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Achievement of Anticoagulation by Using a Weight-based Heparin Dosing Protocol for Obese and Nonobese Patients

William J. Spruill, William E. Wade, W. Gary Huckaby, and Ryan B. Leslie

[Am J Health-Syst Pharm 58(22):2143-2146, 2001. © 2001 ASHP, Inc.]

Abstract and Introduction

Abstract

The need for different heparin dosing protocols for obese and nonobese patients was studied.

A chart review was performed for all patients who received heparin over an eightmonth period at an acute care hospital. Data collected included age, sex, height, actual body weight (ABW), ideal body weight (IBW), initial activated partial thromboplastin time (aPTT), initial heparin bolus dose, initial heparin i.v. infusion rate, time to initial targeted aPTT, and final infusion rate.

Forty patients met criteria for inclusion: 20 obese patients (greater than 30% over IBW) and 20 nonobese patients (less than 20% over IBW). Mean ± S.D. initial heparin infusion rates for the obese and nonobese groups were 14.44 ± 1.29 and 15.04 ± 0.42 units/kg/hr, respectively. Times to targeted aPTT for obese and nonobese patients were 25.86 ± 12.83 and 25.18 ± 14.76 hours, respectively; mean final infusion rates were 12.94 ± 2.56 and 12.36 ± 2.54 units/kg/hr; and percent changes from initial to final infusion rates were 11.84% and 17.76%. There were no significant differences in initial or final infusion rates or time to targeted aPTT between the two groups.

It is appropriate to use ABW in a weightbased heparin dosing protocol for obese patients.

Introduction

Heparin has been used for more than 50 years for the prophylaxis and treatment of venous thrombosis and pulmonary embolism, treatment of atrial fibrillation with embolization, and diagnosis and treatment of acute and chronic consumptive coagulopathies.[1] Traditionally, heparin has been dosed empirically. [2] Dosing by this method varies, but a usual bolus dose equals 5000 units followed by a maintenance i.v. infusion of 1000 units/hr.[2,3] However, this regimen often fails to achieve therapeutic goals within the first 24 hours of therapy.[2]

Research over the past decade has shown the importance of achieving rapid anticoagulation and targeted activated partial thromboplastin time (aPTT) during the first 24 hours after heparin therapy.[2] In 1993 Raschke et al.[3] noted that a weightbased heparin dosing protocol was superior to the standard regimen in achieving goals quickly and reducing the complications associated with the latter. These complications included protracted therapy (increased risk of bleeding), aPTT levels below the targeted range, and increased risk of event recurrence.[3,4] Additionally, this weight-based protocol was more cost-effective, since it reduced the need for laboratory monitoring and changes in therapy and the number of bolus doses required to maintain desired aPTTs.[4]

Although weight-based heparin dosing protocols are now accepted, their utility for obese patients is still unclear. Heparin's volume of distribution (40-70 mL/kg) is very similar to blood volume; therefore, patients with larger blood volumes (e.g., obese patients) would seem to require more heparin.[2,5] However, the blood volume of adipose tissue is less than that of lean tissue.[2] Even though heparin is not distributed into adipose tissue, clinicians recommending doses for obese patients must take into account the extra vasculature of these patients and recognize that the dose may not increase proportionally with body weight.[2,6]

The purpose of our study was to assess the need for different heparin dosing protocols for obese and nonobese patients. Specifically, we examined differences in heparin doses determined with a weight-based protocol that were required to achieve targeted aPTTs in these two patient categories.

Methods

A chart review was performed for all patients who received heparin from July 1, 1999, through February 28, 2000, in an acute care hospital in Athens, Georgia. Data collected included age, sex, height, actual body weight (ABW), and ideal body weight (IBW). Clinical data collected included initial aPTT, initial heparin bolus dose, initial heparin infusion rate, first targeted aPTT, time to targeted aPTT, and final infusion rate.

The patients were divided into obese and nonobese groups. The obese group consisted of patients who exceeded their IBW by at least 30%, and the nonobese group consisted of those who did not exceed their IBW by more than 20%. All patients had to have received a bolus dose, and their records had to contain all the necessary demographic and clinical data.

The hospital had a weight-based heparin dosing protocol in place that was adapted from clinical trials involving such dosing methods.[3,7] A 70-unit/kg bolus dose was followed by an infusion of 15 units/kg/hr. Rates were adjusted on the basis of guidelines provided in the dosing protocol (appendix). Endpoints included the percent change between initial and final infusion rates, the time to targeted aPTT, and the difference in final infusion rates between the two groups. To test for differences between the groups, Student's t tests were performed with Excel 2000 (Microsoft, Redmond, WA). The a priori level of significance was set at 0.05.

