Advertisement

Herz

, Volume 43, Issue 3, pp 214–221 | Cite as

Antikoagulation bei Vorhofflimmern im Alter

Womit und bei wem nicht mehr?
  • P. Bahrmann
  • M. Christ
Schwerpunkt
  • 560 Downloads

Zusammenfassung

Aufgrund etablierter Risiko-Scores wie dem CHA2DS2-VASc-Score besteht bei Patienten über 65 Jahren und mit Vorhofflimmern (VHF) bzw. noch stärker über 75 Jahre eine (relative) Indikation für eine orale Antikoagulation. Vor Beginn der Antikoagulation sollte wegen der bekannten Blutungskomplikationen der Antikoagulation ein geriatrisches Assessment zur Beurteilung der kognitiven Kapazität, der Aktivitäten des täglichen Lebens und des Sturzrisikos durchgeführt werden. Es werden zudem verschiedene Maßnahmen wie Schulung von Angehörigen, Medikationspass oder individuelle Verblisterung der Medikation empfohlen, um die Adhärenz der Patienten zur oftmals lebenslangen Prophylaxe zu gewährleisten. In der VHF-Leitlinie der European Society for Cardiology (ESC) werden für die Antikoagulation bei Patienten mit nichtvalvulärem VHF nicht-Vitamin-K-abhängige orale Antikoagulanzien (NOAK) bevorzugt und Vitamin-K-Antagonisten (VKA) als Alternative empfohlen. Tatsächlich erhalten immer mehr ältere Patienten mit nichtvalvulärem VHF eine Schlaganfallprophylaxe mit NOAK (Faktor-Xa-Inhibitoren: Apixaban, Rivaroxaban, Edoxaban; Thrombininhibitor: Dabigatranetexilat). Die pharmakodynamischen und pharmakokinetischen Charakteristika dieser Substanzen weisen viele Gemeinsamkeiten auf, dennoch ist für die differenzierte Pharmakotherapie auch auf wichtige Unterschiede zu achten. NOAK haben bei älteren Patienten eine Reihe von Vorteilen gegenüber VKA, vorrangig durch das bessere Nutzen-Risiko-Verhältnis durch eine verminderte Zahl von Blutungsereignissen und ein insgesamt geringeres Risiko für Arzneimittelinteraktionen. Hervorzuheben ist auch die einfachere Handhabung der NOAK im Alltag (kein INR[International Normalized Ratio]-Monitoring erforderlich, und unkompliziertere Unterbrechungen der Therapie bei geplanten Interventionen). Bei reduzierter Nierenfunktion sollten bei älteren Patienten NOAK gewählt werden, die auch in dieser Situation sicher eingesetzt werden können. Eine regelmäßige Überprüfung der Indikationsstellung der NOAK (wie auch aller anderen Medikamente) ist unabdingbar. Zusammenfassend weisen NOAK auch bei der Schlaganfallprophylaxe älterer Patienten gegenüber einer Therapie mit VKA viele Vorteile auf und sollten auch älteren Patienten nicht vorenthalten werden.

Schlüsselwörter

Schlaganfallprävention Vorhofflimmern Nicht-Vitamin-K-abhängige orale Antikoagulanzien Geriatrie Assessment 

Anticoagulation in geriatric patients with atrial fibrillation

With what and for whom no more?

