Delayed efficient anticoagulation with heparin in patients with a weight of 110 kg and more treated for acute coronary syndrome

Authors


  • Disclosure: The authors declared no conflict of interest.

Correspondence: Paul Farand (paul.Farand@usherbrooke.ca)

Abstract

Objective

The use of a weight-based nomogram is considered as standard care for prescribing appropriate doses of unfractionated heparin (UFH). Because of the need for multiple other medications that may affect bleeding and that clinical data have relied on similar dosing algorithms, maximum initial bolus and infusion rates have been suggested (capped initial dose). Whether these weight-based heparin nomograms properly address therapeutic dosing in obese patients remains questionable.

Design and Methods

Thirty patients treated for acute coronary syndrome and weighing ≥110 kg were retrospectively compared with 90 controls (three groups of 30 patients, weighting 50-69.9, 70-89.9, or 90-109.9 kg), all treated with UFH, July 2008 to April 2009. The primary end point was the time required to obtain a threshold activated partial thromboplastin time (aPTT).

Results

Mean time to achieve threshold aPTT was longer for obese patients weighing ≥110 kg than for controls (31.47 vs. 12.89 hours; P < 0.0001). At 24 hours, 63% of obese patients weighing ≥110 kg had not reached threshold aPTT vs. 7% of controls (P < 0.0001). However, threshold infusion rate did not differ between weight categories (13.0 vs. 13.1 U/kg/h; P = NS) and approximated the initial infusion rate recommended by nomograms without applying the dose cap (12 U/kg/h).

Conclusions

Adequate anticoagulation time doubled in patients weighing ≥110 kg, suggesting that these patients were not receiving appropriate heparin doses initially to achieve threshold aPTT rapidly. Using initial infusion rate recommended by a nomogram without capping for total body weight is suggested as acceptable in this study. This approach should be further evaluated in a prospective study.

Introduction

Intravenous (IV) unfractionated heparin (UFH) is a proven treatment in the early management of acute coronary syndromes (ACS) [1]. When administered via bolus and continuous IV infusion, its onset of action is rapid [2, 3]. Therefore, initial dosage of UFH should attempt to give each patient a therapeutic activated partial thromboplastin time (aPTT) as fast as possible, since subtherapeutic aPTT may allow clinical thrombosis to progress and is associated with a worst prognosis [4].

Clinical trials suggest that weight-based UFH nomograms, when compared with a fixed dose heparin regimen, significantly lower the risk of recurrent thromboembolism in patients who have an ACS [8]. Hence, the use of weight-based nomograms to determine the initial IV bolus and continuous IV infusion is now considered as standard care for anticoagulation of patients treated with UFH [1, 9].

Because of the need for multiple other medications that may affect bleeding and that clinical data relied on similar dosing algorithms, consensus guidelines [1] have set maximum initial IV bolus and continuous infusion rate for ACS to avoid potential complications of a supratherapeutic aPTT. As capped initial dose is reached at 83 kg [1], standard care weight-based heparin nomograms may not address proper dosing in the increasing population of obese patients. This study evaluated retrospectively the attainment of threshold anticoagulation of our weight-based nomogram using the time required to achieve a threshold aPTT. Our hypothesis was that obese patients require higher doses of heparin, which results in a delay to adequate anticoagulation.

Methods and Procedures

We performed a retrospective chart audit of all patients treated with UFH at the Sherbrooke University Hospital Center in the province of Quebec, Canada. The Sherbrooke University Hospital Center is a 686-bed, tertiary care hospital located on two distinct sites (Hopital Fleurimont and Hopital Hôtel-Dieu). The use of weight-based nomograms was implemented in July 2008 at our centers and data were collected until April 2009 as a safety follow-up procedure study. No changes in infusion protocols, clinical decision support tools, or other were implemented during the study period. Patients were classified as obese patients with a total body weight ≥110 kg and control patients (total body weight <110 kg). We used a cutoff value in kg although various classes of obesity are defined with body mass index (BMI) because commonly used nomograms give incremental scaled dosage in kg. The initial analysis intended to include patient presenting with venous thromboembolism events (VTEs). Therefore, a cutoff value of 110 kg was chosen as it represents the weight at which both ACS and VTE protocols used in our institution reach capped initial dose. However, it has been decided later not to include patients presenting with VTE as recommended initial doses differ from ACS [9] and that only a small number of patients with VTE were available for analysis.

