Where Angels Fear to Tread: DVT & Low Molecular Weight Heparin

Prevention

Treatment - LMWH in the initial treatment of DVT

A number of Bandolier's readers have asked Bandolier to report on the use of low molecular weight heparins in the prevention and treatment of deep vein thrombosis (DVT). This is one of those topics where there seems to be much nuance and some major disagreements. It is one of those areas where angels fear to tread.

The safe way to seek to illuminate the subject, therefore, is to stick with evidence of high quality - from systematic reviews and meta-analyses of randomised controlled trials (see Bandolier #12; Evidence & Effectiveness ).

Last month ( Bandolier #16) we reported on a systematic review and meta-analysis of Graduated Compression Stockings and DVT ). This showed that the prophylactic use of stockings in moderate risk surgery resulted in a reduction in risk of DVTs by 68% and had a NNT of 9 (7 - 13) compared to no treatment. The low molecular weight heparins pose a somewhat different problem - but this month we examine some work on these for comparison.

This leads to the question of what happens if both low molecular weight heparins and compression stockings are used. Right now Bandolier has not found any information about that, but we would be delighted if any reader could uncover suitable reviews of RCTs on this question.

How much controversy is there in this area? We would welcome any evidence-based correspondence - perhaps pointing to the successful use of audit to change practice, or evidence that preventing DVTs confers long term health and economic benefit.

Low molecular weight heparins

There are two systematic reviews which may be useful to readers and institutions trying to develop policy in this area. One is a study of the use of low molecular weight heparins (LMWH) in the prevention of deep vein thrombosis (DVT) in total hip replacement [1], and the other investigates the effects of LMWH in treating such events [2].

1. Prevention

From McMaster University comes a report of the use of LMWH in prevention [1]. Randomised controlled trials (RCTs) which compared LMWH directly with standard heparins in total hip replacement were sought - six were found.

Outcome measures

The principal outcome measure was total DVT incidence. This was subdivided into proximal (popliteal or more proximal leg veins) or distal (isolated deep veins of the calf) events. The principal safety outcome was bleeding, which was subdivided into major and minor bleeding as defined by the studies.

Cost analysis in US$ was based on figures from an actual trial of LMWH and standard heparin carried out at McMaster. It has, therefore, a distinct North American bias, but the cost inferences are probably valid for the British experience.

Studies

There were six studies involving over 1,400 patients. All required that patients were aged 40 years or more, three were double blind, four required patients to have had general anaesthesia and three used elastic stockings in combination with anticoagulant prophylaxis. In five studies the first dose of heparin was given intravenously.

Results

The only statistically significant differences found were for total DVT and proximal DVT. There were no differences for distal DVT or total, major or minor bleeding events.

LMWH resulted in a reduction of total DVT from 149 of 685 patients (22%) to 117 of 735 patients (16%; odds ratio 0.72, 95%CI 0.53 - 0.95) and of proximal DVT from 86 of 685 patients (13%) to 40 of 735 patients (5%; 0.40, 0.28 - 0.59).

Numbers-needed-to-treat

Combining the data, the numbers-needed-to-treat to prevent one episode of total DVT using LMWH compared with standard heparin was 17 (10 - 57) and to prevent one episode of proximal DVT was 14 (10 - 24).

Cost analysis

Analysis showed that proximal DVT increased hospital stay by 5 days. The cost analysis showed that this would add about $1,400 to the total cost.

The relative cost of LMWH to standard heparin was an important factor in the cost analysis. If the relative cost of LMWH was less than 3.7 times that of the standard heparin, the cost analysis favoured LMWH. However, based on the cost of managing 1,000 patients, when the ratio was between 2.6 and 5.0, the balance of costs was only about $50,000 either way - some $50 per patient. Only when the cost of LMWH was 10 times that of standard heparin was there a significant balance of cost in favour of standard heparin. In the UK, LMWH costs about 10 times more than standard heparin.

The cost analysis did not include the cost of managing recurrent DVT and the post thrombotic syndrome, two potentially important long-term complications of DVT. Inclusion of these factors in a cost analysis would favour the use of LMWH.

2. Treatment - LMWH in the initial treatment of DVT

Patients with DVT are at high risk of recurrent thromboembolic events (5 - 10% incidence), death in the months following the initial event and disabling chronic venous insufficiency in subsequent years.

LMWH and standard unfractionated heparin have been compared in the treatment of established DVT. A meta-analysis has looked at results on over 2,000 patients in 16 RCTs [2].

Studies

The 16 studies had a control group treated with standard unfractionated heparin and a treatment group with LMWH. Subcutaneous administration of LMWH was used in 14 studies, in 5 studies of standard heparin. Patient follow up in the studies varied from just the hospital stay to up to 23 months.

Outcomes

The outcomes sought were all recurrent thromboembolic events during the trial period (DVT of the legs and fatal or non-fatal pulmonary embolism), short term major haemorrhages, extension of the thrombus (by venography) and total mortality.

Results

There were non-significant reductions in total mortality, recurrent thromboembolic events and major bleeding associated with the use of LMWH. Significance was only achieved with thrombus extension which occurred with 28 of 597 patients treated with LMWH compared with 60 of 602 patients treated with standard heparin (odds ratio 0.51, 95% CI 0.32 to 0.83).

Numbers-needed-to-treat

Nineteen patients with established DVT would need to be treated with LMWH compared with standard heparin to prevent one incident of thrombus extension.

Venographically determined thrombus extension was the least clinically relevant of all the outcome measures used. The trend in favour of LMWH improving mortality, recurrent thromboembolic episodes or major haemorrhage was not statistically significant. The studies conducted to date were of low power to detect a significant difference; to demonstrate a reduction in mortality from 5% to 2.5% would need 2,500 patients. Since more studies with larger numbers are presently underway, it is entirely possible that LMWH will be shown to be more effective in due course.

References:

DR Anderson, BJ O'Brien, MN Levine, R Roberts, PS Wells, J Hirsh. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Annals of Internal Medicine 1993 119: 1105-12.
A Leizorovicz, G Simonneau, H Decousus, JP Boissel. Comparison of efficacy and safety of low molecular weight heparin and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. British Medical Journal 1994 309: 299-304.

next story in this issue