Abstract

Based on established risk scores, such as the CHA2DS2-VASc score, the indications for oral anticoagulation are given for patients over 65 years old with atrial fibrillation and even more so for patients over 75 years old. Before beginning anticoagulation a geriatric assessment for evaluation of the cognitive ability, the activities of daily living and the risk of falling should be made because of the known complications of anticoagulation. Geriatric patients with non-valvular atrial fibrillation (AF) are increasingly being treated with non-vitamin K antagonist oral anticoagulants (NOAC) to prevent ischemic stroke. The European Society for Cardiology (ESC) guidelines for the management of AF recommended NOACs as the preferred treatment and vitamin K antagonists (VKA) only as an alternative option. Meanwhile, apixaban, rivaroxaban, and edoxaban as factor Xa inhibitors and dabigatran as a thrombin inhibitor, are more commonly used in clinical practice in patients with AF. Although, these drugs have pharmacodynamics and pharmacokinetic similarities and are often grouped together, it is important to recognize that the pharmacology and dose regimens differ between compounds. Especially in elderly patients the new drugs have interesting advantages compared to VKA, i. e., less drug-drug interactions with concomitant medication and a more favorable risk-benefit ratio mostly driven by the reduction of bleeding. Treatment of anticoagulation in elderly patients requires weighing the serious risk of stroke with an equally high risk of major bleeding and pharmacoeconomic considerations. The easier practicality of NOACs in routine practice must be emphasized as no international normalized ratio (INR) monitoring is necessary and the interruption of treatment for planned interventions is uncomplicated. A regular monitoring of the indications for NOACs is indispensable (as for all other medications). Especially elderly patients have the greatest benefit from NOAC along with a low renal elimination rate and they should certainly not be withheld from elderly patients who have a clear need for oral anticoagulation.

Keywords

Stroke prevention Atrial fibrillation Non-vitamin-K-antagonist anticoagulants Geriatrics Assessment 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

