Antiplatelet drug

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

## Contents

* 1 Overview
* 2 The Most Important Antiplatelet Drugs
* 2.1 COX-2 inhibitor / Cyclooxygenase inhibitors
* 2.2 Phosphodiesterase inhibitors
* 2.3 Glycoprotein IIB/IIIA inhibitors (intravenous use only)
* 2.4 P2Y12 (Adenosine diphosphate receptors) inhibitors
* 2.4.1 Thienopyridines
* 2.4.2 Non-thienopyridines
* 3 Comparative studies
* 3.1 Are newer thienopyridine (third-generation) agents better than older thienopyridine (second-generation) agents?
* 3.1.1 Studies of all patients
* 3.2 Are non-thienopyridines agents better than thienopyridine (second-generation) agents?
* 3.2.1 Studies of all patients
* 3.2.2 Studies of patients with CYP2C19 loss-of-function
* 3.3 Is there a best non-thienopyridine antiplatelet drug?
* 4 Should drug selection be driven by genetic testing and platelet function testing?
* 4.1 Platelet function testing
* 4.2 Cytochrome P450 CYP2C19 testing
* 5 See also
* 6 External links
* 7 References

## Overview

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An antiplatelet drug is a member of a class of pharmaceuticals that decreases platelet aggregation and inhibits thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.

They are widely used in primary and secondary prevention of thrombotic cerebrovascular or cardiovascular disease.

## The Most Important Antiplatelet Drugs

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Comparison of oral antiplatelet
P2Y12 (adenosine diphosphate receptors) inhibitors  Drug Group  | Drug  | Time to onset/peak action  | Barriers*  | Cost (UpToDate 08/2022)

|
|
|
|

Thienopyridines  | Ticlopidine(first generation)
Clopidogrel (second generation)
Prasugrel (third generation)  |
50 to 100 mg: 2 days; 5-7 days
<30 minutes; 4 hours  | P2Y12 and CYP2C19
P2Y12 and CYP2C19
P2Y12 | $112
$195
$495 ($331 GoodRx)
Non-thienopyridines  | Ticagrelor  | <30 minutes; 2 hours  | None  | $511
\\* Other factors for thienopyridines may include diabetes, obesity, elderly according to the protocol for the ARCTIC trial[1].

### COX-2 inhibitor / Cyclooxygenase inhibitors

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* Aspirin

### Phosphodiesterase inhibitors

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* Cilostazol (Pletal)

### Glycoprotein IIB/IIIA inhibitors (intravenous use only)

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* Abciximab (ReoPro)
* Eptifibatide (Integrilin)
* Tirofiban (Aggrastat)
* Defibrotide

### P2Y12 (Adenosine diphosphate receptors) inhibitors

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#### Thienopyridines

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These are prodrugs that require in vivo biotransformation to active metabolite by the cytochrome P450 isoenzymes. With the exception of prasugrel, these drugs are effected by common CYP polymorphisms and less commonly by P2Y12 variants.

* First generation: Ticlopidine (Ticlid)
* Second gereration:Clopidogrel (Plavix)
* Third gereration: Prasugrel

#### Non-thienopyridines

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These drugs bind directly to P2Y12.

* Cangrelor (intravenous)
* Ticagrelor (oral)

## Comparative studies

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### Are newer thienopyridine (third-generation) agents better than older thienopyridine (second-generation) agents?

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#### Studies of all patients

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The TRILOGY ACS randomized controlled trial found no benefit of prasugrel versus clopidogrel (primary outcome: 13.9% vs 16%; hazard ratio 0.91; 0.79 to 1.05; P=0.21) among "patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization"[2].

### Are non-thienopyridines agents better than thienopyridine (second-generation) agents?

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#### Studies of all patients

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The ALPHEUS randomized controlled trial found no benefit of ticagrelor versus clopidogrel among stable coronary patients undergoing high-risk elective PCI (primary outcome in 35% vs 36% of patients)[3].

The POPular AGE randomized controlled trial found no benefit of ticagrelor versus clopidogrel among patients aged 70 years or older with non-ST-elevation acute coronary syndrome (MACE in 11% vs 12% of patients)[4]

The ISAR-REACT 5 randomized controlled trial found harm of ticagrelor versus prasugrel (primary outcome: 9.3% vs 6.9%; hazard ratio, 1.36; 95% confidence interval, 1.09 to 1.70; P = 0.006) among patients with "acute coronary syndromes and for whom invasive evaluation was planned"[5].

The CHAMPION PCI randomized controlled trial found no benefit of cangrelor versus clopidogrel among patients "before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes" (MACE in 7.5% vs 7.1% of patients)[6].

The CHAMPION PLATFORM randomized controlled trial found no benefit of cangrelor added to clopidogrel among patients with acute coronary syndrome before percutaneous coronary intervention (PCI) (MACE in 7% vs 8% of patients) percutaneous coronary intervention (PCI).

#### Studies of patients with CYP2C19 loss-of-function

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The CHANCE-2 randomized controlled trial found benefit of ticagrelor versus clopidogrel (primary outcome: 6% vs 7.6%; hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008) among Chinese patients with minor ischemic stroke or transient ischemic attack (TIA) who carried CYP2C19 loss-of-function alleles[5].

