Behavior of Prothrombin Time (INR) in Response to Warfarin Therapy in a Thai Population

Transcription

1 Behavior of Prothrombin Time (INR) in Response to Warfarin Therapy in a Thai Population Sarana Boonbaichaiyapruck,MD, FACC* Pradit Panchavinnin,MD.** Taworn Suthichaiyakul,MD.*** Thanawat Benjanuwatra,MD.**** Bancha Sukanandachai, MD.***** Weera Mahawanakul, MD.****** Adisai Buakumsri,MD.******* Sumon Tansuntornwiwat,MD.******** Sayan Cheepudomvit,MD.* (Statistical Coordinator) Kanungnit Srisala, RN.* (Study Nurse Coordinator) *Ramathibodi Hospital, ** Siriraj Hospital, *** King Chulalongkorn Memorial Hospital, ****ChiangMai University Hospital, ***** Maharaj Nakornratchasrima Hospital, ******Ubonratchathani Hospital, ******* Thammasat University Hospital, ******** Udonthani Hospital Background: Warfarin has been used extensively as an anticoagulant in Thailand for a variety of diseases. We studied the drug responsive in term of anti-coagulation index measured by International Normalized Ratio (INR) in various patients on chronic warfarin therapy. We also compared the response in two different brands of warfarin in clinical practice. Methods: We randomly & retrospectively collected data on patients who were being seen in outpatient clinics and had been on warfarin for longer than 3 months. Most episodes of INR, bleeding and thrombotic complications were recorded. Results: 246 (146 female) patient records were reviewed from 8 hospitals in Thailand. The mean age of the patients was 56 year. 190 patients had atrial fibrillation. 129 had valvular heart diseases, 50 of these had prosthesis. They were on warfarin for an average of 54 months. We evaluated 1378 blood samples during this study. The mean INR was 2.1 with median of 1.9 (range ). An optimal INR (range of 2-3) was noted in 30.9% and was below 2 in 54.7%. INR in the range was seen in 42.7% and INR <1.8 in 46.2% of the time. 6.9% of the population studied had their INR in the range of in all visits. The combined rate of severe bleeding and thromobo-embolic complications was 7.3%. There was no difference between INR responses, rate of bleeding or thrombotic complications between the two brands of warfarin. Conclusion: The INR response to warfarin in clinical practice in Thailand was suboptimal with a rate of bleeding and thrombo-embolic events higher compared to international trials. There was no difference in response in the two types of commercially available warfarin. Thai heart J 2006; 19 : E-Journal : Introduction Cerebral and other thromboembolic events represent serious consequences in patients with cardiac and vascular conditions. Warfarin has been used as standard anticoagulation therapy to prevent such episodes 1. Historically, Prothrombin time was largely used with an ideal drug responsiveness index of Due to variations in reagents, the International Normalized Ratio (INR) was invented to correct for differences in reagent sensitivity. Despite the use of anticoagulants, major systemic embolism and bleeding still occur at the combine rate of 3-5% per year 2. INR of 2-3 has been viewed as optimal with the lowest rate of thromboembolic events and the lowest rate of bleeding complications. Achievement of such an ideal range occurred in 65-70% 3,4,5,6. Warfarin has been in clinical practice in Thailand for more than 30 years. Currently there are two commercially available brands of warfarin, Orfarin by Orion Finland and Befarin by Berlin Thailand. We studied the clinical settings where the drug was being used, the behavior of the INR responses, the rate of

