2014 ESC guidelines update on the diagnosis and management of acute pulmonary embolism

Anticoagulation for the treatment of PE and secondary prevention of VTE

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)

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

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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)

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

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

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

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

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

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

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

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

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

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

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)

Clinical Evidence

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

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

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

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

BACK-UP SLIDES

0 1 ≥20123456

Rivaroxaban SOC

Re

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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

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(%

)

Up to day 30

Full treatment period

Erkens et al, 2013