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
3.
4.
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
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?
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
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?