Venous Thromboembolism (VTE) Recent Advances in Reducing the Disease Burden Gary E. Raskob, Ph. D. Dean, College of Public Health Regents Professor, Epidemiology and Medicine University of Oklahoma Health Sciences Center CDC Division of Blood Disorders, Webinar November 6, 2014
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Venous Thromboembolism (VTE): Recent Advances in Reducing the Disease Burden
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Venous Thromboembolism (VTE)
Recent Advances in Reducing the Disease Burden
Gary E. Raskob, Ph. D.
Dean, College of Public Health
Regents Professor, Epidemiology and Medicine
University of Oklahoma Health Sciences Center
CDC Division of Blood Disorders, Webinar November 6, 2014
Disclosures for Dr. Gary Raskob
Research Support None
Employee None
Consultant Bayer HealthCare, BMS, Daiichi-Sankyo,
Isis, Janssen, Johnson and Johnson,
Pfizer, Quintiles
Patents None
Stockholder None
Honorarium Bayer, BMS, Daiichi, Isis, Janssen,
Johnson and Johnson, Pfizer
Scientific Advisory
Board
Bayer HealthCare, BMS, Daiichi-Sankyo,
Janssen, Johnson and Johnson, Pfizer,
National Blood Clot Alliance
Objectives
Describe the burden of disease from VTE
Describe the clinical features of VTE
Describe the difference between provoked and unprovoked VTE
Describe the risk factors for VTE and the steps people can take to reduce their risk of VTE
Describe the evidence-based recommendations for treatment of VTE
Describe how recent advances in oral anticoagulant therapy may help reduce the burden of VTE
Describe the evidence - based strategies for the prevention of new cases of VTE
Disease Burden of VTE
1 to 3 episodes per 1,000 population
2 to 7 per 1,000 population age > 70 yrs
547,596 hospitalizations with VTE in US 2007- 2009
Estimated 900,000 cases per year in US
100,000 to 300,000 VTE-related deaths in US each year
684,000 DVT, 434,000 PE, and 543,000 VTE-related
deaths in European Union 2004 (pop 454.4 million)
VTE a leading cause of hospital - associated
premature death and disability (DALY) world wide
Heit J, Cohen A, Anderson F. Estimated annual number of incident and recurrent, fatal and non-fatal venous
thromboembolism (VTE) events in the US. Blood 2005;106:267a
Yusuf H et al. MMWR 2012; 61: 22: 401 – 404
ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden.
J Thromb Haemost 2014; 12: doi: 10.111/jth.12698
Venous Thromboembolism (VTE)
Image from VF Tapson. NEJM 2008; 358: 1037
Deep-vein thrombosis (DVT)
Pulmonary embolism (PE)
40% of non-fatal cases
Severity depends on size and
cardiopulmonary reserve
Sub-segmental PE has important
risk of recurrence
30% to 70% have residual DVT
60% of non-fatal cases
Proximal DVT prognostic marker
for recurrence and mortality
Virchow’s triad• Surgery
• Trauma
• Indwelling
catheter
• Atherosclerosis
• Heart valve
disease or
replacement
Venous stasis
• Acute phase postop
• Cancer
• Thrombophilia
• Estrogen therapy
• Pregnancy and
postpartum period
• Inflammatory bowel
disease
• Immobility or paralysis
• Heart failure
• Venous insufficiency or varicose veins
• Venous obstruction from tumour, obesity or pregnancy
Virchow R, ed. Gesammelte Abhandlungun zur Wissenschaftichen Medicin. Von Meidinger Sohn, Frankfurt, 1856.
