Influenza Vaccination and Vitamin K Antagonist Treatment: A Placebo-Controlled, Randomized, Double-blind Crossover Study | Infectious Diseases | JAMA Internal Medicine | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Fiore  AEShay  DKBroder  K  et al. Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP), Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008.  MMWR Recomm Rep 2008;57 (RR-7) 1- 60PubMedGoogle Scholar
Lipsky  BAPecoraro  RERoben  NJde Blaquiere  PDelaney  CJ Influenza vaccination and warfarin anticoagulation.  Ann Intern Med 1984;100 (6) 835- 837PubMedGoogle ScholarCrossref
Holbrook  AMPereira  JALabiris  R  et al.  Systematic overview of warfarin and its drug and food interactions.  Arch Intern Med 2005;165 (10) 1095- 1106PubMedGoogle ScholarCrossref
Kramer  PMcClain  CJ Depression of aminopyrine metabolism by influenza vaccination.  N Engl J Med 1981;305 (21) 1262- 1264PubMedGoogle ScholarCrossref
Renton  KWGray  JDHall  RI Decreased elimination of theophylline after influenza vaccination.  Can Med Assoc J 1980;123 (4) 288- 290PubMedGoogle Scholar
Gomolin  IH Lack of effect of influenza vaccine on warfarin anticoagulation in the elderly.  CMAJ 1986;135 (1) 39- 41PubMedGoogle Scholar
Kramer  PTsuru  MCook  CEMcClain  CJHoltzman  JL Effect of influenza vaccine on warfarin anticoagulation.  Clin Pharmacol Ther 1984;35 (3) 416- 418PubMedGoogle ScholarCrossref
Adachi  YYokoyama  YNanno  TYamamoto  T Potentiation of warfarin by interferon.  BMJ 1995;311 (7000) e292 Accessed January 27, 2010PubMedGoogle ScholarCrossref
Ansell  JHirsh  JPoller  LBussey  HJacobson  AHylek  E The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy [published correction appears in Chest. 2005;127(1):415-416].  Chest 2004;126 (3) ((suppl)) 204S- 233SPubMedGoogle ScholarCrossref
Ansell  JHirsh  JHylek  EJacobson  ACrowther  MPalareti  GAmerican College of Chest Physicians, Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest 2008;133 (6) ((suppl)) 160S- 198SPubMedGoogle ScholarCrossref
Atkinson  WLPickering  LKSchwartz  BWeniger  BGIskander  JKWatson  JCCenters for Disease Control and Prevention, General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP).  MMWR Recomm Rep 2002;51 (RR-2) 1- 35PubMedGoogle Scholar
Rosendaal  FRCannegieter  SCvan der Meer  FJBriet  E A method to determine the optimal intensity of oral anticoagulant therapy.  Thromb Haemost 1993;69 (3) 236- 239PubMedGoogle Scholar
Iorio  AMCamilloni  BBasileo  M  et al.  Influenza vaccination in patients on long-term anticoagulant therapy.  Vaccine 2006;24 (44-46) 6624- 6628PubMedGoogle ScholarCrossref
Commission for Proprietary Medicinal Products, Guidance on Harmonisation of Requirements for Influenza Vaccines Accessed March 12, 1997
Putt  MChinchilli  VM A mixed effects model for the analysis of repeated measures cross-over studies.  Stat Med 1999;18 (22) 3037- 3058PubMedGoogle ScholarCrossref
Bland  JMAltman  DG Measuring agreement in method comparison studies.  Stat Methods Med Res 1999;8 (2) 135- 160PubMedGoogle ScholarCrossref
Arnold  WSMehta  MKRoberts  JS Influenza vaccine and anticoagulation control in patients receiving warfarin.  Br J Clin Pract 1990;44 (4) 136- 139PubMedGoogle Scholar
Bussey  HISaklad  JJ Effect of influenza vaccine on chronic warfarin therapy.  Drug Intell Clin Pharm 1988;22 (3) 198- 201PubMedGoogle Scholar
Jackson  MLNelson  JCChen  RTDavis  RLJackson  LAfor the Vaccine Safety Datalink Investigators, Vaccines and changes in coagulation parameters in adults on chronic warfarin therapy: a cohort study.  Pharmacoepidemiol Drug Saf 2007;16 (7) 790- 796PubMedGoogle ScholarCrossref
MacCallum  PMadhani  MMt-Isa  SAshby  D Lack of effect of influenza immunisation on anticoagulant control in patients on long-term warfarin.  Pharmacoepidemiol Drug Saf 2007;16 (7) 786- 789PubMedGoogle ScholarCrossref
Raj  GKumar  RMcKinney  WP Safety of intramuscular influenza immunization among patients receiving long-term warfarin anticoagulation therapy.  Arch Intern Med 1995;155 (14) 1529- 1531PubMedGoogle ScholarCrossref
Souto  JCOliver  AMontserrat  IMateo  JSureda  AFontcuberta  J Lack of effect of influenza vaccine on anticoagulation by acenocoumarol.  Ann Pharmacother 1993;27 (3) 365- 368PubMedGoogle Scholar
Paliani  UFilippucci  EGresele  P Significant potentiation of anticoagulation by flu-vaccine during the season 2001-2002.  Haematologica 2003;88 (5) 599- 600PubMedGoogle Scholar
Poli  DChiarugi  LCapanni  M  et al.  Need of more frequent international normalized ratio monitoring in elderly patients on long-term anticoagulant therapy after influenza vaccination.  Blood Coagul Fibrinolysis 2002;13 (4) 297- 300PubMedGoogle ScholarCrossref
Weibert  RTLorentz  SMNorcross  WAKlauber  MRJagger  PI Effect of influenza vaccine in patients receiving long-term warfarin therapy.  Clin Pharm 1986;5 (6) 499- 503PubMedGoogle Scholar
Poller  LKeown  MChauhan  N  et al.  Reliability of international normalised ratios from two point of care test systems: comparison with conventional methods.  BMJ 2003;327 (7405) e30 Accessed January 27, 2010Google ScholarCrossref
Sunderji  RGin  KShalansky  K  et al.  Clinical impact of point-of-care vs laboratory measurement of anticoagulation.  Am J Clin Pathol 2005;123 (2) 184- 188PubMedGoogle ScholarCrossref
Granier  HNicolas  XLaborde  JPTalarmin  F Severe autoimmune thrombopenia following anti-influenza vaccination [in French].  Presse Med 2003;32 (26) 1223- 1224PubMedGoogle Scholar
Schattner  A Consequence or coincidence? the occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines.  Vaccine 2005;23 (30) 3876- 3886PubMedGoogle ScholarCrossref
Original Investigation
April 12, 2010

