Clinical trial NCT04165629: Platelet Reactivity in PAD Undergoing Percutaneous Angioplasty
Official title: Influence of Platelet Reactivity in Peripheral Arterial Disease Patients Undergoing Percutaneous Angioplasty on Mid-term Outcomes
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Peripheral Artery Disease
Critical Limb Ischemia
Claudication, Intermittent
Lead sponsor: Clinical Centre of Serbia
Sponsor class: OTHER
First posted: 2019-11-18
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients treated at the Clinic for Vascular and Endovascular Surgery, Clinical Center of Serbia, Belgrade due to PAD (critical limb ischemia {CLI} or intermittent claudication {IC}) with PTA with/without stenting of aorto-iliac, femoro-popliteal and crural disease between January 1st 2020 and January 1st 2022

Brief summary: Dual antiplatelet therapy has a key role in a prevention of thrombosis of treated artery in patients undergoing percutaneous transluminal angioplasty (PTA). Weak therapeutic response and presence of residual platelet activity is related to high risk for stent thrombosis and it is well in known in coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However there are few data on the association between a different entity of platelet inhibition on antiplatelet treatment and clinical outcomes in patients with peripheral artery disease (PAD). The aim of this study was to evaluate the degree of on-treatment platelet reactivity, and its association with ischemic and hemorrhagic adverse events at follow up in PAD patients undergoing PTA.

Detailed description: This is a single-center observational cohort study. All together 450 patients undergoing and elective PTA (both with and without stenting) who are going to be refereed to the Clinic for Vascular and Endovascular Surgery (based on the previous experience) during the two year period (January 1st 2020 and January 1st 2022) are planned to be involved in this study. All interventions will be performed according to the current standards and the type of the endovascular procedure will be at the discretion of operator. All patients will receive at the day of treatment 300mg of Aspirin and 300mg of Clopidogrel. The day after the procedure platelet function will be assessed by "point-of-care" impedance aggregometry test using the Multiplate analyzer. According to the manufacturer proposition, resistancy on Aspirin will be defined as arachidonic acid receptor (ASPI) value \< 600 and ASPI/thrombin receptor activating peptide (TRAP) \< 0.5, and for Clopidogrel adenosine diphosphate (ADP) \< 500 and ADP/TRAP \< 0.5 . After that patients will receive dual antiplatelet therapy (Aspirin 100mg and Clopidogrel 75mg) in the six months period. Follow-up examinations will be scheduled on 1, 6 and 12 months after the intervention. Adherence to antiplatelet treatment will assessed during scheduled or unscheduled examinations. Statistical analysis will be performed using the software package SPSS 20 (SPSS Inc., Chicago, Il, USA). Categorical data will be represented as numbers and percentages. Chi-square test or Fisher exact test as appropriate will be used to compare categorical data. Continuous variables will be represented as mean ± standard deviation and as median and interquartile range, depending on the normality of data. Student's t test or Mann-Whitney U test as appropriate will be used to compare two population groups. We will then assess the ability of ASPI and ADP values to distinguish between patients with and without clinical event at 6 months follow up by receiver-operating characteristic (ROC) curve analysis and the optimal cut-off ASPI and ADP values will be determined by estimating the value resulting in the maximum sum of sensitivity and specificity (area under the curve - AUC). Kaplan-Meier curves with log-rank test will be used to assess difference in the time-to-event end-points. A multivariable Cox proportional hazard model adjusted for clinical and laboratory variables will be performed to evaluate the independent contribution of platelet hyper- or hypo-reactivity to the outcomes. A P-values \<0.05 will be considered statistically significant.

Eligibility criteria: Inclusion Criteria:

- all patients treated due to PAD with PTA with/without stenting of aorto-iliac, femoro-popliteal and crural disease at the mentioned time period with critical limb ischemia (CLI) or intermittent claudication (IC)

Exclusion Criteria:

* younger that 18 and older than 85
* contraindications for Aspirin and Clopidogrel use
* thrombocytopenia (\<100 x 10⁹/l)
* thrombocytosis (\>450 x 10⁹/l)
* kidney insufficiency (stage 4 and 5)
* more severe anemia (Hgb \< 100 g/l)
* severe hepatic disorder
* congestive heart failure
* known hemorrhagic disorder
* known malignant disease
* previous use of drugs with known anti-thrombocyte mechanism of action (dipyridamole, NSAID)
* use oral anticoagulant therapy
* use of corticosteroids
* use of drugs that are metabolized threw CYP3A4 (like erythromycin and rifampicin)

Primary outcomes:
measure: Major Adverse Limb Event (MALE)
timeFrame: 6 months
measure: Mortality
timeFrame: 6 months
Secondary outcomes:
measure: Major Adverse Cardio- and Cerebrovascular Events (MACCE)
timeFrame: 6 months
measure: Bleeding complications
timeFrame: 6 months
Other outcomes:
Locations:
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
Study officials:
affiliation: Clinical Center of Serbia
name: Petar Zlatanovic, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Spiliopoulos S, Pastromas G, Katsanos K, Kitrou P, Karnabatidis D, Siablis D. Platelet responsiveness to clopidogrel treatment after peripheral endovascular procedures: the PRECLOP study: clinical impact and optimal cutoff value of on-treatment high platelet reactivity. J Am Coll Cardiol. 2013 Jun 18;61(24):2428-2434. doi: 10.1016/j.jacc.2013.03.036. Epub 2013 Apr 16.
citation: Grifoni E, Gori AM, Giusti B, Valenti R, Migliorini A, Basili S, Paniccia R, Elmahdy MF, Pulli R, Pratesi C, Antoniucci D, Violi F, Marcucci R. On-Treatment Platelet Reactivity is a Predictor of Adverse Events in Peripheral Artery Disease Patients Undergoing Percutaneous Angioplasty. Eur J Vasc Endovasc Surg. 2018 Oct;56(4):545-552. doi: 10.1016/j.ejvs.2018.06.032. Epub 2018 Jul 17.
citation: Leunissen TC, Peeters Weem SM, Urbanus RT, den Ruijter HM, Moll FL, Asselbergs FW, de Borst GJ. High On-Treatment Platelet Reactivity in Peripheral Arterial Disease: A Pilot Study to Find the Optimal Test and Cut Off Values. Eur J Vasc Endovasc Surg. 2016 Aug;52(2):198-204. doi: 10.1016/j.ejvs.2016.04.019. Epub 2016 May 25.
citation: Pastromas G, Spiliopoulos S, Katsanos K, Diamantopoulos A, Kitrou P, Karnabatidis D, Siablis D. Clopidogrel responsiveness in patients undergoing peripheral angioplasty. Cardiovasc Intervent Radiol. 2013 Dec;36(6):1493-1499. doi: 10.1007/s00270-013-0577-3. Epub 2013 Feb 14.
citation: Spiliopoulos S, Pastromas G. Current status of high on-treatment platelet reactivity in patients with coronary or peripheral arterial disease: Mechanisms, evaluation and clinical implications. World J Cardiol. 2015 Dec 26;7(12):912-21. doi: 10.4330/wjc.v7.i12.912.