Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism

Moshe Vardi; Eran Zittan; Haim Bitterman

doi:10.1002/14651858.CD006771.pub2

Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism

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Referencias

References to studies included in this review

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estudios excluidos
otras referencias

Andersson G, Fagrell B, Holmgren K, Johnsson H, Ljungberg B, Nilsson E, et al. Subcutaneous administration of heparin. A randomised comparison with intravenous administration of heparin to patients with deep‐vein thrombosis. Thrombosis Research 1982;27(6):631‐9.

Belcaro G, Nicolaides AN, Cesarone MR, Laurora G, De Sanctis MT, Incandela L, et al. Comparison of low‐molecular‐weight heparin, administered primarily at home, with unfractionated heparin, administered in hospital, and subcutaneous heparin,administered at home for deep‐vein thrombosis. Angiology 1999;50(10):781‐7.

Bentley PG, Kakkar VV, Scully MF, MacGregor IR, Webb P, Chan P, Jones N. An objective study of alternative methods of heparin administration. Thrombosis Research 1980;18:177‐87.

Doyle DJ, Turpie AG, Hirsh J, Best C, Kinch D, Levine MN, et al. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis. A randomized trial. Annals of Internal Medicine 1987;107(4):441‐5.

Faivre R, Neuhart E, Kieffer Y, Bassand JP, Maurat JP. Efficacy of a very low molecular weight heparin fragment (CY 222) compared to standard heparin in patients with deep venous thrombosis. A randomized study. Journal des Maladies Vasculaires 1987;12(Suppl. B):145‐6.

Faivre R, Neuhart Y, Kieffer Y, Apfe lF, Magnin D, Didier D, et al. A new treatment of deep venous thrombosis: low molecular weight heparin fractions. Randomized study. Presse Medicale 1988;17(5):197‐200.

Handeland GF, Abildgaard U, Holm HA, Arnesen KE. Dose adjusted heparin treatment of deep venous thrombosis: A comparison of unfractionated and low molecular weight heparin. European Journal of Clinical Pharmacology 1990;39(2):107‐12.

Holm HA, Ly B, Handeland GF, Abildgaard U, Arnesen KE, Gottschalk P, et al. Subcutaneous heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin. Haemostasis 1986;16(Suppl. 2):30‐7.

Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal‐vein thrombosis. New England Journal of Medicine 1986;315(18):1109‐14.

Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, et al. Comparison of fixed‐dose weight‐adjusted unfractionated heparin and low‐molecular‐weight heparin for acute treatment of venous thromboembolism. JAMA 2006;296(8):935.

Krähenbühl B, Simon CA, Bouvier CA, Schinas P, Hopf MA, Cochet B. Heparin treatment. Comparison between intravenous and subcutaneous administration. Schweizerische medizinische Wochenschrift 1979;109(36):1322‐5.

Lopaciuk S, Misiak A, Wisawski S, Ciesielski L, Korzycki J, Judkiewicz L, et al. Subcutaneous injections and intravenous infusion of sodium salt of heparin in the treatment of thrombosis of deep veins of the lower extremities. Polski Tygodnik Lekarski 1990;45(47‐48):949‐52.

Lopaciuk S, Meissner AJ, Filipeckil S, Zawilska K, Sowier J, Ciesielski L, et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: A Polish multicenter trial. Thrombosis and Haemostasis 1992;68(1):14‐8.

Peternel P, Terbizan M, Tratar G, Bozic M, Horvat D, Salobir B, et al. Markers of hemostatic system activation during treatment of deep vein thrombosis with subcutaneous unfractionated or low‐molecular weight heparin. Thrombosis Research 2002;105(3):241‐6.

Pini M, Pattachini C, Quintavalla R, Poli T, Megha A, Tagliaferri A, et al. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis? a randomized clinical trial. Thrombosis and Haemostasis 1990;64(2):222‐6.

Prandoni P, Carnovali M, Marchiori A, Galilei Investigators. Subcutaneous adjusted‐dose unfractionated heparin vs fixed‐dose low‐molecular‐weight heparin in the initial treatment of venous thromboembolism. Archives of Internal Medicine 2004;164(10):1077‐83.

Walker MG, Shaw JW, Cumming JGR, Lea Thomas M. Subcutaneous calcium heparin versus intravenous sodium heparin in the treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial. British medical journal 1987;294(6581):1189‐92.

References to studies excluded from this review

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otras referencias

Fagher B, Lundh B. Heparin treatment of deep vein thrombosis. Effects and complications after continuous or intermittent heparin administration. Acta Medica Scandinavica 1981;210(5):357‐61.

Glazier RL, Crowell EB. Randomized prospective trial of continuous vs intermittent heparin therapy. JAMA 1976;236(12):1365‐7.

Gruber UF, Brun M, Brunner R, Gaugler U, Muller J, Schumacher S, et al. Subcutaneous heparin or intravenous dextran?. Helvetica Chirurgica Acta 1979;46(1‐2):65‐8.

Horbach T, Wolf H, Michaelis HC, Wagner W, Hoffmann A, Schmidt A, et al. A fixed‐dose combination of low molecular weight heparin with dihydroergotamine versus adjusted‐dose unfractionated heparin in the prevention of deep‐vein thrombosis after total hip replacement. Thrombosis and Haemostasis 1996;75(2):246‐50.

Lockner D, Bratt G, Tornebohm E, Aberg W, Granqvist S. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis.. Haemostasis 1986;16(Suppl. 2):25‐9.

Marchiori A, Verlato F, Sabbion P, Camporese G, Rosso F, Mosena L, et al. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study. Haematologica 2002;87(5):523‐7.

Monreal M, Lafoz E, Olive A, Rio LD, Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thrombosis and Haemostasis 1994;71(1):7‐11.

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Cohen J. A coefficient of agreement for nominal scales. Educational and Psychological Measurement 1960;20:37‐46.

Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008;112(1):19‐27.

DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177‐188.

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Hommes DW, Bura A, Mazzolai L, Büller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta‐analysis Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta‐analysis. Annals of Internal Medicine 1992;116(4):279‐84.

Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH, et al. Continous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal‐vein thrombosis. New England Journal of Medicine 1986;315(18):1109‐14.

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17(1):1‐12.

Kearon C, et al. Anti thrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Clinical Practice Guidelines (2008). Chest 2008;133:454‐545.

McLean J. The thromboplastic action of cephalin. American Journal of Physiology 1916;41:250‐7.

Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta‐analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta‐analyses. Lancet 1999;354(9193):1896‐900.

Munro A, English C. Subcutaneous heparin is as good as low‐molecular weight heparin in the acute treatment of thromboembolic disease. Emergency Medicine Journal 2008;25:287‐9.

