1. Moderate Pulmonary Embolism
Treated With Thrombolysis
(from the “MOPETT” Trial)
(Am J Cardiol 2012)
Clinical trials registry number?

2. Guidelines for reporting RCTs
• Consolidated standards of reporting trials (CONSORT) statement
– Comprises a 25-item checklist and a flow diagram, along with some
brief descriptive text
• The checklist focuses on how the trial was designed, analysed, and interpreted
• the flow diagram displays the progress of all participants through the trial
– Considered an evolving document, the CONSORT Statement is subject
to periodic changes as new evidence emerges
– Current version is CONSORT 2010
– Is endorsed by prominent general medical journals, many specialty
medical journals, and leading editorial organizations
• Currently over 50% of the core medical journals listed in the Abridged Index Medicus
on PubMed
– Is part of a broader effort, to improve the reporting of different types of
health research, and indeed, to improve the quality of research used in
decision-making in healthcare

5. Background
Thrombolysis is an effective tool in the treatment of massive pulmonary
embolism (PE).
The possibility of ensuing intracerebral haemorrhage has caused a
reluctance to use thrombolysis for symptomatic PE without
haemodynamic instability.
The researchers experience with percutaneous endovenous
intervention for deep venous thrombosis has suggested an exquisitely
favourable pulmonary response to low-dose thrombolysis.
A lower dose of the thrombolytic drug might be effective in PE, with the
additional benefit of an improved safety profile.
No data are available on peripheral IV administration of low-dose
thrombolysis for “moderate” PE in the reduction of pulmonary artery
pressures after 2 years.

6. Objectives
• The purpose of the MOPETT trial was to
assess the effect of low dose tPA (50 mg
for patients weighing ≥50 kg; 0.5 mg/kg for
patients weighing < 50kg ) on the
reduction of pulmonary artery pressure at
28 months in moderate PE

7. Methods
• Single centre, open label, randomised, controlled trial
• 1 centre in the US?
• Enrolment occurred between May 2008 and March 2010
• Enrolment target 120 (110 to satisfy required sample
size)
• Variable duration of follow up (28 ± 5 months)

8. Methods
• All patients received either unfractionated heparin OR
subcutaneous enoxaparin with initial preference given to
the latter drug.
– Enoxaparin was given to 48 of 61 (79%) TG patients and 49 of
60 (81%) CG patients
– Administration of unfractionated heparin was determined by the
presence of renal insufficiency or patient preference

9. Methods
• Treatment group (low dose tPA plus modified
anticoagulation) received
– Enoxaparin 1mg/kg subcut twice daily with initial dose not to exceed
80mg OR unfractionated heparin 70 U/kg bolus not exceeding 6000U
with subsequent dose adjustment to keep the activated partial
thromboplastin time at 1.5 to 2 times the baseline value
– Although tPA was infused the maintenance dose of unfractionated
heparin was kept at 10U/kg/hour not to exceed 1000U/hour
– 3 hrs after termination of thrombolysis heparin increased to 18U/kg/hour
• Control group (best practice anticoagulation alone?)
received
– Enoxaparin at 1 mg/kg subcut twice daily OR unfractionated heparin 80
U/kg bolus followed by 18U/kg/hour with the same partial thromboplastin
time target

10. Eligibility
• Inclusion criteria
– “Adult”
– Moderate PE
• Signs and symptoms of PE plus CT pulmonary angiographic involvement of >70%
involvement of thrombus in ≥2 lobar or left or right main pulmonary arteries or by a high
probability ventilation/perfusion scan showing ventilation perfusion mismatch in ≥2
lobes
– A minimum of ≥2 new signs and symptoms consisting of
• Chest pain
• Tachypnea (RR ≥22 breaths/min)
• Tachycardia (HR ≥90 beats/min)
• Dyspnea
• Cough
• Oxygen desaturation (pO2 <95%)
• Elevated jugular venous pressure ≥12 cm H 2O
– Informed consent

11. Eligibility
• Exclusion criteria
– Onset of symptoms >10 days
– >8 hours since start of parenteral anticoagulation
– SBP <95 or BP ≥200/100 mmHg
– Eligible for full-dose thrombolysis
– A contraindication to unfractionated or low-molecular-weight heparin
– Severe thrombocytopaenia (platelet count <50,000/mm3)
– Major bleeding within 2 months requiring transfusion
– Surgery or major trauma within 2 weeks
– Brain mass
– Neurologic surgery
– Intracerebral haemorrhage or subdural haematoma within 1 year
– End-stage illness with no plan for PE treatment
– Unable to perform echocardiography (chest deformity, bandages, etc.)

12. Randomisation and blinding
• Randomisation occurred after inclusion/exclusion criteria
and informed consent were satisfied
• Randomisation ratio of 1:1 by centralised process
• No blinding

13. Endpoints
• Primary endpoints
– Proportion of patients with pulmonary hypertension
(pulmonary artery SP ≥40 mmHg as assessed by
echocardiography) at intermediate-term follow-up
(described as mean=28, SD=5 months for total
population)
– Proportion of patients with pulmonary hypertension or
recurrent PE at intermediate-term follow-up

14. Endpoints
• Secondary endpoints
– Proportion of patients with recurrent PE at
intermediate-term follow-up
– Proportion of patients deceased at intermediate-term
follow-up
– Proportion of patients with recurrent PE plus
deceased at intermediate-term follow-up
– Hospital LOS
– Bleeding

