E.10 Thrombolytic therapy (PE) · 2017-01-21 · Clinical evidence tables E.10 Thrombolytic therapy...
Transcript of E.10 Thrombolytic therapy (PE) · 2017-01-21 · Clinical evidence tables E.10 Thrombolytic therapy...
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Venous thromboembolic diseases Clinical evidence tables
E.10 Thrombolytic therapy (PE)
What is the effectiveness of open surgical thromboectomy, combination of mechanical and pharmacological thrombolysis, pharmacological thrombolytic therapy and heparin to mange acute PE?
Study
details
Patients Interventions Outcome measures Effect size Comments
Dong 2009 111
Study design: SR included 8 RCTs.
Evidence level: 1++
Setting:
Italy, US, Canada, Norway, Germany and UK.
Patient group:
Adult patients who had symptoms or signs of pulmonary embolism.
Inclusion criteria: PE confirmed by pulmonary angiography or ventilation/perfusion lung scan, or any other validated measurement.
Exclusion criteria: did not include studies that compared to different thrombolytic agents or different doses of the same thrombolytic drug.
All patients N: 679
Group 1
Thrombolytic agent (streptokinase, urokinase, recombinant tissue plasminogen activator (rt-PA) or alteplase.
Group 2 Heparin or placebo plus heparin.
All cause mortality Group1: 15/335
Group 2: 16/344
Risk ratio: 0.90 [0.47, 1.72]
p value: 0.74
Funding: Chinese Cochrane Centre, China (Internal).
Chief Scientist Office, Scottish Government Health Directorates, the Scottish Government, UK (External).
Subgroups:
The Cochrane review did not identify subgroups for examination. However, for the purpose of analyses the studies were split, according to the majority group into haemodynamically unstable (also referred to as massive PE) and haemodynamically stable (also
Major bleeding (defined as a decreased haemoglobin concentration of >2g/dl; retroperitoneal or intracranial bleeding; a transfusion of tow or more units of blood and/or leading to discontinuation of
Group1: 35/335
Group 2: 22/344
Risk ratio: 1.50 [0.92, 2.45]
p value: 0.11
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Study
details
Patients Interventions Outcome measures Effect size Comments
Duration of follow-up:
Duration of follow up varied and deaths were reported from 72 hours – 30 days.
anticoagulant treatment).
referred to as sub-massive PE).
Treatment groups compared were thrombolysis plus heparin vs heparin alone. Consequently, Tibbutt 1974 and Marini 1988 were excluded from analysis and forest plots.
Haemodynamically unstable:
Ly 1978
UPETSG 1970
VTE related mortality Not reported
Chronic thromboembolic Pulmonary hypertension
Not reported
Length of hospital stay Not reported
Heparin induced thrombocytopenia
Not reported
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Venous thromboembolic diseases Clinical evidence tables
Study
details
Patients Interventions Outcome measures Effect size Comments
Haemodynamically stable:
Dalla-Volta 1992
Goldhaber 1993
Konstantinides 2002
Levine 1990
PIOPED 1990
Extracted additional outcomes from the original papers where possible (please see summary of papers and forest plots):
-VTE related mortality
-Chronic thromboembolic Pulmonary -Length of hospital stay hypertension
-Heparin induced thrombocytopenia
Limitations: None of the studies reported on quality of life or healthcare costs.
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Study
details
Patients Interventions Outcome measures Effect size Comments
3/8 appropriate randomisation.
3/8 appropriately reported allocation concealment.
2 single blinded, 4 double blinded. 1 not reported, 1 trial was non-blinded and 1 trail was non-blinded for treatment allocation but pulmonary angiogram evaluation was blinded.
All studies reported withdrawal rate. Intention to treat analysis used.
Additional outcomes:
Recurrence of PE
Minor haemorrhagic events
Escalation of treatment
Pulmonary arterial systolic pressure improvement
Mean pulmonary arterial pressure improvement
Right ventricular end diastolic pressure improvement
Total pulmonary resistance improvement
Cardiac index improvement.
Right ventricular systolic
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Study
details
Patients Interventions Outcome measures Effect size Comments
pressure improvement
Right arterial mean pressure improvement
Arterial venous oxygen difference
Arterial p)2 improvement
Perfusion lung scanning resolution
50% improvement in lung scan
Pulmonary angiogram assessment, improvement
Right ventricular wall improvement
Tricuspid regurgitation improvement
Haemocoagulation variables, fibrinogen
Haemocoagulation variables, D-dimer
Haemocoagulation variables, plasminogen
Study
details
Patients Interventions Outcome measures Effect size Comments
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Study
details
Patients Interventions Outcome measures Effect size Comments
Dotter 1979 113
Study design:
RCT
Setting:
Multi-centre study conducted by the National Heart and Lung institute, Oregon, USA
Duration of follow-up:
Patient group:
Adult patients of either sex who had PE.