Quinlan DJ, McQuillan A, Eikelboom JW. Low‐molecular‐weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta‐analysis of randomized, controlled trials.. Annals of Internal Medicine 2004;140:175‐83.

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. The Journal of American Medical Association 1995;237(5):408‐12.

van Dongen CJJ, van den Belt AGM, Prins MH, Lensing AWA. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/14651858.CD001100.pub2]

Virchow RLK. Gesammelte Abhandlungen zur Wissenschaftlichen. Frankfurt: Meidinger Sohn & Co, 1856.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Andersson 1982

Methods	Study design: Open randomised controlled trial Duration of intervention: at least 5 days to INR target Duration of follow up: Acute phase only Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute DVT Country: Sweden Number of study centres: 3 Setting: In hospital Number: 141(SC UFH group 72; IV UFH group 69) Age mean (range): SC UFH group 64 (23 to 88); IV UFH group 64 (20 to 88) Sex (M/F): SC UFH group 47/25; IV UFH group 41/28 Inclusion criteria: Clinical signs of acute DVT Exclusion criteria: Not stated Diagnostic criteria: Phlebography, venous occlusion plethysmography, thermography
Interventions	Intervention (route, total dose/day, frequency): IV UFH bolus dose (sodium heparin) (5000 IU/ml) followed by SC UFH (2,5000 IU/ml) BID aPTT adjusted + warfarin Control (route, total dose/day, frequency): IV UFH bolus dose (sodium heparin) (5000 IU/ml) followed by continuous IV UFH aPTT adjusted + warfarin Treatment before study: N/A Titration period: N/A
Outcomes	Primary outcome: Therapeutic efficacy with repeat imaging Secondary outcomes: Bleeding, pulmonary emboli, aPTT, heparin dose
Notes	Stated aim of the study: The therapeutic effect and number of complications in the two groups.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Unclear risk	Not stated
Blinding? All outcomes	High risk

Belcaro 1999

Methods	Study design: Open randomised aPTT‐controlled trial Duration of intervention: 3 months for SC heparin; until INR target in LMWH and IV heparin Duration of follow up: 3 months Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English
Participants	Who participated: Patients with acute DVT Country: Italy (Chieti and Pescara), UK Number of study centres: 3 Setting: SC UFH ‐ outpatient; LMWH ‐ out/inpatient; IV UFH ‐ inpatient Number: 325 randomised, 294 completed the study (SC UFH 99; LMWH 98; IV UFH 97) Age (mean): SC UFH 54 ± 9; LMWH 54 ± 11; IV UFH 53 ± 10 Sex (M/F): SC UFH 52/47; LMWH 54/44; IV UFH 57/40 Inclusion criteria: Acute proximal DVT diagnosed by colour duplex ultrasonography Exclusion criteria: Two or more previous episodes of DVT or PE, current active bleeding, active ulcers, bleeding or coagulation disorder, concurrent PE, treatment for DVT with standard heparin > 48 hrs, home treatment not possible, neoplasia requiring surgery or chemotherapy in three months, likelihood of low compliance, pregnancy, Plt < 100,000 x 10⁹/L Diagnostic criteria: Color duplex
Interventions	Intervention (route, total dose/day, frequency): SC heparin (12,500 IU BID), fixed dose (no oral anticoagulation) administered exclusively at home Control (route, total dose/day, frequency): (1) LMWH (100Axa IU/kg BID) administred primarily at home + warfarin; (2) IV bolus (5000 IU) followed by continuous IV UFH aPTT adjusted + warfarin Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: Symptomatic or asymptomatic recurrent DVT or DVT extension at 3 months, bleeding during the administration of the study drug, PE, lenght of stay in hospital, number of patients treated directly at home without admission
Notes	Stated aim of the study: To compare intravenous standard heparin (inhospital) with oral anticoagulant treatment to LMWH and oral anticoagulant treatment administrated primarily at home, to SC heparin administered at home.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Unclear risk	Method not stated
Blinding? All outcomes	High risk	"Open randomised trial"

Bentley 1980

Methods	Study design: Open randomised controlled trial Duration of intervention: 7 days to INR target Duration of follow up: 7 days Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute DVT Country: UK Number of study centres: 1 Setting: Inpatient Age (mean ± SD): SC UFH group 60.49 ± 14.32; IV UFH group 58.18 ± 12.66 Sex (M/F): not specified but describes "well matched for age, sex ..." Inclusion criteria: Acute calf DVT diagnosed by venography Exclusion criteria: Contraindication to heparin, thrombus extension < 5 cm Diagnostic criteria: Venography
Interventions	Intervention (route, total dose/day, frequency): SC UFH (calcium heparin), initial dose 40000 IU/day followed by aPTT‐adjusted dose BID + warfarin Control (route, total dose/day, frequency): IV UFH (sodium heparin), initial dose 40000 IU/day followed by aPTT‐adjusted continous dose + warfarin Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: Cutaneous haematoma, macroscopic haematuria, major bleeding, DVT extension, new or extended PE, aPTT, heparin level
Notes	Stated aim of the study: To compare the safety and efficacy of IV and SC heparin
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Low risk	Sealed envelopes
Blinding? All outcomes	High risk

Doyle 1987

Methods	Study deisgn: Open randomised controlled trial Duration of intervention: 10 days Duration of follow up: 12 months Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute DVT Country: Canada Number of study centres: 1 Setting: Inpatients Number: 103 SC UFH 51; IV UFH 52 Age mean (range): SC UFH 66.6 (31 to 96); IV UFH 64.6 (25 to 94) Sex (M/F): SC UFH 23/28; IV UFH 32/20 Inclusion criteria: Acute proximal or calf DVT diagnosed by venography Exclusion criteria: Clinically suspected PE, active peptic ulceration, bleeding disorder, no informed consent Diagnostic criteria: Venography
Interventions	Intervention (route, total dose/day, frequency): SC UFH (calcium heparin), initial dose 15,000 IU, then BID, aPTT adjusted + warfarin Control (route, total dose/day, frequency): IV UFH (calcium heparin), initial dose 5,000 IU, then continuous, aPTT adjusted + warfarin Treatment before study: N/A
Outcomes	Primary outcome: PE Secondary outcomes: Other lung scan abnormalities, bleeding, leg symptoms, death
Notes	Stated aim of the study: To determine the effiacy and safety of adjusted SC calcium heparin compared with continuous IV calcium heparin as the initial treatment for acute DVT
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	"prescribed randomised arrangement"
Allocation concealment?	Low risk	Sealed envelopes
Blinding? All outcomes	High risk