For every obese patient with a total body weight ≥110 kg, we randomly selected three patients weighing 50-69.9, 70-89.9, and 90-109.9 kg matching for gender. Patients were then matched to control with the closest age. If more than one patient with similar age existed, the one with the order of UFH closest in time to the obese patient with a total body weight ≥110 kg was chosen. The following patients were also excluded from analysis: subsequent alteration of nomogram by physician, infusion stopped before reaching aPTT > 55 seconds, incomplete data, or other reasons that would influence aPTT (such as simultaneous use of warfarin, hemodialysis, and cirrhosis).

Principal baseline characteristics known to influence heparin distribution were collected [10, 11]: age, gender, total body weight, height, lean body weight [12, 13], creatinine values, and indication for anticoagulation. Time and number of dosing adjustments required to achieve a threshold aPTT were recorded. Although this study was not designed to assess patient outcomes, recurrent thrombotic event defined as a new event confirmed by Doppler ultrasonography, ventilation-perfusion lung scans, or pulmonary angio computerized tomography for VTE and coronary angiography for ACS were also recorded. Major hemorrhagic complications were defined as severe or moderate according to the GUSTO bleeding classification [14] that would happen until a 48-hour period after discontinuance of heparin therapy.

UFH adjustment nomogram was standardized according to the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/NonST-Elevation Myocardial Infarction [1] for ACS. Nursing personnel is responsible for collecting blood samples and heparin dosing adjustments in accordance with our standardized prescription nomogram (Table 1). All blood specimens for aPTT were collected in siliconized Vacutainer tubes (BD, Mississauga, Canada) containing buffered citrate. All aPTT were measured locally in our hospital biochemistry laboratory using plain Dade actin FSL thromboplastin (CSL Behring, Ottawa, Canada) and automated coagulation systems BCS (CSL Behring, Ottawa, Canada). The normal range for aPTT (mean aPTT ± 2 SD in patient having no known coagulopathy and not receiving anticoagulants) at our hospital is 23-32 seconds.

Table 1. Weight-based nomograms used at our institution for patients presenting with acute coronary syndrome
aPTT interval (sec)Perfusion rate (units/h)Additional bolus (units)Stop perfusion (min)Next aPTT
  1. aPTT : activated partial thromboplastin time.
  2. Initial bolus of 60 units/kg (maximal initial bolus of 4000 units) followed by an initial perfusion rate of 12 units/kg/h (maximal initial perfusion rate of 1000 units/h). After 6 hours of perfusion, aPTT is measured and perfusion rate is adjusted as above.
  3. aNotify attending doctor.
≤35+3000As calculated for initial bolus 6 hours
35.1–45+2000  6 hours
45.1–55+1000  6 hours
55.1–75Same  Next morning
75.1–95−1000  6 hours
95.1–115−2000 30 minutes6 hours after perfusion is restarted
≥115.1a−3000 60 minutes6 hours after perfusion is restarted

The primary end points were time required to obtain a threshold aPTT defined as an aPTT > 55 seconds (heparin anti-Xa activity level > 0.3 units/ml). This therapeutic threshold is consistent with current guidelines [1, 9]. Secondary end point was the number of dosing adjustment to threshold aPTT and the infusion rate at threshold aPTT.

