anticoagulation and antiplatelet therapy in the treatment ... · the mechanisms of hemostasis and...
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Anticoagulation and Antiplatelet Therapy in the Treatment of PVD
Ian Del Conde, MD
Faculty DisclosuresIan DelConde: Speakers’ Bureau – Bristol Myers Squibb, J&J, Janssen, Lantheus, Merck
Brand names are included in this presentation for participant clarification purposes only. No product promotion should be inferred.
Hemostasis
Hemostasis
Hemostasis
Flowing blood in an artery
Hemostasis
GFP-labeled plateletsThrombosis in vivo
Courtesy: Dr. Tim Kyin
Hemostasis
Platelets Coagulation
Hemostasis
Platelets Coagulation
Two systems working hand-in-hand
Dr. Richard Farndale, Cambridge
Initiation
Propagation
The Mechanisms of Hemostasisand Thrombosis
Platelets CoagulationAm J Pathol. 1966 Jan; 48(1): 19–44
The Mechanisms of Hemostasisand Thrombosis
Platelets Coagulation
Therapeutictargets
Antiplatelet drugs Anticoagulants
TXA2
COX
GP IIb/IIIa(fibrinogenReceptor)
ADP
cAMP
Phosphodiesterase
ThrombinCollagenTXA2
ACTIVATION
ASA
Clopidogrel DipyridamoleTiclopidine
Ticagrelor
Shafer AI. Am J Med. 1996;101:199
Vorapaxar
Prasugrel
ADP
GP IIb/IIIa antagonists(e.g. abciximab)
Aspirin
• More than 1 century old
• Inhibits COX (and TXA2 production)
• Time to peak action = within 1 hr (even faster)
• Pharmacological half-life = 15-20 min
• Full antiplatelet effect with 81 mg
There Are Little Data to Support Aspirin for MACE Prevention in PAD
Berger JS, et al. JAMA. 2009;301(18):1909-1919.
ADP (PDY12) Receptor antagonists
• 1st generation (thienopyridines): Clopidogrel, ticlopidine
• 3rd generation: Ticagrelor, Prasugrel
• Uses: Post-intervention (DAPT); evolving role as monotherapy.
• Drug half-life of oral ADP-R antagonists is about 7 hrs, but its biological half-life is much longer (10-15% of platelets are replaced every day)
Clopidogrel May Be Better than ASA in PAD
CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-1339.
PAD = Previous revascularization of the lowerlimbs for symptomatic disease more than 30days before randomization or hemodynamicevidence of peripheral artery disease, as evidenced by an ankle-brachial index (ABI) of0.80 or less
EUCLID:in PAD,
ticagrelor is NOTbetter thanclopidogrel
Hiatt WR, et al. N Engl J Med. 2017;376(1):32-40.
Ticagrelor Vs Clopidogrel
Limited Data Suggest DAPT May Benefit Some (High-Risk?) PAD Patients
Cacoub PP, et al. Eur Heart J. 2009;30(2):192-201.
TXA2
COX
GP IIb/IIIa(fibrinogenReceptor)
ADP
cAMP
Phosphodiesterase
ThrombinCollagenTXA2
ACTIVATION
ASA
Clopidogrel DipyridamoleTiclopidine
Ticagrelor
Shafer AI. Am J Med. 1996;101:199
Vorapaxar
Prasugrel
ADP
GP IIb/IIIa antagonists(e.g. abciximab)
Bonaca MP, et al. Circulation. 2013;127(14):1522-1529.
Placebo
Vorapaxar
Hospitalization for Acute Limb Ischemia
Placebo
Vorapaxar
Peripheral Revascularization
Bonaca MP, et al. Circulation. 2013;127(14):1522-1529.
Platelets CoagulationAm J Pathol. 1966 Jan; 48(1): 19–44
Can Anticoagulants and Antiplatelet Drugs be Combined Safely in Long-Term Therapy?
• 2161 patients with PAD (including LE and carotids)
• Followed for 35 months
• Warfarin (INR 2-3) + antiplatelet, Vs. antiplatelet alone (92% ASA)
• No benefit for MACE: 12.2% vs 13.3%
(HR 0.92, 95% CI 0.73-1.16; p=0.48)
• No benefit for limb events
• 3-fold increase in the risk of life-threatening bleeding (4.0% vs. 1.2%, P<0.001)
WAVE: Oral Anticoagulation for PAD
WAVE Investigators. NEJM 2007; 357:217-227
Gerhard-Herman MD, et al. JACC. 2017;69:e71-e126
COMPASS Trial Design
Eikelboom JW, et al. N Engl J Med. 2017;377(14):1319-1330.
Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS)
• PAD Eligibility: 7470 patientsü Peripheral artery revascularizationü Limb or foot amputation for PADü Intermittent claudication plus ABI <0.9 or stenosis >50%ü CAD + ABI <0.9ü Carotid revascularization or asymptomatic >50% CAS
Eikelboom JW, et al. N Engl J Med. 2017;377(14):1319-1330.
Rivaroxaban in Stable Peripheral or Carotid Artery disease
Anand SS, et al. Lancet. 2018;391(10117):219-229.
46% RRR
CV
dea
th, M
I, or
Str
oke
(cum
ulat
ive
inci
denc
e ri
sk)
ALI
, CLI
, am
puta
tion
(cum
ulat
ive
inci
denc
e ri
sk)
Low-dose Riva + ASARiva aloneASA alone
Low-dose Riva + ASARiva aloneASA alone
28% RRR
Rivaroxaban in Stable Peripheral or Carotid Artery disease
Anand SS, et al. Lancet. 2018;391(10117):219-229.
46% RRR
CV
dea
th, M
I, or
Str
oke
(cum
ulat
ive
inci
denc
e ri
sk)
ALI
, CLI
, am
puta
tion
(cum
ulat
ive
inci
denc
e ri
sk)
Low-dose Riva + ASARiva aloneASA alone
Low-dose Riva + ASARiva aloneASA alone
28% RRR
Low-Dose Riva/ASA ComboREDUCTION OF ALL-CAUSE MORTALITY
4.1
3.4
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Rivaroxaban 2.5 mg twice daily +
Aspirin 100 mg once daily
Aspirin 100 mg once daily
HR=0.82 (95% CI: 0.71-0.96)*
18% RRR†
Inci
denc
e R
ate
(%)
Eikelboom JW, et al. N Engl J Med. 2017;377(14):1319-1330.
VOYAGER-PAD Trial
• Residual MACE and MALE risk in PAD patients despite antiplatelet therapy.
• COMPASS validates the thesis that combination therapy (very low-dose rivaroxaban/ASA) leads to decreased ischemic/thrombotic complications (MACE/MALE) in stable PAD and CAD.
• The field of anti-thrombotic therapy in PAD (stable and post-revascularization) is rapidly evolving.
Summary
Thanks
Ian Del [email protected]