E.9 Thrombolytic therapy (DVT) - National Center … Venous thromboembolic diseases Clinical evidence tables E.9 Thrombolytic therapy (DVT) What is the effectiveness of thrombolytic

378

Venous thromboembolic diseases Clinical evidence tables

E.9 Thrombolytic therapy (DVT)

What is the effectiveness of thrombolytic therapy and mechanical thrombectomy to manage acute DVT?

Study

details

Patients Interventions Outcome measures Effect size Comments

Arnesen 1978 & 1982

31,32

Study design:

RCT

Comparison:

Streptokinase vs heparin

Setting:

Medical departments of hospital, Norway

Patient group:

Adult patients with clinical evidence of DVT

Inclusion criteria:

Patients under 70 years with extensive thrombosis (proximal extension beyond the calf vein) symptoms for less than 5 days, diagnosis confirmed by phlebography,

Exclusion criteria:

Known bleeding tendency, major surgery within 7 days, GI bleeding or urogenital bleeding, recent cerebrovascular disease, arterial hypertension, hypertensive retinopathy, severe renal or hepatic insufficiency, pregnancy, known

Group 1- Streptokinase

-250,000 IU (in 20mL 0.9% NaCl) loading dose given i.v in 20 minutes, followed by maintenance dose of 100,000 IU/hr was given by continuous iv infusion. Infusion continued until control phlebography performed after 72-90 hours. If complete thrombolyisis then streptokinase infusion discontinued. If partial thrombolysis, infusion continued for another 24-48 hours.

-When streptokinase discontinued, oral anticoagulation with warfarin intiated

All cause mortality Group 1: 1/21 (4.8%)

Group 2: 0/21

Funding: NR

Subgroup:

Systemic

Limitations:

- State that there were 40 sealed envelopes for randomisation- there are 42 patients

-3 patients had started treatment (1 with heparin, 2 with streptokinase) before envelope was opened. Before any evaluation was done they were included in the trial and

VTE related mortality

NR

Recurrent VTE

(PE )

Group1: 1/21 (4.7%)

Group 2: 0/21

Major bleeding

Group1: 4/21

Group 2: 4/21

p value: NR

Duration of hospitalisation

days

NR

PTS (up to 6 months, Group1: 5/21

379


Study

details


Duration of follow-up:

Unclear

malignant disease. All patients N: 42 Age (mean): Drop outs: 1* Group 1 (%) N: 21 Age (mean): 48 (13-70) Drop outs: 1 Male: 14 Group 2 (%) N: 21 Age (mean): 51 (19-72) Drop outs: 0 Male: 13

Heparin given when thrombin clotting time less than twice the normal control value.

-Heparin given iv infusion or s.c. twice a day, unti therapeutic values obtained. Doses of heparin varied between 10,000 – 30,000 IU/day.

- 100mg hydrocortisone given iv before start of therapy, whereafter prednisolone 10mg 3 times daily given orally until streptokinase discontinued.

Group 2- Heparin

Initial dose 15,000 IU iv followed by maintenance dose of 30,000 IU/day as continuous iv infusion. Dose of heparin later adjusted to the clotting time to maintain heparin concentration of 0.5- 1.0 IU/mL of normal plasma. Normal dose range 20,000

including moderate and serious signs) Group 2: 14/21

further treated according to protocol*

*1 dropout, 40 envelopes and 3 patients already treated= 42 patients included

-discrepancy between number of major bleedings in group 2 (3 or 4)

-discrepancy between recurrent VTE reported in Cochrane (reports 4 in each group)

Additional outcomes:

-clinical evaluation of thrombus

-complications

Notes:

-allocation to treatment groups performed by using sealed envelopes performed by

380


Study

details


-50,000 IU/day. Infusion continued until control phlebography after 72-90 hours. Oral anticoagulation starter thereafter. Heparin discontinued when therapeutic values of thrombotest were obtained.

All groups:

No i.m injections in either group

statistician on the basis of random numbers.

-mean streptokinase infusion 96 hours

Study

details


Common Patient group: Group 1- streptokinase All cause mortality Group1: 1/22 Funding:

381


Study

details


1976 & Seaman 1976

95,383

Study design:

RCT

Comparison:

Streptokinase vs heparin

Setting:

Departments of medicine, US and Canada


-Seaman

Adult patients with DVT

Inclusion criteria:

DVT of less than 14 days duration

Exclusion criteria:

NR All patients N: 50 Age (mean): NR Drop outs: 3 Group 1 (%) N: 22 Age (mean): 56 Drop outs: NR Male: NR Group 2 (%) N: 26 Age (mean): 45 Drop outs: NR Male: NR

i.v. for 3 days followed by 7 days of continuous heparin treatment

100mg iv hydrocortisone, loading dose 250,000 IU streptokinase infused over 1

st 30 minutes,

foloowed by maintenance dose of 100,000 IU/ hour. Dose continued as long aas the patients thrombin time did not exceed thrombin time of normal control by ratio of greater than 4:1. Streptokinase dose adjusted if thrombin time not within specified range.

