Slide 1

NOACs or WARFARIN in Pulmonary EmbolismSatyam 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 110.6% and 23.0%, respectively

The 30-day mortality rates for first-time DVT or pulmonary embolism 23.0% and 31%, respectively

Long term sequelae 3DVT Post thrombotic syndrome upto 50%PE CTEPH Upto 4%1 Am J Med 2013;126:832.e13212 Circulation 2014;130:829363 N Engl J Med 2004;350:225764

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 2004Pulmonary 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%Sepsis32Respiratory disease28Hepatobiliary and pancreatic diseases18Cardiovascular disease15Malignancy14CNS diseases10Renal diseases9

FactKeeps coming back!

VTE tends to recur10-year rate of recurrence 25% 1Recurrence peaks in first 6 months - 11% per patient-year 1Decreases after 3 years - 2% per patient-year up to 10 yrs 1Risk for recurrence is similar after DVT or pulmonary embolism 2However, PE comes back as PE, and DVT as DVT 21 BMJ 2011;342:d30362 Ann Intern Med 2003;139:1925

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;8:121622Thromb Haemost 2013;110:83443Lancet 2003;362:5236N Engl J Med 2001;345:1659

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 management

No need of thrombolysis Minor PE

Current standard of care

VK

VaTargets of Older Anticoagulants

Xll

Xl

lX

X

VII

TF

II

I

Fibrin Clot

VIIIa

UFH

LMWH

FondaparinuxUFH = 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

25Targets of Current Anticoagulant TherapiesHeparin: Both UFH and LMWH potentiate antithrombin III and so inhibit Factor Xa, thrombin, and factors XIa and IXa. These agents vary in their affinity for coagulation factors and other proteins.1Synthetic pentasaccharides1:Fondaparinux also potentiates antithrombin III. Its action is more narrowly targeted and inhibits only factor Xa.Argatroban and bivalirudin directly inhibit thrombin.Vitamin K antagonists: Warfarin inhibits vitamin K and interferes with the hepatic production of coagulation factors VII, IX, X, thrombin, and multiple regulatory proteins.2

ReferencesAnsell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost. 2007;5(suppl1):60-64.Hirsh J, ODonnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin: current and future advances. Circulation. 2007;116:552-560.Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy. J Am Coll Cardiol. 2003;41:1633-1652.

Targets of NOACsFocus of clinical trialsVTE prevention and treatmentStroke 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

InhibitionNational Institutes of Health - ClinicalTrials.gov. - last accessed July 2013

26Targets of New Oral Anticoagulant TherapiesThree oral anticoagulant therapies.Two of these therapies directly target factor Xa: rivaroxaban and apixabanOne of these therapies directly targets thrombin: dabigatran etexilatePhase 3 trials for these anticoagulants were/are focused on the following treatment areas:VTE prevention and treatmentStroke prevention in atrial fibrillationSecondary prevention of acute coronary syndrome

ReferencesAnsell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost. 2007;5(suppl1):60-64.Turpie AGG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27:1238-1247.National Institutes of Health. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term=apixaban. Accessed July 16, 2008.National Institutes of Health. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term=rivaroxaban. Accessed July 16, 2008.National Institutes of Health. ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term=dabigatran. Accessed July 16, 2008.

NOAC options

DabigatranEdoxabanRivaroxabanApixabanTrialRECOVER I & IIHOKUSAIEINSTEIN-PEAMPLIFYNumber(n)2539+2568824048325365Mean age (yrs)54.855.857.757.0CrCl < 30 ml/min (%)0.4%-0.1%0.5%Age > 75 y (%)10%13%17%14%Unprovoked VTE35%65%64%90%PE +/- DVT31%40%100%34%Bridge with UFH/LMWHYESYESNO NOTreatment protocol150 mg BD60 mg OD or 30 mg OD15 mg BD for 3 wk; then 20 mg OD10 mg BD for 1 wk; then 5 mg BD

DabigatranEdoxabanRivaroxabanApixabanTrialRECOVER I & IIHOKUSAIEINSTEIN-PEAMPLIFYNumber(n)2539+2568824048325365Mean age (yrs)54.855.857.757.0CrCl < 30 ml/min (%)0.4%-0.1%0.5%Age > 75 y (%)10%13%17%14%Unprovoked VTE35%65%64%90%PE +/- DVT31%40%100%34%Bridge with UFH/LMWHYESYESNO NOTreatment protocol150 mg BD60 mg OD or 30 mg OD15 mg BD for 3 wk; then 20 mg OD10 mg BD for 1 wk; then 5 mg BD

