• No results found

Management of invasive procedures and bleeding compica5ons in pa5ents on NOACs


Academic year: 2021

Share "Management of invasive procedures and bleeding compica5ons in pa5ents on NOACs"


Loading.... (view fulltext now)

Full text


Management  of  invasive  procedures  and  

bleeding  compica5ons  in  pa5ents  on  


Michiel  Coppens  MD  PhD  

Internist-­‐Vascular  Medicine  

Academic  Medical  Center,  Amsterdam,  The  Netherlands   McMaster  University,  Hamilton,  Ontario,  Canada  


Conflicts  of  interest  

Michiel  Coppens  

•  Research  grant  

–  Sanquin  Blood  supply  (manufacturer  of  a  4  factor  PCC)   –  Boehringer  Ingelheim  (dabigatran)  

•  Consulta5on  fees  

–  Boehringer  Ingelheim   –  Bayer  (rivaroxaban)  


Two  clinical  seQngs  


•  Interrup5on  for  invasive  procedures  

–  Elec5ve,  semi-­‐elec5ve  procedures  


•  Major  bleeding  


Non-­‐emergency  interrup5ons  

1.  How  long  un5l  the  an5coagulant  ac5vity  wears  off?  

2.  What  is  the  acceptable  residual  ac5vity  to  proceed  with  

the  invasive  procedure?  


How  long  un5l  the  effect  wears  off?  

Elimina'on  half-­‐life  (T1/2)  

eGFR  (ml/min)   T1/2  (h  +  95%CI)  

Dabigatran   >  80   51-­‐80   30-­‐50   15-­‐30     13   15   18   27*   Rivaroxaban   >  30   15-­‐30     9   ~  10*   Apixaban   >  25     12  


Acceptable  residual  ac5vity  

•  Ideally:  threshhold  blood  level  per  drug  

–  Currently  unavailable  

–  Real  world  data  may  eventually  provide  answers  (similar  to  VKA)  


•  Un5l  that  5me:  a  pragma5c  approach  

–  Very  low  risk  of  bleeding  

•  Don’t  stop;  perform  at  trough  blood  level  

–  Standard  bleeding  risk  

•  2-­‐3  elimina5on  half-­‐lives:  12.5-­‐25%  residual  ac5vity  

–  High  bleeding  risk  


A  prac5cal  scheme    

European  Heart  Rhythm  Associa5on  (EHRA)  Prac5cal  Guide   Europace  2013;15:625-­‐51  


Bridging  with  LMWH?  

•  Is  there  a  ra5onale?  Hardly...  

–  T1/2  NOACs  shorter  than  VKA  

–  T1/2  NOACs  only  modestly  longer  than  LMWH  

•  Lessons  from  bridging  VKA  therapy  

–  Observa5onal  data,  subject  to  bias  *  

•  Increased  risk  of  bleeding  (OR  3-­‐6)  

•  Uncertain  protec5on  from  thrombosis  (OR  0.8  N.S.)  

–  Randomized  studies  ongoing  


•  Management  of  urgent  surgery  

•  Management  of  bleeding  


No  An5dote  for  NOACs!  

•  The  No.  1  concern!  

•  Desirable  to  get  rid  of  ac5vity  at  5me  of  emergency  

•  Goal  of  using  an5dote  

–  To  improve  outcome,  not  to  normalize  a  blood  test  

•  How  important  is  a  reversal  agent?  

–  How  ooen  do  we  need  it?   –  Does  it  improve  outcome?  


How  important  is  an  an5dote?  