Study included haemodynamically unstable PE (71%) and haemodynamically stable PE (29%)
Inclusion criteria: Adult patients of either sex who had PE.
Exclusion criteria: Patients with any of the following conditions: hemorrhagic diathesis, severe systemic hypertenision (Grade III or IV), streptococcal infection, active tuberculosis, serious liver disease with bleeding tendency, recent history of active duodenal ulcer r other gastrointestinal abnormality with bleeding, recent (6 months) cerebrovascular accident, suspected carotid artery thrombosis, atrial
Group 1 - Streptokinase
Administered by constant peripheral vein infusion as a loading dose of 250,000 IU in 5% dextrose over a 20-30 minute period, followed by maintenance dosage of not less that 100,000 IU/hour for 18 to 72 hours. The rate if infusion of the maintenance dose was adjusted on the basis of the thrombin time at periodic intervals during treatment (0, 2, 4, 6, 8, 12, 16, 20 and 24 hours and at 12-hour intervals thereafter).
Group 2 - Heparin
Heparin for 5 or more days followed by oral anticoagulants.
Loading dose of 1500 units/kg followed by a
All cause mortality Group1: 1/15 (6.7%)
Group 2: 2/16 (12.5%)
Funding: Not reported
Subgroup:
Haemodynamically unstable
Limitations:
Method of randomisation and allocation concealment not reported. Number of dropouts or withdrawals post-randomisation not reported (excluded from Cochrane)
Additional outcomes:
-Recurrence of PE
Notes:
VTE related mortality Group1: 1/15 (6.7%)
Group 2: 2/16 (12.5%)
Major bleeding Group1: 1/15 (6.7%)
Group 2: 3/16 (18.75%)
Chronic thromboembolic Pulmonary hypertension
Not reported
Length of hospital stay Not reported
Heparin induced thrombocytopenia
Not reported
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Study
details
Patients Interventions Outcome measures Effect size Comments
fibrillation, recent (10 days) major surgery, pregnancy at any stage or the postpartum period (10 days), recent (10 days) hepatic or renal biopsy, or recent (2 weeks) translumbar aortography.
All patients N: 31 Drop outs: Not reported Group 1 N: 15 Age (range): Not reported Group 2 N: 16 Age (range): Not reported
similar constant rate of infusion. Long-term anticoagulation with warfarin replaced heparin therapy when the prothrombin time reached 2 -2.5x the control and maintained for 3 days.
Study
details
Patients Interventions Outcome measures Effect size Comments
Fasullo 2011
136
Patient group:
Hemodynamically stable patients
Group 1- Alteplase
100 mg alteplase (Actilyse
All cause mortality Group1: 0/37
Group 2: 6/35 (17%)
Funding: NR
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Study
details
Patients Interventions Outcome measures Effect size Comments
Study design:
RCT
Setting:
Multi-centre (three) study Italy
Comparison:
Alteplase+ 9 heparin vs placebo + heparin
Duration of follow-up:
6 month total
aged 18- 75 years with a first episode of submassive PE (SPE)
Inclusion criteria:
Symptoms onset since no more than 6 hours for 1
st episode of SPE,
normal blood pressure, RVD at echocardiogram, positive lung spiral CT scan, dyspnea, chest pain, tachypnea, hypoxaemia, oxygen saturation <90% in room air, D-dimer elevation, electrocardiography with S1-Q3-T3 pattern, inversion of T waves in V1 to V4, a right bundle-branch block or right axis deviation.
Exclusion criteria:
Massive PE. Active internal bleeding, recent intracranial bleeding, intracranial tumour or seizure history, ischaemic stroke until 2 months, neurosurgery during last month, recent surgery within 10 days, trauma within 15 days, uncontrolled hypertension, haemorrhagic disorder of thrombocytopaenia, severe impaired hepatic or renal function,
as a 10 mg bolus followed by 90 mg iv infusion over 2 hours
Group 2- Placebo
Matching placebo
All patients:
Iv bolus 5000 U of UFH just prior to randomisation.
