Challenges in the long term use of dual or triple antiplatelet therapy

Challenges in the Long Term Use 
of Dual or Triple Antiplatelet 
Therapy 
Kwan S Lee MD FSCAI FACC 
Associate Professor of Medicine 
Sarver Heart Center 
University of Arizona 
Relevant Disclosures 
None 
Objectives 
• Understand differences between P2Y12 oral inhibitors 
• Understand differences in DAPT duration after PCI based on stent 
type 
• Recognize influence on DAPT duration based on stable or acute 
presentation 
• Understand DAPT score 
• Understand risk / benefit ratio on deciding duration of therapy 
• Issues related to triple therapy 
• Aspirin hypersensitivity 
• Bioabsorbable vascular scaffold 
Effects of Anti-Platelets Post PCI 
• Decrease risk of stent thrombosis 
– STEMI 
– NSTEMI 
• Prevention of ischemic events remote from stented area 
– Acute coronary syndrome 
– Ischemic stroke 
– Death 
• Increased risk of bleeding 
Which Drugs? 
• Aspirin at 75 – 100 (81 mg), continued indefinitely 
• In addition to 1 oral P2Y12 inhibitor 
– Clopidogrel (Plavix) 75 mg once daily 
– Prasugrel (Effient) 10 mg once daily or 5 mg once daily 
(patients <60 kg) 
– Ticagrelor (Brilinta) 90 mg twice daily within the 1st year 
after PCI or 60 mg twice daily after the first year 
Vorapaxar 
• PAR-1 inhibitor, high-affinity, selectively inhibits thrombin, 
inhibiting platelet aggregation 
• FDA approved for CV MACE in patients with previous MI or 
PAD 
• Contraindicated in patients with stroke 
• Used only in conjunction with aspirin and / or clopidogrel 
• Increases TIMI major / minor, not intracranial bleeding vs 
placebo 
• > 4 week offset 
General Guidelines 
• DAPT Therapy – aspirin dose of 81 mg (range 75 mg to 100 mg 
recommended) 
• Reasonable to use ticagrelor over clopidogrel in ACS PCI 
patients (IIa-BR) 
• Reasonable to use prasugrel over clopidogrel in ACS PCI 
patients (IIa-BR) 
– No high risk of bleeding 
– NO HISTORY OF STROKE OR TIA (III-BR) 
DRUG CLOPIDOGREL PRASUGREL TICAGRELOR 
Class Thienopyridine Thienopyridine CTPT 
Pro / Direct Drug Prodrug Prodrug Direct 
Inhibition Irreversible Irreversible Reversible 
Metabolic Pathway Hepatic CYP P450 Intestine/hepati
c CYP P450 
Hepatic CYP P34/5 
Conversion to active 
metabolite 
15% 85% 90-100% 
Time to steady state 
inhibition 
8 hours post 600 mg 1-2 hours post 
60 mg 
2 hours post 180 mg 
Level of inhibition at 
steady state 
Wide response in 
variability 
Predictable Predictable 
Pharmacodynamic 
offset 
5-7 days Up to 9 days 5-7 days 
Off target effects None significant None significant Inhibition of adenosine 
reuptake (dyspnea, 
bradycardia) 
Activation Pathways 
Schomig A; N Eng J Med 2009 
Special Issues 
• Routine use of platelet function testing and / or 
genetic testing is not recommended (Class III: no 
benefit) 
• Switching oral P2Y12 inhibitors has not been studied 
for clinical outcome 
• Proton pump inhibitors theoretically interfere with 
clopidogrel but does not appear to be clinically 
significant 
• PPIs should be used with prior GI bleeding (Class 1) 
and reasonable for primary prophylaxis in high risk 
patients (Class IIa) 
Aspirin Hypersensitivity 
• No regimen excluding aspirin post PCI has been formally tested 
• Aspirin desensitization is preferred, supervised by allergist in an ICU 
setting 
• Rapid desensitization protocols 
• ACC recommends single oral P2Y12 antiplatelet therapy – clopidogrel / 
prasugrel / ticagrelor (Class 1, LOE B and C) 
• Do not use dual oral P2Y12 therapy 
• ACCP recommends considering cilostazol in place of aspirin 
(*contraindicated in CHF) 
• Dipyridamole not recommended as has been shown to not be 
effective in ACS 
• Potential role of vorapaxar unknown 
How Long? 
– Determine if BMS, DES or BVS 
– Categorize Indication for PCI into Stable Ischemic 
Heart Disease or Acute Coronary Syndrome 
– Evaluate Bleeding Risk 
– Is indication for triple therapy present? 
