SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991

Can the Bleeding Potential of Low Molecular Weight Heparins be Assessed and Minimized in Postsurgery Prophylaxis?

When a surgical team intends to switch to low molecular weight (LMW) heparin for postoperative prophylaxis of deep vein thrombosis (DVT), it is primarily because they are convinced of the efficacy of the drug. However, another point of interest is the bleeding risk. Thus, two main questions arise: 1. How to assess the bleeding potential of the LMW heparin? The clinical team should be provided all the relevant information obtained in preclinical and clinical studies devoted to this LMW heparin. 2. How to minimize the bleeding risk in patients? This largely depends on the physician's attitude.

HOW TO ASSESS THE RISK? Because LMW heparin is derived from unfractionated heparin, there is presumably a potential for bleeding even if the aim of the development of LMW heparin was to reduce the bleeding effect. Since it has been postulated that the antithrombotic capacity of heparin should be attributed to its anti-Xa activity and the activated partial thromboplastin time (APTT) activity should reflect the undesired hemorrhagic effect,1 LMW heparins should theoretically be high in antithrombotic activity yet low in hemorrhagic effect.

Role of Preclinical Studies From a biochemistry viewpoint, we learned of the antithrombin III (AT III) binding sequence structure of

From the Sanofi Recherche, Gentilly, France. Reprint requests: Dr. Toulemonde, Sanofi Recherche, 9, rue du President Allende, 94256 Gentilly, France.

heparin (pentasaccharide) leading to antithrombotic activity. On the other hand, no definite structure relating to the antihemostatic potential of heparin has yet been described. The anti-Xa to anti-IIa ratio is an interesting concept for in vitro evaluation, possibly reflecting a theoretical safety index; however, in vivo it appears to be of poor interest for two reasons: 1. The anti-Xa activity does not reflect the complete antithrombotic activity nor does the anti-IIa activity reflect the bleeding risk. 2. From an ex vivo viewpoint, this ratio shows great variations according to the dosage used, the route of administration, and, importantly, the time after injection.2 Nevertheless, clear evidence is available to allow the following statements to be made: Adenosine triphosphate plays an antihemostatic role in nontreated subjects and after heparin treatment.3 A hemorrhagic role is played by contaminants, such as ethylene diaminetetraacetic acid, present in some heparin preparations.4 From animal model studies, a reduced hemorrhagic potential of LMW heparins has been shown compared with heparin. In most cases, this was significant mainly at intermediate and high dosages. However, there are biologic differences between the effects produced by different LMW heparin fractions even when using the same model (Fig. 1). Fareed has shown different bleeding activities of different fractions compared with heparin and placebo. Based on this information several conclusions can be made:

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FRANCIS TOULEMONDE, M.D.

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SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991 In the early studies in surgical patients, the results are also rather inconclusive concerning the bleeding risk. In his first study, Kakkar evaluated anti-Xa activity and the bleeding time test in 25 surgical patients.6 Large scatter in the data was observed, and neither the patients with longer bleeding times nor higher anti-Xa levels bled.

LARGE-SCALE STUDIES IN HUMANS

1. There is a clear trend, usually significant, of a lesser bleeding potential of LMW heparin compared with heparin. In combination with a similar antithrombotic activity compared with heparin, LMW heparins reflect a larger therapeutic index than heparin. In other words, LMW heparins are safer than heparin. 2. There are, presumably, differences between different LMW heparin fractions regarding the bleeding potential. Thus, each fraction must be studied individually. 3. It is hazardous to extrapolate biologic effects from animal to human. Moreover, observation, evaluation, and minimization of the bleeding potential appears to be, for the most part, a clinical matter. Although these preclinical studies may not lead to answers to all the questions, they are necessary and they have provided some encouraging results; they have, nevertheless, allowed for the use of LMW heparin in humans.

EARLY STUDIES IN HUMANS The first human studies were performed on healthy volunteers and small groups of patients. In healthy volunteers, the aim of these investigations was to obtain a pharmacokinetic profile and a tolerance evaluation using increasing dosages limited to the first side effect observed.5 Clearly, these kinds of studies are usually poor indicators of the bleeding risk for four main reasons: 1. A small number of subjects are studied 2. The first side effect is not always bleeding 3. Experimental procedures are limited to the bleeding time study for practical reasons 4. Surgical patients are different from healthy volunteers.

Determination of the standard fixed best dosage (SFBD) for prophylaxis Validation of the determined SFBD with subsequent trials.

