Journal of Thrombosis and Haemostasis, 3: 100–102
`
`ORIGINAL ARTICLE
`
`The safety of dosing dalteparin based on actual body weight
`for the treatment of acute venous thromboembolism in obese
`patients
`
`E . A L - Y A S E E N , P . S . W E L L S , * J . A N D E R S O N , * J . M A R T I N and M . J . K O V A C S
`London Health Sciences Center, London, Ontario, Canada; and *Ottawa Hospital, Civic Campus, Ottawa, Ontario, Canada
`
`To cite this article: AL-Yaseen E, Wells ps, Anderson J, Martin J, Kovacs MJ. The safety of dosing dalteparin based on actual body weight for the
`treatment of acute venous thromboembolism in obese patients. J Thromb Haemost 2005; 3: 100–02.
`
`Summary. Data evaluating the safety of using weight-based
`low-molecular-weight heparin in the treatment of obese patients
`with acute venous thromboembolism are limited. The product
`monograph of dalteparin suggests the maximum dose should be
`limited to 18 000 U subcutaneously once daily. There are no
`specific data regarding the risk of recurrence or bleeding in
`)1.
`patients given dalteparin in a weight-based dose of 200 IU kg
`We report a retrospective chart review of 193 obese patients
`who weighed more than 90 kg and who received dalteparin at
`)1 actual body weight for 5–7 days for
`or near to 200 IU kg
`acute venous thromboembolism with 90 day follow-up infor-
`mation. Of the patients, 77% had idiopathic venous thrombo-
`embolism, 16% had an underlying malignancy, and 7% had a
`transient risk factor. Warfarin was initiated within 2 days with a
`target International Normalized Ratio range of 2.0–3.0. All
`patients were followed for 12 weeks post diagnosis. Only two
`patients had a major hemorrhage, 4 and 8 weeks from
`diagnosis. This study supports the safety of dosing dalteparin
`based on actual body weight in obese patients.
`
`Keywords: low-molecular-weight heparin, obesity, treatment,
`venous thromboembolism.
`
`Introduction
`
`Data evaluating the safety of using weight-based dosing of low-
`molecular-weight heparin (LMWH) in the treatment of obese
`patients with acute venous thromboembolism are limited.
`These patients have often been excluded from randomized
`trials [1]. In other studies, patients whose weight exceeded the
`manufacturer’s upper limit received the recommended maxi-
`mum dose, regardless of weight [2]. For dalteparin, this dose is
`18 000 IU, which can result in a significant per kilogram dose
`
`Correspondence: P. S. Wells, Ottawa Hospital, Civic Campus, Suite
`F6-47, 1053 Carling Ave, Ottawa, Ontario K1Y4E9, Canada.
`Tel.: +1 613 761 4127; fax: +1 613 761 5351; e-mail: pwells@ohri.ca
`
`Received 21 June 2004, accepted 17 August 2004
`
`reduction in obese patients. Studies based on target anti-factor
`(F)Xa levels suggest that giving the dose according to actual
`body weight to obese patients achieves similar anti-Xa levels as
`in non-obese persons [3,4]. It has been our practice to give
`
`)1 dose (i.e. 200 IU kg)1 actual
`dalteparin at the full 200 IU kg
`body weight) for patients who weigh more than 90 kg. The
`purpose of this retrospective study was to determine the rates of
`major hemorrhage and thromboembolic recurrence for obese
`(> 90 kg) patients treated for acute venous thromboembolism
`with dalteparin dose based on actual body weight.
`
`Patients and methods
`
`In the thrombosis units of our tertiary care centers all patients
`with acute venous thrombosis are followed until anticoagulant
`therapy is discontinued. Patients are seen 1 (occasionally 4),
`12 and 24 weeks after treatment is initiated and each year
`thereafter. All suspected bleeding events and recurrence events
`are investigated and documented. We were therefore able to
`perform a retrospective chart review and analysis on prospec-
`tively collected information. We reviewed our computerized
`records for patients over 90 kg who were treated for acute deep
`vein thrombosis (DVT) or pulmonary embolism (PE) as
`outpatients from May 1996 to July 2003. Patients were
`primarily referred from the emergency department or directly
`from their family physician. The diagnosis of venous throm-
`boembolism was objectively confirmed by compression ultra-
`sound, V/Q scan or spiral computed tomography by previously
`described criteria [5–10]. Patients were included in the study if
`they weighed > 90 kg. Patients were excluded if they had
`chronic renal failure requiring dialysis therapy or were known
`)1 as suggested by the
`to have a serum creatinine > 200 lmol L
`product monograph. All patients treated in our clinic are
`enrolled in our database. No patients were excluded on the
`basis of perceived bleeding risk.