Streptokinase discontinued after 72 hours.

Two hours later heparin started at 1,000 to 1,500 units/hr.

If thrombin time of patient’s plasma remained more than double the thrombin control after 2 hours, an

Group 2: 0/26 US public health service, Hoechst-Roussel pharmaceuticals, general clinical research centres program division of research resources, national institutes of health

Subgroup:

Systemic

Limitations:

-randomisation and allocation concealment NR

-doesn’t state which group participants dropped out from

-no details of doses of heparin, streptokinase or oral anticoagulant given

-Lack of detail in patient demographics


NR

Recurrent VTE

(PE at 7 days)

Outcome from Common 1976

Group1: 0/15

Group 2: 0/12

Major bleeding

“Bleeding requiring interruption of therapy” data used in Cochrane

Group1: 7/22

Group 2: 5/26


days

NR

PTS (up to 6 months, including mild, mod and sever)

NR

382


Study

details


1976- 14 days? Unclear

-Common 1976:18 months (mean 7 months)

additional time interval of 2 hours was permitted to elapse before starting the heparin infusion.

During following 7 days enough heparin given to prolong clotting time to 25-35 minutes.

Group 2-heparin i.v. for 3 days followed by 7 days of continuous heparin treatment

Loading dose 150 units heparin/ kg body weight followed by continuous infusion iv heparin. Lee and White clotting time determined at least twice daily.

Day 7, long term oral anticoagulation therapy with warfarin was instituted in all patients to depress prothrombin-proconvertin test to 10 -20% normal.

-number of patients randomised to each group unclear- NR.

-more details about dose reported in Seaman 1976. 3 separate papers pertaining to this study?


-grade of healing

-lytic response

-patient demographics not reported fully.

Notes:

-2 radiologist blinded to patients evaluated venograms

383


Study

details


All groups:

Long term anticoagulation with sodium warfarin (Coumadin) started on 7

th

day. Dose adjusted to depress prothrombin and proconvertin levels to 10-20% of normal

384


Study

details


Elsharawy 2002

130

Study design:

RCT

Comparison:

Streptokinase followed by anticoagulant vs Anticoagulant alone

Setting:

Patients admitted to Suez canal University hospital


Patient group:

Adult patients with acute iliofemoral DVT

Inclusion criteria:

Acute (< 10 days history) iliofemoral DVT documented with colour duplex or ascending venography, less than 70 years old

Exclusion criteria:

Significant comorbidity or life expectancy less than 6 months, contraindication to thrombolysis (surgery within 14 days, history of CVA or CNS disease, history of major GI bleeding within 1 year, severe hypertension, known or suspected pregnancy etc) All patients N: 35 Age (mean): Drop outs: Group 1 - Streptokinase followed by anticoagulant N: 18

Group 1- Streptokinase followed by anticoagulant

Pulse spray thrombolysis with ipsilateral popliteal approach. Progress assessed at 15 minute intervals by injecting contrast through the catheter. By about 1 hour the paiten had usually received about 1 million units. Further thrombolysis using low dose infusion (100,000 units per hour).Patients returned to radiology department at 12 hr intervals for phlebography and catheter advancement if necessary. Thrombolytic terapy was terminated when there was complete lysis, no progress aftr 12 hr or any major complications

Group 2-Anticoagulant

All cause mortality Group1: 0/18

Group 2: 0/17

Funding: NR

Subgroup:

Catheter of vein directed

Limitations:

- allocation concealment NR


-extent of clot lysis

-venous function after month

Notes:

-randomisation by computer designated cards assigning patient to either group


NR

Recurrent VTE

Symptomatic PE

Group1: 0/18

Group 2: 1/17 (5.8%)

Major bleeding

Group1: 0/18

Group 2: 0/17

p value: NR


Days (median days)

Group1: 7

Group 2: 5.5

P value: 0.43

PTS NR

385


Study

details


6 months Age (median, range): 44 (22-64) Drop outs: NR Male: 6 Duration of symptoms (mean, days): 6 Occlusive thrombus: 14 Current or previous cancer: 2 Previous PE or DVT: 3 Recent surgery 14-60 days): 1 Extent of thrombus -Iliofemoral: 6 -Femoral: 12 Group 2 -Anticoagulant alone N: 17 Age (median, range): 49 (25-67) Drop outs: NR Male: 5 Duration of symptoms (mean, days): 3 Occlusive thrombus: 16 Current or previous cancer: 2 Previous PE or DVT: 5 Recent surgery 14-60 days): 0 Extent of thrombus -Iliofemoral: 5 -Femoral: 12

alone

Standard regimen of heparin- initial bolus of 5,000 U followed by a continuous infusion of adjusted to maintain PTT to twice the normal control value. Warfarin was started the same evening to maintain an INR of 2.0

All groups:

Heparin discontinued 2 hours before randomisation for patients already receiving heparin

386


Study

details


Goldhaber 1990B

165

Study design:

RCT

Comparison:

t-PA or t-PA + heparin vs heparin

Setting:

Multicentre, Boston, Massachusetts

Duration of

Patient group:

Adult patients with symptomatic DVT

Inclusion criteria:

Venographically documented proximal DVT and whose symptoms had begun within 14 days.

