Polly Rimtepathip Pharm D. Candidate September 16, 2011 Outpatient Versus Inpatient Treatment for Patients with Acute Pulmonary Embolism: an International, Open-label, Randomised, Non-inferiority Trial Aujesky D, Roy P, Veschuren F, et al. Lancet 2011; 378: 41-48

 Swiss National Science foundation  Programme Hospitalier de Recherche Clinique  US National Heart, Lung, and Blood Institute  Sanofi-Aventis provided free drug supply in the participating European centers

 Current guideline recommends outpatient care to selected, stable patients with pulmonary embolism (PE), but the management of PE is still predominantly inpatient based.  Previous outpatient care studies were restricted by small sample sizes, retrospective designs, and the absence of a control group.

 One study that looked at inpatient versus outpatient PE management had to be halted prematurely due to the high mortality rate in both treatment groups.  The objective of this Outpatient Treatment of Pulmonary Embolism (OPTE) Trial is to compare the effectiveness, safety, and efficiency of outpatient versus inpatient care for low-risk patients with acute, symptomatic PE as classified by the clinical prognostic model.

 Multi-center, international, open-label, randomized, non-inferiority clinical trial  Conducted in 19 emergency departments across 4 countries: Switzerland, France, Belgium and USA from February 2007 to June 2010  Both groups of patients received a treatment of subcutaneous enoxaparin for 5 or more days followed by oral anticoagulation for 90 or more days.

 Patients with acute, symptomatic PE with a PE severity index risk of class I or II were randomly assigned into outpatient or inpatient treatment group.  The PE severity index uses several factors, such as age and male sex, to assign the score to the patient.  334 patients were enrolled and 172 patients were randomly assigned to each treatment group.

Points Assigned Age+1 per year Male sex+10 Active or history of cancer+30 Heart Failure+10 Chronic lung disease+10 Pulse ≥ 110 beats per min+20 Systolic Blood Pressure <100 mmHg +30 Respiratory rate ≥ 30 breaths per min +20 Temperature < 36°C +20 Altered mental status +60 Arterial oxygen saturation < 90% +20 Class I = score < 66 Class II = score 66-85

 Adults aged 18 or older with acute, symptomatic PE who were at low risk (Class I or II from the PE severity index)  Acute pulmonary embolism is defined as an acute onset of dyspnea or chest pain, together with a new contrast filling defect on spiral computed tomography or pulmonary angiography, a new high-probability ventilation-perfusion lung scan, or documentation of a new proximal deep vein thrombosis either by venous ultrasonography or contrast venography

 Arterial hypoxemia, Systolic BP < 100mmHg, chest pain, active or high-risk of bleeding  Severe renal failure (CrCl < 30mL/min)  Extreme obesity, history of heparin-induced thrombocytopenia  Therapeutic oral anticoagulation at the time of diagnosis of PE (INR ≥ 2.0)  Diagnosis of PE > 23 hours before the time of screening (to avoid enrolling already stabilized patients)  Any barriers to adherence or follow-up and previous enrollment in the trial

 Outpatient group  Discharged from the ER within 24 hours of randomization  Self-inject with SQ enoxaparin 1mg/kg twice daily  If self-injection was not possible, a caregiver or a visiting nurse would administer the shot.  Inpatient group  Admitted to the hospital and received the same enoxaparin regimen as the outpatient group  The treating physician, unrelated to the study, assessed the patient’s readiness for discharge.

 Both treatment groups  Early initiation of oral anticoagulant with vit-K antagonist and continuation for a minimum of 90 days with no specified regimen  The anticoagulation was managed by the PCP or hospital’s anticoagulant personnel.  Enoxaparin was discontinued after ≥ 5 days when the INR was ≥ 2.0 for 2 consecutive days.

 Follow-up  Patients were contacted every day the week after the enrollment, then at day 14, 30, 60 and 90.  Patients were asked about symptoms of recurrent venous thromboembolism (VTE), bleeding and any use of healthcare resources.  All patients were instructed to report any new symptoms suggestive of VTE or any bleeding episodes to the emergency department.

 Primary outcome  Recurrence of symptomatic, objectively confirmed VTE, defined as recurrent pulmonary embolism or new or recurrent deep-vein thrombosis (DVT) within 90 days of randomization  Secondary outcome  Major bleeding within days of randomization and all-cause mortality within 90 days

 Non-inferiority of outpatient to inpatient group were postulated at the margin of 4%.  160 patients per treatment group were calculated to provide 80% power to detect a non-inferiority margin of 4% using a 1- sided alpha of 0.05, assuming the rate of drop out at 5%.  An exact, unconditional permutation test of non-inferiority of outpatient were used to compare the difference in the percentage of outpatients and inpatients having recurrent VTE.  Quantitative measures of resource use between intervention groups with negative binomial regression with a bootstrap variance estimates.

 1/171 in outpatient group (0.6%) and none in inpatient group had a recurrent VTE within 90 days (met criterion for inferiority).  The one VTE occurred in a woman with cervical cancer who initially had bilateral segmental PE.  2 outpatients and no inpatient had major bleeding within 14 days, suggesting non-inferiority.  1 patient in each group died within 90 days, supporting non-inferiority.  156/170 outpatients (92%) and 158/167 inpatients (95%) were satisfied with the medical care.

 The mean time initially spent in the hospital in outpatient group was 0.5 days compared to 3.9 days for inpatient group.  Both groups had the same number of hospital readmissions, emergency department visits and outpatient visits to a doctor’s office within 90 days.  Potential VTE-related medical resource use was about the same between the 2 groups.  Outpatient group had non-significantly more home- nursing visits for enoxaparin injections than did inpatients.

 Outpatient treatment with LMW heparin is not inferior to the inpatient treatment in term of effectiveness and safety and associated with low rates of recurrent VTE, major bleeding and death.  Non-inferiority was shown at 14 days but not at 90 days because of an additional bleeding event in outpatient 50 days after randomization.  Cost-savings from reductions in hospital stay might be partially offset by an increase in frequency of home-nursing visits for outpatient group.

 Duration of treatment with LMW heparin was 2-6 days longer for outpatients than inpatients.  24 patients who had central PE on computed tomography were safely treated as outpatients in the study, suggesting that central PE might not be an absolute indication for hospitalization.  A previous trial comparing the PE management in inpatients and outpatients treatment that was stopped prematurely used a non-validated prognostic model to identify low-risk patients which suggests that only a validated risk stratification methods should be used to select patients for outpatient care.

 Patients enrolled were relatively young and had a low prevalence of cancer.  Patients were only treated with enoxaparin, but the use of fondaparinux or oral direct thrombin inhibitors might further aid outpatient care of VTE and decrease the need for home-nursing visits.  The study was an open-label, could bias medical care and assessments of study outcomes, but the outcomes was adjudicated with a committee blinded to treatment status.  17 patients were not randomly allocated to intervention groups because the treating physician declined participation.

 I believe that outpatient treatment of acute PE is a viable option for selected low-risk patients.  Further studies with different initial agents are needed to compare efficacy and safety between outpatient and inpatient treatment.  A cost analysis between the 2 treatment groups accounting for different insurances will help the physician and the patient determine between outpatient and inpatient treatment.