2 86 Sarana Boonbaichaiyapruck,MD, FACC* thromboembolism and bleeding complications and whether there was any difference in the two available brands of warfarin. Methods Study Design This is a Multi-center Registry type study based on review of medical records. The study was conducted from October 2005 to February Eligible were patients, aged between 20-75, with known heart disease and thromboembolic vascular complications or patients with risk factors and with a high likelihood of developing thromboembolic vascular complication who were on Warfarin therapy for more than 3 months. Approximately patients medical records were chosen randomly from each cooperating clinic each of which was visited by a research nurse. Some were visited more than once. The number of Prothrombin time INR episodes and their values were recorded. All underlying heart or vascular conditions that lead to the use of warfarin were noted. The records were search for thromboembolic phenomenon which were classified as to their severity and if the patient required admission to hospital. The need for Transfusion or admission to the hospital defined Major bleeding complications. Both brands of warfarin were used in some hospitals. To eliminate the initial stabilization period, those with less than 3 months on treatment were not eligible. To have statistically significant data >200 subjects and > 1000 Pro-thrombin samples were the targets. Chi-square was used to compare the discrete (categorical) variables and the Mann Whitney test was used to evaluate the continuous variables. A P value of <0.05 determined statistical significance. We expected prior to the start of the study that 60-70% of all INR samples should be in the range of 2-3 with combined bleeding or thrombo-embolic complication in 2-3% range. Results Eight hospitals, 4 of which located in Bangkok, were visited during the study. 324 patients medical records were reviewed and 246 patients were found eligible. The age range had a mean of 56 years. 190 patients had chronic atrial fibrillation. 129 patients had valvular heart disease with 50 with valvular prosthesis. 7 patients had a history of thromboembolic conditions other than cardiac diseases. They were on warfarin for a mean of 54 months with an average of 5.6 blood samples drawn for INR per patient. We recorded 1378 blood samples for INR from the 246 patient s charts. The INR numbers ranged from 0.78 to 9.1. The mean and median values for all samples were 2.1 (1.05 SD) and 1.9 respectively. However, only 30.9% of the samples fell into the range of 2-3 (Figure 1) and 42.7% fell into the range of In the majority the INR fell into suboptimal levels [i.e. 54.7% of all samples were less than 2 and 46.3% were less than 1.8. Only 1.6% of patients had their INR on every count in the range of 2-3 and only 6.9% of patient had their INR on every count in the range of % 50% 40% 30% 20% 10% 0% 46.3% 54.7% 42.7% 30.9% 9.1% 5.2% <1.8 < >4 Figure 1. The percentage of patient in various INR range categories among 246 patients and 1378 samples The INR behavior among different conditions is shown in Table 1. More patients in the valvular Prosthesis group fell into the optimal range of 2-3 (36.7%) or (49.4%) than in the groups with atrial fibrillation or with other valvular conditions. Table 1. Behavior of INR response in different subgroups Range Mean INR INR Atrial fib % 42.5% Prosthesis % 49.4% Valve all % 32.01%

3 Behavior of Prothrombin Time (INR) in Response to Warfarin Therapy in a Thai Population patients were on Orfarin (Orion, Finland) with 1006 INR samples. Their mean INR was 2.09 (0.96 SD). 30% of the sample size in this group fell into the range of 2-3 and 42.5% fell into the range of patients were on Befarin (Berlin, Thailand) with 372 INR samples. The mean INR was 2.25 (1.23 SD). 33.3% and 43% of the samples fell into the range of 2-3 and respectively. There was no statistically significant difference comparing the percentage of samples in the optimal range, using either the 2-3 or range as shown in Table 2. Table 2. Comparison between the two commercially available brands of warfarin 13 patients out of 246 (5.2%) were noted to have severe bleeding i.e. requiring either blood products or admission to hospital. 5 required blood transfusion. 5 cases of severe thromboembolic phenomenon were noted despite being on anticoagulation therapy. A total of 18 (7.3%) had either severe bleeding or thromboembolic events. Discussion Orfarin Befarin P Value Patients INR sample Mean % INR % 33.3% %INR % 43% We observed unexpected low anticoagulation in terms of the INR response to warfarin using an optimal level of 2-3. Such optimal level was derived from published meta-analyse where the combined rate of thromboembolic events (strokes) and bleeding were the lowest and when INR levels were in the range of 2-3. We recruited patients who had been on warfarin for longer than 3 months to eliminate the initial dose adjustment periods. Most previous clinical trials on warfarin had a dose adjustment period of 12 weeks. Our previous work with subjects who had a variety of warfarin adjustment periods, showed that 67% of INR samples fell into the range of INR 2-3. This is similar to data obtained from international clinical trials. The patients in this study were past the dose adjustment period and presumed to be in a stable state and with a constant dose of warfarin. They had been on warfarin on the average of 54 months with 5.9 samples per patient. The low percentage of INR in the range of either 2-3 or even could be due to several causes. An anticoagulation team, commonly seen in the USA or Europe that makes direct patient contact by a nurse or pharmacist to adjust the dose on a weekly basis, is not generally available in Thailand. Patients in our study had to travel to the hospital, a distance often more than 3 hours away. Timing of blood drawn related to the medicine intake, local food and other drug interaction and compliance may be contributing to the observed number of low proportion of patients in the ideal INR range. The rate of optimal anticoagulation was achieved more often in the valvular prosthesis group. This may reflect a higher level of care in this group 1,2. They may be followed by both cardiac surgeons as well as cardiologists and at a teaching hospital where they could have had INRs checked more often. However despite these possibilities and the addition of aspirin 3, the number of such patient with INRs of less than 2 was still high in our study. The number of satisfactory INR results those with atrial fibrillation may be acceptable if we were to compare them with the initially SPAF-1 trial. 87% of 2,597 monthly prothrombin times were recorded. The Prothrombin time ratio in SPAF-1 averaged 1.45 with 71% of all values falling within the range of , 5% above and 23% below the range. The severe bleeding event rate was high in our observational study but was still in line with other large trials where a 5-9% rate of bleeding was noted 4,5,6,7 A majority of severe bleeding required admission. Out of 13 patients with severe bleeding, 5 needed blood cell transfusion. This reflected the low threshold of admitting patients who were on anticoagulation. GI bleeding was the main cause of such bleeding episode. Peptic Ulcer and Gastritis are common entities in the Thai population due to NSAID and alcohol uses. With or without anticoagulation, GI bleeding usually prompts admission to the hospital.

