobility
VTE Risk Factors
1.46
1.60
1.78
0.0 0.5 1.0
Kahn SR et Al. Thromb Res 2007; 119:145-155
1.5 2.0 2.5
Odds Ratio
3.0 3.5 4.0
Unfractionated Heparin Prophylaxis:
BID vs TID—What Works, What Doesn’t?
Meta-analysis:
12 RCTs
► DVT,
PE, all VTE events, Bleeding
► Proximal
●
●
DVT plus PE
BID VTE event rate:
2.34 events per 1,000
patient days
TID event rate:
0.86 events per 1,000
patient days
P=0.05
► NNT
●
●
676 hospital prophylaxis days
with UFH TID to prevent
1 major bleed with 1,649 hospital
prophylaxis days of TID dosing
King CS et al. CHEST 2007;131:507-516
Heparin, Low Molecular
Weight Heparin Prophylaxis
► Meta-analysis
LMWH vs UFH
► 36
DVT
randomized
controlled trials
Risk
Study
Reduction (95% CI)
Weight %
hospitalized
medical patients
► UFH 5,000 units TID is
more effective in
preventing DVT than
UFH BID
Harenberg et al, 1990
0.70 (0.16-3.03)
3.4
Turpie et al, 1992
0.29 (0.10-0.81)
11.4
Dumas et al, 1994
0.74 (0.38-1.43)
14.4
Bergmann & Neuhart
0.94 (0.39-2.26)
8.1
Lechler et al, 1996
0.25 (0.03-2.23)
3.3
► Low
Hillbom et al, 2002
0.55 (0.31-0.98)
20.5
Kleber, et al 2003
0.77 (0.43-1.38)
19.4
Diener et al, 2006
0.76 (0.42-1.38)
18.9
Overall (95% CI)
0.68 (0.52-0.88)
► 23,000
molecular weight
heparin is 33% more
effective than
unfractionated heparin
in preventing DVT
● RR for DVT 0.68
et al, 1996
Harenberg et al, 1996
(p=0.004)
2.89 (0.30-27.71)
0.1
1.0
Risk Ratio
LMWH Better
Wein L et al. Arch Intern Med. 2007;167:1476-86.
10
LMWH Worse
0.8
BWH/DFCI Partners
Cancer Care Experience
• Consecutive
patients, < 60 days
• 2 Nursing units
• LOS ranged from 3 days to 31 days
• Number of days where doses were omitted ranged from
1 to 6 days
VTE Incidence: More Common
in the Outpatient Setting
►
Medical records of residents (n=477,800)
►
587 VTE events (104 per 100,000 population)
►
30 Day recurrence 4.8 %
Patients receiving prophylaxis
during high risk periods
VTE Event Location
Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777
Thrombosis in Malignancy
7TH ACCP Consensus Conference Recommendations
Initial Phase
Chronic Phase
5-7 days
Dalteparin 200/kg q24h
(GRADE 1A)
Continue anticoagulation
(warfarin or LMWH) long-term or
until malignancy resolves
(GRADE 1C)
5 - 7 days
3 - 6 mos
6 mos - indefinite
Subacute Phase
3 - 6 months
Dalteparin* 150 units/kg q24h
(GRADE 1A)
* Dalteparin Approved for Extended Treatment to Reduce the
Recurrence of Blood Clots in Patients with Cancer
Buller HR, et al. Chest 2004; 126 (suppl 3): 401s-428s
Warfarin vs. Dalteparin for
VTE Treatment in Malignancy
Recurrent Thrombosis
Dalteparin: 200 units/kg/day
x 1 mo, then 150 units/kg/day
Warfarin dosed to INR 2-3
Thromboembolism (%)
Dalteparin: 9.0% of 336
Warfarin:
17% of 336
Probability of Recurrent Venous
25
P=0.002
20
Oral anticoagulant
15
10
Dalteparin
5
0
Duration: 6 months
0
30
60
90
120
150
180
210
Days after Randomization
No. at Risk
Lee AY et al. New Engl J Med 2003; 349:146-53.
Dalteparin
336
301
264
235
227
210
164
Oral anticoagulant
336
280
242
221
200
194
154
Subgroup Analysis
12-month Cumulative Mortality Rate
Dalteparin
Warfarin
P Value
Metastatic
Disease
(n=452)
72%
69%
P = 0.46
Non-metastatic
Disease
(n=150)
20%
36%
P=0.03
Lee AY et al. J Clin Oncol. 2005; 23:2123-9.
