Pulmonary Emboli: To Treat or Not To Treat With NOACs · Pulmonary Emboli: To Treat or Not To Treat With NOACs Martin Strban, MD, FRCPC Respirologist, KW Assistant Clinical Professor

Pulmonary Emboli:To Treat or Not To Treat With

NOACsMartin Strban, MD, FRCPC

Respirologist, KWAssistant Clinical Professor (Adjunct), McMaster U

April 27, 2016

Faculty Disclosure

• Faculty: Martin Strban

• Relationships with commercial interests:

– Grants/Research Support: none

– Speakers Bureau/Honoraria: none

– Consulting Fees: none

– Other: none

Objectives

• Recognize different therapy options for VTE

• Recognize which VTE patient requires hospitalization versus outpatient therapy

• Recognize new developments in VTE

• Recognize new VTE protocol in development

Patient 1

• Mr. AD, 49 year old male, engineer

• Previously healthy

• No meds, cigs, risk factors, constitutional sx

• Acute SOB x 2 d playing hockey

• FD: bloodwork + V/Q scan

• Sent to ER after abnormal V/Q scan:– no distress; HR 78, BP 136/76, RR 16, SaO2 97%

– CXR normal

Patient 1

Patient 1

• ER discussion with Resp-on-call:

– OPD treatment with rivaroxaban (Xarelto 15 mg bid po for 3/52, then 20 mg qd po)

– Early assessment at GIMRAC (1 week)

– Early assessment in Resp office (2 weeks)

• Office visit: asymptomatic, compliant, no bleeding, reassess 3 mos, no hockey! ()

Patient 1

• ER discussion with Resp on call:

– OPD treatment with rivaroxaban (Xarelto 15 mg bid po for 3/52, then 20 mg qd po)

– Early assessment at GIMRAC (1 week)

– Early assessment in Resp office (2 weeks)

• Office visit: asymptomatic, compliant, no bleeding, reassess 3 mos, no hockey! ()

PE Treatment Options

Admit & treat with:

• UFH VKA (warfarin)

• UFH NOAC

• LMWH VKA

• LMWH NOAC

• Fondaparinux VKA/NOAC

• LMWH monotherapy

• NOAC monotherapy


Admit & treat with:


• UFH NOAC

• LMWH VKA

• LMWH NOAC




Outpatient therapy with:

•

•

• LMWH VKA

• LMWH NOAC

•




Admit & treat with:


• UFH NOAC

• LMWH VKA

• LMWH NOAC




Outpatient therapy with:

•

•

• LMWH VKA

• LMWH NOAC

•



VTE Alphabet Soup

• VTE = PE + DVT

• UFH = unfractionated heparin (ie IV heparin)

• LMWH = low molecular weight heparin– Eg enoxaparin, dalteparin, tinzaparin,

• VKA = vitamin K antagonists (eg warfarin)

• NOAC = DOAC– Non-vitamin K (novel) oral anticoagulant

– Direct oral anticoagulant

– Eg dabigatran, rivaroxaban, apixaban, edoxaban

Venous Thromboembolism (VTE)

• 3rd most common cardiovascular disorder– Estimated annual incidence ~ 0.1% - 0.3%– Incidence higher in elderly ~ 0.5%

• PE account for 1/3 of symptomatic VTE• Unprovoked, idiopathic VTE:

– Account for up to 50% all VTE– Associated with high recurrence rate (10% in 1 year; 30% in 5 years)

• Associated with significant morbidity & mortality– 20% of PE pts die before diagnosis or on 1st day– Case fatality rate in first month of therapy is 6% for DVT & 12% for PE

(although dropping markedly in last 20 years)– DVT: up to 20-50% develop post-thrombotic syndrome– PE: up to 1-4% diagnosed with CTEPH

• Significant economic burden: mean LOS 6-8 days (traditional therapy); $43,730 per hospitalization in USA in 2005 (LOS=8.4 d)

