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Rapid Responses: Rapid Responses published:
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ISI for INR values in oral anticoagulation
- Robert S. Richmond, Knoxville TN 37922 USA (9 November 2002)
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Oral anticoagulation for antiphospholipid syndrome
- Gianfranco Ciboddo, Anna Borri M.D. , Cristina Idone M.D. ,Maria Vittoria Lavorato M.D. (4 December 2002)
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Could ambitious therapeutic ranges be counter-productive?
- Martin Utley, David Patterson, Steve Gallivan (19 December 2002)
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Did the anticoagulants cause deaths by inducing mitochondrial dysfuinction?
- Richard G Fiddian-Green (20 December 2002)
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Cause or coincidence? A mortality study of patients on oral anticoagulant therapy.
- VANESSA J MARTLEW, Ewan Wilkinson (3 March 2003)
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High INR-values responsible for adverse events
- Steinar Madsen, Anne B. Breen, Trine E. Vaskinn, Aasmund Reikvam, Eva Skovlund, Harald Lislevand (7 April 2003)
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Robert S. Richmond, pathologist in private practice (locum tenens practitioner), Knoxville TN 37922 USA
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Do the several Swedish clinics whose prothrombin time INR (International Normalized Ratio) data were used in this study all use the same thromboplastin and the same coagulation instrument? Without this information, the authors' conclusions about INR values cannot be applied without adjustment for patients whose INR's are being determined with different prothrombin time reagents and instruments. In particular, the International Sensitivity Index (ISI), the exponent used in the INR calculation for a particular thromboplastin, makes a difference, since thromboplastins with an ISI over 1.8 give results that result in overanticoagulation of patients. Apparently different instruments also do not always give comparable results. As a 63 year old clinical pathologist doing well and back in practice not quite six months after prosthetic replacement of an aortic valve, I have a considerable personal and professional interest in this topic! Competing interests: None declared |
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Gianfranco Ciboddo, Consultant in Rheumatology Ospedale san Raffaele Via Olgettina 60 20132 Milano Italy, Anna Borri M.D. , Cristina Idone M.D. ,Maria Vittoria Lavorato M.D.
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We read with great interest the paper of Odén and Falhlén about oral anticoagulation and risk of death(1). They suggest to keep the international normalised ratio (INR) between 2.2 and 2.3 to minimise the risk of bleeding. The indications for anticoagulation were atrial fibrillation, venous thrombosis and pulmonary embolism, stroke and transient ischaemic attacks, valve prosthesis and myocardial infarct. We didn't see any reference to patients with the antiphospholipid syndrome (APS). Patients who have had a recent thrombotic event and have moderate to high levels of anti phospholipid antibodies (aPL) are at high risk for recurrent thrombotic events(2). There is general consensus that treatment with anticoagulants is able to decrease the rate of recurrent thrombosis and long-term anticoagulation with warfarin, at a relatively high INR ( > or = 3.0 ), is usually recommended and effective(3). It is true that warfarin at high INR is associated with significant morbidity and occasionally with mortality, but probably the correct therapeutic window for APS is higher than for other indications. We think that an INR of 2.5-3.0 is worth of evaluation in this disease. 1)Odén A, Fahlén M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002; 325: 1073-5 2)Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752-63. 3)Roubey RAS. Treatment of the antiphospholipid syndrome. Curr Opin Rheumatol 2002; 14: 238-42 Competing interests: None declared |
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Martin Utley, Senior Research Fellow Clinical Operational Research Unit, University College London, WC1E 6BT, David Patterson, Steve Gallivan
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Oden and Fahlen [1] present useful information regarding oral anticoagulation and the risk of death and conclude that patients with an international normalised ratio (INR) value in the range 2.2-2.3 are at the lowest risk of death. They go on to suggest that anticoagulation treatment should be less intensive and that the therapeutic window for all patients receiving anticoagulation therapy should be narrower with "INR close to 2.2-2.3". We believe that this latter advice requires further consideration. We analysed 26122 INR measurements representing 1696 patients with the therapeutic range 2.0-3.0. Just 13766 (52.7%) of the INR measurements were in range, a result in broad concurrence with those of other studies [2,3]. The proportion of patients in, above and below therapeutic range changed little with duration of anticoagulation treatment (see figure).