Dalteparin Cost Effectiveness
in Recurrent VTE
Cost
Parameter
Dalteparin
(n=338)
Warfarin
(n=338)
Drug
2852
269
Laboratory
303
437
Diagnostic
Tests
253
267
Unscheduled
Visits
286
300
Transfusions
143
208
Major bleeding
97.5
92.3
VTE
Recurrence
228
429
Mean Cost Per
Patient
4162
2003
Dranitsaris G. Pharmacoeconomics 2006; 24(6):5093-607
NCCN Practice Guidelines—Venous
Thromboembolic Disease
Therapeutic Anticoagulation Treatment for
DVT, PE, and Catheter-Associated Thrombosis
Immediate
► LMWH
- Dalteparin (200 units/kg subcutaneous daily)
- Enoxaparin (1 mg/kg subcutaneous every 12 hrs)
- Tinzaparin (175 units/kg subcutaneous daily)
►
Pentasaccharide
- Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [50-100 lg]; 10 mg [>100 kg]
subcutaneous daily
►
Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour,
target aPTT to 2.0-2.9 x control)
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
NCCN Practice Guidelines—Venous
Thromboembolic Disease
Therapeutic Anticoagulation Treatment for
DVT, PE, and Catheter-Associated Thrombosis
Long Term
►
►
LMWH 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
Warfarin (2.5-5 mg every day initially, subsequent dosing based on INR
value; target INR 2.0-3.0)
Duration of Long Term Therapy
►
►
►
Minimum time of 3-6 mo for DVT and 6-12 mo for PE
Consider indefinite anticoaugulation if active cancer or persistent risk
factors
For catheter associated thrombosis, anticoagulate as long as catheter
is in place and for 1-3 mo after catheter removal
http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf
►
What is the best treatment for patients with
cancer with established VTE to prevent recurrent
VTE ?
●
LMWH is the preferred approach for the initial 5-10
days.
LMWH, given for at least 6 months, is the preferred
for long-term anticoagulant therapy.
After 6 months, anticoagulation therapy should be
considered for select patients.
For CNS malignancies, elderly patients
anticoagulation is recommended with careful
monitoring and dose adjustment.
●
●
●
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
►
Should patients with cancer receive
anticoagulants in the absence of
established VTE to improve survival?
●
“Anticoagulants are not recommended to improve
survival in patients with cancer without VTE.”
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
Antithrombotic Therapy Practices
in U.S. Hospitals
►Survey
of 38 U.S.
Hospitals
►n=939
DVT or PE
►50%
patients
reached INR >2 for
2 consecutive days
Therapy
n (%)
LMWH
527 (56.1%)
UFH
562 (59.8%)
UFH SC
78 (8.3%)
DTI
6 (0.6%)
Tapson V et al. Arch Intern Med 2005
Self-Managed Long Term LMWH Therapy
2212 patients with proximal vein thrombosis
assessed for eligibility
737
Randomized
369 assigned to LMWH
1475 excluded for
anticoagulant
violations or
inability to give
written consent
369 assigned to usual care
with heparin and warfarin
3 lost to follow-up
3 lost to follow-up
1 withdrew consent
5 withdrew consent
369 included in analysis
Hull R. Am Jour Med 2007; 120:72-82
369 included in analysis
Self-Managed Long Term LMWH Therapy
Tinzaparin
Usual Care
Absolute Difference
(n=369)
(n=368)
(95% CI)
New VTE at 3 Mos
18 (4.9)
21 (5.7)
-0.8 (-4.2-2.4)
NS
New VTE at 12 Mos
33 (8.9)
36 (9.8)
-0.8 (-5.5-3.5)
NS
All Bleeding
48 (13.0)
73 (19.8)
-6.8 (-12.4--1.5)
p=.011
Major Bleeding
12 (3.3)
17 (4.6)
-1.4 (-4.3-1.4)
NS
Minor Bleeding
36 (9.8)
56 (15.2)
-5.5 (-10.4--0.6)
p=.022
Stratified BleedingHigh Risk
31/144 (21.5)
39/146 (26.7)
-5.2 (-15%-4.6%)
NS
Stratified Bleeding-Low
Risk
17/225 (7.6)
34/222 (15.3)
-7.8 (-13.6--1.9%)
p=.01
Thrombocytopenia
(<150)
21 (5.7)
9 (2.4)
1.6 (-3.6-0.3)
NS
Bone Fracture
4 (1.1)
7 (1.9)
-0.8 (-0.9-2.6)
NS
Outcomes
Hull R. Am Jour Med 2007; 120:72-82
p-value
LMWHs and Bleeding in Patients
with Renal Dysfunction
Dosage adjustments
for renal dysfunction
Lim W et al. Ann Intern Med 2006; 144:673-84
Barriers to Long-term Use of LMWH for
Treatment of Cancer-associated VTE
Initial treatment
LMWH for 3-6 months
UFH/LMWH for 5-7 days
followed by warfarin
19%
81%
Reasons LMWH not used long-term
Not covered by medical insurance
Physician preference
Patient refused long-term injections
History of HIT
Severe renal insufficiency
Wittkowsky AK. J Thromb Haemost. 2006; 4:2090-1.
