Subcutaneous heparin is as good as low-molecular-weight heparin in the acute treatment of thrombo-embolic disease
Date First Published:
September 4, 2007
Last Updated:
November 5, 2007
Report by:
Andrew Munro, Staff Specialist (Coffs Harbour Base Hospital)
Search checked by:
Cain English, Coffs Harbour Base Hospital
Three-Part Question:
In [patients with DVT] is [subcutaneous unfractionated heparin as efficacious as low-molecular-weight heparin] in the [prevention of thrombo-embolic sequelae]?
Clinical Scenario:
An Emergency Department Registrar presented a paper at our journal club showing the efficaciousness and cost effectiveness of home treatment with unfractionated heparin (UFH) in comparison to low-molecular-weight heparin (LMWH). We decided to look at the possibility of altering our outpatient treatment guidelines for DVT and low risk PE as a way of lowering the cost of treatment. As part of the process this BET was produced.
Search Strategy:
Ovid Medline 1950 to week three Oct 2007.
Search Details:
[exp Heparin, Low-Molecular-Weight/or exp Heparin/or heparin.mp.] and [exp Venous Thrombosis/or expThromboembolism/or thrombo$.mp.or exp Thrombosis] and [exp Injections, Subcutaneous/ or subcutaneous.mp.] and [(<versus> or <vs> or <compar$>).ti.] not [(<prophyl$> or <prevent$>).ti.]
Outcome:
154 papers were found, of these 148 were found to be irrelevant or of insufficient quality to answer the question. A further relevant paper (Faivre) which was not found by Ovid, was referenced in a Cochrane meta-analysis (van Dongen) retrieved by the search strategy.
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Subcutaneous heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin. Holm H.A, Ly B, Handeland G.F. et al 1986, Norway | n=56 consecutive patients, phlebographically proven DVT. Heparin dosages were age and sex adjusted. Subsequent adjustment according to plasma anti-factor Xa activity. Randomised to UFH (n= 27) LMWH (n=29). Simultaneously commenced on oral anti-coagulation. |
Double blinded randomised. Repeat venogram at 7 days |
DVT extension on 7th day venogram | LMWH 1/29 UFH2/27 | Small study. All commenced on IV heparin prior to randomisation. 2 patients missed follow-up venogram |
| Major bleeding | Nil | ||||
| Heparin Induced Thromocytopaenia (HIT) | Nil | ||||
| Subcutaneous administration of a low molecular weight heparin (CY 222) compared with subcutaneous administration of standard heparin in patients with acute deep vein thrombosis. Faivre R, Neuhart E, Kieffer Y et al. 1987, France | n= 68 with venographically proven DVT randomised to 10 days of S/C LMWH (Cy 222 fixed dose) n=33 or UFH (initial dose 250 IU BD then adjusted to APTT) n=35. | Randomised Repeat venogram at 10 days. |
DVT extension | LMWH 0 UFH 2/35 | Small study Imaging interpretation may not have been blinded. No long term follow-up. |
| Bleeding | LMWH 0 UFH 3 large heamatomas | ||||
| PE | LMWH 1/33 UFH 1/35 | ||||
| Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Lopacuik S, Meissner A.J, Filipecki S. et al. 1992, Poland | n= 149 Phlebographically proven DVT. Randomised to 10 days of LMWH (Fraxiparine 92 IU/kg 12 hrly) n=74 or UFH (initial IV 5000 IU followed by S/C 250IU/kg 12hrly for 2-3 doses then adjusted to daily APTT) n=75 Oral anti-coagulation commenced on day 7. |
Randomised open label prospective. Blinding of imaging interpretation. Re-imaged at 10 days. |
Extension of DVT or PE at 10 days | LMWH 10/68 UFH 12/66 | Low numbers. No long term follow-up. Seven day delay to commencing oral anti-coagulation. |
| Bleeding | LMWH 10/74 UFH 12/72 1 major sub cutaneous haematoma | ||||
| Symptomatic PE | 1 in UFH | ||||
| HIT | Nil | ||||
| Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to Coumarin. Monreal M, Lafoz E, Olive A. et al. 1994, Spain | n= 80 proven DVT consecutive patients (n=43) or PE (n=37) All with a baseline VQ scan, all PE's had 'High probability' VQ scan and DVT on venography. All with relative or absolute contraindications to oral anti-coagulation. In-hospital intermittent IV UFH according to 'at least' daily APPT during initial phase of treatment. The day prior to discharge patients were randomised to S/C LMWH (fragmin 5,000IU BD) DVT n= 24 PE n= 16 or UFH (10,000IU BD) DVT n = 23 PE n=17. DVT and PE patients were treated S/C for 3 and 6 months respectively |
