The importance of stable therapeutic INR in oral anticoagulation

Valve thrombosis, thromboembolism and bleeding together account for approximately 75% of the complications experienced by patients with prosthetic heart valves. Not all are prosthesis-related, as there is a ‘background incidence’ of stroke/TIA and major bleeding in the general population, rising gradually with age. Nevertheless, despite published guidelines on anticoagulation management, many events occur as the result of under-anticoagulation, over-anticoagulation or very variable anticoagulation.

Using a large prosthetic valve database based on the Medtronic Hall valve, with prospective follow-up data on 1,476 patients undergoing single valve replacement, the relationship between INR variability and outcome was explored. The database contained 10,203 follow-up years and 82,297 INR values for these patients.

Linearised rates for late death rose progressively with increasing decile of anticoagulation variability (ACV) for both aortic and mitral valve replacement (2.7%/yr and 3.3%/yr respectively in deciles 1  and  2 up to 9.5%/yr and 14.6%/yr  respectively in deciles 6 – 10; p < 0.001).  Survival at 15 years after valve replacement was 59% for low ACV (deciles 1 and 2), 55% for intermediate ACV (decile 3) and 28% for high ACV (deciles 4 – 10);  survival at 15 years after mitral valve replacement was 56%, 42% and 24% respectively (p < 0.001 between low/intermediate ACV and high ACV for both aortic and mitral valve replacement).  On multivariate analysis, significant predictors of reduced survival were ACV per 20% increase (hazard ratio 1.8), diabetes (hazard ratio 1.6), decade of age (hazard ratio 1.6), concomitant CABG (hazard ratio 1.5), male sex (hazard ratio 1.4), hypertension (hazard ratio 1.4), NYHA class 3 or 4 (hazard ratio 1.3) and non-sinus rhythm (hazard ratio 1.2).  Patients with low ACV who were in sinus rhythm and did not have diabetes, coronary artery bypass grafting or hypertension had survival equal to the age and sex-matched general population at 15 years.  The incidence of valve-related deaths was significantly higher with high ACV compared to low/intermediate ACV for both aortic valve replacement (1.4% vs 0.5%/yr, p < 0.001) and mitral valve replacement (1.5% vs 0.5%/yr, p < 0.001).  By univariate analysis, high ACV was significantly associated with New York Heart Association class III or IV at 5 years post-operatively (p < 0.001) and with age greater than 60 years at the time of the operation (p = 0.002).

High INR variability was thus the most important independent predictor of reduced survival after valve replacement with a mechanical valve. Measures to improve anticoagulation control to achieve stable therapeutic INR levels should reduce event rates and improve survival for patients with prosthetic heart valves. Particularly close supervision is required in elderly patients, patients in heart failure ad patients on multiple medications.

The detailed results of this study were published in the Journal of Thoracic and Cardiovascular Surgery 2002;123:715-723.

Eric G Butchart
Senior Consultant Cardiothoracic Surgeon
University Hospital of Wales

"Living with anticoagulants" World Congress of Cardiology 2006, Barcelona, 
Chairpersons: J.M. Hasenkam( Aarhus), C. Schaefer (Ratingen),
Nonprofit Organisation Symposium organized by ISMAAP (International Self-Monitoring Association for oral Anticaogulated Patients)
September 3rd, 2006