49.4%
32.0%
13.6%
2.5%
2.5%
Conclusions
Examine your current practices of VTE
prophylaxis and treatment
► Review available guidelines as a benchmark
► Consider the use of a pharmacologic or
mechanical intervention
► Evaluate use of Reminder or Risk Scoring
Systems
► Utilize the regimen providing the best efficacy in
reducing events and offering best compliance
► Follow-up with patients to monitor and avoid
adverse events and to ensure optimal outcomes
A Year 2009 Update for
The Health System Pharmacist
Pharmacologic Prophylaxis of DVT in
Special Populations
Edith Nutescu, PharmD, FCCP
Clinical Associate Professor
Pharmacy Practice
Affiliate Faculty, Center for
Pharmacoeconomic Research
Director, Antithrombosis Center
The University of Illinois at Chicago
College of Pharmacy & Medical Center
Chicago, IL
Objectives
1. Differentiate data with various LMWHs in special
populations
2. Review appropriate dosing and monitoring of
LMWHs in patients with obesity and renal failure
3. Discuss cautions of using emerging agents in
special populations
Risk of Inadequate Therapy
in High Risk Patients
►
524 VTE Patients
●
Active Cancer in 26%
• Only 1/3rd on LMWH monotherapy
●
Weight > 100Kg in 15%
• Under-dosing of LMWH by > 10%
– 36% of > pts 100Kg
– 8% of pts < 100Kg (p < 0.001)
●
CrCL < 30mL/min in 5%
• LMWH tx in 67%
Cook LM, et.al. J Thromb Hemost 2007;5;937-41.
8th ACCP Conference on Antithrombotic
Therapy
Obese Patients
“In obese patients given LMWH prophylaxis or
treatment, we suggest weight-based dosing
(Grade 2C).”
►
What is this weight-based dosing and how does it differ
from typical dosing?
►
At what weight do we move away from standard dosing
and move to weight-based dosing?
Hirsh J et al. Chest. 2008;133(suppl):141S-159S.
Pharmacokinetic Characteristics of
Low Molecular Weight Heparins
Lipid solubility
LOW
Plasma protein binding
HIGH
Tissue binding
LOW
Volume of Distribution
5-7 L
Logical conclusion:
IBW may be a better predictor of LMWH dosing than TBW
LMWH: Maximum Weights Studied
Kinetic
Studies
Clinical Trials
Dalteparin
190 kg
128 kg*
Enoxaparin
144 kg
194 kg
Tinzaparin
165 kg
88 kg
Fondaparinux
* max dose 18,000 - 20,000 IU/day
Duplaga BA et al. Pharmacotherapy 2001; 21:218-34.
Synergy Trial: Data on File
Davidson, et al. J Thromb Haem 2007;5:1191-4
175.5 kg
LMWH Pharmacokinetics in Obesity
Actual body weight correlates best with anticoagulant response to
LMWHs as measured by anti-factor Xa levels
Clin Pharmacol Ther 2002;72:308-18. Thromb Haemost 2002;87:817-23.
Dalteparin
Pharmacokinetics in Obesity
Dose: 200 U/kg qd
Duration: routine
Obese (BMI > 30)
Normal (BMI < 30)
10
10
TBW (mean +/- SD)
106.4 +/- 22.1
69.7 +/- 9.3
LBW (mean +/- SD)
64.1 +/- 12.3
66.1 +/- 8.7
Mean Vd (l)
12.39
8.36
Mean CI (l/hr)
1.30
1.11
N
Yee JYV, Duffull SB. Eur J Clin Pharmacol 2000; 56:293-7.
Dalteparin
Pharmacokinetics In Obesity
Correlation Coefficient Between Vd and:
LBW
0.05
ABW
0.52
TBW
0.55
Correlation Coefficient Between Cl and:
LBW
0.01
ABW
0.32
TBW
0.39
Conclusion:
TBW may be a better predictor of LMWH dose than IBW
Yee JYV et al. Eur J Clin Pharmacol 2000; 56:293-7.
Dalteparin
Pharmacokinetics In Obesity
Dose: 200 U/kg qd
Duration: 5 Days
<20% of
IBW
20-40% of
IBW
> 40% of
IBW
N
13
14
10
Mean Dose (U)
14,030
17,646
23,565
Day 3 Peak
1.01
0.97
1.12 NS
Day 3 Trough
0.12
0.11
0.11 NS
Max TBW: 190kg
Ant-Xa Activity (u/ml)
Conclusion: Body mass does not appear to have an important effect on the
response to LMWH up to a weight of 190kg in patients with normal renal function.
Wilson SJ et al. Hemostasis 2001; 31:42-8.
LMWH Safety and Effectiveness Using TBW
Enoxaparin In ACS (ESSENCE/TIMI IIb)
P=0.39
16.1%
14.3%
P=0.13
1.6%
0.4%
Obese: BMI > 30mg/m2
Enox max weight 158 kg
Spinler SA et al. Am Heart J 2003; 146:33-41
Safety Of TBW-based Dosing of Dalteparin
for Treatment of Acute VTE in Obese Patients
N = 193 patients
> 90 kg
3 month outcomes: major bleeding = 1.0% (n=2)
recurrent VTE = 1.6% (n=3)
WEIGHT
(kg)
N
Mean
Dose
Full dose
+/- 5%
QD
Dosing
BID
Dosing
90-99
40
19,300
39
24
16
100-109
52
20,850
49
25
17
110-119
41
21,470
21
26
15
120-129
25
24,300
22
16
9
130-139
16
25,250
8
10
6
140-149
9
26,920
6
5
4
> 150
10
28,280
6
6
4
Al-Yaseen E et al. J Thromb Haemost 2004; 3:100-2.