Standard Fixed Best Dosage Determination A SFBD for prophylaxis is to be determined because prophylaxis must be as simple as possible. This first step, which is critical to the overall development of the drug, is characterized by the following: A limited knowledge of the action of the LMW heparin fraction in humans Use of different dosages in classic dose-finding studies for the determination of the safety to efficacy ratio for each dosage, leading to elimination of high dosages that induce an unacceptable degree of bleeding In these studies bleeding can be expected due to an as yet unknown SFBD. For example, Planes et al.7 presented a typical study. From November 1983 to January 1985, 228 patients operated on for hip replacement were entered into the study. They were divided into four groups receiving different increasing dosages of a LMW heparin, empirically selected (Table 1). Using only clinical criteria, the SFBD for this LMW heparin in this indication was established without any help from anti-Xa activity evaluations. Subsequent trials also using only clinical criteria confirmed the value of this SFBD.

Validation of the Established Standard Fixed Best Dosage An SFBD, valuable only for the fraction used and for the indication tested, must be confirmed by additional

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FIG. 1. Comparative bleeding time. Seven (1-7) low molecular weight heparins (LMWH) were compared with heparin (8) using the same conditions and the same dosage (2.5 mg/kg subcutaneously) and placebo (9).

It is recognized that, at this stage, little is known about the bleeding risk in patients. It is the role of large-scale studies to try to define this. These studies can be divided into two steps:

BLEEDING POTENTIAL OF LMWH—TOULEMONDE

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TABLE 1. Typical Study of 2 2 8 Patients* High Dose

Lower Dose

Group I (Daily)

Group II (Twice Daily)

Group III (Daily)

Group IV (Twice Daily)

No.

50

28

50

100

Local hematomas (%)

12

22

6

2

6

8

8

8

DVT total (%)

clinical trials. Concerning the bleeding risk, two points are to be emphasized: 1. Surgery itself induces bleeding spontaneously in patients without prophylaxis. Wound hematoma frequency8 and hemoglobin loss9 compared to baseline values are not negligible. 2. Thus, LMW heparin should be compared with a placebo group whenever ethically possible, a method proposed by Claude Bernard as early as 1865.10 Several studies have been published comparing LMW heparin to placebo in general surgery," in hip surgery, 12,13 and prostatectomy.14 The common conclusion of these types of studies can be expressed as follows. When an SFBD is well defined, the results concerning the bleeding induced by the LMW heparin are not statistically different from that of the placebo.

How to Reduce the Risk?

body weight.17 Whether it is correlated to the bleeding risk remains speculative. This suggests that body weight should be taken into consideration for the dosage determination in the extreme cases. However, in elective general surgery and also in orthopedic surgery (hips),7,18 anti-Xa levels seem to be of no interest19 for two main reasons: 1. Per se, anti-Xa levels do not reflect the bleeding risk. Samama observed the same bleeding rate (12 to 13%) in patients with mean anti-Xa levels of 0.08 U/ml (heparin) and 0.46 U/ml (LMW heparin), a sixfold higher plasma level (Fig. 2). 20,21 2. In comparative trials, there was no correlation between bleeding and anti-Xa levels.22 Either the same anti-Xa was found in bleeders and nonbleeders receiving the same prophylaxis with SFBD Fraxiparine23 (Fig. 3) or the same bleeding was observed despite different anti-Xa levels24 (Fig. 4). The common conclusions of these trials could be the comment of Cade et al.25 (using three dosages of the

Minimization of the bleeding risk in surgical patients depends on the physician's attitude.

The Proposed Approach Is Simple History and clinical examination of the patient are of utmost importance. In a recent review, Samama15 concluded that this was, by far, much superior to systematic biologic investigation in detecting gross abnormalities. If some doubts remain, APTT could be of very limited help.16 One should then use the SFBD established for the given LMW heparin for the given indication. All large clinical trials have followed this procedure.

Another Possible Approach Another approach is to include patient monitoring using an anti-Xa assay. It has been shown that the biologic activity, at least anti-Xa, is correlated to the

FIG. 2. Comparison of mean anti-Xa plasma level and clinically important bleeding (%). Data from three different clinical trials comparing subcutaneous heparin (constant dosage) versus low molecular weight heparin (LMWH; three different dosages) are shown. UF: unfractionated.

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*The same dosage (high or lower) was injected once a day or divided into two injections. The regimen of group II was interrupted due to a high percentage of bleeding. Group III was selected as a simpler mode of administration than group IV.

SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991

FIG. 3. Relationship between the mean anti-Xa plasma level and bleeding during prophylaxis using a constant dosage. Patients were stratified according to their mean anti-Xa level. There was no shift to the right in the bleeding group (lower area) compared with the nonbleeding group.

heparinoid ORG 10172 versus placebo in prostatectomy): "The plasma AXa levels did not correlate with DVT nor with bleeding indices. It seems of value only in indicating the presence of circulating material rather than facilitating individual patient control."

