CLOTS AND ZEALOTS: A SCARY COMBINATION?

Associate Professor David Mountain MB BS FACEM

University of Western Australia- Academic Emerg Med

Sir Charles Gairdner Hospital ED

“The only thing more dangerous than an idea is a belief.”

A CRISIS IN CONFIDENCE RE PE DIAGNOSIS WITH CTPA (+/-D-DIMER)

The literature, blogs and media: tales of woe re PE Dx

Pulmonary Emboli Overdiagnosed by CT Angiography- Medscape news

Researchers Find Evidence Of Over-Diagnosis Of Pulmonary Embolisms As A Result Of Computed Tomography Pulmonary Angiography (CTPA)

Pulmonary embolism as a largely meaningless diagnosisMay 18, 2011 by Andy Neill · 8 Comments PE: Pain, Puzzles and PERC - LITFL

PE/ PERC wars that are raging on the web as a result of the clash of two New York titans on EMCrit

IS PE “OVERDIAGNOSIS” A MORAL PANIC

KEY ISSUES RAISED BY RECENT ARTICLES CRITIQUING ED DIAGNOSIS OF PE Anticoagulants for PE – little evidence of benefit If anticoagulants work, ? for all PE Too many tests – particularly CTPA ? D-Dimer False positives- ? population prevalence- low yield

? FP rate of 2-4% SSPE rates increasing- effect of 64x CT

PE mortality not reducing as diagnosis increases? CTPA kills your pts (in droves!)- kidney failure, radiation, cancer Overtreatment can kill you – v. high bleed risks? ED patients versus inpatients- v different, minimal disease , lung lint/ fluff Some (? a lot) of PE‘s don’t kill you?

Subsegmental don’t kill single v multiple, co-morbid

Segmental- single? Asymptomatic Physiologically benign, no RV strain, home therapy

What to do about SSPE

BUT IS CT REALLY THE WORST THING WE HAVE EVER UNLEASHED ON EMERGENCY PATIENTS ?

SOME QUESTIONS?

Who in the audience often feels guilty when ordering

A) a D-Dimer Test

SOME QUESTIONS?

Who in the audience often feels guilty when ordering

B) a CTPA

SOME QUESTIONS?

Who in the audience sometimes feels guilty when:

C) even thinking about PE as a diagnosis

ANTICOAGULANTS- INEFFECTIVE AND DANGEROUS?

NO EVIDENCE ANTI COAGULANTS WORK FOR PE?

Actually is reasonable evidence that recurrent PE < Better agents Better control Longer AC > 4-6/52 VTE plaxis: < occurrence DVT tx + < mortality/ VTE-better agents Early dx/tx with

Jelinek et al EMA, Smith et al Chest 2010

BUT Evidence unclear for mortality for 1/2ary Px/Tx for PE death

Trend but NS Direct evidence- 1 ( ordinary) RCT trial (B+J ) of 50 patients

MAJOR OUTCOME DIFFERENCES BETWEEN HEPARINS: (DVT TX)

Date of download: 4/15/2014

From: Low-Molecular-Weight Heparin Compared with Intravenous Unfractionated Heparin for Treatment of Pulmonary Embolism: A Meta-Analysis of Randomized, Controlled Trials

Ann Intern Med. 2004;140(3):175-183. doi:10.7326/0003-4819-140-3-200402030-00008

Symptomatic venous thromboembolism at the end of treatment in trials comparing low-molecular-weight heparin (LMWH) with unfractionated heparin (UFH) for the treatment of acute pulmonary embolismData for the study by Hull and colleagues (32) are estimated from the published time-to-event curve. OR = odds ratio.

Figure Legend:

Copyright © American College of Physicians. All rights reserved.

Fig 1 Cumulative probability (top) and rate (bottom) of recurrent venous thromboembolism (VTE) after stopping treatment according to initial length of treatment (adjusted for age, sex, study,

location of initial VTE, and presence of temporary risk factor.

Boutitie F et al. BMJ 2011;342:bmj.d3036

©2011 by British Medical Journal Publishing Group

PE recurrence clearly increased with decreased time on AC

Fig 4 Icon array showing absolute risks of recurrent VTE (blue) and major bleeding episodes (red) comparing std v extended therapy (secondary prophylaxis). *Only one study

Castellucci L A et al. BMJ 2013;347:bmj.f5133

©2013 by British Medical Journal Publishing Group

ANTICOAGULANTS-EXCESSIVE BLEEDING

Large meta-analysis 10500 pts-mainly IP (>risk)

276 major bleeds 37 fatal (0.36%) NNH 40-50 in 3/12 NNK 250-300 over 3/12

BLEEDING DEATHS IN LARGE REGISTRY (REAL LIFE – DATA)

