ESC Guidelines on management of acute pulmonaryembolism - is an update needed?

Arnaud PERRIER, MDDivision of General Internal Medicine

Geneva University HospitalsGeneva, Switzerland

Conflicts of interest: consulting fees for bioMérieux

2008

Guidelines update?main topics to be addressed

• Diagnosis

• Prognosis (risk stratification)

• Treatment

What is new?

Guidelines update?

Diagnosis

• Scores for clinical assessment

• D-dimer

• MRI

Assess clinical probability of PEImplicit or prediction rule

NegativeNo treatment

Low/intermediate clinical probabilityor "PE unlikely"

D-dimer

No PENo treatment or

investigate further

MultidetectorCT

PETreatment

High clinical probabilityor "PE likely"

No PENo treatment

PETreatment

PositiveMultidetector CT

SUSPECTED NON HIGH-RISK PEno shock or hypotension

Clinical prediction rules for PEThromb Haemost 2000;83:416-20. Ann Intern Med 2006;144:65-71

Revised Geneva score

Age > 65 years +1

Previous DVT or PE +3

Surgery or fracture (< 1 month) +2

Cancer +2

Unilateral lower limb pain +3

Hemoptysis +2

Heart rate

75 to 94 beats per minute +3

≥ 95 beats per minute +5

Clinical signs of DVT* +4

Low 0 to 3; intermediate 4 to 10; high >11

Wells score

Previous DVT or PE + 1.5

Immobilization or surgery (< 4

weeks)

+ 1.5

Cancer + 1

Alternative diagnosis less probable + 3

Hemoptysis + 1

Heart rate > 100/min + 1.5

Clinical signs of DVT* + 3

*limb edema and pain on palpation of deep veins

• Low 0 to 1; intermediate 2 to 6; high > 7

• PE unlikely: 0 to 2; PE likely: 2.5 or more

Accuracy of clinical prediction rules for PECeriani E et al., J Thromb Haemost 2010;8:957-970.

Score Prevalence of PE, % [95% CI]

3-level rule Low probability Intermediateprobability

High probability

Wells 6 [4-8] 23 [18-28] 49 [43-56]

Geneva revised 9 [8-11] 26 [24-28] 76 [69-82]

2-level rule PE unlikely - PE likely

Wells 8 [6-11] - 34 [29-40]

All accurate, little used: too complicated?

Simplified clinical prediction rules for PEThromb Haemost 2009; 101: 197–200; Arch Intern Med 2008;168:2131-6.

Revised Geneva score

Age > 65 years +1

Previous DVT or PE +1

Surgery or fracture (< 1 month) +1

Cancer +1

Unilateral lower limb pain +1

Hemoptysis +1

Heart rate +1

75 to 94 beats per minute +1

≥ 95 beats per minute +1

Clinical signs of DVT* +1

• Low 0 to 1; intermediate 2 to 4; high 5 or more

• PE unlikely: 0 to 2; PE likely: 3 or more

Wells score

Previous DVT or PE + 1

Immobilization or surgery (< 4

weeks)

+ 1

Cancer + 1

Alternative diagnosis less probable + 1

Hemoptysis + 1

Heart rate > 100/min + 1

Clinical signs of DVT* + 1

*limb edema and pain on palpation of deep veins

• PE unlikely: 0 to 1; PE likely: 2 or more

Simplified revised Geneva score for PEArch Intern Med 2008;168:2131-6.

• 1049 patients from 2 large prospective PE diagnostic trials that

• Still to be prospectivelyvalidated!

Which prediction rule should we select?Ceriani E et al., J Thromb Haemost 2010;8:957-970.

• Similar accuracy

• Prevalence of PE in suspected patients

• > 20%: revised Geneva score

• < 20%: any score

• Setting

• Outpatients, emergency ward: all scores

• Inpatients: Wells score

• D-dimer

• Highly sensitive: 3-level scores

• Less sensitive: 2-level scores

Ruling out PE with point-of-care (POC) D-dimer assaysBMJ 2009;339:b2990

Qualitative (interobserver variability ++)Sn = 85%

6796 patientsPrevalence VTE 18%

5730 patientsPrevalence VTE 8%

Quantitative, only tested in DVTSn= 96%

925 patients Prevalence DVT 34%

Cardiac D-dimer

SimpliRED

Simplify

Specificity01.0

Sen

siti

vity

Combining D-dimer and clinical probability

Clinical prob. low40%

Intermediate55%

High5%

PE unlikely67%

PE likely33%

Less sensitive D-dimer Highly sensitive D-dimer

3-levelscheme

2-levelscheme

Qualitative POC assays

MRI for suspected PE: the PIOPED III studyAnn Intern Med. 2010;152:434-443.

• Multicenter US study including 371 consecutive patients

• MR angiography technically inadequate in 25% (11 to 52%)

• Performance of technically adequate tests:

– Sensitivity 78%, specificity 99%

Guidelines update?

Diagnosis

• Scores for clinical assessment– Extensively validated and simplified

• D-dimer– Point-of-care assays useful but not highly sensitive rule out

PE in low clinical probability or PE unlikely patients

• MRI– Not yet helpful

Guidelines update?

Prognosis

• Clinical scores

• Biomarkers

• CT angiography

Risk stratification for PE

ESC guidelines 2008

PESI rule (Pulmonary Embolism Severity Index)Am J Respir Crit Care Med 2005;172:1041-6

Items Points

Age, per year Age, in years

Male sex 10

History of cancer 30

History of heart failure 10

History of chronic lung disease 10

Pulse ≥110/minute 20

Systolic blood pressure < 100 mm Hg 30

Respiratory rate ≥30/minute* 20

Temperature < 36ºC 20

Altered mental status† 60

Arterial oxygen saturation < 90%* 20

≤65 class I; 66–85 class II; 86–105 class III; 106–125 class IV; and > 125 class V. Patients in risk classes I and II are defined as low-risk.

