Outpatient treatment of pulmonary embolism

Sam Schulman, MD, PhDDept. of Medicine

McMaster University

Faculty/Presenter DisclosureFaculty/Presenter Disclosure

• Faculty: Dr. Sam Schulman• Program: 51st Annual Scientific

Assembly

• Relationships with commercial interests:– Grants/Research Support: N/A– Speakers Bureau/Honoraria: Boehringer

Ingelheim and Bayer Healthcare for work in study-related committees

– Consulting Fees: N/A– Other: N/A

Disclosure of Commercial Disclosure of Commercial SupportSupport

• This program has received financial support from Boehringer Ingelheim and Bayer Healthcare in the form of Honorarium.

• This program has received in-kind support from N/A

Potential for conflict(s) of interest:– Dr. Sam Schulman has received Honorarium from Bayer

Healthcare whose product is being discussed in this program.– Bayer Healthcare sells a product that will be discussed in this

program: rivaroxaban.

Mitigating Potential BiasMitigating Potential Bias

• All treatment alternatives are discussed

Contents

• Case discussion• Epidemiological data• Who is at the highest risk• Extended prophylaxis – when?• Diagnosis – mainly risk stratification• Treatment – a lot easier now• How long after VTE – a dilemma

PE-case

• 37-year old female• Cough and some SOB since 4 weeks, went to

ER 3 weeks ago, got antibiotics.• Slowly getting worse, more since 2 days• Started oral contraceptives 3 months ago but

has been on it for 10 years in the past.• Returns now to ER, HR 95, BP 95/60, RR 20,

SaO2 88% on room air, legs normal

Patient wants to go home

• Has small children to take care of.• After some efforts convinced to stay. HR

increases to 110/min.• Gets t-PA (alteplase) 100 mg over 2 h, rapid

improvement of symptoms

Epidemiology

Data on incidence of VTE

• Worcester, MA – all medical records 1999 with VTE diagnosis: 104 per 100,0001

• Olmsted County, MN – medical records of all residents with VTE 1966-1990, incl PE on autopsy: 117 per 100,0002

• Sweden – Men born 1913, followed from age 50: 387 per 100,0003

• Bretagne, France – Diagnosis data: 184/100,0004

1. Spencer FA. J Gen Intern Med 20062. Silverstein MD. Arch Intern Med 19983. Hansson PO. Arch Intern Med 19974. Oger E and EPI-GETBO. Thromb Haemost 2000

Copyright ©2003 American Heart Association

White, R. H. Circulation 2003;107:I-4-I-8

Annual incidence of VTE among residents of Worcester MA 1986, by age and sex

Effect of age

And then mainly more PE

PE – pulmonary embolism; DVT – deep vein thrombosis

Who is at the highest risk?

• 3 points each– Cancer– Prior VTE– Hypercoagulability

• 2 points– Major surgery

• 1 point each– Age >70– Obesity (BMI >29)– Bed rest– HRT or COC

Increased risk >4 points at any time point after admission

Kucher, N. et al. N Engl J Med 2005;352:969-977

Kucher, N. et al. N Engl J Med 2005;352:969-977

Kaplan-Meier Estimates of the Absence of Deep-Vein Thrombosis or Pulmonary Embolism in the Intervention Group and the Control Group

8.2% 4.9%P<0.001

Major hemorrhage (30 d) 1.5% in both groupsMajor hemorrhage (30 d) 1.5% in both groups

Extended prophylaxis – for whom?

Extended-duration prophylaxis against venous thromboembolism aftertotal hip or knee replacement : a meta-analysis of the randomised trialsEikelboom et al, Lancet 2001; 358: 9-15

Venographic DVT 9.6% vs 19.6%% OR 0.48

Extended prophylaxis after THRExtended prophylaxis after THRSymptomatic VTESymptomatic VTE

Eikelboom JW, et al. Lancet 2001;358:9–15

Venographic DVT: 9.6 vs 19.6%; OR 0.48

Extension with rivaroxaban THR

14

Primary efficacy endpointIn

cide

nce

(%)