P. Bahrmann und M. Christ geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Ohlmeier C, Mikolajczyk R, Haverkamp W, Garbe E (2013) Incidence, prevalence, and antithrombotic management of atrial fibrillation in elderly Germans. Europace 15:1436–1444PubMedCrossRefGoogle Scholar
  2. 2.
    Wilke T, Groth A, Mueller S et al (2013) Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients. Europace 15:486–493PubMedCrossRefGoogle Scholar
  3. 3.
    Kannel WB, Benjamin EJ (2008) Status of the epidemiology of atrial fibrillation. Med Clin North Am 92:17–40PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Go AS, Hylek EM, Phillips KA et al (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 285:2370–2375PubMedCrossRefGoogle Scholar
  5. 5.
    Lin HJ, Wolf PA, Kelly-Hayes M et al (1996) Stroke severity in atrial fibrillation. The Framingham Study. Stroke 27:1760–1764PubMedCrossRefGoogle Scholar
  6. 6.
    Camm AJ, Kirchhof P, Lip GY et al (2010) Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 31:2369–2429PubMedCrossRefGoogle Scholar
  7. 7.
    Camm A, Lip G, Atar D et al (2012) Focused update of the ESC guidelines on the management of atrial fibrillation. Eur Heart J 2012(33):2719–2747Google Scholar
  8. 8.
    Lopes RD, Crowley MJ, Shah BR et al (2013) Stroke Prevention in Atrial Fibrillation. Agency for Healthcare Research and Quality (US); August 2013. Report No.: 13-EHC113-EF. AHRQ Comparative Effectiveness ReviewsGoogle Scholar
  9. 9.
    Schwabe U, Arzneiverordnungs-Report PD (2014) Aktuelle Daten, Kosten, Trends und Kommentare. Springer, Berlin, HeidelbergGoogle Scholar
  10. 10.
    Nabauer M, Gerth A, Limbourg T et al (2009) The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace 11:423–434PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Oldgren J, Healey JS, Ezekowitz M et al (2014) Variations in cause and management of atrial fibrillation in a prospective registry of 15,400 emergency department patients in 46 countries: the RE-LY Atrial Fibrillation Registry. Circulation 129:1568–1576PubMedCrossRefGoogle Scholar
  12. 12.
    De Caterina R, Husted S, Wallentin L et al (2013) Vitamin K antagonists in heart disease: current status and perspectives (section III). Position paper of the ESC working group on thrombosis – task force on anticoagulants in heart disease. Thromb Haemost 110:1087–1107PubMedCrossRefGoogle Scholar
  13. 13.
    Patel MR, Mahaffey KW, Garg J et al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891PubMedCrossRefGoogle Scholar
  14. 14.
    Connolly SJ, Eikelboom J, Joyner C et al (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364:806–817PubMedCrossRefGoogle Scholar
  15. 15.
    Granger CB, Alexander JH, McMurray JJV et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992PubMedCrossRefGoogle Scholar
  16. 16.
    Meschia JF, Bushnell C, Boden-Albala B et al (2014) Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 45(12):3754–3832.  https://doi.org/10.1161/STR.0000000000000046 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Graham DJ, Reichman ME, Wernecke M et al (2014) Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation 131(2):157–164.  https://doi.org/10.1161/CIRCULATIONAHA.114.012061 PubMedCrossRefGoogle Scholar
  18. 18.
    Kaatz S, Kouides PA, Garcia DA et al (2012) Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 87(Suppl 1):S141–5PubMedCrossRefGoogle Scholar
  19. 19.
    Le Heuzey JY, Ammentorp B, Darius H et al (2014) Differences among western European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry. Thromb Haemost 111:833–841PubMedCrossRefGoogle Scholar
  20. 20.
    Sharma M, Cornelius VR, Patel JP et al (2015) Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation 132:194–204PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Bahrmann P, Harms F, Schambeck CM et al (2016) New oral anticoagulants for prophylaxis of stroke. Z Gerontol Geriatr 49:216–226PubMedCrossRefGoogle Scholar
  22. 22.
    Andreotti F, Rocca B, Husted S et al (2015) Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 36:3238–3249PubMedGoogle Scholar
  23. 23.
    Boltz MM, Podany AB, Hollenbeak CS, Armen SB (2015) Injuries and outcomes associated with traumatic falls in the elderly population on oral anticoagulant therapy. Injury 46:1765–1771PubMedCrossRefGoogle Scholar
  24. 24.
    Suárez Fernández C, Formiga F, Camafort M et al (2015) Antithrombotic treatment in elderly patients with atrial fibrillation: a practical approach. BMC Cardiovasc Disord 15:143PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Delafuente JC (2003) Understanding and preventing drug interactions in elderly patients. Crit Rev Oncol Hematol 48:133–143PubMedCrossRefGoogle Scholar