DISCUSSION 1. Data in the literature mixed together the common LMW heparins, a very low molecular weight fragment (CY 222) and an heparinoid (ORG 10172) which is not

a LMW heparin. It seems, however, that the general conclusions were acceptable. 2. It is commonly agreed that specific anti-Xa activity does not accurately reflect the bleeding risk (nor the antithrombotic activity in prophylaxis). Heparin and LMW heparin are polycomponent drugs possessing numerous activities, which probably relate to the bleeding and antithrombotic clinical effects. 3. It is true, obviously, that the more product injected, the higher the bleeding risk, in animals as well as in humans. 4. To minimize the bleeding risk, many studies have been performed to establish an SFBD for each fraction for each of its main indications. When well defined, the SFBD induces a bleeding risk close to that observed in a placebo group, often due to the underlying disease of a particular patient. This is the reason why a careful examination of the patient preoperatively is one of the best means of reducing the bleeding risk in the postoperative period. 5. If monitoring of prophylactic treatments with LMW heparin appears useless, laboratory testing of a few particular cases using the anti-Xa assay could be of interest to detect major hemostatic defects, dosage errors, individual hypersensitivity, or unusual drug accumulation.26 If this prevents even some of these treatment complications, the expense and energy spent would be very cost effective.27

CONCLUSION The great number of patients included in studies designed to establish individual SFBDs and a careful examination of the patient constitute the two main guarantees against bleeding in the perioperative period for patients subjected to LMW heparin prophylaxis. To date, there is no evidence that the conventional bioassays could be of help in general monitoring of LMW heparin prophylaxis.19 However, there is nothing to prohibit one from performing laboratory assays in special cases when the clinical condition is worrisome. The safe upper limit of anti-Xa plasma levels appears to be around 0.2 U/ml (chromogenic method).26

REFERENCES FIG. 4. Relationship between mean anti-Xa plasma levels and urinary blood loss after prostatectomy. In column 3 (bladder washout during day 1) there was no difference in blood loss between the three different dosage groups. The higher dosage (750 U twice daily (bid)) was found to be effective and safe for prophylaxis by Cade et al.25 Anti-Xa was performed with a chromogenic method using ORG 10172 as a standard. Hbg: hemoglobin.

1. Holmer E, K Soderberg, D Bergqvist, U Lindahl: Heparin and its low molecular weight derivatives—anticoagulant and antithrombotic properties. Hemostasis 16 (Suppl 2): 1-7, 1986. 2. Cambus JP, FToulemonde, B Bayrou, R Bierme: Anti-Xa/anti-IIa ratio variations for LMW heparin fragment—a study in healthy volunteers. Tenth International Congress on Thrombosis (Mediterranean League). (Abst.) 1988, p 216.

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3. Nader HB, LS Ivarne, Tersariol, CP Dietrich: Antihemostatic activity of heparin disaccharides and oligosaccharides obtained by chemical fragmentation: Reversal of the hemorrhagic activity by ATP and myosin. Thromb Res 54:207-214, 1989. 4. Casu B, A Naggi, P Oreste, G Torri, J Pangrazzi, A Maggi, M Abbadini, MB Donati: Bleeding associated with heparin contaminant. Lancet 1:1088, 1987. 5. Colburn WA: Controversy V. Phase I, first time in man studies. J Clin Pharmacol 30:210-222, 1990. 6. Kakkar VV, B Djazaeri, J Fok, H Scully, J Westwick: Low molecular weight heparin and the prevention of post operative deep venous thrombosis. In: Witt, I (Ed). Heparin New Biochemical and Medical Aspects. W. de Gruyter, Berlin, 1982, pp 175-206. 7. Planes A, N Vochelle, J Ferru, D Pczyrowski, J Clerc, M Fagola, M Planes: Enoxaparin LMW heparin: Its use in the prevention of deep vein thrombosis following total hip replacement. Heamostasis 16:152-158, 1986. 8. Jourdan M, I Mc Coll: The use of prophylactic subcutaneous heparin in patients undergoing hernia repairs. Br J Clin Pract 38:298-300, 1984. 9. Sasahara A, H Koppenhagen, D Welzel, H Wolf: Low molecular weight heparin plus dihydro-ergotamine for prophylaxis of postoperative deep vein thrombosis. Br J Surg 73:697-700, 1986. 10. Bernard C: Introduction á la médecine expérimentale (1865). In: Hatier J (Ed): Introduction a La Médecine Expérimentale. Paris, 1944, p 112. 11. Ockelford PA, J Patterson, AS Johns: A double blind randomized placebo controlled trial on prophylaxis in major general elective surgery using once daily injections of LMW heparin fragment (fragmin). Thromb Heamost 62(4): 1046-1049, 1989. 12. Turpie AGG, MN Levine, J Hirsh, CJ Carter, MBBS Richard, RM Jay, PJ Powers, M Andrew, RD Hull, M Gent: A randomized controlled trial of a low molecular weight heparin (enoxaparine) to prevent deep vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 315:925-929, 1987. 13. Torholm C, JG Knudsen, PS Jorgensen, P Bjerregaard, PK Jorgensen, K Hagen, L Josefson: Thromboprophylactic effect of a low molecular weight heparin (fragmin) in elective hip surgery. A placebo controlled study. (Abst. 1533) Thromb Heamost 1:62, 1989. 14. Le Gagneux F, A Steg, M Le Guillou: Subcutaneous enoxaparine versus placebo for preventing DVT after transurethral prostatectomy (TURP). Thromb Heamost (Abst. 413) 1:58, 1987. 15. Samama CM: Bilan d'hémostase préopératoire—Quoi de neuf? In: Journées Enseignement Post Universitaire Anesthesiologie Arnette, Paris, 1990, p. 105-112. 16. Suchman AL, Al Mushlin: How well does the APTT predict postoperative hemorrhage? JAMA 256:750-753, 1986.