Results

A total of 212 patients received heparin during the study period. Only 104 patients met the entry requirements for either the obese group (n = 65) or the nonobese group (n = 39). The remaining 109 patients were excluded from the study either because they did not meet the weight requirements for the obese group or because their heparin therapy was discontinued before they reached a targeted aPTT (47-70 seconds). Of the 104 patients, a total of 20 obese patients and 20 nonobese patients had complete data and were included in the analysis.

Table 1 shows the mean ± S.D. demographic data for both study groups. The groups were well matched and did not differ significantly in age, height, or IBW. However, there were significant differences in ABW (p < 0.001) and percentage above IBW (p < 0.001). Table 2 shows initial aPTTs, initial heparin bolus doses, initial heparin infusion rates, first targeted aPTTs, times to targeted aPTT, and final heparin infusion rates for both groups. There were no significant between-group differences in these variables. Table 3 compares the two groups in terms of time to reach targeted aPTT.

Discussion

In 1988, Wheeler et al.[8] reported that physicians treating patients for pulmonary embolism and deep-vein thrombosis frequently underdosed their patients and were slow to change their heparin therapy. Sixty percent of patients studied were below the targeted range by the time the first blood samples for measuring aPTT were drawn (a mean of 11.7 hours after therapy was begun), and it took eight days for 90% of the group to reach the desired aPTTs.

By 1993, Raschke et al.[3] had found that a weight-based heparin dosing protocol would rapidly achieve targeted aPTTs and reduce complications associated with aPTTs below the targeted range. Lackie et al.[4] recommended adopting a weight-based dosing protocol that allowed for rapid achievement of targeted aPTTs to decrease the risk of recurrence of thromboembolic events and to improve clinical outcomes. The weight that should be used to dose heparin remained to be determined.

Yee and Norton[6] assessed the use of ABW, IBW, and dosing weight (DW) (IBW + [0.3(ABW - IBW)]) to determine the heparin bolus dose and infusion rate. They defined obesity as IBW plus 10 kg. The appropriate basis for dosing heparin is especially important in the obese patient, for whom the risk of overdosing heparin and achieving aPTTs above the target is a possibility. Yee and Norton's protocol consisted of an initial heparin bolus of 80 units/kg followed by a continuous infusion of 18 units/ kg/hr; the targeted aPTT was 50-70 seconds. ABW provided the best response to a weight-based protocol (achieving the targeted aPTT within 24 hours). Some 97% of the patients for whom dosing was based on ABW were at or above their targeted aPTT within the first 24 hours. Such outcomes can decrease the risk of thromboembolic complications and should be the goal of any weight-based heparin dosing protocol.[4]

However, Yee and Norton[6] raised concerns about using ABW for patients who were significantly overweight (who weighed more than 100 kg). They suggested setting a maximum limit on loading doses at 10,000 units and recommended that infusion rates not exceed 1,500 units/ hr to avoid overcoagulation. Additionally, since the protocol had frequently produced aPTT levels above the targeted range, these authors recommended a reduction in the infusion rate from 18 to 15 units/kg/hr.

Other investigators have used a dosing weight as part of their heparin weight-based protocol. Price and Colodny[9] used the dosing-weight formula of Yee and Norton[6] to determine heparin doses for their obese patients (obesity was not defined). They stated that these patients required less heparin per kilogram than nonobese patients. However, the study was limited to examining the initiation of a weight-based heparin dosing protocol and did not study the effectiveness of using a dosing-weight formula for obese patients versus their ABW.

Bowden et al.[10] also used a dosing weight in their investigation of a weight-based heparin protocol. The dosing-weight formula (DW = IBW + [0.4(ABW - IBW)]) was used for obese patients (those weighing more than 120% of IBW) to determine the proper heparin dose. This study, too, was limited to the pharmacoeconomic impact of a weight-based protocol and did not examine the effectiveness of using a dosing-weight formula.

