Platelet Aggregation Inhibitors
Platelet Aggregation Inhibitors - Index
Medications listed in the tables and non-FDA approved indications that may be included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage.
- Revision history
- Jan. 23. 2023
- Jan. 22, 2021
- March 2019
- Initially developed
- Dec. 2016
1. Dosage
1.1. Adults
Platelet aggregation inhibitors (PAIs) are FDA-approved to reduce thrombotic cardiovascular events in patients with a history of ischemic stroke, or to prevent stroke in patients with predisposing factors for atherosclerosis or symptomatic cerebrovascular disease.1-12 PAIs work by interfering with pathways that promote normal platelet function: inhibiting cyclooxygenase-1 (e.g., aspirin); inhibiting adenosine uptake into platelets, resulting in increased cyclic-3’,5’-adenosine monophosphate (cAMP) and adenosine levels (e.g., dipyridamole); inhibiting the adenosine diphosphate (ADP) P2Y12 receptor on the platelet surface and blocking activation of the glycoprotein GPIIb/IIIa complex (e.g., clopidogrel, prasugrel, ticagrelor); antagonizing protease-activated receptor 1 (PAR-1), which inhibits thrombin and thrombin receptor agonist peptide activity (e.g., vorapaxar); or inhibiting phosphodiesterase lll (e.g., cilostazol).2-4, 13
Aspirin is available in combination with omeprazole, a proton pump inhibitor, to reduce the risk of aspirin-associated gastric ulcers in those patients requiring aspirin for secondary prevention of cardiovascular and cerebrovascular events.2-4, 10 Aspirin is also available as combination therapy with dipyridamole, pairing two antiplatelet agents with different mechanisms of action for secondary stroke prevention.2-4, 11 Maximum recommended adult dosages for PAIs are summarized in Tables 1 and 2 (1-3, 5-12). Medication profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.
Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
---|---|---|---|
cilostazol (generics) | 50 mg, 100 mg tablets | intermittent claudication | 100 mg twice daily |
clopidogrel (Plavix®, generics) | 75 mg, 300 mg tablets | ACS, including UA/NSTEMI and STEMI | Initial: 300 mg or 600 mg loading dose, followed by 75 mg once daily for up to 12 months in combination with aspirin, followed by aspirin indefinitely |
thromboembolism prophylaxis in patients with recent MI or stroke, or established peripheral vascular disease | 75 mg/day | ||
dipyridamole (generics) | 25 mg, 50 mg, 75 mg tablets | prevention of postoperative thrombotic complications in patients with prosthetic heart valves | 400 mg/day (divided doses, in combination with warfarin) or 400 mg/day (divided doses, in combination with aspirin) |
prasugrel (Effient®, generics) | 5 mg, 10 mg tablets | ACS in patients to be managed with PCI | following a 60 mg loading dose, 10 mg/day+ in combination with aspirin |
ticagrelor (Brilinta®) | 60 mg, 90 mg tablets | reduce risk of death, MI, and stroke in patients with ACS, history of MI, or acute ischemic stroke/ high risk transient ischemic attack | following a 180 mg loading dose, 90 mg twice daily^ in combination with aspirin |
reduce risk of first MI or stroke in patients with CAD at high risk of events | 60 mg twice daily in combination with aspirin | ||
vorapaxar (Zontivity®) | 2.08 mg tablet | MI, stroke, thrombosis prophylaxis in patients with a history of MI or PAD | 2.08 mg/day in combination with aspirin or clopidogrel |
Legend:
- ACS = acute coronary syndrome
- CAD = coronary artery disease
- MI = myocardial infarction
- NSTE-ACS = non-ST-elevation acute coronary syndrome
- NSTEMI = non-ST-elevation myocardial infarction
- PAD = peripheral arterial disease
- PCI = percutaneous coronary intervention
- STEMI = ST-elevation myocardial infarction
- TIA = transient ischemic attack
- UA = unstable angina
- + patients 75 years or older or weigh less than 60 kg may use prasugrel 5 mg/day as maintenance therapy in combination with aspirin to reduce bleeding risk
- ^ ticagrelor dosages are decreased to 60 mg twice daily after 12 months
Drug Name | Dosage Form/ Strength | Treatment Indication | Maximum Recommended Dosage |
---|---|---|---|
aspirin/ omeprazole (Yosprala®) | 81 mg/40 mg, 325 mg/40 mg delayed-release tablets | secondary prevention of cardiovascular and cerebrovascular events in patients predisposed to gastric ulcers | 325 mg/40 mg once daily |
dipyridamole/aspirin (generics) | 200 mg/25 mg extended-release capsule | secondary stroke prevention | 200 mg/25 mg twice daily |
1.2. Pediatrics
Dipyridamole is FDA-approved for use in pediatric patients 12 years of age and older as adjunctive therapy to prevent thromboembolism following cardiac valve replacement. The maximum recommended dose is 100 mg four times daily in combination with warfarin. Dosages exceeding these recommendations will be reviewed.