Randomised open label. PE patients had repeat VQ before discharge. Doctors were blinded during 6-weekly follow-up clinics. Independently assessed follow-up imaging was VQ prior to discharge and at 3 and 6 months in PE patients or repeat venogram if DVT recurrence suspected clinically. |
Recurrent PE (>low probability VQ) | LMWH 2/40 UFH 5/40 all but one of these were originally diagnosed with PE | Low numbers Suspiciously even sex ratio 1:1 for consecutive patient study Duration of initial IV UFH therapy not specified. Routine follow-up venography not done. |
| Recurrent symptomatic or new symptomatic PE | LMWH 0 UFH 2/40 (1 from each diagnostic group) | ||||
| Recurrent DVT | LMWH 2/40 UFH 3/40 | ||||
| Bleeding | LMWH 4/40 UFH 6/40 all 'minor' | ||||
| 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. Belcaro G, Nicolaides A.N, Cesarone M.R. et al. 1999, Italy, England | n=294 with duplex colour U/S proven DVT Randomised to one of LMWH (nadroparin 100IU/kg BD) n= 98, IV heparin n=97 or UFH (Sub-cutaneous, 12,500 IU 12 hrly), n=99. LMWH and IV heparin groups were commenced on oral anti-coagulation on day two. UFH received BD S/C heparin for 3 months. |
Prospective open label randomised. Follow-up colour duplex U/S was done at two weekly intervals for 3 months. |
DVT recurrence or extension during heparin therapy | LMWH 6/98 UFH 6/97 | High drop out rate n=31, 6 of whom died from 'related illness', not clear from which groups. Highly selected treatment group 264 ruled out Imaging not blinded Inclusion of IV therapy group. Unclear rationale for not converting S/C UFH group to oral anti-coagulation |
| Bleeding during heparin therapy | LMWH 3/98 UFH 1/99 all 'minor' | ||||
| HIT | nil | ||||
| Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Prandoni P, Carnovali M, Marchiori A. 2004, Italy | n=720 of whom 119 also had PE and Half each randomised to UFH (intravenous bolus followed by S/C based on weight then adjusted to APTT) or to Nadroparin 85 IU BD Oral anti-coagulation commenced within first two days. Heparin continued at least five days and two consecutive 24 hour INR s were therapeutic (INR > 2). |
Multi-center randomised. In-patient daily clinical follow-up. Follow-up clinics at 1 and 3 months. Patients asked to re-present if signs or symptoms. |
Recurrent DVT | LMWH 8/360 UFH 9/360 | Drug company sponsored Follow-up may not have been blinded. |
| PE | LMWH 6/360 (4 died) UFH 6/360(3 died) | ||||
| Bleeding during heparin therapy | LMWH 3/360 UFH 4/360 | ||||
| HIT | LMWH 1/360 UFH 1/360 | ||||
| Comparison of fixed-dose weight-adjusted unfractionated heparin and low molecular-weight heparin for acute treatment of venous thromboembolism. Kearon C, Ginsberg, J. S, Julian J.A. et al. 2006, Canada, New Zealand | n=708, proven DVT or PE (n=134) Randomised to UFH (First dose 333 IU/kg then 250 IU/kg BD) n=345 or LMWH (100IU/kg enoxaparin or dalteparin n=352. Oral anti-coagulation commenced simultaneously. 68% of patients had thrombo-embolic event diagnosed as outpatient. |
Randomised, open label multi centered. Follow-up at 3 days 1 month and 3 months. APTT samples taken between day 2 and 6 of UFH (in 197 of 345) group and blindly measured upon completion of study. |
Recurrent DVT first 10 days | LMWH 8/352 UFH 11/345 | 10 withdrawals from UFH group. |
| Recurrent PE first 10 days | LMWH 4/352 UFH 2/345 | ||||
| Major bleeding (Hb drop of 2gm/dL or more, transfusion required or critical site (intra-cranial, retroperitoneal) | LMWH 5/352 UFH 4/348 | ||||
| HIT | Nil for all | ||||
| Death first 10 days | LMWH 2/352 UFH 0 |
Author Commentary:
Seven randomised high quality trials clearly demonstrate the efficacy of sub-cutaneous unfractionated heparin when compared with low molecular weight heparin in the acute treatment of thrombo-embolic disease (TED). Cumulative raw data for all trials showed that in 1,946 patients, the rate of recurrent TED was low for both treatment groups; 6.5% and 8.7% for LMWH and UFH respectively. Trials that mandated repeat imaging in their methodology showed the over-whelming majority of recurrent TED to be sub-clinical. Two recent studies which were the largest and most rigorous showed almost identical recurrence rates for LMWH 3.65% and UFH 3.97% and nine patients who died in these studies, six were from LMWH treatment groups (Prandoni, Kearon).