Validation of the PESI ruleThromb Haemost 2008; 100: 943–948

Multicenter prospective validation on 357 consecutive ED patients

Low-risk 1.1% (0.1–3.8)

Higher-risk 11.1% (6.8–16.8)

Pronostic value of biomarkers for PE

Reference n Bio- Assay Cut-off Test + NPV PPVmarkers value % % %

Troponin

Konstantinides et al 106 cTnI Centaur 0.07 ng/mL 41 98 14

Konstantinides et al 106 cTn TElecsys 0.04 ng/mL 37 97 12

Giannitsis et al 56 cTnT TropT 0.10 ng/mL 32 97 44

Janata et al 106 cTnT Elecsys 0.09 ng/mL 11 99 34

Pruszczyk et al 64 cTnT Elecsys 0.01 ng/mL 50 100 25

BNP or NT-proBNP

ten Wolde et al 110 BNP Shionoria 21.7 pmol/L 33 99 17

Kucher et al 73 NT-proBNP Elecsys 500 pg/mL 58 100 12

Kucher et al 73 BNP Triage 50 pg/mL 58 100 12

Pruszczyk et al 79 NT-proBNP Elecsys 153 to 334* pg/mL 66 100 23

PESI score vs. troponin in suspected PEJ Thromb Haemost 2009;8: 517–522

• 567 patients from a single center registry with confirmed acute PE

• PESI and Troponin I compared for prediction of 30-daymortality

• Overall 30-day mortality of 10% [95% CI, 7.6–12.5%].

PESI score vs. troponin in suspected PEJ Thromb Haemost 2009;8: 517–522

1,0%

9,2%

15,2%

12,0%

0,0%

2,0%

4,0%

6,0%

8,0%

10,0%

12,0%

14,0%

16,0%

PESI Troponin

30

-day

mo

rtal

ity

Low risk

High risk

Simplification of the PESI scoreArch Intern Med. 2010;170:1383-1389

Derivation: 995 patients prospectivelyincluded in single-center registry30-day mortality• Low-risk 1.0% (0.0-2.1)• High-risk 10.9% (8.5-13.2)

Validation: 7106 patients retrospectivelyanalysed in RIETE registry30-day mortality• Low-risk 1.1% (0.7-1.5)• High-risk 8.9% (8.1-9.8)

Low-risk, 0 points (30 to 36% of patients)High-risk, 1 or more points

Fatty-acid binding proteins in acute PE

• 126 non shocked patients with PE

• FABP cut-off defined by ROC analysis 6 ng/mL: – Above cut-off: 28% unfavorable outcomes (death, amines,

intubation or CPR)

– Below cut-off: 1%

• Tn and BNP not predictive

CT angiography for risk stratification in PEMoroni AL et al, Eur J Radiol 2010, in press

• 246 patients with PE

• Univariate analysis:

– RV/LV ratio > 1.0 not predictiveof increased mortality

– Must be combined to embolicburden > 40%

• Multivariate analysis

– CT not significant over clinicalpredictors

Guidelines update?

Prognosis

• Clinical scores– Extensively validated, useful for identifying low-rtisk

patients

• Biomarkers– No benefit over clinical assessment, for low-risk– Low positive ppredictive value for high-risk– Combination of biomarkers or with echocardiography?

• CT angiography– "one-stop" risk assessment?– Disappointing, no uniform criteria

Guidelines update?

Treatment

• New anticoagulants

• Duration of treatment

Treatment of PE: durationESC guidelines 2008

Better efficacy-safety profile of the new drugs?

New anticoagulants

FondaparinuxRivaroxaban/

dabigatran

Action via antithrombin yes no

Inactivation of fibrin-linked thrombin yes yes

Monitoring no no

Heparin-induced thrombocytopenia no no

Oral administration no yes

Animal origin no no

Good safety-efficacy ratio ? ?

Rivaroxaban: EINSTEIN-PE

Primary efficacy endpoint: symptomatic recurrent DVT or fatal or non-fatal PEMain safety endpoint: major and clinically relevant non-major bleeding

Dabigatran for acute DVT/PEThe RECOVER study

Schulman et al., N Engl J Med 2009;361:2342-52

• 2564 patients with acute DVT or PE (30%) included in a randomized comparison of

– Dabigatran (direct oral thrombin inhibitor) 2 x 150 mg/day vs.

– Initial parenteral anticoagulants plus warfarin (INR 2.0 to 3.0)

Recurrent VTE or death Bleeding

Dabigatran for acute DVT/PE: The RECOVER studySchulman et al., N Engl J Med 2009;361:2342-52

Clinically relevant non-major bleeding• Skin hematoma of at least> 25 cm2• Nose bleed > 5 min• Macroscopic hematuria, spontaneous or, if intervention, lasting > 24 hours• Rectal bleeding (more than spotting)• Gingival bleeding > 5 min• Bleeding leading to hospitalization and/or requiring surgical treatment• Bleeding leading to a transfusion (< 2 units of whole blood or red cells)• Any other bleeding event considered clinically relevant by the investigator

Guidelines update?

Treatment

• New anticoagulants– Dabigatran effective, safety identical to warfarin– Rivaroxaban?

• Duration of treatment– In unprovoked PE, prolonged treatment stil to be deceide

on an individual basis

Next guidelines for PE: when?

• Soon

Prof. Adam Torbicki, Warsaw, Poland