0

1

2

3

4

5

6

Rivaroxaban10 mg once daily

18/1,595

Enoxaparin40 mg once daily

58/1,558

3.7% 1.1%

RRR=70%

ARD=–2.6% (–3.7, –1.5)

p<0.001

Total VTE

ARD (with 95% CI); mITT population, n=3,153

Eriksson et al., N Engl J Med 2008;358:2765–2775

Eriksson et al., N Engl J Med 2008; 358:2765–75

RECORD1 (THR): summaryIn

cid

ence

(%

)

0.1%0.3%

3.7%

1.1%

2.0%

0.2%

0.5%0.3%

Total VTE Major VTE

RRR 88%

Symptomatic VTE Major bleeding0

1

2

3

4

Enoxaparin 40 mg odRivaroxaban 10 mg od

p<0.001 p<0.001 p=0.22 p=0.18

RRR 70%

Eriksson et al., N Engl J Med 2008;358:2765–2775

Extension with dabigatran THRRE-NOVATE II

Dabigatran150/220 qd

Enoxaparin 40 mg qd

Total VTE 7.7% 8.8%

Major VTE or fatal PE

2.2% 4.2%

Major bleeding

1.4% 0.9%

Clin rel non-major bleed

2.3% 2.0%

P=0.03

Eriksson B et al. Thromb Haemost 2011;105:721-9

Extension with apixaban THRADVANCE 3

Apixaban2.5 mg bid

Enoxaparin 40 mg qd

Total VTE 1.4% 3.9%

Major VTE 0.5% 1.1%

Major bleeding

0.8% 0.7%

Clin rel non-major bleed

4.1% 4.5%

P<0.001

P=0.01

Lassen MR et al. N Engl J Med 2010; 363:2487-98

Extended therapy so much easier now

• Oral medication• No monitoring• Once daily (rivaroxaban or dabigatran) or

twice daily (apixaban)• LU-code to cover patients age 65 after

orthopedic surgery

Other high-risk groups

• Spinal cord injuries – 3 months• Abdominal/pelvic cancer surgery – 1 month• BUT• So far not in medically ill patients

– 3 large trials failed to demonstrate positive benefit/risk ratio

Diagnosis

Symptoms• Most common symptoms

– Pleuritic pain (65%)– Dyspnea (20%)– Syncope (10%)(Hemoptysis is rare)

• Differential diagnosis– Respiratory tract infection– Myocardial infarction– Pericarditis– Musculoskelettal conditions

Suspected PE

Wells’ clinical prediction score for PEPrevious PE or DVT +1.5Heart rate > 100/min +1.5Recent surgery or immobilization +1.5Clinical signs of DVT +3Alternative diagnosis less likely than PE +3Hemoptysis +1Cancer +1Dichotomized rule Unlikely < 4 Likely > 4

Wells PS et al. Thromb Haemost. 2000;83:416-20

Our case

D-dimer

• D-dimer: Not useful– In generally ill patients– Shortly after surgery– Differential vs cellulitis– Very elderly (>80)– Long duration of symptoms

• A neg D-dimer in an outpatient with low pretest probability has a NPV of 99% for VTE in next 3 months

Clinical probability assessment

Low or intermediate High

D-dimer

Below cut-off Above cut-off

CUS 1 or MDCTA 2

Negative 3 Positive

No anticoagulant therapy Anticoagulant therapy

CT or VQ-scan?

• CT easier interpretation – but overdiagnosis?– Radiation >VQ – avoid in fertile women– Requires contrast injection – not in renal failure

• VQ – less available– Actually 3 exams

Echocardiogram

• Transthoracic ECHO– In hemodynamically unstable patient for

assessment of PA-pressure– RV-strain with dilatation and hypokinesia– Paradoxal septal movement– Occasionally clots are seen in RA, RV or right PA

Can my PE-patient in ER go home?