Fondaparinux In Obesity
Results From the Matisse Trials
Fondaparinux:
< 50kg: 5mg qd
50-100kg: 7.5mg qd
> 100kg: 10mg qd
Enoxaparin:
(Matisse DVT)
1mg/kg q12h
Heparin:
(Matisse PE)
Adjusted per aPTT
Davidson BL et al. J Thrombosis Haemost 2007; 5:1191-4.
No weight-dependent
difference in
efficacy or safety
Body Weight and Anti-Xa Activity
for Prophylactic Doses of LMWH
Area under the curve for 10 h
N = 17 patients and 2 volunteers
Enoxaparin 40mg SQ x1 dose
AntiXa levels hourly x10 hours
Regression line
95% CI for line
95% CI for data points
200
150
100
50
0
40
60
80
100
120
Body Weight (kg)
Frederiksen SG et al. Br J Surgery 2003; 90:547-8
140
160
Dalteparin:
Fixed Dosing For VTE Prevention
Subgroup analysis of PREVENT TRIAL (dalteparin vs placebo in medically ill)
BMI (kg/m2)
Patients %
< 25
37.5
25-29.9
33.1
30-34.9
18.9
35-39.9
7.1
> 40
3.3
Favors Dalteparin
Favor Placebo
Overall Prevent Trial
0.01
0.1
0.55 1.0
Relative Risk
10.0
Dalteparin 5,000 units daily was similarly effective in obese and non-obese patients (except pts
with BMI>40) with no observed difference in mortality or major bleeding
Kucher N et al. Arch Int Med 2005;165:341-5.
Enoxaparin VTE Prophylaxis in
TKA/THA/Trauma
31.8%
p<0.001
16.7%
N: 807
Dose: 40 mg qd
Samama MM et al. Thromb Haemost 1995; 73:977.
Obese : BMI>32kg/m2
Enoxaparin:
VTE Prophylaxis in Bariatric Surgery
5.4%
p<0.01
0.6%
30mg bid: n=92
BMI 51.7kg/m2
Scholten Obes Surg 2002; 12:19-24.
40mg bid: n=389
BMI 50.3kg/m2
Dalteparin in Morbid Obesity: Bariatric Surgery
N=135
Bariatric Surgery
Mean Weight: 148.8Kg
Body Weight (kg)
200
Mean BMI: 53.7
Dalteparin: 7,500 IU daily
Anti-factor Xa level
P=0.031
180
P=0.052
P=0.444
160
140
120
0
Under target value Target value Over target value
<>0.5 IU/mL
<0.2 IU/mL
<0.2-0.5 IU/mL
n=13
n-=41
n-=81
Number of patient (%) Body weight (kg)
Below target value (<0.2 UI/ml)
41 (30.4%)
159.4 ± 35.8
Target value (0.2–0.5 UI/ml)
81 (60.0%)
145.7 ± 28.4
Above target value (>0.5 UI/ml)
13 (9.6%)
134.6 ± 24.2
p value
Simonneau MD, et.al. Obes Surg. 2008; [Epub ahead of print]
0.0152
LMWH in Obesity: Summary
►
Treatment: in controlled trials, LMWH dosing has been based on TBW
(max 160-190 kg)
●
Dalteparin
• Dose based on TBW
• PI recommends dose capping
• Recent clinical data supports TBW dosing
– QD or BID dosing
●
Enoxaparin
• Dose based on TBW
• Dose capping NOT recommended
• BID dosing preferred
●
Tinzaparin
• Dose based on TBW, NO dose adjustment or capping
●
►
Anti-Xa monitoring not necessary for TBW < 190kg
Prophylaxis: a 25-30% dose increase (or 50IU/kg in high risk patients)
Nutescu E, et.al. Ann Pharmacother; 2009; in press.
8th ACCP Conference on Antithrombotic Therapy
Renal Impairment
►
For each of the antithrombotic agents, we recommend that
clinicians follow manufacturer-suggested dosing guidelines
(Grade 1C)
►
We recommend that renal function be considered when
making decisions about the use of and/or dose of LMWH or
fondaparinux (Grade 1A)
►
Options for patients with renal impairment (Grade 1B)
●
●
●
Avoid agents that renal accumulate
Use a lower dose
Monitor the drug level or anticoagulant effect
Geerts WH. Chest 2008;133(suppl):381S-453S.
LMWH in Renal Dysfunction
Manufacturer Recommendations
Dalteparin
●
“should be used with caution in patients with severe kidney
insufficiency.”
• Monitor anti-Factor Xa for dose guiding with therapeutic doses
Enoxaparin
●
“adjustment of dose is recommended for patients with severe
renal impairment (CrCL < 30 mL/min).”
Tinzaparin
●
“patients with severe renal impairment should be dosed with
caution.”
Fondaparinux
- Contraindicated in CrCL < 30mL/min
Recent Meta-Analysis of LMWHs and Bleeding
In Patients With Severe Renal Dysfunction
Patients w/
renal insuff.
(n/n)
Patients w/ no
renal insuff.
