Monitoring heparin treatment with the APTT: the effect of methodological changes on the APTT

Netherlands

Journal

of Medicine

49 ( 1996)

13- 18

Original article

Monitoring heparin treatment with the AP’TT: the effect of methodological changes on the APTT J.W.M. Krulder a** , F.J.M. van der Meer b, E. BrGt b, A.E. Meinders a ’ Department of General Internal Medicine, Univgrsity Hospital Leiden, Leiden, Netherlands b Department of Thrombosis and Haemostasis, University Hospital Leiden, Leiden, Netherlands Received

20 November

1995; revised

21 February

1996; accepted

I March

1996

Abstract Objective: To assessthe effect on the desired activated partial thromboplastin time &P’TT) of altered practice in the laboratory control of heparin treatment. Merhods: Descriptive study of the number of ApTTs in the desired range (DR) in 1987 (historical controls) and in 1992/1993. In the latter period, four changes in the implementation of heparin treatment took place: another coagulation analyser was used, laboratory control was intensified with a nomogram as guideline, and the DR was changed from 90-120 to 45-60 s. Furthermore, a standard heparin solution of 417 U/ml was supplied by the hospital pharmacy. Resulrs: The total amount of AFTTs in the desired range increasedfrom 19% in 1987 to 46% in 1992/1993, and the DR was reached in 1987 in 1 day by 14%. and in 1992/1993 by 48% of patients. The mean daily heparin dose was higher in 1992/1993 (34.1~~1000 U, 95% CI 33.4-34.8) than in 1987 (32.3* 1000 U, 95% CI 31.5-33.0). The starting dose of heptin of 400 U/kg during the first day, following an initial bolus injection of 70 U/kg, was correct in 44% of patients,

too low in 46%, and too high in 10%. Conclusions: The new policy in the laboratory control of heparin treatment resulted in an increasednumber of APTTs in the DR, and a shorter time to reach this. Keywords: Activated

partial

thromboplastin

time;

Heparin;

Laboratory

1. Introduction Since the landmark study by Barritt and Jordan [I], heparin has played a key role in the initial treatment of venous thromboembolism [2-41. The goal of treatment is the immediate prevention of progression, recurrence, and late sequelae of thromCorresponding author, present address: Haernatology, Municipal Hospital Leyenburg, l

Department of PO Box 40551,

2504 LN The Hague.Netherlands.Tel.: ( + 3l-70) 3592556:fax: (+31-70)

3295&.

0300-2977/%/$15.00

Copyright

PII SO300-2977(96)00020-4

0

1996 Elsevier

Science

B.V.

control

boembolism, with a minimum of side-effects. To achieve this, the effect of heparin on coagulation is monitored with a laboratory test, usually the activated partial thromboplastin time (AFIT) [2-61. It is generally recommended to aim at a prolongation of 1S-3 times normal [2-61, although ms of different manufacturers do not have the same sensitivity for heparin [7-111, and optimum ranges have to be defined for each reagent and coagulation analyser. It is also unknown which prolongation of the APIT is optimal with regard to clinical outcome of the individual patient. Treatment is often inadequate, in view

All rights

reserved.

14

J. W.M.

Krulder

et al. /Netherlands

of the low percentage of APTTs within the desired range [6,12,13]. Recently we presented the results of a retrospective survey of APTTs obtained from patients who were treated for venous thromboembolism [14]. Only a minority of APlTs was in the desired range (at that time an APTT prolongation of 3-4 times normal), although the mean heparin dose did not differ from that reported by others, and there was no apparent lack of effectivity in patient management. Because the purchase of a new coagulometer was scheduled in the near future, we decided to search for ways to augment the number of APTTs in the desired range. This was achieved by redefinition of the desired range after the acquisition of the new coagulometer, the introduction of a new standard heparin solution by the hospital pharmacist, and more frequent dose adjustments with the use of a nomogram as a guideline. After these changes, the number of AP’ITs at a desired level was again evaluated.