Faivre 1987

Methods	Study design: Randomised controlled trial Duration of intervention: 10 days Duration of follow up: 10 days Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: French
Participants	Who participated: Patients with acute DVT and PE Country: France Number of study centres: 1 Setting: Inpatient Number: 68 SC UFH 35; SC LMWH 33 (number evaluated: 59 SC UFH 29; SC LMWH 30) Age (mean ±) : SC UFH 63.6 ± 16.2; SC LMWH 65.6 ± 14.8 Sex (M/F): 39/29 Inclusion criteria: Acute DVT or PE diagnosed with phlebography or perfusion‐ventilation scan Exclusion criteria: Over 2 weeks of symptoms, massive PE Diagnostic criteria: Phlebography and lung scan
Interventions	Intervention (route, total dose/day, frequency): SC UFH (calcium heparin) 500 IU/kg/day BID, aPTT adjusted Control (route, total dose/day, frequency): SC LMWH 750 anti‐Xa/kg/day BID Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: DVT extension, bleeding, aPTT, anti‐Xa, anti‐IIa
Notes	Stated aim of the study: To assess the efficacy and safety of CY222 for the treatment of DVT compared with SC heparin
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Unclear risk	Not stated
Blinding? All outcomes	Unclear risk	Not stated

Holm 1986

Methods	Study design: Randomised double blind controlled trial Duration of intervention: 7 days Duration of follow up: 7 days Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute DVT Country: Norway Number of study centres: 1 Setting: Inpatients Number: 56 (SC UFH 27; SC LMWH 29) Age mean (± SD): SC UFH 60 ± 15.8; SC LMWH 61 ±15.3 Sex (M/F): 33/23 (SC UFH 17/10; SC LMWH 16/13) Inclusion criteria: Acute DVT below the groin diagnosed by phlebography, with symptoms less than 14 days Exclusion criteria: PE, pregnancy, history of cerebral haemorrhage, surgery in previous 6 days, diastolic BP > 115 mmHg, retinal haemorrhage, impaired renal function, impaired PT Diagnostic criteria: Phlebography
Interventions	Intervention (route, total dose/day, frequency): IV continuous infusion UFH for 24 hours, followed by SC UFH 10000‐15000 IU BID, anti‐Xa adjusted + warfarin Control (route, total dose/day, frequency): IV continuous infusion UFH for 24 hours, followed by SC LMWH 5000‐7500 IU BID, anti‐Xa adjusted + warfarin Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: DVT extension, new PE, anti‐Xa, bleeding, leg pain, death, Hgb, Plt
Notes	Stated aim of the study: To compare subcutaneous heparin and LMWH for the treatment of DVT
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	"the number of patient admission determining the number of vial used"
Allocation concealment?	Low risk	"vials randomised in advance and numbered consecutively"
Blinding? All outcomes	Low risk	"phlebograms were blinded, randomly numbered and subjected to evaluation by 3 independent pairs of radiologists"

Hull 1986

Methods	Study design: Randomised double blind controlled trial Duration of intervention: 10 days Duration of follow up: 3 months Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute DVT Country: Canada Number of study centres: 1 Setting: Inpatients Number: 115 Age (< 60/> 60): SC UFH 10/4; 7 IV UFH 11/47 Sex (M/F): SC UFH 27/30; IV UFH 28/30 Inclusion criteria: Acute proximal (+/‐calf) DVT diagnosed by venography Exclusion criteria: Active bleeding, contraindication to heparin, already on heparin, no outpatient follow up available Diagnostic criteria: Venography
Interventions	Intervention (route, total dose/day, frequency): IV UFH 5000 IU bolus followed by SC UFH 15000 BID, aPTT adjusted + warfarin Control (route, total dose/day, frequency): IV UFH 5000 IU bolus followed by continuous IV UFH aPTT adjusted + warfarin Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: Reccurent DVT, PE, bleeding, aPTT, death
Notes	Stated aim of the study: Compare continuous IV heparin to intermittent SC heparin in the initial treatment of proximal DVT
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	"Computer‐generated prescribed randomised arrangement"
Allocation concealment?	Low risk	"Masked pre‐labelled syringes and intravenous packs were used"
Blinding? All outcomes	Low risk	Those patients assigned to IV heparin also received SC injections of placebo; those assigned to SC heparin also received IV infusion of placebo. "Diagnostic tests were interpreted independently and without knowledge of the results of the other tests or the patient's clinical state or the treatment group to which the patient had been assigned."

Kearon 2006

Methods	Study design: Open‐label, adjudicator‐blinded randomised controlled trial Duration of intervention: 5 days to INR target Duration of follow up: 3 months Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute DVT or PE Country: Canada and New Zealand Number of study centres: 6 Setting: Inpatients and outpatients Number: 708 (SC UFH 355; SC LMWH 353) Age mean (SD): SC UFH 60 (17); SC LMWH 60 (16) Sex (M/F): SC UFH 182/173; SC LMWH 206/147 Inclusion criteria: 18 years or older with newly diagnosed DVT of the legs or PE diagnosed by compression ultrasonography or by venography, and by a high probability ventilation‐perfusion lung scan, by non diagnostic findings on lung scan accompanied by diagnostic findings for DVT, or by computed tomographic angiography. Exclusion criteria: Contraindication to subcutaneous therapy, such as shock or major surgery in the past 48 hours, had active bleeding, a life expectancy of less than 3 months, had already received acute treatment for venous thromboembolism for more than 48 hours, were receiving long term anticoagulant therapy, had a contraindication to heparin or to radiographic contrast, had a creatinine level of greater than 200 µmol/L (2.3 mg/dL), were pregnant, were enrolled in a competing study, or were unable to have follow‐up assessments because of geographic inaccessibility. Diagnostic criteria: Compression ultrasonography or by venography, and by a high probability ventilation‐perfusion lung scan, by non diagnostic findings on lung scan accompanied by diagnostic findings for deep vein thrombosis, or by computed tomographic angiography.
Interventions	Intervention (route, total dose/day, frequency): SC UFH, initial 333 IU/kg followed by 250 IU/kg BID + warfarin Control (route, total dose/day, frequency): SC LMWH 100 IU/kg BID + warfarin Treatment before study: N/A
Outcomes	Primary outcomes: The primary analysis for efficacy was the absolute difference in the proportion of eligible patients who had recurrent venous thromboembolism at 3 months. The primary analysis for safety was the absolute difference in the proportion of patients who received at least 1 dose of study drug who had an episode of major bleeding within 10 days of randomisation. Secondary outcomes: Reccurent VTE at 10 days, major or minor bleeding, death, aPTT
Notes	Stated aim of the study: To determine if fixed‐dose, weight‐adjusted, subcutaneous unfractionated heparin is as effective and safe as low molecular‐weight heparin for treatment of venous thromboembolism.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer generated
Allocation concealment?	Low risk	Clinical centres telephoned an automated centralised system
Blinding? All outcomes	High risk	Open‐label but adjudicator blinded