Pinder et al.[11] studied the initiation of a weight-based heparin dosing protocol for patients on a coronary care unit. They initially used the protocol of Raschke et al.,[3] an 80- unit/kg bolus dose followed by an 18-unit/kg/hr infusion and a targeted aPTT of 42-90 seconds. The investigators used either ABW or a dosing weight if the patient weighed more than 70 kg, with 20% of the total weight above IBW. The dosingweight formula was the same as that of Yee and Norton.[6] However, the protocol was adjusted three months into the study because of the large number of patients with aPTTs above the targeted range. The investigators decided to reduce the bolus dose from 80 to 75 units/kg; the infusion rate remained the same. At 24 hours, 78% of the patients had reached a targeted aPTT, while the rest were above or below the targeted range (13% and 9%, respectively). Among the obese patients, 77% reached targeted aPTTs, while the remainder were above or below the desired range (18% and 5%, respectively). These instances of using a dosing weight, whose derivation attempts to determine the blood-volume differential between lean tissue and adipose tissue, show the need to clarify a weight-based dosing protocol for heparin.

Our results show the use of ABW to be appropriate for determining the most effective heparin dose for both obese and nonobese patients. These findings are similar to those of Yee and Norton,[6] who recommended using ABW to determine heparin infusion rates. Although the weightbased heparin dosing protocol used in our study was less aggressive than Yee and Norton's, it matched their recommended infusion rate. Additionally, our obese patient group was defined more accurately by using a percentage above IBW, as opposed to the set kilogram weight above IBW reported by Yee and Norton. Our protocol was less aggressive than that of Pinder et al.,[11] and their definition of obese used a set weight with a percentage above IBW. Also, they had to reduce their bolus dose to avoid aPTTs above the targeted range, instead of adjusting their infusion rate, as done by Yee and Norton.[6]

Our two groups of patients had similar baseline aPTTs and received similar initial bolus doses. Both groups achieved targeted aPTTs within the same time period. However, at 24 hours, 60% of the nonobese patients had achieved a targeted aPTT, while the rest were either above or below the range (35% and 5%, respectively). In the obese group, 45% of patients were at a targeted aPTT, 45% were above the targeted range, and 10% were below it during the same time frame. Yet 75% of patients in each group reached the targeted aPTT at the 36-hour mark, and 25% of patients in each group took longer than 36 hours to do so. These results are considerably better than those reported by Wheeler et al.[8] in 1988.

The success of the ABW-based protocol leads us to suspect that the extra vasculature that accompanies obesity has a minimal effect on heparin dosing. The weight-based heparin dosing protocol used in this hospital was effective for both patient groups. It allowed both groups to reach targeted aPTTs in the same amount of time and at similar final infusion rates (Table 2). Dosing seemed to be more accurate for the obese group, since the percent change from initial to final infusion rates was less than the change required for the nonobese group (although the difference was not significant).

Of the 20 patients in the obese group, 6 (30%) weighed in excess of 100 kg. Of these 6 patients, only 1 had an aPTT above the targeted range within 24 hours, while 4 had reached targeted aPTTs within the same time frame. This may allay fears of producing aPTTs above the targeted range in the extremely obese patient. The protocol used at this hospital follows the infusion rate recommended by Yee and Norton.[6] This protocol does not set a maximum rate per hour, though. Yee and Norton recommended that the infusion rate not exceed 1500 units/hr, with a maximum loading dose of 10,000 units. However, of the six patients whose weight exceeded 100 kg, four had infusion rates above 1500 units/hr, and none had aPTTs above the targeted range in the first 24 hours. No patient received a loading dose greater than 10,000 units.

Further studies are needed to determine any cost issues in using a weightbased heparin dosing protocol for all patient populations. This will determine whether any cost savings could be obtained if a separate protocol were used for obese patients.

Conclusion

The extra vasculature present in obese patients appears to have minimal effect on the dosing of heparin. Therefore, it is appropriate to use ABW in a weight-based heparin dosing protocol for this patient population.

Side Bar

Appendix -- Heparin drip protocol

aPTT[a] (sec) Bolus Dose (Units) Stop Infusion (min) Infusion Rate Change (mL/hr) Repeat aPTT Test
<37 3000 0 2 6 hr
37-46 0 0 1 6 hr
47-70 0 0 No change Next morning
71-79 0 0 -1 Next morning
80-94 0 30b -2 6 hr
95-140 0 60b -3 6 hr
>140 0 60b -6 6 hr


a aPTT = activated partial thromboplastin time.
b Do not stop infusion within 24 hours of thrombolytic therapy (e.g., alteplase administration).