Journal

of Medicine

Table I Nomogram

49

il996)

13-18

for dose adjustments

Am (seconds)

Adjust tz

< 35

< 1.2

35-45 45-60 60-75 > 75

1.2-1.5 1.5-2 2-2.5 > 2.5

of intravenous heparin

dose

bolus 5000 U iv. + 10000 U/d + 5000 U/d no change -5OOOU/d stop 2 h - lOOOOU/d

heparin

therapy

Next AFTT afier 6-8 after next after after

h

6-8 h morning 6-8 h 8-10 h

The starting dose was 70 U/kg body weight as i.v. bolus injection, followed by 400 U/kg/24 h as continuous i.v. infusion; the APTT was determined after 6-8 h.

Blood samples were taken by venepuncture and collected in vacuum tubes containing citrate/citric acid as anticoagulant (v/v = 9: 1) (Vacutainer, Becton Dickinson Company, Rutherford, NJ, USA). The AP’IT was measured within 4 h of sampling using Cephotest (Nyegaard, Oslo, Norway); in 1987 on an Biomatic BlO (Sarstedt, Etten-Leur, The Netherlands), and in 1992-1993 on an Electra 1OOOc (Medical Laboratory Automation Inc., Pleasantville, NY, USA).

was supplied by the hospital pharmacy. In the first period, heparin dilutions were made by the nursing staff using a stock solution of 25000 U/ml and NaCl 0.9%; in the second period a standard solution of 417 U/ml, which was provided by the hospital pharmacist, was used. As a rule, initial treatment consisted of a loading dose of 70 U/kg body weight as intravenous bolus injection, foliowed by a continuous infusion of 400 U/kg body weight/24 h using an infusion pump. Treatment with oral anticoagulants, usually phenprocoumon, was started at the same day. According to the result of the APTT, the heparin dose was adjusted. In 1987, the target range was defined as an APTT between 90 and 120 s. The target range was determined by comparison of APTT results in patients on heparin treatment with the previously used method (recalcification time). The target range with the recalcification time was assessed on clinical empirical grounds. In 1992 the target range of 45-60 s was assessed by performing APTI’s on coumarin plasmas to which ex vivo heparin was added in various concentrations. Subsequently, the results were validated in patients on heparin treatment by anti-Xa assay. The AP’TT target range corresponds with an anti-Xa assay result of 0.3-0.8 U/ml. Heparin therapy was stopped after 5 days if the INR was sufficiently prolonged @JR 2.5-3.5). In the latter period a dosing nomogram was used (Table 1).

2.2. Treatment

2.3. Statistical analysis

Unfractionated heparin (Thromboliquine, Organon, Oss, The Netherlands) from different lots

The results were compared using a two-tailed Student’s t-test for unpaired samples. The analysis

2. Methods APTT results and daily heparin dose of all medical patients treated for venous thrombosis or pulmonary embolism in 1987 were analysed using the archives of the Thrombosis Service. The same procedure was followed during two 6-month periods in 1992-1993. 2.1. Samples

J. WM. Krulder et al. / Netherlands Journal of Medicine 49 (1996) 13-18 Table 2 AFTT on the first days of heparin treatment 96 in desired Day AFTT range +I +2 +3 +4 Mean

1987

1992/93

1987

65.8k39.2 68 f 39.3 84.1 k55.5 94.6541.1 82.2k49.2

44.5 f 12.8 5 51.8i16.6 14 55.2* 15.0 20 6O.Of18.9 22 51.9* 16.3 19

1992/93 34 47 55 48 46

106

r

P-value 60

< < < < <

t

0.001 o.cm 0.001 0.001 0.001

AFTT values are given in s, as mean f SD. In 1987, the desired range was 90-120 s, in 1992-1993 45-60 s. In 1987, the fust AFTT value was obtained on day + 1; in 1992-1993 on day 0.

was performed using a commercial software package (SPSS for Windows, SPSS Inc., Chicago, IL, USA).