`)1 actual
`Patients were treated with dalteparin 200 IU kg
`)1
`body weight subcutaneously once daily or with 100 IU kg
`twice daily for a minimum of 5 days and until the International
`Normalized Ratio (INR) was > 1.9. Preloaded syringes and
`multidose vials were used at the physicians’ discretion. The first
`
`Ó 2004 International Society on Thrombosis and Haemostasis
`
`MYLAN - EXHIBIT 1026
`
`

`

`Treatment of acute venous thromboembolism in obese patients 101
`
`underlying malignancy and 14 patients (7%) had secondary
`venous thromboembolism.
`The majority of patients (n ¼ 151; 78%) received the
`)1 dalteparin) within
`recommended daily dose (200 IU kg
`± 5%, for 5–7 days. The majority of patients received once
`daily dosing. There were 42 patients who received a daily dose
`)1 ± 5% (enabling use of prefilled
`of dalteparin < 200 IU kg
`these patients received a total dose ¼
`syringes). All of
`18 000 IU daily dalteparin. The mean dose was 21 780 which
`)1. Details on the dosing according
`was on average 191 units kg
`to 10-kg weight increments are outlined in Table 1. Approxi-
`mately half the patients self-injected (with the other half having
`the treatment administered by a visiting nurse).
`There were no patients who had a major bleed within the
`first 2 weeks of diagnosis. By the 3-month follow-up, only two
`patients had a major bleeding event (a lower gastrointestinal
`bleed and a subdural hematoma at 4 and 8 weeks from
`diagnosis, respectively) for a bleeding rate of 1.0% [95%
`confidence interval (CI) 0.1, 3.7). It is unlikely these major
`bleeding events were due to dalteparin therapy. There was one
`bleed in the 122 patients on once-daily dosing (0.8%; 95% CI
`0.02, 4.5) and one in the 71 patients who received twice-daily
`dosing (1.4%; 95% CI 0.03, 7.6). Three patients (1.6%, 95%
`CI 0.3, 4.5) had recurrent venous thromboembolic events in the
`3-month follow-up period (one PE at 2 weeks post diagnosis,
`and two DVTs at 11 weeks post diagnosis). Two recurrences
`occurred in the 122 once-daily dosing group (1.6%; 95% CI
`0.2, 5.8) and one in the 71 twice-daily dosing group (1.4%; 95%
`CI 0.03, 7.6). No patient died within the 3-month follow-up.
`
`Discussion
`
`The reported clinical experience with LMWH for the treatment
`of acute venous thromboembolism in persons > 90 kg (many
`of whom are obese) has been limited. These patients have
`typically been excluded from randomized studies or had their
`dose limited to a maximum as outlined in the product
`monograph [1,2]. In our study, we reported the successful
`outpatient treatment of 193 consecutive patients > 90 kg with
`acute venous thromboembolism, with dalteparin administered
`)1 actual body
`at, or near, an intended dose of 200 IU kg
`weight
`for 5–7 days with concomitant warfarin therapy
`continued for a minimum of 3 months. Only two of 193
`
`Table 1 Dosing information by weight categories in increments of 10 kg
`
`Weight (kg) N
`
`Mean
`dose (SD)
`
`No. full
`dose ± 5%
`
`No. OD
`dosing
`
`No. BID
`dosing
`
`90–99
`100–109
`110–119
`120–129
`130–139
`140–149
`> 150
`
`40
`52
`41
`25
`16
`9
`10
`
`19300 (814)
`20850 (693)
`21470 (1746)
`24300 (2046)
`25250 (2200)
`26920 (3900)
`28280 (4800)
`
`39
`49
`21
`22
`8
`6
`6
`
`24
`35
`26
`16
`10
`5
`6
`
`16
`17
`15
`9
`6
`4
`4
`
`N, Number of patients per category; SD, standard deviation; OD, once
`daily; BID, twice daily.
`
`injection of LMWH was given either in the outpatient clinic or
`at the emergency room prior to referral, with subsequent doses
`being administered at home. Where possible, treatment with
`oral anticoagulation was initiated on the first day, usually with
`a dose of 10 mg of warfarin. Subsequent dosing of warfarin
`was adjusted to achieve an INR between 2.0 and 3.0 according
`to a nomogram with proven efficacy [11]. Treatment with oral
`anticoagulation continued for a minimum of 3 months and
`was supervised in our anticoagulation clinics. For the duration
`of the LMWH therapy, a nurse contacted the patient daily to
`assess for complications and to communicate the warfarin dose
`as instructed by the physician. All patients were subsequently
`assessed in clinic at 1, 4 and 12-week follow-up visits after
`diagnosis. Patients were asked to report any symptoms or signs
`of recurrent venous thromboembolism, as well as any bleeding
`complications.
