Subcutaneous heparin is as good as low-molecular-weight heparin in the acute treatment of thrombo-embolic disease
- Report By: Andrew Munro - Staff Specialist
- Search checked by Cain English - Emergency Registrar
- Institution: Coffs Harbour Base Hospital
- Date Submitted: 4th September 2007
- Date Completed: 8th May 2008
- Last Modified: 5th November 2007
-
Status:
Green (complete)
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.[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 [(
Search 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)
| Author, date and country | Patient group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Holm H.A, 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 | ||||
| Faivre R 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 | ||||
| Lopacuik 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 | ||||
| Monreal M 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' | ||||
| Belcaro G. 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 | ||||
| Prandoni P et al, 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 | ||||
| Kearon C 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 |
Comment(s)
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).Clinical 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. Haemostasis 1986, 16; suppl 2, 30-7.
- 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. Throm Heam 1987 58 (1) Abstract 430.
- 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. Thrombosis and Haemostasis 1992, 68(1) 14-18.
- 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. Thromb and Haemostasis 1994 71(1) 7-11.
- 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. Angiology 1999 October 50(10) 781-87.
- 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. Arch Intern Med 2004, 164, 1077-83.
- 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. JAMA 2006 296(8) 935-42.
- 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. Cochrane Database of Syst. Rev. 2004 Issue 4 Art. No.:CD001100