Skip to main content
SpringerLink
Log in

Argatroban Anticoagulation for Heparin-Induced Thrombocytopenia in Elderly Patients

  • Original Research Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Background

Argatroban, a direct thrombin inhibitor that has reduced clearance in elderly versus younger volunteers, is used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT).

Objective

To evaluate the effect of aging on argatroban therapy, including dosage, anticoagulant responses, clinical outcomes and factors influencing those responses, in elderly patients with HIT or a history of HIT.

Methods

This was a retrospective multicentre database analysis of 118 inpatients treated with argatroban at six medical centres between August 2001 and January 2005. Sixty-two adults aged ≥;65 years were administered argatroban for clinically diagnosed HIT (n = 54) or a history of HIT (n = 8). Argatroban infusion was adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5–3 times baseline. All study measures and analyses were prospectively defined. Argatroban dosage patterns, aPTTs and platelet count responses, and 37-day outcomes (death, amputation, new thrombosis, major bleeding) were summarised for patients stratified by age (65–74 years [n = 31]; 75–84 years [n = 26]; ≥85 years [n = 5]) to identify possible age-related trends. Regression analyses explored relationships between dose and patient age, liver function and renal function. Cox proportional hazards models evaluated the effect of age, dose, gender, aPTT and platelet count on the risk of new thrombosis.

Results

In each age group, the median argatroban dosage was initially 1.0 µg/kg/min and was generally maintained at or near that dose during therapy (median, 5–7 days). Therapeutic aPTTs occurred within 11.5 hours; the median aPTT during therapy was 54.7 seconds, without obvious trend by age. By regression analysis, the initial and mean argatroban dosages decreased 0.08–0.09 µg/kg/min with each 0.2 mg/dL increase in serum creatinine, but no association was detected between dose and patient age, serum total bilirubin, calculated creatinine clearance or blood urea nitrogen. Platelet counts recovered within 6–7 days of initiating therapy, without apparent trend by age. No patient experienced amputation or major bleeding, and no patient in the oldest group died or had new thrombosis. Overall, 13 (21%) patients died (9 in the 65–74 years group; 1 receiving argatroban) and 5 (8%) had new thrombosis (4 in the 65–74 years group; 2 receiving argatroban), comparing favourably with previously reported rates, irrespective of patient age. By univariate (but not multivariate) analysis, the risk of new thrombosis decreased with increasing argatroban dose (hazard ratio 0.020; 95% CI 0.001, 0.757; p = 0.035). No effect of age or the other covariates considered on thrombotic risk was detected.

Conclusion

Argatroban at a median initial dosage of 1.0 µg/kg/min, adjusted to achieve median aPTTs of 54.7 seconds during therapy, generally provided safe, adequate anticoagulation across a wide age range in elderly patients with HIT or a history of HIT. In these elderly patients, age was not a significant determinant of argatroban dosage or thrombotic risk. Prospective evaluation of this initial dose of argatroban in the elderly is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig. 1
Table III

Similar content being viewed by others

References

  1. DeLoughery TG. Critical care clotting catastrophes. Crit Care Clin 2005 Jul; 21(3): 531–62

    Article  PubMed  Google Scholar 

  2. Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update. Thromb Res 2006; 118(2): 165–76

    Article  PubMed  CAS  Google Scholar 

  3. Jang IK, Hursting MJ. When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation 2005 May 24; 111(20): 2671–83

    Article  PubMed  Google Scholar 

  4. Tardy-Poncet B, Tardy B. Heparin-induced thrombocytopenia: minimising the risks in the elderly patient. Drugs Aging 2000 May; 16(5): 351–64

    Article  PubMed  CAS  Google Scholar 

  5. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulation therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103: 1838–43

    Article  PubMed  CAS  Google Scholar 

  6. Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003 Aug 11–25; 163(15): 1849–56

    Article  PubMed  CAS  Google Scholar 

  7. Nand S, Wong W, Yuen B, et al. Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol 1997 Sep; 56(1): 12–6

    Article  PubMed  CAS  Google Scholar 

  8. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996 Nov; 101(5): 502–7

    Article  PubMed  CAS  Google Scholar 

  9. Bartholomew JR. The incidence and clinical features of heparin-induced thrombocytopenia. Semin Hematol 2005 Jul; 42 (3 Suppl. 3): S3–8

    Article  PubMed  Google Scholar 

  10. Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med 2004 Feb 23; 164(4): 361–9

    Article  PubMed  CAS  Google Scholar 

  11. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention. Chest 2004; 126: 311S–37S