DabigatranEdoxabanRivaroxabanApixabanTrialRECOVER I & IIHOKUSAIEINSTEIN-PEAMPLIFYNumber(n)2539+2568824048325365Mean age (yrs)54.855.857.757.0CrCl < 30 ml/min (%)0.4%-0.1%0.5%Age > 75 y (%)10%13%17%14%Unprovoked VTE35%65%64%90%PE +/- DVT31%40%100%34%Bridge with UFH/LMWHYESYESNO NOTreatment protocol150 mg BD60 mg OD or 30 mg OD15 mg BD for 3 wk; then 20 mg OD10 mg BD for 1 wk; then 5 mg BD

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 riskJ Plos one. 2015; 0144 856

Risk-benefit of NOAC vs VKA

First recurrent VTE or VTE related deathBlood 2014;124:1968-1970

Risk-benefit of NOAC vs VKAIntracranial, major GI, fatal, and Clinically relevant Non-major bleedBlood 2014;124:1968-1970

Risk-benefit of NOAC vs VKABlood 2014;124:1968-1970

Cost of careVKA < LMWH < NOACsBut VKA require periodic monitoring overall cost increases

Blood 2014;124:1968-1970

Cost of careVKA < LMWH < NOACsBut VKA require periodic monitoring overall cost increases

ConvenienceNOACs no monitoring required

Blood 2014;124:1968-1970

Cost of careVKA < LMWH < NOACsBut VKA require periodic monitoring overall cost 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 management

Thrombolysis indicated

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

Current standard of care

NOAC option in long term?

NOAC option in long term?Key pharmacokinetics

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

DabigatranEdoxabanRivaroxabanApixabanTrialRECOVER I & IIHOKUSAIEINSTEIN-PEAMPLIFYNumber(n)2539+2568824048325365Mean age (yrs)54.855.857.757.0CrCl < 30 ml/min (%)0.4%-0.1%0.5%Age > 75 y (%)10%13%17%14%Unprovoked VTE35%65%64%90%PE +/- DVT31%40%100%34%Bridge with UFH/LMWHYESYESNO NOTreatment protocol150 mg BD60 mg OD or 30 mg OD15 mg BD for 3 wk; then 20 mg OD10 mg BD for 1 wk; then 5 mg BD

Switching between NOAC and VKA

Place of NOACs

Patient 3

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

Current standard of care

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.DrugTrialPatientsDesign/Tx Before RandomizationStudy DrugvsComparatorLength of Tx (mo.)Primary EfficacyPrimary Safety Apixaban1AMPLIFYExtended Therapy2486Double-blind/6-12 mo. of anticoagulant 2.5 mg or 5 mg BID vsPlacebo 12Symptomatic, recurrent VTE or all-cause deathMajor BleedingRivaroxaban2EINSTEINExtension1197Double-blind/6-12 mo. of VKA or rivaroxaban20 mg QD vsPlacebo 6 or 12Symptomatic, recurrent VTE*Major BleedingDabigatran3RE-SONATE1353Double-blind/6-18 mo. of VKA 150 mg BID vsPlacebo 6Symptomatic, recurrent VTE*Major BleedingDabigatran3RE-MEDY2866Double-blind/3-12 mo. VKA or dabigatran150 mg BID vsWarfarinINR 2.0-3.06-36Symptomatic, recurrent VTE*Major Bleeding

1. Agnelli, 2013,p699, c1, 3 (pts)p699, c1, 2 (design, drug, length)p701, c1, 4 (efficacy)p701, c2, 3 (safety) 3. Schulman, 2013,p712, c1, 1, p714, c2, 1(pts)p710,c2,2, p715,Fig1 (design)p709,c1,2 (drug)p711,c1, 4, p715,Fig1 (length)p711,c1, 5 (efficacy)p711,c1, 5(safety)2. Bauersachs , 2010,p2502, c2, 2 (pts)p2499, c1, 2 (design, drug, length)p2499, c1, 2(efficacy)p2499, c1, 2(safety)3. Schulman, 2013,p712, c1, 1(pts)p710,c2,5, p715,Fig1 (design)p710,c2,5(drug)p711,c1, 4, p715,Fig1 (length)p711,c1, 5 (efficacy)p711,c1, 5(safety) Agnelli G, Bller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013; 2013;368:699-708.Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.55

NOACs VTE Rx Extension Clinical Trials:Patient Characteristics

DrugTrialAge(y)Male (%)Index Event PE (%)Unprovoked (%)Prior VTE (%)Active Cancer (%)History Cancer (%)Known Thrombophilia (%)ApixabanAMPLIFY-EXT~5757.434.691.712.71.7NR3.8(Inherited)RivaroxabanEINSTEIN-EXT~5858.038.073.716.04.6NR8.1DabigatranRE-SONATE~5655.533NR0Excluded6.111.5RE-MEDY~556135NR53.44.2--18.4

56

NOACs VTE Rx Extension Trials: Efficacy ResultsPrimary Efficacy Endpoints*DrugTrialLength of TxComparatorStudy Drug DoseDrug vs Comp, Rates (%)RRP-valueApixaAMPLIFYExtension12 mo.Placebo2.5 mg2.3 vs 9.30.24