  26. 26.
    Lu Y, Won KA, Nelson BJ et al (2008) Characteristics of the amiodarone-warfarin interaction during long-term follow-up. Am J Health Syst Pharm 65:947–952PubMedCrossRefGoogle Scholar
  27. 27.
    Mueller E, Kirch W (2009) Phenprocoumon (Marcumar®): gefährliche Interaktionen. Arzneiverordn Prax 36:141–143Google Scholar
  28. 28.
    De Caterina R, Husted S, Wallentin L et al (2012) New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol 59:1413–1425PubMedCrossRefGoogle Scholar
  29. 29.
    Barat I, Andreasen F, Damsgaard EM (2001) Drug therapy in the elderly: what doctors believe and patients actually do. Br J Clin Pharmacol 51:615–622PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Nikolaus T, Kruse W, Bach M et al (1996) Elderly patients’ problems with medication. An in-hospital and follow-up study. Eur J Clin Pharmacol 49:255–259PubMedCrossRefGoogle Scholar
  31. 31.
    World Health Organisation (2003) Adherence to long-term therapies: evidence for action. http://www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Zugegriffen: 9. Nov. 2014Google Scholar
  32. 32.
    Steering Committee of the Physicians’ Health Study Research Group (1989) Final report on the aspirin component of the ongoing physicians’ health study. N Engl J Med 321:129–135CrossRefGoogle Scholar
  33. 33.
    Tamblyn R, Eguale T, Huang A et al (2014) The incidence and determinants of primary nonadherence with prescribed medication in primary care: a cohort study. Ann Intern Med 160:441–450PubMedCrossRefGoogle Scholar
  34. 34.
    Kripalani S, Yao X, Haynes RB (2007) Interventions to enhance medication adherence in chronic medical conditions: a systematic review. Arch Intern Med 167:540–550PubMedCrossRefGoogle Scholar
  35. 35.
    Ryan R, Santesso N, Lowe D et al (2014) Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. Cochrane Database Syst Rev.  https://doi.org/10.1002/14651858.CD007768.pub3 Google Scholar
  36. 36.
    Gellad WF, Grenard JL, Marcum ZA (2011) A systematic review of barriers to medication adherence in the elderly: looking beyond cost and regimen complexity. Am J Geriatr Pharmacother 9:11–23PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gallagher AM, Rietbrock S, Plumb J, van Staa TP (2008) Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis? J Thromb Haemost 6:1500–1506PubMedCrossRefGoogle Scholar
  38. 38.
    Haynes RB, Ackloo E, Sahota N et al (2008) Interventions for enhancing medication adherence. Cochrane Database Syst Rev.  https://doi.org/10.1002/14651858.CD000011.pub3 PubMedGoogle Scholar
  39. 39.
    Mansoor SM, Krass I, Aslani P (2013) Multiprofessional interventions to improve patient adherence to cardiovascular medications. J Cardiovasc Pharmacol Ther 18:19–30PubMedCrossRefGoogle Scholar
  40. 40.
    Spannagl M, Bauersachs R, Debus ES et al (2012) Dabigatran therapy – perioperative management and interpretation of coagulation tests. Hamostaseologie 32:294–305PubMedCrossRefGoogle Scholar
  41. 41.
    Healey JS, Eikelboom J, Douketis J et al (2012) Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 126:343–348PubMedCrossRefGoogle Scholar
  42. 42.
    Stangier J, Rathgen K, Stahle H et al (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64:292–303PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Stangier J, Stahle H, Rathgen K, Fuhr R (2008) Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 47:47–59PubMedCrossRefGoogle Scholar
  44. 44.
    Troconiz IF, Tillmann C, Liesenfeld KH et al (2007) Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 47:371–382PubMedCrossRefGoogle Scholar
  45. 45.
    Schmitz EM, Boonen K, van den Heuvel DJ et al (2014) Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost 12:1636–1646PubMedCrossRefGoogle Scholar
  46. 46.
    Reilly PA, Lehr T, Haertter S et al (2014) 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 63:321–328PubMedCrossRefGoogle Scholar
  47. 47.
    Avecilla ST, Ferrell C, Chandler WL, Reyes M (2012) Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol 137:572–574PubMedCrossRefGoogle Scholar
  48. 48.
    Samama MM, Contant G, Spiro TE et al (2013) Laboratory assessment of rivaroxaban: a review. Thromb J 11:11PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Lindhoff-Last E, Ansell J, Spiro T, Samama MM (2013) Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays. Ann Med 45:423–429PubMedCrossRefGoogle Scholar