### Is there a best non-thienopyridine antiplatelet drug?

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The POPular Genetics randomized controlled trial found faster onset of action but no benefit of cangrelor versus ticagrelor among patients with "ST-elevation myocardial infarction (STEMI) population treated with primary percutaneous coronary intervention (PPCI"[7].

## Should drug selection be driven by genetic testing and platelet function testing?

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According to the protocol for the ARTIC trial[1], the "VerifyNow P2Y12/aspirin assay measures platelet GPIIb/IIa-dependent aggregation to fibrinogen-coated beads in whole blood"[1]. Variations in function may be due to "insufficient active metabolite generation is the main explanation for clopidogrel antiplatelet response variability, and multiple factors may account for the reduced metabolism: (i) limited intestinal absorption; (ii) polymorphisms in genes encoding for the 2-step process oxidizing clopidogrel into its active metabolite; (iii) interactions with drugs such as lipophilic statins, calcium channel blockers, and proton pump inhibitors. Among these factors, carriage of the Cytochrome P450 CYP2C19*2 polymorphism has been associated with increased risk in stent thrombosis and myocardial infarction especially in patients with ACS who have undergone stent PCI. 6 In addition to the above mechanisms, increased body weight and diabetes have been associated with increased baseline platelet reactivity and a diminished antiplatelet response to clopidogrel"[1].

Guided therapy (drug choice based on genetic testing and platelet function testing may improve outcomes according to a systematic reveiw[8].

#### Platelet function testing

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The ARTIC randomized controlled trial found no benefit from guided therapy with platelet function testing (primary outcomes: 34.6% vs 31.1% ; hazard ratio, 1.13; 95% confidence interval [CI], 0.98 to 1.29; P=0.10) among "patients scheduled for coronary stenting"[9]

* Almost all patients received clopidogrel in the usual care group

* Only 55% of patients had long-term changes in their therapy based on testing

The ANTARCTIC randomized controlled trial found no benefit from guided therapy with platelet function testing (primary outcomes: 28% vs 28%; hazard ratio 1.003, 95% CI 0·78-1·29; p=0·98) among "patients aged 75 years or older who had undergone coronary stenting for acute coronary syndrome"[10]

* Almost all patients in the control group received prasugrel which as less abnormal alleles of cytochrome P450 CYP2C19.

#### Cytochrome P450 CYP2C19 testing

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The POPular Genetics randomized controlled trial found benefit from a cytochrome P450 CYP2C19 guided therapy due to lower (minor) bleeding although the MACE was not reduced (primary outcome: 5.1 vs 5.9%;P = 0.44) among patients undergoing primary PCI with stent implantation[11].

* This trial tested for cytochrome P450 CYP2C19*2 and CYP2C19*2 alleles.
* The accompanying editorial concluded "the POPular Genetics trial provides strong support for a genotype-guided approach to clopidogrel prescribing in patients of European ancestry"[12].

## See also

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* Anticoagulant drug
* Thrombolytic drug
* Antiaggregants

## External links

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## References

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1. ↑ 1.0 1.1 1.2 1.3 Collet JP, Cayla G, Cuisset T, Elhadad S, Rangé G, Vicaut E; et al. (2011). "Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation, 1 year after stenting (ARCTIC) study". Am Heart J. 161 (1): 5–12.e5. doi:10.1016/j.ahj.2010.09.029. PMID 21167334.CS1 maint: Multiple names: authors list (link)
2. ↑ Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG; et al. (2012). "Prasugrel versus clopidogrel for acute coronary syndromes without revascularization". N Engl J Med. 367 (14): 1297–309. doi:10.1056/NEJMoa1205512. PMID 22920930.CS1 maint: Multiple names: authors list (link)
3. ↑ Silvain J, Lattuca B, Beygui F, Rangé G, Motovska Z, Dillinger JG; et al. (2020). "Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial". Lancet. 396 (10264): 1737–1744. doi:10.1016/S0140-6736(20)32236-4. PMID 33202219 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)
4. ↑ Gimbel M, Qaderdan K, Willemsen L, Hermanides R, Bergmeijer T, de Vrey E; et al. (2020). "Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial". Lancet. 395 (10233): 1374–1381. doi:10.1016/S0140-6736(20)30325-1. PMID 32334703 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)  Review in: Ann Intern Med. 2020 Sep 15;173(6):JC28
5. ↑ 5.0 5.1 Wang Y, Meng X, Wang A, Xie X, Pan Y, Johnston SC; et al. (2021). "Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA". N Engl J Med. 385 (27): 2520–2530. doi:10.1056/NEJMoa2111749. PMID 34708996 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)  Review in: Ann Intern Med. 2022 Mar;175(3):JC30
6. ↑ Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM; et al. (2009). "Platelet inhibition with cangrelor in patients undergoing PCI". N Engl J Med. 361 (24): 2318–29. doi:10.1056/NEJMoa0908628. PMID 19915221.CS1 maint: Multiple names: authors list (link)
7. ↑ Ubaid S, Ford TJ, Berry C, Murray HM, Wrigley B, Khan N; et al. (2019). "Cangrelor versus Ticagrelor in Patients Treated with Primary Percutaneous Coronary Intervention: Impact on Platelet Activity, Myocardial Microvascular Function and Infarct Size: A Randomized Controlled Trial". Thromb Haemost. 119 (7): 1171–1181. doi:10.1055/s-0039-1688789. PMID 31129911.CS1 maint: Multiple names: authors list (link)
8. ↑ Galli M, Benenati S, Capodanno D, Franchi F, Rollini F, D'Amario D; et al. (2021). "Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis". Lancet. 397 (10283): 1470–1483. doi:10.1016/S0140-6736(21)00533-X. PMID 33865495 Check `|pmid=` value (help).CS1 maint: Multiple names: authors list (link)
9. ↑ Collet JP, Cuisset T, Rangé G, Cayla G, Elhadad S, Pouillot C; et al. (2012). "Bedside monitoring to adjust antiplatelet therapy for coronary stenting". N Engl J Med. 367 (22): 2100–9. doi:10.1056/NEJMoa1209979. PMID 23121439.CS1 maint: Multiple names: authors list (link)
10. ↑ Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C; et al. (2016). "Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial". Lancet. 388 (10055): 2015–2022. doi:10.1016/S0140-6736(16)31323-X. PMID 27581531.CS1 maint: Multiple names: authors list (link)
11. ↑ Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, van 't Hof AWJ, van der Harst P; et al. (2019). "A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI". N Engl J Med. 381 (17): 1621–1631. doi:10.1056/NEJMoa1907096. PMID 31479209.CS1 maint: Multiple names: authors list (link)
12. ↑ Roden DM (2019). "Clopidogrel Pharmacogenetics - Why the Wait?". N Engl J Med. 381 (17): 1677–1678. doi:10.1056/NEJMe1911496. PMID 31644850.