Registry Numbers % fatal bleed timeframe ED pt mix

ICOPER n 2000 0.2-0.4%* 3/12 Mainly IP

RIETE n 9186 0.9%** 3/12 Mixed 2:1

EMPEROR n 1880 0.2% Initial Stay All ED

Spanish EDs n 1340 0.95% 3/12 All ED

*estimated from free text for stable /no lysis pts** higher risk population, 6.5% direct PE mortality - estimated from tables in paper, some lysis patients - ED population prob < 0.5% bleeding mortality

Fig. 1 Cumulative incidence of fatal PE and major bleeding in 10,461 patients with acute PE, according to hospital status. Comparisons between in- and outpatients: * p &lt; 0.05, † p &lt; 0.01, ‡ p &lt; 0.001. Abbreviations: PE, pulmonary embolism...Ana Maestre , Rosario Sánchez , Vladimir Rosa , Drahomir Aujesky , Alicia Lorenzo , Giovanni Barillari , Manuel M...

Clinical characteristics and outcome of inpatients versus outpatients with venous thromboembolism : Findings from the RIETE Registry

European Journal of Internal Medicine, Volume 21, Issue 5, 2010, 377 - 382

http://dx.doi.org/10.1016/j.ejim.2010.07.004

INCREASED DIAGNOSIS-THE PAYOFF?

INCREASED DIAGNOSIS NO WHAT DOES THIS MEAN? DENOMINATOR V POORLY DOCUMENTED. TREATED PE HAS 0.5-5% MORTALITY?

ISSUES WITH DEATH CERTIFICATES

Death certificate PE – 0.6%BUT PM studies 2-60% PE DC v PM always < 50% accurate

Over-diagnosis also common

Death dominated by sudden untreated PE Hospitals PE deaths considerable < over time

CONCLUSION Certificates death rates are extremely unreliable and cannot determine if tx or dx of PE change mortality White; Circ june 2003, ICOPER registry data,

PE MORTALITY IN TREATED SYMPTOMATIC PE: FOLLOW UP TIME FRAMES MAY VARY

1950-60s –5-10% (Barritt and Jordan 8%-)

1970-80s – 2-8% (Carson JL et al. N Engl J Med 1992;326:1240-1245, PIOPED follow up NEJM.)

1990,s - 1.5-10% (ICOPER 7.5%, mainly IP,, Douketis et al JAMA 1998)

2000’s - 2.4-3% at 3/12 (RIETE –chest December 2006, Vol 130, No. 6)- ED pts

2003-4 3% at 3/12Spanish ED study-Thromb Haemost. 2008 Nov;100(5):937-42.

2010 – on 1.1% (at d/c ?1.5% at 3/12) (Emperor- pollack), other trials

DEATH RATES FOR PROVEN PE –STABLE ?

PM series: diagnosis of PE in hospitals at PM 1950-60s > 10% 1980-90’s 5-6 %? 2011- large series 2% (27% PM rate)

Kopcke;J R Soc Med. Aug 2011; 104(8): 327–331.

OVER-DIAGNOSIS, YIELD, FALSE +VES AND SSPE (LUNG LINT)- Q) ARE THEY IMPORTANT: A) THE WAY BACK IN

Known knowns (probably) Overdiagnosis is bad

Lower yield = greater % overdiagnosis

Known unknownsOptimal yield unknown ? > 15% ( level D evidence)Expected rate of false positivesReal effects of 64-254-320/640 slice CTsSSPE outcomes untreated

Unknown unknowns?

CTPA YIELD IN ED PATIENTS - REGIONAL EFFECTS

Country Study no’s

Range of CTPA yield

No with < 10% yield*

< 15% >20% Yrs

USA 10 3.7%-16.8% 8/10 9/10 1/10 01-09

Australasia 3+(2**) 13-20% 0/5 2/5 0/5 01-11

Canada 4 12.7%-22.6% 0/4 2/4 1/4 01-10

Europe 2 31-37% 0/2 0/2 2/2 2-4

* NB 1 study had yield < 5% ** unpublished data, 2 time series Mountain / WA

Results on CTPA false positive rates in PIOPED2 anFalse positive ratesd CTA–CTV among Patients with a Confirmed Diagnosis of Pulmonary Embolism, According

to the Composite Reference Standard.

STEIN PD ET AL. N ENGL J MED 2006;354:2317-2327. NB FP RATE 3%, 14% OF ALL CTPA?

ONE THOUSAND ED PATIENTS WITH ? PE AND GET A CTPA (1 YEAR AT MY INSTITUTION)

FALSE +VE CTPA (APPLYING PIOPED 2 SENS/SPEC): ONE THOUSAND ED PATIENTS WITH ? PE + CTPA HOW MANY HAVE PE (BLUE)IN MY HOSPITAL/ HOW MANY FALSE +VES (RED)

ONE THOUSAND ED PATIENTS WITH ? PE + CTPA HOW MANY HAVE PE IN EUROPE

ONE THOUSAND ED PATIENTS WITH: HOW MANY HAVE PE IN ? AVERAGE US ED?

