`
`© The Fellowship of Postgraduate Medicine, 1993
`
`Subcutaneous versus intravenous administration of
`heparin in the treatment of deep vein thrombosis; which do
`patients prefer? A randomized cross-over study
`
`A.M. Robinson, K.A. McLean, M. Greaves and K.S. Channer
`
`Department of Cardiology and Haematology, Royal Hallamshire Hospital, Sheffield S/0 2JF. UK
`
`Patient preference for intravenom or subcutaneom heparin in the treatment of deep
`Summary:
`venom thrombosis was~ In a randomized c~ver study. Twenty patients with venograpblcally
`proven deep venous thrombosis were randomized to receive subcutaoeom or lntravenom heparin for 3 days
`followed by 3 days of the other treatment. Discomfort at the injection site, assessed by visual analogue
`sale, was significantly less for the subcutaneous than the intravenous administration route (P < 0.001),
`mobility was thought to be better when receiving subcutaneowi heparin (P < 0.005) and patients' overall
`preference was for subcutaneom treatment (P<0.001).
`
`Introduction
`
`The treatment of deep venous thrombosis (DVT) is
`anticoagulation with heparin. This is usually
`administered intravenously (IV), but can be given
`subcutaneously (SC). The efficacy of the two
`methods of delivery has been assessed in a number
`of
`trials which
`individually have produced
`conflicting results. However, an overview1 suggests
`that there are no significant differences with respect
`to death, pulmonary emboli and significant
`haemorrhage.
`Complications can occur with both methods of
`administration. Intravenous heparin can lead to
`chemical phlebitis and bacteraemia, 1 whilst SC
`heparin is associated with bruising at the site of
`injection. 2 It has been suggested that the SC route is
`preferable because it reduces the time spent by
`medical and nursing staff in administration, 1 and
`the risk of local complications such as chemical
`phlebitis and bacteraemia. No study has examined
`patient preference for either of the treatment
`modalities. This randomized cross-over study com(cid:173)
`pares the patient acceptability for SC versus IV
`heparin in the treatment of DVT.
`
`Method
`
`Twenty patients (7 male; mean age 55 years, range
`20- 85 years) admitted consecutively with a DVT,
`prov.en by venogram were entered into the study.
`Informed written consent was obtained from each
`patient and the study was approved by the hospital
`Ethics Committee. Each patient was randomly
`
`Correspondence: K.S. Channer, M.D.
`Accepted: 4 September 1992
`
`allocated to receive either calcium heparin SC twice
`daily (Calciparine, Sanofi, UK) or IV sodium
`heparin (PumpHep, Leo laboratories, Aylesbury,
`UK) by mains electric infusion pump. After 3 days
`the patients received the other treatment with total
`heparin treatment lasting for 6 days.
`When IV therapy was the first arm of treatment a
`5,000 unit bolus was given, followed by 30,000
`units over 24 hours. The starting dose for sub(cid:173)
`cutaneous heparin was 15,000 units twice daily.
`Activated partial thromboplastin time (AP1T) was
`measured daily between 0900- 1200 hours whilst
`IV heparin was administered and at 6 hours after
`the initial SC injection. The heparin dose was then
`adjusted to maintain the APTT between 1.5 and
`two times the upper limit of the control.
`On the third day of each treatment period blood
`samples were taken from all patients 3 hourly for
`the measurement of APTT and heparin con(cid:173)
`centration from 0900 for 12 hours. This provided
`pharmacokinetic data to assess the efficacy of
`anticoagulation.
`The acceptability by the patients of the two
`methods of administration was assessed using
`visual analogue scales 01 AS), for discomfort in the
`affected leg, pain at the injection site and mobility.
`The extremes (0- 100 mm) of the first two scales
`were marked 'no discomfort' and 'severe discom(cid:173)
`fort', and the scale for mobility was marked 'fully
`mobile' and 'bed bound'. Fresh scales were present(cid:173)
`ed to the patients daily, who were also asked to
`express an overall preference for one or other form
`of treatment at the end of the study.
`Non-parametric statistical analyses were used
`and 95% confidence intervals are quoted. A pro(cid:173)
`bability of P < 0.05 was accepted as significant.
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`FRESENIUS EXHIBIT 1051
`Page 1 of 2
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`116
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`A.M. ROBINSON er al.
