Elderly Patients Treated with Tinzaparin (Innohep^®) Administered once Daily (175 Anti-Xa IU/kg): Anti-Xa and Anti-IIa Activities over 10 Days

 

 Buy Article Permissions and Reprints

Summary

Since low molecular weight heparins (LMWH) are partly eliminated by renal excretion, their pharmacodynamic profile may be modified in very elderly patients with age-related renal impairment. The aim of this prospective study was to determine whether tinzaparin (Innohep^®) 175 anti-Xa IU/kg administered subcutaneously once daily over 10 days does accumulate in hospital patients greater than 70 years of age. Plasma anti-Xa and anti-IIa amidolytic levels and APTT were determined prior to the first injection (day 0), and then, at peak level i.e. 5 h after the second injection (day 2) and subsequently on days 5, 7 and 10.

Thirty consecutive inpatients (6 men, 24 women) requiring LMWHs at a curative dose for acute thromboembolic disease were included. Patients’ characteristics (mean ± SD) were: age 87.0 ± 5.9 years (range 71–96), body weight 62.7 ± 14.6 kg (range 38-90) and creatinine clearance 40.6 ± 15.3 mL/min (range 20–72). The mean actual dose of tinzaparin delivered was 174.8 anti-Xa IU/kg. Since no patient had an anti-Xa activity above 1.5 IU/mL, the dose of tinzaparin remained fixed over 10 days.

Anti-Xa and anti-IIa peak levels measured on day 2 were 0.66 ± 0.20 IU/mL (range 0.26–1.04) and 0.33 ± 0.10 IU/mL (range 0.18–0.55), respectively. Ex vivo anti-Xa/anti-IIa ratios were close to 2.1. APTT ratios (patient/control) were strongly correlated with anti-IIa activity (p <0.01). There was no progressive increase of the anti-Xa and anti-IIa activities after repeated administration of tinzaparin over the 10 day treatment period. No correlation was found between anti-Xa and anti-IIa activities and age, weight, or creatinine clearance. No major bleeding occurred during the study and only one minor haematoma at the injection site was reported. No thromboembolic complication or death occurred.

Tinzaparin may thus be administered safely at a treatment dose (175 anti-Xa IU/kg) in older patients with age-related renal impairment. Neither dose adjustment, nor serial anti-Xa activity monitoring seems to be required in patients with creatinine clearance above 20 mL/min during the first ten day treatment.

• References

• 1 Kessler CM. Low molecular weight heparins: practical considerations. Sem Hematol 1997; 34: 35-42.
  PubMedGoogle Scholar
• 2 Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and a low molecular weight heparin. Chest 1998; 114: 489S-510S.
  CrossrefPubMedGoogle Scholar
• 3 Alhenc-Gelas M, Jestin-Le Guernic C, Vitoux JF, Kher A, Aiach M, Fiessinger JN. for the Fragmin-Study Group. Adjusted versus fixed doses of the low molecular weight heparin Fragmin^® in the treatment of deep vein thrombosis. Thromb Haemost 1994; 71: 698-702.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Boneu B. Low molecular weight heparin therapy: is monitoring needed?. Thromb Haemost 1994; 72: 330-4.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lerner RG, Hall J, Sparling T, Brettell HR, Norton J, Carter CJ, George R, Merli G, Ward J, Mayo W, Rosenbloom D, Brant R. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82.
  CrossrefPubMedGoogle Scholar
• 6 Lindmarker P, Holmström M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin^® with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 72: 186-90.
  Article in Thieme ConnectPubMedGoogle Scholar
• 7 Fiessinger JN, Lopez-Fernandez M, Gatterer E, Granqvist S, Kher A, Olsson CG, Söderberg K. Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996; 76: 195-9.
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Luomanmäki K, Grankvist S, Hallert C, Jauro I, Ketola K, Kim HC, Kiviniemi H, Koskivirta H, Sörskog L, Vilkko P. A multicentre comparison of once-daily subcutaneous dalteparin (low molecular weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Intern Med 1996; 240: 85-92.
  CrossrefPubMedGoogle Scholar
• 9 Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, Laurent M, Hirsh JL, Ferrari E, Bosson JL, Mottier D, Beau B. for the Thésée Study Group. A comparison of low-molecular-weight heparin for acute pulmonary embolism. N Engl J Med 1997; 337: 663-9.
  CrossrefPubMedGoogle Scholar
• 10 Charbonnier BA, Fiessinger JN, Banga JD, Wenzel E, d’Azemar P, Sagnard L. on behalf of the Fraxodi group. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. Thromb Haemost 1998; 79: 897-901.
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 1992; 22: 359-74.
  CrossrefPubMedGoogle Scholar
• 12 Epstein M. Aging and the kidneys. J Am Soc Nephrol 1996; 07: 1106-22.
  PubMedGoogle Scholar
• 13 Mismetti P, Laporte-Simitsidis S, Navarro C, Sié P, d’Azemar P, Necciari J, Duret JP, Gaud C, Decousus H, Boneu B. Aging and venous thromboembolism influence the pharmacodynamics of the anti-factor Xa and antithrombin activities of a low molecular weight heparin (nadroparin). Thromb Haemost 1998; 79: 1162-5.
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 Heilmann JJ. Pharmacokinetic parameters of Innohep^® 175 IU/kg/day in healthy volunteers and in patients with deep vein thrombosis. Personal communication.
  PubMedGoogle Scholar
• 15 Cockroft DW, Gault MN. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
  CrossrefPubMedGoogle Scholar
• 16 Larsen ML, Abilgaard U, Teien AN, Gjesdal K. Assay of plasma heparin using thrombin and the chromogenic substrate H-D-Phe-Pip-Arg-pNA (S-2238). Thromb Res 1978; 13: 285-8.
  CrossrefPubMedGoogle Scholar
• 17 Campbell NRC, Hull RD, Brant R, Hogan DB, Pineo GF, Raskob GE. Aging and heparin-related bleeding. Arch Intern Med 1996; 156: 857-60.
  CrossrefPubMedGoogle Scholar
• 18 Mätzsch T, Bergqvist D, Hedner U, Østergaard P. Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers. Thromb Haemost 1987; 57: 97-101.
  Article in Thieme ConnectPubMedGoogle Scholar