Statistical Analysis

Matching for gender and age was performed to assure the comparability of groups. Hence, groups were considered as independent and all statistical analyses were not paired. Baseline characteristics were compared using ANOVA. Statistical significance for primary and secondary endpoints was determined by Mann-Whitney analysis, as groups are unbalanced and were not distributed normally. Subgroups analyses for primary and secondary end points were performed with Kruskal-Wallis test for all subgroups as a whole and by a Mann-Whitney analysis when two subgroups were compared together with P values adjusted using Bonferroni corrections. A Kaplan-Meier analysis was performed and groups were compared with a Log Rank test for time to achieve threshold aPTT. A Chi-square test was used to compare the number of obese with a total body weight ≥110 kg and control patients who reached threshold aPTT at 24 hours and after initial bolus. A Fisher exact test was performed for patients with recurrent thromboembolic event or major hemorrhagic complications. Post-hoc analysis of primary end points includes a Mann-Whitney test for patient with total body weight ≥83 kg and <83 kg and for BMI ≥30 kg/m2 and total body weight <83 kg and ≥83 kg as maximal IV bolus and infusion rate is reached at 83 kg for ACS nomogram. A Fisher exact test for numbers of protocol violation in initial doses and a Mann-Whitney test for primary end points excluding these patients were also conducted. All statistical analyses were performed with SPSS 17.0 (SPSS Inc., Chicago, Illinois). A P value <0.05 was considered statistically significant.

Results

A total of 1,584 patients with orders for UFH infusion were identified. One hundred and twelve patients were classified as obese patients with a total body weight ≥110 kg and 1,472 as control patients (total body weight <110 kg). From the obese patients with a total body weight ≥110 kg, 82 were excluded from analysis and 172 patients from the control group (Table 2). A total of 120 patients, 30 obese patients weighing ≥110 kg and 90 controls, were included in the final analysis. Protocol violation for initial doses occurred in 10% (3/30) in obese patient weighing ≥110 kg and 26% (24/90) in controls (P = 0.08). All violations were insufficient initial bolus except for one obese patient with total body weight ≥110 kg and two control patients who received a higher than recommended initial perfusion rate and three controls patients who receive insufficient initial perfusion rate. The cumulative effect of protocol violation was a slight increase in the initial dose for patients weighing 110 kg and more, whereas it resulted in a minor decrease for control patients.

Table 2. Reasons for exclusion of patients
 No. of patients excluded
  1. aPTT, activated partial thromboplastin time.
 Obese patients weighing ≥110 kgControls
Simultaneous use of warfarin2741
Perfusion stopped before aPTT >55 s2030
Incomplete data1533
Subsequent alteration of nomogram by physician829
Venous thromboembolism836
Haemodialysis/cirrhosis43

Baselines clinical characteristics of patients are shown in Table 3. Each group (obese patients with a total body weight ≥110 kg and controls) included 25 men and 5 women. Of note, 63% (19/30) of the obese patients with a total body weight ≥110 kg presented class III obesity (BMI ≥40 kg/m2) [15]. Total body weight distribution of these patients included 25 patients with total body weight of 110-129.9 kg, 3 patients of 130-159.9 kg, 1 patient of 160 kg, and 1 patient of 186 kg.

Table 3. Baselines characteristics for obese patients weighing ≥110 kg and matched control
 ≥110 kg (n = 30)<110 kg (n = 90)P value
  1. BMI, body mass index; LBW, lean body weight.
  2. Data are median (range).
Age (y)59.0 (40.0-85.0)59.0 (40.0-86.0)0.743
Total body weight (kg)118 (110-186)80 (50-109)<0.0001
Height (cm)174 (151-185)170 (129-190)0.342
BMI (kg/m2)40.6 (32.4-62.9)28.0 (18.2-39.0)<0.0001
LBW (kg)72.6 (50.5-85.1)55.5 (28.8-74.6)<0.0001
Creatinine value (mg/dl)1.06 (0.61-3.90)1.07 (0.85-2.81)0.376
Patient receiving initial bolus (n)29 (97%)76 (84%)<0.0001
Initial dose (units/kg)34.0 (0.0-54.5)46.5 (0.0-115.6)<0.0001
Initial perfusion rate (units/kg/h)8.6 (5.4-11.8)11.3 (7.3-18.3)<0.0001