  50. 50.
    Steiner T, Bohm M, Dichgans M et al (2013) Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 102:399–412PubMedCrossRefGoogle Scholar
  51. 51.
    Lindeman RD, Tobin J, Shock NW (1985) Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 33:278–285PubMedCrossRefGoogle Scholar
  52. 52.
    Morrill AM, Ge D, Willett KC (2015) Dosing of target-specific oral anticoagulants in special populations. Ann Pharmacother 49:1031–1045PubMedCrossRefGoogle Scholar
  53. 53.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRefGoogle Scholar
  54. 54.
    Shoker A, Hossain MA, Koru-Sengul T et al (2006) Performance of creatinine clearance equations on the original Cockcroft-Gault population. Clin Nephrol 66:89–97PubMedCrossRefGoogle Scholar
  55. 55.
    Levey AS, Coresh J, Greene T et al (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:247–254PubMedCrossRefGoogle Scholar
  56. 56.
    Andrade SE, Martinez C, Walker AM (1998) Comparative safety evaluation of non-narcotic analgesics. J Clin Epidemiol 51:1357–1365PubMedCrossRefGoogle Scholar
  57. 57.
    Wann LS, Curtis AB, January CT et al (2011) ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011(57):223–242CrossRefGoogle Scholar
  58. 58.
    Fuster V, Ryden LE, Cannom DS et al (2011) ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011(123):e269–367CrossRefGoogle Scholar
  59. 59.
    Perera V, Bajorek BV, Matthews S, Hilmer SN (2009) The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing 38:156–162PubMedCrossRefGoogle Scholar
  60. 60.
    Chronopoulos A, Cruz DN, Ronco C (2010) Hospital-acquired acute kidney injury in the elderly. Nat Rev Nephrol 6:141–149PubMedCrossRefGoogle Scholar
  61. 61.
    Deal EN, Pope H, Ross W (2014) Apixaban use among patients with severe renal impairment. Ann Pharmacother 48:1667PubMedCrossRefGoogle Scholar
  62. 62.
    Hohnloser SH, Hijazi Z, Thomas L et al (2012) Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 33:2821–2830PubMedCrossRefGoogle Scholar
  63. 63.
    Halvorsen S, Atar D, Yang H et al (2014) Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 35:1864–1872PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Wehling M, Collins R, Gil VM et al (2017) Appropriateness of oral anticoagulants for the long-term treatment of atrial fibrillation in older people: results of an evidence-based review and international consensus validation process (OAC-FORTA 2016). Drugs Aging.  https://doi.org/10.1007/s40266-017-0466-6 PubMedGoogle Scholar
  65. 65.
    Halperin JL, Hankey GJ, Wojdyla DM et al (2014) Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 130:138–146PubMedCrossRefGoogle Scholar
  66. 66.
    Berthold HK (2012) New oral anticoagulants for the prevention of stroke. Z Gerontol Geriatr 45:498–504PubMedCrossRefGoogle Scholar
  67. 67.
    Kundu A, Sardar P, Chatterjee S et al (2016) Minimizing the risk of bleeding with NOAcs in the elderly. Drugs Aging 33(7):491–500.  https://doi.org/10.1007/s40266-016-0376-z PubMedCrossRefGoogle Scholar
  68. 68.
    Kooiman J, van de Peppel WR, van der Meer FJM, Huisman MV (2011) Incidence of chronic kidney disease in patients with atrial fibrillation and its relevance for prescribing new oral antithrombotic drugs. J Thromb Haemost 9:1652–1653PubMedCrossRefGoogle Scholar
  69. 69.
    Jönsson KM, Wieloch M, Sterner G et al (2011) Glomerular filtration rate in patients with atrial fibrillation on warfarin treatment: a subgroup analysis from the AURICULA registry in Sweden. Thromb Res 128(4):341–345.  https://doi.org/10.1016/j.thromres.2011.04.022 PubMedCrossRefGoogle Scholar
  70. 70.
    Giugliano RP, Ruff CT, Braunwald E et al (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369:2093–2104PubMedCrossRefGoogle Scholar
  71. 71.
    Heidbuchel H, Verhamme P, Alings M et al (2017) Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Eur Heart J 38:2137–2149PubMedGoogle Scholar
  72. 72.
    Bahrmann P, Wehling M, Ropers D et al (2014) Optimale Schlaganfallpravention bei geriatrischen Patienten mit Vorhofflimmern. Konsensbericht eines interdiszipIinaren Expertengremiums. Mmw Fortschr Med 156(Suppl 3):84–88PubMedCrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2017

Authors and Affiliations

  1. 1.Medizinische Klinik IIAsklepios Paulinen Klinik WiesbadenWiesbadenDeutschland
  2. 2.Institut für Biomedizin des AlternsFriedrich-Alexander-Universität Erlangen-NürnbergNürnbergDeutschland
  3. 3.Abteilung für NotfallmedizinLuzerner KantonsspitalLuzernSchweiz

Personalised recommendations