Yeh CH; Blood 2014; 124(7); 1020-8

VTE Therapy Overview

Traditional

NOAC based

Prophylactic

Blondon M; Circulation 2015; 132; 1856-9

NOAC Advantages Over VKA

VKA NOACs

Onset Slow Rapid

Dosing Variable Fixed

Food Effects Yes No

Interactions Many Some

Routine Monitoring Yes No

Elimination Long Short

Patient convenience Less convenient More convenient

Bates S, 2016; 8th McMaster Univ Review Course

VKA Advantages Over NOACs

VKA NOACs

Cost Cheap Not cheap

Ability to assess drug level Yes (INR) Not readily available

Clearance Non-renal Renal 25-80%

Antidote Vit K, PCC, FFP Idarucizumab, Andexanet

Bridging strategies Known Less clear

Ability to assess compliance Yes (INR) No

Impact of missing 1-2 doses Minimal Significant

Bates S, 2016; 8th McMaster Univ Review Course

NOACs Pharmacological Properties

Drug Interactions:Dabigatran: amiodarone, quinidine, verapamil, rifampicin, azolesOral Xa inhibitors: azoles, rifampicin, clarithromycin, HIV protease inhibitors, anticonvulsants (phenytoin, carbamazepine)

Yeh CH; Blood 2014; 124(7); 1020-8

VKAOral

ThrombinInhibitor

OralFactor XaInhibitors

NOACs: Acute Treatment of VTE

Yeh CH; Blood 2014; 124(7); 1020-8

6 NOAC Trials2009-201327,023 patients

NOACs: Acute Treatment of VTE

Drug Study Treatment

Dabigatran RE-COVER I (VTE)RE-COVER II (VTE)

LMWH/UFH x ≥5 days then150 mg bid x 6 mos

Rivaroxaban EINSTEIN-DVTEINSTEIN-PE

15 mg bid x 21 days then20 mg od x 3-12 mos

Apixaban AMPLIFY (VTE) 10 mg bid x 7 days then5 mg bid x 6 mos

Edoxaban Hokusai (VTE) LMWH/UFH x ≥5 days then60 mg od x 3-12 mos

• Rivaroxaban & apixaban given without parenteral therapy• Dabigatran & edoxaban given with (initial) parenteral therapy• Rivaroxaban, apixaban, dabigatran have Health Canada approval for VTE• Edoxaban not available in Canada• Rivaroxaban & apixaban on ODB LU Code #444

NOACs in Acute Treatment of VTE

Risk of recurrent VTE & VTE-related death in 6 NOAC trials

Van Es N; Blood 2014; 124(12); 1968-1975


Van Es N; Blood 2014; 124(12); 1968-1975

Risk of major bleeding in 6 NOAC trials


Van Es N; Blood 2014; 124(12); 1968-1975

Major bleeding in 6 NOAC trials


NOACs equal/better than VKA in certain subgps:

– PE (equal)

– DVT (equal)

– Weight ≥ 100 kg (equal)

– Creatinine clearance 30-49 mL/min (less bleeding)

– Age ≥ 75 years (less VTE recurrence; less bleeding)

– Cancer patients (less VTE recurrence)

Van Es N; Blood 2014; 124(12); 1968-1975


NOACs have not been directly compared however:

– For creat clear 30-50 mL/min consider Xa inhibitors

– For all-oral regimen consider rivaroxaban & apixaban

– For recent UGIB consider apixaban

– For patients with dyspepsia avoid dabigatran

– For history of CAD probably avoid dabigatran

Van Es N; Blood 2014; 124(12); 1968-1975

NOAC Extended Therapy Trials

Yeh CH; Blood 2014; 124(7); 1020-8

NOAC Summary 1

• NOACs are equally effective as VKA in preventing recurrent VTE & VTE-related mortality

• NOACs cause less major bleeding than VKA (ICH, fatal bleeding, CRNM bleeding)

• NOACs don’t require monitoring & are more convenient & reliable to use

• NOACs allow earlier discharge & less utilization

• NOACs are more expensive

• NOAC reversal agents are not yet available

Van Es N; Blood 2014; 124(12); 1968-1975

NOACs for Everyone ?