Median time to achieve threshold aPTT was more than double in obese patients with total body weight ≥110 kg compared to controls (P < 0.0001; Table 4). Kaplan Meier analysis was used to compare duration of UFH perfusion between obese patients weighing ≥110 kg to controls and showed a significant difference in the percentage of achieving threshold aPTT at any given time (P < 0.001) (Figure 1). More importantly, 63% (19/30) of obese patients with total body weight ≥110 kg had not reached threshold aPTT at 24 hours compared to 7% (6/90) of control patients (P < 0.0001, data not shown). Adequate anticoagulation was achieved after initial bolus and infusion rate without other adjustment in only 10% (3/30) of the obese with total body weight ≥110 kg versus 52% (47/90) in the control group (P < 0.001). Number of dosing adjustments required was significantly higher in the obese patients weighing ≥110 kg compared to controls (P < 0.001). All of these dosing adjustments were increased as threshold aPTT was not achieved. The above results did not differ when data were analyzed with a cutoff value of BMI of 40 kg/m2 or higher or when patients with protocol violation at initial doses were excluded. Pearson's correlation for time to achieve threshold aPTT and different weight covariate were not significant [total body weight (P = 0.646), BMI (P = 0.632) and lean body weight (P = 0.417)]. Time to achieve threshold aPTT was 10.21 hours for obese patients (BMI ≥30 kg/m2) weighing <83 kg vs. 22.25 hours for obese patients (BMI ≥30 kg/m2) weighing ≥83 kg (P < 0.001).

Figure 1.

Percentage of obese patients with a total body weight ≥110 kg and control achieving threshold aPTT.

Table 4. Primary and secondary end points for obese patients weighing ≥110 kg and matched control
 Time required to achieve threshold aPTT (h)No. of dosing adjustment
  1. aPTT, activated partial thromboplastin time.
  2. Data are medians (first-third quartile).
  3. aP< 0.0001 vs. obese patients weighing ≥ 110 kg.
Obese patients weighing ≥110 kg (N = 30)31.47 (18.65-44.51)4.00 (2.75-5.00)
Matched control patients (N = 90)12.89 (7.15-17.50)a1.00 (1.00-2.00)a

Seven patients in the control group and no obese patients with a total body weight ≥110 kg group had aPTT values higher than 180 seconds (P = 0.19). No recurrent thrombotic events were noted in either group. Major hemorrhagic complications occurred in 3.3% (1/30) of the obese patient weighing of 110 kg or more versus 7.8% (7/90) in the control group (P = 0.6777).

Subgroup analyses are detailed in Table 5. Time and number of dosing adjustment required to achieve threshold aPTT increased as total body weight increases for patients with ACS. These results were statistically significantly different between control and obese patients with a total body weight ≥110 kg in each weight category (P < 0.05). Moreover, the time was significantly greater for control patients weighting <83 kg and for those weighting ≥83 kg (P < 0.05, data not shown).

Table 5. Subgroup analyses for primary and secondary end points
 Time required to achieve threshold aPTT (h)No. of dosing adjustment
  1. aPTT, activated partial thromboplastin time.
  2. Data are median (first-third quartile).
  3. P< 0.05 for all groups as determined by a Kruskal-Wallis analysis.
  4. aP < 0.05 vs. obese patients weighing ≥110 kg as determined by a Mann-Whitney analysis.
  5. bP < 0.05 vs. controls weighing 90-109.9 kg as determined by a Mann-Whitney analysis.
Obese patients weighing ≥ 110 kg (n = 30)31.47 (18.65-44.51)4.00 (2.75-5.00)
Matched control patients
Weight 90-109.9 kg (n = 30)14.92 (8.48-21.88)a2.00 (1.00-3.00)a
Weight 70-89.9 kg (n = 30)12.07 (6.48-15.50)a, b1.00 (1.00-2.00)a
Weight 50-69.9 kg (n = 30)9.28 (7.12-14.28)a, b1.00 (1.00-2.00)a

Threshold infusion rate by total body weight did not differ significantly (P = NS) as weight increased (Table 6). Results were similar when analysis was performed with infusion rate according to BMI (data not shown).