(n/n)
Collet, et al; 2001
Paulas, et al; 2002
Siguret, et al; 2000
0/28
0/51
0/17
1/83
3/149
0/13
Chow, et al; 2003
0/5
0/13
Khazan, et al. (adj.); 2003
(Prophylactic) 2003
(Therapeutic) 2003
Spinler, et al; 2003
0/10
3/36
2/17
5/69
3/42
3/47
3/61
74/3,432
4.78
14.77
8.62
15.93
0.28 (0.01 – 5.16)
1.33 (0.25 – 7.05)
3.09 (0.35 – 27.31)
10.05 (2.02 – 49.98)
Green, et al; 2005
1/18
0/20
2.66
8.26 (0.16 – 418.42)
Kruse & Lee; 2004
0/50
1/120
2.22
0.24 (0.00 – 17.90)
Macie, et al; 2004
2/7
6/201
2.68
977.78 (19.61 – 48,752.07)
Peng, et al; 2004
0/7
0/43
Thorevska, et al; 2004
7/65
11/171
35.56
1.85 (0.63 – 5.40)
Bazinet, et al; 2005
1/36
2/160
4.75
2.74 (0.15 – 51.73)
21/416
107/4,555
Study; year
Total (95%, CI)
Peto OR
(95%, CI)
Weight
(%)
2.01
6.02
0.26 (0.00 – 23.94)
0.26 (0.02 – 3.50)
Not estimable
Not estimable
Not estimable
100.00
0.01 0.1
1
Favors ↓’ed
10
100
Favors ↑’ed
bleeding
Lim W, et al. Ann Intern Med. 2006;144:673-684.
Peto OR
(95%, CI)
2.25 (1.19 – 4.27)
Dosage adjustments
for renal dysfunction
Enoxaparin PK and PD in Renal Impairment
Result:
Tmax: 3-4 hours
Amax: 10-35% higher in RI groups
CI/F”linearly correlated with CrCl
CL/F
(L/h)
Half-life
(h)
Normals
0.98
6.87
Mild RI
0.87
9.94
20% ↑
Moderate RI
0.76
11.3
21% ↑
Severe RI
0.58
15.9
65% ↑
Day 4
Sanderink GJCM. Thromb Res 2002;105:225-31.
AUC (0-24)
(h●IU/mL)
LMWH Renal Dosing in NSTE ACS Patients
►
56 UA pts with CrCl <60
ml/min
►
Enoxaparin dose empirically
 and anti-Xa level measured
after 3rd dose
•
•
•
•
Dose may be  to 0.6mg/kg/
q12h if CrCL <30mL/min; or 0.8
mg/kg/q12h if CrCl 30-60 ml/min
Anti-Xa monitoring
Doses “appeared safe”
Further prospective evaluation
needed
CrCl
(ml/min)
<30
(n = 28)
>30 and <60
(n =28)
Age
76+/-3
73+/-3
Enoxaparin (mg/kg/12h)
0.64
0.84
Anti-Xa (IU/ml)
0.95
0.95
Collet JP et al. International J Cardiol 2001;80:81-2.
Clinical Use Of Recommended
Enoxaparin Dosage in Renal Impairment
N = 19 pts with Clcr < 30ml/min receiving enoxaparin 1mg/kg q24h
1.0.
6
0.9
TROUGH ANTI-Xa LEVELS
5
0.8
Number of Patients
Antifactor X1 Level (U/mL)
PEAK ANTI-Xa LEVELS
0.7
0.6
0.5
0.4
0.3
4
3
2
1
0.2
0.1
0
First dose
Median
Subsequent doses
(second and third)
25-75% interquartile range
Lachish T et al. Pharmacotherapy 2007; 27:1347-52.
0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55
Trough Antifactor Xa Level (U/mL)
Tinzaparin 175 U/kg
Peak Anti-Xa Levels According to Renal Function
No correlation between peak anti-Xa activity and Clcr
No accumulation of Anti-Xa activity after 10 days of therapy
Siguret V et al. Thromb Haemost 2000;84:800-4.
Pharmacokinetics of Prophylactic
Enoxaparin vs Tinzaparin
Enoxaparin 40mg qd
or
Tinazaparin 4500 IU qd
N = 52 patients
Mean age = 87.7 yrs
Mean wt = 52.3kg
Mean Clcr = 34.7ml/min
Mahe I et al. Thromb Haemost 2007; 97:581-6.
Dalteparin 100 U/kg q12h
Peak Anti-Xa Levels According to Renal Function
Clcr
Mean peak
anti-Xa level
after 5-6 doses
> 80
0.47
< 40
0.55
Antifactor Xa Level (U/mL)
No difference in peak anti-Xa activity between normal patients and
patients with renal impairement
1.5
1.0
0.5
x
x
0
Subjects without
Renal impairment
N=11
Shprecher AR et al. Pharmacotherapy 2005; 25:817-22.
Subjects with
Renal impairment
N=11
Pharmacokinetics of
Prophylactic Doses of Dalteparin
N = 115 elderly (age > 65) pts with acute medical illness and elevated SCr
Tx: dalteparin 5000 U or 2500 U SQ qd (risk-based) for VTE prophylaxis
Renal Failure
Mild
(n=12)
Moderate
(n=73)
Severe
(n=24)
CrCL (ml/min)
60-89
30-59
<30
Day 6 peak anti-Xa
0.030
0.033
0.048
Minor Bleeding
0
3
0
Major Bleeding
0
0
0
P=0.72
► No evidence of accumulation of anti-Xa activity
► No relationship between the degree of renal impairment and peak
anti-Xa level on Day 6
► No association between creatinine clearance and anti-Xa levels
Tincani E et al. Haematologica 2006; 91:976-9.
