Personalizing Thromboprophylaxis for Patients With Peripheral Artery Disease

Official title

Personalizing Post Surgical Thromboprophylaxis for Patients With Peripheral Artery Disease

Overview

The goal of this clinical trial is to determine whether a personalised blood clot prevention plan is more effective than standard treatment in adults with peripheral artery disease (PAD) who have undergone a procedure to restore blood flow to their legs. The main questions it aims to answer are: * Does the personalized plan lower the rate of blood clots in the treated leg one year after the procedure? * Does the personalized plan lower rates of amputation, repeat procedures, bleeding, and death compared to standard treatment? Researchers will compare the personalized TARGET plan which uses a blood test to tailor each person's blood clot prevention medication to the standard treatment to see if the personalized approach works better. Participants will: * Be randomly assigned to either the personalized TARGET plan or standard treatment after their procedure * Have blood tests at 1 week and at 1, 3, 6, 9, and 12 months after their procedure * Have medications adjusted based on blood test results if assigned to the TARGET group

Detailed description

SCIENTIFIC RATIONALE Graft and stent thrombosis occurs in approximately 17% of PAD patients within 6 months of lower extremity revascularization and is the leading driver of amputation and death in this population. Current standard-of-care (SOC) thromboprophylaxis applies a uniform antiplatelet regimen despite well-documented inter-patient variability in platelet reactivity and drug response - up to 60-65% of PAD patients demonstrate resistance to aspirin or clopidogrel. The absence of personalized, objective thromboprophylaxis strategies represents a critical gap in PAD management.

TECHNOLOGY: THROMBOELASTOGRAPHY WITH PLATELET MAPPING (TEG-PM)

TEG-PM is a whole-blood, point-of-care assay providing real-time assessment of a patient's complete coagulation profile. TEG characterizes clot initiation (R time), kinetics (K time, α angle), maximum clot strength (mA), and fibrinolysis (Lysis 30), enabling discrimination between hypo- and hypercoagulable states. Platelet Mapping quantifies platelet inhibition via arachidonic acid (AA) and adenosine diphosphate (ADP) agonist assays, yielding a platelet inhibition percentage that reflects each patient's real-time pharmacodynamic response to antiplatelet therapy. All samples are analyzed on a TEG 6s (Haemonetics®) Hemostasis Analyzer within validated processing windows using citrated and sodium heparin tubes.

PRELIMINARY DATA A prospective observational study of 162 PAD patients identified platelet inhibition as the sole independent predictor of post-revascularization thrombosis. A threshold of 29% identified high thrombotic risk (87% sensitivity, 71% specificity; AUC 0.756), while an upper threshold of 86% identified elevated bleeding risk (71% sensitivity, 87% specificity; AUC 0.84), defining a therapeutic window of 29-86%. A separate analysis of 521 TEG-PM samples from 143 PAD patients confirmed extensive inter-patient variability in platelet inhibition response, supporting the case against uniform treatment strategies.

Pilot implementation in 34 patients produced a thrombosis rate of 3.8% vs. 20% under SOC (p\<0.05) with no increase in bleeding. A subsequent prospective comparison of 70 protocol-guided patients against 267 SOC patients demonstrated thrombosis rates of 4.3% vs. 20.6%, with fewer bleeding events in the protocol-guided arm.

THE TARGET PROTOCOL The Thromboprophylaxis for Arterial Revascularization to Guide Elderly Therapy (TARGET) protocol integrates serial TEG-PM assessments into clinical decision-making to maintain platelet inhibition within the 29-86% therapeutic window throughout 12 months. TEG-PM is first performed at 7 days postoperatively. If platelet inhibition falls outside the therapeutic range, the antiplatelet regimen is adjusted per a prespecified escalation/de-escalation algorithm, with repeat testing 7 days after each change. Once the target range is achieved, monitoring continues at 1, 3, 6, 9, and 12 months with adjustments made as needed. Patients refractory to stepwise adjustments are referred to hematology once for further evaluation and remain enrolled on their last recommended regimen. All patients who receive clopidogrel for at least 7 days undergo VerifyNow P2Y12 resistance testing at a single timepoint to inform agent selection. Control arm patients receive SOC therapy throughout; TEG-PM is collected for data purposes only with no medication adjustments made.

COAGULATION TESTING SCHEDULE TEG-PM samples are collected at: preoperative baseline, 1 week (7-20 days post-op), 1 month (27-47 days), 3 months (85-105 days), 6 months (180-210 days), 9 months (270-295 days), and 12 months (365-390 days). Unscheduled samples may be collected at the PI's discretion in response to clinical events such as thrombosis, bleeding, or inconclusive results.

