Newer Oral Anticoagulants or warfarin in DVT/PE

Satyam Rajvanshi
SR Cardiology

Fact
VTE is deadly!
It nibbles after it bites!

 30-day and 1-year case-fatality rates after VTE 1
 10.6% and 23.0%, respectively
 The 30-day mortality rates for first-time DVT or pulmonary
embolism 2
 3.0% and 31%, respectively
 Long term sequelae 3
 DVT – Post thrombotic syndrome – upto 50%
 PE – CTEPH – Upto 4%
1 Am J Med 2013;126:832.e13–21
2 Circulation 2014;130:829–36
3 N Engl J Med 2004;350:2257–64

 Retrospective data 1996-2005
 Incidence of VTE : 17.46 per 10 000 admissions
(438 667 admissions, 722 were diagnosed with VTE)
 45% had primary DVT while 55% had secondary DVT. No significant age or sex
differences between primary and secondary DVT (36.8 vs. 51.8 years).
 Incidence due to surgery: 5 per 10000
(236 532 operations, 119 patients had DVT - none had received prophylaxis for DVT)
 Pulmonary embolism : 14.9% of the 722 patients
 Mortality in those with PE : 50% !!
Eur J Vasc Endovasc Surg, 2009:37;482-85

Clinical and Applied Thrombosis/Hemostasis 2008:14(2);159-67
November 1997 to January 2004
Pulmonary embolism fatal + significant
contribution to death – 126 patients (79.2%)
Clinical diagnosis of PE was suspected
antemortem only in 15 patients (9.4%)
Primary Diagnosis %
Sepsis 32
Respiratory disease 28
Hepatobiliary and
pancreatic diseases
18
Cardiovascular
disease
15
Malignancy 14
CNS diseases 10
Renal diseases 9

 VTE tends to recur
 10-year rate of recurrence 25% 1
 Recurrence peaks in first 6 months - 11% per patient-year 1
 Decreases after 3 years - 2% per patient-year up to 10 yrs 1
 Risk for recurrence is similar after DVT or pulmonary embolism 2
 However, PE comes back as PE, and DVT as DVT 2
1 BMJ 2011;342:d3036
2 Ann Intern Med 2003;139:19–25

Fact
Even if its treated well, its still not SAFE out there!

 During well-conducted anticoagulation
 Rate of recurrent VTE - 2% at 3 months!
 Major bleeding - 2.2% at 3 months!
 Case fatality and morbidity remains high
 After anticoagulant stopped, recurrence rate
 3% per year in Surgery/Trauma provoked
 10% per year in cancer-associated VTE
 15% at 2 years in unprovoked VTE
J Thromb Haemost 2010;8:1216–22
Thromb Haemost 2013;110:834–43
Lancet 2003;362:523–6
N Engl J Med 2001;345:165–9

Patient 1
 A 50-year-old woman is re-admitted to the hospital with
mild-to-moderate dyspnoea 10 days after surgical
cholecystectomy. Examination reveals a swollen right calf
and no other pathological findings. She is on regular
NSAIDs for rheumatoid arthritis.
 Acute subsegmental pulmonary embolism (PE) and
proximal deep vein thrombosis are confirmed by CTPA and
USG, respectively.
 She strongly desires to be discharged immediately and
receive treatment at home.

Patient 2
 A 78-year old man, known case of diabetic nephropathy
stage 3, with a recent (4 weeks ago) admission to hospital
for hip replacement under general anaesthetic. During
prior admission, he received antiembolism stockings and
S/C LMWH as VTE prophylaxis.
 He now presents with 3-day history of breathlessness. He
has hypotension and hypoxia. CTPA revealed PE in
segmental arteries. USG revealed right proximal
iliofemoral DVT. Echo revealed RV dysfunction.

Patient 3
 A 42-year-old bussinessman presents to your OPD
department following referral from his physician. He
reports shortness of breath at rest and chest pain. On
direct questioning he admits to pain in the right calf for a
month, which he put down to muscle sprain.
 His vital signs are normal. Echo was normal. But D-dimer
was positive. CTPA revealed emboli in subsegmental
branches bilaterally. Lower limb venous doppler was
normal.

 Middle aged female after surgery.
 Acute subsegmental PE and DVT.
 Mild symptoms.
 On NSAIDs.
 Wants early discharge and home medication.

