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Optimal Duration of Dual Anti-Platelet Therapy

December 19, 2015

John S. MacGregor, M.D., Ph.D. Professor of Medicine

University of California San Francisco

Source: The New Yorker

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Optimal Duration of Dual Anti-Platelet Therapy

•  P2Y12 Inhibitors •  Optimal Duration of Therapy •  Interruption of Therapy •  Strategies with DAPT plus OAC

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Clinical Predictors of Stent Thrombosis

Numerous factors integrate to predict development of stent thrombosis

¡  Patient factors •  Compliance with DAPT •  Genetic predisposition •  Diabetes, smoking, CKD

¡  Lesion factors •  Lesion length, complexity of lesion (including bifurcation)

¡  Stent factors •  Under expansion •  Alloy, Polymer, Drug

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Overall Definite or Probable Stent Thrombosis Rates after STEMI

8.3% cumulative hazard at 5 years

Mortality after Stent Thrombosis

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STARS  Trial  30  Day  Stent  Thrombosis  

Aspirin  plus  Ticlopidine    0.5%  Aspirin  Alone        3.6  Aspirin  plus  Warfarin      2.7      

Leon,  NEJM  (1998),  339:1665-­‐71  

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P2Y12  Antagonists  

Agent   Route   Prodrug?   Reversible?   Onset  of  ac7on  

Offset  of  ac7on  

Status  

Ticlopidine   Oral  (BID)   Yes   No   6  hours   ~5  days   Approved  1991  

Clopidogrel   Oral  (QD)   Yes   No   2  to  8  hours  

~5  days   Approved  1997  

Prasugrel   Oral  (QD)   Yes   No   0.5  to  4  hours  

~5  days   Approved  2009  

Ticagrelor   Oral  (BID)   No   Yes   0.5  to  2  hours  

~1  to  3  days  

Approved  2011  

Cangrelor   IV   No   Yes   Immediate   60  minutes   Approved  2015  

Clopidogrel  v.  Newer  P2Y12  Antagonists    

Study   Year   Follow-­‐Up   Comparison   Stent  Throm-­‐  bosis  

P  Value  

TIMI  Major  Bleeding  

P  Value  

TRITON   2007    

15  months   Clopidogrel  Prasugrel  

2.4%  1.1  

<0.001   1.8  2.4  

0.03  

PLATO   2009   12  months   Clopidogrel  Ticagrelor  

2.9  2.2  

0.009   7.7  7.9  

0.57  

CHAMPION   2009   48  hours   Clopidogrel  Cangrelor  

0.3  0.2  

0.34   0.3  0.4  

0.39  

CHAMPION  PHOENIX  

2009   48  hours   Clopidogrel  Cangrelor  

1.4  0.8  

0.01   0.1  0.1  

0.99    

OASIS-­‐7   2010   30  days   Clopidogrel  2X  Clopidogrel  

2.3  1.6  

<0.001   0.7  1.0  

0.074  

Adapted  from  Claessen,  (2014)  JACCI,  7:1081-­‐92  

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April 2015

Transi_on  Strategies  from  Cangrelor  to  Oral  An_platelet  Therapy  

P2Y12  Inhibitors:    Cau_ons/Warnings  and  Considera_ons  

Clopidogrel                          -­‐    Consider  alterna_ve  in  CYP2C19  poor  metabolizer                          -­‐    Avoid  use  with  drugs  that  are  moderate  to  strong    CYP2C19  inhibitors  

Prasugrel                          -­‐    Not  recommended  for  age  >75,  weight  <60  Kg  or  prior  stroke/TIA                          -­‐    Significantly  increased  fatal  bleeding  (0.4%  v.  0.1%;  p=0.002)    

Ticagrelor                          -­‐    Maintenance  dose  of  aspirin  >100mg/day  reduces  effec_veness                          -­‐    Incidence  of  Dyspnea  (blocks  reuptake  of  adenosine  by  RBCs)                          -­‐    BID  dosing  

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DAPT  Trial    

•  9961  pa_ents  with  DES  randomized  aier  12  months  of  DAPT  to  either  con_nue  DAPT  for  18  months  or  d/c  thienopyridine  and  take  ASA  alone  

•  Co-­‐primary  end  points  were  ST  and  MACE  •  Primary  safety  end  point,  moderate  or  severe  bleeding    

Mauri, NEJM, 371:2155

MACE:  L-­‐DAPT  vs  S-­‐DAPT  

Mauri  L,  et  al.  

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MACE:  L-­‐DAPT  vs  S-­‐DAPT  

Incidence  of  All  Cause  Mortality  L-­‐DAPT  vs  S-­‐DAPT  

Mauri  L  et  al.  Eur  Heart  J  November  2015  

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All  Cause  Mortality  S-­‐DAPT  vs  L-­‐DAPT  

Yeh  R,  et  al.  Lancet  386  October  17,  2015  

Mehran R et al. Lancet 2013

Cumulative Incidence of Dual Antiplatelet Cessation (PARIS Study)

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Risk  of  MACE  (PARIS  Study)  

Mehran R et al. Lancet 2013

One  year  Clinical  Outcomes  According  to  6  Month  DAPT  Adherence  

Any  Nonadherence  (n  =  208)  

Full  Adherence  (n  =  1,951)  

P  Value  

All-­‐cause  mortality   5.0   1.7   0.005  

Cardiac  death   2.5   0.9   0.028  

MI   4.7   1.5   0.002  

Death  or  MI   7.6   3.0   <0.001  

Definite  or  Prob.    ST   2.0   0.9   0.123  

Major  bleeding   16.2   2.7   <0.001  

Stroke   3.5   0.6   <0.001  

Cutlip,  (2015)  JACCI;  8:404-­‐410  

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ITALIC  Trial  

•  2,031  pa_ents  not  resistant  to  ASA  were  randomized  to  either  24  months  or  6  months  of  DAPT.  