Krähenbühl 1979

Methods	Study design: Randomised controlled trial Duration of intervention: 7 days Duration of follow up: 6 weeks Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: French
Participants	Who participated: Patients with acute DVT of the lower limb Country: Switzerland Number of study centres: 1 Setting: Inpatients Number: 48 (SC UFH 23; IV UFH 25) Age: not stated Sex (M/F): SC UFH 18/5; IV UFH13/12) Inclusion criteria: DVT of lower limbs diagnosed by phlebography or colour duplex US, with symptoms < 1 week Exclusion criteria: none stated Diagnostic criteria: Phlebography or color duplex ultrasound
Interventions	Intervention (route, total dose/day, frequency): IV bolus UFH (sodium heparin) 5000 IU, followed by SC UFH 15,000U/day BID (aPTT adjusted) Control (route, total dose/day, frequency): IV bolus UFH (sodium heparin) 5000 IU followed by IV continuous UFH (aPTT adjusted) Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: Symptoms duration, DVT extension, PE, aPTT
Notes	Stated aim of the study: To compare heparin administration methods
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Drawing of lots
Allocation concealment?	Unclear risk	Not stated
Blinding? All outcomes	High risk

Lopaciuk 1990

Methods	Study design: Open randomised controlled trial Duration of intervention: 7 days Duration of follow up: 3 months Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: Polish.
Participants	Who participated: Patients with acute proximal or calf DVT (with or without PE) Country: Poland Number of study centres: 5 Setting: Inpatients Number: 94 (SC UFH 48; IV UFH 46) Age: Sex (M/F): SC UFH 23/25; IV UFH 24/22 Inclusion criteria: Calf or proximal DVT diagnosed by phlebography, age 20 to 79 years Exclusion criteria: PE necessitating thrombolysis, gastric or doudenal ulcer Diagnostic criteria: Phlebography
Interventions	Intervention (route, total dose/day, frequency): Bolus IV UFH (sodium heparin) 5000 IU, followed by SC UFH 500 IU/kg/day BID, aPTT adjusted + sintron (after 7 days) Control (route, total dose/day, frequency): Bolus IV UFH (sodium heparin) 5000 IU, followed by continuous IV UFH aPTT adjusted + sintron (after 7 days) Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: DVT extension, aPTT, Plt, PE, bleeding, death
Notes	Stated aim of the study: To compare efficacy and safety of SC heparin versus IV heparin for DVT
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	"Kopert method"
Allocation concealment?	Unclear risk	Not stated
Blinding? All outcomes	High risk

Lopaciuk 1992

Methods	Study design: Open, stratified randomised controlled trial with blind evaluation of phlebographic results Duration of intervention: 10 days Duration of follow up: 3 months Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute proximal or calf DVT Country: Poland Number of study centres: 6 Setting: Inpatients Number: 149 (SC UFH 75 (3 excluded from analysis); SC LMWH 74) Age (mean ± SD): SC UFH 47.8 ±15.4; SC LMWH 49.1 ± 15.4 Sex (M/F): SC UFH 42/30; SC LMWH 39/35 Inclusion criteria: Calf or proximal DVT diagnosed by phlebography, symptoms shorter than 10 days Exclusion criteria: Clinically suspected PE, phlegmasia caerulea dolens, treatment with anticoagulation prior to enrollment, VTE in previous 2 years, surgery or trauma in recent 3 days, contraindication to heparin, pregnancy, ATIII deficiency Diagnostic criteria: Phlebography (blind evaluation of phlebographic results)
Interventions	Intervention (route, total dose/day, frequency): Bolus IV UFH 5000 IU, followed by SC UFH 250 IU/kg BID, aPTT adjusted + sintron Control (route, total dose/day, frequency): SC LMWH 225 IU/kg BID, fixed dose + sintron Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: DVT extension, reccurent DVT, PE, bleeding, death
Notes	Stated aim of the study: To determine the efficacy and safety of subcutaneous LMWH compared with SC UFH as the initial treatment of DVT of the lower limbs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Low risk	Sealed envelopes
Blinding? All outcomes	High risk

Peternel 2002

Methods	Study design: Open randomised controlled trial Duration of intervention: To INR target Duration of follow up: 7 days Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English.
Participants	Who participated: Patients with acute proximal DVT Country: Slovenia Number of study centres: 1 Setting: Inpatients Number: 59 (SC UFH 28; SC LMWH 31) Age (years): SC UFH 68 ± 13; SC LMWH 69 ±14 Sex (M/F): SC UFH 15/13; SC LMWH 17/14 Inclusion criteria: Proximal DVT diagnosed by ultasound duplex Exclusion criteria: Anticoagulant treatment with heparin or coumarins in the period of 10 days before admission, clinically significant pulmonary embolism or pregnancy Diagnostic criteria: Ultrasound duplex
Interventions	Intervention (route, total dose/day, frequency): Bolus IV UFH, followed by SC UFH BID or TID, aPTT adjusted + warfarin Control (route, total dose/day, frequency): SC LMWH 200 IU/kg QD + warfarin Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: Major bleeding, death, aPTT, haemostatic markers (F1+2, TAT, D‐dimer)
Notes	Stated aim of the study: The aim of this study was to compare these markers in the acute phase of DVT during treatment either with subcutaneous aPTT‐adjusted UFH or with weight‐adjusted LMWH in order to estimate control of hemostatic system activation during both regimens
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Method not stated
Allocation concealment?	Unclear risk	Not stated
Blinding? All outcomes	High risk

Pini 1990

Methods	Study design: Open randomised controlled trial Duration of intervention: 7 days Duration of follow up: 7 days Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English
Participants	Who participated: Patients with acute DVT Country: Italy Number of study centres: 1 Setting: Inpatients Number: 271(SC UFH 138; IV UFH 133) Age mean (range): SC UFH 63.4 (16 to 87); IV UFH 60.9 (11 to 86) Sex (M/F): SC UFH 83/55; IV UFH 72/61 Inclusion criteria: Acute DVT diagnosed with strain‐gauge plethysmography or venography Exclusion criteria: Bleeding disorder, abnormal results in hemostatic function screening tests, active peptic disease, on heparin treatment + acenocoumarol Diagnostic criteria: Plethysmography or venography in diagnosis not concluded
Interventions	Intervention (route, total dose/day, frequency): SC UFH (calcium heparin) 250 U/kg BID + acenocoumarol Control (route, total dose/day, frequency): IV UFH (sodium heparin bolus) followed by continuous IV UFH 500 U/Kg/day + acenocoumarol Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: DVT extension, PE, death, bleeding
Notes	Stated aim of the study: To compare IV and SC heparin for acute DVT in a large population study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	"Patients were assigned by computer‐generated random numbers"
Allocation concealment?	Unclear risk	Not stated
Blinding? All outcomes	High risk