Acute management
 No need of thrombolysis – Minor PE

Current ‘standard of care’

VK
Va
Targets of Older Anticoagulants
Xll
Xl
lX
X
VII
TF
II
I
Fibrin Clot
VIIIa
UFH
LMWH
Fondaparinux
UFH = unfractionated heparin; LMWH = low molecular-weight heparin; VK = vitamin K; ATIII = antithrombin III.
Adapted from Ansell J. J Thromb Haemost. 2007;5(suppl 1):60-64.
Hirsh J et al. Circulation. 2007;116:552-560.
Hirsh J et al. J Am Coll Cardiol. 2003;41:1633-1652.
Argatroban
Vitamin K
antagonists
ATIII
ATIII
Bivalirudin

Targets of NOACs
Focus of clinical trials
 VTE prevention and
treatment
 Stroke prevention in AF
Va
Xll
Xl
lX
X
VII
TF
II
I
Fibrin Clot
VIIIa
Factor Xa inhibitors
Direct thrombin inhibitors
*Dabigatran was approved for VTE prophylaxis in Canada, the EU, and Columbia in 2008.
Adapted from Ansell J. J Thromb Haemost. 2007;5(suppl 1):60-64. Turpie AGG. Arterioscler Thromb Vasc Biol. 2007;27:1238-124
Inhibition
National Institutes of Health - ClinicalTrials.gov. - last accessed July 2013

Dabigatran Edoxaban Rivaroxaban Apixaban
Trial RECOVER I &
II
HOKUSAI EINSTEIN-PE AMPLIFY
Number(n) 2539+2568 8240 4832 5365
Mean age (yrs) 54.8 55.8 57.7 57.0
CrCl < 30 ml/min
(%)
0.4% - 0.1% 0.5%
Age > 75 y (%) 10% 13% 17% 14%
Unprovoked VTE 35% 65% 64% 90%
PE +/- DVT 31% 40% 100% 34%
Bridge with
UFH/LMWH
YES YES NO NO
Treatment protocol 150 mg BD 60 mg OD or
30 mg OD
15 mg BD for
3 wk; then
20 mg OD
10 mg BD for
1 wk; then
5 mg BD

Journal.pone.0144856 December 30, 2015

All NOACs showed similar efficacy to standard
treatment
All NOACs showed non-inferiority in bleeding risk
Apixaban showed superiority in bleeding risk
J Plos one. 2015; 0144 856

Risk-benefit of NOAC vs VKA
First recurrent VTE or VTE related death
Blood 2014;124:1968-1970

Intracranial, major GI, fatal, and Clinically relevant Non-major bleed
Blood 2014;124:1968-1970

Blood 2014;124:1968-1970

 Cost of care
 VKA < LMWH < NOACs
 But VKA require periodic monitoring – overall cost increases
Blood 2014;124:1968-1970

 Cost of care
 Convenience
 NOACs – no monitoring required
Blood 2014;124:1968-1970

 Cost of care
 Convenience
 NOACs – no monitoring required
 Rivaroxaban, Apixaban – showed similar efficacy to standard
treatment WITHOUT overlap
Blood 2014;124:1968-1970

 Elderly male after hip surgery.
 Acute massive PE and DVT.
 Severe symptoms.
 Underlying renal dysfunction.

Acute management
 Thrombolysis indicated
 Initial Heparin indicated - UFH
 No outcome data with NOACs in Massive PE - excluded

NOAC option in long term?
 Key pharmacokinetics

NOAC option in long term?
 Renal function impact on NOAC half lives

Switching between NOAC and VKA

 Middle aged male.
 Unprovoked minor subsegmental PE.
 Mild symptoms.

NOACs VTE Rx Extension Clinical Trials: Design
Head-to-head studies do not exist, and direct comparisons between agents should not be made.
* Defined in several studies as the composite of DVT or nonfatal or fatal PE. PE was considered the cause of death if there was objective
documentation (eg, autopsy) or if death could not be attributed to a documented cause and PE could not be confidently ruled out.
1. Agnelli G et al. N Engl J Med. 2013;368:699-708.
2. Bauersachs R et al. N Engl J Med. 2010;363:2499-2510.
3. Schulman S et al. N Engl J Med. 2013;368:709-718.
Drug Trial Patients
Design/
Tx Before
Randomization
Study Drug
vs
Comparator
Length
of Tx
(mo.) Primary Efficacy
Primary
Safety
Apixaban1
AMPLIFY
Extended
Therapy
2486
Double-blind/
6-12 mo. of
anticoagulant
2.5 mg or
5 mg BID
vs
Placebo
12
Symptomatic,
recurrent VTE
or all-cause death
Major
Bleeding
Rivaroxaban2 EINSTEIN
Extension
1197
Double-blind/
6-12 mo. of VKA
or rivaroxaban
20 mg QD
vs
Placebo
6 or 12
Symptomatic,
recurrent VTE*
Major
Bleeding
Dabigatran3 RE-SONATE 1353
Double-blind/
6-18 mo.
of VKA
150 mg BID
vs
Placebo
6
Symptomatic,
recurrent VTE*
Major
Bleeding
Dabigatran3 RE-MEDY 2866
Double-blind/
3-12 mo.
VKA or
dabigatran
150 mg BID
vs
Warfarin
INR 2.0-3.0
6-36
Symptomatic,
recurrent VTE*
Major
Bleeding