- 7 -
LACK OF AWARENESS THAT CANCER, HOSPITALIZATION, AND RECENT SURGERY ARE MAJOR RISK FACTORS FOR VTE
16%
CANCER
Among countries measured, an average (mean) of 16% of respondents considered
a risk factor for blood clots
25%HOSPITAL STAYS
Among countries measured, an average of 25% of respondents considered
a risk factor for blood clots
36%
SURGERY
Among countries measured, an average of 36% of respondents considered
a risk factor for blood clots
Clinical Presentations of VTE
Provoked (70% of all patients)
Associated with known risk factors
Hospital, surgery, cancer, medical illness
Risk factors may be continuing (cancer, APLA)
If risk factor reversible (transient), 2% per year recurrence
after 3 months of anticoagulant therapy
Unprovoked (30% of all patients)
Absence of identifiable risk factor
Also called “idiopathic”
7% to 11% per year recurrence for DVT or PE
if anticoagulant therapy stopped after 3, 6,12 or 24 months
Kearon C, Akl E. Blood 2014; 123 (12) 1794-1801.
Boutitie F et al. BMJ 2011, May 24;342:d3036
Goals of Treatment for VTE
Prevent death from pulmonary embolism
Prevent symptomatic recurrent VTE25% risk of symptomatic recurrent VTE during 3 if inadequate therapy
Prevent and/or reduce morbidity frompost-thrombotic syndrome (PTS) 25% at 2 yr
chronic pulmonary hypertension 4% at 2 yr
Minimize the risk of bleeding and other side effects
Evidence- based Guidelines for Treatment of VTE
AHA Guidelines PE, iliofemoral DVT, CTEPH Jaff M et al Circulation 2011; 123: 1788 – 1830
American College of Chest Physicians (ACCP) 9th ed 2012 Kearon et al CHEST 2012; 141: (2) Suppl: e419s-e494s
International Union of Angiology - Consensus Statement Nicolaides AN et al Int Angiology 2013; 32: 111-260
Treatment of Venous Thromboembolism Wells P et al JAMA 2014; 311: 717-728
European Society of Cardiology 2014 ESC Guideline on the diagnosis and management of acute pulmonary embolism European Heart Journal 2014; doi 10.1093/eurheart/ehu283
Treatment of VTE
9th ACCP Guideline Recommendations Anticoagulant therapy over other approaches for most
acute DVT or PE (2C) parenteral therapy using LMWH or fondaparinux (1B) long-term therapy for at least 3 months (1B) evaluate risk-benefit of extended therapy
Catheter - Directed Thrombolytic (CDT) therapy for DVTanticoagulant therapy alone over CDT most patients (2C) selected patients with DVT may benefit
Anticoagulant therapy over no anticoagulation for extensive superficial vein thrombosis (2B) (fondaparinux over LMWH, 2C)
Thrombolytic therapy for PE acute PE + hypotension (2C) acute PE, high risk of hypotension, low risk of bleeding (2C) intracranial bleeding in 2 to 3% in contemporary studies
Inferior vena cava filter anticoagulants contraindicated (1B) Kearon et al CHEST 2012; 141:
(2) Suppl: e419s - e494s
5 to 10 days 3 to 6 months > 6 months
Vitamin K Antagonists
LMWH
Heparin
LMWH
Fondaparinux
Thrombolysis
Thrombus Removal
IVC filter
Treatment of Venous Thromboembolism
Initial treatment
Long term-treatment
Extended treatment
Vitamin K Antagonists
Direct oral anticoagulants
Generic
Name
Brand
Name
Enzyme
Target
Renal
Clearance
Half
Life (hr)
Dabigatran Pradaxa Thrombin 80% 14 - 17
Rivaroxaban Xarelto Xa 33% 7 - 11
Apixaban Eliquis Xa 25% 8 - 12
Edoxaban Savaysa Xa 35% 8 - 10
Wells P et al JAMA 2014; 311: 717 - 728
Direct oral anticoagulants for VTE
