Outpatient treatment of pulmonary embolism Sam Schulman, MD, PhD Dept. of Medicine McMaster University

Faculty/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 Support 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 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 Spencer FA. J Gen Intern Med 2006 Silverstein MD. Arch Intern Med 1998 Hansson PO. Arch Intern Med 1997 Oger E and EPI-GETBO. Thromb Haemost 2000

Effect of age White, R. H. Circulation 2003;107:I-4-I-8 Annual incidence of VTE among residents of Worcester MA 1986, by age and sex White, R. H. Circulation 2003;107:I-4-I-8 Copyright ©2003 American Heart Association 12 12

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

Major hemorrhage (30 d) 1.5% in both groups 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 Figure 1. Kaplan-Meier Estimates of the Absence of Deep-Vein Thrombosis or Pulmonary Embolism in the Intervention Group and the Control Group. P Major hemorrhage (30 d) 1.5% in both groups Kucher, N. et al. N Engl J Med 2005;352:969-977 15

Extended prophylaxis – for whom?

Extended prophylaxis after THR Symptomatic VTE Venographic DVT: 9.6 vs 19.6%; OR 0.48 Eikelboom JW, et al. Lancet 2001;358:9–15

Extended prophylaxis in THR % VTE % P=0.001 Hull et al. Ann Intern Med 2001;135:858 Prandoni et al. Arch Intern Med 2002;162:1966 Samama CM et al Arch Intern Med 2002;162:2191

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

RECORD1 (THR): summary RRR 70% Rivaroxaban 10 mg od 4 3.7% Enoxaparin 40 mg od Rivaroxaban 10 mg od 3 RRR 88% 2.0% Incidence (%) 2 1.1% 1 0.5% 0.3% 0.3% 0.2% 0.1% Total VTE Major VTE Symptomatic VTE Major bleeding p<0.001 p<0.001 p=0.22 p=0.18 Eriksson et al., N Engl J Med 2008;358:2765–2775

Extension with dabigatran THR RE-NOVATE II Dabigatran 150/220 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 THR ADVANCE 3 Apixaban 2.5 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 Differential diagnosis Pleuritic pain (65%) Dyspnea (20%) Syncope (10%) (Hemoptysis is rare) Differential diagnosis Respiratory tract infection Myocardial infarction Pericarditis Musculoskelettal conditions

Suspected PE Our case Wells’ clinical prediction score for PE Previous PE or DVT +1.5 Heart rate > 100/min +1.5 Recent surgery or immobilization +1.5 Clinical signs of DVT +3 Alternative diagnosis less likely than PE +3 Hemoptysis +1 Cancer +1 Dichotomized rule Unlikely < 4 Likely > 4 Wells PS et al. Thromb Haemost. 2000;83:416-20

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

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 Our case Age 37 SBP 95 SaO2 88% =87 p 85 p or less = low risk of fatal PE – NPV = 99% Aujesky D et al. Am J Resp Crit Care Med 2005;172:1041–6 External validation in: J Intern Med 2007;261:597-604

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 Any YES response = admit to hospital Zondag W et al. Thromb Haemost 2013;109:47-52

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 RCT 90 days Treatment Outpatient Inpatient Randomized/ analyzed 172/ 171 172/ 168 Days on LMWH 11.5 8.9 VKA managed by GP 73% 75% Recurrent VTE 1 (0.6%) Major bleeding 3 (1.8%) Death (no PE) Another RCT stopped prematurely due to high mortality in both arms Otero R, Uresandi F, Jimenez D, et al. Home treatment in pulmonary embolism. Thromb Res 2010; 126: e1–5. Aujesky D et al. Lancet 2011;378:41-8

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) Results Cohort A Cohort B Thrombotic event 3 (0.95%) 10 (3.8%) Major bleed 4 (1.5%) Deaths* 9 (2.9%) 13 (5%) *Almost all due to cancer Kovacs MJ et al. J Thromb Haemost 2010; 8:2406-11 Erkens PMG et al. J Thromb Haemost 2010; 8:2412-7

Start treatment on suspicion 5.2.1. In patients with a high clinical suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic tests (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 option Einstein 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 algorithm Hemodynamic Instability (shock) Large PE But stable Submassive PE Rivaroxaban 15 mg bid  20 mg q.d. t-PA Heparin IV  LMWH 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 m 0.9% 1.1% *based on diagnostic algorithm and neg CTPA Carrier M et al. J Thromb Haemost 2010; 8: 1716–22

Duration of anticoagulation ???

A meta-analysis on individual data N=2474 PE as a risk factor A meta-analysis on individual data N=2474 Pinede et al. ASH 2003

Recommended duration of Rx 6.2. In patients with PE provoked by a nonsurgical transient risk factor, we recommend treatment with 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) extended therapy if there is a high bleeding risk (Grade 1B) . We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low 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 D-dimer Dx 0 3-6 m +1 m +3 m Neg Neg Pos 27%/yr Neg Neg Neg 2.9%/yr 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.

Why did I get the PE? (I was on COC for 10 years before) Thrombosis Threshold With factor V Leiden or prothrombin mutation +COC +COC Risk of VTE Healthy person Age

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