2014 esc guidelines update on the diagnosis and management of acute pulmonary embolism...
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2014 ESC guidelines update on the diagnosis and management of acute pulmonary embolism
Anticoagulation for the treatment of PE and secondary prevention of VTE
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Pulmonary embolism: a major cause of morbidity and mortality
PE: a major cause of mortality, morbidity (including CTEPH) and hospitalization• Most serious clinical
presentation of VTE with a high risk of early mortality*– 9–11% 30-day mortality– 8.6–17% 3-month mortality
• Few PEs are diagnosed correctly before death
Konstantinides et al, 2014
34%
59%
7%
VTE-related mortality rates#
Sudden fatal PE Undiagnosed PEPre-diagnosed PE
N=317,000
*Registries and hospital discharge datasets of unselected patients; #2004 data from 6 EU countries (total population 454.4 million)
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Persistent threat of VTE recurrence
• Risk of recurrence is highest early after index event, and declines thereafter1,2
– Poor quality of anticoagulation (failure to maintain therapeutic levels with VKAs) is a risk factor for early recurrence1
• Risk of recurrence never disappears
– Even after 10 years, risk of recurrence is not zero3
• Typically, a recurrent event occurs in the same clinical form as index event1
1. Konstantinides et al, 2014; 2. Limone et al, 2013; 3. Prandoni et al, 2007
Ve
no
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Rates of recurrent VTE following the index DVT/PE event2
1 2 3 4 5 6 7 8 9 10 11 120
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Time period after index event (weekly intervals)
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Anticoagulants for VTE treatment and secondary prevention
For acute VTE, fast, effective anticoagulation is essential to prevent:• Death from PE1
• Progression of DVT to PE1
• Recurrent VTE2
For acute treatment • VKAs: slow onset of action that necessitates an overlap period with a
fast-acting parenteral anticoagulant (~5 days), or until INR is 2.0–3.0 for at least 24 hours3
• Novel OACs: all have a fast onset of action and have many advantages over VKAs
1. Kearon, 2003; 2. Limone et al, 2013; 3. Coumadin (warfarin sodium) Prescribing Information, 2011
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Management of acute PE according to PE severity
• Spectrum of clinical presentation of PE is highly variable1,2
• PE can be stratified and managed according to the risk of
early death* assessed at presentation of suspected PE1,2
• Risk stratification impacts on recommended diagnostic and treatment strategies1,2
1. Torbicki et al, 2008; 2. Konstantinides et al, 2014
>15% <1%
Shock and/or hypotension
*In-hospital death or death within 30 days of diagnosis
Risk of early mortality*
High risk Low riskIntermediate risk
No shock and/or hypotension – further risk stratification required
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Classification of PE severity according to early mortality risk
• Initial risk stratification of suspected or confirmed PE: recommended to identify patients at high risk of early mortality# (IB)
Konstantinides et al, 2014
*Defined as systolic blood pressure <90 mm Hg, or a systolic pressure drop by ≥40 mm Hg, for >15 mins, if not caused by new-onset arrhythmia, hypovolaemia or sepsis; #in-hospital death or death within 30 days of diagnosis
Suspected acute PE
Shock or hypotension?*
NoYes
High-risk Not high-risk
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Classification of PE severity according to early mortality risk
Early mortality risk Risk parameters and scores
Shock or hypotension
PESI class
III–V or sPESI >1*
Signs of RV dysfunction
on an imaging test
Cardiac laboratory biomarkers
High + (+)# + (+)#
Intermediate Intermediate-high - + Both positive
Intermediate-low - + Either one (or none) positive‡
Low - - Assessment optional; if assessed, both negative‡
Konstantinides et al, 2014
*PESI class III–V: moderate to very high 30-day mortality risk; sPESI ≥1 point(s): high 30-day mortality risk; #neither calculation of PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock; ‡patients with PESI class I–II/sPESI of 0, and elevated cardiac biomarkers/signs of RV dysfunction, are to be considered as intermediate-low risk
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Comparison of original and simplified Pulmonary Embolism Severity Index (PESI)
*sPESI: not validated in a prospective home treatment trial; 2014 ESC update does not give preference to one score over another
Konstantinides et al, 2014
Parameter Original version Simplified PESI*
Age Age in years 1 point (age >80 years)
Male sex +10 points -
Cancer +30 points 1 point
Chronic heart failure +10 points 1 point
Chronic pulmonary disease +10 points 1 point
Pulse rate ≥110 bpm +20 points 1 point
Systolic blood pressure <100 mm Hg +30 points 1 point
Respiratory rate >30 breaths/min +20 points -
Temp <36 °C +20 points -
Altered mental status +60 points -
Arterial oxyhaemoglobin saturation <90% +20 points 1 point
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Risk-adjusted PE management algorithm
Konstantinides et al, 2014
Clinical suspicion of PE
High
Yes No
Diagnostic algorithm as for suspected not high-risk PE
Diagnostic algorithm as for suspected high-risk
PE
Intermediate-low
PE confirmed
Primary reperfusionAnticoagulation;
monitoring; consider rescue reperfusion
Hospitalization; anticoagulation
Consider early discharge and home treatment, if feasible
PE confirmedIntermediate risk
RV function and laboratory testing
One positive/both ‘–’Both ‘+’
PESI class III–VI/sPESI ≥1
PESI class I–II/sPESI=0
Shock or hypotension?
