Download pptx - Newer Oral Anticoagulants or warfarin in DVT/PE

NOACs or WARFARIN in Pulmonary Embolism

Satyam RajvanshiSR Cardiology

Background

Fact

FactVTE is deadly!

FactVTE 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.e13–212 Circulation 2014;130:829–363 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 patientsMortality 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 32Respiratory

disease28

Hepatobiliary and pancreatic diseases

18

Cardiovascular disease

15

Malignancy 14CNS diseases 10Renal diseases 9

FactKeeps coming back!

VTE tends to recur10-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:d30362 Ann Intern Med 2003;139:19–25

FactEven if its treated well, its still not SAFE out there!

During well-conducted anticoagulationRate 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;362:523–6N Engl J Med 2001;345:165–9

CLINICAL CASE SCENARIO

Patient 1A 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.

Management?

Patient 2A 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.

Management?

Patient 3A 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.

Management?

Thrombolysis?Heparin?VKA?Alternatives?Bleeding risk?Duration of OAC to prevent recurrence?

Patient 1

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

Acute managementNo need of thrombolysis – Minor PE

Current ‘standard of care’

VKVa

Targets of Older AnticoagulantsXll

Xl

lX

XVII

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

XVII

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

NOAC options

Dabigatran

Edoxaban Rivaroxaban

Apixaban

Trial RECOVER I & II

HOKUSAI EINSTEIN-PE

AMPLIFY

Number(n) 2539+2568 8240 4832 5365Mean age (yrs) 54.8 55.8 57.7 57.0CrCl < 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

Dabigatran


Apixaban


HOKUSAI EINSTEIN-PE

AMPLIFY


0.4% - 0.1% 0.5%


YES YES NO NO

Treatment protocol




Dabigatran


Apixaban


HOKUSAI EINSTEIN-PE

AMPLIFY


0.4% - 0.1% 0.5%


YES YES NO NO

Treatment protocol




Journal.pone.0144856 December 30, 2015

Journal.pone.0144856 December 30, 2015

J Plos one. 2015; 0144 856

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 careVKA < LMWH < NOACsBut VKA require periodic monitoring – overall cost

increases

Blood 2014;124:1968-1970


increases

ConvenienceNOACs – no monitoring required

Blood 2014;124:1968-1970


increases

ConvenienceNOACs – no monitoring required

Rivaroxaban, Apixaban – showed similar efficacy to standard treatment WITHOUT overlap

Blood 2014;124:1968-1970

Place of NOACs

Patient 2

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

Acute managementThrombolysis indicated

Initial Heparin indicated - UFHNo outcome data with NOACs in Massive PE -

excluded


NOAC option in long term?

NOAC option in long term?Key pharmacokinetics

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

Dabigatran


Apixaban


HOKUSAI EINSTEIN-PE

AMPLIFY


0.4% - 0.1% 0.5%


YES YES NO NO

Treatment protocol




Switching between NOAC and VKA

Place of NOACs

Patient 3

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 Drugvs

Comparator

Length

of Tx (mo.)

Primary Efficacy

Primary Safety

Apixaban1AMPLIFYExtended Therapy

2486Double-blind/6-12 mo. of

anticoagulant

2.5 mg or 5 mg BID

vsPlacebo

12Symptomatic, recurrent VTE

or all-cause death

Major Bleeding

Rivaroxaban2

EINSTEINExtension 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 1353Double-blind/

6-18 mo. of VKA

150 mg BID vs

Placebo 6 Symptomatic,

recurrent VTE*Major

Bleeding

Dabigatran3 RE-MEDY 2866Double-blind/

3-12 mo. VKA or

dabigatran

150 mg BID vs

WarfarinINR 2.0-3.0

6-36 Symptomatic, recurrent VTE*

Major Bleeding

NOACs VTE Rx Extension Clinical Trials:Patient Characteristics

Drug TrialAge(y)

Male

(%)

Index Event PE (%)

Unprovoked (%)

Prior

VTE (%)

Active Cancer

(%)

History

Cancer (%)

Known Thrombophili

a (%)

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 TrialLength

of TxComparato

rStudy Drug

Dose

Drug vs Comp,

Rates (%) RR P-value

Apixa AMPLIFYExtension 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 EINSTEINExtension 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 TrialLength

of TxComparato

rStudy Drug

Dose

Drug vs Comp,

Rates (%) RR P-value

Apixa AMPLIFYExtension 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 EINSTEINExtension 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 TxComparato

r Dose

Primary Safety Outcome(Major Bleeding) Major or CRNM Bleeding

Drug vs Comp

Rates (%) HRP-

value

Drug vs Comp

Rates (%) HRP-

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 <0.00

1

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 <0.00

1

= primary safety outcomes

NOACs VTE Rx Exension Trials: Safety Results

60

Study

Drug Trial

Length

of TxComparato

r Dose

Primary Safety Outcome(Major Bleeding) Major or CRNM Bleeding

Drug vs Comp

Rates (%) HRP-

value

Drug vs Comp

Rates (%) HRP-

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 <0.00

1

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 <0.00

1

= primary safety outcomes

All NOACs showed noninferiority in the

reduction of their primary safety outcome when compared to placebo

Place of NOACs

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

HOW TO CHOOSE : GUIDE

Acute managementCharacteristic Drug choice RationaleExtensive DVT/Massive PE

UFH Require advanced MxExcluded from NOAC trials

High initial bleeding risk

UFH Rapid dose titration; Antidote +

PregnancyBreast feedingChildren

LMWH VKA, NOACs cross placentaVKA enter breast milkNOAC safety not proven in these groups

Active Cancer LMWH, VKA Under-represented in NOAC trials

All-oral MxHome-only Mx

RivaroxabanApixaban

Only NOACs evaluated in all-oral Mx

Blood 2014;124:1020-1028

Acute managementCharacteristic Drug choice RationaleCRF : 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;124:1020-1028JACC 2016;67:1941-1955

Chronic managementCharacteristic Drug choice RationaleUnable 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 trialsDyspepsia/APD Rivaroxa,

Apixa, EdoxaDyspepsis in upto 10% in Dabigatran studies

Blood 2014;124:1020-1028JACC 2016;67:1941-1955

CONCLUSION

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

THANK YOU !