Prandoni 2004

Methods	Study design: Open randomised controlled trial Duration of intervention: 5 days to INR Duration of follow up: 3 months Run‐in period: N/A Intention‐to‐treat analysis: yes Language of publication: English.
Participants	Who participated: Patients with acute VTE (DVT+PE) Number of study centres: 19 Setting: Inpatients Number: 720 (SC UFH 360; SC LMWH 360) Age (mean ± SD): SC UFH 65.7 ± 15.6; SC LMWH 67.0 ± 14.8 Sex M/F: SC UFH 158/202; SC LMWH 167/193 Inclusion criteria: Patients with DVT of the lower extremities and/or PE were eligible for the study, provided that the suspicion was objectively confirmed. Exclusion criteria: Age less than 18 years, pregnancy, contraindications to anticoagulant treatment, full‐dose anticoagulant treatment (either heparin or oral anticoagulants) for more than 24 hours, hemodynamic instability, previous (less than 1 year earlier) episode of VTE, life expectancy less than 3 months, poor compliance, and geographic inaccessibility for follow‐up. Diagnostic criteria: A positive result of at least 1 of the following tests was accepted for patient inclusion: ascending phlebography, compression ultrasound of the proximal vein system, echo color Doppler scan of the calf vein system in the case of clinical suspicion of DVT, ventilation‐perfusion scanning, spiral computed tomographic scanning, and pulmonary angiography in the case of clinical suspicion of PE. In the presence of abnormal results of an ultrasound test of the lower extremities, the diagnosis of PE was also accepted if a perfusion lung scan was compatible with a high probability of PE when compared with the chest x‐ray.
Interventions	Intervention (route, total dose/day, frequency): IV bolus UFH (calcium heparin) 4000‐5000 IU followed by SC UFH BID, aPTT adjusted + warfarin Control (route, total dose/day, frequency): SC LMWH 85 U/kg BID + warfarin Treatment before study: N/A
Outcomes	Primary outcome: Reccurent VTE at 3 month follow up Secondary outcomes: Reccurent VTE during heparin treatment, bleeding during heparin treatment, death
Notes	Stated aim of the study: The value of UFH or LMWH in treating the full spectrum of patients with VTE, including recurrent VTE and PE.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Computer generated
Allocation concealment?	Low risk	"24‐hour telephone service that recorded patient information before disclosure of the treatment assigned"
Blinding? All outcomes	High risk	Open trial

Walker 1987

Methods	Study design: Open randomised controlled trial Duration of intervention: 14 days Duration of follow up: 14 days Run‐in period: N/A Intention‐to‐treat analysis: no Language of publication: English
Participants	Who participated: Patients with acute lower limb DVT Country: UK Number of study centres: 5 Setting: Inpatients Number: 100 (SC UFH 50; IV continuous UFH 50) Age mean (SD): SC UFH M 61 (11), F 63 (16); IV continuous UFH M 60 (14), F 63 (15) Sex (M/F): SC UFH 25/25; IV continuous UFH 28/22 Inclusion criteria: Patients with DVT of the legs (calf + proximal), phlebography proven, with a thrombus > 5 cm Exclusion criteria: PE or occlusive thrombus Diagnostic criteria: Phlebography
Interventions	Intervention (route, total dose/day, frequency): SC UFH (calcium heparin) 250 U/kg, aPTT adjusted + warfarin Control (route, total dose/day, frequency): IV continuous UFH (sodium heparin) aPTT adjusted + warfarin Treatment before study: N/A
Outcomes	Outcomes not specified as primary or secondary Outcomes: DVT extension, injection site pain, PE, Hgb, Plt, aPTT
Notes	Stated aim of the study: To compare the efficacy and safety of SC versus IV heparin for leg DVT
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Random number table
Allocation concealment?	Low risk	Sealed envelopes
Blinding? All outcomes	High risk

aPTT: activated partial thromboplastin time
AT: antithrombin
BID: twice daily
BP: blood pressure
DVT: deep vein thrombosis
Hgb: haemoglobin
INR: international normalised ratio
IU: international units
IV: intravenous
LMWH: low molecular weight heparin
N/A: not applicable
PE: pulmonary embolism
Plt: platelets

QD: four times per day
SC: subcutaneous
UFH: unfractionated heparin
US: ultrasound
VTE: venous thromboembolism

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Fagher 1981	RCT comparing continuous versus intermittent Intraveneous heparin administration in patients diagnosed with DVT
Glazier 1976	RCT comparing continuous versus intermittent Intraveneous heparin administration in patients with PE
Gruber 1979	RCT comparing subcutaneous heparin and dextran for the prophylaxis of VTE
Horbach 1996	RCT comparing subcutaneous LMWH with subcutaneous UFH for the prophylaxis of VTE
Lockner 1986	RCT comparing Intraveneous UFH with intravenous LMWH in patients diagnosed with DVT
Marchiori 2002	RCT of patients diagnosed with superficial vein thrombosis
Monreal 1994	RCT comparing long term treatment of patients with VTE

DVT: deep vein thrombosis
LMWH: low molecular weight heparin
PE: pulmonary embolism
RCT: randomised controlled trial
VTE: venous thromboembolism

Data and analyses

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Comparison 1. Clinical efficacy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DVT resolution (partial/full) ‐ end of heparin treatment Show forest plot	9	886	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]
Open in figure viewer Analysis 1.1 Comparison 1 Clinical efficacy, Outcome 1 DVT resolution (partial/full) ‐ end of heparin treatment.
2 Recurrent DVT during 3 months follow up Show forest plot	4	1628	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.92, 3.04]
Open in figure viewer Analysis 1.2 Comparison 1 Clinical efficacy, Outcome 2 Recurrent DVT during 3 months follow up.
3 New clinical pulmonary embolism Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 Clinical efficacy, Outcome 3 New clinical pulmonary embolism.
3.1 During heparin treatment	8	958	Odds Ratio (M‐H, Fixed, 95% CI)	1.10 [0.46, 2.62]
3.2 During 3 months follow up	4	1626	Odds Ratio (M‐H, Fixed, 95% CI)	1.18 [0.54, 2.56]
4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy Show forest plot	2	109	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.25, 2.81]
Open in figure viewer Analysis 1.4 Comparison 1 Clinical efficacy, Outcome 4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy.