US CENTRES WITH 5-6% YIELD- 3 X AS MANY SCANS, 3X FP, SAME PE?

CTPA- KILLING KIDNEYS! KILLING PATIENTS? Newman /Schriger paper Claims from 1 prospective

paper :Mitchell Clin J Am Soc Neph

CIN in 13% (1:7) Dialysis in 1.1% Renal Death in 0.7% (used 0.3%)

All renal dysfunction and outcomes presumed due to CIN

Recent metanalyses- Moos eur j rad 2013, Macdonald JS Radiology 2013 x2

CIN in 4.6/ 6.4% (1:20-1:15)? Dialysis in 0.3%- MacDonald Renal death not calculated but no

difference in overall deaths

Recent v large retrospective review 150000 CTs (50000 pts) + Meta 25000 No evidence of causality for venous contrast in imaging

SSPE META-ANALYSIS, > RATES WITH MDCT? CARRIER M, RIGHINI M, WELLS PS, PERRIER A, ANDERSON DR, RODGER MA, ET AL. SUBSEGMENTAL PULMONARY EMBOLISM DIAGNOSED BY COMPUTED TOMOGRAPHY: INCIDENCE AND CLINICAL IMPLICATIONS. A SYSTEMATIC REVIEW AND META-ANALYSIS OF THE MANAGEMENT OUTCOME STUDIES: SUBSEGMENTAL PULMONARY EMBOLISM DIAGNOSED BY COMPUTED TOMOGRAPHY. JOURNAL OF THROMBOSIS AND HAEMOSTASIS. 2010 AUG;8(8):1716–22.

  SDCT All MDCTMDCT 4 detectors

MDCT 16 detectors

MDCT 64 detectors

1.CI, confidence intervals; MDCT, multi-detectors computed tomography; SDCT, single-detector computed tomographic pulmonary angiography; SSPE, subsegmental pulmonary embolism.

Number of patients

1123 1534 461 207 100

Proportion of SSPE (%, 95% CI)

4.7 (2.5–7.6)

9.4 (5.5–14.2)

7.1 (3.8–11.3)

6.9 (0.7–23.3)

15.0 (7.7–24.1)

Table 3.   Rates of subsegmental pulmonary embolism diagnosis

ISSUES FOR SSPE

30-70% false +ve : PIOPED1,2 Low mortality/ morbidity untreated? Increasing with multislice CT? Increased % in low yield populations Equipoise for NNT=NNH? SSPE = low prob VQ? e.g. we know what to do

MORTALITY IN UNTREATED PTS WITH LOW RISK VTE (MAINLY SSPE)

PIOPED 1 follow up: 20 untreated, 1 VTE death(5%) Stein; Chest 1995

Undiagnosed symptomatic PE in 5 (poss7)- no deaths 20 incidental (asymptomatic PE ) – 0 deaths

Radiology May 2006 Engelke

104 SSPE v PE 1050 22 left untreated: no recurrence or deaths

Donato 2010. Thromb res 2010

SSPE really benignCumulative recurrence risk SSPE vs proximal PE. Cumulative risk of recurrent VTE for patients with SSPE vs patients with proximal (defined

as segmental or central) PE (P = .42 from the log-rank test).

den Exter P L et al. Blood 2013;122:1144-1149

©2013 by American Society of Hematology

AVOIDING TX IN SSPE A Study to Evaluate the Safety of Withholding Anticoagulation in

Patients With Subsegmental PE Who Have a Negative Serial Bilateral Lower Extremity Ultrasound (SSPE) Carrier M (Ottawa) et al Multicentre, multinational trial

Prospective cohort study of no therapy in SSPE

Outcomes –1ary recurrence, PE mortality

WHAT TO DO ABOUT SSPE- OPTIONS

Treat them all = major overtreatment BUT m-legally safe

Don’t treat any of them; Best of luck if they die!

Ask pt to await current Canadian SSPE no tx study

My plan or similar; Muddle around in the middle

MUDDLING IN THE MIDDLE

Make sure you risk stratify Any SSPE needs films reviewed

preferably blinded/ expert/x2-3 Do another test –VQ / VQ SPECT / PA??-do findings match

D-Dimer if not done already –ve: good evidence old or false +ve

US bilateral leg see if clot load/source/risk, reduces post test prob- Treat it like a low prob VQ

If looks/is real consider patient risk-benefit If severe comorbid, poor C-R reserve-clearly treat Severe co-morbid +high bleed risk, discuss with pt/ specialists If low morbid and high bleed risk prob not– watchful wait, rpt US If low morbidity/ low bleed risk- decide with patient

CONCLUSIONS/ QUESTIONS? ACs reduce recurrent PE by >50%, Mortality effect ? CTPA (and DD)-v useful,

use wisely not fearfully, direct harms small CTPA abuse is patient abuse Yields < 10% increase FP dramatically Low yield plus >64 slice CT: prob v. high SSPE SSPE on CTPA mandates

further Ix + consultant input Benign PE/ lung lint- not well enough defined

SSPE –await new evidence ? RCT of no tx ?? OP / low risk groups Asymptomatic PE- ripe for RCT

HISTORICAL DATA OF PM + CLINICAL PE WITH AND WITHOUT TX-

Do anticoagulants improve survival in patients presenting with venous thromboembolism?- Kelly J : J Int Med Dec 2003

DO ANTICOAGULANTS IMPROVE SURVIVAL IN PATIENTS PRESENTING WITH VENOUS THROMBOEMBOLISM?