Influenza Vaccination and Vitamin K Antagonist Treatment: A Placebo-Controlled, Randomized, Double-blind Crossover Study

Author Affiliations

Author Affiliations: Departments of Internal and Cardiovascular Medicine (Drs A. Iorio, Basileo, Marcucci, and Guercini) and Medical and Surgical Specialties and Public Health (Drs Camilloni and A. M. Iorio), University of Perugia, and Local Health Agency No. 2 of Perugia (Drs Paccamiccio and Vecchioli), Perugia, Italy.

Arch Intern Med. 2010;170(7):609-616. doi:10.1001/archinternmed.2010.49

Background  Among millions of persons vaccinated against influenza virus each year, many are older patients treated with several drugs, including vitamin K antagonists (VKAs), among which warfarin is the most commonly used. Due to high interpatient and intrapatient variability, the therapeutic dose of VKA has to be individualized by monitoring of international normalized ratio (INR) values. The objectives of this study were to evaluate variation in the INR and warfarin weekly dose variation after influenza vaccination administration and to follow up patients for related hemorrhagic and thrombotic events to evaluate the safety of the influenza vaccine and to assess the immunogenicity of the influenza vaccination in patients receiving VKAs.

Methods  One hundred four patients on a stable VKA regimen and with an indication for influenza vaccination were randomized to receive influenza vaccination and subsequent placebo administration, or vice versa. All patients were tested for coagulation variables, clinical events, and antibody response against vaccine components.

Results  Similar mean prothrombin times, expressed as the INR and VKA weekly dose, were found in patients after receiving vaccine or placebo. The absence of any vaccination effect on VKA treatment was confirmed using a linear mixed-effects model. The percentages of time that patients were in therapeutic range were 70.7% after receiving vaccine and 72.4% after receiving placebo (P = .57). There were no fatal or major bleeding events and 11 minor mucocutaneous hemorrhagic events. After vaccination, the percentage of seroprotected patients ranged from 92.0% to 100.0% depending on the vaccine antigen examined.

Conclusions  Influenza vaccination had no significant effect on INR values or warfarin sodium weekly doses. Close monitoring of INR values is not required after influenza vaccination in patients on stable long-term VKA regimens.

Trial Registration Identifier: NCT00222638