3. Results The patient groups in the two observation periods did not differ significantly regarding age, sex and diagnosis. In 1987, 92 patients (46 male, 46 female; age 53.6 f 18.6, range 16-87 years) were treated with heparin. The APTTs are shown in Table 2. In 19% of all APTT measurements after starting heparinisation the result was in the desired range (90-120 s); 64% of all APTTs was below the desired range, the remainder above. The desired threshold was passed by approximately half of the patients on the third day after starting hepatin treatment and by two-thirds on the fourth day (Fig. 1). The daily mean heparin dose (32.3 * 1000 U, 95% CI 31.5-33.0) increased steadily over the days from 26.8 * 1000 U (bolus injection not included, 95% CI 25.7-27.8) on the starting day, to 34.8 * 1000 U (95% CI 32.9-36.7) 4 days later (Table 3). The starting dose proved to be correct in 15% of cases. In 1992-1993, 135 patients (70 male, 65 female; age 56.9 f 18.9, range 16-91 years) were treated for venous thromboembolism. At that time, the desired range was defined as an APTT between 45 and 60 s, the new standard heparin solution was used, and the dosage nomogram was followed. In 46% of all measurements the APTT was in the desired range and approximately equal numbers were either too high (25%) or too low (29%). The starting dose of heparin

0

1

2

3

4

Fig. 1. Cumulative percentage of patients who have reached the desired threshold (for 1987, 90 s; for 1992-1993, 45 s). 0 1987, 0 1992-1993.

of 400 U/kg/d was correct in 44% of patients, too low in 46%, and too high in 10%. Within 24 h after starting heparinisation, 47% of patients had reached the desired level. On the second day after starting heparin treatment, 70% of patients had passed the desired threshold. On day +4, this was achieved by 90% of patients (Fig. I). The number of desired AP’TT values for each of the first 4 days after starting heparin treatment was significantly higher in 1992-1993 than in 1987 (P
Table 3 Daily heparin dose 1987

1992-1993

P-value

Bolus Day 0 Day +I Day +2 Day +3 Day +4 Mean

5.0 (4.7-5.3) 29.5 (28.4-30.7) 34.4 (33.1-35.7) 35.8 (34.2-37.4) 35.9 (34.1-37.7) 35.0 (33.1-36.9) 34.1 (33.4-34.8)

n.s. < 0.001 < 0.001 < 0.05 n.s. n.s. < 0.001

5.4 (5.0-5.6) 26.8 (25.7-27.8) 30.0 (28.7-3 I .4) 32.8 (31.4-34.3) 34.3 (32.5-36. I) 34.8 (32.9-36.7) 32.3 (31.5-33.0)

The daily heparin dose is given in thousand units [mean (95% CD]. The dose on day 0 does not include the bolus injection.

16

J. WM.

Krulder

et al. /Netherlands

was insufficient to reach a desired level of anticoagulation. Furthermore, dose adjustments on the first treatment days as a response to more frequent laboratory monitoring had a significant effect on the mean daily heparin dose. In 1987, on average 0.91 APTTs were performed per patient per day. In 1992- 1993, laboratory control was increased to 1.08 times daily on average per patient, with a maximum of 1.13 on day + 1. Patients with a clinical presentation of pulmonary embolism did not need more heparin than patients with only symptoms of a deep venous thrombosis.

4. Discussion In this study we described the effect of changes in monitoring of heparin treatment on the percentage of APTTs in the desired range. Conclusions on the clinical relevance cannot be drawn because we have neither measured systematically the extent of the thromboembolism before and after treatment nor assessed the side-effects. However, with data from other studies for comparison, the fact that the desired range was reached earlier and more often in 19921993 than in 1987 suggests that treatment might also have been improved. In 1987, we evaluated the laboratory results of heparin treatment for venous thromboembolism [14]. The percentage of desired APITs turned out to be 19%. Several remarks have to be made here. The desired range-90120 s as measured with Cephotest on the Biomatic BlO (normal < 35 s&was defined in the past when we moved from the recalcification time to the APTT. This range implicated an APTT prolongation of almost 3-4 times, which is more than the commonly advised prolongation of 1.5-3 times normal [2-61. This knowledge, although not necessarily transferable to our own situation, led to somewhat cautious changes, if any, in heparin dosing when the APTT approximated the target range. This can be illustrated by an additional 21% of APTTs in the I’suboptimal ‘I range between 70 and 90 s. Because at that time the purchase of a new coagulation analyser was imminent, we decided to redefine the target range during the transition period of old and new methods. The new target range was validated in patients on heparin treatment by anti-Xa assay. The

