Polly RimtepathipPharm D. CandidateSeptember 16, 2011

Outpatient Versus Inpatient Treatment for Patients with Acute

Pulmonary Embolism: an International, Open-label,

Randomised, Non-inferiority TrialAujesky 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 14-90 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.