Table 1. Baseline Demographic Characteristics

Variable Mean ± S.D. Value
Obese Group
(n = 20)		 Nonobese Group
(n = 20)
Age (yr) 60.35 ± 14.36 63.90 ± 17.34
Height (in) 66.54 ± 3.61 68.20 ± 3.60
Actual body weight (kg) [b] 95.01 ± 14.04 69.88 ± 12.52[a]
Ideal body weight (kg)b 62.54 ± 9.72 66.53 ± 9.86
% above ideal body weight 51.76 ± 14.46 5.33 ± 11.74[a]


a Significantly different from corresponding value for obese group (p < 0.001).
b For men, 50 kg plus 2.3 kg for every inch over 5 ft; for women, 45.5 kg plus 2.3 kg for every inch over 5 ft.

Table 2. Results for Study Endpoints

Variable Mean ± S.D. Value [a]
Obese Group
(n = 20)		 Nonobese Group
(n = 20)
Initial aPTT (sec)[b] 27.55 ± 3.46 29.30 ± 2.51
Initial bolus dose (units/kg) 64.05 ± 9.71 68.21 ± 6.06
Initial infusion rate (units/kg/hr) 14.44 ± 1.29 15.04 ± 0.42
First therapeutic aPTT (sec) 61.20 ± 7.27 59.75 ± 11.93
Time to first therapeutic aPTT (hr) 25.86 ± 12.83 25.18 ± 14.76
Final infusion rate (units/kg/hr) 12.94 ± 2.56 12.36 ± 2.54
% change from initial to final infusion rates 11.84 ± 15.86 17.76 ± 16.97


a None of the differences between groups were significant.
b aPTT = activated partial thromboplastin time.

Table 3. Time to Targeted Activated Partial Thromboplastin Time

Time (hr) No. (%) Patients Reaching Target[a]
Obese Group
(n = 20)		 Nonobese Group
(n = 20)
24 9 (45) 12 (60)
>24-30 4 (20) 1 (5)
>30-36 2 (10) 2 (10)
>36-42 1 (5) 3 (15)
>42 4 (20) 2 (10)


a None of the differences between groups were significant.

References

  1. McEvoy GK, ed. AHFS drug information 99. Bethesda, MD: American Society of Health-System Pharmacists; 1999.
  2. Schaefer DC, Hufnagle J, Williams L. Rapid heparin anticoagulation: use of a weight-based nomogram. Am Fam Physician. 1996; 54:2517-21.
  3. Raschke RA, Reilly BM, Guidry JR et al. The weight-based heparin dosing nomogram compared with a "standard care" nomogram. Ann Intern Med. 1993; 119: 874-81.
  4. Lackie CL, Luzier AB, Donovan JA et al. Weight-based heparin dosing: clinical response and resource utilization. Clin Ther. 1998; 20:699-710.
  5. Cipolle RJ, Rodvold KA. In: Evans WE, Schentag JJ, Jusko WJ et al., eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. Vancouver, WA: Applied Therapeutics; 1992:30-1-39.
  6. Yee WP, Norton LL. Optimal weight base for a weight-based heparin dosing protocol. Am J Health-Syst Pharm. 1998; 55:159-62.
  7. Hirsh J, Raschke R, Warkentin TE et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1995; 108:258S-75S.
  8. Wheeler AP, Jaquiss RD, Newman JH. Physician practices in the treatment of pulmonary embolism and deep vein thrombosis. Arch Intern Med. 1988; 148: 1321-5.
  9. Price CK, Colodny L. Partnering with nurses to manage heparin therapy with a weight-based protocol. Am J Health-Syst Pharm. 2000; 57:110-6.
  10. Bowden C, Carter K, Birtcher K et al. Pharmacoeconomic impact of a weightbased heparin protocol. Am J Health-Syst Pharm. 1998; 55(suppl):S29-32.
  11. Pinder T, Daughtry W, Shah Z et al. A weight-based heparin protocol for improved anticoagulation in a coronary care unit. J Clin Outcomes Manage. 1999; 6(5): 27-33.
William J. Spruill, PHARM.D., FASHP, is Associate Professor and William E. Wade, PHARM.D., FASHP, FCCP, is Professor, Department of Clinical and Administrative Sciences, College of Pharmacy, University of Georgia (UG), Athens. W. Gary Huckaby is Pharm.D. degree candidate and Clinical Coordinator, Pharmacy Department, St. Mary's Health System, Athens. Ryan B. Leslie, PHARM.D., is Fellow, Department of Clinical and Administrative Sciences, College of Pharmacy, UG.

Address correspondence to Dr. Spruill at the Department of Clinical and Administrative Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602-2354 (bspruill@mail.rx.uga.edu). Presented in part at the ASHP Midyear Clinical Meeting, Las Vegas, NV, December 5, 2000.


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