Exclusion criteria:

Major bleeding or a known chronic bleeding disorder, stroke, severe head or spinal trauma within 3 month period, gastrointestinal or genitourinary bleeding within prior 4 weeks, trauma or major surgery with prior 14 days, diastolic blood pressure greater than 100mm Hg, severe hepatic or renal disease, warfarin thereapy (unless prothrombin time was no more than 3 seconds greater than control), less than 100,000 platelets/mm3, lactation or pregnancy and know

Group 1- t-PA or t-PA + anticoagulation

Dose of t-PA was 0.5 mg/kg/hour as a continuous peripheral intravenous infusionover 24 hours, not exceeding a total dose of 150mg.

Some patients received heparin at the same time, the dose was 100U/kg bolus, followed by a continuous intravenous infusion beginning at 1000 U/hour.

The target partial thromboplastin time in heparin-treated patients was 1.5 to 2.5 times the upper limit of normal. Heparin was adjusted accordingly by increments of 25% and the partial thromboplastin time was measured approximately every 4 hours after any change in heparin infusion rate.

All cause mortality NR Funding: -NR

Subgroup:

Systemic

Limitations:

- Consecutively numbered sealed envelope according to 2:2:1 allocation scheme.

- Separate treatment assignments for each hospital were generated by block random number sequences.

- Not blinded to patient or investigator

- Radiologists were not aware of treatment when examining venograms.


NR

Recurrent VTE (at 6 month follow up)

NR

Major Bleeding

Group1: 1/53 (%)

Group 2: 0/12 (%)

p value: NR


days

NR

PTS NR

387


Study

details


follow-up:

hypersensitivity or other contraindication to contrast agent.

All patients N: 65 Age (mean): NR Drop outs: Group 1 - t-PA or t-PA + anticoagulation N: 53 Age (mean): 52.3 n=36 t-PA 47.8 n=17 t-PA + heparin Drop outs: Male: 33 Group 2- heparin N: 12 Age (mean): 47.9 Drop outs: Male: 9

After the 24 hour intial treatment, the t-PA alone group received heparin and heparin was continued in the other two groups.

Group 2- heparin

As above.

Both groups:

Warfarin beginning day after initiating treatment.


Clot lysis

Notes:

388


Study

details


Kakkar 1969a 214

Study design:

RCT

Comparison:

Heparin vs Streptokinase vs Arvin

Setting:

Medical and Surgical wards


Unclear

Patient group:

Adult medical and surgical patients with symptomatic DVT

Inclusion criteria: signs and symptoms of DVT which had first appeared in the legs within the preceeding 4 days. Assessed by ascending functional phlebography to confirm presence of thrombi in legs

Exclusion criteria: No patient treated within 3 days of operation or when extensive skin flaps considered unhealed. People with peptic ulcers excluded, and those with a diastolic bp of >100mmHg

All patients N: 30 Age (mean): Drop outs: Group 1 - Streptokinase N: 10

Group 1- Streptokinase

(Kablikase)

-Loading dose: 500,000 units in 30 minutes

-Maintenance dose:900,000 units every 6 hours

Group 2- Arvin

-Loading dose: 80 units in 6 hours, followed by 80 units in 15 minutes

-Maintenance dose: 40-80 units every 6 hours

Group 3- Heparin

-Loading dose: 10,000 units in 5 minutes

-Maintenance dose: 10,000-15,000 units every 6 hours

All cause mortality Group1: 2/10 (20%)

Group 2: 0/10

Grou p3: 2/10 (20%)

p value:

Funding: Hospital Research trust, Pfizer, Kabi pharmaceuticals, Twyford laboratories

Subgroup:

Systemic

Limitations:

-major bleeding not defined, but does state cause of bleeding.

-follow up period unclear

-allocation concealment?