Both groups continued to receive iv UFH (1000 U/hr)in combination with warfarin (started on day 1 after randomisation) until the INR was in therapeutic range for 2 consecutive days, after this point heparin was stopped and only warfarin was kept at discharge and follow up
APTT measured at 6 hour
p value: 0.027 Limitations:
Dropouts not reported
Subgroup:
Haemodynamically stable
Additional outcomes:
-Death from irreversible RVD
-Minor bleeding
-RVD
-DVT persistence
- Recurrent PE
Notes:
Randomisation using computer algorithm, assignment of all patients decided at admission by at least 2 external physicians who
VTE related mortality
Fatal recurrent PE
Group1: 0/37
Group 2: 4/35 (11%)
p value: NR
Major bleeding (considered major if it was fatal, intracranial, required transfusion or intervention for haemodynamic deteriation)
Group1: 2/37 (5%)
Group 2: 1/35 (3%)
p value: Not significant
Chronic thromboembolic Pulmonary hypertension
Not reported
Length of hospital stay Not reported
Heparin induced thrombocytopenia
Not reported
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Study
details
Patients Interventions Outcome measures Effect size Comments
GI bleeding within 10 days, pregnancy, older than 75 years. Arterial aneurysm or arterial/ venous malformation and cancer if increased risk for bleeding. Patients with chronic pulmonary hypertension, severe COPD and who had received therapeutic doses of heparin (UF or LMWH) for >72 hours before randomisation, thrombolytic treatment within the previous 4 days, or glycoprotein IIb/ IIIa antagonists within the preceeding 7 days, patients on oral anticoagulation.
All patients N: 72 Age (mean): NR Drop outs: NR Group 1 Alteplase N: 37 Age (mean): 55+/-16.7 Drop outs: NR Sex (m/f): 21/16 Previous or concomitant disease: -cardiovascular: 6 -pulmonary: 3 -DVT: 24 Smoking habit: 14 -Oral contraceptive: 8
intervals for first day after randomisation, then every 12 hours thereafter for at least 4 days
were blinded to study protocol.
Allocation concealment not reported.
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Study
details
Patients Interventions Outcome measures Effect size Comments
-surgery within the last 4 weeks: 4 Group 2 Placebo N: 35 Age (mean): 57+/-15.5 Drop outs: NR Sex (m/f): 20/15 Previous or concomitant disease: -cardiovascular: 8 -pulmonary: 4 -DVT: 27 Smoking habit: 17 -Oral contraceptive: 7 -surgery within the last 4 weeks: 5
Study
details
Patients Interventions Outcome measures Effect size Comments
Jerjes-Sanchez 1995
206
Study design:
RCT
Patient group:
Massive PE and cardiogenic shock.
Inclusion criteria:
patient age ≥ 15 years
Group 1: Streptokinase and heparin.
1,500,000 IU streptokinase over one hour by the peripheral vein, followed by a bolus of 10,000 U of heparin
All cause mortality Group1: 0/4 (0%
Group 2: 4/4 (100%)
p value: 0.02
Funding: Not reported.
Subgroup:
Haemodynamically unstable
VTE related mortality
Group1: 0/4 (0%
Group 2: 4/4 (100%)
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Study
details
Patients Interventions Outcome measures Effect size Comments
Setting: Mexico
Duration of follow-up:
2 years.
previously healthy
PE diagnosis sustained by high clinical suspicion
PE proven by high probability VQ lung scan, suggestive echocardiogram
Or DVT by radiovenogram
Massive PE, defined as > 9 obstructed segments on VQ lung scan with or without cardiogenic shock (systolic BP<90 mmHg)
< 9 obstructed segments on VQ lung scan but with right ventricular dysfunction and /or extensive DVT, and
Symptoms or signs of PE within 14 days after the onset of symptoms.
Exclusion criteria:
Previous PE
Patients with < 3 segmental defects on VQ lung scan, with normal echocardiogram and without DVT, and
Absolute contraindication for thrombolytic therapy: active or recent haemorrhage, intracranial disease, head
and then a constant infusion of 1000 u/hr of heparin titrated to a partial thromboplastin time of 2-2.5 times control.
Group 2: heparin alone
Heparin group followed the same routine as group 1 but without the streptokinase.
In the survivors of the acute phase, on the fifth day heparin was overlapped with Coumadin and was stopped on day. The patients were kept on Coumadin aiming for an INR of 2-3 for 3 months or more, depending on the presence of major risk factors.
p value: 0.02 Limitations:
Suspicion of PE but not proven.
Intervention group arrived at emergency department from 1 to 4 hours after the onset of symptoms of PE, whereas patients in the control group had a first PPE in other hospitals.
Additional outcomes:
None reported.
Notes:
Trial terminated due to mortality results.
Major bleeding Not reported
Chronic thromboembolic Pulmonary hypertension
Not reported
Length of hospital stay Not reported
Heparin induced thrombocytopenia
Not reported
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Study
details
Patients Interventions Outcome measures Effect size Comments
trauma, neurologic or major surgery within previous 6 weeks, or any concurrent condition considered to limit survival to a few months.