This arguably poor quality of anticoagulation control is certainly not for the want of trying. Rather, the complex pharmacology of warfarin and uncertainty concerning the large number of drugs and medical conditions which may effect warfarin dose-response [4] makes anticoagulation control very challenging. A narrow therapeutic window close to 2.2-2.3 is therefore likely to prove unrealistic and unachievable. Many clinicans would of course claim that they are used to being set unrealistic and unachievable targets. However, it is plausible that attempting to achieve such narrow target ranges could degrade the quality of control delivered to patients. Anticoagulation control has strong parallels with extensively studied control engineering methods [5] that are used in non-medical applications. Such studies suggest that aiming to achieve and maintain INRs within a narrow target range could result in system instability, poorer control and an excessive amount of adjustment. One analogy is the type of system behaviour many novice drivers experience when they first try to steer a car and find that it snakes from side to side despite their increasingly desperate attempts to keep it going in a straight line. In the case of anticoagulation therapy, one is further hampered since the "steering wheel" of dose modification has a patient-specific, non-linear and time-varying response and one's eyes are closed to the results of the "steering" until the next outpatient appointment. By attempting to achieve and maintain INR values within a narrow target INR range, it is conceivable that patients may be subject to excessive dose changes and monitoring. Oden and Fahlen [1] provide an excellent starting point for further investigation of control engineering analysis of anticoagulation therapy. Yours sincerely, Martin Utley, David Patterson, Steve Gallivan References [1] Oden A, Fahlen M, Oral anticoagulation and risk of death: a medical record linkage study, BMJ 2002;325:1073-5 [2] Rose P., Audit of anticoagulant therapy, J Clin Pathol, 1996;48:5 -9 [3] Doble N., Baron J.H., Anticoagulation control with warfarin by junior doctors, J R Soc Med 1987;80:627 [4] Wells PS, Holbrook AM, Crowther NR et al, Interactions of warfarin with drugs and food, Ann Intern Med. 1994;121:676-683. [5] Burghes D, Graham A, Introduction to control theory including optimal control, Chichester, Ellis Horwood, 1980. References Competing interests: � None declared |
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Richard G Fiddian-Green, None None
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Anticoagulants were found in this meta-analysis to be associated with a dose-related increase in death from all causes (1). One possible cause not considered for the deaths, other than those due to the anticoagulation per se, is mitochondrial dysfunction. Anticoagulants may cause mitochondrial damage in lymphocytes (2) and reduce ATP content and impair viability in hepatocytes (3). The adverse effects are independent of the anticoagulant effect for they are not inhibited by vitamin K (4). They appear, rather, to be due to the inhibition of coenzyme Q10 synthesis. Coenzyme Q is essential for normal functioning of the electron transport chain and hence for ATP resynthesis by mitochondrial oxidative phosphorylation. As statins may also inhibit coenzyme Q10 synthesis the adverse effects of anticoagulants in the present study might, therefore, have been greatest in those patients taking stains (5). Chronic heart failure is known to be associated with a depletion of coenzyme Q10 (6) and in preliminary reports coenzyme Q10 supplements improved outcome in patients who had suffered cardiac arrest and those having coronary artery bypass grafting (7,8). 1. Anders Odén and Martin Fahlén Oral anticoagulation and risk of death: a medical record linkage study BMJ 2002; 325: 1073-1075 2. Berkarda B, Arda O, Tasyurekli M, Derman U. Mitochondria-lytic action of warfarin in lymphocytes. Int J Clin Pharmacol Ther Toxicol. 1992 Aug;30(8):277-9 3. Gjerde H, Helgeland L. Effect of warfarin on ATP content, viability, glycosylation and protein synthesis in isolated rat hepatocytes. Acta Pharmacol Toxicol (Copenh). 1984 May;54(5):385-8. 4. Combs AB, Porter TH, Folkers K. Anticoagulant activity of a naphthoquinone analog of vitamin K and an inhibitor of coenzyme Q10- enzyme systems. Res Commun Chem Pathol Pharmacol. 1976 Jan;13(1):109-14 5. Bleske BE, Willis RA, Anthony M, Casselberry N, Datwani M, Uhley VE, Secontine SG, Shea MJ. The effect of pravastatin and atorvastatin on coenzyme Q10. Am Heart J. 2001 Aug;142(2):E2. 6. Mortensen SA, Vadhanavikit S, Muratsu K, Folkers K. Coenzyme Q10: clinical benefits with biochemical correlates suggesting a scientific breakthrough in the management of chronic heart failure. Int J Tissue React. 1990;12(3):155-62. Review 7. Damian MS, Ellenberg D, Gildemeister R, Lauermann J, Simonis G, Sauter W, Georgi C. Combining hypothermia with coenzyme Q10 improves survival after cardiac arrest. Third conference of the International Coenzyme Q10 Association 2002. Programme and abstracts. pp56-58. 8. Pepe S, Lyon W, Marasco S, Wowk M, Sheeran F, Ou R, Smith JA, Pick A, Rabinov M, Davis BB, Esmore DS, Rosenfeldt FRL. A randonised, double-blind placebo controlled trial of preoperative coenzyme Q10 therapy: improved outcome in coronary artery bypass surgery. Circulation 2001;104 (Suppl II):521: abstract. Competing interests: None declared |
