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

1.1. 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.

Table 1. Maximum Daily Adult Dosages for PAIs – Monotherapy1-8
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
Table 2. Maximum Daily Adult Dosages for PAIs – Combination Therapy1,2,9,10
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.

Table 3. PAI Recommended Treatment Duration (Adults) – Monotherapy1-4,6-8
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
Table 4. Adult PAI Recommended Combination Therapy Treatment Duration1,2,9,10
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.

Table 5: Major Platelet Aggregation Inhibitor Drug-Drug Interactions1-10
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

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed October 10, 2022.
  2. 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.
  3. Cilostazol tablets package insert. Teva Pharmaceuticals USA, Inc., July 2022.
  4. Clopidogrel tablets (Plavix®) package insert. Sanofi-Aventis US, September 2022.
  5. Dipyridamole tablets package insert. ANI Pharmaceuticals, Inc., November 2021.
  6. Prasugrel tablets (Effient®) package insert. Cossette Pharmaceuticals, Inc., February 2022.
  7. Ticagrelor tablets (Brilinta®) package insert. AstraZeneca Pharmaceuticals, May 2022.
  8. Vorapaxar tablets (Zontivity®) package insert. WraSer Pharmaceuticals, October 2022.
  9.  Aspirin/omeprazole tablets (Yosprala®) package insert. Genus Lifesciences, Inc., March 2022. 
  10. Aspirin/dipyridamole tablets (Aggrenox®) package insert. Boehringer Inelheim Pharmaceuticals, Inc., May 2021.