Journal of Internal MedicineVolume 254, Issue 6, pages 527-539, 27 NOV 2003 DOI: 10.1111/j.1365-2796.2003.01206.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2003.01206.x/full#f2

DO ANTICOAGULANTS IMPROVE SURVIVAL IN PATIENTS PRESENTING WITH VENOUS THROMBOEMBOLISM?

Journal of Internal MedicineVolume 254, Issue 6, pages 527-539, 27 NOV 2003 DOI: 10.1111/j.1365-2796.2003.01206.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2003.01206.x/full#f1

ASYMPTOMATIC PE- ALL GOOD WITHOUT TX?

Meta-analysis of incidental PE in 12 studies 2.6% prevalence in 10000 pts Only 4 studies followed up clinically V few left untreated- of those that did:

4 of 12 recurrent VTE in one 1 in 4 progressed in another Independent predictor ( 5 v 14/12)of survival in cancer pts

• P < 0.001 Dentali June 2010, Thromb Research

MUDDLING IN THE MIDDLE Any SSPE needs films reviewed

preferably blinded/ expert/x2-3 Do another test

VQ / VQ SPECT (mine)/ PA (unlikely)and see if findings match D-Dimer if not done already

–ve: good evidence old or false +ve US bilateral leg see if clot load/source/risk, reduces post test

prob If looks/is real consider patient risk-benefit

If severe comorbid, poor reserve-clearly treat Severe co-morbid and high bleed risk, discuss with pt/

specialists If low morbid and high bleed risk prob not– watchful wait, rpt

US If low morbidity/ low bleed risk- decide with patient

BEST EVIDENCE THAT NOT ALL PE NEED TREATMENT OR HIGH MORTALITY

MSCT v SSCT- no change in follow up outcomes OP tx of ED PE pts (v low recurrence/ mortality) Low/ Low VQ (1-2% PE) Low /Int prob VQ/PTP and –ve US (1-3% PE) Negative CTPA – no tx, sens 90%- (1.5-2% PE)

Everyone (almost) accepts silly and unfeasible to find all PE 2% “missed” is what we and pts can liveKey issue: the 2% missed are v. selected 2%

e.g. small, minimal associated clot, not unwell

INADEQUATE TREATMENT OF VTE ? DIFFERENT OUTCOMES- DIFFERENT REGIMES ? 50-70% RCT of SC v IV Heparin + 3 /12 OAC - symp prox DVT

If non tx response ( poor APPT) 11/53 recurrent (1 fatal) v 1/62 with tx

Hull et al NEJM 86

RCT DVT UFH SC v OACs for 6/12 weeks 9/19 recurrent VTE v 0/17 with OAC

Hull et al NEJM 79

RCT of OAC v IV hep and OAC for Prox DVT 20% v 7% symptomatic recurrence 40 v 8% extension of DVT

Brandtjes et al NEJM 1992

DR CLOTS: SOMETIMES WE ARE THE PROBLEM!

Fig. 2. Box and whisker plot of d-dimer concentration depicting quartiles, stratified according to largest involved pulmonary artery.

Am J Respir Crit Care Med, http://www.atsjournals.org/doi/abs/10.1164/ajrccm.165.3.2104099

Published in: WOUTER DE MONYÉ; BERND-JAN SANSON; MELVIN R. MAC GILLAVRY; PETER M. T. PATTYNAMA; HARRY R. BÜLLER; ANNETTE A. VAN DEN BERG-HUYSMANS; MENNO V. HUISMAN; Am J Respir Crit Care Med  2002, 165, 345-348.DOI: 10.1164/ajrccm.165.3.2104099© 2002 The American Thoracic Society

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SSPE RATES OVER LAST 40 YEARS PIOPED 1- Stein Henry 6 /1997 (Chest),

PA in all- 6% rate of SSPE only, > in low VQ DE Monye 2002 – 20% SSPE

VQ + CTPA or Angio if non high VQ, discordant results Sijens 2000 – 37% SSPE ( Some multiple)

Population US –ve VQ +ve- all had PA

CARNAGE IN REAL LIFE CT READS ?