NOACs VTE Rx Extension Clinical Trials:
Patient Characteristics
Drug Trial
Age
(y)
Male
(%)
Index
Event
PE (%)
Unprovoked
(%)
Prior
VTE
(%)
Active
Cancer
(%)
History
Cancer
(%)
Known
Thrombophilia
(%)
Apixaban
AMPLIFY-
EXT
~57 57.4 34.6 91.7 12.7 1.7 NR
3.8
(Inherited)
Rivaroxaban
EINSTEIN-
EXT
~58 58.0 38.0 73.7 16.0 4.6 NR 8.1
Dabigatran
RE-
SONATE™
~56 55.5 33 NR 0 Excluded 6.1 11.5
RE-
MEDY™
~55 61 35 NR 53.4 4.2 -- 18.4

NOACs VTE Rx Extension Trials: Efficacy Results
Primary Efficacy Endpoints*
Drug Trial
Length
of Tx Comparator
Study Drug
Dose
Drug vs Comp,
Rates (%) RR P-value
Apixa AMPLIFY
Extension
12 mo. Placebo
2.5 mg 2.3 vs 9.3 0.24 <0.0001 (sup)
5 mg 1.7 vs 9.3 0.19 <0.0001 (sup)
Riva
EINSTEIN
Extension
6-12 mo. Placebo 20 mg 1.3 vs 7.1 0.18 <0.001 (sup)
Dabi RE-SONATE™ 6 mo. Placebo 150 mg 0.4 vs 5.6 0.08 <0.0001 (sup)
Dabi RE-MEDY™ 6-36 mo. Warfarin 150 mg 1.8 vs 1.3 1.44 0.01 (NI)
= primary efficacy outcomes

NOACs VTE Rx Extension Trials: Efficacy Results
Primary Efficacy Endpoints*
Drug Trial
Length
of Tx Comparator
Study Drug
Dose
Drug vs Comp,
Rates (%) RR P-value
Apixa AMPLIFY
Extension
12 mo. Placebo
2.5 mg 2.3 vs 9.3 0.24 <0.0001 (sup)
5 mg 1.7 vs 9.3 0.19 <0.0001 (sup)
Riva
EINSTEIN
Extension
6-12 mo. Placebo 20 mg 1.3 vs 7.1 0.18 <0.001 (sup)
Dabi RE-SONATE™ 6 mo. Placebo 150 mg 0.4 vs 5.6 0.08 <0.0001 (sup)
Dabi RE-MEDY™ 6-36 mo. Warfarin 150 mg 1.8 vs 1.3 1.44 0.01 (NI)
= primary efficacy outcomes
All NOACs achieved superiority in
the reduction of their primary
efficacy outcome when compared
to placebo
Dabigatran was non-inferior to
warfarin in RE-MEDY

NOACs VTE Rx Exension Trials: Safety Results
59
Study
Drug Trial
Length
of Tx Comparator Dose
Primary Safety Outcome
(Major Bleeding) Major or CRNM Bleeding
Drug vs
Comp Rates
(%) HR P-value
Drug vs
Comp Rates
(%) HR P-value
Apixa
AMPLIFY
Extension
12 mo. Placebo
2.5 mg 0.2 vs 0.5 0.49 0.39 3.2 vs 2.7 1.2 0.51
5 mg 0.1 vs 0.5 0.25 0.18 4.3 vs 2.7 1.62 0.07
Riva
EINSTEIN
Extension
6 or 12
mo.
Placebo 20 mg 0.7 vs 0 NA 0.11 6.0 vs 1.2 5.19 <0.001
Dabi RE-SONATE™ 6 mo. Placebo 150 mg 0.3 vs 0 NA 1.0 5.3 vs 1.8 2.92 0.001
Dabi RE-MEDY™
6-36
mo.
Warfarin 150 mg 0.9 vs 1.8 0.52 0.06 5.6 vs 10.2 0.54 <0.001
= primary safety outcomes

