What evidence evaluates rectal administration of P2Y12 inhibitors?

Introduction
The P2Y12 inhibitors are potent antiplatelet agents integral to the management of acute coronary syndrome and ischemic stroke.1,2 The oral agents—clopidogrel, prasugrel, and ticagrelor—are available exclusively in tablet form.3 In cases where enteral administration is contraindicated or impractical, cangrelor offers an intravenous (IV) alternative.2,3 However, in rare situations where neither oral nor IV administration is feasible, rectal administration of oral tablets may be considered as a temporary administration option.

Literature review
Evidence supporting rectal administration of P2Y12 inhibitors is limited to an animal study and case reports/series.4-6

In a 2025 abstract presentation, Cox et al from the University of Texas Southwestern Medical Center presented a case series describing rectal administration of clopidogrel in one patient and prasugrel in another.4 In the first case, rectal clopidogrel was administered after enteral access was lost in a 68-year-old female with Barrett’s esophagus who had undergone percutaneous revascularization complicated by retroperitoneal bleeding. In the second case, rectal prasugrel was administered to a 69-year-old female with acute stent thrombosis and respiratory failure 10 days after percutaneous revascularization. This case was further complicated by emphysematous gastritis and suspected gastric perforation. Platelet aggregation studies demonstrated adequate adenosine diphosphate (ADP) response after 2 doses in both cases, and rectal administration was continued for 8 days with no reported bleeding or ischemic complications. There were few details reported on the rectal formulation or dosage; however, both drugs were compounded with a suppository vehicle to optimize upper rectum drug delivery.

Nowrozi et al (2024) reported a single case involving rectal administration of ticagrelor in an abstract presentation of a 63-year-old female presenting with hematemesis and chest pain.5 The patient received 2 drug-eluting stents and loading doses of aspirin 325 mg and clopidogrel 600 mg. A duodenal perforation was also identified requiring partial duodenectomy and end-to-end anastomosis. Rectal aspirin and ticagrelor were initiated postoperatively given the contraindication to enteral access and lack of IV antiplatelet availability. Levels of P2Y12 were adequately suppressed by 48 hours and remained between 40 and 70 platelet reactivity units (PRU) (reference range 194 to 418 PRU). The patient was eventually transitioned to oral therapy. No additional clinical outcomes or rectal formulation details were reported.

Kechyn et al (2021) compared absorption of 75 mg rectal clopidogrel to 75 mg oral clopidogrel in a rat model.6 Platelet aggregation was inhibited to a greater extent with rectal administration both at 6 hours (44.6% vs 40.4%) and on day 5 (67.7% vs 58.8%). No other parameters were reported, and the clinical applicability of this study is limited.

Considerations and Conclusions
There is limited evidence supporting the use of rectal P2Y12 inhibitors. A single case report exists for each of the oral agents – clopidogrel, prasugrel, and ticagrelor. While all reports indicate positive laboratory outcomes, there is minimal reporting of clinical outcomes. In addition, details regarding formulation and administration are lacking which limits implementation in clinical settings.

While prasugrel and ticagrelor offer a theoretical advantage over clopidogrel in this context due to their more predictable pharmacokinetics and lack of reliance on metabolic activation, current evidence is insufficient to support the preferential use of any specific agent. Moreover, the available data on rectal administration of P2Y12 inhibitors are extremely limited; thus, this route should be reserved for cases requiring urgent platelet inhibition when alternative administration routes are not viable.

References

  1. Gawaz M, Geisler T, Borst O. Current concepts and novel targets for antiplatelet therapy. Nat Rev Cardiol. 2023;20(9):583-599. doi:10.1038/s41569-023-00854-6
  2. Rao SV, O’Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2025 Apr;151(13):e865. doi: 10.1161/CIR.0000000000001328.]. Circulation. 2025;151(13):e771-e862. doi:10.1161/CIR.0000000000001309
  3. Clinical Pharmacology. Elsevier. 2025. Accessed June 16, 2025. https://www.clinicalkey.com
  4. Cox K, Skariah LK, Tonleu FH, et al. Platelet aggregometry guidance for rectal P2Y12 inhibition administration following acute myocardial infarction – a case series. J Am Coll Cardiol. 2025;85(12 Suppl A):3131. Presentation number: 985-05. doi:10.1016/S0735-1097(25)03615-0
  5. Nowrozi A, Kim M, Gavrilos G, Hadley S, Kabbany M. Efficacy of rectal dual antiplatelet therapy after percutaneous coronary intervention. Crit Care Med. 2024;52(1):S68. doi: 10.1097/01.ccm.0000998936.01098.49
  6. Kechyn IL, Hladyshev VV, Drozdov OL, Kharaponova OB, Hladysheva SA. Comparative study of specific activity of rectal suppositories with clopidogrel. Current Issues in Pharmacy and Medicine: Science and Practice. 2021;14 (3):314-319. doi: 10.14739/2409-2932.2021.3.242242
  7. Beavers CJ, Patel P, Naqvi IA. Clopidogrel. StatPearls. Updated January 19, 2025. Accessed June 16, 2025. https://www.ncbi.nlm.nih.gov/books/NBK470539

Prepared by:
Courtney Krueger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2025

The information presented is current as June 9, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.