Compared local reads v 2 “expert readers” (+ tertiary adj)

8% of PE were overdiagnosed (false +ve) 3/42

23% were “missed” (7 of 31)- all segmental (?sub) Experts disagreed in 7/15 segmental/subsegmental level PE

All 7 patients without tx- 0 recurrent VTE diagnosed

Lucassen WAM, Beenen LFM, Büller HR, Erkens PMG, Schaefer-Prokop CM, van den Berk IAH, et al. Concerns in using multi-detector computed tomography for

diagnosing pulmonary embolism in daily practice. A cross-sectional analysis using expert opinion as reference standard. Thromb Res. 2013 Feb;131(2):145–9.

TPHYLAXIS MEDICAL/SURGICAL HIGH RISK PTS

Reviewed all meta-analysis of high risk general VTE t-prophylaxis with any regime

Clear evidence of reduced symptomatic VTE (DVT and PE) for both medical and surgical pts

Guyatt et alChest. 2012;141(2_suppl):e185S-e194S

FALSE POSITIVE RATES IN CTPA V PA Review of PIOPED 2 data

Initial PIOPED2 suggest false +ve rates of 14%! When reviewed side by side CTPA true +ve in 87% of

discordant reads for PA Reduced false +ve rate by a half e.g. 7% Composite gold std prob underestimates CTPA performance If this is real means 1.5-2% of all CTPA will give a false +ve read

Qanadli- CTPA v PA 154 scans – 59 PE on PA CTPA 3 false +ves (3/62 e.g. 5% false +ve) NB on expert review 1 considered true +ve -possibly 2

FALSE POSITIVE RATES FOR VQ V PA

PIOPED 1 6% of PA had only subsegmental PE Agreement between readers for SSPE -66% NB this is a very low SSPE rate

Stein, Henry,Gottschalk; Radiology Mar 1999 http://pubs.rsna.org/doi/full/10.1148/radiology.210.3.r99mr41689

SSPE- ARE THEY REALLY THERE?

Small study 125 patients, 32 possible PE (30 def) 25 Segmental or larger-25 agreed on consensus

7 SSPE actually/ possibly present – 5/2 16-20% SSPE rate 3 readers agreed 5, 1 reader only for 2 SSPE

Original interpretations only had 45 % IO agreement Mainly overcalls e,g 13 SSPE on initial scans

NB all readers over-interpreted and had false +ve rates Required multiple expert readers to reduce to 5(?7)

If initial reads used = 50% + overcall of SSPE NB almost as many agreed SSPE were missed initially!

SSPE BENIGN - THERAPY NEEDED?

Large study of 800+ve PE 2400 PE –ve patients: 16% (118) had SSPE by CTPA At follow up SSPE group (all treated) were similar to segmental+

PE in terms of recurrent VTE (3.2%v 2.5% NS ), Deaths NS ( 10% v 6.5%) SSPE > in older, male, oestrogen users SSPE had OR of 3.8 for recurrent VTE v untreated PE-ve

NB none of these patients were routinely screened for DVT

Den Exter et al Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism

NO ONE DIES OF PE FROM THE ED ANY MORE? Current reported rates of death from PE in ED populations

In hospital PE mortality- overall 6% mortality If normotensive on arrival– 1.5% mortality If no RV strain on Echo- 0% in hospital

Grifoni et al Circulation. 2000; 101: 2817-2822

EMPEROR data base- registry 1800 PE 1.1% mortality rate (20) –direct from PE at 30/7 Mortality in non-hypotensive , 0.9% Mortality without evidence of RV strain-0.65% (1:154) 0.16% haemorrhagic mortality (3)

NB EMPEROR in US patients, where CTPA +ve rate routinely <10% e.g. high false positive rates likely ? 50%

META-ANALYSIS OF PROSPECTIVE OP MX STUDIES FOR ED PATIENTS

Table 1. Modified from original data in Piran et al . Thrombosis Research 2013 Baseline Characteristics and Three Month Outcomes of the Studies Included in the Systematic Review.

Study Design N Malignancy (%)Risk Stratification Management Mortality (%) Fatal PE (%)

Fatal ICH (%)

VTE Recurrence (%) Major Bleeding (%)

Agterof 2010 Cohort 152 20 (13.2)

Low NT-proBNP (< 500 pg/mL) Outpatient 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Aujesky 2011 RCT 171 1 (1)

PESI (Class I or II) Outpatient 1 (0.6) 0 (0) 0 (0) 1 (0.6) 3 (1.8)

Beer 2003 Cohort 43 NAGeneva Score (Score ≤ 2) Outpatient 0 (0) 0 (0) 0 (0) 1 (2.3) 0 (0)

Davies 2007 Cohort 157 NA Clinical gestalt Early discharge 3 (1.9) 0 (0) 0 (0) 0 (0) 0 (0)

Kovacs 2000 Cohort 108 24 (22.2) Clinical gestaltOutpatient and early discharge 4 (3.7) 0 (0) 0 (0) 6 (5.6) 2 (1.9)

Olsson 2006 Cohort 102 NA Clinical gestalt Outpatient NA NA NA NA NA

Otero 2010 RCT 72 6 (4.5)Uresandi score > 2 Early discharge 3 (4.2) 1 (1.4) 0 (0) 2 (2.8) 1 (1.4)