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Comparison 2. Laboratory measures

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration Show forest plot	5		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.1 Comparison 2 Laboratory measures, Outcome 1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration.
1.1 SC UFH vs. IV UFH	3	489	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.32, 0.04]
1.2 SC UFH vs. SC LMWH	2	92	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.15 [‐1.61, ‐0.69]
2 Number of patients below therapeutic range Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.2 Comparison 2 Laboratory measures, Outcome 2 Number of patients below therapeutic range.
2.1 SC UFH vs. IV UFH	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

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Comparison 3. Adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding Show forest plot	14	4390	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.36]
Open in figure viewer Analysis 3.1 Comparison 3 Adverse events, Outcome 1 Major bleeding.
1.1 During heparin treatment	14	2721	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.64, 1.79]
1.2 During 3 months follow up (including acute phase)	4	1669	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
2 Minor bleeding Show forest plot	10	2755	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.71, 1.36]
Open in figure viewer Analysis 3.2 Comparison 3 Adverse events, Outcome 2 Minor bleeding.
2.1 During heparin treatment	10	1806	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.64, 1.59]
2.2 During 3 months follow up (including acute phase)	3	949	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.61, 1.52]
3 Platelet fall Show forest plot	5	1343	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.40, 3.11]
Open in figure viewer Analysis 3.3 Comparison 3 Adverse events, Outcome 3 Platelet fall.
4 Hemoglobin fall Show forest plot	2	200	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.16, 3.41]
Open in figure viewer Analysis 3.4 Comparison 3 Adverse events, Outcome 4 Hemoglobin fall.

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Comparison 4. Death

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total death Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.1 Comparison 4 Death, Outcome 1 Total death.
1.1 During heparin treatment	7	1349	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.01, 0.01]
1.2 During 3 months follow up (including acute phase)	6	1887	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.02]
2 VTE or bleeding related death Show forest plot	13		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.2 Comparison 4 Death, Outcome 2 VTE or bleeding related death.
2.1 During heparin treatment	9	1549	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]
2.2 During 3 months follow up (including acute phase)	7	2181	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]

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Comparison 5. Clinical efficacy ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DVT resolution (partial/full) ‐ end of heparin treatment Show forest plot	9	886	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]
Open in figure viewer Analysis 5.1 Comparison 5 Clinical efficacy ‐ by control, Outcome 1 DVT resolution (partial/full) ‐ end of heparin treatment.
1.1 IV UFH as control	6	641	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.31, 2.56]
1.2 SC LMWH as control	3	245	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.46, 1.26]
2 Recurrent DVT during 3 months follow up Show forest plot	4	1628	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.92, 3.04]
Open in figure viewer Analysis 5.2 Comparison 5 Clinical efficacy ‐ by control, Outcome 2 Recurrent DVT during 3 months follow up.
2.1 IV UFH as control	1	115	Odds Ratio (M‐H, Fixed, 95% CI)	3.29 [0.64, 17.06]
2.2 SC LMWH as control	3	1513	Odds Ratio (M‐H, Fixed, 95% CI)	1.49 [0.78, 2.84]
3 New clinical pulmonary embolism Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.3 Comparison 5 Clinical efficacy ‐ by control, Outcome 3 New clinical pulmonary embolism.
3.1 During heparin treatment ‐ IV UFH as control	6	756	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.42, 2.92]
3.2 During heparin treatment ‐ SC LMWH as control	2	202	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.14, 7.63]
3.3 During 3 months follow up ‐ IV UFH as control	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	3.11 [0.62, 15.61]
3.4 During 3 months follow up ‐ SC LMWH as control	2	1417	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.31, 2.05]
4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy Show forest plot	2	109	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.25, 2.81]
Open in figure viewer Analysis 5.4 Comparison 5 Clinical efficacy ‐ by control, Outcome 4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy.

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Comparison 6. Laboratory measures ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration Show forest plot	5		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 6.1 Comparison 6 Laboratory measures ‐ by control, Outcome 1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration.
1.1 SC UFH vs. IV UFH	3	489	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.32, 0.04]
1.2 SC UFH vs. SC LMWH	2	92	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.15 [‐1.61, ‐0.69]
2 Number of patients below therapeutic range Show forest plot	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]
Open in figure viewer Analysis 6.2 Comparison 6 Laboratory measures ‐ by control, Outcome 2 Number of patients below therapeutic range.
2.1 SC UFH vs. IV UFHp	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

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Comparison 7. Adverse events ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding Show forest plot	14	4390	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.36]
Open in figure viewer Analysis 7.1 Comparison 7 Adverse events ‐ by control, Outcome 1 Major bleeding.
1.1 During heparin treatment ‐ IV UFH as control	8	972	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.42, 1.61]
1.2 During heparin treatment ‐ SC LMWH as control	6	1749	Odds Ratio (M‐H, Fixed, 95% CI)	1.57 [0.69, 3.58]
1.3 During 3 months follow up ‐ IV UFH as control	1	94	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.06, 15.77]
1.4 During 3 months follow up ‐ SC LMWH as control	3	1575	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.31, 1.32]
2 Minor bleeding Show forest plot	9	2461	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.74, 1.43]
Open in figure viewer Analysis 7.2 Comparison 7 Adverse events ‐ by control, Outcome 2 Minor bleeding.
2.1 During heparin treatment ‐ IV UFH as control	6	601	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.32, 1.27]
2.2 During heparin treatment ‐ SC LMWH as control	3	911	Odds Ratio (M‐H, Fixed, 95% CI)	1.94 [0.96, 3.89]
2.3 During 3 months follow up ‐ IV UFH as control	1	94	Odds Ratio (M‐H, Fixed, 95% CI)	3.0 [0.30, 29.94]
2.4 During 3 months follow up ‐ SC LMWH as control	2	855	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.56, 1.45]
3 Platelet fall Show forest plot	5	1343	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.40, 3.11]
Open in figure viewer Analysis 7.3 Comparison 7 Adverse events ‐ by control, Outcome 3 Platelet fall.
3.1 IV UFH as control	3	465	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.15, 2.37]
3.2 SC LMWH as control	2	878	Odds Ratio (M‐H, Fixed, 95% CI)	2.98 [0.47, 18.95]

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Comparison 8. Death ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total death Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 8.1 Comparison 8 Death ‐ by control, Outcome 1 Total death.
1.1 During heparin treatment	7	1349	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.01, 0.01]
1.2 During 3 months follow up (including acute phase)	6	1887	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.02]
2 VTE or bleeding‐related death Show forest plot	12		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 8.2 Comparison 8 Death ‐ by control, Outcome 2 VTE or bleeding‐related death.
2.1 During heparin treatment	8	1490	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]
2.2 During 3 months follow up (including acute phase)	7	2181	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]

Figure 1

Adapted QUOROM flow chart of studies selection

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Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 4

Funnel plot of comparison: Recurrent DVT during 3 months follow up.

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Figure 5

Funnel plot of comparison: New clinical pulmonary embolism.