Aspirin as Durlaza®, cilostazol, prasugrel, ticagrelor, vorapaxar, aspirin/omeprazole, and dipyridamole/aspirin are not recommended for use in pediatric patients as safety and efficacy have not been established for these agents in this patient population. Although not FDA-approved, clopidogrel has effectively been used in pediatric patients to reduce thrombosis risk in infants and children with select types of heart disease, or as an alternative in patients with Kawasaki disease or ischemic stroke when aspirin is not tolerated.2, 3, 14-17
2. Duration of Therapy
There is no basis for limiting PAI therapy duration when prescribed to prevent thromboembolic events associated with cardiovascular or cerebrovascular disease. However, PAI therapy duration varies based on medication utilized and indication for use. PAI treatment durations are summarized in Tables 3 and 4.
Drug Name | Treatment Indication | Maximum Treatment Duration |
---|---|---|
cilostazol | intermittent claudication | indefinite |
clopidogrel | acute coronary syndrome (NSTE-ACS and STEMI) | up to 1 year, in combination with aspirin; aspirin then continued indefinitely + |
thromboembolism prophylaxis | indefinite | |
prasugrel | ACS in patients to be managed with PCI | at least 12 months, in combination with aspirin, after stent placement |
ticagrelor | ACS | 90 mg twice daily x 1 year in combination with aspirin; then, 60 mg twice daily in combination with aspirin indefinitely |
vorapaxar | MI, stroke, thrombosis prophylaxis in patients with a history of MI or PAD | indefinite, in combination with aspirin or clopidogrel |
Legend:
- ACS = acute coronary syndrome
- CAD = coronary artery disease
- MI = myocardial infarction
- NSTE-ACS = non-ST-elevation acute coronary syndrome
- NSTEMI = non-ST-elevation myocardial infarction
- PAD = peripheral arterial disease
- PCI = percutaneous coronary intervention
- STEMI = ST-elevation myocardial infarction
- TIA = transient ischemic attack
- + in patients with aspirin allergy, clopidogrel monotherapy may be continued indefinitely
Drug Name | Treatment Indication | Maximum Treatment Duration |
---|---|---|
aspirin/omeprazole | secondary prevention of cardiovascular and cerebrovascular events in patients predisposed to gastric ulcers | indefinite |
dipyridamole/aspirin | stroke prevention | indefinite |
3. Duplicative Therapy
Adjunctive therapy with aspirin and clopidogrel, dipyridamole, prasugrel, ticagrelor, or vorapaxar has documented efficacy for acute coronary syndrome or thrombotic event prevention; concurrent therapy with clopidogrel and ticagrelor or vorapaxar is also FDA-approved for thromboembolic event prophylaxis or acute coronary syndrome (see Tables 1-4).1-11,18-19
4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for platelet aggregation inhibitors are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.
Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
---|---|---|---|---|
aspirin | methotrexate (MTX) | potential for increased MTX serum levels, risk of enhanced pharmacologic/ toxic effects as NSAIDs can reduce MTX clearance | avoid concurrent aspirin use within 10 days of high-dose MTX; otherwise, use cautiously together; monitor for increased myelosuppressive, GI adverse effects; may consider using longer leucovorin rescue | major (DrugReax) 1-severe (CP) |
cilostazol, dipyridamole | riociguat (Adempas®) | concurrent administration may result in increased hypotension risk | avoid concurrent use | contraindicated (DrugReax) dipyridamole: 1-severe; cilostazol: 3-moderate (CP) |
cilostazol, ticagrelor, vorapaxar | itraconazole, strong CYP3A4 inhibitors | co-administration may result in elevated serum concentrations of select platelet aggregation inhibitors (PAIs) and potential bleeding complications as cilostazol, ticagrelor, and vorapaxar metabolized by CYP3A4 | avoid use; ticagrelor therapy should not be initiated for at least 2 weeks after itraconazole discontinuation; if adjunctive administration necessary, use cautiously and monitor patient closely for enhanced pharmacologic/ adverse effects, especially bleeding | ticagrelor: contraindicated; cilostazol, vorapaxar: major (DrugReax) ticagrelor: 1-severe; cilostazol, vorapaxar: 2-major (CP) |
clopidogrel | dasabuvir/ombitasvir/paritaprevir/ritonavir (Viekira®) | adjunctive administration with clopidogrel (strong CYP2C8 inhibitor) contraindicated by manufacturer, as dasabuvir metabolized by CYP2C8, which increases risk for dasabuvir-induced QT interval prolongation; ritonavir, a CYP3A4 inhibitor, may limit clopidogrel conversion to active metabolite | avoid concurrent use | 1-severe (CP) |
clopidogrel | omeprazole | strong CYP2C19 inhibitor (e.g. omeprazole) may result in reduced plasma concentrations of clopidogrel active metabolite and diminish antiplatelet activity | avoid concurrent use; consider alternative proton pump inhibitor (e.g. pantoprazole) | major (DrugReax) 2-major (CP) |
PAIs | defibrotide | increased risk of hemorrhage when used adjunctively with antithrombotic/ fibrinolytic drugs like PAIs | avoid concurrent use | contraindicated (DrugReax) 1-severe (CP) |
PAIs, including aspirin | low molecular weight heparins | potential for additive bleeding adverse effects; PAIs inhibit platelet aggregation and have increased bleeding risk, prolonged bleeding time | avoid concurrent therapy, if possible; if drug combination necessary, use cautiously, monitor for signs/symptoms of bleeding | major, moderate (DrugReax) 2-major, 3-moderate (CP) |
PAIs, including aspirin | selective serotonin reuptake inhibitors (SSRIs)/, serotonin norepinephrine reuptake inhibitors (SNRIs) | increased bleeding risk with combined therapy; SSRIs/SNRIs deplete platelet serotonin, which may impair platelet aggregation | monitor for signs/symptoms of bleeding; may consider substituting tricyclic antidepressant for SSRI/SNRI | SSRIs –major; SNRIs-major (DrugReax) 3-moderate (CP) |
PAIs, including aspirin | anticoagulants | combined administration may increase bleeding risk, due to additive effects | if combined therapy necessary, monitor patients closely for bleeding signs/symptoms | major (DrugReax) 2-major, 3-moderate (CP) |
PAIs | nonsteroidal anti-inflammatory drugs (NSAIDs) | concurrent use may increase risk for bleeding especially with chronic NSAID use | monitor for signs of bleeding with concurrent use | major (DrugReax) 3-moderate (CP) |
ticagrelor, vorapaxar | strong CYP3A inducers (e.g., rifampin) | strong inducers substantially reduce ticagrelor, vorapaxar exposure and efficacy as both are CYP3A4 substrates | avoid use | major (DrugReax) 2–major (CP) |
ticagrelor | simvastatin, lovastatin | adjunctive use may increase lovastatin, simvastatin serum levels as ticagrelor is CYP3A4 inhibitor and lovastatin and simvastatin are metabolized by CYP3A4 | avoid lovastatin, simvastatin doses higher than 40 mg; observe for adverse effects if combined use necessary | moderate (DrugReax) 2–major (CP) |
5. References
- Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed October 10, 2022.
- IMB Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed October 10, 2022.
- Cilostazol tablets package insert. Teva Pharmaceuticals USA, Inc., July 2022.
- Clopidogrel tablets (Plavix®) package insert. Sanofi-Aventis US, September 2022.
- Dipyridamole tablets package insert. ANI Pharmaceuticals, Inc., November 2021.
- Prasugrel tablets (Effient®) package insert. Cossette Pharmaceuticals, Inc., February 2022.
- Ticagrelor tablets (Brilinta®) package insert. AstraZeneca Pharmaceuticals, May 2022.
- Vorapaxar tablets (Zontivity®) package insert. WraSer Pharmaceuticals, October 2022.
- Aspirin/omeprazole tablets (Yosprala®) package insert. Genus Lifesciences, Inc., March 2022.
- Aspirin/dipyridamole tablets (Aggrenox®) package insert. Boehringer Inelheim Pharmaceuticals, Inc., May 2021.