Rodrà guez-Cerrillo 2009 Cohort 30 4 (13.3) Clinical gestalt Outpatient 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Siragusa 2005 Cohort 36 36 (100) Clinical gestalt Outpatient NA NA NA NA NA

Wells 2005 RCT 90 NA Clinical gestalt Outpatient 3 (3.3) 0 (0) 0 (0) 2 (2.2) 0 (0)Zondag 2011 Cohort 297 28 (9.4) Hestia criteria Outpatient 3 (1) 0 (0) 1 (0.33) 6 (2) 2 (0.67)

TOTALS3 RCT, 8 cohort 1258 6 Clin gestalt 8.5 ED d/c 17(1.58%) ? ? 18(1.47%) 8 (0.81%)

LOW RISK ED POPULATIONS- OP THERAPY OP tx of PE 40% managed as OP, (non hypoxic, stable)

Erkens et al 2010- retro “consecutive” pts 400 pts Home tx 3/12 PE mortality 0%, 3.6% VTE recurrence, Maj bleed 1.5% No PE or bleeding related deaths in 3/12 reported

Otero et al Thrombosis research 2008 RCT 132 patients 0.75% VTE mortality ( R atrial thrombus)- early arm 0.75% hage mortality (early tx) arm, 1.5% major bleed 3% recurrent VTE (all PE)

HESTIA study Zondag et al J Thromb Haemostasis 2011 Prospective follow 300 PE with home tx-predefined criteria VTE recurrence 3/12- 2%, no VTE deaths 2 major haemorrhages (0.66%) - 1 death

Aujesky et al Lancet 2011 MC-RCT of OP tx, PESI 1-2, n 300 No C-R compromise, low bleeding risk <25% randomised of assessed Overall VTE recurrence 1 pt 0.3% ( CI, 0-2.6%) Major bleeds 1%, No VTE or Tx deaths

OUTPATIENT THERAPY FOR ED PATIENTSDO THEY REALLY NEED IT? Study Type No.s Excluded

No.sRecurrent VTE(deaths)

Major haemorrhage (deaths)

Erkens J Thromb haemost. 2010

Retro consecutive cohort, one centre

260 245 3.6% (0) 1.5% (0)

HESTIA; ZondagJ Thromb haemost. 2011

Prospective M-C cohort: predefined

297 243 2% (0) 0.8% (0.4%)

Otero Thrombosis Research 2008

RCT – multicentre 132 884 3% (0.75%) 1.5% (0.75%)

Aujesky Lancet 2011

RCT – multicentre 344 1148 0.3% (0) 1% (0)

1033 patients: 1 VTE death, 2 bleeding deaths, 20 recurrent VTE, 11 major bleeds

Date of download: 5/27/2014Copyright © 2014 American Medical Association.

All rights reserved.

From: Computed Tomographic Pulmonary Angiography vs Ventilation-Perfusion Lung Scanning in Patients With Suspected Pulmonary Embolism:  A Randomized Controlled Trial

JAMA. 2007;298(23):2743-2753. doi:10.1001/jama.298.23.2743

Figure Legend:

ISSUES WITH EUROPEAN V US DATA- MORE EVIDENCE OF OVERDIAGNOSIS/ POOR SELECTION IN LOW PREVALENCE DISEASE- EMPEROR V RIETE OP SETS

NB –when comparing RIETE OP data with US EMPEROR data it seems clear we are dealing with different risk populations. In particulalr mortality rates at 3/12 directly from PE are around 3 % in European data v 1% in the US data. However in Europe rates of positive CTPA are around 20-30% whereas in US they are around 5-10%. It may well be that false positive diagnosis explains a lot of this difference- e.g. you are unlikely to die from PE if you didn’t have the disease in the first place. ? How much does this explain-possibly half the difference ? more depending on how low the yield dropped to in US departments

Fig. 1 Cumulative incidence of fatal PE and major bleeding in 10,461 patients with acute PE, according to hospital status. Comparisons between in- and outpatients: * p &lt; 0.05, † p &lt; 0.01, ‡ p &lt; 0.001. Abbreviations: PE, pulmonary embolism...Ana Maestre , Rosario Sánchez , Vladimir Rosa , Drahomir Aujesky , Alicia Lorenzo , Giovanni Barillari , Manuel M...

Clinical characteristics and outcome of inpatients versus outpatients with venous thromboembolism : Findings from the RIETE Registry

European Journal of Internal Medicine, Volume 21, Issue 5, 2010, 377 - 382

http://dx.doi.org/10.1016/j.ejim.2010.07.004

Figure 2. Annual number of PEs diagnosed by CTPA, number of PEs without associated RV abnormalities or myocardial injury, and number of PEs with associated RV dysfunction and/or dilatation and/or myocardial injury.

