A Method to Determine the Optimal Intensity of Oral Anticoagulant Therapy

Summary

Oral anticoagulant therapy has been shown to be effective for several indications. The optimal intensity of anticoagulation for each indication, however, is largely unknown. To determine this optimal intensity, randomised clinical trials are conducted in which two target levels of anticoagulation are compared. This approach is inefficient, since the choice of the target levels will be arbitrary. Moreover, the achieved intensity is not taken into account.

We propose a method to determine the optimal achieved intensity of anticoagulation. This method can be applied within a clinical trial as an “efficacy-analysis”, but also on data gathered in day-to-day patient care.

In this method, INR-specific incidence rates of events, either thromboembolic or hemorrhagic, are calculated. The numerator of the incidence rate is based on data on the INR at the time of the event. The denominator consists of the person-time at each INR value, summed over all patients, and is calculated from all INR measurements of all patients during the follow-up interval. This INR-specific person-time is calculated with the assumption of a linear increase or decrease between two consecutive INR determinations. Since the incidence rates may be substratified on covariates, efficient assessment of the effects of other factors (e.g. age, sex, comedication) by multivariate regression analysis becomes possible.

This method allows the determination of the optimal pharmacological effects of anticoagulation, which can form a rational starting point for choosing the target levels in subsequent clinical trials.

• References

• 1 Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865-1875
• 2 International Committee for Standardization in Haematology, International Committee on Thrombosis and Haemostasis. ICSH/ICTH recommendations for reporting prothrombin time in oral anticoagulant control. Thromb Haemostas 1985; 53: 155-156
• 3 Turpie AGG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988; i: 1242-1245
• 4 Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities on anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-432
• 5 Breslow NE, Day NE. Statistical Methods in Cancer Research: II. The Design and Analysis of Cohort Studies. IARC, Lyon 1987; 48-79
• 6 Rothman KJ. Modern Epidemiology. Little, Brown and Company. Boston 1986: 23-31
• 7 Cannegieter SC, Rosendaal FR, Briët E. The optimal intensity of oral anticoagulation therapy in patients with prosthetic heart valves (abstract). Thromb Res 1992; 65 (Suppl. 00) 80
• 8 Van der Meer FJM, Rosendaal FR, Vandenbroucke JP. Briet EBleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med. 1993 (in press).