-blinding not adequate


-laboratory parameters

-Adverse events


All PE related

Group1: NR

Group 2: NR

Group3: 1/10 (10%)

p value: NR

Major bleeding

Group1: 4/10 (40%)

Group 2: 0/10

Group 3: 2/10 (20%)

p value: NR


days

NR

PTS NR

389


Study

details


Age (mean, range): 50, 18-73 Drop outs: 1 Sex (m/f): 4/6 Duration of symptoms (hours) [range]: 52, 12-72 Site of thrombus: -tibials: 2 Tibials and popliteal:1 Tibials, politeal and iliofemoral:7 Precipitating factors: -postoperative: 8 -neoplasma: 1 -oral contraceptive: 0 -post MI: 0 -Unknown: 1 Group 2 - Arvin N: 10 Age (mean, range): 58, 20-70 Drop outs: 0 Sex (m/f):4/6 Duration of symptoms (hours) [range]: 54, 12-96 Site of thrombus: -tibials: 1 Tibials and popliteal: 2 Tibials, politeal and iliofemoral:7 Precipitating factors: -postoperative:6 -neoplasm:1 -oral contraceptive:2 -post MI: 0 -Unknown: 1 Group 3 - Heparin N: 10 Age (mean, range): 58, 44-77

Both groups:

All drugs were dissolved in 0.9% saline and given by continuous intravenous infusion, uninterrupted for 5 days unless the phlebograms showed complete clearance of thrombi before this.

Infusions continued beyond 5 days if thrombi still visible on the phlebogram.

At the end of the infusion, oral anticoagulants were given to all patients.

All patients confined to bed for the duration of the trial. Foot of the bed was raised and they were encouraged to move their legs as much as possible in bed. They all wore thick elastic bandages which

Notes:

-thirty envelopes sealed, numbered in sequence, each contained on of three possible treatments in a random order

-IV infusion

390


Study

details


Drop outs: 1 Sex (m/f): 4/6 Duration of symptoms (hours) [mean, range]: 38, 12-48 Site of thrombus: -tibials: 4 -Tibials and popliteal: 1 Tibials, politeal and iliofemoral:5 Precipitating factors: -postoperative:5 -neoplasm:1 -oral contraceptive:0 -post MI: 2 -Unknown: 2

were frequently reapplied to give external support.

391


Study

details


Kiil 1981 220

Study design:

RCT

Comparison:

Urokinase + heparin vs heparin

Setting:


6 days

Patient group:

Adult patients with clinical evidence of DVT

Inclusion criteria:

Adult patients with clinical evidence of DVT of a duration less than 72 hours.

Presence of thrombus confirmed by ascending phlebography

Exclusion criteria:

All patients N: 20 Age (median, range): Drop outs: Group 1 - Urokinase + heparin N: 11 Age (median, range): 66, 17-79 Drop outs: 0 Male: 7

Group 1- Urokinase + heparin

Urokinase Leo 200,000 Ploug units dissolved in 1,000 mL 0.9% NaCl given as a continuous infusion for 24 hours through a cannula in dorsal foot vein.

18 hours later- 15,000units of heparin Leo was given iv at a loading dose of, followed by a sustaining dose of heparin 40,000 units per 24 hours given in saline.

Infusion maintained for not less than 6 days.

Day 4- oral anticoagulation initiated (marcoumar), infusion of heparin continued unitl PP value was below 25%.

Group 2- Heparin


Group 2: 1/9 (10%)

p value: NR

Funding: NR

Subgroup:

Systemic

Limitations:

-did group 2 receive oral anticoagulation? Not clear.

-states that allocation completed by one of the participants and therefore double blind; it is not clear whether the study is double blind.


-course of DVT (improved, unimproved)

Notes:

-Overt bleeding described in paper-


All PE related

Group1: 0/11

Group 2: 0/9

p value: NR


NR

Major bleeding

(in hospital)

Not defined –“overt bleeding”

Group1: 3/11 (27%)

Group 2: 4/9 (40%)

p value: NR


days

NR

PTS NR

392


Study

details


Group 2 - Heparin N: 9 Age (median, range): 67, 49-85 Drop outs: 1 (due to serious bleeding) Male: 7

Received heparin alone for not less than 6 days using same schedule as group 1.

Day 6- heparin infusin discontinued, new phlebography performed

interpreted as major bleeding. Instances of bleeding described individually.

-clinical evaluation and interpretation of the phlebograms were performed in a double blind fashion

393


Study

details


Schulman 1986

376

Study design:

RCT

Subgroup: Systemic

Comparison:

Streptokinase + heparin vs heparin

Setting:

Department of internal medicine, University hospital.


Patient group:

Adult patients with symptomatic DVT (calf vein thrombosis)

Inclusion criteria:

Venographically confirmed DVT of the calf, not extending above the knee joint, duration of symptoms not exceeding 7 days

Exclusion criteria:

previous thrombosis in the same leg, contraindication to thrombolytic therapy.

All patients N: 36 Age (mean): NR Drop outs: 2

Group 1 Streptokinase + heparin N: 17 Age (mean, range): 50.3 (26-69) Drop outs: 1 Male: 8 Duration of thrombus (mean, SD):

Group 1- Streptokinase + heparin

Started when an interval of 2 hours had elapsed after discontinuation of the initial heparin infusion.