All patients N: 8 Drop outs: NR(4 died) Group 1 N: 4 Age (SD): 51±22.89 Group 2 N: 4 Age (range): 46.5±10.28
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E.10.1 Summary of studies for PE thrombolysis
Study ID Population and subgroup N
Intervention
(Group 1) Control (Group 2) Limitations and notes
All cause mortality
VTE related mortality
Major bleeding
Chronic thromboembolic Pulmonary hypertension
Length of hospital stay
Heparin induced thrombocytopenia
Dalla-Volta 1992
99
Open multi-centre RCT
Hospital,
Italy
Clinical signs and symptoms indication PE, within 10 days of onset, pulmonary angiogram showing vascular obstruction > 30% corresponding to Miller index score>11.
Subgroup: Haemodynamically stable
36 Alpetase + heparin (n=20)
Heparin infusion (n=16)
Randomisation method unclear
Allocation concealment – unclear
Blinding – single for evaluation of angiography and lung scan
No missing data
Group1: 2/20
Group 2: 1/16
Group1: 0/20
Group 2: 1/16
Group1: 3/20
Group 2: 2/16
NR NR NR
Dotter 1979
113
Multi-centre study Oregon, USA
Adult patients of either sex who had PE. Study included haemodynamically unstable PE (71%) and stable PE (29%).
Subgroup:
31 Streptokinase + heparin (n=15)
Heparin (n=16)
Method of randomisation and allocation concealment not reported. Number of dropouts or withdrawals post-randomisation not reported
Group1: 1/15
Group 2: 2/16
Group1: 1/15
Group 2: 2/16 (
Group1: 1/15
Group 2: 3/16
NR NR NR
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Study ID Population and subgroup N
Intervention
(Group 1) Control (Group 2) Limitations and notes
All cause mortality
VTE related mortality
Major bleeding
Chronic thromboembolic Pulmonary hypertension
Length of hospital stay
Heparin induced thrombocytopenia
Haemodynamically unstable
A positive pulmonary angiogram was required for admission onto the study.
Fasullo 2011
136
RCT
Multi-centre (three) study Italy
Haemodynamically stable patients aged 18-75 with a first episode of submassive PE.
Subgroup: Haemodynamically stable
After randomisation all patients underwent ECG and spiral CT.
72 Alteplase + heparin (n=37)
Placebo (n=35)
Randomisation using computer algorithm, assignment of all patients decided at admission by at least 2 external physicians who were blinded to study protocol.
Allocation concealment not reported.
Dropouts not reported.
Group1: 0/37
Group 2: 6/35
Group1: 0/37
Group 2: 4/35
Group1: 2/37
Group 2: 1/35
NR NR NR
Goldhaber 1993
162
Single centre, RCT
Hospital,
18 years or over, symptoms and signs of PE within 14 days; PE confirmed by high probability
101 Rt-PA 100mg perfused through a peripheral vein over 2 hours +
Continuous intravenous heparin (n=55)
Randomisation – adequate
Allocation concealment – sealed envelopes
Blinding – no
Intention to treat
Group1: 0/46
Group 2:
Group1: 0/46
Group 2:
Group1: 3/46
Group 2:
NR NR NR
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Venous thromboembolic diseases Clinical evidence tables
Study ID Population and subgroup N
Intervention
(Group 1) Control (Group 2) Limitations and notes
All cause mortality
VTE related mortality
Major bleeding
Chronic thromboembolic Pulmonary hypertension
Length of hospital stay
Heparin induced thrombocytopenia
US V/Q scan and/or pulmonary angiogram.
Subgroup: Haemodynamically stable
heparin (n=46)
2/55
2/55
1/55
Jerjes-Sanchez 1995
206
RCT
Mexico
Massive PE and cardiogenic shock
Subgroup: Haemodynamically unstable
PE confirmed by high probability V/Q scan, suggestive ECG or DVT.
8 Streptokinase + heparin (n=4)
Streptokinase and heparin (n=4)
Randomisation – adequate
Allocation concealment – adequate
Blinding not reported
No missing data
Study stopped early due to mortality rates.
Group1: 0/4
Group 2: 4/4
Group1: 0/4
Group 2: 4/4
NR NR NR NR
Konstantinides 2002
234
Multi-centre RCT.
Medical centres, Germany
Acute PE and pulmonary hypertension or right ventricular dysfunction.
Subgroup: Haemodynamically stable.