    Article  PubMed  CAS  Google Scholar 

  12. Keeling D, Davidson S, Watson H. The management of heparin-induced thrombocytopenia. Br J Haematol 2006 May; 133(3): 259–69

    Article  PubMed  CAS  Google Scholar 

  13. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001 Apr 26; 344(17): 1286–92

    Article  PubMed  CAS  Google Scholar 

  14. Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135: 502–6

    PubMed  CAS  Google Scholar 

  15. Escolar G, Bozzo J, Maragall S. Argatroban: a direct thrombin inhibitor with reliable and predictable anticoagulant actions. Drugs Today (Barc) 2006 Apr; 42(4): 223–36

    Article  CAS  Google Scholar 

  16. Matthai Jr WH, Hursting MJ, Lewis BE, et al. Argatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia. Thromb Res 2005; 116(2): 121–6

    Article  PubMed  CAS  Google Scholar 

  17. Levine R, Hursting MJ, McCollum D. Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction. Chest 2006; 129(5): 1167–75

    Article  PubMed  CAS  Google Scholar 

  18. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000 Mar; 20(3): 318–29

    Article  PubMed  CAS  Google Scholar 

  19. Baghdasarian S, Singh I, Militello M, et al. Argatroban dosage in critically ill patients with HIT [abstract]. Blood 2004; 104(11): 493a

    Google Scholar 

  20. Koster A, Buz S, Hetzer R, et al. Anticoagulation with argatroban in patients with heparin-induced thrombocytopenia antibodies after cardiovascular surgery with cardiopulmonary bypass: first results from the ARG-E03 trial. J Thorac Cardiovasc Surg 2006 Sep; 132(3): 699–700

    Article  PubMed  Google Scholar 

  21. Zahn R, Hamm CW, Schneider S, et al. Predictors of death or myocardial infarction during follow-up after coronary stenting with the sirolimus-eluting stent: results from the prospective multicenter German Cypher Stent Registry. Am Heart J 2006; 152(6): 1146–52

    Article  PubMed  CAS  Google Scholar 

  22. Bhattacharya S, Saha SP, Basu A, et al. A 5-years prospective study of incidence, morbidity and mortality profile of stroke in a rural community of eastern India. J Indian Med Assoc 2005; 103(12): 655–9

    PubMed  Google Scholar 

  23. Kaushik S, Tan AG, Mitchell P, et al. Prevalence and associations of enhanced retinal arteriolar light reflex: a new look at an old sign. Ophthalmology 2007; 114(1): 113–20

    Article  PubMed  Google Scholar 

  24. De Lusignan S, Hague N, van Vlymen J, et al. A study of cardiovascular risk in overweight and obese people in England. Eur J Gen Pract 2006; 12(1): 19–29

    Article  PubMed  Google Scholar 

  25. Maio V, Yuen EJ, Novielli K, et al. Potentially inappropriate medication prescribing for elderly outpatients in Emilia Romagna, Italy: a population-based cohort study. Drugs Aging 2006; 23(11): 915–24

    Article  PubMed  Google Scholar 

  26. Duh MS, Mody SH, McKenzie RS, et al. Dosing patterns and treatment costs of erythropoietic agents in elderly patients with pre-dialysis chronic kidney disease in managed care organizations. Drugs Aging 2006; 23(12): 969–76

    Article  PubMed  CAS  Google Scholar 

  27. Egger SS, Bachmann A, Hubmann N, et al. Prevalence of potentially inappropriate medication use in elderly patients: comparison between general medical and geriatric wards. Drugs Aging 2006; 23(10): 823–37

    Article  PubMed  Google Scholar 

  28. Schiff MH, Yu EB, Weinblatt ME, et al. Long-term experience with etanercept in the treatment of rheumatoid arthritis in elderly and younger patients: patient-reported outcomes from multiple controlled and open-label extension studies. Drugs Aging 2006; 23(2): 167–78

    Article  PubMed  CAS  Google Scholar 

  29. Saab YB, Hachem A, Sinno S, et al. Inappropriate medication use in elderly Lebanese outpatients: prevalence and risk factors. Drugs Aging 2006; 23(9): 743–52

    Article  PubMed  Google Scholar 

  30. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16(1): 31–41

    Article  PubMed  CAS  Google Scholar 

  31. Cox D. Regression models and life tables. J Royal Stat Soc Series B 1972; 24: 187–220

    Google Scholar 

  32. Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759–65

    Article  PubMed  CAS  Google Scholar 

  33. Swan SK, St Peter JV, Lambrecht LJ, et al. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects. Pharmacotherapy 2000; 20: 756–70