Table 6. Threshold infusion rate by weight
 Threshold infusion rate by weight (U/kg/h)
(n = 120)
  1. P = NS for all groups.
  2. Data are means (standard deviation).
Obese patients (weight ≥110 kg)13.0 (2.4)
Matched control patients
Weight 90-109.9 kg12.5 (2.2)
Weight 70-89.9 kg12.9 (1.8)
Weight 50-69.9 kg13.8 (2.6)

Discussion

Our data showed that the currently recommended [1, 9] standard care weight-base nomograms resulted in considerable delays (i.e., doubled) to achieve threshold aPTT in obese patients weighing ≥110 kg.

Pharmacokinetic data suggest that UFH volume of distribution approximates blood volume or plasma volume (40-70 ml/kg) [2]. Consequently, patients with larger blood volumes should require larger bolus dosages of heparin [16]. Moreover, heparin clearance in obese patients is unknown [16]. Therefore, an obese patient having a higher blood volume and a variable clearance may require higher initial bolus and perfusion rate of heparin to achieve adequate anticoagulation. Our data suggest that capping the doses with maximal initial IV bolus and continuous infusion rate [as recommended by currently available consensus guidelines [1]] leads to underdosing of UFH in obese patients with total body weight ≥110 kg, which in turn results in a clinically significant delay for adequate anticoagulation. Indeed, higher numbers of dosing adjustments were necessary to achieve a threshold aPTT. Evidence of the maximal dose effect can also be illustrated by the fact that statistical differences in the time to achieve threshold aPTT between subgroups of total body weight appears at the cut points from which the nomogram switches from a weight-base to capped dosage (83 kg).

As the severity of obesity increases, blood volume does not increase proportionally to the increase in total body weight because blood volume in adipose tissue is lower than in lean tissue [16]. Heparin's distribution volume by weight should therefore be proportionally lower in the obese patient. This was evidenced by lower heparin doses by weight necessary for adequate anticoagulation in previous studies [20]. Although we believe that body composition in obese patients may influence heparin requirement, the difference in threshold infusion rate between total body weight categories was nonstatiscally significant in this study. Moreover, these threshold infusion rates are near the initial infusion rate recommended by our nomogram (12 U/kg/h) if a initial maximal dose (capping) was not applied. Whether this approach is appropriate will need to be evaluated in a prospective study.

Time to achieve threshold aPTT in the control group of our study was comparable to findings of previous studies evaluating standard care weight-base nomogram in nonobese patients [23]. Few studies have addressed the issues of UFH dosing in the obese [21, 25, 27]. Moreover, controversy exists whether total body weight or ideal body weight provides better anticoagulation results [29]. Available literature seems to support the use of total body weight with specified maximum initial bolus and infusion rates for obese patients [21, 25, 27, 28]. Maximum doses were suggested to avoid higher aPTTs than desired and an increased risk of bleeding as heparin requirements do not increase linearly with obese body weight [20, 21]. However, most of these previous studies [21, 25, 27] included small numbers of obese patients weighing ≥110 kg.

Riney et al. [20] performed a prospective observation cohort study of 285 patients who received an order of UFH. Interestingly, they did not find a difference in the time to first therapeutic aPTT between obese and nonobese patient. This may be explained by a time to therapeutic aPTT for nonobese patients of 30.0 ± 77.0 hours, which is at odd with our results and previous studies [23] involving nonobese patients. This could be since, unlike the present study, most patients in the study from Riney et al. [20] did not receive an initial bolus. Moreover, time to therapeutic aPTT for morbidly obese patients was lower than our results. Another difference is that their therapeutic infusion rate differed between BMI groups. This may be due to the small number of patients in our study. However, although statiscally significant, the absolute difference was small which is compatible with our results. We did not find any similar study comparing time to threshold aPTT that explored the effect of capping the initial doses.