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17. Vitoux JF, M Aiach, M Roncato, JN Fressinger: Should thromboprophylaxis dosage of low molecular weight heparin be adopted to patients' weight? Thromb Heamost 59:120, 1988. 18. Leyvraz PF, M Postel: Prévention des accidents thrombo-emboliques en chirurgie prothétique de la hanche (Fraxiparine versus heparine standard en doses ajustées). Etude multicentrique européenne randomisée. Bonnameaux H, M Samama, JW Ten Cate (Eds.): Fraxiparine. Second Symposium International, Monte Carlo. Schattauer, Stuttgart 1989. 19. Hoppensteadt D, A Encke, K Breddin, JM Walenga, N Bender, J Fareed: Intérêt des activités AXa et AIIa et d'autres paramétres biologiques dans l'évaluation de l'efficacité clinique de la Fraxiparine. In K Breddin, J Fareed, M Samama (Eds): Fraxiparine: First International Symposium, Paris. III-121. Schattauer, Stuttgart, 1987, III-121. 20. Samama M, P Bernard, JP Bonnardo, S Combe-Tamzali, Y Lanson, E Tissot: LMW heparin in prevention of post operative thrombosis. Br J Surg 75:128-131, 1988. 21. Samama M: Correlation between anti-Xa activity and occurrence of DVT and hemorrhage in post-surgical patients treated with either logiparin or standard heparin. (Abst. 1470). Thromb Heamost 1:62, 1989. 22. Ten Cate H, CP Henny, JW Ten Cate, HR Buller, NF Dabhoiwala: Randomized double blind study, placebo controlled safety study of a LMW heparinoid in patients undergoing trans-urethral resection of the prostate. Thromb Heamost 57:92-96, 1987. 23. Potron GM, H Choisy, CL Droulle, PV Nguyen, JJ Vaissie, FX Frapaise: Suivi prospectif post-marketting de la fraxiparine á reims. Breddin K, Fareed J, Samama M (Eds): Fraxiparine. First International Symposium, Schattauer, Stuttgart 1989. 24. Gallus A, W Murphy, J Nacey, M Morris, P Sutherland, V Marshall, H Magnani: The influence of ORG 10172, an antithrombotic heparinoid, on urinary blood loss after transurethral prostatectomy. Thromb Res 56:229-238, 1989. 25. Cade JF, M Wood, HN Magnani, GW Westlake: Early clinical experience of a new heparinoid ORG 10172 in prevention of deep vein thrombosis. Thromb Res 45:497-503, 1987. 26. Redelmeier DA, A Tersky: Discrepancy between medical decisions for individual patients and for groups. N Engl J Med 322:1162-1164, 1990. 27. Abildgaard U: Monitoring heparin treatment. In: Lane DA, U Lindahl (Eds): Heparin Chemical and Biological Properties— Clinical Applications. Edward Arnold, London, 1989, pp 495515. 28. Turpie AGG: The relationship between ex-vivo anti-factor Xa levels and efficacy/safety of low molecular weight heparin. Br J Clin Pract 43(Suppl 65): 18-25, 1989.

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BLEEDING POTENTIAL OF LMWH—TOULEMONDE

Can the bleeding potential of low molecular weight heparins be assessed and minimized in postsurgery prophylaxis?

SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991 Can the Bleeding Potential of Low Molecular Weight Heparins be Assessed and Minimized in...
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