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Analysis 1.1

Comparison 1 Clinical efficacy, Outcome 1 DVT resolution (partial/full) ‐ end of heparin treatment.

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Analysis 1.2

Comparison 1 Clinical efficacy, Outcome 2 Recurrent DVT during 3 months follow up.

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Analysis 1.3

Comparison 1 Clinical efficacy, Outcome 3 New clinical pulmonary embolism.

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Analysis 1.4

Comparison 1 Clinical efficacy, Outcome 4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy.

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Analysis 2.1

Comparison 2 Laboratory measures, Outcome 1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration.

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Analysis 2.2

Comparison 2 Laboratory measures, Outcome 2 Number of patients below therapeutic range.

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Analysis 3.1

Comparison 3 Adverse events, Outcome 1 Major bleeding.

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Analysis 3.2

Comparison 3 Adverse events, Outcome 2 Minor bleeding.

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Analysis 3.3

Comparison 3 Adverse events, Outcome 3 Platelet fall.

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Analysis 3.4

Comparison 3 Adverse events, Outcome 4 Hemoglobin fall.

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Analysis 4.1

Comparison 4 Death, Outcome 1 Total death.

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Analysis 4.2

Comparison 4 Death, Outcome 2 VTE or bleeding related death.

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Analysis 5.1

Comparison 5 Clinical efficacy ‐ by control, Outcome 1 DVT resolution (partial/full) ‐ end of heparin treatment.

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Analysis 5.2

Comparison 5 Clinical efficacy ‐ by control, Outcome 2 Recurrent DVT during 3 months follow up.

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Analysis 5.3

Comparison 5 Clinical efficacy ‐ by control, Outcome 3 New clinical pulmonary embolism.

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Analysis 5.4

Comparison 5 Clinical efficacy ‐ by control, Outcome 4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy.

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Analysis 6.1

Comparison 6 Laboratory measures ‐ by control, Outcome 1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration.

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Analysis 6.2

Comparison 6 Laboratory measures ‐ by control, Outcome 2 Number of patients below therapeutic range.

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Analysis 7.1

Comparison 7 Adverse events ‐ by control, Outcome 1 Major bleeding.

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Analysis 7.2

Comparison 7 Adverse events ‐ by control, Outcome 2 Minor bleeding.

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Analysis 7.3

Comparison 7 Adverse events ‐ by control, Outcome 3 Platelet fall.

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Analysis 8.1

Comparison 8 Death ‐ by control, Outcome 1 Total death.

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Analysis 8.2

Comparison 8 Death ‐ by control, Outcome 2 VTE or bleeding‐related death.

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Summary of findings for the main comparison. Subcutaneous unfractionated heparin compared to Other treatment modalities for Venous thromboembolism‐ clinical efficacy

Subcutaneous unfractionated heparin compared to Other treatment modalities for Venous thromboembolism‐ clinical efficacy
Patient or population: Venous thromboembolism‐ clinical efficacy Settings: Intervention: Subcutaneous unfractionated heparin Comparison: Other treatment modalities
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Other treatment modalities	Subcutaneous unfractionated heparin
Recurrent DVT during 3 months follow up Follow‐up: 0‐3 months	Medium risk population		OR 1.68 (0.92 to 3.04)	1628 (4 studies)	⊕⊕⊕⊝ moderate¹
	23 per 1000	38 per 1000 (21 to 67)
New clinical pulmonary embolism during heparin treatment Follow‐up: 0‐10 days	Medium risk population		OR 1.1 (0.46 to 2.62)	958 (8 studies)	⊕⊕⊕⊝ moderate¹
	18 per 1000	20 per 1000 (8 to 46)
New clinical pulmonary embolism during 3 months follow up Follow‐up: 0‐3 months	Medium risk population		OR 1.18 (0.54 to 2.56)	1626 (4 studies)	⊕⊕⊕⊝ moderate¹
	17 per 1000	20 per 1000 (9 to 42)
Major bleeding Follow‐up: 0‐3 months	Medium risk population		OR 0.9 (0.6 to 1.36)	4390 (14 studies)	⊕⊝⊝⊝ very low
	14 per 1000	13 per 1000 (8 to 19)
Minor bleeding Follow‐up: 0‐3 months	Medium risk population		OR 0.98 (0.71 to 1.36)	2755 (10 studies)	⊕⊕⊕⊝ moderate
	40 per 1000	39 per 1000 (29 to 54)
Total death ‐ During 3 months follow up (including acute phase)	Medium risk population		OR 1.02 (0.67 to 1.55)	1887 (6 studies)	⊕⊕⊕⊝ moderate
	43 per 1000	44 per 1000 (29 to 65)
VTE or bleeding related death during 3 months follow‐up (including acute phase) Follow‐up: 0‐3 months	Medium risk population		RD 0.0 (‐0.01 to 0.01)	2181 (7 studies)	⊕⊕⊕⊝ moderate
	0 per 1000	0 per 1000 (0 to 0)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Selection, performance, attrition and detection bias exist in some of the trials assessed.

Summary of findings for the main comparison. Subcutaneous unfractionated heparin compared to Other treatment modalities for Venous thromboembolism‐ clinical efficacy

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Table 1. Overall quality of included studies ‐ three point scale

Study	Selection bias	Performance bias	Attrition bias	Detection bias	Overall quality
Andersson 1982	Unclear	No	No	No	C
Belcaro 1999	Unclear	Unclear	No	No	C
Bentley 1980	Yes	No	No	+/‐	C
Doyle 1987	Yes	No	No	+/‐	C
Faivre 1987	Unclear	No	No	+/‐	C
Holm 1986	Unclear	Yes	No	+/‐	C
Hull 1986	Yes	Yes	Unclear	Unclear	B
Kearon 2006	Yes	No	No	Yes	C
Krähenbühl 1979	Unclear	No	No	Yes	C
Lopaciuk 1990	Yes	No	No	Yes	C
Lopaciuk 1992	Unclear	No	No	Yes	C
Peternel 2002	Unclear	No	No	Unclear	C
Pini 1990	Unclear	No	No	Unclear	C
Prandoni 2004	Unclear	No	Yes	Yes	C
Walker 1987	Unclear	No	No	Yes	C

Table 1. Overall quality of included studies ‐ three point scale

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Comparison 1. Clinical efficacy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DVT resolution (partial/full) ‐ end of heparin treatment Show forest plot	9	886	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]

2 Recurrent DVT during 3 months follow up Show forest plot	4	1628	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.92, 3.04]

3 New clinical pulmonary embolism Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 During heparin treatment	8	958	Odds Ratio (M‐H, Fixed, 95% CI)	1.10 [0.46, 2.62]
3.2 During 3 months follow up	4	1626	Odds Ratio (M‐H, Fixed, 95% CI)	1.18 [0.54, 2.56]
4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy Show forest plot	2	109	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.25, 2.81]