4 88 Sarana Boonbaichaiyapruck,MD, FACC* The rate of thromboembolic events was not high given the level of anticoagulation achieved. However, when combining the bleeding and thromboembolic events together, the number was quite alarming. Weekly self monitored Prothrombin time INR may help to achieve better anticoagulation status and avoid these bleeding and thromboembolic complications. Currently there are two brands of warfarin commercially available. The Original Coumadin, by Dupont, was removed from the market during the Asian Economy Crisis (1997). Orfarin is an imported product from Orion, Finland. Befarin is locally produced by the Berlin Pharmaceutical Company. The level of optimal anticoagulation among the two commercially available brands of warfarin did not appear to be different in our study. However, our study did not answer whether the two can be used interchangeably. Conclusion The number of patients who had optimal anticoagulation levels measured by INR in our registry was suboptimal compared to international standards. We noted a higher rate of severe bleeding. The relatively high rate of thrombo-embolic events might reflect the overall less than optimal level of anticoagulation. The two commercially available brands of warfarin (Orfarin and Beferin) provided the same results. References 1. British Society for Haematology. Guidelines on oral anticoagulation: second edition. J Clin Pathol 1990;43: Bloomfield P, Wheatley DJ, Prescott RJ, Miller HC. Twelve-year com parison of a Bjork-Shiley mechanical heart valve with porcine bioprosthesis. N Engl J Med 1991;324: Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Final Results. Circulation 1991;84: Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed dose warfarin plus aspirin for highrisk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomized clinical trial. Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996;348: J.P. Mohr, J.L.P. Thompson, R.M.Lazar, B.Levin, R.L.Sacco, K.L.Furie, J.P.Kistler, G.W.Albers, L.C.Pettigrew, H.P.Adams, Jr.,C.M.Jackson, P.Pullicino. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. The Warfarin-Aspirin Recurrent Stroke Study Group. N Engl J Med 2001;345: Marc L. Chimowitz, Michael J.,Harriet Howlett-Smith, Barney J. Stern., Vicki S.Hertzberg., Michael R.Frankel.,Steven R.Levine.,Seemant Chaturvedi, Scott E.Kasner, Curtis G.Benesch.,Cathy A.Sila.,Tudor G.Jovin.,Jose G.Romano. Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis. The Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. N Engl J Med 2005; Fuster V, Badimon L, Badimon JJ, Chesebro J. Prevention of throm boembolism induced by prosthetic heart valves. Semin Thromb Hemost 1988;14: Stein PD, Kantrowitz A. Antithrombotic therapy in mechanical and biological prosthetic heart valves and saphenous vein bypass grafts. Chest 1989;95:Suppl:107S-117S. 9. Turpie A, Gent M, Laupacis A, et al. A comparison of Aspirin with Placebo in Patients treated with Warfarin after Heart Valve Replacement. N Eng J Med 1993;329; Landefeld CS. Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 1993;95: Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, Whjite RH. The risk for and severity of bleeding complications in the elderly patients treated with warfarin. Ann Intern Med 1996;124: Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 1998;105: McMahan DA, Smith DM, Carey MA, Zhou XH. Risk of major hem orrhage for out-patient treated with warfarin. J Gen Intern Med 1998;13:311-6

5 Behavior of Prothrombin Time (INR) in Response to Warfarin Therapy in a Thai Population. 89 ก Prothrombin time (INR) Warfarin ก ก,.*,.** ก,. ***,.****,.***** ก,.******,.*******,.********,.* ( ),.* ( ) *, **,, ***, ก ****, *****, ก, ******, ก, *******, ********, ก, ก ก ก International Normalized Ratio (INR) warfarin ก 2 ก ก ก ก warfarin 3 ก ก INR bleeding thrombotic event ก ก 246 ก ก atrial fibrillation ก warfarin 54 ก INR 1378 INR 2.1 ก (median) 1.9 ( ) 30.9% INR % INR ก % INR % INR ก % INR ก bleeding thromoboembolism 7.3% ก ก INR ก ก ก warfarin 2 ก ก ก INR warfarin ก ก ก ก ก ก ก ก ก warfarin 2