Assess clinical risk (PESI or sPESI*)
*sPESI: not validated in a prospective home treatment trial; 2014 ESC update does not give preference to one score over another
Intermediate-high Low
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Early discharge and home treatment of PE
Recommendations for early discharge and home treatment
Class of recommendation
Level of evidence
Patients with acute low-risk PE should be considered for early discharge and continuation of treatment at home if proper outpatient care and anticoagulant treatment can be provided
IIa B
Konstantinides et al, 2014
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Novel OACs: a treatment choice for low- to intermediate-risk PE patients (acute treatment)
Recommendations for novel OACs as alternatives to VKA/parenteral anticoagulation
Class of recommendation
Level of evidence
Rivaroxaban (15 mg bid for 3 weeks, followed by 20 mg od) I B
Apixaban (10 mg bid for 7 days, followed by 5 mg bid) I B
Dabigatran (150 mg bid, or 110 mg bid for patients ≥80 years of age or those under concomitant verapamil treatment) following acute-phase parenteral anticoagulation
I B
Edoxaban* following acute-phase parenteral anticoagulation I B
Rivaroxaban, apixaban, dabigatran and edoxaban are not recommended in patients with severe renal impairment# III A
*Edoxaban is in EU regulatory review for VTE treatment; #CrCl <30 ml/min for rivaroxaban, dabigatran and edoxaban, and <25 ml/min for apixaban
Konstantinides et al, 2014
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Duration of treatment recommendations
Recommendations for duration of oral anticoagulation Class of recommendation
Level of evidence
PE secondary to a transient (reversible) risk factor: 3 months I B
Unprovoked PE: ≥3 months I A
First episode of unprovoked PE and low bleeding risk: consider extended treatment (>3 months) IIa B
Second episode of unprovoked PE: indefinite duration I B
Risk–benefit of continuing anticoagulation should be reassessed at regular intervals I C
Currently, no assessment score for risk of VTE recurrence: persistent risk factors (as opposed to major, temporary) may affect decision on duration of anticoagulation after index PE
Konstantinides et al, 2014
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Rivaroxaban, dabigatran and apixaban should be considered for extended anticoagulation
Recommendations for extended anticoagulation Class of recommendation
Level of evidence
Novel OACs: considered an alternative to VKA (except in patients with severe renal impairment*)
• Rivaroxaban: 20 mg od
• Dabigatran: 150 mg bid (or 110 mg bid for patients >80 years old /those taking verapamil)
• Apixaban: 2.5 mg bid
IIa B#
For patients refusing to take or unable to tolerate OACs, aspirin may be considered IIb B
*CrCl <30 ml/min for rivaroxaban and dabigatran, and <25 ml/min for apixaban; #B refers to the level of evidence available for each drug separately
Konstantinides et al, 2014
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Summary of updates to the ESC PE guidelines
• Broad principles of PE risk stratification remain the same, but the process has been refined – Patients identified as having truly low risk of 30-day mortality
(PESI class I–II or sPESI = 0) can be considered for at-home treatment– Further risk stratification into ‘intermediate-low’ and ‘intermediate-high’
categories can be considered to further aid management strategy decisions
• Novel OACs are recommended for acute phase PE treatment as an alternative option to LMWH/VKA, for patients with intermediate- or low-risk PE (class I level B)
• Novel OACs are recommended for extended therapy if required as an alternative option to VKA treatment (class IIa level B)
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Clinical Evidence
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Dosing regimens of novel OACs for treatment of VTE and prevention of recurrence
Rivaroxaban 15 mg bid (21 days), followed by 20 mg od1*
Apixaban 10 mg bid (7 days), followed by 5 mg bid (day 8 to month 6), followed by 2.5 mg bid (>6 months)2
Single oral drug