256 100mg Alteplase (10 mg bolus , followed by a 90 mg intravenous infusion over a period of two hours)+ unfractionat
Unfractionated heparin + matching placebo (n=138)
Randomisation method unclear
Allocation concealment unclear
Double blind study
Intention to treat - unclear
Group1: 4/118
Group 2: 3/138
Group1: 2/118
Group 2: 2/138
Group1: 1/118
Group 2: 5/138
NR NR NR
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Study ID Population and subgroup N
Intervention
(Group 1) Control (Group 2) Limitations and notes
All cause mortality
VTE related mortality
Major bleeding
Chronic thromboembolic Pulmonary hypertension
Length of hospital stay
Heparin induced thrombocytopenia
PE confirmed by V/Q scan, spiral CT or pulmonary angiogram.
ed heparin (n=118)
Levine 1990
250
Multi-centre RCT,
Hospital, Canada
Acute symptomatic pulmonary embolism documented by pulmonary angiogram or V/Q scan, plus DVT confirmed by venography or ultrasonography.
Subgroup: Haemodynamically stable
58 Rt-PA (n=33) & intravenous heparin bolus followed by heparin by continuous infusion.
Placebo (n=25) & intravenous heparin bolus followed by heparin by continuous infusion.
Randomisation method and allocation concealment unclear. Double blind. No missing data
Intervention – one patient felt hot and diaphoretic within 10 minutes of infusion. Another patient felt hot and developed mild hypotension. A third patient experienced mild hypotension associated with urticaria which resolved within 15 minutes of injection. One patient in the placebo group experienced hypotension shortly after administration of placebo.
Group1: 1/33
Group 2: 0/25
Group1: 1/33
Group 2: 0/25
Group1: 0/33
Group 2: 0/25
NR NR NR
Ly 1978 264
Single centre
Symptoms (< 5 days) of acute major PE confirmed by
25 Streptokinase (n=14)
To avoid anaphylactic
Heparin – initial dose by i.v.
Randomisation and allocation concealment adequate. Blinding unclear – single blind
Group1: 1/14
Group 2:
Group1: 1/14
Group 2:
Group1: 4/14
Group 2:
NR NR NR
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Venous thromboembolic diseases Clinical evidence tables
Study ID Population and subgroup N
Intervention
(Group 1) Control (Group 2) Limitations and notes
All cause mortality
VTE related mortality
Major bleeding
Chronic thromboembolic Pulmonary hypertension
Length of hospital stay
Heparin induced thrombocytopenia
RCT.
Hospital, Norway
angiography.
Subgroup: Haemodynamically unstable.
PE confirmed by selective bi-lateral or non-selective pulmonary angiogram in acute stage on admission and repeated after 3-4 days treatment.
reactions, 100mg of soluble hydrocortisone was given before the loading dose. Heparin was given to some patients.
followed by maintenance as a continuous i.v. infusion. (n=11)
for interpretation of PA.
Incomplete outcome data not addressed (45% of patients in heparin group withdrawn with an angiographic response to 72 hours treatment)
A rise in temperature more frequent in intervention group but more serious anaphylactic reactions was not seen.
2/11 2/11 2/11
PIOPED 1990
412
Multi-centre, RCT
Hospitals, US
Acute PE.
Subgroup: Haemodynamically stable.
PE confirmed by angiography.
13 Rt-PA (n=9) and heparin simultaneously (n=8). Started at dose of 80mg but reduced to 40mg after one major haemorrhage.
Placebo + heparin (n=4)
Randomisation – unclear
Allocation concealment – unclear
Double blind
No missing data
Study stopped early and varying doses.
Group1: 1/9
Group 2: 0/4
Group1: 0/9
Group 2: 0/4
Group1: 1/9
Group 2: 0/4
NR NR NR
UPETSG Well 160 Urokinase Heparin Randomisation – Group1: Group1: Group1: NR NR NR
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Venous thromboembolic diseases Clinical evidence tables
Study ID Population and subgroup N
Intervention
(Group 1) Control (Group 2) Limitations and notes
All cause mortality
VTE related mortality
Major bleeding
Chronic thromboembolic Pulmonary hypertension
Length of hospital stay
Heparin induced thrombocytopenia
1970 1
Multi-centre, RCT
US
documented clinical episode suggesting PE had occurred within 5 days of the institution of therapy.
Subgroup: Haemodynamically unstable.
PE confirmed by pulmonary angiogram.
(n=82). Followed by heparin intravenously for a minimum of 5 days followed by orally administered therapy.
intravenously (n=78)
adequate
Allocation concealment – adequate
Double blind
No missing data
6/82
Group 2: 7/78
1/82
Group 2: 0/78
22/82
Group 2: 11/78
(a) Summary of studies for PE thrombolysis included in forest plots