Interventions

• Drug Aspirin
  Aspirin is an oral antiplatelet agent that inhibits cyclooxygenase-mediated thromboxane A2 production, reducing platelet aggregation. It serves as the foundational antiplatelet agent in both study arms following lower extremity endovascular revascularization.
• Drug Clopidogrel
  Clopidogrel is an oral P2Y12 platelet inhibitor used as part of postoperative antiplatelet therapy following lower extremity endovascular revascularization. In the SOC arm, it is administered as part of a fixed dual antiplatelet regimen. In the TARGET arm, it serves as an initial antiplatelet agent, with continuation or substitution determined by TEG-PM platelet inhibition results and VerifyNow P2Y12 resistance testing. If clopidogrel resistance is identified or platelet inhibition remains below
• Drug Ticagrelor
  Ticagrelor is an oral, reversible P2Y12 platelet inhibitor. Unlike clopidogrel, ticagrelor demonstrates minimal resistance and more consistent platelet inhibition, making it a preferred escalation agent.
• Drug Rivaroxaban
  Rivaroxaban is an oral factor Xa inhibitor used in both study arms. In the SOC arm, low-dose rivaroxaban combined with aspirin represents one of two standard postoperative regimens, administered per surgeon preference. In the TARGET arm, rivaroxaban may be initiated or substituted based on TEG-PM platelet inhibition results and clopidogrel resistance testing findings. Full-dose rivaroxaban is reserved for patients who remain persistently hypercoagulable despite stepwise antiplatelet escalation,
• Device Thromboelastography with Platelet Mapping
  Whole-blood, viscoelastic point-of-care assay used to assess real-time coagulation status and platelet function.

Primary outcome measures

• Incidence of Arterial Thrombosis in the Treated Limb [Time frame: 12 months post-revascularization]

Secondary outcome measures (4)

• Amputation-Free Survival (AFS) [Time frame: 12 months post-revascularization]
• All-Cause Mortality [Time frame: 12 months post-revascularization]
• Reintervention Rate [Time frame: 12 months post-revascularization]
• Incidence of Bleeding Events [Time frame: 12 months post-revascularization]

Eligibility criteria

Inclusion criteria

• Patients with a named arterial extremity injury or named vessel revascularization for atherosclerosis requiring open and/or closed revascularization.
• Patients at the age of 18 or older

Exclusion criteria

• Patients who are younger than 18 years old
• Known pregnancy (females of childbearing potential will have a pregnancy test prior to surgery as per standard of care)
• Prisoners, defined as those who have been directly admitted from a correctional facility.
• No atherosclerosis
• Subject has active stomach ulcers
• Subject has severe hepatic impairment
• Subject has a recent history of intracranial hemorrhage. If the patient has a history of cerebral hemorrhage with no new central nervous system disease of >1 year, the study team will consult with the

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Massachusetts General Hospital — Boston
• Salem Hospital (Mass General Brigham) — Salem

Publications

• Lee I, Suarez S, Hall R, Majumdar M, Bellomo T, Jessula S, Nuzzolo K, Jefferson DM, Zacharias N, Dua A. Optimizing platelet inhibition in peripheral artery disease: A comparison of mono-antiplatelet therapy and dual-antiplatelet therapy using thromboelastography. Vascular. 2025 Feb;33(1):3-18. doi: 10.1177/17085381241237005. Epub 2024 Mar 5. PMID 38441042
• Bates KJ, Moore MM, Cibotti-Sun M. 2024 Lower Extremity Peripheral Artery Disease Guideline-at-a-Glance. J Am Coll Cardiol. 2024 Jun 18;83(24):2605-2609. doi: 10.1016/j.jacc.2024.04.003. Epub 2024 May 14. No abstract available. PMID 38752900
• Suarez S, Agrawal A, Patel S, Grobman B, Ghandour S, Morena L, Rodriguez A, Machlus K, Roy T, Eagleton M, Dua A. The Impact of Sex on Antiplatelet and Anticoagulant Thromboprophylaxis in Patients With Peripheral Artery Disease Post-revascularization. Ann Surg. 2024 Sep 1;280(3):463-472. doi: 10.1097/SLA.0000000000006375. Epub 2024 Jun 11. PMID 38860382
• Suarez Ferreira S, Agrawal A, Lee I, Rodriguez A, Cieri I, Young E, Patel S, Ghandour S, Morena L, Hagos F, Grobman B, Machlus K, Roy T, Dua A. The Use of Clot Strength as a Predictor of Thrombosis in Peripheral Artery Disease. Ann Vasc Surg. 2024 Dec;109:273-283. doi: 10.1016/j.avsg.2024.06.041. Epub 2024 Jul 26. PMID 39069123
• Majumdar M, Hall RP, Feldman Z, Goudot G, Sumetsky N, Jessula S, Kirshkaln A, Bellomo T, Chang D, Cardenas J, Patell R, Eagleton M, Dua A. Predicting Arterial Thrombotic Events Following Peripheral Revascularization Using Objective Viscoelastic Data. J Am Heart Assoc. 2023 Jan 3;12(1):e027790. doi: 10.1161/JAHA.122.027790. Epub 2022 Dec 24. PMID 36565191
• Majumdar M, Waller D, Poyant J, McElroy I, Lella S, Feldman ZM, Levine E, Kim Y, Nuzzolo K, Kirshkaln A, DeCarlo C, Dua A. Variability of antiplatelet response in patients with peripheral artery disease. J Vasc Surg. 2023 Jan;77(1):208-215.e3. doi: 10.1016/j.jvs.2022.08.015. Epub 2022 Aug 24. PMID 36028157
• Hess CN, Norgren L, Ansel GM, Capell WH, Fletcher JP, Fowkes FGR, Gottsater A, Hitos K, Jaff MR, Nordanstig J, Hiatt WR. A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative. Circulation. 2017 Jun 20;135(25):2534-2555. doi: 10.1161/CIRCULATIONAHA.117.0 PMID 28630267
• Owens CD, Ho KJ, Conte MS. Lower extremity vein graft failure: a translational approach. Vasc Med. 2008 Feb;13(1):63-74. doi: 10.1177/1358863X07083432. PMID 18372442

Identifiers

NCT: NCT07613840 · 2024P002975

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