Loading dose: 50000 U in 50-100 mL 0.9% NaCl over 15 minutes followed by maintenance infusion of 100000 U SK and 5000 Heparin in 500 mL 0.9% Na Cl over 12 hours. Infusion continued for a maximum of 7 days

SK dose titrated:

-fibrinogen >1 g/L after 12-24 hours procedure repeated daily until fibrinogen 0.4 g/L (therapeutic). Upon discontinuation of SK, heparin started after interval of 2 hours. Heparin infused in same manner as group 2, and oral anticoagulation

All cause mortality Group1: 1/17 (5.8%)

Group 2: 1/19 (5.2%)

p value:

Funding: Grants from Karolinska institute

Limitations:

-not all patients wore compression stockings (17 did, 18 did not), not stated what proportion of each group did or did not wear stockings.


-foot volumetry

-venous insufficiency

-venographic score

Notes:

-patients randomly allocated using sealed envelopes


NR


NR

Major bleeding

Group1: 3/17 (17.6%)

Group 2: 1/19 (5.3%)

p value: NR


days

NR

PTS NR

394


Study

details


2 years 3.0 (1.7) Initial venographic score (mean, SD): 9.4 (5.1) Group 2 - Heparin N: 19 Age (mean, range): 50.3 (29-74) Drop outs: 1 Male: 8 Duration of thrombus (mean, SD): 3.5 (1.9) Initial venographic score (mean, SD): 8.4 (4.8)

initiated in the same manner

Group 2- Heparin

Given as continuous iv infusion as detailed below., dose titrated to achieve APTT of 2-3 times normal range.

Oral anticoagulation with warfarin started simultaneously with heparin and monitored with prothrombin time assay

Both groups:

Loading dose of 5000 U Heparin iv, followed by an infusion of 15000 U heparin in 500 mL NaCl at 42 mL/ h until diagnosis radiologically established. Mean duration of the delay was 4.5 hours

395


Study

details


Schweizer 1998

381

Study design:

RCT

Comparison:

Setting:

rtPA + UFH vs urokinase + UFH vs UFH


12 months

Patient group:


Inclusion criteria:

Acute lower leg or popliteal DVT, without PE. Diagnosis confirmed by phlebography and colour duplex sonography.

Exclusion criteria:

Previous DVT in same leg, affecting only the veins in the calf, clinical signs of DVT that had existed for more than 7 days, history of GI ulcers or inflammatory bowel diseasewithin the last year, acute pancreatitis, urogenital bleeding within the last year, surgical intervention within last 4 weeks, im injections within last 10 years, arterial hypertension, history of cerebral disease, malignant disease not completely in remission, diabetes with diabetic retinopathy,

Group 1- 20mg rtPA + standard UFH

rtPA infused directly into the dorsal pedal vein of the affected leg over a 4 hr period each day. Treatment lasted for 7 days. UFH administered continuously iv and adjusted according to APTT value

Patients kept in bed and leg bandaged from forefoot to groin

Group 2- Urokinase + UFH

100,000 IU/hr infused directly into the affected leg via the dorsal pedal vein; administered continuously for a maximum of 7 days

Group 3- standard UFH

All cause mortality NR Funding: NR

Subgroup: Vein directed

Limitations:

-allocation concealement not described

-major bleeding not described

-discrepancy in numbers in group 3


-reflux measurement in popliteal vein

-morphological findings on colour duplex sonogrophy

-INR values after 12 months

Major bleeding

Group1: 2/23 (8.7%)

Group 2: 2/23 (8.7%)

Group 3: 0/23

p value: NR

PTS (Reported at 12 months

Grade II-IV included)

Group1: 16/22

Group 2: 12/22

Group 3: 18/23

p value: NR


NR

Recurrent VTE

NR


days

NR

396


Study

details


renal failure, hepatic failure, pregnancy or lactation, haemorrhagic diathesis All patients N: 69 Age (mean): 22-58 (range) Drop outs: 2 Group 1 - rtPA N: 23 Age (mean): 40 (22-58) Drop outs: 1 Male: 7 Mean age of thrombosis: 4.8 (1.3) Group 2 - urokinase N: 23 Age (mean): 39 (25-55) Drop outs: 1 Male: 8 Mean age of thrombosis: 4.1 (1.2) Group 3 - UFH N: 23 Age (mean): 41 (21-63) Drop outs: unclear Male: 6 Mean age of thrombosis: 4.5 (1.3)

UFH administered continuously iv and adjusted according to APTT value

Patients kept in bed and leg bandaged from forefoot to groin

Both groups: UFH administered and compression bandages applied. All ptients receivied consistent compression treatment and oral anticoagulation over 12 months

-degree of thrombolysis

Notes:

-Randomisation according to a code by a biometrician not involved in the study.