FDA approved indications and regimens
Rivaroxaban (November 2012) Treatment of Deep Vein Thrombosis (DVT) Treatment of Pulmonary Embolism (PE) Reduction in the risk of recurrence of DVT and PE 15 mg orally twice daily with food for first 21 days (initial treatment), then 20 mg orally once daily with food
Dabigatran (April 2014) Treatment of Deep Venous Thrombosis and Pulmonary Embolism Reduction in the risk of recurrence of DVT and PE 150 mg orally twice daily after 5 to 10 days of parenteral anticoagulation
Apixaban (August 2014) Treatment of Deep Vein Thrombosis Treatment of Pulmonary Embolism 10 mg orally twice daily for 7 days, then 5 mg orally twice daily Reduction in the risk of recurrence of DVT and PE2.5 mg orally twice daily
VTE treatment studies Direct oral anticoagulants
Hokusai-VTE AMPLIFY EINSTEIN-DVT
EINSTEIN-PE
RE-COVER I
RE-COVER II
Drug Edoxaban Apixaban Rivaroxaban Dabigatran
Study design Double-blind Double-blind Open label Double-blind
Heparin lead-in At least 5 days None None At least 5 days
Dose 60 mg qd
30 mg qd
(CrCl, bw, P-gp)
10 mg bid x 7 days
then 5 mg bid
15 mg bid x 3 wk
then 20 mg qd
150 mg bid
Non-inferiority
margin
1.5 1.8 2.0 2.75
Sample size 8,292 5,400 EINSTEIN-DVT
3,449
EINSTEIN-PE
4,832
RE-COVER I
2,564
RE-COVER II
2,568
Treatment
duration
Flexible
3 to 12 months
6 months Pre-specified
3, 6, or 12 months
6 months
Adapted from Raskob et al. J Thromb Haemost 2013; 11: 1287 - 1294
Clinical Trials of Rivaroxaban for VTE
16
N=1,197
Double-blind, superiority
Rivaroxaban 20 mg od
Placebo
6 or 12 months
ROpen-label, non-inferiority
N~4,50015 mg bid
Rivaroxaban
Day 21
Enoxaparin bid for at least 5 days, plus
VKA target INR 2.5 (INR range 2–3)
20 mg od
Rivaroxaban
R
3, 6, or 12 months
15 mg bidN=3,449
Rivaroxaban
Day 21
Enoxaparin bid for at least 5 days, plus
VKA target INR 2.5 (INR range 2–3)
3, 6, or 12 months
20 mg od
Rivaroxaban
R
Open-label, non-inferiority
Outside of the EINSTEIN programme
Patients with confirmed symptomatic DVT
or PE completing 6 or 12 months of VKA
N Engl J Med 2010;363:2499-510
N Engl J Med 2012; 366:1287 -1297
EINSTEIN DVT Trial Recurrent VTE
1717
Cu
mu
lati
ve e
ven
t ra
te (
%)
0 30 60 90 120 150 180 210 240 270 300 330 360
0
1.0
2.0
3.0Rivaroxaban (N=1,731)
Enoxaparin/VKA (N=1,718)4.0
Time to event (days)
Rivaroxaban
(n / N)
Enox / VKA
(n / N)
HR
(95% CI)
No. of
events
36 / 1,731
2.1%
51 / 1,718
3.0%
0.68
(0.44–1.04)
1.00 0
0.44 1.040.68
Hazard ratio
Rivaroxaban
superior
Rivaroxaban
non-inferior
Rivaroxaban
inferior
p=0.076 for superiority (two-sided) p<0.0001 for non-inferiority (one-sided)
* Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin group respectively
** Denominator is number of patients with index PE : 1650 and 1669 in edoxaban and warfarin group respectively
Hokusai VTE Trial Bleeding outcomes
Edoxaban
(N=4118)
Warfarin
(N=4122)
Hazard ratio
(95% CI)P Value
First major or clinically
relevant non major – no. (%) 349 (8.5) 423 (10.3) 0.81
(0.71-0.94)0.004
superiority
Major – no. (%) 56 (1.4) 66 (1.6) 0.84
(0.59-1.21)
0.35 superiority
Fatal 2 (<0.1) 10 (0.2)
Intracranial 0 6 (0.1)
Non-Fatal in Critical Sites 13 (0.3) 25 (0.6)
Intracranial 5 (0.1) 12 (0.3)
Non-Fatal in Non-Critical Sites 41 (1.0) 33 (0.8) †
Clinically Relevant Non-
Major– no. (%)
298 (7.2) 368 (8.9) 0.80
(0.68-0.93)
0.004 superiority
29† some patients have more than 1 bleeding
