At-home treatment of proximal DVT with low-molecular weight heparin
In previous studies, subcutaneous administration of low-molecular-weight
heparin has been shown to compare favorably to intravenous heparin for
the in-hospital treatment of proximal deep-vein thrombosis of the legs.
Because of the ease of subcutaneous administration, and particularly because
LMW heparin is administered at a fixed, weight-based dosage, without adjustment
based on blood tests, it should be well suited to treatment of DVT at home,
either as initial therapy or after a shortened hospital stay. These two
studies, one from Canada and one from Europe, Australia and New Zealand,
examine this approach.
A comparison of low-molecular-weight heparin administered primarily at
home with unfractionated heparin administered in the hospital for proximal
Authors: Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, et al.
Source: New England Journal of Medicine 334:677-81. March
Institutions: multi-institutional, in Canada.
Financial support: none indicated.
Treament of venous thrombosis with intravenous unfractionated heparin administered
in the hospital as compared with subcutaneous low-molecular-weight heparin
administered at home
Authors: Koopman M, Prandoni P, Piovella F, Ockelford P, Brandjes
D, et al.
Source: New England Journal of Medicine 334:682-7. March
Institutions: multi-institutional in Holland, Italy, Australia
and New Zealand.
Financial support: Sanofi-Winthrop and Dutch Heart Foundation.
Summary / Comparison of the two trials
||European / Australian Study
||2230 patients with acute DVT (popliteal or more proximal)
confirmed by venogram or duplex ultrasound. Patients had to be candidates
for initial treatment at home, or for early discharge.
||692 patients with acute DVT (popliteal or more proximal)
confirmed by venogram or duplex ultrasound. Patients were not required
to be candidates for home therapy or early discharge.
32% - home treatment excluded because of coexisting illness (cancer, infection,
5% - home treatment excluded because of geographic distance
10% - concurrent symptomatic PE
6% - already treated with heparin for 48 hours or more
5% - two or more prior DVT's or PE's
13% - other reasons (bleeding disorder, coagulopathy, pregnancy)
5% - DVT or PE within prior two years
5% - suspected PE
4% - already treated with heparin for 24 hours or more
5% - geographic inaccessibility, making follow-up impractical
12% - other reasons (short life expectancy, combinations of the above reasons)
||739 patients offered randomization. 239 declined (128 because of desire
to be admitted to hospital). Randomized: 500 patients.
Randomization stratified according to center, to mode of diagnosis (ultrasound
or venography) and according to "category" (outpatients with initial home
therapy; outpatients treated initially with heparin; patients hospitalized
for other reasons with in-hospital diagnosis of DVT).
|476 patients offered randomization. 76 declined. Randomized:
Randomization stratified according to center.
Heparin: In-hospital therapy; 5000 unit bolus and infusion adjusted to
keep PTT 60-85 secs.
LMW heparin: 1 mg/kg enoxaparin administered subcutaneously, twice daily.
Warfarin (both groups): started on day one, daily PT measurements, adjusted
to maintain INR 2.0-3.0, heparin stopped when two subsequent days of target
INR reached (but at least 5 days of heparin). At least three months of
therapy with warfarin.
Heparin: In-hospital therapy; 5000 unit bolus and infusion adjusted to
keep PTT 1.5-2.0 times control.
LMW heparin: nadroparin, adjusted to patient's weight, administered subcutaneously
Warfarin (both groups): Same protocol as in Canadian study.
Patients assessed monthly for three months after randomization, urgently
if any symptoms of recurrent DVT or PE.
Principal outcome events: recurrent DVT or PE within 90 days after randomization,
or bleeding during administration of study drug.
Patients contacted daily during initial treatment, then at 4, 12 and 24
Principal outcome events: recurrent DVT or PE within 6 months after randomization,
or bleeding within three months after randomization.
Also measured: a quality of life index, and utilization of resources in
the two groups.
|Treatment at home and hospital stay
LMW heparin group: 49% were never admitted to the hospital; mean hospital
stay: 1.1 days.
Standard heparin group: mean hospital stay: 6.5 days
LMW heparin group: 36% were never admitted to the hospital; mean hospital
stay: 2.7 days for patients without "events".
Standard heparin group: mean hospital stay: 8.1 days for patients without
|Recurrent venous thromboembolism
||During the 90 day f/u period, there was no significant difference in
the incidence of recurrent DVT / PE between LMW heparin and standard heparin
groups (13 vs 17 patients).
||Similar results to Canadian study: no significant difference between
LMW heparin and standard heparin during 6-month f/u (14 vs. 17 patients).
||During the study drug period plus 48 hours, there was no significant
difference in major hemorrhagic complications between LMW heparin and standard
heparin (5 patients vs. 3 patients).
||No significant difference between LMW and standard heparin (1 patient
vs. 4 patients with major bleeding).
||During the 90 day follow-up period, there was no significant difference
in mortality between LMW heparin and standard heparin (11 patients vs 17
||No significant difference between LMW and standard heparin during 6
month follow-up period (14 patients vs. 16 patients died).