Comparison 1. Clinical efficacy

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Comparison 2. Laboratory measures

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration Show forest plot	5		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 SC UFH vs. IV UFH	3	489	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.32, 0.04]
1.2 SC UFH vs. SC LMWH	2	92	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.15 [‐1.61, ‐0.69]
2 Number of patients below therapeutic range Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 SC UFH vs. IV UFH	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

Comparison 2. Laboratory measures

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Comparison 3. Adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding Show forest plot	14	4390	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.36]

1.1 During heparin treatment	14	2721	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.64, 1.79]
1.2 During 3 months follow up (including acute phase)	4	1669	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
2 Minor bleeding Show forest plot	10	2755	Odds Ratio (M‐H, Fixed, 95% CI)	0.98 [0.71, 1.36]

2.1 During heparin treatment	10	1806	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.64, 1.59]
2.2 During 3 months follow up (including acute phase)	3	949	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.61, 1.52]
3 Platelet fall Show forest plot	5	1343	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.40, 3.11]

4 Hemoglobin fall Show forest plot	2	200	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.16, 3.41]

Comparison 3. Adverse events

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Comparison 4. Death

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total death Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

1.1 During heparin treatment	7	1349	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.01, 0.01]
1.2 During 3 months follow up (including acute phase)	6	1887	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.02]
2 VTE or bleeding related death Show forest plot	13		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

2.1 During heparin treatment	9	1549	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]
2.2 During 3 months follow up (including acute phase)	7	2181	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]

Comparison 4. Death

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Comparison 5. Clinical efficacy ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 DVT resolution (partial/full) ‐ end of heparin treatment Show forest plot	9	886	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [1.06, 1.84]

1.1 IV UFH as control	6	641	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.31, 2.56]
1.2 SC LMWH as control	3	245	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.46, 1.26]
2 Recurrent DVT during 3 months follow up Show forest plot	4	1628	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.92, 3.04]

2.1 IV UFH as control	1	115	Odds Ratio (M‐H, Fixed, 95% CI)	3.29 [0.64, 17.06]
2.2 SC LMWH as control	3	1513	Odds Ratio (M‐H, Fixed, 95% CI)	1.49 [0.78, 2.84]
3 New clinical pulmonary embolism Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 During heparin treatment ‐ IV UFH as control	6	756	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.42, 2.92]
3.2 During heparin treatment ‐ SC LMWH as control	2	202	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.14, 7.63]
3.3 During 3 months follow up ‐ IV UFH as control	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	3.11 [0.62, 15.61]
3.4 During 3 months follow up ‐ SC LMWH as control	2	1417	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.31, 2.05]
4 New pulmonary embolism on routine lung scan ‐ end of heparin therapy Show forest plot	2	109	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.25, 2.81]

Comparison 5. Clinical efficacy ‐ by control

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Comparison 6. Laboratory measures ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Anticoagulation measures (aPTT, anti‐Xa) ‐ after titration Show forest plot	5		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 SC UFH vs. IV UFH	3	489	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.32, 0.04]
1.2 SC UFH vs. SC LMWH	2	92	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.15 [‐1.61, ‐0.69]
2 Number of patients below therapeutic range Show forest plot	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

2.1 SC UFH vs. IV UFHp	3	434	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.89, 1.92]

Comparison 6. Laboratory measures ‐ by control

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Comparison 7. Adverse events ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Major bleeding Show forest plot	14	4390	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.36]

1.1 During heparin treatment ‐ IV UFH as control	8	972	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.42, 1.61]
1.2 During heparin treatment ‐ SC LMWH as control	6	1749	Odds Ratio (M‐H, Fixed, 95% CI)	1.57 [0.69, 3.58]
1.3 During 3 months follow up ‐ IV UFH as control	1	94	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.06, 15.77]
1.4 During 3 months follow up ‐ SC LMWH as control	3	1575	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.31, 1.32]
2 Minor bleeding Show forest plot	9	2461	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.74, 1.43]

2.1 During heparin treatment ‐ IV UFH as control	6	601	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.32, 1.27]
2.2 During heparin treatment ‐ SC LMWH as control	3	911	Odds Ratio (M‐H, Fixed, 95% CI)	1.94 [0.96, 3.89]
2.3 During 3 months follow up ‐ IV UFH as control	1	94	Odds Ratio (M‐H, Fixed, 95% CI)	3.0 [0.30, 29.94]
2.4 During 3 months follow up ‐ SC LMWH as control	2	855	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.56, 1.45]
3 Platelet fall Show forest plot	5	1343	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.40, 3.11]

3.1 IV UFH as control	3	465	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.15, 2.37]
3.2 SC LMWH as control	2	878	Odds Ratio (M‐H, Fixed, 95% CI)	2.98 [0.47, 18.95]

Comparison 7. Adverse events ‐ by control

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Comparison 8. Death ‐ by control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total death Show forest plot	10		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

1.1 During heparin treatment	7	1349	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.01, 0.01]
1.2 During 3 months follow up (including acute phase)	6	1887	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.02, 0.02]
2 VTE or bleeding‐related death Show forest plot	12		Risk Difference (M‐H, Fixed, 95% CI)	Subtotals only

2.1 During heparin treatment	8	1490	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]
2.2 During 3 months follow up (including acute phase)	7	2181	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.01, 0.01]

Comparison 8. Death ‐ by control

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Referencias

References to studies included in this review

Andersson 1982 {published data only}

Belcaro 1999 {published data only}

Bentley 1980 {published data only}

Doyle 1987 {published data only}

Faivre 1987 {published data only}

Holm 1986 {published data only}

Hull 1986 {published data only}

Kearon 2006 {published data only}

Krähenbühl 1979 {published data only}

Lopaciuk 1990 {published data only}

Lopaciuk 1992 {published data only}

Peternel 2002 {published data only}

Pini 1990 {published data only}

Prandoni 2004 {published data only}

Walker 1987 {published data only}

References to studies excluded from this review

Fagher 1981 {published data only}

Glazier 1976 {published data only}

Gruber 1979 {published data only}

Horbach 1996 {published data only}

Lockner 1986 {published data only}

Marchiori 2002 {published data only}

Monreal 1994 {published data only}

Additional references

Cohen 1960

Dahlback 2008

DerSimonian 1986

Dolovich 2002

Gould 1999

Higgins 2002

Higgins 2003

Higgins 2005

Hommes 1992

Hull 1986

Jadad 1996

Kearon 2008

McLean 1916

Moher 1999

Munro 2008

Quinlan 2004

Schulz 1995

van Dongen 2004

Virchow 1856

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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