•  Phase  3  trials  provide  insight  

•  Comparisons  of  outcome  of  bleeding  

–  VKA  (specific  an5dote  available)  

–  NOAC  (no  specific  an5dote  available)  

•  Hypothesis:  outcome  beqer  for  VKA  than  for  NOACs  by  

virtue  of  the  an5dote  


RE-­‐LY  trial  

dabigatran  vs.  VKA  in  AF  (N=18,113)  


Management  of  Major  Bleeding


Dabigatran   Warfarin   P  

Pts  with  major  bleeding   741   421  

RBC  transfusion   59.2%   49.9%   0.002   FFP  transfusion   19.8%   30.2%   <0.001   Vitamin  K  used   9.4%   27.3%   <0.001   Factor  concentrates   (PCC,  rVIIa,  others)   2.2%   2.9%   0.38   Majeed,  Circula5on  2013   1.2%   3.6%   0.6%   0.1%   3.5%   2.1%   1.9%   0.2%   6.1%   7.0%  


RE-­‐LY  trial  

Dabigatran  vs.  VKA:  AF  (N=18,113)  


Outcome  of  Major  Bleeding


Dabigatran   Warfarin   P   OR  (95%CI)  

Pts  with  major  bleeding   741   421  

Length  of  stay  (days)   8.4   8.9   0.48   Nights  in  ICU/CCU  (days)   1.6   2.7   0.01   Requiring  surgery   12.1%   15.0%   0.17  

30  day  mortality   9.1%   13.0%   0.06   0.56  (0.36-­‐0.86)‡  

Majeed,  Circula5on  2013   ‡  Adjusted  for  age,  sex,  weight,  renal  func5on  and  concomitant  use  of  an5platelet  drugs  



Rivaroxaban  vs.  VKA:  VTE  treatment  (N=8,246)  

Rivaroxaban   VKA/LMWH  

Major  bleeding  episodes   40   72   Life  threatening  requiring  immediate  and  

elaborate  measures  to  avoid  death,  incl   -­‐  surgical/endoscopic/radiological   -­‐  factor  concentrates  (PCC,  rVIIa)  

11.1%   21.5%  

Mortality   7.5%   11.1%  

Eerenberg,  Abstract  OC  02.2,  ISTH  Amsterdam  2013  

1.0%   1.7%  





Emergency  surgery  


Dabigatran   VKA  

Emergency  surgery   248   111  

•  Major  bleeding   17.7%   21.6%   N.S.   Surgery  <24  h  aoer  discon5nua5on  

•  Major  bleeding   4.8%   15.4%   0.01  


NOACs  vs.  VKA  

Lessons  from  the  phase  3  trials  

1.  Factor  concentrates  rarely  necessary/used  

–  Max  2%  of  pa5ents  with  major  bleeding  

–  <1%  of  pa5ents  using  dabigatran/rivaroxaban  

2.  Compared  with  VKA  bleeds  

–  No  increased  mortality  

–  More  RBC  use,  less  FFP  use  


Lessons  from  phase  3  trials  


•  Trial  pa5ents  are  healthier  

–  Will  this  apply  to  daily  prac5se?  

•  Were  warfarin  bleeds  op5mally  managed?  

–  Vitamin  K  use  27%,  PCC  use  1.2%  

–  Does  not  seem  to  match  European  prac5se    

Prospec7vely  collected  (phase  4)  data  necessary  to  verify  trial  



Immediate  reversal  of  NOACs  

•  Non-­‐specific  prohaemosta5c  agents  

–  Prothrombin  complex  concentrate  

•  4  factor  or  3  factor  (II,  IX,  X  only)  

–  Recombinant  ac5vated  factor  VII  

–  Ac5vated  PCC  (FEIBA)  


Non-­‐specific  prohaemosta5c  agents  

•  Evidence  from  humans  with  bleeding  complica5ons  

–  Non-­‐existent  thus  far  

–  Placebo  controlled  RCT  considered  unethical   –  Case  series  awaited  

•  Alterna5ves  

–  Poten5al  to  normalize  coagula5on  tests  in  non-­‐bleeding   volunteers  


Poten5al  to  normalize  coagula5on  tests  


Animal  studies  

Mice,  intracranial  bleeding



Summary  non-­‐specific  prohaemosta5c  agents  

•  Healthy  human  volunteers  

–  PCC  50  U/kg  may  work  for  rivaroxaban   •  Similar  results  for  3  factor  PCC*  