• Pulmonary Embolism Severity Index (PESI)– Age 1 p / yr SBP <100 30 p– Male sex 10 p Pulse >110 20 p– Cancer 30 p RR>30 20 p– CHF 10 p Temp <36 20 p– Chron lung dis. 10 p SaO2 <90% 20 p

– mental status 60 p

Aujesky D et al. Am J Resp Crit Care Med 2005;172:1041–6 External validation in: J Intern Med 2007;261:597-604

85 p or less = low risk of fatal PE – NPV = 99%

Our caseAge 37SBP 95SaO2 88%=87 p

Simplified PESI• Retrospective analysis of RIETE registry

– Age >80 1 p– History of Cancer 1 p– Chron cardiopulmonary dis. 1 p– Pulse >110 1 p– CHF 1 p– SBP <100 1 p– SaO2 <90% 1 p

• 0 = low risk, 1 or more = high risk

Jiménez D et al. Arch Intern Med. 2010;170:1383-9

Simplified PESI result

Jiménez D et al. Arch Intern Med. 2010;170:1383-9

Other risk stratification - Hestia• Hemodynamically unstable (SBP <100, HR >100, ICU)• Thrombolysis/embolectomy required• High risk for bleeding (recent GI-bleed, CVA, Sx; Plt <75, SBP >180)• O2 to maintain SaO2 >90% >24h

• Pulmonary embolism on anticoag Rx• IV pain medication >24 h• Medical or social reason for hospitalization >24 h• CrCl <30 mL/min (CG formula)• Severe liver impairment• Pregnancy• History of HIT

Zondag W et al. Thromb Haemost 2013;109:47-52

Any YES response = admit to hospital

Comparison sPESI vs Hestia

• Both decision rules identified >50% of patients as ”low risk”

• Negative predictive value for 30-day mortality– Hestia 99%– sPESI 100%

ESC criteria for outpatient Rx of PE• Low risk: Hemodynamically stable + no RV

dysfunction (RV/LV 1.0)• Intermediate risk: Asymptomatic RV

dysfunction• High risk: Cardiovascular shock/ SBP

<100/assessed as hemodynamically unstable by physician

• Comparison Hestia vs. ESC: NPV 100% vs 99%• Some Hestia-low risk had RV dysfunction

Zondag W et al. J Thromb Haemost 2013;11:686-92

Summary Diagnostic Rules

• PESI/sPESI most validated – 7 items• HESTIA more complex – 11 items• ESC is minimalistic, although requires

asessment of RV dysfunction, perhaps more dependent on how the physician assesses

Laboratory test in risk-strat?

• N-terminal pro-Brain Natriuretic Peptide or NT-proBNP is associated with myocardial damage and prognosis after PE.

• 152 of 351 patients with PE were hemodynamically stable and NT-proBNP <500 pg/mL outpatient management

• No death, PE or major bleed in 3 months;7 patients readmitted during 1st week but no new PE.

Agterof MJ et al. J Thromb Haemost 2010;8:1235-41

RCT on outpatient Rx of PE

• Open label, non-inferiority trial• 19 ER-sites in Switzerland, France, Belgium

and US• PESI score 85 (= low risk; class I or II) were

eligible.• Randomized (within mean 13 h) to outpatient

or 5 days in hospital.• Enoxaparin VKA for 90 days

Aujesky D et al. Lancet 2011;378:41-8

Results outpatient PE Rx RCT90 days

Aujesky D et al. Lancet 2011;378:41-8

Treatment Outpatient Inpatient

Randomized/ analyzed

172/171

172/168

Days on LMWH 11.5 8.9VKA managed by GP 73% 75%

Recurrent VTE 1 (0.6%) 0

Major bleeding 3 (1.8%) 0Death (no PE) 1 (0.6%) 1 (0.6%)

2 Canadian management studies• Retrospective, single centre studies,

treatment out of hospital, 3-month F-U.• A. 314 (49%) patients (London, ON)• B. 260 (55%) patients (Ottawa, ON)

Kovacs MJ et al. J Thromb Haemost 2010; 8:2406-11Erkens PMG et al. J Thromb Haemost 2010; 8:2412-7

Results Cohort A Cohort BThrombotic event

3 (0.95%) 10 (3.8%)

Major bleed 3 (0.95%) 4 (1.5%)

Deaths* 9 (2.9%) 13 (5%)

*Almost all due to cancer

Start treatment on suspicion

5.2.1. In patients with a high clinical suspicionof acute PE, we suggest treatment with parenteralanticoagulants compared with no treatmentwhile awaiting the results of diagnostictests (Grade 2C) .