Increasing complexity
VKA (INR adjusted, day 1 onwards)
Parenteral agent (≥5 days)Bridging4
1. Xarelto SPC, 2014; 2. Eliquis SPC, 2014; 3. Pradaxa SPC, 2014; 4. Coumadin (warfarin sodium) Prescribing Information, 2011
*In patients with moderate (CrCl 30–49 ml/min) or severe (CrCl 15–29 ml/min) renal impairment,15 mg od should be considered if patient’s assessed risk for bleeding outweighs risk for recurrent DVT/PE; #110 mg bid for patients ≥80 years or patients who receive concomitant verapamil
Parenteral agent (≥5 days)
Dabigatran 150 mg bid3#Switching
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1. The EINSTEIN Investigators, 2010; 2. The EINSTEIN–PE Investigators, 2012; 3. Agnelli et al, 2013;4. Schulman et al, 2009; 5. Schulman et al, 2014; 6. The Hokusai-VTE Investigators 2013
Phase III VTE treatment studies
Drug Trial Design Treatments and dosage
Duration (months)
Patients (n)
Index event*
Primary efficacy
event
Principal safety
outcome
Rivaroxaban EINSTEIN DVT1
Open-label
Riva (15 mg bid for 3 weeks, then
20 mg od) vs enoxaparin/VKA
3, 6 or 12 3449 DVT Recurrent VTE
Major/clinically relevant non-
major bleedingEINSTEIN
PE2
4832 PE
Apixaban AMPLIFY3 Double-blind,
double-dummy
Apix (10 mg bid for 7 days, then 5 mg
bid) vs enoxaparin/
warfarin
6 5395 DVT/PE
Recurrent VTE or related death
Major bleeding
Dabigatran RE-COVER4
Double-blind,
double-dummy
Parenteral/dabi (150 mg bid)* vs
parenteral/warfarin
6 2539 DVT/PE
Recurrent VTE or related death
Major bleeding
RE-COVER II5
2589 DVT/PE
Edoxaban Hokusai-VTE6
Double-blind,
double-dummy
Parenteral/edox(60 mg od or30 mg od*) vs
parenteral/warfarin
3–12 8240 DVT/PE
Recurrent VTE
Major/clinically relevant non-
major bleeding
*All index DVT/PE events were acute, symptomatic and objectively confirmed
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Novel OACs for VTE treatment: summary of clinical evidence
• All novel OACs were at least as effective (non-inferior) as parenteral/VKA treatment in phase III studies of VTE treatment and the prevention of recurrence:– Rivaroxaban: similar incidence of major/non-major clinically relevant bleeding
(principal safety outcome) and significant reductions in major bleeding1
– Apixaban: significant reductions in incidence of major bleeding (principal safety outcome) and major/non-major clinically relevant bleeding2
– Dabigatran (with initial parenteral therapy): similar incidence of major bleeding (principal safety outcome) and a reduction in major/non-major clinically relevant bleeding3
– Edoxaban (with initial parenteral therapy): significant reductions in major/non-major clinically relevant bleeding (principal safety outcome) and a similar incidence of major bleeding4
1. Prins et al, 2013; 2. Agnelli et al, 2013; 3. Schulman et al, 2014; 4. The Hokusai-VTE Investigators, 2013
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Rivaroxaban for VTE treatment: summary of clinical evidence
• Rivaroxaban provides a single-drug approach for the treatment and secondary prevention of VTE with a convenient and effective dosing regimen– Rivaroxaban is the only novel OAC to be tested in a separate trial for patients with
PE (with or without DVT), and offers insights into the largest study population of its kind
• Rivaroxaban may provide an equally effective treatment option to conventional therapy for patients with both low- and intermediate-risk PE, with lower rates of major bleeding complications versus parenteral/VKA treatment
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BACK-UP SLIDES
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0 1 ≥20123456
Rivaroxaban SOC
Re
cu
rre
nt
VT
E (
%)
Simplified PESI: post hoc analysis of EINSTEIN PE
• 0–1: low rates of major clinical outcome events during first 30 days of treatment versus scores ≥2
• ≥2: more frequent adverse outcomes initially and longer term versus scores 0–1
• Rivaroxaban showed lower rates of recurrent VTE and fewer instances of major bleeding in high-risk sPESI (≥2) patients versus LMWH/VKA
0 1 ≥20
1
2
3
4
5
6
sPESI score
Ma
jor
ble
ed
ing
(%
)
Up to day 30
Full treatment period
Erkens et al, 2013