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`Results
`
`140
`
`Nineteen patients completed the study, one being
`withdrawn because of bleeding whilst receiving JV
`heparin (APTT within the therapeutic range). The
`VAS scores were analysed by the Wilcoxon mat(cid:173)
`ched pairs signed rank test. When the two methods
`of administration were compared for all the
`patients, significantly less discomfort was felt at the
`injection site (median (range)) for SC heparin
`(3 mm (0-61 mm)) compared with IV heparin
`(12 mm (0- 97 mm), P<0.001, 95% confidence
`intervals for difference I, 15 mm).
`The patients' perception of mobility was
`significantly better for the final 4 days of treatment
`when this was SC heparin (41 mm (0-100 mm))
`compared with IV heparin (72 mm (23-99 mm),
`P<0.005, 95% confidence intervals (12, 43 mm).
`The discomfort felt in the affected leg was no
`different foreitbermethod of treatment (P = 0.54).
`Heparin and APTI levels were not significantly
`different for either SC or IV heparin (Figures l and
`2). The proportion of time for which the APTT was
`the therapeutic range was similar to
`within
`previous studies,1 and there was no significant
`difference between IV (50%) and SC (46%).
`Fifteen of the 19 patients expressed a preference
`for the SC route for administration of heparin.
`Two preferred the IV route and two gave no
`preference (x2 = 10.5, P<0.001).
`
`Discussion
`
`The majority of patients in this study preferred SC
`to IV heparin in the treatment of uncomplicated
`deep venous thrombosis. Published trials indicate
`that the two methods are equally efficient in the
`prevention of pulmonary emboli and that SC
`heparin is not associated with an increase in major
`complications.1- 5
`There are several potential advantages of SC
`over IV heparin treatment, including a reduction in
`the time taken to administer, no break in treatment
`whilst a new heparin infusion is prepared and the
`
`Refeffl!ces
`
`I. Hommes, D .W .• Bura, A., Mazzolai, L., Buller, H.R. & ten
`Cate, J.W. Subcutaneous heparin compared with continuous
`intravenous heparin administration in the initial treatment of
`deep vein thrombosis. A meta-analysis. Ann Intern Med 1992,
`116: 279-284.
`2. Wallcer, M .G., Shaw, J.W., Thompson, G.J.L. et al. Sub(cid:173)
`cutaneous calcium heparin versus intravenous sodium heparin
`in treatment of established acute deep vein thrombosis of the
`legs: a multicentre prospective randomised trial. Br Med J
`1987, 294: 1189- 1192.
`3. Doyle, D.J., Turpie, A.G.G., Hirsh, J. et al. Adjusted sub(cid:173)
`cutaneous heparin or continuous intravenous heparin in
`patients with acute deep vein thrombosis. Ann Intern Med
`1987, 107 (4): 441 - 445.
`
`120
`
`-;,
`,:,
`5 100
`~
`~ t 80
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`Cl..
`4:
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`60
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`40 '-- - -------------
`18:00
`15:00
`12:00
`Time (24 hour clock)
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`21:00
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`9:00
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`Figure I This shows the mean and interquartile range
`for activated partial thromboplastin time during treat(cid:173)
`ment with SC (e ) and IV (0) heparin in 19 patients with
`deep vein thrombosis on the third day of each treatment
`period.
`
`1.0
`
`9:00
`
`18:00
`15:00
`12:00
`Time (24 hour clock)
`Figwe 2 This shows the mean and interquartile range
`for b lood heparin level during treatment with SC<•) and
`IV (0) heparin in 19 patients with deep vein thrombosis
`on the third day of each treatment period.
`
`21 :00
`
`cost (£ 1.98/day for SC heparin compared with
`£2.30/day for IV heparin). Given that there is no
`difference in efficacy or safety, the most important
`factor should be patient acceptability. We suggest
`therefore that SC heparin is the treatment of choice
`in deep venous thrombosis.
`
`4. Andersson, G., Fagrell, 8., Holmgren, K. et al. Subcutaneous
`administration of heparin; a randomised comparison with
`intravenous administration of heparin to patients with deep(cid:173)
`vein thrombosis. Thromb Res 1982, r/: 631- 639.
`5. Bentley, P.G .. Kaklcar, V.V., Scully, M.F. et al. An objective
`study of alternative methods of heparin administration.
`Thromb Res 1980, 18: ITI-187.
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