Schissler AJ, Rozenshtein A, Kulon ME, Pearson GDN, et al. (2013) CT Pulmonary Angiography: Increasingly Diagnosing Less Severe Pulmonary Emboli. PLoS ONE 8(6): e65669. doi:10.1371/journal.pone.0065669http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065669

INCREASING CTPA-DECREASING YIELD? CHANDRA BMC PULM MED. 2013;13(9)

Incidence, mortality, and case fatality of pulmonary embolism in United States, 1993-2006.26.

Wiener R S et al. BMJ 2013;347:bmj.f3368

©2013 by British Medical Journal Publishing Group

WHY DOES PE HAVE SUCH A BAD NAME

Mortality at 3/12 Treated-11-12% Hx-ic mortality rate 15-30% Untreated now-? Initial ED assessment with

correct diagnosis - 90%+ Admitted with an incorrect /

unknown diagnosis < 5%

Mortality at 30/7 Treated 10-12% Hx-ic mortality 15-35% Untreated now ? Initial ED assessment with

correct diagnosis-30-40% Admitted with incorrect/

unknown diagnosis ≈ 65%

PE AMI

CRIT CARE PTS (MED/SURG)-PPHYAXIS WITH HEPS

Asympt DVT and PE < 50%, Hep v nothing. Mort NS reduced

LMWHx v UFH –reduced PE and symp PE , no mort effect

• Alhazzani et al Crit care med Sept 2013 Heparin Thromboprophylaxis in Medical-Surgical Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Trials*

Fig 4 Icon array showing absolute risks of recurrent VTE (blue) and major bleeding episodes (red) comparing std v extended therapy (secondary prophylaxis). *Only one study

Castellucci L A et al. BMJ 2013;347:bmj.f5133

©2013 by British Medical Journal Publishing Group

Fig 2 Odds ratio (95% credible interval) for recurrent VTE and major bleeding episodes in Bayesian network meta-analysis versus placebo or observation.

Castellucci L A et al. BMJ 2013;347:bmj.f5133

©2013 by British Medical Journal Publishing Group

SSPE – REALLY BENIGN?

LARGE PROSPECTIVE DATASET3769 (2 studies n 3306 and n 463) 1032 excluded by D Dimer + PTP (28.7%)2688 had a CTPA of which 789 were positive (29.3% of all CTPA performed and 21% of total population)(41/789 ( excluded)) as localisation not recorded SSPE=15% (116) of 748 +ves

SSPE patients were much more similar to larger PE patients ( e.g. NS differences) than those with PE excluded (p <0.05) Including 4/6 major risk factors, rate of recurrent PE, bleeding outcomes, overall mortality Recurrence rates in SSPE were similar SSPE (3.8% v 2.5%) – 1/4 death in SSPE, 9/14 VTE =

deaths in large PE Maj haemorrhage in 1.6% both PE groups (2 deaths in larger PE)

Exter PL den, Es J van, Klok FA, Kroft LJ, Kruip MJHA, Kamphuisen PW, et al. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood. 2013 Aug15;122(7):1144–9.

KEY Q’S RAISED IN EXCESSIVE DIAGNOSIS OF PE

Anticoagulants in PE? How many tests are too many? False positives- the effect of population prevalence

FP rate in reality? If Yes - beneficial for all PE? Which PE‘s don’t (unlikely to)kill you?

Subsegmental, single v multiple, co-morbid Segmental- single Asymptomatic Physiologically benign, no RV strain

ED patients versus inpatients- how different are they PE mortality not reducing as diagnosis increases?

One-Year Mortality Curve in 399 Patients with Pulmonary Embolism.

CARSON JL ET AL. N ENGL J MED 1992;326:1240-1245.

HEPARIN DEFINITELY REDUCES DVTS- COCHRANE REVIEWSLMWH v control, DVT px in lower limb OP POP

DVT: reduced by 50%Low molecular weight heparin for prevention of venous thromboembolism in adults with lower-leg immobilization in an outpatient setting Testroote M, Stigter WAH, de Visser DC, Janzing HMJ

High risk surgery patients Heparin + mechanical px PE Rate from 2.7 to 1.1% (DVT 4 to 1.6%) e.g. 60% reductions

Combined intermittent pneumatic leg compression and medication for the prevention of deep vein thrombosis and pulmonary embolism in high-risk patients Kakkos SK, Caprini JA, Geroulakos G, Nicolaides AN, Stansby G, Reddy DJ

LMWH for 2-4 weeks post abdominal surgery Symptomatic VTE decreased from 1.7% to 0.2% (e.g. 90% reduction)

Prolonged administration of low molecular weight heparin lowers the number of blood clots in the lower limbs after operation in the abdomen or pelvisRasmussen MS, Jørgensen LNannestad, Wille-Jørgensen P

NB: none of these reviews of 1000’s of patients could prove mortality benefits or improvements in symptomatic or fatal PE