Journal

qf Medicine

49 119961 13-18

fact that both the old and the new APTT target range reflect a similar level of anticoagulation as measured as factor Xa inhibition is supported by the prescription of higher, rather than lower, amounts of heparin in the latter period. The increased frequency of laboratory control in the second observation period, compared to standard once-daily control in 1987, led to a faster adjustment of insufficient heparin dosages. To our surprise, analysis of the data from 1987 revealed that laboratory control was only performed on 91% of treatment days. In 1992-1993 laboratory control was intensified with the nomogram as a guideline. In that period, the average number of APTT measurements increased to 1.08 per treatment day. The result is a higher percentage of desired AP’ITs (46 vs. 19%). and a faster achievement of this level (48 vs. 14% on day + 1). Hull et al. recently stressed the importance of passing the lower limit of the target range as soon as possible [ 151. This advice is based on an earlier report [ 161 which showed that the risk of recurrent thrombosis was 18% in cases with insufficient APTI prolongation, while 41 patients with an adequate APIT did not have a recurrent thrombosis. A Dutch study comparing acenocoumarol and heparin with acenocoumarol alone in the treatment of proximal vein thrombosis supported the need for an immediate anticoagulant effect because in the group receiving acenocoumarol alone asymptomatic thrombus extension was observed in 39.6% of patients versus 8.2% in the acenocoumarol plus heparin group [4]. In our study, the higher mean heparin dose in the first days reflects both the effect of more frequent dose adjustments and the appreciation that the maintenance dose during the first day of treatment of 400 U/kg is often too low to reach the desired level. Several recent reports show that heparin treatment is often inadequate, as determined by the amount of APTTs in the target range. Our 19% of desired APTTs in 1987 is comparable with that in the literature [6,12,17]. Several authors decribed the beneticial effect of a heparin-dosing nomogram [ 13,17-201. The separate effect of the introduction of the nomogram on the number of APTTs in the target range cannot be deduced from our results. We expect the effect to be relatively small because advice about adjustment of the heparin dosage was routinely given by the staff of the Thrombosis Service in both

J.W.M.

Krulder

et al./Netherlands

periods, and the nomogram was more a formalisation of, than a change in, common practice. However, a nomogram may be a useful tool in the hands of those who are not familiar with anticoagulation. In 1991, the hospital pharmacy started the supply of a new standard heparin solution containing approximately 417 U/ml, to make dosage adjustments easier. In former years the heparin was diluted on the ward to a fixed amount of 50 ml with a variable concentration (depending on the dosage) which was infused in 24 h with an infusion pump. When the dosage changed, a new heparin dilution had to be prepared. With the introduction of the 417 U/ml heparin solution, an infusion rate of 1.O ml/h results in a daily dose of 10000 U (24*417 = 10000). Adjustments in the heparin dosage can be made easily, if necessary with steps of 1000 U/d, by changing the infusion rate. Recalculations of infusion rate and preparation of new heparin dilutions on the ward are no longer necessary, and it is likely that this has a beneficial effect on the accuracy of dosing. Because oral anticoagulant therapy was started together with heparin, some influence of coumarin on the AP’lT result is acceptable. Because in this respect there has been no change in policy between 1987 and 1992, we think that our results are not influenced by the use of heparin and coumarin at the same time. This study illustrates how difficult it is apparently to reach and maintain a desired level of anticoagulation with unfractionated heparin, as measured with the APIT. Recent reports have stressed the importance of passing a threshold, the lower limit of the target range, as soon as possible [15]. However, it is important to realize that optimum ranges have to be defined for each laboratory because the test result depends on many variables [7-9,111. The fact that slightly more heparin was needed in 1992-1993 to reach a, seemingly lower, desired AFTT illustrates this effect of different test conditions, such as the reagents and apparatus used. Furthermore, the optimal prolongation of any AP’IT in relation to clinical outcome is unknown. Finally, there appears to be a diurnal rhythm in the effect of heparin on coagulation with a more pronounced effect at night than at daytime [21,22]. This further complicates aiming at a stable level of anticoagulation. The development of low-molecular-weight heparins, which have been

Journal

of Medicine

49 (1996)

13-18

17

proven to be at least as effective in the treatment of venous thrombosis without the need for laboratory control, is therefore very promising [23]. Because venous thrombosis and pulmonary embolism are different aspects of the same disease [24], it is possible that low-molecular-weight heparin will be the treatment of choice in the near future.