Rogers R; Chest 2013; 144(1): 8

Patient 2

• Mr. MM, 65 year old male, recently retired

• PMH: HTN on quinapril/HCTZ; LBP

• Acute dyspnea x 1/52 with syncope ER

• No c/p, no leg sx, no risks, no constitutional sx

• ER: no distress; HR 104, BP 110/76, RR 16, SaO2 94%

• Isolated hypotension SBP 70 mmHg gone with IVF

• Normal CK & cTnI despite ECG

• ↑ D-dimer CTPA

Patient 2

Patient 2

Patient 2

Admitted to Observation Unit:– Treated with IV heparin

– Early echo:• Normal LV systolic function

• RV severely enlarged with severe RV dysfunction

• RVSP 38 mmHg

– BP improved without further syncope

– Serial cardiac enzymes normal

– Asymptomatic

– Converted to rivaroxaban & discharged home Day #4

Choice of Anticoagulant in Acute VTE

Yeh CH; Blood 2014; 124(7); 1020-8


Kearon C; Chest 2016; 149(2); 315-352


• NOAC contradictions:– Severe kidney disease (creat clear < 15mL/min)

– Interacting drugs

– Mechanical valves

• NOAC “grey” zones:– Venous thrombosis in unusual sites (eg portal

vein, cerebral vein)

– Cardiac thrombosis (eg LV thrombus)

– Cancer-related thrombosis

Eikelboom J, 2016; 8th McMaster Univ Review Course

Kelly Kamowski: Medical Cartoons

Acute VTE: Hospital v OPD Treatment

• OPD therapy:– DVT: good evidence for OPD therapy (Grade 1B)

– PE: limited evidence for OPD therapy (Grade 2B)

• OPD PE therapy varies across countries:– Broadly implemented in carefully selected patients in

Europe & Canada

– Some Canadian tertiary centres: up to 50% are OPD

– USA registry of 22 EDs: 1.1% are OPD (2011)

• NOAC studies did not report OPD stats although probably uncommon

Acute VTE: Hospital v OPD Treatment

Vinson DR, Ann Emerg Med 2012; 60(5); 651-662

Pulmonary Embolism Severity Index

PESI

Points

Age +1 per yr

Male sex +10

Cancer +30

Heart failure +10

Lung disease +10

Pulse ≥ 110 bpm +20

SBP < 100 mmHg +30

RR ≥ 30 bpm +20

Temp < 36 C +20

Altered mental stat +60

SaO2 < 90% +20

Risk Class PESI Score 30 d Mortality

I < 65 1.1%

II 66-85 3.1%

III 86-105 6.5%

IV 106-125 10.4%

V > 125 24.5%

Aujesky D; AJRCCM 2005; 172(8); 1041-6

2016 ACCP Guidelines: OPD PE Rx

• “Patients who satisfy all of the following criteria are suitable for treatment of acute PE out of hospital:1. Clinically stable with good cardiopulmonary reserves;2. No contraindications such as recent bleeding, severe

renal or liver disease, or severe thrombocypenia(platelets <70,000);

3. Expected compliance with therapy;4. Patient feels well enough to be treated at home (with

adequate home circumstances).

