Pulmonary Emboli: To Treat or Not To Treat With NOACs · Pulmonary Emboli: To Treat or Not To Treat...
Transcript of Pulmonary Emboli: To Treat or Not To Treat With NOACs · Pulmonary Emboli: To Treat or Not To Treat...
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
• 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
PE Treatment Options
Admit & treat with:
• UFH VKA (warfarin)
• UFH NOAC
• LMWH VKA
• LMWH NOAC
• Fondaparinux VKA/NOAC
• LMWH monotherapy
• NOAC monotherapy
Outpatient therapy with:
•
•
• LMWH VKA
• LMWH NOAC
•
• LMWH monotherapy
• NOAC monotherapy
PE Treatment Options
Admit & treat with:
• UFH VKA (warfarin)
• UFH NOAC
• LMWH VKA
• LMWH NOAC
• Fondaparinux VKA/NOAC
• LMWH monotherapy
• NOAC monotherapy
Outpatient therapy with:
•
•
• LMWH VKA
• LMWH NOAC
•
• LMWH monotherapy
• NOAC monotherapy
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
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
NOACs in Acute Treatment of VTE
Van Es N; Blood 2014; 124(12); 1968-1975
Risk of major bleeding in 6 NOAC trials
NOACs in Acute Treatment of VTE
Van Es N; Blood 2014; 124(12); 1968-1975
Major bleeding in 6 NOAC trials
NOACs in Acute Treatment of VTE
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 in Acute Treatment of VTE
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 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
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
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
• 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
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
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
2016 ACCP Guidelines for VTE
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
2016 ACCP Guidelines for VTE
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
2016 ACCP: Bleeding Risk
Risk Factors for Bleeding on Rx Estimated Bleeding Risk by Category
Kearon C; Chest 2016; 149(2); 315-352
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
Eikelboom J, 2016; 8th McMaster Univ Review Course
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 ?
Eikelboom J, 2016; 8th McMaster Univ Review Course
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