Multiple case reports have suggested the use of various modified or adjusted “dosing weight” (DW) for calculation of doses in obese patients [30]. Delays varied from 10 to 48 hours to achieve a threshold aPTT. However, none compared delays with nonobese patients. The use of lean body weight may also represent a promising avenue for dosing medication in the obese patients [12]. Our results, however, have not shown a positive correlation with time to achieve threshold aPTT. Although we believe that the use of a modified DW is interesting, larger studies are needed to validate such approach [33].

An important limitation of our study is that it is a retrospective analysis of a single-center practice. Dosing nomograms and DW may differ from centers and capping, although recommended by ACS guidelines [1], may not be applied in all hospitals. Another limitation is that we were not able to assess all potential confounders that may affect heparin requirement. Although patients with warfarin were excluded, other comedication that may have altered aPTT and heparin dosage was not recorded. Obese patients are also more prone to suffer from many conditions also known to alter heparin's pharmacokinetic such as diabetes, thyroid disease, and tobacco use [2, 3, 34] or may be of a different ethnicity [35].

Controversy exists whether subtherapeutic aPTT increases the risk of recurrent thromboembolic events [4, 23, 38, 39]. Although it is reasonable to believe that a greater delay to reach threshold anticoagulation should lead to a greater number of adverse arterial and venous thrombotic events, the limited number of patients in this study does not permit to evaluate such clinical end points. Moreover, evidence of new ischemia documented by electrocardiogram findings and or chest pain was not noted if they did not lead to a supplemental coronary angiogram. Also, it will be of critical importance to assure that major hemorrhagic complications will not be higher in obese patient if capping is not used.

The inclusion of patients with protocol violation in the initial doses may have introduced a bias. However, results did not differ when these patients where excluded from the analysis. Moreover, protocol violations in patients weighing 110 kg and more resulted in an increased initial dose, whereas it decreased the initial dose in control patient. The inclusion of these patients is therefore expected to lead to a smaller difference in the time to achieve therapeutic aPTT.

Measurement of nomogram implementation integrity was not documented such as interval between the diagnosis and initiation of heparin as well as the interval between phlebotomy for aPTT measurements and subsequent heparin dose adjustment. Physician may also have altered the nomograms to increase the doses in response to the control aPTT. Such interventions, however, would be expected to reduce time necessary to achieve a threshold aPTT.

Compared with measurement of factor Xa levels, aPTT is subjected to greater variability in representing the concentrations of plasma heparin [40] and is associated with a increased number of dosage adjustments [27]. However, aPTT remains the most widely used and accepted method for monitoring UFH [41].

Finally, the relative importance of BMI versus total body weight is difficult to balance when analyzing these data as a significant proportion of our control group (30/90) effectively qualifies as being obese (BMI ≥30 kg/m2). Although Pearson's correlation was nonsignificant for aPTT at 24 hours for both total body weight and BMI, the fact that the difference in time to achieve threshold aPTT for obese patient (BMI ≥30 kg/m2) weighing <83 kg vs. ≥83 kg remained significant suggests that total body weight may be more important than BMI for explaining delays in anticoagulation.

Conclusion

Although weight-based nomograms have improved the ability to appropriately administer UFH, our data demonstrated significant delay to achieve threshold aPTT in obese patients with total body weight ≥110 kg presenting with ACS. Given the obesity epidemics, to determine the optimal initial dosing in obese patients is mandatory. Until such dosing is better defined, we recommend that clinicians pay better attention to results of aPTT in obese patients with total body weigh of 110 kg or more when adjusting infusion rate and IV bolus.

Ancillary