• PESI can be an “aid in decision-making” (but low-score not necessary for consideration for home rx)

• Grade 2B recommendation

Kearon C; Chest 2016; 149(2); 315-352

2016 ACCP Guidelines for VTE


Selected highlights:

• For VTE without cancer, NOACs are suggested over VKA (Grade 2B)

• Duration of rx for first unprovoked VTE:1. Low/moderate bleeding risk: extended rx (no scheduled

stop date) over 3 mos rx (Gr 2B)

2. High bleeding risk: 3 mos rx over extended rx (Gr 1B)

• Patient sex & D-dimer at 1 month may influence decision

• Extended rx should be reassessed annually

• ASA suggested if stopping rx in unprovoked VTE (Gr 2B)

Kearon C; Chest 2016; 149(2); 315-352


Risk Factor 5-Year Recurrence Rate After Stopping Rx

Surgical (major transient risk) 3%

Non-surgical transient riskeg estrogen, preg, leg injury, flight > 8h

15%

Unprovoked (“idiopathic”) 30%

Cancer 15% per year

Kearon C; Chest 2016; 149(2); 315-352

Further stratification:1. Isolated distal DVT – half the risk of VTE2. Second unprovoked VTE – 1.5 fold risk of first


Reducing VTE recurrence after stopping rx:

• Extended NOAC trials: ≥ 80% ↓ in VTE

• ASA trials: 33% ↓ in VTE (Grade 2B)

• SURVET trial (sulodexide): 50% ↓ in VTE

• DODS trial

Kearon C; Chest 2016; 149(2); 315-352Andreozzi GM; Circulation 2015; 132(20); 1891-7

D-Dimer Optimal Duration Study

DODS

• 410 pts w unprovoked VTE after 3-7 mos rx

• D-dimer groups:

1. +’ve continue rx

2. -’ve x 2; male no rx

3. -’ve x 2; estrogen female no rx

4. -’ve x 2; nonestrogenfemale no rx

9.7%

5.4%

1.2%0%

Kearon C, Ann Intern Med 2015; 162; 27-34

NOACs

2016 ACCP: Bleeding Risk

Risk Factors for Bleeding on Rx Estimated Bleeding Risk by Category

Kearon C; Chest 2016; 149(2); 315-352

HAS-BLED Bleeding Risk Score

UpToDate 2016

Reversal of NOACs

• Activate coagulation to overcome effects of the drug (PCC, aPCC)– Prothrombin complex concentrates (3-factor or 4-

factor): Beriplex, Octaplex

– Activated PCC: FEIBA

– Recombinant FVIIa

• Remove drug– Hemodialysis or hemofiltration for dabigatran

• Neutralize drug– Specific reversal agents


NOAC Specific Reversal Agents

Idarucizumab Andexanet Alfa

Structure Humanized Fab fragment Human rXa variant

Target Dabigatran Factor Xa inhibitors

Binding Non-competitiveHigh affinity

Competitive

Phase 2 results Rapid, complete reversal Rapid, complete reversal

Phase 3 trial Ongoing but FDA approved Ongoing – 2017 ?


Approach to NOAC-Related Bleeding

Siegel DM; Blood 2014; 123(8); 1152-8

Bridging & VTE

Douketis J; Chest 2012;141(2):e326S-e350S

Stopping NOACs Prior to Surgery

www.thrombosiscanada.ca

SMGH VTE Order Set

SMGH VTE Order Set

NOAC Summary 1

• NOACs are equally effective as VKA in preventing recurrent VTE & VTE-related mortality

• NOACs cause less major bleeding than VKA (ICH, fatal bleeding, CRNM bleeding)

• NOACs don’t require monitoring & are more convenient & reliable to use

• NOACs allow earlier discharge & less utilization

• NOACs are more expensive

• NOAC reversal agents are not yet available

Van Es N; Blood 2014; 124(12); 1968-1975

NOAC Summary 2

• Consider OPD therapy for VTE, including PE, in carefully selected patients

• ACCP 2016 Guidelines recommend NOACs as anticoagulants of choice for most patients

• Exceptions where NOACs aren’t appropriate include: cancer, pregnancy, severe renal insufficiency, severe liver disease, non-compliant patients, mechanical valves, or if rapid reversal is needed

Documents

Pulmonary Emboli: To Treat or Not To Treat With NOACs · Pulmonary Emboli: To Treat or Not To Treat With NOACs Martin Strban, MD, FRCPC Respirologist, KW Assistant Clinical Professor