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VANESSA J MARTLEW, Consultant Haematologist Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, Ewan Wilkinson
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Sir, In their comprehensive review of the monitoring of anticoagulant therapy in Sweden, Oden and Fahlen(1) emphasise the excess mortality associated with high INR values(2), particularly in those whose dose of anticoagulant had recently been increased. They do not, however, discuss the implications of sub-therapeutic INR in those for whom oral anticoagulant therapy has been recommended. We recently conducted a mortality study over a 2 year period of 4686 patients registered for monitoring of oral anticoagulant therapy in a central teaching hospital. 523 (11%) died during the 24 months. In 52 of these it was considered likely that anticoagulant control may have influenced the outcome of the terminal illness. In 13, a high INR was associated with bleeding (5 intra cerebral haemorrhage, 6 intra abdominal bleeding and 2 “stroke”). A haemorrhagic death occurred in a further 25 patients when the INR was within the therapeutic range (9 intra cerebral haemorrhage, 11 acute “stroke”, 3 gastrointestinal bleeding, 1haemothorax and 1 dissecting aneurysm). Of the 14 patients who died when their INR was subtherapeutic, 10 had a thrombotic cause (3 pulmonary embolism and 7 cerebral thrombosis). Amongst those who died there were also 20 whose anticoagulant therapy had been discontinued some weeks or months before without notification to the anticoagulant clinic and amongst these 11 (55%) of these succumbed to a thrombotic death (8 ‘stroke’, 2 venous thrombembolism, 1 mesenteric vascular occlusion). There were, therefore, a total of 21 patients out of 76 studied who died as a result of thrombosis when either anticoagulant therapy had been discontinued or its dosage was subtherapeutic. We would therefore, caution equally against sub optimal anticoagulation in those for whom there is a clear indication for its prescription. The morbidity after stopping Warfarin demonstrates that a very careful assessment of risk versus benefit must be undertaken before treatment is discontinued. Great care is taken, quite properly, to avoid the severe consequences of haemorrhagic complications of oral anticoagulant therapy but our study highlights the equally serious outcome of under-coagulation in patients at risk of stroke(3) Yours faithfully DR Vanessa J Martlew, Consultant Haematologist, Dr Ewan Wilkinson, Consultant in Public Health Medicine, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP 1. Oden A and Fahlen M Oral anticoagulation and risk of death: a medical record WH Kay Study BMJ 2002 325: 1073-1075 2. Haemostasis & Thrombosis Task force of the British Committee for Standards in Haematology – Chair: ID Walker. Guidelines on Oral Anticoagulant Therapy: 3rd Edition Brit J Haematol. 1998 101: 374-374 3. Stroke Prevention in Atrial Fibrillation Investigations. Adjusted does Warfarin versus low-intensity fixed dose Warfarin plus Aspirin for high risk patients with atrial fibrillation. Lancet: 1996: 633-638 Competing interests: None declared |
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Steinar Madsen, chief consultant Norwegian Medicines Agency, Sven Oftedalsvei 8, N-0950 Oslo, Norway, Anne B. Breen, Trine E. Vaskinn, Aasmund Reikvam, Eva Skovlund, Harald Lislevand
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Recently we completed a survey of adverse bleeding events associated with oral anticoagulation in Norway. Records from patients with bleeding related to warfarin (n = 713) reported during an eleven year period (1990-2000) were included. Data on age, sex, indication for treatment, duration of treatment, INR-value at the time of the adverse event, bleeding site, concomitant medication and outcome were obtained. The most frequent indications were atrial fibrillation (39%), deep vein thrombosis (19%) and mechanical heart valve (9%). The INR-values at the time of bleeding was obtained in 82.7 % of the patients (n = 590). 73.6% of the patients had INR values above recommended ranges with a mean INR-value of 4.4. Bleeding occurred within five days of treatment in 30% of the patients. Mean INR-value in these patients was 4.2. Patients using platelet inhibitors, NSAIDs and heparin/low molecular weight heparin (n=123)had a mean INR of 4.5 at the time of bleeding. In 53% of the patients bleeding was fatal. Our study showed that the majority of adverse events occur in patients with INR-values above recommended ranges and during the initial period of treatment. Odèn and Fahlèn found that an optimal INR-value is 2.2-2.3 irrespective of diagnosis. Recently, excellent results were obtained with even lower INR-values in patients with deep vein thrombosis (1). These data suggest that careful initiation of treatment and aiming at INR- values at the lower end of recommended ranges is a safe and probably effective way of reducing severe and fatal adverse events. 1. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425-34 Competing interests: None declared |
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