UFH dosing varied between trials from approximately 150 to 250 IU/kg BD. Loading doses varied also. Most studies used APTT to guide UFH dose adjustment. Although controversial, it seems likely that APTT monitoring may not be required for home treatment with S/C UFH.
A trial that followed 99 patients who were treated for 3 months with twice daily S/C UFH also did not measure APTT (Belcaro). Kearon et al collected serum samples between days 2 and 6 of initial heparin therapy, these were kept until after the trial had ceased. APTT was then blindly measured. No DVT sequelae were noted in those who were sub-therapeutic, n = 39 and there was no bleeding in those who had a high APTT, n=121. This was not found to be the case with Prandoni and co-workers, where they comment that the rate of recurrence was three fold higher in patients in whom therapeutic APTT was not reached in the first 24 hours.
Bleeding was also a rare event occurring in 2.8% and 3.2% for LMWH and UFH respectively.
Overall there were only two patients who experienced HIT (one from each treatment group), this included two trials with patients on S/C therapy for extended periods of up to six months (Monreal, Belcaro).
UFH dosing varied between trials from approximately 150 to 250 IU/kg BD. Loading doses varied also. Most studies used APTT to guide UFH dose adjustment. Although controversial, it seems likely that APTT monitoring may not be required for home treatment with S/C UFH.
A trial that followed 99 patients who were treated for 3 months with twice daily S/C UFH also did not measure APTT (Belcaro). Kearon et al collected serum samples between days 2 and 6 of initial heparin therapy, these were kept until after the trial had ceased. APTT was then blindly measured. No DVT sequelae were noted in those who were sub-therapeutic, n = 39 and there was no bleeding in those who had a high APTT, n=121. This was not found to be the case with Prandoni and co-workers, where they comment that the rate of recurrence was three fold higher in patients in whom therapeutic APTT was not reached in the first 24 hours.
Bleeding was also a rare event occurring in 2.8% and 3.2% for LMWH and UFH respectively.
Overall there were only two patients who experienced HIT (one from each treatment group), this included two trials with patients on S/C therapy for extended periods of up to six months (Monreal, Belcaro).
Bottom Line:
Subcutaneous unfractionated heparin is an attractive alternative to low-molecular-weight heparin for the acute treatment of thrombo-embolic disease. It is cheap, effective and safe and may not require laboratory monitoring.
References:
- Holm H.A, Ly B, Handeland G.F. et al. Subcutaneous heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin.
- Faivre R, Neuhart E, Kieffer Y et al.. Subcutaneous administration of a low molecular weight heparin (CY 222) compared with subcutaneous administration of standard heparin in patients with acute deep vein thrombosis.
- Lopacuik S, Meissner A.J, Filipecki S. et al.. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial.
- Monreal M, Lafoz E, Olive A. et al.. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to Coumarin.
- Belcaro G, Nicolaides A.N, Cesarone M.R. 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.
- Prandoni P, Carnovali M, Marchiori A.. Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism.
- Kearon C, Ginsberg, J. S, Julian J.A. et al.. Comparison of fixed-dose weight-adjusted unfractionated heparin and low molecular-weight heparin for acute treatment of venous thromboembolism.
- van Dongen CJJ, van den Belt MH, Prins MH et al.. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.