•  25  U/kg,  37.5  U/kg:  analyses  underway   –  No  effect  in  dabigatran  treated  pa5ents   –  Apixaban:  analyses  underway  

–  APCC,  rVIIa  not  tested  

•  Animal  models  

–  Somewhat  conflic5ng  studies  

–  4  factor  PCC  may  be  effec5ve  at  25-­‐100  U/kg  dose  


The  Future:  specific  an5dotes  


•  Humanized  an5body  fragment  directed  at  dabigatran  

•  Phase  2  (145  healthy  male  volunteers  treated  with  

dabigatran):  immediate  and  sustained  full  reversal  

•  Phase  3  (bleeding  pa5ents)  to  start  in  2014    


Specific  an5dote  

Factor  Xa  inhibitors  

•  Andexanet  alfa  

–  Recombinant  factor  Xa  

•  GLA  domain  deleted;  ac5ve  site  modifica5on   –  Compe55ve  inhibi5on  of  all  Xa  inhibitors  

•  apixaban,  rivaroxaban,  betrixaban,  LMWH  

–  Ongoing  phase  2  apixaban  (abstract  of  first  few  pa5ents)   •  Dose  dependent  reversal  of  apixaban  


How  to  manage  NOAC  bleeding  in  2013?  

1.  Have  a  protocol  in  your  hospital  

2.  Time  is  your  best  friend  

–  Every  12  h  wait:  50%  decrease  in  blood  levels  

3.  Suppor5ve  measures  will  likely  be  sufficient  in  the  vast  

majority  of  pa5ents  

4.  Source  control:  endoscopy,  radiological  interven5ons,  



How  to  manage  NOAC  bleeding  in  2013?  

5.  Consider:  

–  Platelet  transfusion  in  case  of  an5platelet  drugs   –  Tranexamic  acid?  

–  FFP  for  replacement  of  blood/plasma  loss   –  Dialysis  for  dabigatran?  

6.  For  the  most  severe  cases  /  life-­‐threatening  bleeding  

–  PCC  25-­‐50  U/kg   –  Recombinant  VIIa?  



1.  NOACs  

–  if  we  want  the  phase  3  trial  results  to  apply  to  our  pa5ents:  use   NOACs  properly!  

–  Check  renal  func5on  

–  Check  potent  interac5ons  (strong  CYP3A4,  P-­‐gp  inhibitors)   –  Who  provides  follow-­‐up  

2.  Non-­‐emergency  interrup5ons  

–  Timing  of  cessa5on  based  on  T1/2  and  type  of  procedure   –  LMWH  bridging  not  advised  



3.  Major  bleeding  

–  Specific  an5dotes  are  only  needed  in  a  minority  of  


–  Suppor5ve  measures  usually  sufficient  

–  Most  severe  cases:  consider  non-­‐specific  agents  

–  Specific  an5dotes  are  coming  


Related documents

The system can also link Canon and third-party diagnostic eye care instruments to create an integrated environment that streamlines practice workflow and efficiency by

This implies that her costs of providing incen- tives are relatively high and that her expected payoff is relatively low (compared to the orthodox model which neither

This research follows a similar approach, as I take as my main object of study a process of transnational governance, accounting for its many constituent parts: Refugees in a

Methods: Retrospective case series; data collected include results of complete ophthalmic examinations: best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, indirect

Veteran cords are in approved for veteran students to wear, we just need to figure out how we are going to pay for them, (should the VA office buy them ahead of time and

This information coupled with the potential hardware vulnerabilities discovered earlier provides the red team with nearly everything it would need to start exploiting

To mitigate concerns that differences in plan- and firm-level characteristics between treatment and comparison groups are responsible for post-period labor supply decisions,

Table 3 gives the results of the estimated predictive abilities for the correctly specified and the two misspeci- fied normal imputation models. Full cohort analysis and MI