`The primary outcome for this retrospective study was a
`major hemorrhage in the 3-month follow-up period, although
`it is likely that bleeding beyond the first 2 weeks of treatment is
`unrelated to LMWH therapy. A major hemorrhage was
`defined as one or more of the following: (i) clinically overt
`)1; (ii)
`bleeding with a drop in hemoglobin of > 20 g L
`clinically overt and requiring 2 units or more of packed red
`cell transfusion; (iii) hemorrhage requiring permanent cessation
`of anticoagulant therapy; (iv) any retroperitoneal or intracra-
`nial hemorrhage.
`Secondary outcomes included recurrent venous thrombo-
`embolism and death [12,13].
`
`Results
`
`There were 193 patients identified from May 1996 to July 2003
`which consisted of 116 (60%) men and 77 (40%) women with
`an age range of 20–88 years (mean 54 years). All patients
`weighed more than 90 kg with a mean weight of 114.2
`(± 18.3) kg (range 91–182 kg). All patients were weighed by
`the clinic personnel (physician or nurse). The distribution of
`patient weight is shown in Fig. 1. There were 126 patients
`(66.5%) with DVT, 55 (28.5%) with PE and 12 (6%) with both
`DVT and PE. One hundred and forty-eight patients (77%) had
`idiopathic venous thromboembolism, 31 patients (16%) had an
`
`51
`
`40
`
`42
`
`24
`
`17
`
`9
`
`95
`
`105
`
`115
`
`125
`
`135
`145
`weight (kg)
`
`3
`
`4
`
`1
`
`2
`
`155
`
`165
`
`175 185
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Number of patients
`
`Fig. 1. Histogram demonstrating weight distributions in study patients.
`
`Ó 2004 International Society on Thrombosis and Haemostasis
`
`

`

`102 E. Al-Yaseen et al
`
`patients had a major hemorrhage (lower gastrointestinal and a
`subdural hematoma) at 4 and 8 weeks post diagnosis of venous
`thromboembolism, respectively. Hence, these bleeding events
`were unlikely to be due to dalteparin therapy. This bleeding
`rate is similar to rates previously reported in all patients of all
`weights from our centers, suggesting that a full dose of
`dalteparin does not increase the risk of major bleeding [12].
`Due to the small numbers of patients studied we cannot
`comment on the relative safety and efficacy of once vs. twice-
`daily dosing in these patients.
`Our study provides evidence that it is safe to dose LMWH in
`patients based on their actual weight. These data support the
`results of previous studies measuring anti-Xa levels that
`suggested full per weight dosing achieves similar LMWH
`anti-Xa levels as non-obese persons [3,4]. Wilson and col-
`leagues showed that body mass does not have a significant
`effect on the response to LMWH up to a weight of 190 kg in
`patients with normal or near normal renal function. The anti-
`Xa levels in their patient population were similar to non-obese
`patients (i.e. mean trough and peak anti-Xa levels on day
`
`)1 and 0.11 and 1.12 IU mL)1 for
`3 were 0.12 and 1.01 IU mL
`non-obese and obese patients, respectively). These levels are all
`within the manufacturer’s recommended range for once-daily
`)1 and peak
`dosing of dalteparin (trough < 0.3 U mL
`)1) [3]. A similar observation was made by
`< 1.7 U mL
`Sanderink et al., who showed that enoxaparin was well
`tolerated in both obese and non-obese volunteers when
`administered subcutaneously [4]. Subcutaneous enoxaparin
`administration yielded similar levels of LMWH in obese and
`non-obese volunteers, and steady state for anti-Xa and anti-
`factor IIa activities was reached at similar times.
`If full per weight dosing in obese individuals does not lead to
`increased anti-Xa levels as previous studies suggest, and does
`not lead to an increased risk of bleeding as our study suggests,
`then limiting these patients to a maximum daily dose of
`)1 could be considered Ôunder-dosingÕ. This could
`200 IU kg
`potentially lead to an increased risk of recurrent venous
`thromboembolism. No studies to date have assessed this
`possibility.
`The main limitation of our study is its retrospective nature;
`however, all patients were treated prospectively according to a
`standardized protocol,
`information on adverse events was
`collected in all patients prospectively, and no patients were lost
`to follow-up. We did not measure anti-Xa levels since we used
`an outpatient population and assessment of anti-Xa levels
`would have been impractical.
`Our study suggests that it is safe to administer dalteparin at
`or near full dose based on actual body weight for the treatment
`of acute venous thromboembolism without an increased risk of
`major hemorrhage. Limiting the dose of dalteparin to
`18 000 IU could lead to an increased risk of recurrence of
`venous thromboembolism. Randomized studies would be
`required to assess this risk.
`
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`Ó 2004 International Society on Thrombosis and Haemostasis
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`