- Query number of dropouts from group 3- doesn’t appear to be any but there is an error in the table, not sure whether n=23 or 22

397


Study

details


Schweizer 2000

382

Study design:

RCT

Comparison:

Urokinase + heparin + compression vs streptokinase + heparin + compression vs heparin + compression

Setting:

Hospitals in Chemnitz and Dresden

Patient group:

Adult patients with symptomatic acute leg or groin thrombosis

Inclusion criteria:

Adult patients with symptomatic acute leg or groin thrombosis. Diagnosis by date and initial clinical symptoms, venogrpahy and colour coded duplex sonography. Evidence of thrombosis on sonography was carried out by compression findings and by diagnosing absence of colour flow. Patients can only by included if estimated age of leg or pelvic DVT in the two sonographic examinations did not differ by more than 3 days and provided the thrombus was less than 9 days old.

Exclusion criteria:

Patients with PE, DVT solely at one level, existence of DVT for more than 9 days, previous DVT in the

Group 1- Locoregional rtPA

20 mg rtPA (alteplase) infused directly into the affected leg via dorsal pedal vein over a 4 hour period each day for 4-7 days.

During this time standard UFH was continuously administered at a rate of 1,000 IU/h with the dosage adjusted to the aPTT value (2-3 times normal) patients were kept in bed and the affected leg was bandaged from forefoot to groin

Group 2- Locoregional urokinase

100,000 IU/h urokinase was infused directly and continuously for up to 7


Group 2: 0/50

Group 3: 0/50

Group 4: 0/50

Group 5: 0/50

Funding: NR

Subgroup: systemic AND vein directed

Limitations:

-randomisation and allocation concealment NR

-major bleeding not defined, individual instances described

-iv dosing schedule of heparin not described for control group


-change in number of closed vein segments

-venous reflux, reflux time and pressure


NR

Recurrent VTE

(PE at 7 days)

Group1: 0/50

Group 2: 0/50

Group 3: 4/50 (8%)

Group 4: 5/50 (10%)

Group 5: 0/50

Major bleeding

Group1: 2/50 (4%)

Group 2: 1/50 (2%)

398


Study

details



4-7 day acute treatment phase, followed by year long follow up.

same leg or thrombosis in calf veins only, urogenital of GI bleeding, inflammatory bowel disease, within the last 12 months, acute pancreatitis, surgical intervention or cerebral trauma within the last three months, im injection within the last 10 days, arterial hypertension or diabetes, history of cerebral disease, malignant disease renal failure or hepatic failure, haemorrhagic diathesis, pregnancy or lactation, delivery within the last 20 days.

All patients N: 250 Age (mean, SD): 39.9 (10.4) Drop outs: NR Group 1 - Locoregional rtPA N: 50 Age (mean, range): 40(22-64) Drop outs: NR Male: 20 Mean , (SD) age thrombosis (days): 5.5 (1.6 Total no. vessel sections: 455

Group 2 - Locoregional urokinase N: 50 Age (mean, range): 39 (25-58)

days. Infusion was stoped if the fibrinogen was below 1.5 g/L or if the plasminogen values were less than 60%. Concomitant treatment was carried out with UFH and compression bandages.

Group 3- Systemic urokinase

Bolus of 5,000,000 IU urokinase daily, infused over a 4 hour period for a maximum of 7 days along with UFH and compression bandages

Group 4- Systemic streptokinase After pre-medication with 100 mg hydrocortisone, 50mg ranitidine and 2 mg clemastine, patients were given a daily intravenous infusion of 3,000,000 IU streptokinase over 6

Group 3: 4/50 (8%)

Group 4: 5/50 (10%)

Group 5: 0/50

p value: NR

decreases after 12 months

-number of closed vein segments after 7 day lysis treatments

Notes:

-vein directed and systemic administration

-dedicated radiologist, blinded to patients treatment evaluated the venograms and another assessed the sonographic data


days

NR

PTS -

Data not included - PTS was only defined by venography and not by clinical measures.

399


Study

details


Drop outs: NR Male: 23 Mean , (SD) age thrombosis (days): 5.6 (2.0) Total no. vessel sections: 454 Group 3 - Systemic urokinase N: 50 Age (mean, range): 41 (23-60) Drop outs: NR Male: 20 Mean , (SD) age thrombosis (days): 5.4 (1.9) Total no. vessel sections: 452 Group 4- Systemic streptokinase N: 50 Age (mean, range): 37 (22-60) Drop outs: NR Male: 20 Mean , (SD) age thrombosis (days): 5.7 (2.0) Total no. vessel sections: 458 Group 5- Heparin control N: 50 Age (mean, range): 41 (21-63) Drop outs: NR Male: 25 Mean , (SD) age thrombosis (days): 5.3 (1.9) Total no. vessel sections: 457

hours in conjunction with heparinisation and compression bandages for up to 7 days.

Group 5- Heparin control

During the first 7 days or less the only treatment receivied was heparinisation and compression bandages

All groups:

Heparin and compression bandages

After 7 days all groups continued with compression and oral anticoagulation with phenocoumon to achieve and INR of 2.5- 4.

