Presentation on theme: "Outpatient treatment of pulmonary embolism Sam Schulman, MD, PhD Dept. of Medicine McMaster University."— Presentation transcript:
Outpatient treatment of pulmonary embolism Sam Schulman, MD, PhD Dept. of Medicine McMaster University
Faculty/Presenter Disclosure Faculty: Dr. Sam Schulman Program: 51 st 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, SaO 2 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
Data on incidence of VTE Worcester, MA – all medical records 1999 with VTE diagnosis: 104 per 100,000 1 Olmsted County, MN – medical records of all residents with VTE 1966-1990, incl PE on autopsy: 117 per 100,000 2 Sweden – Men born 1913, followed from age 50: 387 per 100,000 3 Bretagne, France – Diagnosis data: 184/100,000 4 1.Spencer FA. J Gen Intern Med 2006 2.Silverstein MD. Arch Intern Med 1998 3.Hansson PO. Arch Intern Med 1997 4.Oger E and EPI-GETBO. Thromb Haemost 2000
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
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 groups
Extended prophylaxis – for whom?
Extended prophylaxis after THR Symptomatic VTE Eikelboom JW, et al. Lancet 2001;358:9–15 Venographic DVT: 9.6 vs 19.6%; OR 0.48
Extended prophylaxis in THR % VTE% 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 P=0.001
Extension with rivaroxaban THR Eriksson et al., N Engl J Med 2008; 358:2765–75
RECORD1 (THR): summary Incidence (%) 0.1% 0.3% 3.7% 1.1% 2.0% 0.2% 0.5% 0.3% Total VTEMajor VTE RRR 88% Symptomatic VTEMajor bleeding 0 1 2 3 4 Enoxaparin 40 mg od Rivaroxaban 10 mg od p<0.001 p=0.22p=0.18 RRR 70% 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 VTE7.7%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 VTE1.4%3.9% Major VTE0.5%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
Suspected PE 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 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
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 / yrSBP <10030 p – Male sex10 pPulse >11020 p – Cancer30 pRR>3020 p – CHF10 pTemp <3620 p – Chron lung dis.10 pSaO 2 <90%20 p – mental status60 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 case Age 37 SBP 95 SaO 2 88% =87 p
Simplified PESI Retrospective analysis of RIETE registry – Age >801 p – History of Cancer 1 p – Chron cardiopulmonary dis.1 p – Pulse >110 1 p – CHF1 p – SBP <100 1 p – SaO 2 <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, ICU) Thrombolysis/embolectomy required High risk for bleeding (recent GI-bleed, CVA, Sx; Plt 180) O 2 to maintain SaO 2 >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 RCT 90 days Aujesky D et al. Lancet 2011;378:41-8 TreatmentOutpatientInpatient Randomized/ analyzed 172/ 171 172/ 168 Days on LMWH 11.58.9 VKA managed by GP 73%75% Recurrent VTE1 (0.6%)0 Major bleeding3 (1.8%)0 Death (no PE)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; 8:2406-11 Erkens PMG et al. J Thromb Haemost 2010; 8:2412-7 ResultsCohort ACohort B Thrombotic event 3 (0.95%)10 (3.8%) Major bleed3 (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 suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic tests (Grade 2C). 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) t-PA Large PE But stable Heparin IV LMWH Submassive PE 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 detectorMulti-detector CTPA Incidence: 4.7%9.4% Suspected PE left untreated* - TE at 3 m 0.9%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 data N=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 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). 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 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%/yr Neg Neg Neg 2.9%/yr
Why did I get the PE? (I was on COC for 10 years before) Risk of VTE Thrombosis Age Healthy person With factor V Leiden or prothrombin mutation +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