N Engl J Med 2013; 369:1406-15
NNT = 56
Anticoagulant Treatment of VTE
Risk-Benefit of DOAC vs. Vitamin K Antagonist DOAC VKA
Absolute risk of recurrent VTE
RR 0.90 (95% CI 0.77 to 1.06)2.0 % 2.2 %
Absolute risk of major bleeding
NNT = 147 1.1 % 1.8 %
Absolute risk of intracranial
bleeding
NNT = 588
0.1 % 0.3 %
Absolute risk of fatal bleeding
NNT = 1, 2500.1 % 0.2 %
van Es N et al. Blood 2014; doi 10.1182/blood-2014-04-571233
Acute PE without shock or hypotension
ESC 2014 Guideline Recommendations
Anticoagulant is recommended with objective to prevent both early death and recurrent symptomatic or fatal VTE parenteral anticoagulation LMWH or fondaparinux (I A) in parallel, VKA target INR 2.5 (range 2.0- 3.0) (I B)
Alternative to combined parenteral anticoagulation with VKA rivaroxaban 15 mg bid x 3 weeks, followed by 20 mg daily (I B) apixaban 10.0 mg bid x 7 days, followed by 5.0 mg bid (I B)
Alternative to VKA treatment , following parenteral anticoagulation dabigatran 150 mg bid (110 mg age > 80 yr, or verapamil) (I B) edoxaban (subject to regulatory review) (I B)
European Heart Journal 2014
doi:10.1093/eurheartj/ehu283
Duration of Anticoagulant Therapy
9th ACCP Recommendations
First episode VTE
Provoked
(surgery or reversible risk factor) 3 months over longer therapy (1B)
Unprovoked at least 3 months (1B), evaluate for extended therapy
Qaseem A et al. Venous thromboembolism prophylaxis in hospitalizedpatients: A Clinical Practice Guideline from the
American College of Physicians. Annals of Internal Medicine 2011; 155: 625-632.
American College of Chest Physicians Guidelines: 9th Edition
• For the Non-surgical and Non-orthopedic surgical chapters, a primary shift is towards an individualized approach of risk assessing the patients’ bleeding risk factors as well as their VTE risk factors for the appropriate thromboprophylactic strategy
Kahn et al. CHEST 2012; 141:(2 Suppl): e195S-226S
Absolute Risk Differences
Study Major VTE Major Bleeding
EXCLAIM (n= 5,963) - 1.5 % + 0.5 %
enoxaparin 40 mg od NNT 67 NNH 200
MAGELLAN (n= 8,101) - 1.3 % + 0.7 %
rivavoxaban 10 mg od NNT 77 NNH 143
ADOPT (n= 6,528) - 0.39 % (NS) + 0.3 %
apixaban 2.5 mg bid NNT ? NNH 333
Clinical Trials of Extended Duration (28 - 35 days)
vs 10 days of Prophylaxis in Medical Patients
Hull R et al Ann Intern Med 2010; 153: 8-18.
Cohen et al. N Engl J Med 2013; 368: 513 - 523
Goldhaber et al. N Engl J Med 2011; 365: 2167-2177
9th ACCP Recommendations
2.8. For acutely ill hospitalized medical
patients who receive an initial course of
thromboprohylaxis, we suggest against
extending the duration of
thromboprophylaxis beyond the period
of patient immobilization
or acute hospital stay (Grade 2B)
Kahn et al. CHEST 2012;141;e195S-e226S
Primary Endpoint: Composite of Symptomatic VTE or VTE-Related Death
Sample size Placebo RRR ARR Events Power for
superiority
2 sided α
8,000 2.5% 40% 1.0% 161 90% 5%
Estimated Sample Size
Reducing the Disease Burden of VTE
VTE is a “winnable battle”
Improve utilization of effective prevention
If you are hospitalized or having surgery,
ask about your VTE risk and prevention
New oral anticoagulants improve safety and
enhance secondary prevention of recurrent VTE
Improve public awareness of VTE, risk factors
and prevention
Continued research
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