400


Study

details


Sharifi 2010 385

Study design:

RCT

Comparison:

PEVI + anticoagulation vs anticoagulation

Setting:


6 months

Patient group:


Inclusion criteria:

Symptomatic DVT involving popliteal vein or more proximal venous segments were potentially eligible for the study.

Exclusion criteria:

Serious bleeding in the previous 4 weeks, contraindicated to UFH or LMWH or severe thromboctopaenia All patients N: 183 Age (mean): NR Drop outs: Group 1- PEVI + anticoagulation N: 91 Age (mean): 61+/-11.3 Drop outs: Male: 51 (56) Previous or concomitant disease: -hypertension: 48 (53) -diabetes: 31 (34) -cardiovascular: 47 (52)

Group 1- PEVI + anticoagulation

Taken to angiography suite within 24hr of presentation. Parenteral anticoagulation was stopped as soon as INR became therapeutic.

A retrievable IVC was placed in all patients. Patient placed in the prone position with popliteal area exposed. Micropuncture needle was used under ultrasound guidance and access to the popliteal vein was gained. A 6-8 french sheath was placed through which venography and intervention were performed. PEVI undertaken using Angiojet DVX catheter, trellis device or manual aspiration with 8F guide catheter. Use based on

All cause mortality Group1: 3/91 (3%)

Group 2: 6/92 (7%)

p value: NR

Funding: -NR

Subgroup: Vein and catheter directed

Limitations:

-allocation concealment and randomisation NR


- Level of PTS

- Edem Reduction index

- Change in skin in duration (mm)

- Subjective change

Notes:


All PE related

Group1: 1/91 (1%)

Group 2: 4/92 (4%)

p value: NR


Group1: 2/91 (2%)

Group 2: 12/92 (13%)

p value: NR

Major bleeding

(defined as more than 2g/dl drop of haemoglobin or blood transfusion)

Group1: 2/91 (2%)

Group 2: 1/92 (1%)

p value: 0.57


days

Group1: 2.7+/-1.1

Group 2: 5.8+/-1.3

p value: <0.001

PTS (up to 6 months, including mild, mod and severe)

Group1: 3/91 (3.4%)

Group 2: 22/92 (27.2%)

401


Study

details


-hypercholesterolaemia: 33 (36) -pulmonary: 15 (16) -renal: 9 (10) Surgery or trauma within previous 3/12: 12 (13) -oestrogen therapy: 6 (7) -Cancer:-active: 10 (11) -history: 4 (4) -known thrombotic state: 5 (5) -previous VTE: 16 (18) Concomitant PE: 20 (22) Concomitant DVT at other site: 22 (24) -On warfarin at presentation: 14 (15) -Therapeutic INR at presentation: 9 (10) Group 2 - anticoagulation N: 92 Age (mean): 61+/-10.2 Drop outs: Male: 52 (57) Previous or concomitant disease: -hypertension: 49 (53) -diabetes: 32 (35) -cardiovascular: 48 (52) -hypercholesterolaemia: 31 (34) -pulmonary: 16 (17) -renal: 11 (12) Surgery or trauma within previous 3/12: 12 (13)

operator discretion and availability

Group 2- anticoagulation Parenteral therapy in the control group was continued for a minimum of 5 days with at least one day of overlap with therapeutic INR of 2-3.

Both groups:

s.c. enoxaparin at 1 mg/kg twice daily

Patients with renal insufficiency or massive PE were given UFH. Warfarin initiated on admission.

Received thigh high graded compression stockings at 30-40mmHg and were advised to wear

p value: <0.001 -DVT diagnosed by venous duplex sonography or mulitslice CT venography

-All PEVI patients received an IVC filter before intervention- reduce potential risk for iatrogenic fatal PE during the procedure

402


Study

details


-estrogen therapy: 5 (5) -Cancer: -active: 10 (11) -history: 5 (5) -known thrombotic state: 4 (4) -previous VTE: 14 (15) Concomitant PE: 19 (21) Concomitant DVT at other site: 20 (22) -On warfarin at presentation: 15 (16) -Therapeutic INR at presentation: 9 (10)

for a minimum of 6 months

Study

details


Turpie 1990 436

Study design:

RCT

Patient group:

Patients less than 75 with venographically confirmed proximal DVT of the lower limbs and symptoms of less than seven days duration.

Group 1- rt-PA

Two chain rt-PA, 0.5mg/kg infused IV over 4 h or one-chain rt-PA 0.5mg/kg infused over 8 h and repeated in 24 h.

Group 2- placebo

All cause mortality NR Funding: -NR

Subgroup: systemic

Limitations:


NR


NR

403


Study

details


Comparison:

rt-PA vs placebo

Setting:


Inclusion criteria:

Patients less than 75 with venographically confirmed proximal DVT of the lower limbs and symptoms of less than seven days duration were eligible.

