Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service – results from the prospective, multi-center, observational cohort study thrombEVAL

BMC Medicine

Philipp S Wild¹  Thomas Münzel⁴  Hugo ten Cate²  Christoph Bickel⁶  Ulrich Walter⁴  Christina Baer³  Zaid Al-Bayati³  Claus Jünger³  Heidrun Lamparter³  Alexander Ullmann³  Meike Coldewey⁵  Karsten Keller⁵  Sebastian Göbel⁴  Jürgen H Prochaska⁵ 

[1]Preventive Cardiology and Preventive Medicine, 2. Medizinische Klinik und Poliklinik, University Medical Center Mainz, Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany

[2]Thrombosis Center Maastricht, Cardiovascular Research Institute Maastricht and Maastricht University Medical Center, Maastricht, 6200 MD, the Netherlands

[3]Center for Thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany

[4]German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Langenbeckstr. 1, Mainz, 55131, Germany

[5]2. Medizinische Klinik und Poliklinik, University Medical Center Mainz, Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany

[6]Department of Medicine I, Federal Armed Forces Central Hospital Koblenz, Rübenacher Str. 170, Koblenz, 56072, Germany

关键词: Telemedicine;    Quality of therapy;    Oral anticoagulation;    Health care research;    Epidemiology;    Coagulation service;   

Others  :  1127608
DOI  :  10.1186/s12916-015-0268-9

 received in 2014-09-16, accepted in 2015-01-06,  发布年份 2015

【 摘 要 】

Background

The majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service.

Methods

In the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution.

Results

Overall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (inte rquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001).

Conclusions

Quality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability.

Trial registration

ClinicalTrials.gov, unique identifier NCT01809015 webcite, March 8, 2013.

