Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06089577 |
| Other study ID # |
373 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2023 |
| Est. completion date |
October 2026 |
Study information
| Verified date |
January 2024 |
| Source |
Federico II University |
| Contact |
Luigi Di Serafino, MD, PhD |
| Phone |
+390817462235 |
| Email |
luigi.diserafino[@]unina.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Dual Antiplatelet Therapy represents the main therapy for patients presenting with chronic
coronary syndromes and undergoing elective PCI. However, most of these patients are not
properly covered in terms of inhibition of platelets aggregation at the time of PCI, and are
exposed to an higher risk of microvascular damage which in turns might be responsible of
residual symptoms persistence and the findings of residual ischemia at the non-invasive
tests. In naïve patients, cangrelor can be administered at the time of PCI potentially
protecting coronary microcirculation. The aim of this randomized study is indeed to evaluate
the use of Cangrelor as compared with standard practice (with Clopidogrel) in terms of
incidence of coronary microvascular dysfunction following elective PCI of functionally
significant intermediate coronary stenoses. All consecutive patients, fulfilling inclusion
and exclusion criteria, will be enrolled and both FFR and CFR/IMR will be measured before and
after PCI. Platelet reactivity will be also evaluated mainly during PCI procedure. At 30 days
of follow up, patients will be interrogated about symptoms persistence and will be asked to
complete the specific Seattle Angina Questionaty (SAQ7). At 3 months a SPECT could be
performed in order to evaluate the presence of residual ischemic area in the myocardial
territory downstream to the treated vessel. With this study we will be able to evaluate the
potential benefit of using Cangrelor, as compared with standard therapy with Clopidogrel, in
terms of protection of coronary microcirculation during elective PCI and reduction of both
residual symptoms and ischemia at clinical follow up.
Description:
Background and state of the art Dual antiplatelet therapy (DAPT) is the main therapy for
patients presenting with chronic coronary syndrome (CCS) undergoing elective percutaneous
coronary interventions (PCI). It is mainly represented by acetylsalicylic acid (ASA) and
Adenosine-diphosphate (ADP) receptor antagonists, such as Clopidogrel, Prasugrel and
Ticagrelor. However, pretreatment with DAPT in patients undergoing elective PCI is only
considered optional, thereby a large proportion of these patients is not adequately treated
at the moment of PCI.1, 2 Manipulations of the coronary arteries during PCI, particularly
when complex procedures are performed, might favor platelets aggregation and small thrombus
formations with distal embolization.3, 4 In addition, the higher platelet reactivity in this
context is associated with endothelial dysfunction which might favour the higher incidence of
microvascular damage during PCI.5-9 This latter might be responsible of persistence of angina
symptoms even after successfull PCI.10-12 In the setting of CCS and elective PCI, ASA is
mainly associated with Clopidogrel. This latter is an oral pro-drug which needs to be
converted by the liver in an active metabolite which is able to inhibit the ADP receptor in
few hours after the loading dose. However, some patients might be resistent to Clopidogrel
with inadeguate platelets inhibition and higher risk of ischemic events.1, 2 Normally, in
naïve patients, Clopidogrel is administered at the end of the procedure with an oral loading
dose of 600mg, followed by 75mg per day, while ASA can be administered as soon as possible by
endovenous bolus (250mg).
Cangrelor is an analogous of the ADP which inhibits platelets aggregation in few minutes
after endovenous administration, thereby it can be administered at the moment of PCI
potentially reducing the risk of microvascular damage as compared with regular practice.13
This drug is currently recommended by the European guidelines for coronary revascularization
in CCS patients, not on treatment with other ADP receptor antagonists.
Objectives The main purpose of the present randomised and open-label study will be the
comparison between Cangrelor and regular practice with Clopidogrel in terms of incidence of
microvascular damage in CCS patients undergoing elective PCI. The assessment of microvascular
damage will be performed by measuring the index of microvascular resistance (IMR) before and
after PCI. Even though recommended by the current European guidelines, cangrelor has never
been evaluated with the purpose to protect microcirculation during PCI and this study might
highlight the potential benefit of Cangrelor, as compared with regural practice, in the
context of elective PCI. In addition, as secondary objectives, the occurrence of
peri-procedural myocardial infarction (MI) will be evaluated and platelets reactivity will be
also assessed with the aim to correlate platelets reactivity with IMR values, supporting the
correlation between platelets reactivity and endothelial dysfunction.