In previous studies, subcutaneous low-molecular-weight heparin has been
shown to compare favorably with standard, unfractionated heparin for the
in-hospital treatment of proximal deep-vein thrombosis. The two studies
presented here demonstrate that, in selected patients, subcutaneous low-molecular-weight
heparin can be administered at home without compromising patient safety.
Thus hospitalization can be shortened or avoided altogether. Before we
say "take two enoxaparin and call me in the morning", however, a few caveats:
Home therapy of proximal DVT appears to be safe in a very selected population.
It is sure to benefit from support by the increasingly active medical cost-cutting
movement. This approach needs to be applied with discrimination and common
sense, however, not automatically or by guideline.
Patients with pulmonary emboli were excluded from both trials. Safety of
at-home treatment cannot be assumed for these patients based on the results
Patients at significant risk for bleeding were excluded from the larger,
Canadian study. Although this was not a formal exclusion from the European/Australian
study, only 36 percent of patients from that trial were treated exclusively
at home and 25 percent were not even discharged early from the hospital.
Overall, only 5.4% of patients screened for the first trial and 10.4% of
those screened for the second trial were actually treated entirely at home.
Even doubling these figures (since patients were randomized) yields a relatively
small proportion of screened patients treated totally at home.
Date: Thu April 18, 1996
Informative article. Will LMWH someday replace unfractionated Heparin
for most uses? I'm an orthopaedic surgeon and I use LMWH for DVT prophylaxis.
From: Tom Huddleston <firstname.lastname@example.org>
For reviews of the efficacy of LMWH in DVT prophylaxis (Kakkar)
and in the treatment of established thromboembolic disease (Hirsh) see
the July, 1995 issue of Thromb Haemost 74 (1). See also a review by Tapson
and Hull in the June, 1995 Clin Chest Med, 16(2). Low molecular weight
heparins seem to be better drugs in some settings and are easier to use,
but are more expensive than unfractionated heparin. Of course, certain
associated costs are lower with their use (blood drawing / PTT determination
/ IV equipment / possibly hospital stay). Seems like LMWH use (currently
FDA approved for DVT prophylaxis in the US) will expand, but I would be
interested in other readers' comments on their future role. -- mj
Date: Sat, 20 Apr 1996
Ultimately I think that many of the uses of heparin which are
primarily limited to inpatient settings will migrate to the outpatient
Robert Hogan M.D.
Date: Tue, 23 Apr 1996
From: "Albert J. Kirshen, MD, MSc, FRCPC" <email@example.com
Baycrest Centre for Geriatric Care & Faculty of Medicine, Univ.
LMWH appears to be effective in this group. I don't have the article
in front of me, but were the elderly not excluded? What about the educational
level of the participants? From a policy standpoint who would pay for this
if the person isn't in hospital?
There were no specific age cut-offs in either study. In the Canadian
study, the mean age in the LMWH group was 57 years (+/- 17). In the European
study, 59 (+/- 17).
The educational level of the participants wasn't specified, but in
the Canadian study "likelihood of non-compliance" was an exclusion criterium;
in the European study, initial therapy at home was not mandated.
Exclusions and limitations in studies such as this one are an important
issue. A given course of action is validated under favorable conditions
and then the conclusions are extended to patients some of whom are quite
different from the original study group. Particularly when a treatment
or diagnostic approach saves money, there is the risk that it will be applied
indiscriminately. This needs to be borne in mind, particularly by those
involved in promulgating guidelines.
Who will pay? This will vary from country to country, but presumably
at-home treatment will turn out to be cheaper, even if visiting nurse service
is required. Whoever ultimately foots the bill for medical therapy would
pay for at home treatment (similarly to home IV antibiotics for conditions
requiring prolonged therapy). -- mj
Date: Mon, 29 Apr 1996
From: "Albert J. Kirshen, MD, MSc, FRCPC" <firstname.lastname@example.org>
Organization: Baycrest Centre for Geriatric Care & Faculty of Medicine,
Univ. of Toronto
The articles aren't generalizable to my population of frail, infirm
Agreed. Even if a study is perfectly valid, it won't be applicable
to every patient. Determining whether valid study results are generalizable
to a specific patient or group of patients is a key part of "evidence-based
medicine" (see the links to other sites for more
about EBM). -- mj
August 29, 1996
to the editor about these articles from the New England Journal
of Medicine's website.
Journal Club on the Web home
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