E.10 Thrombolytic therapy (PE) · 2017-01-21 · Clinical evidence tables E.10 Thrombolytic therapy (PE) What is the effectiveness of open surgical thromboectomy, combination of mechanical

408

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

409


Study

details


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

410


Study

details


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.

411


Study

details


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

412


Study

details


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


413


Study

details


Dotter 1979 113

Study design:

RCT

Setting:

Multi-centre study conducted by the National Heart and Lung institute, Oregon, USA


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)


-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%)


Not reported



Not reported

414


Study

details


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


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

415


Study

details


Study design:

RCT

Setting:

Multi-centre (three) study Italy

Comparison:

Alteplase+ 9 heparin vs placebo + heparin


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


-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


Not reported



Not reported

416


Study

details


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.

417


Study

details


-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


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:



Group1: 0/4 (0%

Group 2: 4/4 (100%)

418


Study

details


Setting: Mexico


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.


None reported.

Notes:

Trial terminated due to mortality results.

Major bleeding Not reported


Not reported



Not reported

419


Study

details


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

420


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


Major bleeding


Length of hospital stay


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

421



Intervention


All cause mortality


Major bleeding





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.


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

422



Intervention


All cause mortality


Major bleeding




US V/Q scan and/or pulmonary angiogram.


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

423



Intervention


All cause mortality


Major bleeding




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.


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

424



Intervention


All cause mortality


Major bleeding




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

425



Intervention


All cause mortality


Major bleeding




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

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E.10 Thrombolytic therapy (PE) · 2017-01-21 · Clinical evidence tables E.10 Thrombolytic therapy (PE) What is the effectiveness of open surgical thromboectomy, combination of mechanical