outpatient treatment of pulmonary embolism sam schulman, md, phd dept. of medicine mcmaster...
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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