    Article  PubMed  CAS  Google Scholar 

  34. Arpino PA, Hallisey RK. Effect of renal function on the pharmacodynamics of argatroban. Ann Pharmacother 2004; 38: 25–9

    Article  PubMed  CAS  Google Scholar 

  35. Smythe M, Stephens JL, Koerber JM, et al. A comparison of lepirudin and argatroban outcomes. Clin Appl Thromb Hemost 2005; 11: 371–4

    Article  PubMed  CAS  Google Scholar 

  36. Kiser TH, Jung R, MacLaren R, et al. Evaluation of diagnostic tests and argatroban or lepirudin therapy in patients with suspected heparin-induced thrombocytopenia. Pharmacotherapy 2005; 25: 1736–45

    Article  PubMed  CAS  Google Scholar 

  37. Kodityal S, Nguyen PH, Kodityal A, et al. Argatroban for suspected heparin-induced thrombocytopenia: contemporary experience at a large teaching hospital. J Intensive Care Med 2006; 21: 86–92

    Article  PubMed  Google Scholar 

  38. Murray PT, Reddy BV, Grossman EJ, et al. A prospective study of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int 2004; 66: 2446–53

    Article  PubMed  CAS  Google Scholar 

  39. Tang IY, Cox DS, Patel K, et al. Argatroban and renal replacement therapy in patients with heparin-induced thrombocytopenia. Ann Pharmacother 2005; 39: 231–6

    Article  PubMed  CAS  Google Scholar 

  40. Guzzi LM, Hursting MJ, McCollum DA. Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2006; 22: 169–76

    Article  PubMed  CAS  Google Scholar 

  41. Davoren A, Aster RH. Heparin-induced thrombocytopenia and thrombosis. Am J Hematol 2006 Jan; 81(1): 36–44

    Article  PubMed  CAS  Google Scholar 

  42. Arepally GM, Ortel TL. Clinical practice: heparin-induced thrombocytopenia. N Engl J Med 2006 Aug 24; 355(8): 809–17

    Article  PubMed  CAS  Google Scholar 

  43. Alving BM. How I treat heparin-induced thrombocytopenia and thrombosis. Blood 2003; 101(1): 31–7

    Article  PubMed  CAS  Google Scholar 

  44. Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia, 3rd ed. New York (NY): Marcel Dekker, 2004: 335–70

    Google Scholar 

  45. Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis 2005 Jun; 19(3): 183–8

    Article  PubMed  CAS  Google Scholar 

  46. Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2005 Jul 2005; 11(3): 279–87

    Article  CAS  Google Scholar 

  47. Harder S, Graff J, Klinkhardt U, et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and ecarin clotting time. Thromb Haemost 2004 Jun; 91(6): 1137–45

    PubMed  CAS  Google Scholar 

  48. Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001 Mar; 85(3): 435–40

    PubMed  CAS  Google Scholar 

  49. Srinivasan AF, Rice L, Bartholomew JR, et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med 2004 Jan 12; 164(1): 66–70

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by GlaxoSmithKline (GSK). GSK personnel offered critical comment on the statistical analysis plan and draft manuscript. The acceptance or rejection of the suggestions was fully at the authors’ discretion, as was the decision to submit the manuscript for publication.

Dr Bartholomew has been a speaker for GSK. Dr Hursting has received consultancy fees from GSK. Dr Pietrangeli has no conflicts of interest that are directly relevant to the content of this study.

The authors express their gratitude to David A. McCollum, MS, for his assistance with the statistical analysis, Eliezer Katz, MD, FACS, for his critical comments and Jenna Tincher-Mann, BA, for her editorial assistance.

Author information

Authors and Affiliations

  1. The Cleveland Clinic, Cleveland, Ohio, USA

    John R. Bartholomew

  2. CTI Clinical Trial and Consulting Services, Cincinnati, Ohio, USA

    Carolynn E. Pietrangeli

  3. Clinical Science Consulting, Austin, Texas, USA

    Marcie J. Hursting

Authors
  1. John R. Bartholomew
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carolynn E. Pietrangeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcie J. Hursting
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John R. Bartholomew.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bartholomew, J.R., Pietrangeli, C.E. & Hursting, M.J. Argatroban Anticoagulation for Heparin-Induced Thrombocytopenia in Elderly Patients. Drugs Aging 24, 489–499 (2007). https://doi.org/10.2165/00002512-200724060-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002512-200724060-00005

Keywords

Search

Navigation