Dalteparin Thromboprophylaxis in Critically Ill Patients
with Severe Renal Insufficiency: The Direct Study
●
●
●
●
●
N=138 critically ill patients
CrCl < 30 ml/min
• Mean CrCL 18.9ml/min
Dalteparin 5000 IU sc daily
Serial anti Xa levels measured on days 3, 10, and 17
Bioaccumulation defined as trough anti-Xa level > 0.40 IU/mL
Results:
•
•
•
The median duration of dalteparin exposure was 7 (4-12)
days
No patient had a trough anti Xa level > 0.4 IU/ml
Based on serial measurements
• peak anti-Xa levels were 0.29 to 0.34 IU/mL
• trough levels were lower than 0.06 IU/mL
Douketis, et al. Arch Intern Med. 2008 Sep 8;168(16):1805-12.
Dosing of LMWHs In Renal Impairment
Recommendations
FOR CrCL < 30 ml/min
►
Enoxaparin:
●
●
►
Prophylaxis doses: 30 mg sq QD
Treatment doses: 1mg/Kg sq QD
Dalteparin and Tinzaparin:
●
●
●
no specific dosing guidelines
No or lower degree of accumulation expected
Anti-Factor Xa activity monitoring
FOR CrCL 30-50 mL/min
►
No specific recommendations
►
Concern with prolonged use > 10 days with enoxaparin (15-25%
dose decrease ?)
►
Monitoring anti-Xa ?
Nutescu E, et.al. Ann Pharmacother; 2009; in press.
Unresolved Issues in
Renal Dosing of LMWHs
CrCl (mL/min)
< 30
< 20-15
Recommendations
Dose of enoxaparin should be adjusted; dalteparin and
tinzaparin no short term accumulation expected.
LMWHs have not been adequately studied as repeated doses
for prophylaxis and treatment indications; UFH is preferred in
these patients.
Issues with anti-factor Xa testing include:
true therapeutic range, standardization, availability,
recommendations for dose adjustment
Anti-Xa Activity Level Monitoring
Enoxaparin 1mg/kg SQ pharmacokinetic profile
Peak (goal ~ 0.5-1 U/ml) at 3-4 hrs
Trough (goal < 0.5 U/ml) at 11-12 hrs
Laposata et al. Arch Pathol Lab Med. 1998;122:799-807.
ANTI-Xa MONITORING: Recommendations
Level 3 Evidence: (isolated anecdotal studies or the consensus of experts)
► Laboratory monitoring using an anti-Xa assay MAY be of value in certain
clinical settings
► Use peak levels 4 hrs after SQ dose
► Through levels in renal impairment maybe preferred
► Use chromogenic, not clot-based assays
► Peak:
•
for BID dosing:
•
•
for QD dosing:
1.0-2.0 U/ml
Through: < 0.4 U/ml
0.5-1.1U/ml
Laposata et al. Arch Pathol Lab Med. 1998;122:799-807.
Nutescu E, et.al. Ann Pharmacother; 2009; in press.
Fondaparinux Pharmacokinetics
100% bioavailable
Pentasaccharide*
concentration (µg/mL)
0.35
0.25
Cmax = 0.34 µg/mL (SD: 0.04)
Tmax = 1.7 h (SD: 0.4)
T1/2 = 17.2 h (SD: 3.2)
0.2
Elimination = RENAL
0.3
0.15
0.1
0.05
0
0
4
8
12
16
20
Time (h)
Donat F, et al. Clin Pharmacokinetics 2002; 41 (suppl 2):1-9.
24
28
32
36
Fondaparinux Use in Patients
with Impaired Renal Function
► Total clearance lower than in patients
with normal renal function
Fondaparinux: PI
●
Mild impairment
~25%
●
Moderate impairment
~40%
●
Severe impairment
~55%
Incidence (%)
Full-dose Fondaparinux
Risk Of Major Bleeding
4.8%
3.8%
1.6%
2.4%
n=504
n=1288
n=1565
Clcr
80
mL/min
Data on file, GlaxoSmithKline
Clcr
50–80
mL/min
Clcr
30–50
mL/min
Clcr
< 30
ml/min
Influence of Renal Function
Fondaparinux vs Enoxaparin in ACS
OASIS-5:
Fondaparinux 2.5mg qd
vs enoxaparin 1mg/kg q12h
for 2-8 days
Fox KAA et al. Ann Intern Med 2007; 147:304-10.
A Year 2009 Update for
The Health System Pharmacist
Electronic Alerts:
Future Horizons
Karen Fiumara, PharmD
Medication Safety Officer
Brigham and Women’s Hospital
Adjunct Assistant Professor of Pharmacy Practice
Massachusetts College of Pharmacy and Allied Health Sciences
Adjunct Assistant Professor of Pharmacy Practice
Bouve’ College of Health Sciences Northeastern University
Boston, MA
Background
►
Past 10 years the prevention of medication errors
has become a primary focus in healthcare
►
In 1995 Bates et al. published landmark study
indicating 28% of hospital admissions are
attributed to preventable medication errors
►
The IOM report “To Err is Human” have led to
increased research and development of both
medical informatics and computerized alerting
systems
Bates DW et al. JAMA 1995;274:1311-16
CPOE : Friend or Foe?