15. Statistical Analysis
• Sample size based on a reduction in pulmonary artery systolic
pressure of 10% (from 50 mmHg to 45 mmHg?), 90% power, two
sided α=5%, SD=9 (both groups?)
– number needed = 110 (55 TG: 55 CG) (comparison of means)
– Allowing for drop outs = 120 (60 TG: 60 CG)
• For primary end points (pulmonary hypertension, pulmonary
hypertension or recurrent PE) Fisher’s exact test was used
(comparison of proportions)
• For secondary end points Fisher’s exact test (recurrent PE, all
cause mortality, recurrent PE or all cause mortality) and unpaired t-
test (hospital LOS) were used (comparison of means)
• For other end points (pulmonary artery systolic pressure) unpaired t-
test?
• All tests two-tailed, α not stated

16. Flow diagram

17. Baseline characteristics

18. Results - Primary endpoints

19. Results – Secondary endpoints

20. Results – Other

21. PICO
P patients with moderate PE, ineligible for full-dose
thrombolysis
I low dose tPA plus modified anticoagulation
C best practice anticoagulation alone
O pulmonary hypertension alone or, pulmonary
hypertension or recurrent PE, at intermediate-term
follow-up
Research question:
In patients with moderate PE, ineligible for full-dose
thrombolysis does low dose tPA plus modified anticoagulation
result in a lower rate of pulmonary hypertension alone or,
pulmonary hypertension or recurrent PE, at intermediate-term
follow-up compared with best practice anticoagulation alone?

22. PICO
P patients with moderate PE, ineligible for full-dose
thrombolysis
I low dose tPA plus modified anticoagulation
C best practice anticoagulation alone
O pulmonary hypertension alone or, pulmonary
hypertension or recurrent PE, at intermediate-term
follow-up
Research question:
In patients with moderate PE, ineligible for full-dose
thrombolysis does low dose tPA plus modified anticoagulation
result in a lower rate of pulmonary hypertension alone or,
pulmonary hypertension or recurrent PE, at intermediate-term
follow-up compared with best practice anticoagulation alone?

23. PICO
P patients with moderate PE, ineligible for full-dose
thrombolysis
I low dose tPA plus modified anticoagulation
C best practice anticoagulation alone
O pulmonary hypertension alone or, pulmonary
hypertension or recurrent PE, at intermediate-term
follow-up
Research question:
In patients with moderate PE, ineligible for full-dose
thrombolysis does low dose tPA plus modified anticoagulation
result in a lower rate of pulmonary hypertension alone or,
pulmonary hypertension or recurrent PE, at intermediate-term
follow-up compared with best practice anticoagulation alone?

24. PICO
P patients with moderate PE, ineligible for full-dose
thrombolysis
I low dose tPA plus modified anticoagulation
C best practice anticoagulation alone
O pulmonary hypertension alone or, pulmonary
hypertension or recurrent PE, at intermediate-term
follow-up
Research question:
In patients with moderate PE, ineligible for full-dose
thrombolysis does low dose tPA plus modified anticoagulation
result in a lower rate of pulmonary hypertension alone or,
pulmonary hypertension or recurrent PE, at intermediate-term
follow-up compared with best practice anticoagulation alone?

25. PICO
P patients with moderate PE, ineligible for full-dose
thrombolysis
I low dose tPA plus modified anticoagulation
C best practice anticoagulation alone
O pulmonary hypertension alone or, pulmonary
hypertension or recurrent PE, at intermediate-term
follow-up
Research question:
In patients with moderate PE, ineligible for full-dose
thrombolysis does low dose tPA plus modified anticoagulation
result in a lower rate of pulmonary hypertension alone or,
pulmonary hypertension or recurrent PE, at intermediate-term
follow-up compared with best practice anticoagulation alone?

26. Was the assignment of patients to
treatments randomised?

27. Were the groups similar at the start
of the trial?

28. Aside from the allocated treatment,
were groups treated equally?

29. Were all patients who entered the trial
accounted for? – and were they
analysed in the groups to which they
were randomised?

30. Were measures objective or were the
patients and clinicians kept “blind” to
which treatment was being received?

31. How large was the treatment effect?

32. How large was the treatment effect?
• Pulmonary hypertension at intermediate
term follow-up
– TG 9/58 (16%) vs CG 32/56 (57%) p<0.001
• ARR 41%
• NNT = 2.4

33. How large was the treatment effect?
• Composite endpoint at intermediate term
follow-up
– TG 9/58 (16%) vs CG 35/56 (63%) p<0.001
• ARR 47%
• NNT = 2.1

34. How precise was the estimate of the
treatment effect?

35. How precise was the estimate of the
treatment effect?
• Pulmonary hypertension at intermediate
term follow-up
– TG 9/58 (16%) vs CG 32/56 (57%) p<0.001
• ARR 41% (95%CI 24%-56%)
• NNT = 2.4 (95%CI 1.8 to 4.2)

36. How precise was the estimate of the
treatment effect?
• Composite endpoint at intermediate term
follow-up
– TG 9/58 (16%) vs CG 35/56 (63%) p<0.001
• ARR 47% (95%CI 30%-61%)
• NNT = 2.1 (95%CI 1.6 to 3.3)

37. Will the results help me in caring for my
patient? (External validity/Applicability)
The questions that you should ask before you
decide to apply the results of the study to your
patient are:
– Is my patient so different to those in the study that the
results cannot apply?
– Is the treatment feasible in my setting?
• Will the potential benefits of treatment outweigh
the potential harms of treatment for my patient?