anticoagulation and antiplatelet therapy in the treatment ... · the mechanisms of hemostasis and...

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

Flowing blood in an artery

Hemostasis

GFP-labeled plateletsThrombosis in vivo

Courtesy: Dr. Tim Kyin

Hemostasis

Platelets Coagulation

Hemostasis


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


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


Rivaroxaban in Stable Peripheral or Carotid Artery disease

Anand SS, et al. Lancet. 2018;391(10117):219-229.

46% RRR

CV

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Str

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ALI

, CLI

, am

puta

tion

(cum

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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

(%)


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]

anticoagulation and antiplatelet therapy in the treatment ... · the mechanisms of hemostasis and...

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