►
Recently, institutions are beginning to critically
assess electronic systems, such as CPOE
►
VA Medical Center in Salt Lake City:
●
●
●
►
74% of medication errors occur during prescribing
11% during administration
0% during transcription
Bates et al. study:
●
●
●
56% of medication errors - prescribing
24% of medication errors – administration
6% of medication errors – transcription
Nebeker JR et al. Arch of Intern Med 2005;165:1111-16.
CPOE : Friend or Foe?
►
VA Medical Center attributed low error rates
during the transcription and administration to
information system upgrades such as:
●
►
Bar code technology during administration, EMAR and
computerized drug-drug interaction and allergy
screening
Concluded that their systems are working as
designed but lack decision support within CPOE
leading to high error rates during prescribing
Nebeker JR et al. Arch of Intern Med 2005;165:1111-16.
CPOE Alerts
►
Institutions that utilize decision support and
computerized alerts during prescribing have
reported high rates of physician override
►
A study conducted at BIDMC reported that
94.2% of computerized alerts were overridden
►
Reviewers concluded of the 189 rules studied,
36.5% of the rules were invalid and agreed
with the physician’s decision 97.9% of the
time
Weingart SN et al. Arch of Intern Med 2003;163:2625-31.
Saving CPOE from Extinction
► CPOE must evolve to keep up with the growing
demand for effective medical informatics and
technology solutions
► Next generation of CPOE will utilize algorithms
that take into account patient specific factors and
generate prescribing recommendations to
providers
► One area in which CPOE has proven beneficial is
VTE prophylaxis
Medical Error Rates
►
►
Two errors per day = 99% proficiency level
If 99% was good enough:
–Airline industry = 2 unsafe landings per day
–Mail industry = 16,000 pieces of mail lost every hour
–Banking industry = 32,000 checks deducted from the wrong
account per hour
►
How do we transform health care into a high
reliability industry?
Leape LL. JAMA. 1994;272:1851-7.
Background
►
At Brigham and Women’s Hospital,
we have initiated a series of trials
aimed at increasing prophylaxis by:
●
●
Changing MD behavior and
Improving the implementation of
prophylaxis strategies
Types of Interventions
►
Electronic computer generated alerting
systems
►
Efficacy of these alerting systems have
been studied in:
●
●
RCT trial of a 1-screen alert
Cohort study of a 3-screen alert
First Generation Electronic Alerts
►
BWH utilizes BICS (Brigham Integrated
Computing System) for all order entry functions
●
►
Admitting records, demographic information,
lab results, medication orders, etc.
VTE group utilized computer system to screen
all patients admitted to the hospital for High Risk
VTE status
First Generation Alert: Development
►
Aim: to increase rate of prophylaxis in patients
at risk for DVT and PE
►
Developed computer program to detect and
identify which patients were at risk
►
Alert the responsible physician of high risk
patient (via e alert) and offer opportunity to
order appropriate prophylaxis
Study Schema
All Adult Patients
DVT Risk Score > 4
YES
Presence of
Prophylaxis
NO
Generate Alert
Definition of “High Risk”
VTE risk score ≥ 4 points:
►
►
►
►
►
►
►
►
Cancer
Prior VTE
Hypercoagulability
Major surgery
Bed rest
Advanced age
Obesity
HRT/OC
3
3
3
2
1
1
1
1
(ICD codes)
(ICD codes)
(Leiden, ACLA)
(> 60 minutes)
(“bed rest” order)
(> 70 years)
(BMI > 29 kg/m2)
(order entry)
Randomization
VTE Risk Score > 4
No Prophylaxis
N = 2506
Intervention
Control
Single Alert
No Alert
n = 1255
n = 1251
Kucher N, et al. NEJM 2005;352:969-977
Physician Notification of Alerts
First Generation
Computerized Alerts for VTE Prevention
►
Utilization of computer
generated alerts to house
staff reduced the
incidence of VTE by 41%
►
VTE prophylaxis was
prescribed in 33.5% of
patients in the
intervention group
►
Following study
conclusion a follow up
cohort study was
conducted
Kucher N, et al. NEJM. 2005;352:969-977.
Alerts
Second Generation:
Electronic Computer
Generated Alerts
BWH VTE Alerts: The Future
►
Goals:
● Engage the house officer with an
interactive alert to increase acceptance
and gain feedback
●
Update the DVT prophylaxis template to
meet current practice guidelines
●
Provide real-time knowledge links
Interactive Techniques
►
Provide objective data to the house officer
that this alert positively impacts patient
outcome
►
Create opportunity to capture rationale for
declining alert
●
Hypothesized that many physicians fear a risk
of bleeding with anticoagulation
►
Provide a final opportunity to order
mechanical prophylaxis
►
Alert attending physician if alert is not
acknowledged after 24 hours
DVT Alert Screen
Rule Logic – Alert Details
Option A
Option C or “Done”
Escalation and Timing of Alerts
►
Alerts should be set up to generate each day
at 8:30 AM
►
If an alert was not acknowledged after 24
hours the attending physician on record
should be text paged.