Bioabsorbable Vascular Scaffold 
ABSORB III vs. EES 
DEFINITE / PROBABLE STENT 
THROMBOSIS 
ABSORB EES P value 
Composite 1.5 % 0.7% 0.13 
Early: 0-30 days 1.1 % 0.7% 0.46 
Acute <24 h 0.2 % 0.6% 0.19 
Subacute >24 h to 30 days 0.9 % 0.1% 0.04 
Late 31 days to 1 year 0.5 % 0% 0.10 
Definite 1.4 % 0.7% 0.21 
Probable 0.2% 0% 0.55 
Stable Ischemic Heart Disease Post PCI 
• In addition to 75-100 mg (81 mg) of aspirin (1-BNR) 
• Bare Metal Stent 
– At least 1 month of clopidogrel (1-A) 
– >1 month may be reasonable if low bleeding risk & no events on DAPT 
(2b-A) 
• Drug Eluting Stent 
– At least 6 months of clopidogrel (1-BR) 
– > 6 months may be reasonable if low bleeding risk & no events on DAPT 
(2b-A) 
– If bleeding or risk high, may discontinue after 3 months (2b-C-LD) 
• Bioabsorbable Vascular Scaffold 
– At least 12 months of clopidogrel / prasugrel or ticagrelor 
Acute Coronary Syndrome Post PCI 
• In addition to 75-100 mg (81 mg) of aspirin (1-BNR) 
• With either BMS, DES or BVS 
• At least 12 months of clopidogrel, prasugrel or 
ticagrelor (1-BR) 
• >12 months may be reasonable if low bleeding risk & 
no events on DAPT (IIb-A) 
• With BMS or DES, if bleeding or high risk may 
discontinue after 6 months (IIb-C-LD) 
Factor Favoring Longer Duration DAPT 
(Increased Ischemic or Stent 
Thrombosis Risk) 
• Ischemic Events 
– Advanced Age 
– ACS Presentation 
– Multiple prior MI 
– Extensive CAD 
– Diabetes Mellitus 
– CKD 
• Stent Thrombosis 
– ACS Presentation 
– Diabetes Mellitus 
– LVEF <40% 
– 1st Generation DES (Cypher / Taxus) 
– Stent under-sizing / under-deployment 
– Small stents ( example 2.25, 2.5 mm) 
– Long stents ( example > 20 mm in length ) 
– Bifurcations stents 
– In-stent restenosis 
Factors Favoring Shorter Duration DAPT 
(Increased Bleeding Risk) 
• Prior bleeding 
• Oral anticoagulant therapy 
• Females 
• Advanced age 
• Low body weight 
• CKD 
• Diabetes mellitus 
• Anemia 
• Chronic steroid or NSAID therapy 
Discussion at 12 months 
• If no bleeding or cost issues 
• Consider DAPT score to decide continuation of 
thienopyridine up to 30 months post PCI 
• Note DAPT study did not include ticagrelor 
• Ticagrelor beyond 1 year studied in PEGASUS TIMI-54 
suggesting preference for 60 mg PO bid dose 
The DAPT Trial – 12 vs. 30 months post DES 
Mauri L et al. N Eng J Med 2014 
Moderate or Severe bleeding 
2.5% vs 1.6% with thienopyridine 
Yeh RW et al.JAMA 2016 
Low Risk Score = 2 
The DAPT Score 
DAPT SCORE 
• Score 2 or above 
prolonged DAPT 
favorable benefit / risk 
• Score <2 prolonged DAPT 
unfavorable benefit / risk 
Variable Points 
Age >75 y -2 
Age 65– 75 y -1 
Age <65 y 0 
Current tobacco 1 
Diabetes mellitus 1 
MI at presentation 1 
Prior PCI or prior MI 1 
Stent diameter <3 mm 1 
Paclitaxel-eluting stent 1 
CHF or LVEF <30% 2 
SVG PCI 2 
Long Term Ticagrelor, PEGASUS TIMI-54 
Patients 1-3 years after MI 
80% underwent PCI 
Ticagrelor 60 mg 
equivalent to 90 mg in 
MACE reduction up to 
study duration of 3 years 
TIMI Major bleeding 
increased without 
increased rate of fatal 
bleeding or intrcranial 
hemorrhage - 2.6% vs. 
2.3% vs 1.1% 
Bonaca MP et al. N Eng J Med 2015 
Triple Therapy (DAPT + Anticoagulant) 
• 2-3 x increased bleeding 
• Assess ischemic and bleeding risks (HAS-BLED) 
• Duration as short as possible 
• Clopidogrel is drug of choice 
• Dual therapy (no aspirin) may be considered 
• Consider INR 2.0-2.5 
• No NOAC data, Warfarin is preferred 
• Paradigm may change as reversal agents are approved 
• PPIs should be used for bleeding prophylaxis in high risk GI 
bleeding patients 
Conclusions 
• DAPT therapy post PCI decreases stent thrombosis & CV 
MACE 
• DAPT therapy increases bleeding, especially with other 
agents 
• Multiple permutations are possible with complex 
differences 
• Risk of stent thrombosis decreases with time post PCI and 
is dependent on the type of stent 
• Multiple DAPT duration options are now available – 1 
month, 3 months, 6 months, 12 months and up to 30 
months post PCI 
• Scoring systems are now available for DAPT duration 
decisions 
Thank You 
Thank You