At 30 and 90 days of follow-up, patients will report on the persistence of angina symptoms by
completing a specific questionary (SAQ7). This point is also of interest, since coronary
microvascular dysfunction (IMR>25) might be responsible of angina symptoms regardless of the
presence of epicardial stenosis. Microvascular dysfuction can be detected either before PCI
or after PCI as result of microvascular damage. Although with poor prognostic value,
microvascular damage might be responsible of persistence of typical symptoms and ischemic
signs at non-invasive tests despite a successful PCI, leading patients towards the esecution
of several and useless non-invasive and invasive tests. Thereby, the protection of the
coronary microcirculation during elective PCI might significantly reduce the persistence of
typical symptoms in post-PCI patients and finally provide a significant savings for the heath
care system.
Methodology and work plan This will be a randomised and open-label study, including all
consecutive patients presenting with chronic coronary syndromes not on treatment with any of
the ADP receptor antagonists, and undergoing elective PCI of functionally significant
intermediate de-novo coronary artery stenoses. Patients presenting with ACS or heart failure
(left ventricle ejection fraction < 30%) will be excluded as well as patients with a subtotal
occlusion of a major coronary artery not requiring FFR evaluation.
- Pre-procedural assessment. All patients will be screened before the procedure and will
be asked to answer the specific angina questionary (Seattle Angina Questionnaire SAQ-7),
for the assessment of the severity of the angina symptoms.
- Coronary angiography and functional assessment of intermediate coronary artery stenoses.
Coronary angiography will be performed as per regular practice through the radial or
femoral access in order to evaluate the presence of any epicardial stenoses in a major
vessel. In this case, the ischemic potential of each stenosis will be assessed with the
Fractional Flow Reserve (FFR), as also recommended by the current European
guidelines.14, 16 Briefly, a pressure/temperature guidewire will be advanced beyond the
stenosis and during i.v. adenosine induced maximal hyperemia the ratio between distal
(Pd) and proximal (Pa) pressures will be calculated. A FFR value ≤ 0.80 will identify a
functionally significant coronary stenosis with indication to perform PCI. With the same
guidewire, and the same setting, it will be also possible to measure both the Coronary
Flow Reserve (CFR) and the Index of Microcirculatory Resistance (IMR).17-19
- Randomization and PCI procedure. After the evaluation of both inclusions and exclusions
criteria, patients will be randomised in a 1:1 allocation ratio in two groups: 1)
Experimental Group 2) Control Group. RedCap software will be used to randomise and to
manage patients data. In the Experimental group, before performing PCI, all patients
will be treated with Cangrelor (Kangrexal) with an i.v. loading bolus (30mg/Kg) followed
by i.v. infusion (4mg/Kg/min) for 2 hours. At the end of the infusion, as per current
clinical practice, a loading dose of Clopidogrel (600mg) will be administered. A
manteinance daily dose of 75mg will be associated with oral ASA (100mg). In the Control
group, either before or after PCI a loading dose of Clopidogrel will be administered and
a manteinance daily dose of 75mg will be associated with oral ASA (100mg). PCI procedure
will be performed as per current cinical practice, according clinical guidelines and at
operator discretion.14
- Assessment of Platelets reactivity (PR). Blood samples for platelet function analysis
will be collected in the catheterization laboratory through the arterial sheath. PR will
be measured with the VeryfyNow system in three different time points, without
interfering with the regular PCI procedure:
- Time 0: Before PCI and Cangrelor/Clopidogrel administration;
- Time 1: At the end of the PCI procedure and within 1 hour from the administration
of Cangrelor/Clopidogrel.
- Time 2: At 4-6 hours from PCI procedure.
- Post PCI assessment. Both FFR and CFR/IMR will be assessed at the end of the PCI with
the purpose to evaluate 1) the completeness of the revascularization from a functional
standpoint and 2) the occurrence of microvascular damage. This latter will be diagnosed
in case of Post-PCI IMR values > 25 if Pre-PCI IMR values are normal (<25) or, in case
of abnormal Pre-PCI IMR values, if Post-PCI values will be 20% higher.
- Non-invasive Post-PCI assessment. Blood samples will be collected at 12 and 24 hours
with the aim to evaluate the occurrence of peri-procedural MI defined as follow:
- The finding of high sensitive Troponine I (hsTrop-I) values higher than 5X the ULN,
in patients with normal hsTrop-I before PCI;
- The finding of hsTrop-I values higher than 20% the baseline values, in patients
with abnormal hsTrop-I before PCI;
In addition, the following criteria should also be fulfilled:
- ECG ischemic modification after PCI
- The findings of new Q waves at ECG
- The findings at the angiography of some modifications consistent with the hdTrop-I
increase (i.e. side branch occlusion/dissection, distal embolization).
- Follow-up. Patients will be followed up at 30 and 90 days. Besides clinical
assessment, patients will be asked to complete SAQ7 questionary in order to
evaluate the severity of residual symptoms, if any. In addition, at 90 days only,
all patienst will perform a single photon emission computed tomography (SPECT) in
order to evaluate the presence of ipoperfused areas downstream to the treated
vessel.