YOUNGER PATIENTS <56 WITH MINIMAL OTHER DISEASE- MINIMAL RISK?RECURRENT PE, VTE DEATH AND FATAL BLEED

3500 patients with 1ary PE <56 followed up for 6/12 1 co-morbidity max Outcomes

Recurrent PE 13% at 5 yrs (440) Recurrent PE 3% at 1 month (100) ; 6% at 6 months (204) Death due to PE

1.5% at 1/12 (50 ; 25 in day1-2), 1.7% at 6/12 (56) Death due to bleeding

0.05% at 6/12 (2)

NB from 28/7 to 6/12 still 6x as many VTE deaths v fatal bleed

ISSUES WITH POPULATION BASED PE MORTALITY AS A MARKER FOR THERAPEUTIC OUTCOMES

Many from PM done for ? cause of death/sudden death 40 years of PM show clinical diagnosis poor

- always < 50% diagnosed Death certificates filled by juniors/ GPs Treated PE has low mortality rate <5% from PE Death is not the only outcome of interest

Recurrent DVT-PE Pulm Hypertension/ deconditioning

Cancer and PE

Date of download: 4/24/2014Copyright © 2014 American Medical Association.

All rights reserved.

From: Duration of Anticoagulation Following Venous Thromboembolism:  A Meta-analysis

JAMA. 2005;294(6):706-715. doi:10.1001/jama.294.6.706

The period for defining incidence rates for measurement purposes begins when short-term anticoagulation is stopped but long-term therapy continues. The period ends at study completion, which was at least 3 months after long-term therapy had been stopped. Studies are ranked according to the duration of therapy in the group receiving short-term therapy, with the studies having the shortest duration at the top. As the duration of therapy increases, the magnitude of the benefit of long-term therapy decreases in terms of both relative risk and risk difference (P = .04 and P = .005, respectively). Sizes of data markers are proportional to the weight of each study in the meta-analysis. Error bars indicate 95% confidence intervals.

Figure Legend:

Cumulative VTE risk SSPE* vs no PE. Cumulative risk of VTE during follow-up for patients with SSPE vs patients with no PE (P = .03 from the log-rank test).

den Exter P L et al. Blood 2013;122:1144-1149 *NB SSPE all treated

©2013 by American Society of Hematology

SPECIFICITY OF CTPA (MAINLY SINGLE SLICE)-

Date of download: 4/24/2014

Copyright © The American College of Cardiology. All rights reserved.

From: Clinical Characteristics, Management, and Outcomes of Patients Diagnosed With Acute Pulmonary Embolism in the Emergency Department: Initial Report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry)

J Am Coll Cardiol. 2011;57(6):700-706. doi:10.1016/j.jacc.2010.05.071

In-Hospital and 30-Day Outcomes

Figure Legend:

ONE THOUSAND ED PATIENTS WITH ? PE FOR NEW SLIDES TEMPLATE

ONE THOUSAND ED PATIENTS WITH ? BACKGD-ALL PATIENTS REMOVED, TO MAKE NEW SLIDES

ONE THOUSAND ED PATIENTS WITH ? BACKGD-ALL PATIENTS REMOVED, TO MAKE NEW SLIDES

KEY ARGUMENTS THAT PE IS OVERDIAGNOSED IN ED No evidence that anticoagulants work for PE Increase use of CTPA- > diagnosis no change in PE mortality Decreasing yield/size-

The amazing disappearing PEs ( ? USA only) What yield is appropriate ( Kline/Newman/ Making the Best Use of a CTPA, Guidelines for Doctors, Department of Clinical

Radiology, The Royal College of Radiologist, 6th edition, 2007.

Too many small ones and increasing? Are little ones even there? Little ones don’t /won’t kill you- don’t need therapy Risk: benefit much > for Ed patients from over,dx

Major harms from Radiation AKI from dye- see papers re underlying AKI rates in hospital and v rare that anyone gets

dialysis ( Aaron Chakera-personal communication) Overdiagnosis with excessive AC-bleeding problems Excessive costs/ excessive time

PE not what it used to be: maybe it never was ED PE not really a killer

ONE THOUSAND ED PATIENTS WITH ? PE AND CTPA IN A LOW PREVALENCE 5% PE POPULATION? THE REAL Q IS IF 1000 PTS OR REALLY 3-4000 ?

ONE THOUSAND ED PATIENTS WITH CTPA YIELD OF 5%!

ONE THOUSAND ED PATIENTS WITH ? PE + CTPA HOW MANY HAVE PE IN EUROPE

Date of download: 6/9/2014

From: Management of Venous Thromboembolism: A Systematic Review for a Practice Guideline

Ann Intern Med. 2007;146(3):211-222. doi:10.7326/0003-4819-146-3-200702060-00150

Systematic Reviews Comparing Low-Molecular-Weight Heparin with Unfractionated Heparin (n = 10)*

Figure Legend:

Copyright © American College of Physicians. All rights reserved.