5.2.1. In patients with a high clinical suspicionof acute PE, we suggest treatment with parenteralanticoagulants compared with no treatmentwhile awaiting the results of diagnostictests (Grade 2C) .

No studies address this

• Most patients have relatively low risk of bleeding – 1 dose of anticoagulants is unlikely to harm

• The higher the suspicion, the more justified to give a dose.

• For untreated PE a progression is potentially worse than for untreated DVT

Rivaroxaban – a new optionEinstein PE

Major or clinically relevant bleeding in 10.3% (riva) vs. 11.4% (standard Rx)

Büller HR et al. NEJM 2012

Rivaroxaban - Important to know• Starting dose 15 mg BID• Switch after 3 weeks to 20 mg daily• Must be taken with food• Tablets contain lactose (some get stomach

pain)• Severe renal failure (CrCl <30 mL/min) or

concomitant ketokonazole or other azoles, rifampicin and ritonavir are contraindications

• Few of the study patients hade extensive DVT or large PE. These patients might benefit from intial parenteral Rx.

Acute treatment algorithmHemodynamicInstability(shock)

t-PA

Large PEBut stable

Heparin IV LMWH

SubmassivePE

Rivaroxaban 15 mg bid 20 mg q.d.

Vitamin K antagonist

LMWH therap dose

cancer

Treat subsegmental PE?• SR with 22 articles on CTPA reporting

subsegmental PE (ssPE).• Single detector Multi-detector CTPA• Incidence:

4.7% 9.4%

• Suspected PE left untreated* - TE at 3 m0.9% 1.1%

Carrier M et al. J Thromb Haemost 2010; 8: 1716–22

*based on diagnostic algorithm and neg CTPA

Duration of anticoagulation ???

Pinede et al. ASH 2003

A meta-analysis on individual dataN=2474

PE as a risk factor

Recommended duration of Rx

6.2. In patients with PE provoked by a nonsurgical

transient risk factor, we recommend treatmentwith anticoagulation for 3 months over(i) treatment of a shorter period (Grade 1B) ,(ii) treatment of a longer time-limited period(eg, 6 or 12 months) (Grade 1B) , and (iii)

extendedtherapy if there is a high bleeding risk (Grade 1B)

.We suggest treatment with anticoagulation for3 months over extended therapy if there is alow or moderate bleeding risk (Grade 2B) .

6.2. In patients with PE provoked by a nonsurgical

transient risk factor, we recommend treatmentwith anticoagulation for 3 months over(i) treatment of a shorter period (Grade 1B) ,(ii) treatment of a longer time-limited period(eg, 6 or 12 months) (Grade 1B) , and (iii)

extendedtherapy if there is a high bleeding risk (Grade 1B)

.We suggest treatment with anticoagulation for3 months over extended therapy if there is alow or moderate bleeding risk (Grade 2B) .

Typical practice

• More respect for a PE than DVT.• Particularly if massive PE• Most will anticoagulate for 6 months

– Some for 12 months

Management strategy – unprovoked VTE

Dx

0 3-6 m +1 m

D-dimer

Pos

Neg Pos 8.9%/yr

Neg Neg 3.5%/yr

Verhovsek M. Ann Intern Med. 2008;149:481-490. Cosmi B, et al. Blood. 2010;115:481-488.

+3 m

Neg Neg Pos 27%/yrNeg Neg Neg 2.9%/yr

Why did I get the PE?(I was on COC for 10 years before)

Ris

k of

VT

E

Thrombosis

Age

Healthy personWith factor V Leiden or prothrombin mutation

+COC

+COC

Threshold

Conclusions

• PE occurs in about 1/3 of VTE patients– Proportionally more in elderly

• High risk in cancer, prior PE, certain surgeries• Diagnosis – usually with CT

– Fertile female or severe renal failure VQ-scan

• Treat on suspicion• Rivaroxaban p.o. A new option