Exclusion criteria:

Underlying bleeding disorder, active peptic ulcer, active bleeding process, cerebrovascular accident or other intracranial process within two months, or had undergone major surgery, major trauma, obstetric delivery, organ biopsy, or puncture of a non-compressible vessel within seven days.

All patients N: 83 Age (mean): NR Drop outs: Group 1 - rt-PA N: 41 Age (mean):

Identical placebo regimen to rt-PA

Both groups:

Initial intravenous (IV) heparin bolus of 5000 U followed by a heparin infusion administered at a starting dose of 30,000 U/24 h and adjusted to maintain the activated partial thromboplastin time (APTT) at 1.5 to 2 times control.

Heparin was continud during the study drug infusion, then continued for seven to ten days, and followed by oral anticoagulant therapy with warfarin, the does of which was adjusted to maintain INR at 2.0 to 3.0.

Major Bleeding –

if clinically over and associated with a drop in haemoglobin of 2g/dl or more, if it led to an infusion of two or more units of blood, or if it was retroperitoneal, intracranial, intraocular, or intra-articular.

Group1: 5/41

Group 2: 2/42

p value: NR

- Allocation concealment and randomisation method NR


Thrombolysis – venous patency

Notes:


days

NR

PTS NR

404


Study

details


Drop outs: Male: Group 2- placebo N: 42 Age (mean): Drop outs: Male:

Warfarin continued for three months.

405


Study

details


Verhaegher 1989 A

448

Study design:

RCT

Comparison:

Rt PA vs rt PA vs placebo

Setting:

Hospitalised patients in Belgium, Switzerland or france.


Unclear

Patient group:

Adult patients with acute or subacute thrombotic occlusion of the popliteal or more proximal veins of the lower extremeties and/ or pelvic veins with or without calf thrombosis

Inclusion criteria:

Aged 22-74 years, onset of clinical symptoms of DVT within 10 days prior to selection for the trial, diagnosis confirmed by venography within 24 hours preceeding initiation of trial treatment

Exclusion criteria:

Pregnancy, history of thoracic or neurosurgery performed in the previous 72 hours, a CVA in the previous 6 months, major head injury in the last month, uncontrolled arterial hypertension, major hepatic or renal disease, known aactive peptic ulcer, known bleeding disorder, contraindication

All groups:

Heparin administered to all patients. iv bolus of 5,000 IU given before start of the infusion of study medication, followed by iv infusion of 1,000 IU per hour at least until the 2

nd phlebography

All trial infusions were daily intravenous infusions of 8 hours on 2 consecutive days. The second infusion was started approximately 24 hours after the initiation of the 1

st infusion.

Open label phase

100 mg rt-PA on the first day and 50 mg rt-PA on the second day

All cause mortality NR Funding: NR

Subgroup:

Systemic

Limitations:

-Randomisation and allocation concealment NR

-open label phase before randomisation

-doesn’t state when second phlebography was carried out- heparin continued until this point, therefore unclear how long heparin administered for.

-unclear whether participants in open label trial then proceeded to


NR

Recurrent VTE

(PE at 7 days)

NR

Major bleeding

(in hospital) more than 2g/dl drop of haemoglobin or blood transfusion

Group1: 6/8 (75%)

Group 2: 2/6 (33%)

Group 3: 0/7

p value: NR


days

NR

PTS NR

406


Study

details


to heparin administration All patients N: 32 Age (mean): Drop outs: NR Group 1- rt-PA Dose 1 N: 8 Age (mean): 49 (27-65) Drop outs: Male: 6 Time from onset of symptoms to initiation of study treatment: 5.9 (3-9) Surgery within last 6 months: 2 Central assessment of phlebogaphic score (units)[mean, SD]: 23.7 (4.9) Group 2 - rt-PA Dose 2 N: 6 Age (mean): 50 (21-73) Drop outs: Male: 5 Time from onset of symptoms to initiation of study treatment: 4.7 (2-7) Surgery within last 6 months: 3 Central assessment of phlebogaphic score (units)[mean, SD]: 19.8 (4.6) Group 3 - placebo

Randomised phase:

Group 1- rt-PA Dose 1

1st

day- 100mL 100mg rt-PA

2nd


Group 2- rt-PA Dose 2

1st

day-100mL 50mg rt-PA

2nd


Group 3- placebo

1st

day- placebo

2nd

day-placebo

randomisation or whether these were separate trials. (n=11 in open label trial)


Change in phlebographic score

Notes:

-major bleeding defined

-two radiologists blinded to patients interpreted venography

407


Study

details


N: 7 Age (mean): 50 (22-64) Drop outs: Male: 4 Time from onset of symptoms to initiation of study treatment: 4.4 (2-6) Surgery within last 6 months: 1 Central assessment of phlebogaphic score (units)[mean, SD]: 20.2 (11.5)

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