Quality Assurance
►
Weekly reports are reviewed
►
Allows core team to review all aspects of the
alerts including:
● Type of action taken
● Rate of overrides
● Rational for declining the alerts
►
Results coming soon
Alerts
Pharmacy/Physician
Collaboration
Human Alerts
VTE Prophylaxis: hALERT
►
Multicentered RCT of human alerts (hALERT).
►
Objective: to recruit hospitals that differ from BWH
re: IT, community vs. academic, urban vs.
suburban/rural, location within USA.
►
Can a human alert be more effective than an
electronic alert?
Methodology
►
Patients admitted to the hospital are screen by
human for increased VTE risk
►
High risk patients are randomized to alert or no
alert
►
Physicians of patients in alert group receive
page alerting them of high risk status
►
Records are checked for prophylaxis order 48
hours after alert
►
90 day follow up for clinically significant VTE
and clinically importing bleeding
hALERT: Capturing New
Prophylaxis Orders
►
Enrolled patients must be reexamined in 24-48
hours to determine whether prophylaxis orders
were written.
►
Capturing prophylaxis orders after enrollment
applies to both the Intervention Group and to the
Control Group.
Human Alert Trial
1. Human (often RN or pharmacist) issues the
Alert, not a computer
2. The attending physician, not the intern,
receives the Alert
3. Diversity of centers: community, suburban,
throughout the USA
4. Will attendings pay more attention than house
staff?
Conclusions
►
Changing behavior is challenging
►
Multi-disciplinary team involvement is critical to
successful implementation
►
Need to engage providers and obtain feedback
►
Designing “smart alerts” that include decision
support functionality or “human alerts” that require
face to face contact may be effective
Alerts
Electronic Alerts to
Prevent Infusion Errors
Patient Case—Infusion Pump Error
Error Description
► 57 YOM endstage CMP
►
8:45 PM aPTT = 75.1
►
►
1:13 AM Protamine 25mg
►
1:28 AM aPTT = >150
►
3:13 AM aPTT = >150
►
3:32 AM Protamine 26mg
►
2 Units PRBC
►
4:08 AM aPTT = >150
►
8:21 AM aPTT = 44.4
►
►
►
►
EF = 10%
Heart transplant candidate
with BIVAD
Receiving UFH 900 units
per hour (9 mls/hr)
New order to reduce
Heparin 800 units per hour
@ 10:22 PM
Infusion pump set for 800
mls per hour
Background
National Data
Rank
Medications Causing Harm
•Heparin has been identified both
nationally and internally at BWH as a
medication frequently associated with
ADE
1.
Insulin
2.
Morphine
•Removed access to different formulations
3.
Heparin
•Standardized UFH Concentration
4.
Warfarin
•Calculate infusion rates in OE
5.
Potassium
6.
Furosemide
7.
Vancomycin
8.
Hydromorphone
9.
Meperidine
10.
Diltiazem
MEDMARXSM 2001. The United States Pharmacopoeia
(USP)Convention Inc.
UFH Error Analysis: BWH
►
1 event per 1,000 patients
●
●
●
►
52% - Administration related
31% - Equipment failure, rate or dosing error
23% - Infusion Pump
6% - Prolonged LOS or significant harm
***Patient Safety Initiative: Hospital invested 3
million dollars in state of the art infusion pumps***
Fanikos J et al. Medication Errors associated with anticoagulation therapy in the hospital. Am J Cardiol
2004;94:532-535
Objectives
►
Evaluate impact of “smart” infusion
technology on anticoagulation
administration
►
To determine if infusion technology
equipped with drug libraries may
reduce medication errors
Features of the “Smart” Pumps
►
“Smart” pumps share safety features of older
pumps including dose calculation functions, freeflow protection and occlusion alerts
►
“Smart” pumps also equipped with a drug library
●
●
Provide dose and rate limits on commonly used
medications
Provide users with overdose and underdose
alerts based on predetermined limits defined by
the drug library
Methods
►
►
►
We programmed the drug
library to alert for overdoses
or underdoses
Underdose
Alert
Overdose
Alert
Alerts where subsequently
recorded in the device’s
electronic memory, along
with the user’s next action
UFH
<300 units/hour
>2,800
units/hour
Argatroban
<0.5 mcg/kg/min >10 mcg/kg/min
We retrospectively reviewed
all anticoagulant alerts and
the user’s next action for all
devices from 10/2003
through 1/2005
Lepirudin
<5 mg/hour
>16.5 mg/hour
Bivalirudin
<0.2 mg/kg/hour
>1.8
mg/kg/hour
Medication
Dosing Errors and their Magnitude
Data Entry Errors Frequently
Repeated with UFH
27.2 % entry errors User
repeated the error
Alerts by Time of Day
Conclusions
►
The drug library and its alerting system
intercept programming errors
►
Despite alerts, data entry errors are
frequently repeated by the user
►
The highest alert incidence occurs on
weekdays between 2 PM and 4 PM,
corresponding to Nursing Shift change