•  Xience  V  stent  •  Primary  end  point:    Death,  MI,  emergency  TVR,  stroke,  or  major  bleeding  

ITALIC  Trial  MACE:  S-­‐DAPT  vs  L-­‐DAPT  

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MI:  S-­‐DAPT  vs  L-­‐DAPT  

Major  Bleeding:  S-­‐DAPT  vs  L-­‐DAPT  

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Outcomes:  L-­‐DAPT  vs  S-­‐DAPT  

Collet  J,  et  al.  Lancet    384,  2014  

Death

Major Bleeding

Considerations for Temporary Discontinuation of DAPT

•  Duration of therapy? •  Complexity of anatomy (multiple stents,

overlapping, bifurcation, LM/prox LAD)?

•  Caliber of vessels stented? •  Type of stent? •  Minimize time off DAPT (5 d), resume as

soon as possible with loading dose •  Do not stop ASA if possible

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ACC/AHA Recommendations

•  Consider doing surgery on DAPT •  Continue aspirin, if possible •  Resume DAPT as soon as possible

after surgery (loading dose) •  Do surgery in a facility with available

cath lab with PCI capability •  Monitor patient

Grines, Circ (2007)115:813-818

ACC/AHA  Guidelines:  An_platelet  Therapy  for  NSTE-­‐ACS  (2014)  

CLASS  I  •  Pa_ents  on  chronic  ASA  should  take  81  to  325  mg  of  non-­‐enteric  coated  ASA  prior  to  PCI.  

•  Pa_ents  not  on  ASA  should  take  325  mg  ASAP  prior  to  PCI.  

•  Aier  PCI  ASA  should  be  taken  indefinitely  at  a  dose  of  81  to  325  mg  per  day.  

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ACC/AHA  Guidelines:  An_platelet  Therapy  for  NSTE-­‐ACS  (2014)  

CLASS  I  A  loading  dose  of  P2Y12  inhibitor  should  be  given  prior  stent  procedure.  

– Clopidogrel  600  mg  – Prasugrel  60  mg  – Ticagrelor  180    For  pa_ents  with  NSTE-­‐ACS  and  high-­‐risk  features,  who  are  not  adequately  pre-­‐treated  with  clopidogrel    or  _cagrelor,  GP  IIb/IIIa  inhibitor  is  useful.        

ACC/AHA  Guidelines:  An_platelet  Therapy  for  NSTE-­‐ACS  (2014)  

CLASS  I  In  pa_ents  receiving  a  stent  (BMS  or  DES)  for  NSTE-­‐ACS,  P2Y12  inhibitor  therapy  should  be  con_nued  for  at  least  12  months.                    -­‐    Clopidogrel  75  mg/day                    -­‐    Prasugrel  10  mg/day                    -­‐    Ticagrelor    90  mg  BID  

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ACC/AHA  Guidelines:  An_platelet  Therapy  for  NSTE-­‐ACS  (2014)  

CLASS  IIa  •  It  is  reasonable  to  choose  _cagrelor  over  clopidogrel.  

•  It  is  reasonable  to  choose  prasugrel  over  clopidogrel  in  pa_ents  not  at  high  bleeding  risk.  

 

ACC/AHA  Guidelines:  An_platelet  Therapy  for  NSTE-­‐ACS  (2014)  

CLASS  IIa  •  If  the  risk  of  morbidity  from  bleeding  outweighs  the  an_cipated  benefit,  early  discon_nua_on  of  P2Y12  inhibitor  (eg,  <12  months)  is  reasonable.  

CLASS  IIb  •  Con_nua_on  of  DAPT  beyond  12  months  may  be  considered.  

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Strategies  for  DAPT  Decision  Making  

DAPT  and  OCT:  WOEST  Study  

Dewilde  W,  et  al.  Lancet  2013;  381:  1107–15  

Any Bleeding MACE

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MACE  and  Major  Bleeding:    ISAR-­‐TRIPLE  Trial    

ACC/AHA  Guideline:    Triple  Therapy    (Circ.  2014)  

Class  I  The  dura_on  of  triple  an_thrombo_c  therapy  with  a  vitamin  K  antagonist,  aspirin,  and  P2Y12  receptor  inhibitor  should  be  minimized  to  the  extent  possible  to  limit  the  risk  of  bleeding.  Proton  pump  inhibitor  should  be  prescribed  in  pa_ents  with  a  history  of  GI  bleeding.  

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ACC/AHA  Guideline:    Triple  Therapy    (Circ.  2014)  

Class  IIa  Proton  pump  inhibitor  use  is  reasonable  in  pa_ents  without  a  history  of  GI  bleeding.  Class  IIb  Target  INR  to  lower  end  of  therapeu_c  range  (2.0  to  2.5).