* v
* t
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Antithrombotics (thrombolytics, anticoagulants and antiplatelet drugs) (B01)

Antiplatelet drugs|

| Glycoprotein IIb/IIIa inhibitors|

* Abciximab
* Eptifibatide
* Orbofiban
* Roxifiban
* Sibrafiban§
* Tirofiban

|

ADP receptor/P2Y12 inhibitors|

* Thienopyridines
* Clopidogrel
* Prasugrel
* Ticlopidine
* Nucleotide/nucleoside analogs
* Cangrelor
* Elinogrel
* Ticagrelor

Prostaglandin analogue (PGI2)|

* Beraprost
* Iloprost
* Prostacyclin
* Treprostinil

COX inhibitors|

* Acetylsalicylic acid/Aspirin#
* Aloxiprin
* Carbasalate calcium
* Indobufen
* Triflusal

Thromboxane inhibitors|

* Thromboxane synthase inhibitors
* Dipyridamole (\+ aspirin)
* Picotamide
* Terbogrel
* Receptor antagonists
* Terbogrel
* Terutroban§

Phosphodiesterase inhibitors|

* Cilostazol
* Dipyridamole
* Triflusal

Other|

* Cloricromen
* Ditazole
* Vorapaxar

Anticoagulants|

| Vitamin K antagonists
(inhibit II, VII, IX, X)|

* Coumarins: Acenocoumarol
* Coumatetralyl
* Dicoumarol
* Ethyl biscoumacetate
* Phenprocoumon
* Warfarin#
* 1,3-Indandiones: Clorindione
* Diphenadione
* Phenindione
* Other: Tioclomarol

|

Factor Xa inhibitors
(with some II inhibition)|

| Heparin group/
glycosaminoglycans/
(bind antithrombin)|

* Low molecular weight heparin
* Bemiparin
* Certoparin
* Dalteparin
* Enoxaparin
* Nadroparin
* Parnaparin
* Reviparin
* Tinzaparin
* Oligosaccharides
* Fondaparinux
* Idraparinux§
* Heparinoids
* Danaparoid
* Dermatan sulfate
* Sulodexide

|

Direct Xa inhibitors ("xabans")|

* Apixaban
* Betrixaban
* Darexaban§
* Edoxaban
* Otamixaban§
* Rivaroxaban

Direct thrombin (IIa) inhibitors|

* Bivalent: Hirudin
* Bivalirudin
* Desirudin
* Lepirudin
* Univalent: Argatroban
* Dabigatran
* Efegatran
* Inogatran§
* Melagatran‡
* Ximelagatran‡

Other|

* Antithrombin III
* Defibrotide
* Protein C
* Drotrecogin alfa‡
* Ramatroban
* REG1

Thrombolytic drugs/
fibrinolytics|

* Plasminogen activators: r-tPA
* Alteplase
* Reteplase
* Tenecteplase
* Desmoteplase†
* UPA
* Saruplase
* Urokinase
* Anistreplase
* Monteplase
* Streptokinase#
* Other serine endopeptidases: Ancrod
* Brinase
* Fibrinolysin

Non-medicinal|

* Citrate
* EDTA
* Oxalate

* #WHO-EM
* ‡Withdrawn from market
* Clinical trials:
* †Phase III
* §Never to phase III

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