【 授权许可】

   
2015 Prochaska et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Hart RG, Benavente O, McBride R, Pearce LA: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999, 131:492-501.
• [2]Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, et al.: Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008, 133:160-98. doi:10.1378/chest.08-0670
• [3]Wilke T, Groth A, Mueller S, Pfannkuche M, Verheyen F, Linder R, et al.: Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients. Europace 2013, 15:486-93.
• [4]Ericson L, Bergfeldt L, Björholt I: Atrial fibrillation: the cost of illness in Sweden. Eur J Health Econ 2011, 12:479-87.
• [5]Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, et al.: Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003, 349:1019-26.
• [6]Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, et al.: Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008, 118:2029-37.
• [7]Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E: A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993, 69:236-9.
• [8]Wan Y, Heneghan C, Perera R, Roberts N, Hollowell J, Glasziou P, et al.: Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circ Cardiovasc Qual Outcomes 2008, 1:84-91.
• [9]van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ: Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest 2006, 129:1155-66.
• [10]Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al.: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009, 361:1139-51.
• [11]Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al.: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011, 365:883-91.
• [12]Samsa GP, Matchar DB, Goldstein LB, Bonito AJ, Lux LJ, Witter DM, et al.: Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med 2000, 160:967-73.
• [13]Kalra L, Yu G, Perez I, Lakhani A, Donaldson N: Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness. BMJ 2000, 320:1236-9.
• [14]Wieloch M, Själander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ: Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011, 32:2282-9.
• [15]Sullivan PW, Arant TW, Ellis SL, Ulrich H: The cost effectiveness of anticoagulation management services for patients with atrial fibrillation and at high risk of stroke in the US. Pharmacoeconomics 2006, 24:1021-33.
• [16]Beinema M, Brouwers JRBJ, Schalekamp T, Wilffert B: Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 2008, 100:1052-7.
• [17]Gadisseur AP, van der Meer FJ, Adriaansen HJ, Fihn SD, Rosendaal FR: Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon. Br J Haematol 2002, 117:940-6.
• [18]Baker WL, Cios DA, Sander SD, Coleman CI: Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009, 15:244-52.
• [19]Behr S, Andersohn F, Garbe E: Risk of intracerebral hemorrhage associated with phenprocoumon exposure: a nested case-control study in a large population-based German database. Pharmacoepidemiol Drug Saf 2010, 19:722-30.
• [20]De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al.: General mechanisms of coagulation and targets of anticoagulants (Section I). Position paper of the ESC Working Group on Thrombosis–Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013, 109:569-79.
• [21]Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al.: The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014, 63:321-8.
• [22]FDA drug safety communication. Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate). [http://www.fda.gov/drugs/drugsafety/ucm282724.htm]
• [23]Prochaska JH, Coldewey M, Gobel S, Keller K, Hendelmeier M, Konstantinides S, et al.; for the thrombEVAL Study Group. Evaluation of oral anticoagulation therapy: rationale and design of the thrombEVAL study programme. Eur J Prev Cardiol. 2014. [Epub ahead of print].
• [24]Ansari AR, Bradley RA: Rank-sum tests for dispersions. Ann Math Stat 1960, 31:1174-89.
• [25]Gadisseur AP, Breukink-Engbers WG, van der Meer FJ, van den Besselaar AM, Sturk A, Rosendaal FR: Comparison of the quality of oral anticoagulant therapy through patient self-management and management by specialized anticoagulation clinics in the Netherlands: a randomized clinical trial. Arch Intern Med 2003, 163:2639-46.
• [26]ROCKET-AF Study Investigators: Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: rationale and design of the ROCKET AF study Am Heart J 2010, 159:340-7.
• [27]Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al.: Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011, 365:981-92.
• [28]Buller HR, Prins MH, Lensin AWA, Decousus H, Jacobson BF, et al.: EINSTEIN-PE Investigators: Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012, 366:1287-97.
• [29]Fihn SD, Gadisseur AAP, Pasterkamp E, van der Meer FJM, Breukink-Engbers WGM, Geven-Boere LM, et al.: Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb Haemost 2003, 90:260-6.
• [30]Li T, Lange LA, Li X, Susswein L, Bryant B, Malone R, et al.: Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet 2006, 43:740-4.
• [31]Mushiroda T, Ohnishi Y, Saito S, Takahashi A, Kikuchi Y, Saito S, et al.: Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet 2006, 51:249-53.
• [32]Witt DM, Delate T, Clark NP, Martell C, Tran T, Crowther MA, et al.: Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood 2009, 114:952-6.
• [33]Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al.: Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013, 369:1206-14.
• [34]Cromheecke ME, Levi M, Colly LP, de Mol BJ, Prins MH, Hutten BA, et al.: Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison. Lancet 2000, 356:97-102.
• [35]van den Besselaar AM, van der Meer FJ, Gerrits-Drabbe CW: Therapeutic control of oral anticoagulant treatment in the Netherlands. Am J Clin Pathol 1988, 90:685-90.
• [36]Reynolds MW, Fahrbach K, Hauch O, Wygant G, Estok R, Cella C, et al.: Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 2004, 126:1938-45.
• [37]Cannegieter SCS, Rosendaal FRF, Wintzen ARA, van der Meer FJF, Vandenbroucke JPJ, Briët EE: Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995, 333:11-7.
• [38]Samsa GP, Matchar DB: Relationship between test frequency and outcomes of anticoagulation: a literature review and commentary with implications for the design of randomized trials of patient self-management. J Thromb Thrombolysis 2000, 9:283-92.
• [39]van Walraven C, Oake N, Coyle D, Taljaard M, Forster AJ: Changes in surrogate outcomes can be translated into clinical outcomes using a Monte Carlo model. J Clin Epidemiol 2009, 62:1306-15.
• [40]Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, et al.: Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010, 376:975-83.
• [41]Hylek EM, Singer DE: Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994, 120:897-902.
• [42]Rose AJ, Miller DR, Ozonoff A, Berlowitz DR, Ash AS, Zhao S, et al.: Gaps in monitoring during oral anticoagulation: insights into care transitions, monitoring barriers, and medication nonadherence. Chest 2012, 143:751-7.
• [43]Wilke T, Groth A, Mueller S, Pfannkuche M, Verheyen F, Linder R, et al.: Oral anticoagulation use by patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients. Thromb Haemost 2012, 107:1053-65.
• [44]Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE: Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med 1999, 131:927-34.
• [45]Hirsh J, Fuster V, Ansell J, Halperin JL: American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003, 107:1692-711.
• [46]Van Spall HGC, Wallentin L, Yusuf S, Eikelboom JW, Nieuwlaat R, Yang S, et al.: Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 2012, 126:2309-16.
• [47]Kim Y-K, Nieuwlaat R, Connolly SJ, Schulman S, Meijer K, Raju N, et al.: Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost 2010, 8:101-6.
• [48]Poller L, Keown M, Ibrahim S, Lowe G, Moia M, Turpie AG, et al.: An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage. J Thromb Haemost 2008, 6:935-43.
• [49]Cohen D: Concerns over data in key dabigatran trial. BMJ 2014, 349:g4747.
• [50]Cohen D: Dabigatran: how the drug company withheld important analyses. BMJ 2014, 349:g4670.
• [51]Moore TJ, Cohen MR, Mattison DR: Dabigatran, bleeding, and the regulators. BMJ 2014, 349:g4517.