NOACs VTE Rx Exension Trials: Safety Results
60
Study
Drug Trial
Length
of Tx Comparator Dose
Primary Safety Outcome
(Major Bleeding) Major or CRNM Bleeding
Drug vs
Comp Rates
(%) HR P-value
Drug vs
Comp Rates
(%) HR P-value
Apixa
AMPLIFY
Extension
12 mo. Placebo
2.5 mg 0.2 vs 0.5 0.49 0.39 3.2 vs 2.7 1.2 0.51
5 mg 0.1 vs 0.5 0.25 0.18 4.3 vs 2.7 1.62 0.07
Riva
EINSTEIN
Extension
6 or 12
mo.
Placebo 20 mg 0.7 vs 0 NA 0.11 6.0 vs 1.2 5.19 <0.001
Dabi RE-SONATE™ 6 mo. Placebo 150 mg 0.3 vs 0 NA 1.0 5.3 vs 1.8 2.92 0.001
Dabi RE-MEDY™
6-36
mo.
Warfarin 150 mg 0.9 vs 1.8 0.52 0.06 5.6 vs 10.2 0.54 <0.001
= primary safety outcomes
All NOACs showed noninferiority
in the reduction of their primary
safety outcome when compared to
placebo

NOAC endorsement by evidence
based guidelines: CHEST 2016 ACCP
 Based on less bleeding with NOACs and greater
convenience for patients and healthcare providers, we now
suggest that a NOAC is used in preference to VKA for the
initial and long-term treatment of VTE in patients without
cancer. (Grade 2B)
 Based on indirect comparisons, the risk of bleeding may be
lower with apixaban than with the other NOACs
Kearon C et al Antithrombotic Therapy for VTE Disease: CHEST Guideline, Chest
2016;149:315-352

Acute management
Characteristic Drug choice Rationale
Extensive DVT/Massive
PE
UFH Require advanced Mx
Excluded from NOAC trials
High initial bleeding
risk
UFH Rapid dose titration; Antidote +
Pregnancy
Breast feeding
Children
LMWH VKA, NOACs cross placenta
VKA enter breast milk
NOAC safety not proven in these
groups
Active Cancer LMWH, VKA Under-represented in NOAC trials
All-oral Mx
Home-only Mx
Rivaroxaban
Apixaban
Only NOACs evaluated in all-oral
Mx
Blood 2014;124:1020-1028

Acute management
CRF : CrCl 30-50
ml/min
Rivaroxa, Apixa,
Edoxa
Less affected by CRF than Dabi;
If Edoxa – 30 mg OD
CRF : CrCl < 30 ml/min
(Stage 4 or 5 CRF)
VKA Excluded from NOAC trials
Recent ACS Rivaroxa, Apixa,
Edoxa
Small MI signal in Dabi trials
Recent GI bleed Apixaban Least GI bleed in NOAC vs Warf
On Verapamil,
Dronedarone Rx
VKA or
Rivaroxaban
Significant interaction
On Carbamazepine,
phenytoin, Barbiturate
VKA Significant interaction with
NOAC
Blood 2014;124:1020-1028
JACC 2016;67:1941-1955

Chronic management
Unable to afford NOAC LMWH f/b VKA Cost of NOAC > LMWH
Limited access to clinic;
irregular follow – up
NOAC Fixed dose regime
Elderly NOAC Less bleeding risk; Fixed dose
regime
High bleeding risk NOAC Less major and relevant minor
bleed with NOAC vs Warf
Stage 4 or 5 CRF VKA Excluded from NOAC trials
Dyspepsia/APD Rivaroxa, Apixa,
Edoxa
Dyspepsis in upto 10% in
Dabigatran studies
Blood 2014;124:1020-1028
JACC 2016;67:1941-1955

 Venous thromboembolism (VTE) is a common disease
associated with high risk for recurrences, death, and late
sequelae, accounting for substantial health care costs.
 Anticoagulant agents are the mainstay of treatment for
deep vein thrombosis and pulmonary embolism.

 In Phase III trials, rivaroxaban, apixaban, edoxaban
(antifactor Xa agents), and dabigatran (an antithrombin
agent) were noninferior and probably safer than
conventional anticoagulation therapy
 Thus, the recent availability of oral anticoagulant agents
that can be administered in fixed doses, without laboratory
monitoring and dose adjustment, is a landmark change in
the treatment of VTE

Newer Oral Anticoagulants or warfarin in DVT/PE

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