References [I]

[2]

[3] [4]

[5]

[6]

[7]

181

[9]

[lo]

[ 1 I]

1121

Banitt DW. Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 196O:i:l309-1312. Hull RD. Raskob GE. Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990:322: l2601264. Hirsh J. Heparin. N Engl J Med 1991;324:1565-1574. Brandjes DPM, Heijboer H, Biiller HR. De Rijk M. Jagt H. Ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the treatment of proximal-vein thrombosis. N Engl J Med 1992;327: 1485-1489. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972:287:32543247. Fennerty AC. Thomas P, Backhouse G, Bentley P, Campbell IA. Routledge PA. Audit of control of heparin treatment. Br Med J 1985:290:27-28. Soloway HB, Cornett BM, Grayson JW. Comparison of various activated partial thromboplastin reagents in the laboratory control of heparin therapy. Am J Clin Pathol 1973;59:587-590. Gawoski JM. Arkin CF, Bovill T. Brandt J, Rock WA, Triplett DA. The effects of heparin on the activated partial thromboplastin time of the College of American Pathologists survey specimens. Arch Path01 Lab Med 1987: I I 1:785-790. Shojania AM, Tetreault J, Tumbull G. The variations be tween heparin sensitivity of different lots of activated partial thromboplastin time reagent produced by the same manufacturer. Am J Clin Pathol 1988;89:19-23. Van den Besselaar AMHP, Meeuwisse-Braun J, Bertina RM. Monitoring heparin therapy: relationships between the activated partial thromboplastin time and heparin assays based on ex-vivo heparin samples. Thromb Haemostas 1990:63: 16-23. D’ Angelo A, Seveso MP, D-Angelo SV, Gilardoni F, Dettori AG, Bonini P. Effect of clot-detection methods and reagents on activated partial thromboplastin time (APlT). Am J Clin Pathol 1990:94:297-306. Wheeler AP. Jaquiss RDB, Newman JH. Physician practices in the treatment of pulmonary embolism and deep venous thrombosis. Arch Intern Med 1988;148:1321-1325.

18 [13]

[ 141 [15]

[ 161

1171

[ 18)

J. WM. Krulder et al./ Netherlands Journal of Medicine 49 (1996) 13-18 Cruickshank MK, Levine MN, Hirsh I, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991;151:333-337. Krulder JWM. Controle van heparinetherapie met behulp van een APTT. Tijdschr NVKC 1990;15:133-134. Hull RD. Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992;152:1589-1595. Hull RD. Raskob GE, Hiih J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109-1114. Kershaw B, White RH, Mungall D, Van Houten J, Brettfeld S. Computer-assisted dosing of hepatin. Management with a pharmacy-based anticoagulation service. Arch Intern Med 1994;154:1005-1011. Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a nstandard care. nomogram. A randomized controlled trial. Ann Intern Med 1993;119:874-881.

1191 Felding P, Bremmelgaard, Wiiel P. Adjusted-dose intravenous heparin treatment. Evaluation of an automated and a non-automated schedule. Thromb Res 1988;5 1447-452. [20] Elliott CG, Hihunen SJ, Suchyta M, et al. Physician-guided treatment compared with a heparin protocol for deep vein thrombosis. Arch Intern Med 1994;154:999-1004. [21] Decousus HA, Croze M, Levi FA, et al. Circadian changes in anticoagulant effect of heparin infused at a constant rate. Br Med J 1985;290:341-344. [22] Krulder JWM, Van den Besselaar AMHP, Van der Meer FJM, Meinders AE, Bri8t E. Diurnal changes in heparin effect during continuous constant rate infusion. A study in nine patients with venous thromboembolism. J Intern Med 1994;235:411-417. [23] Lensing AWA, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparms. A meta-analysis. Arch Intern Med 1995;155:601-607. 124) Huisman MV, Butler HR. Ten Catc JW, et al. Unexpected high prevalence of silent ptdrnonary embolism in patients with deep venous thrombosis. Chest 1989;95:498-502.